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Eye Pathology
An Atlas and Text
THIRD EDITION

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Eye Pathology
An Atlas and Text
THIRD EDITION

Ralph C. Eagle Jr, MD

Director, Department of Pathology
The Noel T. and Sara L. Simmonds Professor of Ophthalmic Pathology
Wills Eye Hospital
Professor of Ophthalmology and Pathology
Sidney Kimmel Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania

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3rd edition

Copyright © 2017 Wolters Kluwer

Copyright © 2011 by Wolters Kluwer Health / Lippincott Williams & Wilkins.

First Edition copyright © 1999 by W.B. Saunders. All rights reserved. This book is
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Library of Congress Cataloging-in-Publication Data

Names: Eagle, Ralph C., Jr., author.
Title: Eye pathology : an atlas and text / Ralph C. Eagle, Jr.
Description: Third edition. | Philadelphia : Wolters Kluwer, [2017] | Includes
bibliographical references and index.
Identifiers: LCCN 2016026753 | ISBN 9781496337177
Subjects: | MESH: Eye Diseases—pathology | Eye—pathology | Atlases
Classification: LCC RE67 | NLM WW 17 | DDC 617.7—dc23 LC record available
at https://lccn.loc.gov/2016026753

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This work is no substitute for individual patient assessment based upon healthcare

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professionals’ examination of each patient and consideration of, among other
things, age, weight, gender, current or prior medical conditions, medication history,
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 In Memory of Ewa
This book is also dedicated to my teachers, Myron Yanoff, Ramon
L. Font, and Ben S. Fine, and to my former chief, William S.
Tasman, for his friendship and strong and unwavering support of
ophthalmic pathology during his long and distinguished tenure as
ophthalmologist-in-chief at the Wills Eye Hospital.

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PREFACE

During the past four decades, I have taught ophthalmic pathology to

medical students, interns, and ophthalmologists-in-training at the Wills
Eye Hospital, the Lancaster Course in Ophthalmology, and eye hospitals
and academic institutions on four continents. I wrote this book because I
believed that there was a need for a well-illustrated text that could serve as
an introduction to eye pathology. The book has been well received, but a
third edition is now necessary because there have been dramatic changes
in ophthalmic science and practice since the second edition was submitted
for publication in 2010.
In this relatively short time, spectral domain optical coherence
tomography has revolutionized the diagnosis and treatment of retinal
disorders and is becoming increasingly important in glaucoma and neuro-
ophthalmology. SD-OCT has rapidly become the standard of care and
continues to increase in quality and resolution. The in vivo digital images
of ocular anatomy and pathology disclosed by this powerful noninvasive
imaging technique are very reminiscent of histologic sections. The
accurate interpretation of SD-OCT’s striking visual imagery requires a
firm foundation in ocular histology and pathology.
Major developments in cornea and external disease have occurred as
well. Penetrating keratoplasty is performed less often in this era of
resurgent lamellar keratoplasty, and specimens from DALK, DSEK, and
refractive surgical procedures present new challenges in interpretation and
diagnosis. Specimens from patients with corneal dystrophies are
accessioned less often and typically bear the stigmata of prior treatments
such as phototherapeutic keratoplasty, which significantly delays surgery
in many patients.
Currently, fewer eyes with intraocular tumors are being enucleated as
most uveal melanomas undergo eye-sparing radioactive plaque
brachytherapy, and an increasing number of infants with retinoblastoma
are treated with chemotherapy, delivered intra-arterially or by intravitreal
injection. The trend toward evisceration has also decreased the number of
blind, painful eyes that are enucleated. Interpretation of the tissue
fragments comprising ocular evisceration specimens is often challenging.

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 Immunohistochemistry is now used routinely to assess and diagnose
ocular specimens. In addition, the classification and prognostic assessment
of ocular and adnexal neoplasms relies increasingly on powerful molecular
genetic tests that profile the expression of tumor genes or detect specific
translocations and gene fusion proteins that are diagnostic and prognostic.
The genes and molecular mechanisms responsible for an ever-growing
number of hereditary ocular disorders continue to be identified, and gene
sequencing, which is becoming easier and less expensive to perform,
undoubtedly will play a progressively more important role in the
tomorrow’s medicine.
Ophthalmologists and pathologists need to be familiar with these
advances in knowledge and practice that are changing the landscape of
ophthalmology and ophthalmic pathology. This text, now in its third
edition, has been revised to meet that need.
Written and illustrated solely by the author, Eye Pathology: An Atlas
and Text serves as a basic introduction to eye pathology that is concise
enough to be read and mastered during an ophthalmic pathology rotation.
It also is a well-illustrated resource for ophthalmologists-in-training who
are studying for board certification in ophthalmology or OKAP
examinations. The text should also benefit surgical pathologists who wish
to learn more about the pathology of the eye and need a short, well-
illustrated reference by the grossing bench or microscope.
The text in the third edition has been updated and lengthened slightly.
Some figures have been revised, and new figures and large color
photomontages have been added. In addition, 300 new multiple choice
questions with explanatory answers have been added to the book’s online
resources. The online self-assessment quiz section now comprises more
than 800 multiple choice questions including 200 based on photos or
photomicrographs. The online resources also include a digital version of
the book and an image bank.
Why study ophthalmic pathology? Most would agree that a thorough
understanding of ocular disease and pathologic mechanisms that cause
blindness are prerequisites for quality ophthalmic practice. A physician
cannot diagnose a disease that he or she has never heard of. Moreover,
ophthalmologists need this knowledge so they can understand, critically
assess, or even question the accuracy of diagnoses rendered by
pathologists who may have little or no training in ophthalmic pathology.
More than 30 years ago, Dr. Frederick A. Jakobiec eloquently

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addressed this question in his introduction to a special issue of the journal
Ophthalmology dedicated to basic science and ophthalmology. Dr.
Jakobiec’s* words still ring true today…“Unless one knows the natural
course of a disease, it is not possible to decide whether an intervention has
been efficacious or not. At a time when we are witnessing the progressive
commercialization of ophthalmology and the slackening of traditional
standards of professional behavior, one of the few remaining constraints
that might prevent us from becoming high-tech mountebanks, peddling
star wars’ nostrums that are expensive and potentially meretricious, is our
well-founded and ethically enhancing knowledge of ocular disease.”
Ralph C. Eagle Jr,
MD May, 2016

*Jakobiec, FA. Understanding ocular disease: science in the service of ethics

(guest editorial), Ophthalmology. 1984;91(6):41A–42A.

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Contents

Dedication
Preface

Chapter 1. An Introduction to Ocular Anatomy and Histology

Chapter 2. Congenital and Developmental Anomalies

Chapter 3. Inflammation

Chapter 4. Ocular Trauma

Chapter 5. Conjunctiva

Chapter 6. Cornea and Sclera

Chapter 7. The Lens

Chapter 8. Glaucoma

Chapter 9. Retina

Chapter 10. Vitreous

Chapter 11. Intraocular Tumors in Adults

Chapter 12. Retinoblastoma and Simulating Lesions

Chapter 13. Eyelid

Chapter 14. Orbit

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Chapter 15. Optic Nerve

Chapter 16. Laboratory Techniques and Special Stains

Index

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 1 An Introduction to
Ocular Anatomy and
Histology

A paired, hollow, spherical organ, the human eye is slightly less than an
inch in diameter (Fig. 1-1A). Internally, it is divided into anterior and
posterior chambers and a much larger vitreous cavity, which comprises
most of its posterior segment. The anterior chamber is bounded anteriorly
by the cornea and posteriorly by the anterior surfaces of the iris and lens
(Fig. 1-1B). The posterior chamber is bounded anteriorly by the iris
pigment epithelium (IPE) and laterally by the ciliary processes that form
the pars plicata of the ciliary body and posteriorly by the “face” or anterior
surface of the vitreous humor. Both anterior and posterior chambers are
filled with watery aqueous humor, which is secreted by the ciliary
epithelium on the ciliary processes.

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 FIG. 1-1. A. Slightly less than an inch in diameter, the eye is composed of an
anterior chamber and a much larger posterior vitreous cavity. B. The anterior
chamber is bounded anteriorly by the cornea and posteriorly by the iris and lens.
The lens is situated in the posterior chamber behind the pupil. C. The eye is
composed of three concentric coats that are easily separated during dissection. D.
Posteriorly, the three coats are evident as the sclera, the pigmented choroid, and
the retina.

The vitreous humor fills most of the posterior segment. The most delicate
connective tissue in the body, the vitreous humor is a transparent gel
composed of hyaluronic acid and a framework of delicate fibrils of type 2
collagen. Centrally, the anterior face of the vitreous abuts the posterior
surface of the lens, which is located directly behind the iris in the posterior
chamber, and is supported by a suspensory ligament of zonular fibers. The
concavity in the anterior face of the vitreous that conforms to the posterior
surface of the lens is called the patellar fossa, and the retrolental space of
Burger is interposed between the lens and vitreous. Posteriorly, the
vitreous lines the inner surface of the retina. Anteriorly, it is firmly
adherent to the vitreous base, which straddles the ora serrata, the junction
between the peripheral retina and the pars plana of the ciliary body. The
vitreous also has relatively firm attachments to the margin of the optic disc
and major retinal vessels. A curved channel called the Cloquet canal runs
through the center of the vitreous from the lens to the optic nerve.

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Overlying the optic nerve head, the posterior part of the Cloquet canal
widens to form a space resembling an inverted funnel called the area of
Martegiani.
The eye wall is composed of three concentric coats that vary markedly
in their cellularity and composition (Fig. 1-1C,D). These three layers are
readily separated during gross dissection. The outer coat includes the white
sclera, which merges with the transparent cornea at the corneoscleral
limbus. Paucicellular and composed largely of dense collagenous
connective tissue, the outer layer constitutes the eye’s tough fibrous
exoskeleton that confines and protects its contents of fluid and delicate
neural tissues. The collagenous lamella of the sclera is larger and more
irregular than those of the cornea.
The innermost coat of the eye is composed of neuroectodermal tissues
derived from the optic cup. Highly cellular and largely devoid of
connective tissue, these structures include the neurosensory retina, the
retinal pigment epithelium (RPE), the ciliary epithelium, and the IPE.
Embryologically, this inner layer of neuroectodermal tissues is derived
from an outpouching of the forebrain called the optic vesicle. The
neuroectoderm is a polarized layer of epithelial cells with characteristic
apical and basal features. Microvilli and cilia typically are found on the
apical surface of the cells, which are joined near their apices by
intercellular connections called terminal bars. The bases of the cells rest on
a basement membrane or basal lamina. The basal lamina serves as the
attachment for extracellular matrix material.
The optic vesicle is lined externally by a basement membrane, and the
apical surface of its neuroectodermal cells projects into its lumen. Later, as
the optic vesicle invaginates to form the optic cup on day 27 of gestation,
the apical surfaces of the inner and outer layer of cells become
approximated. This “apex-to-apex” orientation continues throughout life.
The inner layer of the optic cup goes on to form the posterior layer of IPE,
the inner nonpigmented layer of ciliary epithelium, and the neurosensory
retina. Its outer layer forms the anterior half of the iris pigment epithelial,
which includes the dilator muscle, the outer pigmented layer of ciliary
epithelium, and the RPE.
The two layers of cells that comprise the iris and ciliary epithelia retain
the “apex-to-apex” orientation found in the optic cup with basal laminae
on their external surfaces. Both layers are firmly fused together. Both of
the layers are pigmented in the IPE. The ciliary epithelium is a half-
pigmented bilayer of cells; its outer layer is pigmented, and its inner layer

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is nonpigmented (see Fig. 1-5D). During microscopy, this “two-toned”
bilayer readily serves to identify ciliary body tissue. At the ora serrata, the
outer layer of pigmented ciliary epithelium continues posteriorly as the
RPE, and the inner layer of nonpigmented ciliary epithelium abruptly
thickens to form the neurosensory retina, with its complex lamellar
architecture. Posterior to the ora serrata, the layers derived from the inner
and outer layers of the optic cup are not fused together as they are in the
IPE and ciliary body epithelium. A potential space called the subretinal
space is interposed between the retina and the RPE. The apical surfaces of
both tissues project into the subretinal space and interdigitate. Retinal
detachment or separation is marked by the accumulation of fluid in this
potential space.
In routine microscopic sections, the IPE appears to be a single layer,
since its dual architecture is largely obscured by intense cytoplasmic
pigmentation (Fig. 1-2D). Both layers are apparent in bleached sections,
however. The iris dilator muscle appears as an eosinophilic band on the
anterior surface of the IPE. The dilator is not a separate structure. Rather, it
is composed of nonpigmented cellular processes with smooth muscle
differentiation that arise from the basal surface of the anterior layer of
cells. The sphincter muscle of the iris, which encircles and constricts the
pupil, is also derived from the IPE, but separates from it during
development to form a distinct structure. Continuity of the sphincter
muscle with the IPE can be observed microscopically in fetal eyes. The
sphincter is about 1 mm in width and is separated from the IPE by a layer
of connective tissue that becomes more prominent with increasing age.

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 FIG. 1-2. The iris. A. The pigment in this brown iris is concentrated in the
melanocytes of the anterior border layer. The posterior IPE is maximally
pigmented. Cuffs of collagen highlight iris stromal vessels. B. SEM shows
circumferential ridges on the posterior surface of neuroectodermal IPE. Iris
stroma is derived from neural crest. C. Termination of IPE at pupillary margin
forms beaded pigment ruff. D. The two layers comprising the IPE are fused and
maximally pigmented. The dilator muscle is evident as an eosinophilic band on
its stromal surface. It is composed of cellular processes with smooth muscle
differentiation. (B. SEM ×40, C. SEM ×320, D. H&E ×250.)

Clinically, the IPE is visible at the edge of the pupil as the pigment ruff or
frill, which corresponds to the margin of the optic cup (Fig. 1-2C). This is
the only neuroectodermal tissue of the eye that can be seen with the slit
lamp biomicroscope without supplementary lenses. The granules of
neuroepithelial melanin in the iris pigment epithelial cells are large and
spherical in shape in contrast to retinal pigment epithelial granules, which
typically are ellipsoidal. Granules of neuroectodermal melanin are always
larger than the dust-like melanosomes found in uveal stromal cells. The
IPE is maximally pigmented in all eyes.
A peripheral colony of brain-like tissue, the neurosensory retina is a
complex, highly cellular tissue composed of cells that are arranged in
regular layers (Fig. 1-3A). Ten retinal layers including the RPE are
identified. It is relatively easy to remember the microscopic anatomy of the

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retina if one recalls that the retina is a three-neuron system composed of
three layers of cells: photoreceptors and first- and second-order neurons.
Regarding orientation, the term inner refers to retinal layers that are
located closest to the vitreous cavity or the center of the eye. Outer denotes
layers that are located nearer the sclera. The nuclei of retinal cells are
arranged in distinct bands called nuclear layers. The nuclei of the
photoreceptors and first-order neurons (bipolar cells) form the outer
nuclear layer (ONL) and inner nuclear layer (INL), respectively. The
retinal ganglion cells (the second-order neurons) comprise the innermost
layer of nuclei in the retina. The ganglion cell layer (GCL) varies
markedly in thickness. Surrounding the fovea, the GCL is five or more
cells thick. Multilamination of the GCL is an excellent histologic marker
for the macula or perifoveal part of the retina. The GCL is thin in the
peripheral retina. Peripheral to the vascular arcades formed by the superior
and inferior temporal retinal arterioles, the ganglion cells form a
discontinuous monolayer.

FIG. 1-3. The retina. A. The retina is composed of orderly layers of cell nuclei
(nuclear layers) and plexiform layers composed of axons and dendrites. The
photoreceptors rest on the RPE on the inner surface of the choroid. B. The MLM
(top right) is a linear band of synapses connecting photoreceptor cell axons and
bipolar cell dendrites in the anterior part of the OPL. C. The inner and outer
segments of the photoreceptors project through the fenestrated XLM into the

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 subretinal space. The tips of the outer segments interdigitate with pigmented
processes on the apical surface of the RPE. D. False colorized SEM highlights
inner and outer segments of rods and cones. Cones are distinguished by the
conical configuration of their inner segments. Photoreceptor nuclei comprise
ONL. (A. H&E ×50, B. toluidine blue ×250, H&E ×250, SEM ×2,500.)

The plexiform layers of the retina are composed of axons and dendrites.
The outer plexiform layer (OPL) is interposed between the ONL and INL,
and the inner plexiform layer separates the INL from the GCL. The inner
plexiform layer is truly plexiform: its whole breadth comprises of an
intricately interweaving tangle of ramifying neuronal processes. In
contrast, only the narrow inner band of the OPL is truly plexiform. Its
wider outer part contains an orderly parallel array of photoreceptor axons
called Henle fibers. Although Henle fibers occur throughout the retina, the
eponym generally is applied to the radially oriented photoreceptor axons
that surround the fovea. A line of synaptic connections comprising cone
pedicles, rod spherules, and the dendrites of bipolar cells delimits the outer
margin of the truly plexiform inner part of the OPL (Fig. 1-3B). This linear
row of synapses is called the middle limiting membrane (MLM). Like the
retina’s external limiting membrane (XLM), the MLM is not a basement
membrane (the only true basement membrane of the retina is the internal
limiting membrane or ILM). The MLM delimits the vascularized inner
part of the retina; capillaries from the central retinal artery penetrate no
deeper than the MLM. External to the MLM, the retina is avascular and
depends on the choroidal circulation for oxygen and nutrients. The OPL is
a watershed zone between the dual vascular supplies of the retina. This
factor contributes to the localization of edema fluid and hard exudates in
OPL.
The INL contains the nuclei of bipolar, amacrine, horizontal, and
Müller cells. Bipolar cells predominate. The horizontal cell nuclei are
found in the outer, and the amacrine cell nuclei in the inner part of the
INL. The nuclei of the Müller cells can lie at any level of the INL.
Accessory glial cells including fibrous and protoplasmic astrocytes and
oligodendrocyte-like cells are confined to the nerve fiber, ganglion cell,
and inner plexiform layers of the retina. Hence, gliosis does not occur after
central retinal artery occlusion because these cells are killed.
As we have seen, the orientation of cells in the optic vesicle and optic
cup persists in the adult eye. The ILM of the retina corresponds to the
basal lamina on the inner layer of the optic cup. A true basement
membrane, the ILM is synthesized by the basal foot processes of the giant

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glial cells of Müller, which span the entire thickness of the retina. The
ILM serves as an attachment point for the fine fibrils of type II collagen
that comprise the fibrillar component of the vitreous humor. Intricately,
interweaving processes of the Müller cells totally fill the interstices
between the retinal neurons and serve to segregate their receptive surfaces.
There is little or no extracellular space in the retina.
The Müller cells are polarized. Electron microscopy discloses
microvilli on their apical surfaces, which project into the subretinal space
between the photoreceptors forming the fiber baskets of Schultze. A belt
desmosome of intercellular junctions called the XLM is found in the outer
or apical part of the neurosensory retina. Not a true basement membrane,
the XLM is composed of permeable adherent junctions (zonulae
adherentes) that join the apices of the Müller cells and the rods and cone
cells. The XLM is permeable and does not form a barrier to fluid or
macromolecules. The inner and outer segments of the rods and cones
project through this membrane into the subretinal space where they are
surrounded by extracellular matrix material rich in hyaluronidase-resistant
acid mucopolysaccharide and interdigitate with cellular processes on the
apical surfaces of the RPE cells (Fig. 1-3C). Cone cell nuclei are located
next to the XLM in the ONL.
Rods and cones are distinguished light microscopically by the shape of
their inner segments (Fig. 1-3D). The inner segments of rods are slender
rod-like cylinders, while extrafoveal cones are conical in shape. Highly
specialized cones that resemble rods are densely packed in the cone-rich
fovea. The inner segments of photoreceptor are divided into two parts: the
proximal myoid located nearest to the XLM and more prominent distal
ellipsoid (Fig. 1-3C). The myoid contains Golgi apparatus and rough
endoplasmic reticulum but few mitochondria. In contrast, the ellipsoid of
the inner segments is packed with mitochondria that provide energy for the
photochemistry of vision, which occurs in the photoreceptor outer
segments. The mitochondria in the ellipsoid are thought to be responsible
for the second of the four hyperreflective bands in the outer retina revealed
by spectral domain ocular coherence tomography (SD-OCT) that serves as
a clinical marker for healthy photoreceptors.
The inner and outer segments of the photoreceptors are joined by a
connecting cilium that has the characteristic 9 + 0 pattern of microtubular
doublets found in central nervous system cilia. Photoreceptors probably
are derived from modified cilia, which are found on the apical surface of
cells. Several inherited retinal disorders are caused by mutations in genes

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coding constituents of cilia.
The outer segments of the photoreceptor contain thin discs composed
of cellular membranes that are arranged in stacks. The arrangement of the
membranous discs has been likened to a stack of coins or potato chips
packaged in cylindrical containers. Visual pigments including rhodopsin
are incorporated as transmembrane proteins in the disc membranes.
Separate, free-floating discs occur in rods. The discs in cone outer
segments are not separate structures; they comprise a continuous,
sinuously folded structure formed by invaginations of the outer cell
membrane.
Photoreceptor outer segments project from the apical surface of the
retina into the subretinal space where they are enveloped by microvillous
processes on the apical surface of the RPE, the polarized monolayer of
pigmented cells derived from the outer layer of the optic cup. The RPE
cells are firmly joined near their apices by a girdle of intercellular
connections called zonulae occludentes. These tight junctions form a
barrier to the passage of molecules and constitute the outer part of the
blood–retinal barrier. Large ellipsoidal granules of melanin pigment
measuring ~1 μ in diameter are found in the apical cytoplasm of the RPE
cells. Granules of lipofuscin pigment fill the basal cytoplasm. The latter
“wear-and-tear” pigment is derived from the incomplete digestion of
photoreceptor outer segments by the RPE’s phagolysosomal system and
gradually accumulates with age. The lipofuscin is relatively inapparent in
routine hematoxylin and eosin (H&E) sections, but the pigment is
autofluorescent and is vividly disclosed by UV fluorescent microscopy
(Fig. 1-4D). The nuclei of the RPE cells are located in the basal cytoplasm
near Bruch membrane.

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FIG. 1-4. The retinal pigment epithelium (RPE). A. The RPE is largely
responsible for the color of the fundus. Rip in pigmented layer discloses large
vessels in underlying choroid separated by uveal pigment. B. SEM shows
hexagonal monolayer of RPE cells covering inner surface of the Bruch
membrane. C. Photomicrograph shows elliptical granules of RPE melanin in
apical cytoplasm of RPE cells. The choriocapillaris abut the outer surface of the
Bruch membrane. D. Fluorescent microscopy (bottom right) discloses yellow
granules of autofluorescent lipofuscin pigment in the basal cytoplasm of the RPE
cells. (B. SEM ×1,250, C. toluidine blue ×250, UV fluorescent microscopy
×400.)

An intact layer of RPE is vital to the health and function of the adjacent
neurosensory retina (Fig. 1-4). In flat preparations, the cells comprising
this pigmented monolayer are hexagonal in shape, resembling the familiar
pattern of bathroom tile (Fig. 1-4B). The pigment in the RPE is largely
responsible for the reddish-brown color of the fundus seen grossly or
ophthalmoscopically (Fig. 1-4A). This is readily demonstrated in the
laboratory by focally denuding the Bruch membrane with a cotton swab.
Removal of the RPE discloses the larger choroidal vessels, which are
visible through the Bruch membrane, which is semitransparent. Melanin
pigment within choroidal melanocytes between the vessels serves to
highlight the latter. In heavily pigmented people, the density of
pigmentation between the vessels may impart a tigroid or tiger-striped

22
appearance to the fundus.
The RPE rests on a specialized layer of connective tissue called the
Bruch membrane, which rests on, and delimits the inner surface of the
choroid (Fig. 1-4C). The Bruch membrane is a sandwich-like structure
composed of extracellular matrix material. Its inner and outermost layers
are the basement membranes of the RPE cells and the endothelial cells of
the choriocapillaris, respectively. The basement membrane of the RPE
corresponds to the basement membrane on the outer surface of the optic
cup. The Bruch membrane is largely composed of type 1 collagen and has
a central core of elastic tissue. As we age, the Bruch membrane gradually
thickens and becomes increasingly periodic acid–Schiff (PAS) positive.
Basophilic foci of calcification are often found in the posterior parts of the
Bruch membrane in the elderly. Transmission electron microscopy
demonstrates that the thickening of the Bruch membrane is caused by the
gradual accumulation of linear and vesicular structures.
The choroid is the posterior and largest part of the uveal tract, the
eye’s central coat, which is interposed between the outer sclera and the
innermost layer of neuroectodermal tissue (Fig. 1-1D). Intermediate in
cellularity, the uveal tract is pigmented and richly vascular. The term uveal
reflects the fanciful resemblance of this coat to a black-purple grape (uva =
grape in Latin) noted when early anatomists removed the sclera. Derived
from neural crest, the uvea comprises the iris stroma, the stroma of the
ciliary body, and the choroid.
The highly vascular choroid contains three layers of blood vessels that
increase in size as they near the sclera (Fig. 1-3A). An interconnected layer
of leaky, fenestrated capillaries called the choriocapillaris rests directly
beneath the Bruch membrane (Fig. 1-3A,C). A second layer of medium-
size vessels called the Sattler layer and an outer layer of larger vessels
called the Haller layer also are present. The choroidal stroma contains
connective tissue and dendritic melanocytes that vary in their pigment
content depending on the patient’s race and eye color. An equivalent
number of melanocytes is present in all races, but darkly pigmented
individuals have larger cells filled with larger melanin granules. The
melanin granules found in uveal melanocytes are quite small and dust like.
They are readily distinguished from the large ellipsoidal granules of
melanin found in the apical cytoplasm of the RPE cells.
The middle part of the uveal tract called the ciliary body is interposed
between the iris and the choroid (Fig. 1-5). The ciliary body has two major
components, the pars plicata (also called the “corona ciliaris”) and the pars

23
plana (Fig. 1-5B). The anterior pars plicata is composed of a ring of 70 to
80 ciliary processes. The ciliary processes project into and encircle the
posterior chamber, and their nonpigmented epithelial cells secrete the
watery aqueous humor that fills that cavity and the anterior chamber. The
aqueous humor flows through the pupil toward specialized “drains”
located in the anterior chamber “angle” formed by the junction of the iris
and cornea. Small white nodules occasionally are observed incidentally on
individual ciliary processes during gross dissection, particularly in the eyes
of older individuals. These represent small foci of pseudoadenomatous
proliferation of the nonpigmented ciliary epithelium called Fuchs (or
coronal) adenomas. They undoubtedly represent the smallest eponymic
“neoplasms” in the human body.

FIG. 1-5. Ciliary body. A. The pars plicata of the ciliary body is composed of
ciliary processes, which project into the posterior chamber directly behind the
iris. B. The flat pars plana is interposed between the ring of ciliary processes
comprising the pars plicata and the retina. The ora serrata is the junction between
the pars plana and the retina. The nasal ora serrata, shown here, has prominent
dentate processes and concave oral bays. C. Scanning electron micrograph shows
convoluted surface of ciliary processes and circumferential folds on the posterior
surface of IPE. D. The ciliary epithelium, shown here on the pars plana, is a half-
pigmented bilayer. Its nonpigmented inner layer is continuous with the retina at
the ora serrata. (C. SEM ×50, D. H&E ×250.)

24
The ciliary processes of infants are smooth and pigmented. With age, the
processes become increasingly thickened, convoluted, and hyalinized as
collagenous connective tissue accumulates around the vessels in their
cores (Fig. 1-5C,D). The hyalinized ciliary processes in older patients
appear white. With experience, one can roughly estimate a patient’s age
from the degree of hyalinization evident grossly or microscopically. The
pars plana or flat part of the ciliary body is located posterior to the pars
plicata and forms a circular band that extends to the ora serrata. The term
ora serrata, which means “toothed mouth,” is derived from the serrated
appearance of this junction caused by the presence of anteriorly projecting
dentate processes of peripheral retina separated by concavities called oral
bays (Fig. 1-5B). Dentate processes and oral bays are prominent in the
nasal ora serrata, while the temporal ora is relatively smooth. This finding
can serve as anatomic landmark to orient the eye during gross
examination. In some eyes, elongated dentate processes of peripheral
retinal tissue called meridional complexes deeply invade, or even bridge,
the pars plana. Posterior to the ora, the peripheral retina often has a moth-
eaten pattern of darker spaces reflecting the almost ubiquitous presence of
peripheral microcystoid degeneration (see Chapter 9).
The bilayer of half-pigmented ciliary epithelium that forms part of the
eye’s inner neuroectodermal layer (Fig. 1-5D) is discussed above. The
stroma of the ciliary body is composed largely of smooth muscle. In
routine histologic sections, the ciliary muscle appears as an elongated
triangle, but in actuality, the structure is a circular sphincter. The ciliary
muscle has longitudinal, radial, and circular parts. The longitudinal ciliary
muscle of Brücke attaches to the sclera spur, a ridge of connective tissue
that is located directly behind the trabecular meshwork and the canal of
Schlemm. The scleral spur is the only spot where the ciliary body is firmly
attached to the sclera. The ciliary muscle’s primary function is focusing or
accommodation, which is discussed in the lens section below.
The iris is the anterior, visible part of the uveal tract (Fig. 1-2). The
structure is named after Iris, the Greek goddess of the rainbow, an
appellation that undoubtedly reflects the range of eye colors found in
different peoples. The iris has two components, the posterior IPE derived
from neuroectoderm (see above) and the iris stroma, derived from neural
crest. Its major component, the iris stroma, is a loosely arranged tissue that
contains pigmented and nonpigmented cells set in an abundant
extracellular matrix containing bundles of type I collagen fibrils and
hyaluronidase-sensitive glycosaminoglycans. The cells include

25
melanocytes and fibroblasts. The greatest concentration of iris
melanocytes is found in the avascular anterior border layer deep to an
inconspicuous discontinuous sheet of fibroblasts (Fig. 1-2A). The iris
vessels have an undulating radial orientation. Ensheathed by a thick mantle
of collagen fibers, these “thick-walled” vessels have a characteristic
histologic appearance that is not encountered elsewhere in the body. The
characteristic histologic appearance of its vessels serves to distinguish iris
from choroidal tissue in evisceration specimens. Most iris vessels are
located in the middle layers of the iris stroma. In blue irides, radiating iris
vessels are visible clinically because the melanocytes comprising the
anterior border layer lack pigment and are transparent. The melanocytes in
darker irides are opacified by pigment, obscuring the vessels. In general,
the number and size of melanin granules within iris melanocytes increases
in darker irides.
The anterior surface of the iris has an irregular contour. The pupillary
portion of the iris, which is located central to the roughly stellate collarette
is thinner. Embryologically, this thinning results from atrophy of the
anterior stromal caused by resorption of the pupillary membrane. The
anterior surface of broader, thicker peripheral ciliary zone is grooved by
contraction furrows. Defects in the anterior stroma called the crypts of
Fuchs are evident clinically. The iris muscles are discussed above. Heavily
pigmented, rounded clump cells of Koganei are often found in the stroma
near the sphincter muscle. These can be melanophages (type 1) or
displaced neuroepithelial (type 2) cells.
The crystalline lens is situated in the posterior chamber behind the iris
(Fig. 1-6). The lens is the only large transparent cellular tissue in the body
and is the only intraocular structure that is derived embryologically from
the surface ectoderm. Early in gestation, the surface ectoderm overlying
the optic vesicle thickens to form the lens placode, which subsequently
invaginates to form the lens vesicle, as the neuroectodermal optic vesicle
invaginates to form the optic cup. The epithelial cells of the posterior part
of the vesicle elongate anteriorly forming the primary lens fibers that fill
the cavity of the optic vesicle. These fibers persist as the central embryonic
nucleus in the adult lens. The anterior layer of cells persists as the anterior
lens epithelium throughout life (Fig. 1-6B). Secondary lens fibers are
formed by division of lens epithelial cells near the equator of the lens.
Seven to eight millimeters in length, these long, strap-like cells extend
from the anterior to the posterior pole of the lens, totally enveloping the
nucleus. The formation of secondary lens fibers continues throughout life;

26
new fibers are laid down peripherally as concentric lamellae in an onion-
like fashion. The nuclei of the newly formed peripheral lens fibers form a
curved bow near the equator (Fig. 1-6C). These highly specialized
epithelial cells lose their nuclei shortly after formation. Tightly packed in a
nearly paracrystalline fashion (Fig. 1-6D), the lens fibers are joined
together by ball-and-socket joints that minimize extracellular space. The
lens has no vessels or nerves and is almost totally devoid of connective
tissue, except for its thick enveloping capsule of basement membrane (Fig.
1-6B). The anterior capsule is much thicker than the posterior capsule,
whose caliber is less than the diameter of an erythrocyte. Like other
basement membranes, the lens capsule stains intensely with the PAS stain.
The lens epithelial cells retain the ability to synthesize collagen and may
do so under pathologic conditions.

FIG. 1-6. The lens. A. The lens is situated in the posterior chamber behind the
iris. The lens is composed of highly differentiated epithelial cells called lens
fibers. B. A monolayer of cuboidal lens epithelial cells is present beneath the
anterior lens capsule. The posterior capsule is much thinner. C. The epithelial
monolayer terminates at the equatorial lens bow, where the cells elongate to form
the secondary lens fibers. D. SEM shows that the lens fibers are tightly packed in
a paracrystalline fashion. (B. H&E ×100, B. top and bottom, PAS ×250, D. SEM
×160.)

27
The primary optical function of the lens is focusing or accommodation.
Divergent light rays from near objects must be bent or refracted more to
sharply focus them on the retina. When a near object (e.g., this page) is
examined, the ciliary muscle contracts, relaxing the tension on the zonular
fibers that form the suspensory ligament of the lens (Fig. 1-7). The ciliary
muscle is a circular or sphincter muscle. Its central aperture becomes
smaller when it contracts. When distant objects are examined and the eye
is at rest, the zonular fibers pull on the lens and flatten it. Relaxation of the
zonular fibers during accommodation allows the lens to assume a more
spherical configuration, which has a shorter radius of curvature and greater
refractive power. Refractive power is inversely proportional to the radius
of curvature of a lens.

FIG. 1-7. The suspensory ligament of the lens. A. SEM discloses zonular fibers
traversing the pars plana. B. Bundles of zonular fibers pass through valleys
between ciliary processes. C. Two groups of zonular fibers are disclosed by
retroillumination in macrophoto. D. Anterior and posterior groups of zonular
fibers delimit the triangular canal of Hanover at the lens equator. (A. SEM ×10,
B. SEM ×80, D. SEM ×20.)

The cornea (Fig. 1-8) is the eye’s major refractive element with an optical
power of ~45 diopters. It is the anterior, transparent part of the eye’s tough
outer fibrous coat and is continuous with the sclera at the limbus. The bulk

28
of the cornea is composed of interweaving lamellae of type I collagen
fibers, which are spaced in an exquisitely regular fashion. Artifactitious
clefts separate the stromal lamella in routine histologic sections (Fig. 1-
8A). The stroma contains flattened dendritiform fibroblast-like cells called
keratocytes. A nonkeratinized epithelium five cells in thickness covers the
anterior surface of the cornea (Fig. 1-8B). This is composed of basal cells,
wing cells, and flattened surface squamous cells. The epithelium normally
has an inconspicuous basement membrane and rests on a feltwork of
modified stroma called the Bowman membrane or layer, which appears as
a homogeneous, hyaline band. A delicate monolayer of flattened
endothelial cells, derived embryologically from the neural crest, lines the
posterior surface of the cornea (Fig. 1-8C,D). The endothelium secretes a
thick basement membrane called the Descemet membrane, which stains
intensely with the PAS stain (Fig. 1-8C). Anvil-shaped, hyaline
excrescences called Hassall-Henle warts stud the inner surface of the
peripheral part of Descemet membrane in older patients. They resemble
the guttae that occur in the central cornea in Fuchs endothelial dystrophy.

FIG. 1-8. The cornea. A. Most of the cornea is composed of collagenous stroma
with keratocytes and lamellae separated by artifactitious clefts. B. The corneal
epithelium rests on the anterior surface of the Bowman layer, a hyaline band of
modified stroma. The epithelium is typically five cells in thickness. C. A
flattened monolayer of corneal endothelial cells rests on the posterior surface of

29
 the Descemet membrane, which is PAS positive (below). D. SEM discloses a
regular mosaic of endothelial cells. (A. H&E ×50, B. H&E ×250, C. top, H&E
×250, bottom, PAS ×250, D. SEM ×160.)

The intraocular pressure is governed by a delicate balance between the

production of aqueous humor by the nonpigmented ciliary epithelial cells
and its egress or outflow from the eye. Most aqueous humor exits via the
traditional aqueous outflow pathway that consists of the trabecular
meshwork and the canal of Schlemm, which are located in the peripheral
anterior chamber in the anterior or corneoscleral part of the angle formed
by the cornea and peripheral iris (Fig. 1-9). Smaller amounts of aqueous
exit through nontraditional pathways that include iris vessels and posterior
uveoscleral outflow via the ciliary body and the vortex veins.

FIG. 1-9. The iridocorneal angle and aqueous outflow pathways. A. Electronic
charging artifact highlights the trabecular meshwork in the periphery of the
anterior chamber in this SEM. B. Thin trabecular beams comprising inner part of
trabecular meshwork are evident in SEM. C. Arrow in SEM points to the canal of
Schlemm in the outer wall of the iridocorneal angle external to the trabecular
meshwork. D. The trabecular meshwork and canal of Schlemm are nestled in the
anterior crotch of the scleral spur. The longitudinal ciliary muscle inserts onto the
posterior aspect of the spur. (A. SEM ×20, B. SEM ×80, C. SEM ×60, D. H&E
×50.)

30
The trabecular meshwork is a sieve-like structure that is nestled in the
anterior crotch of the scleral spur (Fig. 1-9B–D). The scleral spur serves as
an important anatomic landmark in both clinical and pathologic practice.
The longitudinal fibers of the ciliary muscle are firmly attached to the
posterior aspect of the scleral spur (Fig. 1-9D). During microscopy, the
spur is found by following the ciliary muscle fibers to their insertion. The
trabecular meshwork is composed of an interconnected network of small
beams or trabeculae (Fig. 1-9B). The beams are made of collagen with a
central core of elastic tissue and are encompassed by trabecular endothelial
cells and a thin layer of endothelial basement membrane. The inner,
corneoscleral part of the meshwork is composed of concentrically oriented
plates of connective tissue containing pores, which are out of register. The
interstices of the meshwork do not communicate directly with the lumen of
the canal of Schlemm, but are separated from it by a thin layer of
extracellular matrix material called the juxtacanalicular connective tissue.
Schlemm canal is a modified vein that is lined by a continuous layer of
endothelial cells. Schlemm canal runs circumferentially around the
chamber angle, giving off branches or collector channels that traverse the
sclera and discharge their contents into the epibulbar veins via the aqueous
veins of Ascher.
The anterior surface of the eyeball and the posterior surface of eyelids
are covered by a delicate transparent mucous membrane called the
conjunctiva. The term conjunctiva is derived from Latin meaning “to bind
together.” It connects the eye with the eyelids.
The conjunctiva consists of a nonkeratinized stratified columnar
epithelium that rests on a connective tissue stroma or substantia propria
(see Fig. 5-1). The conjunctival epithelium is two to five cells in thickness
and contains mucous glands called goblet cells whose contents appear
clear or bluish in routine H&E sections and are vividly PAS positive.
Goblet cells are more numerous nasally, especially in the semilunar fold
(plica semilunaris).
Topographically, the conjunctiva is divided into bulbar, forniceal, and
tarsal (or palpebral) parts. The bulbar conjunctiva covers the anterior
surface of the eyeball and is freely movable. The stroma or substantia
propria of the bulbar conjunctiva is composed of loose, areolar connective
tissue and is easily ballooned-up by edema fluid (chemosis) or injected
anesthetic. In contrast, the palpebral conjunctiva is firmly adherent to the
tarsal plate and does not move freely. Multiple epithelial invaginations or
crypts called the pseudoglands of Henle usually occur in the palpebral

31
conjunctiva. The forniceal conjunctiva that arches around the superior and
inferior cul-de-sacs is redundant and folded to facilitate eye movements.
Several small accessory lacrimal glands of Krause are found beneath the
forniceal conjunctiva, and accessory glands of Wolfring occur at the upper
and lower margins of the tarsal plates. Lymphocytes and plasma cells
normally are found in the conjunctival stroma and constitute part of the
eye’s normal defense mechanisms.
The caruncle is a small fleshy nodule located on the nasal surface of
the eye medial to the semilunar fold. The term caruncle means “a little
piece of flesh.” An island of skin surrounded by conjunctiva, the caruncle
is covered by keratined squamous epithelium with fine vellus hairs. In
addition to pilosebaceous units, the stroma contains fat and lobules of
accessory lacrimal gland tissue (the glands of Popoff).
The eyelids are flaps of modified skin with highly modified epidermal
appendages that cover and protect the eye (Fig. 13-1A–F). The anterior
surface of the eyelid is covered by skin, and its posterior surface is lined
by a mucous membrane, the palpebral conjunctiva, which is closely
applied to the tarsal plate. The tarsal plate is a curved plate of dense
connective tissue that serves as the lid’s internal skeleton. Striated fibers of
the orbicularis muscle are found between the skin and the anterior surface
of the tarsus. The orbicularis muscle encircles the eyelid fissure forming a
large sphincter that functions during eyelid closure. The bundles of the
orbicularis are sectioned transversely in standard histologic sections. A
mucocutaneous junction between eyelid skin and conjunctiva occurs near
the eyelid margin. Here, the epidermis is mildly thickened and has small
rete ridges. Just anterior to the lid margin, slit lamp biomicroscopy
discloses a line of tiny meibomian gland orifices. The meibomian glands
are large sebaceous glands that occupy almost the entire length of the
tarsal plate and are oriented perpendicular to the lid margin. The oily
secretion of the meibomian glands helps to retard evaporation of the tear
film. About 25 meibomian glands are present in the upper lid and 20 in the
lower lid. The meibomian glands in the upper lid are much longer,
reflecting the greater length of the upper tarsal plate (11 mm). The upper
lid is identified grossly and in tissue sections by the length of the tarsal
plate and the lid’s roughly rectangular shape. The shape of the lower lid is
roughly triangular. The greater mass of meibomian gland tissue in the
upper tarsus probably explains why sebaceous carcinoma occurs most
often in the upper lid. The eyelid fissure is encircled by a protective ring of
cilia (eyelashes). The hair bulbs of the cilia are located deep within the lid

32
next to the tarsal plate. Malignant tumors such as sebaceous gland
carcinoma that arise deep in the substance of the lid often produce loss of
lashes (madarosis).
Other eyelid glands bear eponyms. The sebaceous glands that
accompany the eyelashes are the glands of Zeis. Sebaceous glands are
holocrine glands. The glandular secretion called sebum is composed of
entire cells (holos—whole). Cellular division occurs in the peripheral
germinative layer of sebaceous gland lobules. As new cells form, the older
cells are pushed toward the center of the glandular lobule. The cells
degenerate as they mature. Their nuclei become karyorrhectic and
pyknotic, and the cytoplasm becomes intensely lipidized and foamy.
The glands of Moll are apocrine sweat glands. Their dilated lumina are
lined by tall, eosinophilic cells capped with the “apical snouts” that
characterize apocrine decapitation secretion. Eccrine sweat glands, which
bear no eponym, also are found. Glandular epithelial cells remain intact
during eccrine secretion. The glands of Wolfring or Ciaccio are small
accessory lacrimal glands that are located at the proximal margins of the
tarsal plates. There are two to five glands of Wolfring at the upper margin
of the superior tarsal plate and two glands at the lower margin of the lower
tarsus. Other accessory lacrimal glands called the glands of Krause are
found near the conjunctival fornix. The accessory lacrimal glands are
responsible for baseline tear secretion. The main lacrimal gland releases
copious amounts of watery secretion (endogenous irrigating fluid) in
response to emotional stimuli or severe ocular irritation.
The eye is contained in a protective pear-shaped cavity in the skull
called the orbit, which contains about 30 mL of highly specialized tissue
(see Fig. 14-1). Other orbital contents include the optic nerve, which is a
specialized tract of the central nervous system; the cartilaginous trochlea,
smooth and striated muscle; vessels; nerves; fatty and fibrous connective
tissue; and the lacrimal gland, a minor salivary gland. The orbit
communicates with the intracranial cavity through several fissures and
foramina, and several of its bony walls contain paranasal sinuses. The eye
and the remainder of the orbital contents, which are delimited anteriorly by
a septum of fibrous tissue, are protected by the eyelids, retractable flaps of
skin equipped with highly specialized epidermal appendages. The
epithelial-lined components of the nasolacrimal drainage system are
located in the inferonasal part of the orbit.
The optic nerve is a tract of the central nervous system that connects
the eye and the brain (Fig. 1-10). The nerve has intraorbital,

33
intracanalicular, and intracranial portions and is about 50 mm in total
length. It is composed of the axons of the retinal ganglion cells; interstitial
cells including oligodendrocytes, astrocytes, and microglia; and
fibrovascular septa of the pia mater. The retinal nerve fibers exit the eye
through the lamina cribrosa in the posterior sclera and extend to the optic
chiasm and then to the lateral geniculate body via the optic tracts. Behind
the lamina cribrosa, the axons are myelinated. Here, the nerve measures
about 3 mm in diameter. In contrast, the diameter of the optic disc is only
1.5 mm. Dense collagenous dura, the spidery trabeculated arachnoid and
the vascularized pia mater comprise the meninges of the optic nerve. The
optic nerve is encompassed by firmly adherent pia mater, and its substance
is compartmentalized by septa of pial connective tissue.

FIG. 1-10. The optic nerve. A. The optic disk is ~1.5 mm in vertical diameter. B.
Longitudinally sectioned optic nerve shows abrupt termination of creamy myelin
at the posterior margin of the lamina cribrosa. C. SEM of optic nerve meninges
shows spidery arachnoidal processes bridging cleft between the optic nerve (at
right) and the dura (at left). Septa of pia mater extend into the substance of the
nerve, compartmentalizing its axons. D. Pial septa and central retinal vessels are
seen in photomicrograph of transversely sectioned nerve. (C. SEM ×160, D.
H&E ×100.)

BIBLIOGRAPHY
34
Fine BS, Yanoff M. Ocular Histology: A Text and Atlas, 2nd ed. Hagerstown,
MD: Harper & Row, 1979.
Hogan MJ, Alvarado JA, Weddell JE. Histology of the Human Eye. Philadelphia,
PA: W.B. Saunders, 1971.
Jakobiec FA. Ocular Anatomy, Embryology, and Teratology. Philadelphia, PA:
Harper & Row, 1982.
Snell RS, Lemp MA. Clinical Anatomy of the Eye, 2nd ed. Boston, MA:
Blackwell Scientific Publications, 1998.
Wobmann PR, Fine BS. The clump cells of Koganei. A light and
electronmicroscopic study. Am J Ophthalmol 1972;73(1):90–101.

35
 2 Congenital and
Developmental Anomalies

Congenital anomalies are developmental disorders that are present at birth.

Congenital malformations are caused by chromosomal abnormalities,
mutant genes, and major environmental factors such as infections, drugs
and toxins, or radiation. In many instances, the cause is unknown.
Heritable disorders are genetically determined and may or may not affect
the phenotype. Heritable traits may be manifest at birth, or they may
become obvious later in life.
Etiologic factors that act early during embryogenesis (conception to 2
weeks) or the initial stages of ocular organogenesis (2 weeks to 3 months)
tend to have profound effects on ocular development. The development of
the eye commences about 24 days after fertilization when the optic pits
form in the anterior part of the embryo’s neuroectodermal plate. The pits
subsequently evaginate to form the optic vesicles, which invaginate to
form the optic cups 4 days later. The neuroectoderm constituting the inner
layer of the optic cup is destined to form the neurosensory retina, the
nonpigmented ciliary epithelium, and the posterior layer of iris epithelium,
while the outer layer of the optic cup gives rise to the retinal pigment
epithelium, the pigmented ciliary epithelium, and the anterior layer of iris
pigment epithelium, which includes the dilator muscle. The optic vesicles
induce the formation of the lens placodes in the overlying surface
ectoderm. The lens placodes invaginate to form the lens vesicles as the
optic cups form. Transitory fissures develop in the outer wall of the optic
cups on day 29. These embryonic fissures give the hyaloid arteries access
to the interior of the developing eye. The fissures subsequently are
obliterated by fusion, which usually is complete by the 6th week of
gestation. Abnormalities affecting each of these events can become
manifest as severe developmental anomalies.
Primary anophthalmos is a rare anomaly caused by failure of optic

36
vesicle evagination. Primary anophthalmos usually is bilateral and occurs
sporadically in otherwise healthy individuals. Secondary anophthalmos is
caused by suppression of the entire anterior part of the neural tube, which
is lethal. In consecutive anophthalmos, the optic vesicle evaginates and
then undergoes degeneration. Histologic examination of the orbit usually
discloses rudimentary neuroectodermal structures, which are absent in
primary anophthalmos.
Synophthalmia/cyclopia is a striking anomaly caused by a failure of
formation or induction of the anterior neural tube including the eye fields
(Fig. 2-1A,B). Although it is often called a fusion anomaly,
synophthalmia/cyclopia actually reflects a failure of complete bicentricity
to emerge. The disorder is a continuum of anomalies that involves the
brain, nose, orbits, and bones in addition to the eyes. Bicentricity fails to
emerge at an early stage; cells that are induced as eye tissue complete all
stages of development with a high degree of fidelity. The greatest degree
of ocular differentiation occurs anteriorly and laterally; there is duplication
of anterior ocular structures and fusion posteriorly with a single optic
nerve. A rudimentary nose or nasal proboscis is present above the single
midline orbit (Fig. 2-1A). The proboscis is caused by faulty migration of
the frontonasal processes. Failure of bicentricity also involves the
forebrain, invariably producing a malformation called holoprosencephaly,
which is marked by failure of the brain to divide into right and left
hemispheres. Most cases of this clinical spectrum have synophthalmia;
true cyclopia is exceedingly rare. The lethal malformation usually is
sporadic, but it may be a manifestation of trisomy 13. Dominantly and
recessively inherited familial cases have been reported. Holoprosencephaly
has been linked to mutations in a number of genes including the human
sonic hedgehog gene on chromosome 7q36 and the SIX3 sine oculo
homeobox gene on chromosome 2p21. Pregnant ewes who ingest toxic
alkaloids from the false hellebore plant Veratrum californicum on the 14th
or 15th day of gestation give birth to cyclopic lambs.

37
FIG. 2-1. Trisomy 13. A. Synophthalmia, trisomy 13. A pedunculated nasal
proboscis is located above the single midline orbit. B. Synophthalmia, trisomy
13. Small, synophthalmic eye from infant shown in (A) has two lenses and a
single optic nerve. Septum between lenses contains two foci of hyaline cartilage.
Mass of dysplastic retina fills vitreous cavity. C. Coloboma and retinal
dysplasia, trisomy 13. Mass of disorderly dysplastic retina containing large
multilayered rosettes adheres directly to the scleral within the coloboma. The
choroid is absent. D. Intraocular cartilage, trisomy 13. Mesenchymal tissue
filling coloboma surrounds a focus of hyaline cartilage (at left) in severely
microphthalmic eye. (C. Hematoxylin–eosin, ×25, D. Hematoxylin–eosin, ×10.)

Congenital cystic eye is a very rare anomaly caused by complete failure of

optic vesicle invagination. Partial arrest in vesicle invagination probably
causes extreme microphthalmos, which may simulate anophthalmos
clinically. Congenital nonattachment of the retina is caused by faulty
invagination of the optic cup and failure of its inner and outer layers to
meet posteriorly.
Uveal colobomas are developmental anomalies caused by faulty
closure of the embryonic fissure. Derived from the Greek word for
“mutilation,” coloboma is defined as “a condition where a portion of the
structure of the eye is lacking.” Colobomas typically are located
inferonasally in the territory of the fissure. They can involve the iris,
ciliary body, choroid, or any combination of the three and also may affect

38
the optic nerve. Because the primary defect in a typical coloboma is in the
neuroectoderm, absence of the mesectodermal uveal stroma is a secondary
phenomenon. Occasionally, the uveal tissue undergoes dysplasia or
metaplasia forming cartilage, muscle, or fat. An absolute scotoma is
present in the region of the coloboma because the overlying retina is
absent or dysplastic.
Although most colobomas are sporadic, they occasionally are inherited
as isolated ocular defects, usually in an autosomal dominant fashion with
incomplete penetrance. Colobomas occur in infants with CHARGE
syndrome and the cat’s-eye, Kabuki, Wolf-Hirschhorn (4p−), and 13q
deletion syndromes as well. In addition to colobomas, infants with
CHARGE syndrome have congenital heart defects, choanal atresia, mental
retardation, and genital and ear anomalies. CHARGE syndrome is
associated with mutations or complete deletion of the CHD7 (helicase
DNA-binding protein-7) gene on chromosome 8q12. Colobomas also are
characteristic findings in several syndromes caused by the duplication or
deletion of chromosomes or chromosomal fragments including trisomy 13.
Colobomas in severely microphthalmic (<10 mm) eyes from infants with
trisomy 13 often contain foci of hyaline cartilage and dysplastic retina
(Fig. 2-1C,D).
Microphthalmos with colobomatous cyst is a severe form of
embryonic fissure anomaly characterized by a cystic outpouching of
ectatic scleral that communicates with the interior of the eye through a
posterior coloboma (Fig. 2-2). The intraocular contents protrude outward
through the fissure, and the cyst is lined by a layer of atrophic or dysplastic
neuroectodermal tissue. The cyst may become much larger than the eye
(microphthalmos with cyst).

39
 FIG. 2-2. Microphthalmos with colobomatous cyst. Cystic outpouching of ectatic
scleral is larger than microphthalmic eye. The lumen of the cyst was lined by
atrophic neuroectodermal tissue, and it communicated with the interior of the eye
through an optic nerve coloboma. The cyst ruptured intraoperatively.

Atypical colobomas are not related to closure of the embryonic fissure and
can occur anywhere. Macular colobomas probably result from intrauterine
infections such as congenital toxoplasmosis. Colobomas of the eyelid
occur in the facial microsomia or Goldenhar syndrome.
Optic nerve aplasia usually is unilateral and occurs sporadically in
individuals who have no systemic abnormalities. The optic nerve is absent,
and the retina is avascular and lacks ganglion cells and axons.
Malformations that are localized to a single ocular structure usually are
related to damage that occurs during the fetal period of ocular
development (3rd to 9th month). Most are discussed in the chapters on
individual ocular structures that follow.

Chromosomal Anomalies
Ocular malformations occur in a number of chromosomal duplication or
deletion syndromes. Down syndrome (trisomy 21) is the most common
chromosomal syndrome and the most common cause of mental retardation.

40
The “mongoloid” appearance of patients with Down syndrome is caused
by an up- and outwardly slanting of their palpebral fissures, which are
almond shaped. Other ocular findings include epicanthal folds, significant
refractive errors, especially high myopia, cataract, and strabismus, usually
esotropia, which occurs in approximately 40%. Congenital ectropion, iris
hypoplasia, keratoconus with acute hydrops, and an increased number of
retinal vessels crossing the optic disk margin also occur.
Brushfield spots appear as a concentric ring of white or yellowish
spots on the anterior surface of the iris in 85% of blue- or hazel-eyed
patients with Down syndrome (Fig. 2-3). Brushfield spots are focal
condensations of stromal collagen that are visible through the transparent
anterior border layer of the blue iris and tend to be accentuated by
concurrent iris atrophy. Discrete stromal condensations that resemble
Brushfield spots called Kruckman-Wolfflin bodies occur in some normal
persons with blue or hazel eyes.

FIG. 2-3. Brushfield spots, trisomy 21. Focal stromal condensations form a ring
of white spots in the middle third of the iris in a blue-eyed patient with Down
syndrome. (Photo courtesy of Dr. Edward A. Jaeger, from Eagle RC Jr.
Congenital, developmental and degenerative disorders of the iris and ciliary body.
In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology.

41
 Clinical Practice. Philadelphia, PA: Saunders, 1993, vol. 1: 367–389.)

Severe ocular malformations including anophthalmos,

synophthalmia/cyclopia, microphthalmia, PFV/PHPV, retinal dysplasia,
colobomas, and intraocular cartilage occur in infants with trisomy 13
(Patau syndrome) (Fig. 2-1). Affected infants have cleft lips and palates,
cardiac and pulmonary defects, arrhinencephaly, and holoprosencephaly.
Few survive the first year of life.
Epicanthal folds, ptosis, blepharophimosis, microphthalmos, corneal
opacities, and congenital glaucoma are found in trisomy 18 (Edward
syndrome), the second most common autosomal trisomy.
Retinoblastoma occurs in the 13q− syndrome if the deletion includes
the q1-4 band. The 22q+ syndrome includes microphthalmia, the posterior
ulcer of von Hippel and severe retinal dysplasia. Ocular abnormalities
have been reported in the 18p−, 18q−, 18 ring chromosome, 5p− (cri-du-
chat), and the 4p− (Wolf-Hirschorn) syndromes.

Heritable Disorders with Ocular

Manifestations
A variety of heritable disorders caused by genetic mutations have ocular
manifestations.
Most cases of aniridia are caused by mutations in the PAX6 gene on
the short arm of chromosome 11. The term aniridia is a misnomer; most
cases have severely hypoplastic irides that are hidden clinically by opaque
limbal tissues (Fig. 2-4). Aniridia is a spectrum of ocular disease that also
includes foveal and optic nerve hypoplasia, cataract, secondary glaucoma,
and corneal opacification (Fig. 6-3). Eighty-five percent of aniridic
patients have autosomal dominant familial aniridia, which is an isolated
ocular defect. The association of sporadic aniridia and Wilms tumor or
nephroblastoma is called Miller syndrome and accounts for about 13% of
cases. Miller syndrome is caused by deletions in the short arm of
chromosome 11 that include both the PAX6 gene and another closely
linked tumor suppressor gene (WT1) involved in the pathogenesis of
Wilms tumor. The PAX6 gene plays a central role in ocular development
throughout the animal kingdom. PAX6 mutations have been identified in
patients with other anterior segment malformations including Peters
anomaly and autosomal dominant keratitis.

42
 FIG. 2-4. Aniridia. A. Overhang of opaque limbal tissue hides skirt of
hypoplastic iris in peripheral anterior chamber. The lens dislocated during
sectioning of eye obtained postmortem from adult with familial aniridia. B.
Stubby hypoplastic iris leaflet from eye seen grossly in (A) has thickened
pigment epithelium and lacks sphincter and dilator muscles. (Hematoxylin–eosin,
×25.)

A number of heritable ocular diseases are caused by mutations in genes on

the X chromosome and show X-linked recessive inheritance. They include
color blindness (daltonism), juvenile x-linked retinoschisis, some cases of
retinitis pigmentosa, the Nettleship-Falls type of ocular albinism, Fabry
disease, Hunter disease, Norrie disease, and Lowe syndrome. Incontinentia
pigmenti (Bloch-Sulzberger) shows X-linked dominant inheritance. It
occurs only in females and males with Klinefelter syndrome and is lethal
in normal males.
Other ocular disorders occur predominantly in males because they are
caused by mutations in maternally transmitted mitochondrial DNA. These
include Leber hereditary optic neuropathy and the Kearns-Sayre, MERRF,
and MELAS syndromes.
Autosomal recessively inherited disorders with prominent ocular
manifestations include several types of albinism (foveal hypoplasia);
systemic mucopolysaccharidoses including Hurler, Scheie, and
Maroteaux-Lamy syndromes (corneal clouding); the lysosomal storage
diseases Tay-Sachs disease and Niemann-Pick disease (macular cherry red
spot); Wilson disease (Kayser-Fleischer ring); the sickle
hemoglobinopathies (neovascular sea fans); myotonic dystrophy (presenile
cataract); alkaptonuria (scleral pigmentation); osteogenesis imperfecta
(blue scleral); homocystinuria (ectopia lentis); and ocular-scoliotic Ehlers-
Danlos syndrome (corneal and scleral rupture).

43
Phakomatoses (Familial Tumor
Syndromes)
The term phakomatosis is applied to several heritable disorders that have
important systemic and ocular findings. The primary phakomatoses
include von Recklinghausen neurofibromatosis (NF1), tuberous sclerosis
complex (TSC) and von Hippel-Lindau disease (VHL), which are
autosomal dominant disorders, and Sturge-Weber syndrome (SWS), which
is sporadic. Recent advances in molecular genetics have made the basic
concept of phakomatosis outdated. Mutations in recessive tumor
suppressor genes have been identified in all three of the classic dominantly
inherited phakomatoses. The WHO classification of tumors of the central
nervous system no longer includes the term phakomatosis. NF1, TSC, and
VHL are included as familial tumor syndromes.
Von Recklinghausen neurofibromatosis (NF-1) (Figs. 2-5 to 2-8) is
one of the most common hereditary diseases, because the NF1 gene, which
is located on chromosome 17 (17q11.2), is quite large and is subject to
mutation. Neurofibromin, the protein product of the NF1 gene, normally
interacts with the protein product of the ras oncogene to dampen growth
stimulatory signals. NF1 is characterized by tumors composed of Schwann
cells, which typically occur on the skin as multiple fibroma molluscum.
Deforming elephantiasis neuromatosa is caused by diffuse
neurofibromatous infiltration (Fig. 2-5). The presence of more that six
cutaneous café au lait spots >1.5 cm in diameter is a diagnostic criterion.

44
FIG. 2-5. Elephantiasis neuromatosa, von Recklinghausen neurofibromatosis
(NF-1). Pendulous mass of hamartomatous tissue involves right upper lid and
forehead. (Courtesy of Dr. Dario Savino-Zari, Caracas, Venezuela.)

FIG. 2-6. von Recklinghausen neurofibromatosis (NF-1) Choroidal infiltrate,

NF-1. A. The choroid is massively thickened by a hamartomatous infiltrate that

45
 contains an increased number of melanocytes and nonpigmented ovoid bodies
that resemble tactile corpuscles. B. Ovoid body in choroidal infiltrate, NF-1.
Delicately laminated appearance of ovoid body reflects the presence of concentric
Schwann cell processes. (A. Hematoxylin–eosin, ×50, B. Hematoxylin–eosin,
×250.)

FIG. 2-7. Lisch nodules, NF-1. A. Multiple tan or pale brown dome-shaped
nodules on surface of iris of patient with NF-1. Lisch nodules occur in nearly all
affected adults with NF-1 and are a useful diagnostic criterion. B. Focus of
partially pigmented cells rests on anterior iridic surface. Lisch nodules are
melanocytic hamartomas. (B. Hematoxylin–eosin, ×250.)

FIG. 2-8. Plexiform neurofibroma, NF-1. A. Infant with NF-1 has bilateral
plexiform neurofibromas of upper eyelids and enlarged corneas indicative of
secondary buphthalmos. B. Markedly enlarged nerves forming plexiform
neurofibroma are swollen by a disorderly proliferation of Schwann cells and
endoneural fibroblasts in a mucinous matrix. (Hematoxylin–eosin, ×25.)

Ocular findings in NF1 are numerous and include plexiform

neurofibromas of the eyelid and orbit; an “s”-shaped lid fissure; congenital
glaucoma, particularly if the upper lid is involved by neurofibromatous
tissue; Lisch nodules on the iris, hamartomatous infiltration of the uvea
with tactile corpuscle-like ovoid bodies (Fig. 2-6); retinal and optic nerve

46
gliomas; dysplasia of the sphenoid bone (Orphan Annie sign); pulsating
exophthalmos; and a slight increased risk for uveal melanoma. Lisch
nodules (Fig. 2-7) are the most common ocular manifestation of NF-1.
These melanocytic hamartomas are a useful diagnostic criterion for NF-1
because they are found on the anterior surface of the iris in nearly all
affected adults and develop before cutaneous neurofibromas. Plexiform
neurofibromas are composed of a plexus consisting of markedly enlarged
nerves that are swollen by a disorderly proliferation of Schwann cells and
endoneural fibroblasts in a mucinous matrix (Fig. 2-8).
Neurofibromatosis type 2 (NF-2) is a totally separate disease caused
by mutations in the NF2 or merlin gene on chromosome 22 (22q12.2).
Bilateral schwannomas of the eighth cranial nerve are the disorder’s
classic manifestation. Ocular findings include presenile posterior
subcapsular cataracts, epiretinal membranes, combined hamartoma of the
RPE and retina, and optic nerve sheath meningiomas.
The TSC is caused by mutations in either of two genes, TSC1 located
on chromosome 9q34 and TSC2 on chromosome 16p13, which encode for
the proteins hamartin and tuberin, respectively. Hamartin and tuberin form
a complex that normally suppresses mTOR signaling. The classic clinical
triad of the TSC includes epilepsy, mental retardation, and facial lesions
called adenoma sebaceum, which actually are angiofibromas. Astrocytic
hamartomas and astrocytomas occur in the retina in about half of patients
with tuberous sclerosis. Astrocytomas overlying the optic disk have been
called giant drusen of the optic nerve. Retinal astrocytomas may be
confused clinically with retinoblastoma. More mature lesions typically
contain calcospherites and have been called mulberry nodules. The
astrocytic hamartomas of the retina are typically nonprogressive. Larger
retinal giant cell astrocytomas are encountered rarely (Fig. 2-9). These
resemble subpendymal giant cell astrocytomas of the CNS
histopathologically and often grow causing total retinal detachment and
lost eyes. Large astrocytomas in the brain typically have a tuber-like
appearance and may calcify forming “brain stones.” Visceral tumors in
TSC include renal angiomyolipomas and cardiac rhabdomyomas. Pleural
cysts can predispose to spontaneous pneumothorax. Other skin lesions
include subungual fibromas, shagreen patches, and ash leaf lesions.

47
 FIG. 2-9. A. Tuberous sclerosis complex, retinal giant cell astrocytoma.
Large bilobed astrocytoma caused retinal detachment in young girl with well-
documented tuberous sclerosis. The macroscopic appearance of the tumor
resembles retinoblastoma. B. Photomicrograph of retinal giant cell astrocytoma in
(A) shows large astrocytes with copious amounts of eosinophilic cytoplasm. A
few basophilic spherules of calcium (calcospherites) are seen below. Other parts
of the tumor were extensively necrotic. (Hematoxylin–eosin, ×50.)

von Hippel-Lindau disease (VHL, angiomatosis retinae) is a dominantly

inherited familial cancer syndrome caused by germ-line mutations in the
VHL tumor suppressor gene located on chromosome 3p25. VHL protein is
part of a complex that normally targets proteins for degradation including
hypoxia-inducible factor 1a (HIF1a), an important transcription factor that
stimulates tumors by inducing abnormal cellular growth and angiogenesis.
Cherry-like retinal angiomas with large feeding and draining vessels
are the characteristic ocular manifestation of the syndrome (Fig. 2-10A).
These retinal lesions should be called retinal hemangioblastomas because
they are identical histologically to hemangioblastomas that occur in the
cerebellum of many affected patients (Fig. 2-10B,C). The retinal
hemangioblastomas are bilateral in 50% of cases, can arise from the retina
in an exophytic or endophytic fashion, may involve the optic disc or nerve,
and often produce a Coats-like exudative maculopathy.
Histopathologically, the hemangioblastomas are composed of capillaries
within a matrix of foamy, lipidized stromal cells. Molecular genetic studies
demonstrating loss of heterozygosity within the stromal cells indicate that
they are the primary constituent of the neoplasm. The capillaries are a
secondary response to up-regulation of VEGF by the stromal cells.

48
 FIG. 2-10. Retinal hemangioblastoma, von Hippel-Lindau syndrome. A. Large
dilated retinal vessels feed large reddish endophytic hemangioblastoma. A
small amount of retinal exudate is present. B. Histopathologically, the tumor is
composed of a mass of capillary caliber vessels and foamy stromal cells, seen in
higher magnification in (C). The stromal cells show loss of heterozygosity,
indicating that they are the neoplastic cells. Capillary proliferation is caused by
up-regulation of VEGF. (B. H&E, ×250, C. H&E, ×500.)

Patients are also at risk for pheochromocytoma and renal cell carcinoma.
Endolymphatic sac tumors cause hearing loss or tinnitus in about 10% of
patients with VHL.
Sturge-Weber syndrome (SWS, encephalotrigeminal angiomatosis) is
a nonheritable congenital syndrome characterized by a facial port-wine
mark or nevus flammeus, an ipsilateral hemangioma of the meninges and
brain, and “train track” intracranial calcification. Ocular findings include
ipsilateral glaucoma and a diffuse cavernous hemangioma of the ipsilateral
choroid (Fig. 2-11). Somatic mosaic mutations in the GNAQ gene have
been found in the port-wine marks from patients with the SWS and in
patients with nonsyndromic port-wine marks as well. The R183Q mutation
in GNAQ is not present in unaffected parts of the skin.

49
 FIG. 2-11. Sturge-Weber syndrome. A. Diffuse hemangioma obscures normal
details of choroid and imparts “tomato ketchup” appearance to right fundus.
Severe glaucomatous cupping of the right optic disk is present. B. The left eye is
normal. The patient had a right facial nevus flammeus that involved the upper
eyelid.

Other disorders that have been included with the phakomatoses include
cavernous hemangioma of the retina (Fig. 2-12), the Wyburn-Mason
syndrome, the organoid nevus (nevus sebaceus of Jadassohn) syndrome,
and ataxia telangiectasia. Large, nonleaking retinal arteriovenous
malformations occur in the nonhereditary syndrome of Wyburn and
Mason. Twenty to thirty percent of patients have associated midbrain
AVMs. The organoid nevus syndrome is characterized by cutaneous
sebaceous nevi that may spawn basal cell carcinomas, seizures, epibulbar
complex choristomas, and yellow fundus lesions that may represent
intrascleral cartilage or bone. Ataxia–telangiectasia (A-T) is a pleiotropic
autosomal recessive disorder characterized by cerebellar ataxia,
immunodeficiency, specific developmental defects, profound
predisposition to cancer, and acute radiosensitivity. Ocular findings
include telangiectatic conjunctival vessels and oculomotor apraxia. The
ATM gene normally is involved in DNA and cellular repair mechanisms.

FIG. 2-12. Cavernous hemangioma the retina. A. Macrophoto shows large grape-
like clusters of vessels in the detached retina. B. The substance of retina is
replaced by a mass of large cavernous blood channels lined by endothelial cells.
Hyalinized stroma separates many vessels. The residual retinal tissue is gliotic,
and focal RPE hyperplasia is present. (B. H&E, ×50.)

Infections that occur during pregnancy and other harmful factors in the
maternal environment such as drugs, toxins, and radiation can have
devastating effects on the fetus. The most severe complications are

50
associated with events that occur early in the first trimester. Maternal
infections with ocular complications include rubella, toxoplasmosis,
syphilis, cytomegalic inclusion disease, herpes simplex virus, Zika virus
and AIDS. Drugs that cause congenital ocular anomalies include
thalidomide, retinoic acid, LSD, cocaine, and ethanol (fetal alcohol
syndrome).

BIBLIOGRAPHY
General References
de Paula Freitas B, de Oliveira Dias JR, Prazeres J, et al. Ocular findings in
infants with microcephaly associated with presumed Zika virus congenital
infection in Salvador, Brazil. JAMA Ophthalmol 2016;134(5):529–535.
Duke-Elder S, ed. System of Ophthalmology, The Iris. Congenital Deformities,
vol. 3, part 2. London, UK: Henry Kimpton, 1964:256.
Glaser T, Jepeal L, Edwards JG, et al. PAX6 gene dosage effect in a family with
congenital cataracts, aniridia, anophthalmia and central nervous system
defects. Nat Genet 1994;7:463–471.
Mann I. The Development of the Human Eye. New York: Grune & Stratton, 1950.
Mann I. Developmental Abnormalities of the Eye. Philadelphia, PA: JB
Lippincott, 1957.
Pagon RA. Ocular coloboma. Surv Ophthalmol 1981;25:223–223.
Pagon RA, Graham JM, Zonana J, et al. Coloboma, congenital heart disease, and
choanal atresia with multiple anomalies: CHARGE association. J Pediatr
1981;99:223–227.
Rosias PR, Sijstermans JM, Theunissen PM, et al. Phenotypic variability of the
cat eye syndrome. Case report and review of the literature. Genet Couns
2001;12:273–282.
Schubert HD. Schisis-like rhegmatogenous retinal detachment associated with
choroidal colobomas. Graefes Arch Clin Exp Ophthalmol 1995;233:74–79.
Schubert HD. Structural organization of choroidal colobomas of young and adult
patients and mechanism of retinal detachment. Trans Am Ophthalmol Soc
2005;103:457–472.
Torczynski E, Jacobiec FA, Johnston MC, et al. Synophthalmia and cyclopia: a
histopathologic, radiographic, and organogenetic analysis. Doc Ophthalmol
1977;44:311–378.
Traboulsi EI, ed. Genetic Diseases of the Eye (Oxford Monographs on Medical
Genetics), 2nd ed. Oxford, UK: Oxford University Press, 2011.
Waardenburg P, Franceschetti A, Klein D. Genetics and Ophthalmology.
Springfield, IL: Charles C Thomas, 1961.

51
Chromosomal Anomalies
Brushfield T. Mongolism. Brit J Child Dis 1924;21:241.
Donaldson D. The significance of spotting of the iris in mongols. Brushfield’s
spots. Arch Ophthalmol 1961;65:26–31.
Down JLH. Observations on an ethnic classification of idiots. London Hospital
Reports 1866;3:259–262.
Hoepner J, Yanoff M. Ocular anomalies in trisomy 13-15: an analysis of 13 eyes
with two new findings. Am J Ophthalmol 1972;74:729–737.
Howard RO. Classification of chromosomal eye syndromes. Int Ophthalmol
1981;4:77–91.
Jaeger E. Ocular findings in Down’s syndrome. Trans Am Ophthalmol Soc
1980;78:808–845.
Wilcox LJ, Bercovitch L, Howard R. Ophthalmic features of chromosome
deletion 4p-(Wolf-Hirschhorn syndrome). Am J Ophthalmol
1978;86:834–839.

Aniridia and Other Iris Anomalies

Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary
aniridia. Hum Mol Genet 1993;2:2093–2097.
Duke-Elder S. Persistent pupillary membrane. Congenital Deformities, vol 3, part
2. London, UK: Henry Kimpton, 1964:775.
Edward D, Al Rajhi A, Lewis RA, et al. Molecular basis of Peters’ anomaly in
Saudi Arabia. Ophthalmic Genet 2004;25:257–270.
Elsas F, Maumenee I, Kenyon K, et al. Familial aniridia with preserved ocular
function. Am J Ophthalmol 1977;83:718–724.
Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation
and aniridia mutations in the human PAX6 gene. Nat Genet 1992;2:232–239.
Graw J. Genetic aspects of embryonic eye development in vertebrates. Dev Genet
1996;18:181–197.
Grindley JC, Davidson DR, Hill RE. The role of Pax-6 in eye and nasal
development. Development 1995;121:1433–1442.
Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found
in heterogeneous anterior segment malformations including Peters’ anomaly.
Nat Genet 1994;6:168–173.
Hingorani M, Williamson KA, Moore AT, et al. Detailed ophthalmologic
evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci
2009;50:2581–2590.
Lee H, Khan R, O’Keefe M. Aniridia: current pathology and management. Acta
Ophthalmol 2008;86:708–715.
Mackman G, Brightbell F, Opitz J. Corneal changes in aniridia. Am J Ophthalmol
1979;87:497–502.
Margo CE. Congenital aniridia: a histopathologic study of the anterior segment in

52
 children. J Pediatr Ophthalmol Strabismus 1983;20:192–198.
Miller R, Fraumeni JJ, Manning M. Association of Wilms’ tumor with aniridia,
hemihypertrophy, and other congenital malformations. N Engl J Med
1964;270:922–927.
Mirzayans F, Pearce WG, MacDonald IM, et al. Mutation of the PAX6 gene in
patients with autosomal dominant keratitis. Am J Hum Genet
1995;57:539–548.
Nelson LB, Spaeth GL, Nowinski T, et al. Aniridia: a review. Surv Ophthalmol
1984;28:621–642.
Ramaesh K, Ramaesh T, Dutton GN, et al. Evolving concepts on the pathogenic
mechanisms of aniridia related keratopathy. Int J Biochem Cell Biol
2005;37:547–557.
Warburg M, Mikkelsen M, Andersen SR, et al. Aniridia and interstitial deletion of
the short arm of chromosome 11. Metab Pediatr Ophthalmol 1980;4:97–102.

Neurofibromatosis
Anonymous. Neurofibromatosis. Conference statement. National Institutes of
Health Consensus Development Conference. Arch Neurol 1988;45:575–578.
Huson SM, Compston DA, Harper PS. A genetic study of von Recklinghausen
neurofibromatosis in south east Wales. II. Guidelines for genetic counselling.
J Med Genet 1989;26:712–721.
Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis. Incidence of
iris hamartomata. Ophthalmology 1981;88:348–354.
Lisch K. Ueber Beteiligung der Augen, insbesondere das Vorkommen von
Irisknotchen bei der Neurofibromatose (Recklinghausen). Zeitschrift fur
Augenheilkunde 1937;93:137–143.
Mindel JS, Rubenstein AE, Wallace S, et al. Congenital Horner’s syndrome does
not alter Lisch nodule formation. Ann Neurol 1994;35:123–124.
Perry H, Font R. Iris nodules in von Recklinghausen’s neurofibromatosis.
Electron microscopic confirmation of their melanocytic origin. Arch
Ophthalmol 1982;100:1635–1640.
Ragge NK, Falk RE, Cohen WE, et al. Images of Lisch nodules across the
spectrum. Eye 1993;7:95–101.
Ragge NK, Traboulsi EI. The phakomatoses. In: Traboulsi EI, ed. Genetic
Diseases of the Eye. New York, NY: Oxford University Press, 1998:
733–775.
Sakurai T. Multiple neurofibroma patient showing multiple flecks on the anterior
surface of the iris. Acta Soc Ophthalmol Jpn 1935;39:87–93.
Traboulsi EI. A Compendium of Inherited Disorders and the Eye. New York, NY:
Oxford University Press, 2005.
Williamson TH, Garner A, Moore AT. Structure of Lisch nodules in
neurofibromatosis type 1. Ophthalmic Paediatr Genet 1991;12:11–17.

53
Tuberous Sclerosis Complex
Alper JC, Holmes LB. The incidence and significance of birthmarks in a cohort of
4,641 newborns. Pediatr Dermatol 1983;1:58–68.
Au KS, Pollom GJ, Roach ES, et al. TSC1 and TSC2 gene mutations: detection
and genotype/phenotype correlation. Am J Hum Genet 1998;63S:350.
Au KS, Williams AT, Gambello MJ, et al. Molecular genetic basis of tuberous
sclerosis complex: from bench to bedside. J Child Neurol 2004;19:699–709.
Davies DM, Johnson SR, Tattersfield AE, et al. Sirolimus therapy in tuberous
sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med
2008;358:200–203.
Eagle RC Jr, Shields JA, Shields CL, et al. Hamartomas of the iris and ciliary
epithelium in tuberous sclerosis complex. Arch Ophthalmol
2000;118:711–715.
El-Hashemite N, Zhang H, Henske EP, et al. Mutation in TSC2 and activation of
mammalian target of rapamycin signalling pathway in renal angiomyolipoma.
Lancet 2003;361:1348–1349.
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and
characterization of the tuberous sclerosis gene on chromosome 16. Cell
1993;75:1305–1315.
Gunduz K, Eagle RC Jr, Shields CL et al. Invasive giant cell astrocytoma of the
retina in a patient with tuberous sclerosis. Ophthalmology 1999;106:639–642.
Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in
tuberous sclerosis. Retina 1993;13:155–159.
Robertson DM. Ophthalmic manifestations of tuberous sclerosis. Ann N Y Acad
Sci 1991;615:17–25.
Shields JA, Eagle RC Jr, Shields CL, et al. Aggressive retinal astrocytomas in
four patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc
2004;102:139–147.
Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina.
Differentiation of sporadic tumors from phakomatosis-associated tumors.
Arch Pathol Lab Med 1984;108:160–163.
Weiner DM, Ewalt DH, Roach ES, et al. The tuberous sclerosis complex: a
comprehensive review. J Am Coll Surg 1998;187:548–561.
Yeung RS. Multiple roles of the tuberous sclerosis complex genes. Genes
Chromosomes Cancer 2003;38:368–375.

Von Hippel-Lindau Syndrome

Chan CC, Collins AB, Chew EY et al. Molecular pathology of eyes with von
Hippel-Lindau (VHL) disease: a review. Retina 2007;27:1–7.
Chew EY. Ocular manifestations of von Hippel-Lindau disease: clinical and
genetic investigations. Trans Am Ophthalmol Soc 2005;103:495–511.
Couch V, Lindor NM, Karnes PS, et al. von Hippel-Lindau disease. Mayo Clin

54
 Proc 2000;75:265–272.
Decker HJ, Weidt EJ, Brieger J. The von Hippel-Lindau tumor suppressor gene.
A rare and intriguing disease opening new insight into basic mechanisms of
carcinogenesis. Cancer Genet Cytogenet 1997;93: 74–83.
Friedrich CA. Von Hippel-Lindau syndrome. A pleomorphic condition. Cancer
1999;86(11 Suppl):2478–2482.
Grossniklaus HE, Thomas JW, Vigneswaran N, et al. Retinal hemangioblastoma.
A histologic, immunohistochemical, and ultrastructural evaluation.
Ophthalmology 1992;99:140–145.
Jakobiec FA, Font RL, Johnson FB. Angiomatosis retinae: an ultrastructural study
and lipid analysis. Cancer 1976;38:2042–2056.
Kim HJ, Butman JA, Brewer C et al. Tumors of the endolymphatic sac in patients
with von Hippel-Lindau disease: implications for their natural history,
diagnosis, and treatment. J Neurosurg 2005;102:503–512.
Lonser RR, Kim HJ, Butman JA, et al. Tumors of the endolymphatic sac in von
Hippel-Lindau disease. N Engl J Med 2004;350: 2481–2486.
Singh A, Shields J, Shields C. Solitary retinal capillary hemangioma: hereditary
(von Hippel-Lindau disease) or nonhereditary? Arch Ophthalmol
2001;119:232–234.
Singh AD, Nouri M, Shields CL, et al. Retinal capillary hemangioma: a
comparison of sporadic cases and cases associated with von Hippel-Lindau
disease. Ophthalmology 2001;108:1907–1911.

Sturge-Weber Syndrome
Goldberg RE, Pheasant TR, Shields JA. Cavernous hemangioma of the retina: a
four-generation pedigree with neurocutaneous manifestations and an example
of bilateral retinal involvement. Arch Ophthalmol 1979;97:2321–232.
Hamm H. Cutaneous mosaicism of lethal mutations. Am J Med Genet
1999;85(4):342–345.
Happle R. Lethal genes surviving by mosaicism: a possible explanation for
sporadic birth defects involving the skin. J Am Acad Dermatol
1987;16:899–906. Am Acad Ophthalmol Otolaryngol 1978;85:276–286.
Messmer E, Font RL, Laqua H, et al. Cavernous hemangioma of the retina.
Immunohistochemical and ultrastructural observations. Arch Ophthalmol
1984;102:413–418.
Nakashima M, Miyajima M, Sugano H, et al. The somatic GNAQ mutation
c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. J
Hum Genet 2014;59(12):691–693.
Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Trans Am
Acad Ophthalmol Otolaryngol 1978;85:276–286.
Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine
stains caused by somatic mutation in GNAQ. N Engl J Med
2013;368(21):1971–1979.

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 3 Inflammation
INTRODUCTION
During the evolutionary struggle for survival, a complex series of defense
mechanisms (that we in its totality call inflammation) has evolved. The
inflammatory response involves a variety of specialized effector cells and
bewilderingly complex interplay of cells, mediators, and biochemical
reactions that serves to protect the body against microorganisms and
cancer. In addition, the inflammatory process includes mechanisms to
repair and restore tissues that have been damaged by foreign invaders,
trauma, or chemical and physical agents. The wide spectrum of
opportunistic infections and tumors that afflict untreated patients who have
the acquired immune deficiency syndrome (AIDS) underscores generally
how effective the intact immune system, the cornerstone of the
inflammatory process, is in protecting us from potential invaders.
Inflammation has been defined as “a reaction of the microcirculation
characterized by movement of fluid and white blood cells from the blood
into the extravascular tissues. This is frequently an expression of the host’s
attempt to localize and eliminate metabolically altered cells, foreign
particles, microorganisms, or antigens.” The inflammatory cells and the
biochemical mediators of inflammation largely reside within the lumina of
blood vessels. In contrast, the majority of the body’s cells are located in
the extravascular compartment, where invasion by microorganisms also
generally begins. Hence, inflammatory cells and macromolecules such as
antibodies and components of the complement system must leave the
vessels and enter the tissues if they are to combat microbial invaders or
dispose of dead or damaged cells or other materials. Vasoactive
inflammatory mediators such as histamine, serotonin, kinins,
prostaglandins, and platelet-activating factor cause vasodilation and
increase vascular permeability, allowing cells and antibodies access to the
tissues. A second heterogeneous group of nonimmunoglobulin protein
mediators called cytokines recruit and stimulate inflammatory cells.

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Cytokines are synthesized and secreted by inflammatory cells and include
the interleukins (ILs), interferons, and colony-stimulating factors. Other
cell adhesion molecules including integrins and cadherins are involved in
cellular homing, adhesion, and cell-to-cell interactions. The details of this
complex series of interactions are beyond the scope of this introductory
chapter.
Vasodilation and increased vascular permeability are responsible for
several of the cardinal manifestations of inflammation including tumor or
swelling, calor or heat, and rubor or redness (Fig. 3-1). Heat and redness
reflect increased blood flow and swelling, the collection of serum and
other blood components in the extracellular space. Some inflammatory
mediators (e.g., some of the prostaglandins) cause pain and stimulate the
contraction of smooth muscle. Spasm of the ciliary muscle and sphincter
muscles of the iris contributes to the pain of anterior uveitis, which usually
is ameliorated by strong cycloplegic drugs such as atropine. Pain, pupillary
miosis, and photophobia are helpful clinical markers that serve to
differentiate iridocyclitis from conjunctivitis.

FIG. 3-1. Acute dacryocystitis. Signs of acute inflammation including swelling

and erythema are evident in the region of infected lacrimal sac and lower lid.

The increased vascular permeability that occurs in inflammation is readily

57
evident to the ophthalmologist during slit-lamp biomicroscopy. Aqueous
humor normally is almost totally devoid of protein and clear. The protein
content rises when inflammation disrupts the blood–ocular barrier. A
focused beam of light illuminating the anterior chamber becomes visible,
just as a projector beam is visible in a smoky room. This phenomenon,
which is termed aqueous “flare” or “ray,” is caused by the Tyndall effect.
The intensity of the aqueous flare correlates fairly well with the severity of
the inflammation and may be roughly quantified and noted in the clinical
record. Individual inflammatory cells also are evident on slit-lamp
examination as motes of light. The quantity of cells is also roughly
estimated and recorded. The cells normally move with the convection
currents in the aqueous. (They sink anteriorly where the aqueous humor is
cooled by the cornea and rise posteriorly where it is heated by the iris.)
Absence of cellular convection currents may indicate clotting of fibrin-rich
aqueous in a case with severe vascular permeability. Adhesions readily
form in the fibrin-rich milieu of ocular inflammation. Adhesions between
the iris and the lens called posterior synechiae can block the flow of
aqueous humor through the pupil from the posterior chamber. The pupil is
said to be secluded if its entire circumference is bound down by posterior
synechiae (seclusio pupillae). Secondary closed-angle glaucoma can
develop if the synechiae are not broken. Cycloplegic/mydriatic drugs help
to prevent these adhesions by dilating the pupil. Aggregates of
inflammatory cells called keratic precipitates or KPs form on the posterior
surface of the cornea. The KPs may be small or large and lardaceous. The
latter, which are often called “mutton-fat” keratin precipitates, typically
occur in eyes that have chronic granulomatous inflammation.
Functio laesa or loss of function is the final cardinal manifestation of
inflammation. Although many common ocular inflammations such as
conjunctivitis or chalazion are short-lived incapacitations or annoyances,
severe inflammations or infections, particularly those that affect the
interior of the eye, can cause blindness. Stereotyped inflammatory
responses that are designed to protect the body against external invaders
can totally destroy the delicate tissues of the eye. A small bacterial
infection may be inconsequential in the skin, but it can totally destroy an
eye. Even if an intraocular bacterial infection is expediently sterilized, the
normal processes of regeneration and repair often cause blindness. A
delicate membrane of connective tissue <1 mm long can profoundly affect
visual acuity if it forms in an inopportune location. Likewise, minor
alterations in the structure of the transparent ocular media (cornea, lens, or
vitreous) can markedly degrade their optical properties. One must also

58
remember that the eye’s neurosensory components are incapable of
regeneration or repair like central nervous system tissue. Blindness caused
by retinal damage or destruction is irrevocable and untreatable.

THE CLASSIFICATION OF
INFLAMMATION
Histopathologically, inflammation is categorized into acute and chronic
categories based on the type of inflammatory cells that are found in the
tissue or exudate. Acute inflammation usually is characterized by the
presence of polymorphonuclear leukocytes or “polys.” Lymphocytes and
plasma cells are found in chronic nongranulomatous inflammation, and
their presence generally denotes involvement of the immune system.
Activated macrophages or epithelioid histiocytes and inflammatory giant
cells characterize chronic granulomatous inflammation.

POLYMORPHONUCLEAR
LEUKOCYTES
The polymorphonuclear leukocyte, neutrophil or “poly,” is the primary
cell found in acute inflammation (Fig. 3-2A). The polymorphonuclear
leukocyte is the body’s first line of cellular defense. These cells
phagocytize bacteria and other foreign material, and their cytoplasm
contains many primary and secondary granules that harbor a wide variety
of digestive enzymes that they use to kill and digest microorganisms. Polys
have pink cytoplasm and a multilobed (typically trilobed) nucleus in
routine sections stained with hematoxylin and eosin (H&E). Degenerated
polys with round karyorrhectic nuclei frequently are observed in focal
collection of polys called abscesses. The term suppurative inflammation
refers to the presence of an exudate called pus, which is composed of
numerous polys and tissue destruction. Polymorphonuclear leukocytes do
not proliferate at the site of inflammation. They are produced in the bone
marrow and delivered via the bloodstream to the site of inflammation,
where they die. They are attracted to the site of injury by chemotactic
gradients, adhere to receptors or adhesion molecules on the vascular
endothelial cells (margination), and pass through the capillary wall into the
tissue (diapedesis). The cell walls of polys have receptors for the Fc
component of immunoglobulin. These Fc receptors aid in the phagocytosis

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of bacteria that have been bound to antibodies in a process called
opsonization.

FIG. 3-2. Inflammatory cells. A. Polymorphonuclear leukocytes. Polys have

multilobed nuclei and eosinophilic cytoplasm. The polys in this field are well
preserved. A few mononuclear histiocytes also are present in the acute
inflammatory infiltrate. B. Eosinophils. The cytoplasm of eosinophils contains
intensely eosinophilic granules. The nuclei are bilobed. The presence of
eosinophils usually suggests the presence of allergy or a parasite. C.
Lymphocytes. Lymphocytes have round, intensely basophilic nuclei and scanty
cytoplasm that usually is inapparent in routine light microscopic sections. Many
subtypes of lymphocytes can be identified with special immunohistochemical
stains. D. Plasma cells. Plasma cells have round, eccentrically located nuclei
with a cartwheel or clock face pattern of chromatin clumping. The cytoplasm is
basophilic because it contains large quantities of ribosomal RNA used in
antibody synthesis. The Golgi apparatus is evident light microscopically as a
perinuclear “hof.” (A–D. H&E ×250.)

Clinically, acute inflammation is characterized by the presence of pus.

Copious quantities of purulent exudate occur in patients who have
hyperacute conjunctivitis like that caused by gonococcus. A layered
collection of polys called a hypopyon accumulates in the inferior part of
the anterior chamber in eyes with acute keratitis or endophthalmitis.
Vitreous abscesses form in acute purulent endophthalmitis. The polys in

60
the vitreous abscess occasionally are arranged in a linear fashion,
reflecting the orientation of the type II collagen fibrils that constitute the
framework of the vitreous humor.

EOSINOPHILS
Eosinophilic leukocytes or eosinophils are recognized by their intensely
eosinophilic, orange, granular cytoplasm and their bilobed nuclei (Fig. 3-
2B). Eosinophils are about the same size as polys. Their cytoplasmic
granules have a characteristic rhomboid crystalloid configuration disclosed
by electron microscopy. The eosinophil granules are rich in acid
phosphatase and other lysosomal enzymes and also contain a unique
eosinophilic major basic protein that is toxic to certain parasites and
normal host cells. Eosinophils are involved in the phagocytosis of antigen–
antibody complexes and are known to modulate inflammatory reactions
mediated by mast cells. The presence of numerous eosinophils in tissue
sections is highly suggestive of either an allergic reaction or parasitic
infestation.

LYMPHOCYTES
Lymphocytes are mononuclear cells that are 7 to 8 μm in diameter.
Lymphocytes appear as blue spheres in smears and tissue sections; their
nuclei are round and intensely basophilic, and the cytoplasm is so scanty
that it is often inapparent (Fig. 3-2C). Lymphocytes play a dominant role
in chronic inflammation and in both humoral and cell-mediated immunity.
Multiple subtypes of lymphocytes have been characterized. B lymphocytes
are formed in the bone marrow and are involved in humoral immunity. B
lymphocytes differentiate into plasma cells, the chief antibody-producing
cells of the body. T lymphocytes, which originate in the thymus, include
effector and regulatory subtypes. Effector T cells participate in delayed
hypersensitivity and mixed lymphocyte reactions and are a prominent
constituent of benign reactive lymphoid infiltrates. Regulator T cells (T
helper/amplifier [T4] and suppressor/cytotoxic [T8] cells) modulate the
immune response. T4 cells, which are responsible for initiating the
immune response, are preferentially infected and killed by human
immunodeficiency virus (HIV), which binds to the CD4 receptor. Other
lymphocyte subtypes include killer, natural killer, and null cells.

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PLASMA CELLS
Plasma cells are activated B lymphocytes. Plasma cells are the body’s
primary source of circulating antibodies. These antibody factories have a
characteristic appearance (Fig. 3-2D). Round and eccentrically located, the
nucleus has dense clumps of chromatin that adhere to the inner surface of
its membrane in a pattern that has been likened to a cartwheel or clock
face. Unlike lymphocytes, plasma cells have an abundant quantity of
cytoplasm, which is largely occupied by rough endoplasmic reticulum
(RER) used to synthesize immunoglobulin. In routine sections stained with
H&E, the cytoplasm of plasma cells has a distinctly basophilic or purple
hue caused by the affinity of the basic dye hematoxylin for ribosomal
RNA in the RER. The Golgi apparatus of plasma cell is apparent light
microscopically as a lighter staining crescent next to the nucleus called the
perinuclear “hof” (German, “courtyard”). The cytoplasm of plasma cells
may become eosinophilic as the cells produce large quantities of
immunoglobulin. Eosinophilic crystals of immunoglobulin called Russell
bodies occasionally form in the cytoplasm of plasma cells (Fig. 3-3).
Usually round but occasionally square or even hexagonal, Russell bodies
reflect the “terminal constipation” plasma cells by immunoglobulin. They
generally denote an inflammatory process of some chronicity and may be
found intracellularly or free in the tissue. Dutcher bodies are similar
smaller crystalline inclusions of antibody molecules that appear to be
intranuclear but actually reside in an intranuclear cytoplasmic inclusion.
Positive staining with the periodic acid–Schiff (PAS) stain indicates that
Russell or Dutcher bodies are composed of either IgA or IgM molecules.
A cell that contains multiple small intracytoplasmic Russell bodies is
called a morula cell of Mott.

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FIG. 3-3. Russell bodies. The uniformly eosinophilic spherules in this chronic
inflammatory infiltrate are crystalloids of immunoglobulin called Russell bodies.
A rare hexagonal Russell body is seen in the inset. (Both figures, H&E ×250.)

An inflammatory infiltrate composed of lymphocytes and varying numbers

of plasma cells characterizes chronic nongranulomatous inflammation.
Although lymphocytes and plasma cells occasionally constitute an acute
inflammatory response to certain viral infections, the presence of these
cells usually indicates that the immune system has been activated. In
nongranulomatous iritis, the stroma of the iris contains an infiltrate of
lymphocytes and plasma cells (Fig. 3-4). Special stains for microorganism
generally are nonrevealing in chronic nongranulomatous inflammation.

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 FIG. 3-4. Iritis. A. Inflamed eye had pupillary miosis and an anterior chamber
reaction. No exudate is seen. The patient had pain and photophobia. B.
Histopathology exam of another case shows massive thickening of the iris stroma
by an infiltrate of lymphocytes and plasma cells. The iris pigment epithelium
adheres to an anterior subcapsular cataract. Neovascularization of the iris is
present. No microorganisms were detected. (B. H&E ×50.)

MAST CELLS
Mast cells are often called tissue basophils, although there is evidence that
they are derived from different precursor cells in the bone marrow. Mast
cells play an extremely important role in acute anaphylaxis (type I
hypersensitivity reaction). IgE antibody molecules made by allergic
individuals bind to Fc receptors on the plasma membrane of mast cells.
Subsequent interaction between the appropriate antigen and two IgE
molecules causes mast cell degranulation and the release of potent
vasoactive substances including histamine, serotonin, and heparin, which
have an immediate effect on vascular permeability. Severe itching and the
acute onset of conjunctival edema or chemosis are clinical symptoms and
signs of acute allergic conjunctivitis of the anaphylactic type (Fig. 3-5B).

FIG. 3-5. A. Mast cells. Mast cells (arrows) in tissue sections have round,
centrally located nuclei. The cytoplasm is mildly basophilic in routine sections
stained with H&E and stains intensely with PAS. B. Acute allergic
conjunctivitis. Conjunctival chemosis is evident in photo of laboratory worker
with acute anaphylactic conjunctivitis. The patient was allergic to animal dander
and experienced the sudden onset of severe itching. (A. H&E ×250.)

Mast cells vaguely resemble plasma cells in tissue sections but have a
centrally placed nucleus (Fig. 3-5A). In routine H&E sections, they lack
the prominent array of basophilic granules disclosed by Wright stain. The
cytoplasm of mast cells is PAS positive and its constituent granules are

64
stained intensely blue by the acid-fast stain. Mast cells are found in the
conjunctival substantia propria in allergic disorders such as vernal
conjunctivitis and giant papillary conjunctivitis. They are also common in
some neoplasms like neurofibromas.

MACROPHAGES
Macrophages or histiocytes are the body’s second line of cellular defense
and its chief phagocytic cell. Macrophages are derived from circulating
monocytes. They are relatively large mononuclear cells (larger than polys)
that have an eccentric reniform or kidney-shaped nucleus. Macrophages
have a great capacity to phagocytize material, but unlike polys, they cause
little tissue damage. Prior to phagocytosis, newly formed macrophages
have a modest amount of eosinophilic cytoplasm. In ophthalmic
pathology, macrophages generally are characterized by the substances that
they have phagocytized (Fig. 3-6). They include macrophages that have
ingested blood breakdown products such as hemosiderin and erythrocyte
ghost cells, lipid material seen as foamy vacuoles, and other materials such
as degenerated lens protein or melanin.

FIG. 3-6. Macrophages. A. Lipid-laden macrophages, subretinal fluid. The

frothy vacuolated cytoplasm is filled with lipid vacuoles and scattered elliptical
granules of RPE melanin. The surrounding subretinal fluid is protein rich and
intensely eosinophilic. The patient had radiation retinopathy. B. Lens-laden
macrophages, phacolytic glaucoma. These macrophages have copious
quantities of eosinophilic cytoplasm that reflects the ingestion of degenerated lens
protein released from an advanced cortical cataract. C. Melanophages,
melanocytomalytic glaucoma. Macrophages have ingested melanin pigment
released from a necrotic iris melanocytoma. (A–C. H&E, original magnification
×250.)

Macrophages play an important role as antigen-presenting cells in the

initial stages of the immune response. They phagocytize and process
antigenic material and present appropriate epitopes to helper T cells in
conjunction with class II major histocompatibility molecules (called HLA-

65
DR in humans), which are located in their cell membranes. During
activation, macrophages produce a lymphokine called IL-1, which
produces fever and is thought to induce the production of a second cellular
messenger IL-2 by the T cells. They also secrete a wide variety of
powerful biologic molecules called monokines that are important, even
pivotal, participants in the inflammatory response. Two types of
macrophages are recognized: M1 macrophages that stimulate
inflammation and M2 macrophages that decrease inflammation and
encourage tissue repair. In addition, M2 macrophages are thought to be
proangiogenic and tumor promoting.

EPITHELIOID HISTIOCYTES AND

GIANT CELLS
Under certain circumstances, macrophages or histiocytes transform into
more metabolically active forms called epithelioid cells or epithelioid
histiocytes (Fig. 3-7). Activation typically occurs when the histiocytes
encounter large quantities of antigenic material that is relatively insoluble
or indigestible. Some microorganisms, particularly those that proliferate
intracellularly, stimulate the formation of epithelioid histiocytes. Classic
examples include the mycobacteria that cause tuberculosis and leprosy,
fungi, and parasites such as schistosomes.

FIG. 3-7. A. Epithelioid histiocytes, sarcoidosis. The epithelioid histiocytes

comprising the discrete granuloma have abundant quantities of eosinophilic
cytoplasm and vesicular nuclei with nucleoli. B. Positive conjunctival biopsy,
sarcoidosis. Substantia propria contains several discrete granulomas consistent
with sarcoidosis. (A. H&E ×250. B. H&E ×100.)

Epithelioid histiocytes are termed “epithelioid” (-oid, resembling;

epithelioid, resembling epithelium) because these cells have abundant

66
eosinophilic cytoplasm and superficially resemble simple epithelial cells
(Fig. 3-7A). If epithelioid histiocytes are observed histopathologically in a
chronic inflammatory infiltrate, the inflammation is termed
granulomatous. Epithelioid histiocytes are required for the diagnosis of
chronic granulomatous inflammation. Inflammatory giant cells are another
characteristic feature of chronic granulomatous inflammation.
Inflammatory giant cells are a multinucleated syncytium formed by the
fusion of epithelioid histiocytes.
Several kinds of inflammatory giant cells are recognized
histopathologically. The Langhans giant cell, which typically is seen in
tuberculosis, has a peripheral rim of nuclei and homogenous cytoplasm
(Fig. 3-8A). Foreign body giant cells have nuclei, which are randomly
dispersed or are centrally located, and their cytoplasm contains particulates
of foreign material in large vacuoles (Fig. 3-9). When an extremely large
foreign body is encountered, numerous foreign body giant cells adhere to
its outer surface, forming an encompassing cytoplasmic barrier that
“insulates” the foreign material from the rest of the body. The Touton
giant cell occurs in chronic xanthogranulomatous inflammation (Fig. 3-
8B). The classic Touton giant cell is shaped like a target. The “bull’s-eye”
is a central zone of eosinophilic cytoplasm, which is encircled by a ring of
nuclei, which in turn is surrounded by a peripheral wreath of foamy
lipidized cytoplasm. Although Touton giant cells classically are associated
with juvenile xanthogranuloma (JXG), they also are found in other
xanthogranulomatous disorders that affect the ocular adnexa including
Erdheim-Chester disease, necrobiotic xanthogranuloma with
paraproteinemia, and orbital xanthogranuloma with adult-onset asthma.

FIG. 3-8. A. Inflammatory giant cells, Langhans type. The nuclei are located
peripherally. The cytoplasm is uniformly eosinophilic. Langhans giant cells are
found in tuberculosis and other granulomatous diseases. B. Touton giant cells,
juvenile xanthogranuloma. Fully developed Touton giant cells have a target

67
 configuration. A peripheral rim of frothy lipidized cytoplasm surrounds a ring of
nuclei, which in turn encompasses a central bull’s eye of eosinophilic cytoplasm.
Touton giant cells are found in JXG and other xanthogranulomatous diseases. (A.
H&E ×100, B. H&E ×250.)

FIG. 3-9. Foreign body giant cell. A. The cytoplasm of the giant cell at left
contains an oval cellulose fiber. B. The foreign body shows vivid birefringence
during polarization microscopy (at right). The nuclei of foreign body giant cells
are arranged haphazardly. (A. H&E ×250, B. H&E with crossed polarizers ×250.)

GRANULOMATOUS
INFLAMMATION
By definition, to be classified as chronic granulomatous, an inflammatory
infiltrate must contain epithelioid histiocytes and/or inflammatory giant
cells. Clinically, the term granulomatous is applied to ocular inflammation
when large lardaceous “mutton-fat” KPs are observed. Mutton-fat KPs are
miniature granulomas composed of aggregates of epithelioid histiocytes. If
granulomatous inflammation is noted clinically or histopathologically, a
causative organism or specific etiologic agent should be sought. If
granulomatous inflammation is encountered in tissue sections, it is
imperative that stains for acid-fast organisms, fungi, and bacteria (and
occasionally silver stains for spirochetes) be performed. The specimen
should also be examined with polarization microscopy to rule out the
presence of foreign material, which can be inconspicuous. Sarcoidosis is a
relatively common cause of granulomatous ocular inflammation (Fig. 3-7).
A diagnosis of exclusion, sarcoidosis should be suspected when a
characteristic pattern of discrete noncaseating granulomas is found and
special stains for microorganisms are negative. Granulomatous
inflammation occasionally is a response to endogenous material. Examples
include the response to lipid in chalazia and the thick layer of giant cells

68
bordering keratin in the lumen of dermoid cysts with discontinuous
epithelial linings.

PATTERNS OF CHRONIC
GRANULOMATOUS
INFLAMMATION
The arrangement of the epithelioid histiocytes and other inflammatory
cells differs in various chronic granulomatous disorders. These histologic
patterns are often helpful in the diagnostic assessment of ocular specimens.
Diffuse, discrete, and zonal patterns of granulomatous inflammation occur
in ocular tissues.
The diffuse pattern of chronic granulomatous inflammation
characteristically occurs in sympathetic uveitis (ophthalmia) (Fig. 4-5) and
other diseases such as lepromatous leprosy. The epithelioid histiocytes and
inflammatory giant cells are diffusely scattered among a background
infiltrate composed of lymphocytes and plasma cells. The arrangement of
the cellular elements has been likened to salt and pepper, the eosinophilic
epithelioid histiocytes with their abundant cytoplasm comprising the
“salt,” which is diffusely dispersed within a “peppery” background of
basophilic lymphocytes.
Discrete, well-circumscribed aggregates of epithelioid histiocytes
characteristically occur in sarcoidosis (Fig. 3-10A). Hence, the discrete
pattern of chronic granulomatous inflammation is often called the
sarcoidal pattern. The tubercles of epithelioid histiocytes and giant cells in
sarcoidosis are sharply delimited from the surrounding infiltrate of round
cells, which is comprised largely of helper T lymphocytes. The discrete
granulomas in sarcoidosis are noncaseating and they typically lack the
cheesy or caseous central necrosis that is a characteristic feature of
tuberculosis. Sarcoidosis is a diagnosis of exclusion, however, and special
stains for microorganisms should always be performed. Discrete
granulomas do occur in other diseases like miliary tuberculosis and
tuberculoid leprosy. In addition, polarization microscopy should be done
to exclude particles of foreign material. Silica and beryllium can incite
granulomatous inflammation that can mimic sarcoidosis.

69
FIG. 3-10. Patterns of granulomatous inflammation. A. Discrete granuloma,
chronic dacryoadenitis, sarcoidosis. An infiltrate of lymphocytes, rich in helper
T cells, surrounds a discrete noncaseating granuloma composed of epithelioid
histiocytes and inflammatory giant cells. Scattered acini and ducts persist. B.
Zonal granulomatous reaction, phacoantigenic uveitis (phacoanaphylaxis).
Polymorphonuclear leukocytes infiltrating substance of ruptured lens (below)
constitute first zone of inflammatory cells. A second zone of epithelioid
histiocytes surrounds the polys. The clear space separating the two zones of cells
is a sectioning artifact. A third zone of nongranulomatous inflammation occurs
peripherally. (A. H&E ×50. B. H&E ×100.)

Concentric zones of inflammatory cells surround a central nidus of

antigenic material in the zonal pattern of chronic granulomatous
inflammation. The classic example in general pathology is the palisading
granuloma that surrounds a nidus of devitalized collagen in rheumatoid
arthritis. Classic examples of zonal granulomatous inflammation in the eye
are rheumatoid scleritis (Fig. 6-38) and the rare autoimmune disorder
phacoanaphylactic endophthalmitis (phacoantigenic uveitis).
Phacoantigenic uveitis or phacoanaphylactic endophthalmitis
(phacoanaphylaxis) is a severe zonal granulomatous inflammatory reaction
that envelops the lens and follows trauma (Fig. 3-10B). In the past, the
avascular encapsulated lens was thought to be an immune-sequestered
structure, and, phacoanaphylaxis, in turn, was considered the body’s
attempt to reject this “foreign tissue” after its antigens were exposed by
injury. These classic concepts are now known to be erroneous. The lens is
not an immune-sequestered structure; lens proteins or crystallins are
expressed elsewhere in the body, and antilens antibodies have been found
in the sera of normal individuals using modern sensitive assay techniques.
Furthermore, if the immune sequestration theory were valid,
phacoantigenic uveitis should be an extremely common disease in the era
of early extracapsular surgery. Residual undenatured lens material nearly

70
always remains in the capsular bag after planned extracapsular surgery.
Despite this, phacoanaphylactic endophthalmitis remains an extremely rare
disease, and very few cases have been documented after extracapsular
surgery and intraocular lens implantation.
Phacoanaphylaxis is currently thought to be an immune complex
disease (type III hypersensitivity reaction) involving loss of immune
tolerance. Histopathologically, the zonal inflammatory reaction is centered
around a lens whose capsule is ruptured, or fragments of lens substance
(Fig. 3-10B). The central zone of inflammatory cells that infiltrates the
substance of the lens is composed of polymorphonuclear leukocytes (first
line of cellular defense). The polys are attracted by chemotactic molecules
such as C5a that are generated when complement is activated by the
formation of immune complexes of antilens antibodies and lens antigens.
A second zone of granulomatous inflammation composed of epithelioid
histiocytes (activated macrophages, the second line of cellular defense)
and giant cells surrounds the inner collection of polys. A third zone of
nongranulomatous inflammation containing granulation tissue and
lymphocytes and plasma cells occurs peripherally.
Granulation tissue forms during the reparative phase of inflammation
and plays an important role in wound healing. Granulation tissue is
composed of proliferating capillaries, activated fibroblasts with contractile
properties called myofibroblasts, and a mixture of inflammatory cells
including polys, lymphocytes, plasma cells, macrophages, and eosinophils
(Fig. 3-11). The myofibroblasts are involved in scar contraction. A
“pyogenic granuloma” is an inappropriate, exuberant proliferation of
granulation tissue that typically arises after minor trauma (Fig. 5-15).

71
 FIG. 3-11. Granulation tissue. A mixed inflammatory infiltrate composed of
lymphocytes, plasma cells, polys, and macrophages surrounds proliferating
capillaries and spindle-shaped myofibroblasts. (H&E ×250.)

ENDOPHTHALMITIS AND
PANOPHTHALMITIS
Endophthalmitis is defined as inflammation, usually acute and infectious
in cause, that involves one or more of the ocular coats and adjacent
intraocular cavities. Clinically, the term usually denotes an infection that
involves the vitreous. As the name implies, panophthalmitis is a more
extensive ocular infection that has spread to involve all of the ocular coats
including the sclera, and occasionally the orbit as well.
Endophthalmitis and panophthalmitis usually are caused by bacteria
and less often by yeast and filamentous fungi. The ocular contents,
especially the vitreous humor, are an excellent culture medium that will
support the growth of relatively avirulent organisms including
saprophytes. These intraocular infections usually are suppurative, that is,
they are acute and are characterized by the presence of myriad
polymorphonuclear leukocytes (polys) that accumulate in the vitreous
cavity as a vitreous abscess. Tissue destruction, a hallmark of suppurative

72
inflammation, is caused by the release of digestive enzymes by
degenerating polys. The visual prognosis in endophthalmitis is often poor
because the retina and other structures bordering the abscess may be
destroyed.
Bacterial endophthalmitis usually presents 1 to 2 days postoperatively
with severe pain, turbid media, and a hypopyon. Eyes with acute purulent
bacterial endophthalmitis typically contain a large solitary vitreous abscess
(Fig. 3-12A,D). Histopathology shows extensive necrosis and dissolution
of uveal and retinal tissues and occasionally intraocular hemorrhage (Fig.
3-12B,C,E). In contrast to the infiltrate of polys in the vitreous, the choroid
often contains lymphocytes and plasma cells because Bruch membrane
acts as a natural barrier that confines the acute inflammation. In chronic
cases, an ingrowth of granulation tissue from the uvea breaches the
neuroepithelium and invades and organizes the vitreous abscess. Bacterial
colonies may be conspicuous in some cases, but extensive dispersion of
ocular pigment can make identification of bacteria difficult. The clinical
course of fungal endophthalmitis usually is more indolent than bacterial
endophthalmitis. Multiple vitreous microabscesses are a characteristic
finding in fungal endophthalmitis (Fig. 3-13).

FIG. 3-12. Vitreous abscess, acute bacterial endophthalmitis. A. Enucleated eye

contains large “wall-to-wall” vitreous abscess, a characteristic finding in bacterial
endophthalmitis. B, C. Retinal necrosis, acute bacterial endophthalmitis. Polys
fill the vitreous (above). Necrotic retina shows loss of normal lamellar

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 architecture. Focal hemorrhage is present. D–G. Acute purulent endophthalmitis
secondary to gram-positive cocci. D. Abscess fills with the vitreous cavity. E.
Retina deep to the vitreous abscess retains only a suggestion of residual lamellar
architecture. F. Polymorphonuclear leukocytes in the vitreous abscess show
varying degrees of necrosis and degeneration. G. Numerous bacteria were
identified. The necrotic cocci in this area have lost their gram positivity. (B.
H&E, ×20, C. H&E ×50, E. H&E ×100, F. H&E ×400, G. H&E ×400.)

FIG. 3-13. Fungal endophthalmitis. A. Multiple small vitreous microabscesses

are present. Vitreous microabscesses are a characteristic finding in fungal
endophthalmitis. B. Photomicrograph shows characteristic microabscesses in
posterior chamber. C. GMS fungal stain discloses fungal hyphae within a
microabscess. (B. H&E ×10, C. Gomori methenamine–silver ×250.)

Endophthalmitis is called exogenous when the eye is invaded by

organisms from the external environment. Exogenous endophthalmitis
usually is caused by bacteria or fungi introduced during ocular surgery or
penetrating trauma (Fig.3-14A). Other avenues of exogenous infection are
infected corneal ulcers that perforate or infected filtering blebs in patients
who have undergone fistulization surgery for glaucoma (Fig. 3-15).
Staphylococci, streptococci, gram-negative rods, and fungi are common
causes of exogenous endophthalmitis. The term localized endophthalmitis
refers to infection by relatively avirulent organisms such as
Propionibacterium acnes or Candida parapsilosis, which are sequestered
within the lens capsular bag during extracapsular cataract extraction with
intraocular lens implantation (Fig. 3-16). Such infections tend to be
chronic and smoldering and often incite a granulomatous response.

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FIG. 3-14. A. Exogenous endophthalmitis following nonsurgical trauma. Bacillus
cereus endophthalmitis developed rapidly in a farmer who sustained a corneal
laceration in the barnyard. The anterior chamber is flat, and an abscess composed
of polymorphonuclear leukocyte fills the vitreous cavity. B. Endogenous
endophthalmitis following dental procedure. A purportedly healthy young man
developed “uveitis” several days after having his teeth cleaned. This progressed
to endophthalmitis. The retina is thickened and detached, and purulent material
fills the vitreous. In exogenous endophthalmitis, organisms from the external
environment gain access to the interior of the eye via wounds or perforations.
Septicemia is typically the source of the microorganisms in cases of endogenous
endophthalmitis.

FIG. 3-15. Exogenous endophthalmitis due to infected filtering bleb. A.

Polymorphonuclear leukocytes (inset) infiltrate filtering bleb on surface of
infected globe and are present within gaping wound in posterior cornea (B). C
Polys detach ILM of perifoveal retina, which shows severe glaucomatous atrophy
and scattered hemorrhages. (A. H&E ×25 (inset ×400), B. H&E ×100, C. H&E
×300.)

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FIG. 3-16. Propionibacterium acnes localized endophthalmitis. A. Large
intracapsular colony of bacteria forms whitish plaque within excised lens capsular
bag. Chronic granulomatous uveitis developed months after extracapsular
cataract extraction. B. Large colony of sequestered diphtheroids forms basophilic
granular deposit within explanted lens capsular bag. C. Bacterial colony beneath
anterior lens capsule is composed of pleomorphic gram-positive bacteria. (B.
H&E ×50, C. Tissue Gram stain ×250.)

Endogenous endophthalmitis usually is caused by the hematogenous

dissemination of organisms to the eye (Fig. 3-14B). Endogenous
endophthalmitis can complicate septicemia, subacute bacterial
endocarditis, meningococcemia, and systemic fungal infections such as
candidiasis, aspergillosis, or nocardiosis in immunocompromised patients
(Figs. 3-17 and 3-18). The posterior segment usually harbors the bulk of
the inflammatory process in an endogenous infection. Other important
endogenous infections are the necrotizing retinitides caused by the
herpesviruses cytomegalovirus (CMV), varicella-zoster virus (VZV), and
herpes simplex virus (HSV) and the protozoan parasite Toxoplasma
gondii.

FIG. 3-17. Endogenous fungal endophthalmitis, aspergillosis. A. The posterior

retina is thickened and necrotic, and the posterior choroid is thickened.
Inflammatory cells partially opacify the vitreous. B. Fungal stain discloses

76
characteristic linear array of fungal hyphae on the inner surface of Bruch
membrane. Branching septate hyphae also infiltrate the retina and choroidal
stroma. (B. Gomori methenamine–silver, ×50.)

FIG. 3-18. Endogenous endophthalmitis secondary to Nocardia. A. Fundus photo

shows focally hemorrhagic inflammatory mass involving macula with overlying
retinal detachment and retinal “hypopyon.” B. Sectioned eye shows vitreous
opacification and inflammation involving thickened posterior retina and
subretinal space. C. Most of the retina is intensely inflamed and destroyed. A
vitreous abscess adheres to its inner surface. The choroid is scarred and inflamed,
and inflammation involves the retrobulbar tissues and orbital fat. D. Filamentous
gram-positive bacteria consistent with Nocardia species are present on either side
of Bruch membrane. Numerous polymorphonuclear leukocytes are present. (C.
H&E ×10, D. Tissue Gram stain ×400.)

VIRAL RETINITIS
CMV retinitis (Fig. 3-19) is a common opportunistic intraocular infection
in untreated patients who have HIV/AIDS and can also affect patients who
are immunosuppressed following transplant surgery or cancer
chemotherapy. Before the institution of HAART therapy, nearly one third

77
of patients with HIV/AIDS developed CMV retinitis. CMV retinitis is a
devastating ocular complication of AIDS because it causes total retinal
destruction and blindness if untreated.

FIG. 3-19. Cytomegalovirus retinitis. A. Full-thickness destruction of the retina

and RPE are present. Infected retina contains enlarged cells. The patient had
received chemotherapy for lymphoma. B. Infected retina contains multinucleated
giant cell with viral inclusion. C. Clear haloes surrounding large Cowdry type A
intranuclear inclusions of CMV impart “owl’s eye” appearance to infected nuclei.
Smaller cytoplasmic inclusions also are present. (A. H&E ×100, B. H&E ×120,
C. H&E ×400.)

Ophthalmoscopically, acute CMV infection causes coagulative necrosis

and opacification of the retina, which appears yellowish-white. Posterior
retinal infections usually begin along vessels and often are marked by
heavy infiltration and hemorrhage, which are responsible for an
ophthalmoscopic appearance that has been likened to “crumbled cheese
and ketchup.” Peripheral lesions have a granular appearance and little or
no hemorrhage.
The term cytomegalovirus is derived from the cellular enlargement
that is a characteristic cytopathic effect of the virus. In this regard, CMV
differs from the other herpesviruses that cause necrotizing retinitis. All
retinal herpesvirus infections are characterized histopathologically by the
presence of Cowdry type A intranuclear inclusions composed of virions.
The intranuclear inclusions found in cells infected by CMV are often
called “owl’s eye” inclusions because they typically are quite large and are
surrounded by a clear halo (Fig. 3-19C). Multiple intracytoplasmic
inclusions also occur in cells infected with CMV.
Light microscopy discloses markedly enlarged abnormal retinal cells
containing “owl’s eye” inclusions in the necrotic retina (Fig. 3-19C). Areas
that are opaque clinically typically show full-thickness retinal destruction

78
(Fig. 3-19A). The transition between healthy and totally necrotic retina is
often abrupt. The underlying choroid contains acute and chronic
inflammatory cells. CMV can also infect the retinal pigment epithelium
(RPE). The vitreous in CMV retinitis is often relatively clear in contrast to
the intense vitritis seen in ocular toxoplasmosis.
Necrotizing retinitis caused by HSV or VZV occurs in the acute retinal
necrosis (ARN) or bilateral acute retinal necrosis (BARN) syndromes.
Classic ARN syndrome occurs in presumably healthy patients who are not
immunosuppressed. A similar ocular infection can occur in
immunosuppressed patients, however. The Cowdry type A intranuclear
inclusions are smaller than the “owl’s eye” inclusions of CMV and
cytomegaly is not observed. The visual prognosis in patients who have
ARN is often poor because severe postinfectious retinal atrophy
predisposes to retinal holes and detachment. VZV infection of the retina in
AIDS patients causes the progressive outer retinal necrosis (PORN)
syndrome, which begins with deep multifocal retinal opacification and
rapidly progresses to total retinal necrosis (Fig. 3-20).

FIG. 3-20. Progressive Outer Retinal Necrosis (PORN) syndrome. Necrosis

involves all retinal layers including RPE. Cowdry type A intranuclear inclusions
of VZV are seen in inset. The patient had HIV/AIDS (Main figure, H&E ×100;
inset, H&E ×250). (Case presented by Dr. Curtis Margo at the 1994 meeting of
the Verhoeff Society, Rochester, Minnesota.)

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Eosinophilic viral inclusions are found postmortem in retinal neurons and
glial cells in children who have subacute sclerosing panencephalitis
(SSPE), a slow virus infection of the CNS by the measles virus. SSPE can
present with visual loss from a macular neuroretinitis (measles
maculopathy). The average age at onset is age 7 years, and males are
predominantly affected (3:1). As mental deterioration progresses toward
decerebration, patients develop seizures and myoclonic jerks with
distinctive EEG changes.

TOXOPLASMA
RETINOCHOROIDITIS
Ocular toxoplasmosis is an infestation by the obligatory intracellular
protozoan parasite Toxoplasma gondii, whose definitive host is the cat.
Toxoplasmosis is a retinochoroiditis; the neurotropic parasite infests the
retina and the central nervous system primarily. The multiplicative activity
of the organisms themselves causes coagulative necrosis of retinal tissue;
Toxoplasma proliferates in the cytoplasm of the parasitized retinal cells
until the cells rupture. Infected portions of the retina are totally destroyed,
and the area of primary retinal infection is usually sharply demarcated
(Fig. 3-21). The primary retinitis is associated with a secondary chronic
choroiditis that may spread to involve the sclera producing a focal or
segmental panophthalmitis. An example of a zonal granulomatous
inflammatory reaction modified by anatomy, the inflammatory infiltrate is
confined to the choroid by the structural barrier of Bruch membrane and
usually contains epithelioid histiocytes.

FIG. 3-21. Toxoplasma retinochoroiditis. A. The infected retina is almost totally

necrotic. The choroid is thickened by chronic granulomatous inflammation. B.
Arrow denotes Toxoplasma tachyzoite in largely necrotic retina. C. Three
intraretinal Toxoplasma cysts filled with bradyzoites are present. (A. H&E ×50,

80
 B. H&E ×250, C. H&E ×250.)

The name Toxoplasma (toxon = bow) derives from the crescentic shape of
the tachyzoites, which are the rapidly multiplying free form of the parasite.
Tachyzoites occasionally are identified in the infected retina (Fig. 3-21B),
but the diagnosis usually is confirmed by the identification of Toxoplasma
cysts in sections stained with PAS (Fig. 3-21C). Toxoplasma cysts are
filled with hundreds of slowly proliferating bradyzoites, which are released
when the cyst walls rupture. Reactivation of infection in adults is caused
by the release of organisms that have remained encysted and dormant in
the margins of old congenital chorioretinal scars.
In the United States, most cases of ocular toxoplasmosis are acquired
in utero by transplacental transmission of the parasite from a newly
infected mother to her fetus. Acquired toxoplasmosis is more common
than previously thought, however, and acquired disease related to dietary
habits and poor hygiene is relatively common in some parts of the world.
Congenital retinochoroiditis produces atrophic and pigmented crater-
like chorioretinal scars, which typically are located in the macula and were
once called atypical colobomas. The macular region is affected primarily
because it is profusely vascularized and parasite is disseminated
hematogenously. The old scars of ocular toxoplasmosis appear white
because the sclera has been bared by full-thickness choroidal destruction.
Intensely pigmented clumps of hyperplastic RPE also typically are found.
Active infection causes focal retinal opacification and necrosis and an
intense inflammatory infiltrate in the vitreous composed of histiocytes and
lymphocytes. The intense vitritis markedly reduces visual acuity and may
partially obscure the underlying focus of white infected retina. This latter
appearance has been likened to a “headlight in the fog.” Toxoplasmosis is
one of the opportunistic infections that can occur in patients with
HIV/AIDS.

UVEITIS
Uveitis refers to inflammation of the uveal tract, the middle pigmented and
heavily vascularized coat of the eye that includes the iris, ciliary body, and
choroid. Endogenous chronic nongranulomatous iridocyclitis, a poorly
understood immunological disorder, is encountered most frequently in
clinical practice. Uveitis is often idiopathic, but it may be associated with
systemic disorders including juvenile rheumatoid arthritis, ankylosing

81
spondylitis, reactive arthritis, ulcerative colitis, regional enteritis, or
Behçet disease. Microscopy discloses an infiltrate of lymphocytes and
plasma cells in the uveal stroma in eyes with nongranulomatous uveitis
(Fig. 3-4). Russell bodies and morula cells may be quite common in
chronic cases.
Clinical or pathological evaluation may disclose a specific cause in
patients who have chronic granulomatous uveitis. Sarcoidosis is the most
common cause of granulomatous uveitis. Approximately 38% of patients
with systemic sarcoidosis will have ocular involvement at some point in
their disease. Granulomatous intraocular inflammation can also be caused
by tuberculosis, leprosy, syphilis, parasites, and fungal infections including
candidiasis, coccidioidomycosis, histoplasmosis, blastomycosis, and
sporotrichosis. Granulomatous inflammation is also found in sympathetic
uveitis and Vogt-Koyanagi-Harada disease.
Behçet disease is a systemic immune complex disease that causes
occlusive vasculitis. Genital and oral aphthous ulcers and recurrent
nongranulomatous iridocyclitis with hypopyon are characteristic
manifestations and diagnostic criteria. Ocular involvement also is marked
by retinal vasculitis, which leads to hemorrhagic retinal infarction and
retinal detachment. Especially common in the Middle and Far East, Behçet
disease is associated with HLA phenotypes HLA-B5 and its subtype HLA-
Bw51. Patients who have ocular Behçet disease usually become blind if
they are not treated with immunosuppressive drugs.

THE SEQUELAE OF OCULAR

INFLAMMATION
The sequelae of ocular inflammation include corneal scarring and
vascularization, band keratopathy, cataract, and secondary glaucoma. The
latter is often closed angle in type and is caused by inflammatory posterior
synechiae between the iris and lens. Intraocular fibrosis and membranes
are caused by the organization of inflammatory debris. A cyclitic
membrane is a fibrous membrane that bridges the anterior part of the
vitreous cavity behind the lens from ciliary body to ciliary body (Fig. 3-
22). Cyclitic membranes are caused by fibrous organization of the anterior
vitreous. Contraction of inflammatory membranes causes tractional
detachment of the ciliary body or retina. Ocular hypotony and shrinkage
frequently result from the disorganization and destruction of intraocular

82
structures. Clinically, the term phthisical is applied to blind hypotonus
eyes that are soft, partially collapsed and have a vaguely cuboid shape
caused by rectus muscle traction (Fig. 3-23A). The pathologic diagnosis
phthisis bulbi (atrophia bulbi with shrinkage and disorganization) is
reserved for eyes that are markedly atrophic and disorganized and have
thickened folded sclera (Fig. 3-23B). The interior of such phthisical eyes
usually is filled with scar tissue and intraocular structures are
unrecognizable. The term atrophia bulbi with shrinkage is used if
intraocular structures can be identified. Intraocular ossification (osseous
metaplasia of the RPE) is commonly observed in phthisical and atrophic
eyes that have chronic retinal detachments (Fig. 3-23C).

FIG. 3-22. Cyclitic membrane. A. Chronically detached retina adheres anteriorly

to white mass of fibrous connective tissue filling posterior chamber. Cyclitic
membranes are caused by fibrous organization of the vitreous. B. Cyclitic
membrane incorporates lens remnants. The iris is incarcerated in central corneal
wound. (B. H&E ×5.)

FIG. 3-23. A. Pathological phthisis bulbi (atrophia bulbi with shrinkage and
disorganization). Phthisical eye has characteristic cuboidal shape caused by
traction of rectus muscles on hypotonus globe. B. Mass of totally detached
gliotic retina and metaplastic bone fills disorganized interior of chronically

83
blind, painful eye. The angle is closed by peripheral anterior synechiae. An
intraocular lens is present. C. Osseous metaplasia of the RPE. A large focus of
metaplastic bone containing fatty marrow rests on the inner surface of choroid.
Intraocular bone is often found in phthisical eyes.

BIBLIOGRAPHY
General References
Chensue SW, Ward PA. Inflammation. In: Damjanov I, Linder J, eds. Anderson’s
Pathology, 10th ed. St. Louis, MO: CV Mosby, 1996:387–415.
Cotran RS, Kumar V, Robbins SL. Inflammation and repair. In: Cotran RS,
Kumar V, Robbins SL, eds. Pathologic Basis of Disease, 5th ed. Philadelphia,
PA: WB Saunders, 1994:51–92.
Fantone JC, Ward PA. Inflammation. In: Rubin E, Farber JL, eds. Pathology.
Philadelphia, PA: JB Lippincott, 1994:32–67.
Gallin JI, Goldstein IM, Snyderman R, eds. Inflammation: Basic Principles and
Clinical Correlates. New York, NY: Raven Press, 1988.
Green WR. Inflammatory diseases and conditions of the eye. In: Spencer W, ed.
Ophthalmic Pathology: An Atlas and Textbook, vol. 3. Philadelphia, PA: WB
Saunders, 1996:1864–2110.
Howes EL, Rao NA. Basic mechanisms in pathology. In: Spencer W, ed.
Ophthalmic Pathology: An Atlas and Textbook, vol. 4. Philadelphia, PA: WB
Saunders, 1996:2935–3044; Chapter 13.
Naumann GOH, Naumann LR. Intraocular inflammations. In: Naumann GOH,
Apple DJ, eds. Pathology of the Eye. New York, NY: Springer-Verlag,
1986:99–184.
Ormerod LD, Margo CE. Changing patterns of ocular infectious disease. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.
Ophthalmol Clin North America 1995;8:109–124.
Pepose JS, Holland GN, Wilhelmus KR, eds. Ocular Infection & Immunity. St.
Louis, MO: CV Mosby, 1996.
Proia AD. Inflammation. In: Garner A, Klintworth GK, eds. Pathobiology of
Ocular Disease. A Dynamic Approach. New York, NY: Marcel Dekker,
1994:63–100.
Roitt I, ed. Essential Immunology. Oxford, England: Blackwell Scientific
Publications, 1988.

Inflammatory Mediators
Albelda SM, Buck CA. Integrins and other cell adhesion molecules. FASEB J
1990;4:2868–2880.
Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury.

84
 FASEB J 1994;8:504–512.
Arai KI, Lee F, Miyajima A, et al. Cytokines: coordinators of immune and
inflammatory responses. Annu Rev Biochem 1990;59:783–836.
Cochrane CG, Gimbrone MA Jr, eds. Cellular and Molecular Mechanisms of
Inflammation. Vascular Adhesion Molecules. San Diego, CA: Academic
Press, 1991:1–181.
Cochrane CG, Gimbrone MA Jr, eds. Cellular and Molecular Mechanisms of
Inflammation. Signal Transduction in Inflammatory Cells, Part A. San Diego,
CA: Academic Press, 1992:1–195.
Dinarello CA. Biology of interleukin 1. FASEB J 1988;2:108–115.
Harlan JM, Liu DY, eds. Adhesion. Its Role in Inflammatory Disease. New York,
NY: WH Freeman and Company, 1992:1–202.
Kunkel SL, Remick DG, eds. Cytokines in Health and Disease. New York, NY:
Marcel Dekker, 1992:1–568.
Le J, Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple
overlapping biological activities. Lab Invest 1987;56:234–248.
Movat HZ. Tumor necrosis factor and interleukin-1: role in acute inflammation
and microvascular injury. J Lab Clin Med 1987;110:668–681.

Inflammatory Cells
Adams DO, Hamilton TA. The activated macrophage and granulomatous
inflammation. Curr Top Pathol 1989;79:151–167.
Becker EL. Leukocyte stimulation: receptor, membrane, and metabolic events.
Introduction and summary. Fed Proc 1986;45:2148–2150.
Bronkhorst IH, Jager MJ. Uveal melanoma: the inflammatory microenvironment.
J Innate Immun 2012;4(5–6):454–462.
Bronkhorst IH, Ly LV, Jordanova ES, et al. Detection of M2-macrophages in
uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci
2011;52(2):643–650.
Bronkhorst IH, Vu TH, Jordanova ES, et al. Different subsets of tumor-
infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in
uveal melanoma. Invest Ophthalmol Vis Sci 2012;53(9):5370–5378.
Cochrane CG. Mechanisms coupling stimulation and function in leukocytes.
Introduction. Fed Proc 1984;43:2729–2731.
Elsbach P, Weiss J. Oxygen-dependent and oxygen-independent mechanisms of
microbicidal activity of neutrophils. Immunol Lett 1985;11:159–163.
Fantone JC, Ward PA. Role of oxygen-derived free radicals and metabolites in
leukocyte-dependent inflammatory reactions. Am J Pathol 1982;107:395–418.
Herwig MC, Bergstrom C, Wells JR, et al. M2/M1 ratio of tumor associated
macrophages and PPAR-gamma expression in uveal melanomas with class 1
and class 2 molecular profiles. Exp Eye Res 2013;107:52–58.
Herwig MC, Grossniklaus HE. Role of macrophages in uveal melanoma. Expert
Rev Ophthalmol 2011;6(4):405–407.

85
Johnston RB Jr. Current concepts: immunology. Monocytes and macrophages. N
Engl J Med 1988;318:747–752.
Kay AB. The eosinophilic leukocyte. In: Dale MM, Foreman JC, eds. Textbook of
Immunopharmacology. Oxford, England: Blackwell Scientific Publications,
1989:68–76.
Lewis CE, McGee GOD, eds. The Natural Immune System. The Macrophage.
Oxford, England: IRL Press at Oxford University Press, 1992.
Thomas R, Lipsky PE. Monocytes and macrophages. In: Kelley WN, Harris ED
Jr, Ruddy S, et al., eds. Textbook of Rheumatology, 4th ed. Philadelphia, PA:
WB Saunders, 1993:286–303.
van Furth R. Development and distribution of mononuclear phagocytes. In: Gallin
JI, Goldstein IM, Snyderman R, eds. Inflammation. Basic Principles and
Clinical Correlates. New York, NY: Raven Press, 1992:325–340.
Weiss SJ, LoBuglio AF. Phagocyte-generated oxygen metabolites and cellular
injury. Lab Invest 1982;47:5–18.
Weller PF. The immunobiology of eosinophils. N Engl J Med
1991;374:1110–1118.
Granulomatous Inflammation
Boros DL. Granulomatous inflammation. In: Zembala M, Asherson GL, eds.
Human Monocytes. San Diego, CA: Academic Press, 1989:313–381.
Ferry AP. The histopathology of rheumatoid episcleral nodules: an extra-articular
manifestation of rheumatoid arthritis. Arch Ophthalmol 1969;82:77–88.
Font RL, Fine BS, Messmer E, et al. Light and electron microscopic study of
Dalen-Fuchs nodules in sympathetic ophthalmia. Ophthalmology
1982;90:66–75.
Jakobiec FA, Marboe CC, Knowles DM II, et al. Human sympathetic ophthalmia.
An analysis of the inflammatory infiltrate by hybridoma-monoclonal
antibodies, immunochemistry, and correlative electron microscopy.
Ophthalmology 1983;90:76–95.
Lubin JR, Albert DM, Weinstein M. Sixty-five years of sympathetic ophthalmia.
A clinicopathologic review of 105 cases (1913–1978). Ophthalmology
1980;87:109–121.
Marak GE. Phacoanaphylactic endophthalmitis. Surv Ophthalmol
1992;36:325–329.
Obenauf CD, Shaw HE, Wyndor CF, et al. Sarcoidosis and its ocular
manifestations. Am J Ophthalmol 1978;86:648–655.
Rao NA, Marak GE, Hidayat AA. Necrotizing scleritis. A clinicopathologic study
of 41 cases. Ophthalmology 1985;92:1542–1549.
To KW, Jakobiec FA, Zimmerman LE. Sympathetic uveitis. In Albert DM,
Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical
Practice, vol. 1. Philadelphia, PA: WB Saunders, 1994:496–503.

Bacterial Endophthalmitis

86
Allen HF, Mangiaracine AB. Bacterial endophthalmitis after cataract surgery.
Arch Ophthalmol 1974;91:3–7.
Jensen AD, Naidoff MA. Bilateral meningococcal endophthalmitis. Arch
Ophthalmol 1973;90:396–398.
Meisler DM, Mandelbaum S. Propionibacterium-associated endophthalmitis after
extracapsular cataract extraction: review of reported cases. Ophthalmology
1989;96:54–61.
Meisler DM, Palestine AG, Vastein DW, et al. Chronic Propionibacterium
endophthalmitis after extracapsular cataract extraction and intraocular lens
implantation. Am J Ophthalmol 1986;102:733–739.
O’Brien TP, Green WR. Endophthalmitis. In: Mandell GL, Douglas RG Jr,
Bennett JE, eds. Principles and Practice of Infectious Diseases, 4th ed. New
York, NY: Churchill Livingstone, 1993.
Piest KL, Kincaid MC, Tetz MR, et al. Localized endophthalmitis: a newly
described cause of the so-called toxic lens syndrome. J Cataract Refract Surg
1987;13:498–510.
Shammas HF. Endogenous E. coli endophthalmitis. Surv Ophthalmol
1977;21:428–435.

Fungal Endophthalmitis
Abbott RL, Forster RK, Rebell G. Listeria monocytogenes endophthalmitis with a
black hypopyon. Am J Ophthalmol 1978;86:715–719.
Brod RD, Clarkson JG, Flynn HM Jr, et al. Endogenous fungal endophthalmitis.
In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology. New York,
NY: Harper & Row, 1990:1–39.
Caya JG, Farmer SG, Williams GA, et al. Bilateral Pseudallescheria boydii
endophthalmitis in an immunocompromised patient. Wis Med J
1988;87:11–14.
Chen CJ. Nocardia asteroides endophthalmitis. Ophthalmic Surg
1983;14:502–505.
Demicco DD, Reichman RC, Violette EJ, et al. Disseminated aspergillosis
presenting with endophthalmitis. A case report and a review of the literature.
Cancer 1984;53:1995–2001.
Edwards JE Jr, Foos RY, Montgomerie JA, Gutz LB. Ocular manifestations of
Candida septicemia: review of 76 cases of hematogenous Candida
endophthalmitis. Medicine 1974;53:47–75.
Ferry AP, Font RL, Weinberg RS, et al. Nocardial endophthalmitis: report of two
cases studied histopathologically. Br J Ophthalmol 1988;72:55–61.
Fine BS, Zimmerman LE. Exogenous intraocular fungus infections with
particular reference to complications of intraocular surgery. Am J Ophthalmol
1959;48:151–165.
Gregor RJ, Chong CA, Augsburger JJ, et al .Endogenous Nocardia asteroides
subretinal abscess diagnosed by transvitreal fine-needle aspiration biopsy.

87
 Retina 1989;9:118–121.
Ho PC, Tolentino FI, Baker AS. Successful treatment of exogenous aspergillus
endophthalmitis: a case report. Br J Ophthalmol 1984;68:412–415.
McGuire TW, Bullock JD, Bullock JD Jr, et al. Fungal endophthalmitis. An
experimental study with a review of 17 human ocular cases. Arch Ophthalmol
1991;109:1289–1296.
Michelson PE, Stark WJ, Reeser F, et al. Endogenous Candida endophthalmitis.
Report of 13 cases and 16 from the literature. Int Ophthalmol Clin
1971;11:125–147.
O’Brien TP, Green WR. Fungus infections of the eye and periocular tissues. In:
Garner A, Klintworth GK, eds. Pathology of Ocular Disease. A Dynamic
Approach, 2nd ed. New York, NY: Marcel Dekker, 1993.
Weishaar PD, Flynn HW Jr, Murray TG, et al. Endogenous aspergillus
endophthalmitis. Clinical features and treatment outcomes. Ophthalmology
1998;105:57–65.
Wong KW, Tasman W, Eagle RC Jr, et al. Bilateral Candida parapsilosis
endophthalmitis. Arch Ophthalmol 1997;115:670–672.

HIV/AIDS
Pepose JS, Holland GN, Nestor MS, et al. Acquired immune deficiency
syndrome: pathogenic mechanisms of ocular disease. Ophthalmology
1985;92:472–484.
Rajeev B, Rao NA. Advances in ocular pathology in AIDS. In: Grossniklaus HE,
Margo CE, eds. Advances in Ophthalmic Pathology. Ophthalmol Clin North
America 1995;8:125–141.
Rao NA, Zimmerman PL, Boyer D, et al. A clinical, histopathologic, and electron
microscopic study of Pneumocystis carinii choroiditis. Am J Ophthalmol
1989;107:218–228.

Viral Retinitis
Culbertson WW, Blumenkranz MS, Haines H, et al. The acute retinal necrosis
syndrome. 2. Histopathology and etiology. Ophthalmology
1982;89:1317–1325.
Duker JS, Blumenkranz MS. Diagnosis and management of the acute retinal
necrosis (ARN) syndrome. Surv Ophthalmol 1991;35:327–343.
Fisher JP, Lewis ML, Blumenkranz M, et al. The acute retinal necrosis syndrome.
1. Clinical manifestations. Ophthalmology 1982;89:1309–1316.
Font RL, Jenis EH, Tuck KO. Measles maculopathy associated with subacute
sclerosing panencephalitis. Arch Pathol 1973;96:168–174.
Holland GN. The progressive outer retinal necrosis syndrome. Int Ophthalmol
1994;18:163–165.
Murray HW, Knox DL, Green WR, et al. Cytomegalovirus retinitis in adults: a

88
 manifestation of disseminated viral infection. Am J Med 1977;63:574–584.
Pavesio CE, Mitchell SM, Barton K, et al. Progressive outer retinal necrosis
(PORN) in AIDS patients: a different appearance of varicella-zoster retinitis.
Eye 1995;9:271–276.
Pepose JS, Holland GN. Cytomegalovirus infections of the retina. In: Ryan S, ed.
Retina, 2nd ed., vol. 2. St. Louis, MO: Mosby, 1994:1559–1570.

Uveitis
Bell R, Font RL. Granulomatous anterior uveitis caused by Coccidioides immitis.
Am J Ophthalmol 1972;74:93–98.
Inomata H, Kohno T, Rao NA, et al. Vasculitis and intraocular neovascularization
in Behçet’s disease: histopathology of the early and advanced late stages. In:
Dernouchamps JP, Verougstraete C, Caspers-Velu L, et al., eds. Proceedings
of the Third International Symposium on Uveitis. Brussels, Belgium, May 24–
27, 1992. New York, NY: Kugler Publications, 1993:349–355.
Knox DL. Uveitis associated with systemic disease. In: Albert DM, Jakobiec FA,
eds. Principles and Practice of Ophthalmology: Clinical Practice, vol. 1.
Philadelphia, PA: WB Saunders, 1994:465–474.
Mullaney J, Collum LM. Ocular vasculitis in Behçet’s disease. A pathological
and immunohistochemical study. Int Ophthalmol 1985;7:183–191.
O’Brien JM, Albert DM, Foster CS. Anterior uveitis. In: Albert DM, Jakobiec
FA, eds. Principles and Practice of Ophthalmology: Clinical Practice, vol. 3.
Philadelphia, PA: WB Saunders, 1994: 1745–1770.
Park SS, To KW, Friedman AH, et al. Infectious causes of posterior uveitis. In:
Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology:
Clinical Practice, vol. 1. Philadelphia, PA: WB Saunders, 1994:450–464.

Parasitic Infection
Anderson J, Font RL. Ocular onchocerciasis. In: Binford CH, Connor DH, eds.
Pathology of Tropical and Extraordinary Diseases, vol. II. Washington, DC:
Armed Forces Institute of Pathology, 1976:360.
Gagliuso DJ, Teich SA, Freidman AH, et al. Ocular toxoplasmosis in AIDS
patients. Trans Am Ophthalmol Soc 1990;88:63–86.
Naumann G, Gunders AE. Pathogenesis of the posterior segment lesion of ocular
onchocerciasis. Am J Ophthalmol 1973;75:82–89.
O’Connor GR. Manifestations and management of ocular toxoplasmosis. Bull N Y
Acad Sci 1970;174:192–210.
Perkins ES. Ocular toxoplasmosis. Br J Ophthalmol 1973;57:1–17.

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 4 Ocular Trauma
Many eyes that are enucleated have a past history of nonsurgical or
surgical trauma. The eye can be totally destroyed by severe injuries that
violate the integrity of its protective coats and scatter its contents. Less
devastating injuries cause blindness by disrupting the normal anatomical
and functional relationships between the eye’s highly specialized tissues.
Retinal detachment, retinal avulsion anteriorly from the ora serrata or
posteriorly from the optic nerve, avulsion of the optic nerve from the
globe, irido- or cyclodialysis, lens dislocation, and choroidal rupture are
examples. By disrupting pristine anatomical relationships, trauma also
exposes new surfaces that cells can proliferate on. These include the inner
and outer surfaces of the retina after retinal detachment, the posterior face
of the vitreous exposed by vitreous detachment, or anterior chamber
structures made accessible to surface epithelium by poorly apposed
wounds in the cornea. Cellular proliferation on these newly exposed
surfaces leads to permanent adhesions between structures, membrane
formation, fibrosis, traction, retinal detachment, and glaucoma.
Hemorrhage commonly complicates trauma. The blood opacifies
transparent ocular media like the vitreous and may cause secondary
glaucoma by occluding aqueous outflow pathways. In addition, intraocular
hemorrhage causes expulsion and irrevocable loss of vital intraocular
structures when it accumulates in the suprauveal space and fills the interior
of the eye (expulsive choroidal hemorrhage). Blindness also can result
when the body’s normal mechanisms of regeneration and repair cause
scarring, which affects highly differentiated transparent tissues, or when
fibrous membranes exert traction on vital structures. For example, the
fibrous organization of tracts of hemorrhage in the vitreous left by
perforating missiles ultimately can cause tractional retinal detachment.
Trauma also predisposes to infection by destroying the eye’s normal
protective barriers. Infection is always a danger after ocular trauma, even
minor injuries such as corneal abrasions. Organisms introduced by
penetrating injuries or contaminated intraocular foreign bodies of metallic,

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vegetable, or even endogenous animal (e.g., hair, skin) composition can
cause exogenous endophthalmitis.
The terms penetrating and perforating are commonly applied to ocular
injuries that produce defects in the integrity of the ocular coats (Fig. 4-1).
A penetrating injury partially cuts or tears a structure. A perforation is a
through-and-through injury that completely cuts or tears through a
structure. To use these terms properly, one must specify the structure that
is involved. For example, a corneal laceration is both a perforating injury
of the cornea and a penetrating injury of the globe. Most corneal foreign
bodies produce a small penetrating injury in the anterior stroma that is
filled by the corneal epithelium forming an epithelial facet (Fig. 4-2A).

FIG. 4-1. A. Limbal perforation/penetrating injury of the globe. Lens and

detached retina are incarcerated in sutured limbal wound. The anterior chamber is
flat, and one iris leaflet is absent. A massive suprauveal hemorrhage fills half of
the posterior segment. The latter presumably contributed to loss of intraocular
contents and incarceration in wound. B. Perforating injury of the globe (BB
injury). The sclera is drawn centrally at the site of a gaping perforation that
extends from the limbus to the equator. Parts of the totally detached retina are
incarcerated in the wound. C. Perforating injury of the globe (BB injury).
Ocular perforation caused by BB gun is a through-and-through injury with
entrance and exits wounds in limbus and posterior sclera, respectively. Fresh
blood marks the track of the projectile. Posteriorly detached vitreous also
contains ochre-colored degenerated blood.

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 FIG. 4-2. A. Epithelial facet, cornea. Epithelium fills crater in Bowman
membrane and anterior stroma caused by corneal foreign body. B. Corneal
abrasion. Sliding epithelium healing corneal abrasion has tapering margin. (A.
H&E ×100, B. H&E ×100.)

The ophthalmic pathology laboratory frequently processes eyes that have

been ruptured by severe blunt trauma, have severe corneoscleral
lacerations caused by sharp objects, or have been perforated by missiles
such as BBs (Fig. 4-3). Pathologic examination of some severely
traumatized eyes reveals a disrupted scleral shell filled with blood and
scant remnants of intraocular tissue. Most cases show intraocular
hemorrhage and loss or incarceration of intraocular structures. Massive
intraocular hemorrhage typically involves the vitreous and subretinal and
suprauveal spaces. Loss of intraocular contents is caused by the space-
occupying effect of expanding suprauveal hemorrhage and compression of
the eye by the surrounding orbital tissue and forceful eyelid closure. Both
mechanisms elevate the intraocular pressure (IOP) and expel the
intraocular tissues through the open wound. Tissues that frequently are lost
or incarcerated in the wound include the iris, lens, ciliary body, vitreous,
and occasionally the retina and choroid. Prolapsed intraocular tissue
excised during the repair of corneoscleral lacerations should always be
submitted for pathologic examination. If the retina is found, the prognosis
is poor.

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FIG. 4-3. A. Ruptured globe. Clotted blood fills gaping laceration in the cornea
and sclera. There was extensive loss of intraocular contents. B. Corneal
laceration. A sutured laceration is present in the central cornea. The lens and half
of the iris are absent, and the detached retina is drawn toward the wound. Most of
the blood filling the interior of the eye is located in the suprauveal space. C.
Uveal and retinal incarceration in limbal wound. Pigmented uveal tissue and
orange band of the detached retina extend extraocularly through scleral wound.
Degenerated blood fills the interior of the globe. D. Old ruptured globe.
Organized vitreous is incarcerated in central corneal scar. Anterior uvea and lens
are absent.

Expulsive choroidal hemorrhage caused by an expanding suprauveal

hematoma is a dreaded complication of ocular surgery. Intraoperative
rupture of a sclerotic arteriole caused by the sudden hypotony of surgery
causes the expanding hemorrhage in the suprachoroidal space.
Spontaneous expulsive choroidal hemorrhage can also complicate corneal
perforation in glaucomatous eyes (Fig. 4-4).

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 FIG. 4-4. Spontaneous expulsive hemorrhage. A. Knuckle of uveal tissue is
expelled extraocularly through the lips of gaping perforation in the infected
cornea by massive suprauveal hemorrhage. A hypopyon fills the residual anterior
chamber. B. Detached retina and hemorrhagic detachment of choroid extend
extraocularly through perforation in the infected cornea. Blood detaches the
ciliary body at right. Neovascular glaucoma predisposed to acute keratitis and
corneal perforation. (H&E ×5.)

SYMPATHETIC UVEITIS
(SYMPATHETIC OPHTHALMIA)
Expedient enucleation of eyes that are severely traumatized and hopelessly
blind is strongly advised as prophylaxis against a rare autoimmune
disorder called sympathetic uveitis, which affects and potentially can blind
both eyes after unilateral trauma. Sympathetic uveitis (ophthalmia) is a
severe bilateral granulomatous inflammation of the uveal tract that follows
unilateral trauma or surgery, which usually is complicated by the
incarceration of uveal tissue in the wound (Fig. 4-5). Blurred vision,
photophobia, and signs of granulomatous inflammation develop in the
uninjured or sympathizing eye simultaneous with exacerbation of signs
and symptoms in the injured or exciting eye.

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 FIG. 4-5. Sympathetic uveitis. A. The choroid is massively thickened by a
diffuse granulomatous infiltrate of epithelioid histiocytes, giant cells, and
lymphocytes. B. Sparing of the choriocapillaris. Arrows denote persistent
choriocapillaris beneath Bruch membrane and the RPE. C. Dalen-Fuchs nodule,
sympathetic uveitis. Aggregate of epithelioid histiocytes on inner surface of
Bruch membrane focally detaches RPE. Underlying choroid contains diffuse
granulomatous inflammatory infiltrate rich in epithelioid histiocytes. D. Giant
cells in choroidal infiltrate contain granules of melanin pigment. (A. H&E ×25,
B. H&E ×100, C. H&E ×100, D. H&E ×250.)

Sympathetic uveitis is thought to be a T-cell–mediated autoimmune

response to uveal or retinal antigens released by the injury. Uveal pigment,
retinal S antigen, and interphotoreceptor retinoid-binding protein could be
possible antigens. Sympathetic uveitis occurs between 2 weeks and 1 year
postinjury in about 90% of cases, most cases occurring during the 3-week
to 3-month interval. Sympathetic uveitis generally will not develop if the
injured eye is enucleated within 1 week of the injury. If enucleation of the
injured eye is delayed, the noninjured eye still remains at risk. There is
some evidence that enucleation of the inciting eye decreases the severity of
the inflammation in the sympathizing eye after bilateral uveitis develops.
The risk of sympathetic ophthalmia after ocular evisceration compared to
enucleation is a controversial topic. Rare cases of sympathetic uveitis have
been reported after ocular evisceration. These probably are related to

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antigenic material left behind in scleral emissarial canals, which typically
are involved by granulomatous inflammation.
Sympathetic uveitis is a clinicopathologic diagnosis. There must be a
history of unilateral trauma followed by bilateral uveitis. Four
characteristic features are found on histopathologic examination. The uvea
is thickened by a diffuse granulomatous infiltrate composed of epithelioid
histiocytes, inflammatory giant cells, and lymphocytes of the T-
suppressor/cytotoxic subtype (Fig. 4-5A). The choriocapillaris is not
destroyed by the inflammation (sparing of the choriocapillaris) (Fig. 4-
5B). The epithelioid histiocytes and giant cells usually contain granules of
phagocytized uveal pigment (Fig. 4-5D). Nodular aggregates of epithelioid
cells, which focally detach the retinal pigment epithelium (RPE), are found
on the inner surface of Bruch membrane (Fig. 4-5C). These Dalen-Fuchs
nodules are not pathognomonic for sympathetic uveitis because they also
occur in sarcoidosis and Vogt-Koyanagi-Harada disease. The uveal
infiltrate rarely contains plasma cells. Eosinophilia may be found in deeply
pigmented patients, in whom the inflammation typically is more severe.
Sympathetic uveitis usually spares the retina. One should consider another
diagnosis if retinal involvement is found distant from the site of injury.
Although their immunopathogenic mechanisms differ, both sympathetic
ophthalmia and phacoantigenic uveitis may occur concurrently in the same
traumatized eye. Atypical histopathologic features occur in some cases,
generally are associated with severe choroidal inflammation, and may be a
response to high doses of antigenic material. Progressive subretinal
fibrosis with multifocal granulomatous chorioretinitis is thought to be a
variant of sympathetic ophthalmia.

CONTUSION INJURIES
Minor contusion injuries often cause abrasions of the corneal epithelium
that rapidly heal by epithelial sliding (Fig. 4-2B). Severe contusion injuries
can rupture the cornea and/or sclera. A rupture caused by blunt trauma can
occur directly at the site of impact. In other instances, the thinnest parts of
the globe such as the limbus or the scleral behind the insertion of the rectus
muscles or adjacent to the optic nerve are involved indirectly by force
vectors transmitted by the essentially incompressible globe.
Contusion injuries need not disrupt the integrity of the cornea or sclera
to wreak severe intraocular havoc. Ocular contusion injuries can rupture
Descemet membrane, the lens, or choroid, detach or avulse the retina from

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its attachments to the ora serrata (Fig. 4-6) or optic nerve, or fracture
photoreceptor outer segments causing Berlin edema or commotio retinae.
Late cystoid macular degeneration or macular holes are common sequelae.
Other anterior segment complications include lens dislocation, contusion
rosette cataract (Fig. 4-7A), postcontusion angle recession, iridodialysis,
cyclodialysis, and hyphema.

FIG. 4-6. Anterior retinal avulsion, contusion injury. The retina’s attachments to
the ora serrata have been disrupted. A hyphema fills the anterior chamber.

FIG. 4-7. A. Contusion rosette cataract. Patelliform configuration of traumatic

cataract reflects damage to superficial lens fibers. This type of cataract serves as a
clinical marker for ocular contusion injury. B. Siderotic cataract. Iron from
intraocular foreign body has formed rusty deposits beneath anterior capsule of

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 cataractous lens. C. Prussian blue reaction highlights iron in the lens epithelium.
(C. Iron stain, ×100.)

Blood staining of the corneal stroma is a potential complication of chronic

hyphema (Fig. 4-8). Whether corneal blood staining develops or not
depends on the health of the corneal endothelium, the IOP, and the
duration of the hyphema. Blood staining may occur within 48 hours if the
IOP is high. The corneal stroma contains small particles of hemoglobin,
not intact erythrocytes. Golden brown granules of hemosiderin are found
in the cytoplasm of the keratocytes.

FIG. 4-8. Corneal blood staining. A. Central cornea is opacified by ochre deposit.
B. Histopathology of corneal stroma discloses small particles of hemoglobin that
are much smaller than intact erythrocytes. C. Iron stain reveals iron in
keratocytes. (B. H&E ×400, C. Iron stain ×400.)

During a contusion injury of the anterior segment, the lens and iris act
together as a ball valve that confines the aqueous humor to the anterior
chamber. The incompressible aqueous humor conveys the force of the
blow to the weakest parts of the anatomy, which are subject to damage.
The iris may be ripped from the ciliary body at its root where it is very thin
(iridodialysis). In other cases, the tenuous attachment of the ciliary muscle
to the scleral spur is disrupted, causing detachment of the ciliary body or
cyclodialysis (Fig. 4-9D).

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 FIG. 4-9. Contusion injuries, anterior segment. A. Acute angle recession,
contusion injury. Tear into the face of ciliary body is located internal to the
longitudinal part of the ciliary muscle, which remains attached to the scleral spur.
A layer of blood rests on the anterior surface of the iris, which shows early
necrosis. B. Postcontusion angle recession. The iris root is displaced posteriorly,
markedly widening the ciliary body band. Arrow points to scleral spur. The
ciliary processes are displaced posteriorly, and the residual ciliary muscle has a
fusiform configuration. Incidental pseudoexfoliation is present. C. Postcontusion
angle recession. Arrow in SEM denotes trabecular meshwork. The iris root is
displaced posteriorly, widening the ciliary body band. The ciliary muscle is
fusiform in shape. D. Cyclodialysis, contusion injury. The ciliary body has been
avulsed from its attachment to the scleral spur. The iris shows early necrosis. A
hyphema is present. (A. H&E ×25, B. H&E ×50, C. SEM ×40, D. H&E ×25.)

Tears into the anterior face of the ciliary body cause postcontusion angle
recession (Fig. 4-9A–C). The tear usually extends between the external
longitudinal fibers of the ciliary muscle and its radial and circumferential
fibers, which are located centrally (Fig. 4-9A). The injury usually detaches
the inner uveal part of the trabecular meshwork and disrupts the greater
arterial circle of the iris causing anterior chamber hemorrhage (hyphema).
The root of the iris is displaced posteriorly by the tear. Afterward,
gonioscopy discloses widening of the ciliary body band. Microscopic
examination of acutely traumatized eyes often reveals ischemic necrosis of

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the iris and ciliary body. In chronic cases, the residual ciliary muscle
typically has a fusiform configuration reflecting ischemic atrophy of its
inner parts.
Postcontusion angle recession can cause late-onset unilateral open-
angle glaucoma. When they are stable, patients who have had hyphemas
always should be gonioscoped to exclude traumatic angle recession. Less
than 10% of patients who have postcontusion angle recession actually
develop glaucoma. Microscopic examination of blind glaucomatous eyes
with recessed angles that are enucleated typically reveals a new layer of
Descemet membrane on the inner surface of the damaged trabecular
meshwork.

INTRAOCULAR FOREIGN BODIES

Fragments of foreign material often are left inside the eye during
perforating injuries (Fig. 4-10). How well the eye tolerates an intraocular
foreign body depends on the chemical composition of the foreign material
and whether it is sterile or contaminated with microorganisms. Foreign
bodies composed of vegetable matter are often contaminated with fungi
and typically cause a violent inflammatory response. In contrast, foreign
bodies of glass and plastic usually are inert and are well tolerated. Iron
foreign bodies, which are relatively common, have a toxic effect on the
retina, lens epithelium, and aqueous outflow pathways if they are
chronically retained. Ferrous iron is more toxic than ferric iron. Ocular
siderosis is marked by the deposition of iron in epithelial or
neuroectodermal derivatives (epithelia of cornea, lens, and ciliary body,
iris musculature, retina, and RPE) (Fig. 4-11). An identical deposition of
hematogenous iron (hemosiderosis) can complicate repeated chronic
intraocular hemorrhage (Fig. 4-12A). Foreign bodies comprised of >90%
copper incite a severe sterile purulent reaction, while retained fragments of
brass or bronze that contain 70% to 90% copper cause deposition in
Descemet membrane and the lens capsule (chalcosis) (Fig. 4-12B). An
analogous deposition of copper occurs in these thick basement membranes
in Wilson hepatolenticular degeneration and are responsible for the
characteristic Kayser-Fleischer ring and sunflower cataract.

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FIG. 4-10. Intraocular foreign body (BB). Arrow denotes BB surrounded by
blood and disrupted retina and choroid in disorganized interior of ruptured globe.
Pars plana entrance wound is seen at the top left. Inset shows foreign body.

FIG. 4-11. Siderosis. A. Ciliary processes in eye with chronically retained

intraocular iron foreign body show rusty discoloration. B. Intense Prussian blue
reaction discloses iron in neurosensory retina and RPE. (B. Iron stain ×100.)

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FIG. 4-12. A. Heterochromia iridum, hemosiderosis. Iris of blind, exotropic
left eye shows greenish discoloration caused by iron deposition. Chronic vitreous
hemorrhage caused ocular hemosiderosis. B. Chalcosis lentis. Sunflower cataract
caused by copper deposition in lens capsule developed in the eye with intraocular
foreign body composed of copper alloy. The central disk of the “sunflower”
corresponds to the diameter of the undilated pupil and the petals to radial ridges
in the iris pigment epithelium. (Courtesy of Prof. Dr. med. Wolfgang Lieb,
University of Würzburg, from Eagle RC Jr. Congenital, developmental and
degenerative disorders of the iris and ciliary body. In: Albert DM, Jakobiec FA,
eds. Principles and Practice of Ophthalmology. Clinical Practice, vol. 1.
Philadelphia, PA: Saunders, 1993:367–389.)

CHEMICAL INJURIES
Chemical injuries by strong acid and alkali usually involve the anterior
part of the eye. The severity of the injury usually depends on the nature
and strength of the agent and the duration of contact. Acid burns are
nonprogressive and generally are less severe than alkali burns because
penetration is limited by a buffering action of the tissues. Histology
usually shows superficial coagulative necrosis of the conjunctival and/or
corneal epithelium. In contrast, alkali penetrates deeply causing
denaturation of protein, saponification of fat, and necrosis of intraocular
structures (Fig. 4-13). Alkali injuries usually are progressive because the
alkali is difficult to neutralize and the necrosis of stromal fibroblasts
precludes replacement or repair of denatured corneal collagen. In addition,
vascular occlusion caused by necrosis of the vascular endothelium
produces tissue ischemia. A white porcelain appearance of the conjunctiva
after an alkali burn is a clinical marker for severe ischemia and poor
prognostic sign. Collagenase made by polymorphonuclear leukocytes
infiltrating the necrotic stroma contributes to corneal dissolution and
ulceration.

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 FIG. 4-13. Alkali injury. A. Patient was blinded by strong alkali drain cleaner
poured on his eyes while asleep. B. Alkali has penetrated deep into the eye
causing total necrosis of the iris, which adheres to the posterior surface of the
cornea. Necrotic iris and cornea appear acellular. (B. H&E ×50.)

WOUND HEALING
Many complications that occur after ocular surgery are related to poor
wound healing. Ocular wounds heal by the formation of scar tissue. The
mechanisms involved in wound healing differ depending on what ocular
tissue is involved.
The healing of limbal wounds involves a proliferation of granulation
tissue derived from the episclera and the substantia propria of the
conjunctiva. Epithelial migration and an early proliferation of granulation
tissue rapidly seal the superficial aspect of well-apposed wounds, and a
plug of fibrin, which polymerizes on the exposed collagen in the wound,
prevents the leakage of aqueous humor. The posterior wound gapes
slightly and elastic Descemet membrane curves inwardly. Granulation
tissue enters the external part of the wound at about 8 days and has
extended the full length of the wound by 2 weeks. By this time, migrating
endothelial cells have covered the posterior wound. These cells eventually
will synthesize a new layer of Descemet membrane. The fibroblastic
component of the granulation tissue produces collagen, which is initially
randomly arranged. As the scar matures and becomes less vascularized,
collagen is progressively produced, and the fibers mature and undergo
reorientation.
Unlike the limbus, the central corneal is an avascular site. Hence,
granulation tissue is not involved in the healing of central corneal wounds
(Fig. 4-14). Initially, the lips of the wound swell, functionally sealing the
wound, which gapes anteriorly and posteriorly. A fibrin plug forms and

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Descemet membrane retracts and curves inwardly. Neighboring corneal
endothelial cells are lost. The anterior surface of the wound is
reepithelialized by surface epithelial sliding, which enters the gaping
anterior part of the wound and fills it with an epithelial plug. The anterior
surface of the wound usually is reepithelialized by 12 hours. Three or four
days following an injury, stromal fibroblasts enter the wound and begin to
elaborate collagen. The plug of surface epithelium regresses as stromal
wound healing proceeds, and regression generally is complete by 2 weeks.
By that time, the sliding endothelium has extended across the posterior
defect and has begun to lay down a new layer of Descemet membrane.
During the next 6 months, the cellularity of the scarred area gradually
decreases and the character and orientation of the collagen becomes more
regular.

FIG. 4-14. Scar of corneal laceration. Periodic acid–Schiff (PAS) stain (at right)
highlights gap in Descemet membrane in scar of well-healed and fairly well-
approximated corneal laceration. (A. H&E ×50, B. PAS ×50.)

Unsutured wounds of the iris do not heal. Iridectomies remain patent

unless they are closed by pigment epithelial migration. Most wounds in the
lens lead to cataract formation. Small rents in the capsule may be closed by
posterior synechiae and be repaired by fibrous metaplasia of lens
epithelium and capsular reformation. The sclera itself does not participate

104
in the healing of defects. Full-thickness scleral wounds heal by an
ingrowth of granulation tissue from both the episclera and the superficial
choroid. Retinal cells do not regenerate. Retinal scars are produced by glial
cells, not fibroblasts. The internal limiting membrane and Bruch
membrane provide architectural planes for glial scarring. RPE cells may
contribute to the retinal scars.

SURGICAL COMPLICATIONS
Poorly apposed or poorly healed limbal surgical wounds cause a variety of
postoperative complications. Leaky wounds cause hypotony, serous
choroidal detachments, and loss and flattening of the anterior chamber,
which can lead to secondary angle closure or corneal endothelial damage
as a result of lens-corneal touch. Poorly healed wounds also allow
microorganisms to enter the interior of the eye and can provide an avenue
for surface epithelial invasion of the anterior chamber. Incarceration of
uvea or vitreous in wounds can contribute to permanent fistula formation
(vitreous wick) and increase the chance of postoperative infection or
epithelial downgrowth.
Epithelial downgrowth (ingrowth) is a devastating complication of
surgical or nonsurgical trauma in which corneal or conjunctival epithelium
gains access to the anterior chamber and proliferates on the back of the
cornea, the trabecular meshwork, the anterior surface of the iris, and on
even more posteriorly located structures (Fig. 4-15A). Most cases occur
after cataract surgery or penetrating keratoplasty. Patients typically present
with a translucent sheet of epithelial cells that slowly grows down the back
surface of the cornea. In occasional instances where posterior corneal
epithelialization is not obvious, epithelial downgrowth may present several
months postoperatively with pain, glaucoma, and intensifying
inflammatory signs. Several mechanisms can obstruct aqueous outflow in
eyes with epithelial downgrowth. These include sheets of epithelium
covering the trabecular meshwork, peripheral anterior synechia formation,
and blockage of the trabecular meshwork by desquamated epithelial cells.

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 FIG. 4-15. A. Epithelial downgrowth. A sheet of corneal epithelium introduced
by trauma covers trabecular meshwork and flattens anterior iridic surface. B.
Fibrous ingrowth. Thick membranes of dense collagenous connective tissue
have formed on scaffold of vitreous incarcerated in central corneal wound. An
extensive anterior synechia is seen at the top left. Arrow denotes anterior vitreous
face. (A. H&E ×50, B. H&E ×5.)

Histopathologically, the intraocular epithelium may approximate the

normal surface epithelium in thickness or it may be markedly attenuated.
The advancing edge of the epithelial sheet on the posterior corneal surface
typically is prominent. Epithelium growing on vascularized structures like
the iris often is thicker than that on the cornea. The anterior surface of the
iris usually is flattened by the epithelial sheet. Occasionally, the epithelium
extends through the pupil onto the iris pigment epithelium and ciliary
body, and rarely, it may extend onto the inner surface of the peripheral
retina causing a tractional retinal detachment.
Clinically, the presence of epithelium on the iris can be confirmed by
laser photocoagulation, which causes blanching of the transparent cells.
The prognosis of epithelial downgrowth usually is poor. Although some
cases can be cured by extensive en bloc resection of ocular tissue, the
intraocular epithelial proliferation is often diffuse, extensive, and
impossible to totally eradicate. Experimental studies suggest that a healthy
population of corneal endothelial cells tends to retard epithelial migration
by means of cellular contact inhibition.
Fibrous ingrowth also complicates poor wound closure, particularly
when there has been intraoperative vitreous loss (Fig. 4-15B). Incarcerated
vitreous serves as a growth scaffold for fibroblasts, which invade the
interior of the eye, produce collagen, and transform the vitreous into a
mass of dense fibrous scar tissue.
Fibrous metaplasia of the RPE is another major source of intraocular

106
scarring. RPE hyperplasia and metaplasia typically occur after retinal
detachment, which abolishes the outer retina’s normal inhibitory effect on
RPE proliferation. Papillary proliferation, the formation of large drusen-
like structures, and pseudoadenomatous proliferation of the RPE ensue.
The RPE synthesizes large quantities of extracellular matrix material,
including granular drusenoid material, collagen, and ultimately bone.
Massive fibrous and osseous metaplasia of the RPE are commonly found
in chronically blind phthisical eyes, which often must be decalcified before
they can be dissected. The bone always is found on the inner surface of
Bruch membrane. The bone is a mature lamellar bone and may contain
fatty marrow (Fig. 3-23C).
The term phthisis bulbi is applied clinically to blind hypotonus eyes,
which are soft, shrunken, partially collapsed and have a vaguely cuboid
configuration caused by traction of the four rectus muscles (Fig. 3-23A).
Pathologically, the diagnosis of phthisis bulbi (atrophia bulbi with
shrinkage and disorganization) is reserved for profoundly atrophic globes,
which have markedly thickened and folded sclera and generally
unrecognizable intraocular structures (Fig. 3-23B). If the intraocular
structures can be identified, the term atrophia bulbi with shrinkage is used.
Superficial absorption of ultraviolet light causes punctate keratopathy
(welder’s flash, snow blindness). Relatively low doses of ionizing
radiation can cause cataract. Radiation-induced occlusion of the retinal
capillary bed is the cause of radiation retinopathy.
Foci of extramedullary hematopoiesis occasionally are found in
traumatized eyes with significant amounts of chronic intraocular
hemorrhage (Fig. 4-16).

FIG. 4-16. Extramedullary hematopoiesis, traumatized eye with chronic

intraocular hemorrhage. A. Choroid in ruptured globe enucleated more than 1

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week after injury contains foci of extramedullary hematopoiesis including
myeloid precursors (B) and nucleated red cells (C). (A. H&E ×200, B. H&E
×400, C. H&E ×400.)

BIBLIOGRAPHY
Surgical Trauma
Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a
historical and histochemical review. Surv Ophthalmol 1984;29:1–54.
Apple DJ, Mamalis N, Olson RJ, et al. Intraocular Lenses: Evolution, Designs,
Complications and Pathology. Baltimore, MD: Williams & Wilkins, 1989.
Bettman JW Jr. Pathology of complications of intraocular surgery. Am J
Ophthalmol 1969;68:1037–1050.
Cerasoli JR, Kasner D. A follow-up of vitreous loss during cataract surgery
managed by anterior vitrectomy. Am J Ophthalmol 1971;71:1040–1043.
Friedman AH, Henkind P. Corneal stromal overgrowth after cataract extraction.
Br J Ophthalmol 1970;54:528–534.
Gass JDM, Norton EWD. Cystoid macular edema and papilledema following
cataract extraction. Arch Ophthalmol 1966;76: 646–661.
Kohnen T, Koch DD, Font RL. Lensification of the posterior corneal surface. An
unusual proliferation of lens epithelial cells. Ophthalmology
1997;104:1343–1347.
Kuchle M, Green WR. Epithelial ingrowth: a study of 207 histopathologically
proven cases. Ger J Ophthalmol 1996;5:211–223.
Magnante DO, Bullock JD, Green WR. Ocular explosion after peribulbar
anesthesia: case report and experimental study. Ophthalmology
1997;104:608–615.
McDonnel PJ, Patel A, Green WR. Comparison of intracapsular and extracapsular
cataract surgery: histopathologic study of eyes obtained postmortem.
Ophthalmology 1985;92:1208–1225.
Sassani JW, John T, Cameron JD, et al. Electron microscopic study of corneal
epithelial endothelial interactions in organ culture. Ophthalmology
1984;91:553–557.
Swan KC. Fibroblastic ingrowth following cataract surgery. Arch Ophthalmol
1973;89:445–449.
Von Domarius D, Naumann GOH. Accidental and surgical trauma and wound
healing of the eye. In: Naumann GOH, Apple DJ, eds. Pathology of the Eye.
New York, NY: Springer-Verlag, 1986:185–248.
Wiener MJ, Trentacoste J, Pon DM, et al. Epithelial downgrowth: a 30-year
clinicopathological review. Brit J Ophthalmol 1989;73: 6–11.
Williams DK, Rentiers PK. Spontaneous expulsive choroidal hemorrhage. A
clinicopathologic report of two cases. Arch Ophthalmol 1970;83:191–194.

108
Winslow RL, Stevenson W III, Yanoff M. Spontaneous expulsive hemorrhage.
Arch Ophthalmol 1974;92:33–36.
Wolter JR. Expulsive hemorrhage: a study of histopathological details. Albrecht
Von Graefes Arch Klin Exp Ophthalmol 1982;219:155–158.

Nonsurgical Trauma
Barr CC, Mitchell D. Penetrating ocular injury caused by nylon cord fragment
from electric lawn trimmer. Ophthalmic Surg 1983;14:741–743.
Blanton FM. Anterior chamber angle recession and secondary glaucoma. Arch
Ophthalmol 1964;72:39–43.
Broderick JD. Corneal blood staining after hyphema. Br J Ophthalmol 1972;56:
589–593.
Cox MS, Schepens CL, Freeman HM. Retinal detachment due to ocular
contusion. Arch Ophthalmol 1966;76: 678–685.
Dunn ES, Jaeger EA, Jeffers JB, et al. The epidemiology of ruptured globes. Ann
Ophthalmol 1992;24:405–410.
Esmaeli B, Elner SG, Schork MA, et al. Visual outcome and ocular survival after
penetrating trauma. A clinicopathologic study. Ophthalmology
1995;102:393–400.
Gregor Z, Ryan SJ. Combined posterior contusion and penetrating injury in the
pig eye. I. A natural history study. Br J Ophthalmol 1982;66:793–798.
Gregor Z, Ryan SJ. Combined posterior contusion and penetrating injury in the
pig eye. II. Histologic features.. Br J Ophthalmol 1982;66:799–804.
Hagler WS, North AW. Retinal dialysis and retinal detachment. Arch Ophthalmol
1968;79:376–388.
Helveston EM. Eye trauma in childhood. Pediatr Clin North Am
1975;22:501–511.
Honig MA, Barraquer J, Perry HD, et al. Forceps and vacuum injuries to the
cornea: histopathologic features of twelve cases and review of the literature.
Cornea 1996;15:463–472.
Kempster RC, Green WR, Finkelstein D. Choroidal rupture. Clinicopathologic
correlation of an unusual case. Retina 1996; 16:57–63.
Manche EE, Goldberg RA, Mondino BJ. Air bag-related ocular injuries.
Ophthalmic Surg Lasers 1997;28:246–250.
Martin DF, Awh CC, McCuen BW II, et al. Treatment and pathogenesis of
traumatic chorioretinal rupture (sclopetaria). Am J Ophthalmol
1994;117:190–200.
Meredith TA, Gordon PA. Pars plana vitrectomy for severe penetrating injury
with posterior segment involvement. Am J Ophthalmol 1987;103:549–554.
Messmer EP, Gottsch J, Font RL. Blood staining of the cornea: a histopathologic
analysis of 16 cases. Cornea 1984;3:205–212.
Pearlstein ES, Agapitos PJ, Cantrill HL, et al. Ruptured globe after radial
keratotomy. Am J Ophthalmol 1988;106:755–756.

109
Rudd JC, Jaeger EA, Freitag SK, et al. Traumatically ruptured globes in children.
J Pediatr Ophthalmol Strabismus 1994;31:307–311.
Russell SR, Olsen KR, Folk JC. Predictors of scleral rupture and the role of
vitrectomy in severe blunt ocular trauma. Am J Ophthalmol
1988;105:253–257.
Ryan SJ. Penetrating ocular trauma and pars plana vitrectomy. Trans New
Orleans Acad Ophthalmol 1983;31:129–136.
Schein OD, Hibberd PL, Shingleton BJ, et al. The spectrum and burden of ocular
injury. Ophthalmology 1988;95:300–305.
Smiddy WE, Green WR. Retinal dialysis: pathology and pathogenesis. Retina
1982;2:94–116.
Spalding SC, Sternberg P Jr. Controversies in the management of posterior
segment ocular trauma. Retina 1990;10:76–82.
Sternberg P Jr, de Juan E Jr, Green WR Jr, et al. Ocular BB injuries.
Ophthalmology 1984;91:1269–1277.
Winthrop SR, Cleary PE, Minckler DS, et al. Penetrating eye injuries: a
histopathological review. Br J Ophthalmol 1980;64:809–817.
Wolff SM, Zimmerman LE. Chronic secondary glaucoma associated with
retrodisplacement of the iris root and deepening of the anterior chamber
secondary to contusion. Am J Ophthalmol 1962;54:547–562.

Sympathetic Uveitis
Auw-Haedrich C, Loeffler KU, Witschel H. Sympathetic ophthalmia: an
immunohistochemistry study of four cases. Ger J Ophthalmol 1996;5:98–103.
Aziz HA, Flynn HW Jr, Young RC, et al. Sympathetic ophthalmia:
clinicopathologic correlation in a consecutive case series. Retina
2015;35(8):1696–1703.
Castiblanco CP, Adelman RA. Sympathetic ophthalmia. Graefes Arch Clin Exp
Ophthalmol 2009;247:289–302.
Croxatto JO, Galentine P, Cupples HP, et al. Sympathetic ophthalmia after pars
plana vitrectomy-lensectomy for endogenous bacterial endophthalmitis. Am J
Ophthalmol 1981;91:342–346.
Font RL, Fine BS, Messmer E, et al. Light and electron microscopic study of
Dalen-Fuchs nodules in sympathetic ophthalmia. Ophthalmology
1982;90:66–75.
Furusato E, Shen D, Cao X et al. Inflammatory cytokine and chemokine
expression in sympathetic ophthalmia: a pilot study. Histol Histopathol
2011;26:1145–1151.
Gass JD. Sympathetic ophthalmia following vitrectomy. Am J Ophthalmol
1982;93:552–558.
Green WR, Maumenee AE, Sanders TE, et al. Sympathetic uveitis following
evisceration. Trans Am Acad Ophthalmol Otolaryngol 1972;76:625–644.
Jakobiec FA, Marboe CC, Knowles DM II, et al. Human sympathetic ophthalmia.

110
 An analysis of the inflammatory infiltrate by hybridoma-monoclonal
antibodies, immunochemistry, and correlative electron microscopy.
Ophthalmology 1983;90:76–95.
Kaneko Y, Wu GS, Saraswathy S et al. Immunopathologic processes in
sympathetic ophthalmia as signified by microRNA profiling. Invest
Ophthalmol Vis Sci 2012;28;53:4197–4204.
Lubin JR, Albert DM, Weinstein M. Sixty-five years of sympathetic ophthalmia.
A clinicopathologic review of 105 cases (1913–1978). Ophthalmology
1980;87:109–121.
Marak GE. Phacoanaphylactic endophthalmitis. Surv Ophthalmol
1992;36:325–329.
Morse PH, Duke JR. Sympathetic ophthalmitis. Report of a case, proven
pathologically, eight years after original injury. Am J Ophthalmol
1969;68:508–512.
Payal AR, Foster CS. Long-term drug-free remission and visual outcomes in
sympathetic ophthalmia. Ocul Immunol Inflamm 2016;25:1–6.
To KW, Jakobiec FA, Zimmerman LE. Sympathetic uveitis. In: Albert DM,
Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical
Practice, vol. 1. Philadelphia, PA: WB Saunders, 1994:496–503.
Wilson MW, Grossniklaus HE, Heathcote JG. Focal posttraumatic choroidal
granulomatous inflammation. Am J Ophthalmol 1996;121:397–404.

Intraocular Foreign Bodies

Hanna C, Fraunfelder FT. Lens capsule change after intraocular copper. Ann
Ophthalmol 1973;5:9–12.
Masciulli L, Andersen DR, Charles S. Experimental ocular siderosis in the
squirrel monkey. Am J Ophthalmol 1972;74:638–661.
Rosenthal AR, Appleton B, Hopkins JL. Intraocular copper foreign bodies. Am J
Ophthalmol 1974;78:671–678.
Seland JH. The nature of capsular inclusions in lenticular chalcosis. Report of a
case. Acta Ophthalmol (Copenh) 1976;54: 99–108.
Talamo JH, Topping TM, Maumenee AE, et al. Ultrastructural studies of cornea,
iris and lens in a case of siderosis bulbi. Ophthalmology 1985;92:1675–1680.

Chemical Burns
Brown SI, Weller CA, Akiya S. Pathogenesis of ulcers of the alkali-burned
cornea. Arch Ophthalmol 1970;83:205–208.
Hirst LW, Fogle JA, Kenyon KR, et al. Corneal epithelial regeneration and
adhesions following acid burns in the rhesus monkey. Invest Ophthalmol Vis
Sci 1982;23:764–773.

Radiation Injuries

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Bagan SM, Hollenhorst RW. Radiation retinopathy after irradiation of intracranial
lesions. Am J Ophthalmol 1979;88:694–697.
Brown GC, Shields JA, Sanborn G, et al. Radiation optic neuropathy.
Ophthalmology 1982;89:1489–1493.
Brown GC, Shields JA, Sanborn G, et al. Radiation retinopathy. Ophthalmology
1982;89:1494–1501.
Buschke W, Friedenwald JS, Moses SG. Effect of ultraviolet irradiation on
corneal epithelium: mitosis, nuclear fragmentation, post-traumatic cell
movements, loss of tissue cohesion. J Cell Comp Physiol 1945;26:147–164.
Cogan DG, Donaldson DD. Experimental radiation cataracts. I. Cataracts in the
rabbit following single x-ray exposure. Arch Ophthalmol 1951;45:508–522.
Noble KG, Kupersmith MJ. Retinal vascular remodelling in radiation retinopathy.
Br J Ophthalmol 1984;68:475–478.

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 5 Conjunctiva
The conjunctiva is a delicate mucous membrane that covers the anterior
surface of the eyeball and the posterior surface of eyelids. The term
conjunctiva is derived from the Latin meaning “to bind together.”
The nonkeratinized stratified columnar epithelium of the conjunctiva is
two to five cells in thickness and contains mucous glands called goblet
cells whose contents appear clear or bluish in routine hematoxylin–eosin
(H&E) sections and are vividly periodic acid–Schiff (PAS) positive (Fig.
5-1). Goblet cells are more numerous nasally, especially in the semilunar
fold (plica semilunaris).

FIG. 5-1. Conjunctival epithelium. The stratified squamous epithelium of the

conjunctiva is nonkeratinized and contains mucin-producing goblet cells, which
are most numerous in the nasal bulbar conjunctiva. Chronic inflammatory cells
normally are present in the substantia propria. (H&E ×250.)

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Topographically, the conjunctiva is divided into bulbar, forniceal, and
tarsal (or palpebral) parts. The bulbar conjunctiva covers the surface of the
eyeball and is freely movable. The stroma or substantia propria of the
bulbar conjunctiva is composed of loose, areolar connective tissue and is
easily ballooned up by edema fluid (chemosis) or injected anesthetic. In
contrast, the palpebral conjunctiva adheres firmly to the tarsal plate and
does not move freely. Multiple gland-like epithelial invaginations or crypts
called pseudoglands of Henle usually occur in the palpebral conjunctiva.
The forniceal conjunctiva that arches around the superior and inferior cul-
de-sacs is redundant and folded to facilitate eye movements. Several small
accessory lacrimal glands of Krause are found beneath the forniceal
conjunctiva, and accessory glands of Wolfring occur at the upper and
lower margins of the tarsal plates. Lymphocytes and plasma cells normally
are found in the conjunctival stroma and constitute part of the eye’s normal
defense mechanisms.

DEVELOPMENTAL LESIONS
Congenital epibulbar dermoids are choristomatous masses that usually
occur at the limbus temporally. They are composed of coarse,
interweaving bundles of collagenous connective tissue and are covered by
conjunctival or corneal epithelium or skin-like epithelium with epidermal
appendages (Fig. 5-2A,B). Epibulbar dermoids that contain cartilage
and/or ectopic lacrimal gland tissue are called complex choristomas (Fig.
5-2E). (A choristoma is a congenital tumor composed of tissue that is not
normally found in an area.) Solid epibulbar dermoids should not be
confused with dermoid cysts, which usually occur in the superotemporal
orbit, or so-called conjunctival dermoids, which are a rare variant of cystic
dermoid that occurs in the nasal orbit and is lined by conjunctival
epithelium. Dermolipomas (lipodermoids) are solid dermoids composed
largely of adipose tissue (Fig. 5-2D). These yellowish-tan, soft fusiform
tumors usually are located in the superotemporal or temporal quadrants.
Bilateral epibulbar dermoids and dermolipomas occur in two thirds of
patients with Goldenhar syndrome (hemifacial microsomia), which also
includes vertebral anomalies, preauricular appendages, and aural fistulas.
Epibulbar dermoids also occur in the Schimmelpenning-Feuerstein-Mims
syndrome (organoid nevus syndrome or nevus sebaceus of Jadassohn).
Other congenital lesions of the conjunctiva include ectopic lacrimal gland
and episcleral osseous choristoma. Episcleral osseous choristomas are
plaques of mature bone that typically are located on the surface of the

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globe in the superotemporal quadrant (Fig. 5-3).

FIG. 5-2. Developmental lesions. A. Solid epibulbar dermoid. Choristomatous

mound of skin-like tissue at temporal limbus of a child with Goldenhar
syndrome. B. Epidermis-like epithelium with epidermal appendages covers apex
of epibulbar choristoma and merges with nonkeratinized ocular surface
epithelium at base. The stroma is composed of coarse interweaving bundles of
collagen and fat. C. Child also has preauricular appendage. D. Dermolipoma
(lipodermoid). A dermolipoma is a solid epibulbar dermoid composed largely of
adipose tissue. Most dermolipomas occur on the superotemporal surface of the
globe. E. Complex choristoma, organoid nevus syndrome. This epibulbar
complex choristoma contains hyaline cartilage, ectopic lacrimal gland, and fat.
The surface of the choristoma was lined by skin-like epithelium with epidermal
appendages. A choristoma is a congenital tumor composed of tissue that is not
normally found in an area.

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 FIG. 5-3. Osseous choristoma, conjunctiva. A. Epibulbar osseous choristoma
appears as subepithelial nodule on temporal bulbar conjunctiva. B. Osseous
choristoma is composed of a plaque of mature bone lamellar bone. C.
Polarization microscopy highlights collagenous matrix of lamellar bone. (B. H&E
×10, C. H&E with crossed polarizers and retardation plate ×100.)

CONJUNCTIVITIS
Most inflammatory diseases of the conjunctiva are treated medically and
are rarely seen in the ophthalmic pathologic laboratory except as scrapings
or smears.
Conjunctivitis can be acute or chronic and can be caused by numerous
infectious or noninfectious agents including bacteria, viruses, fungi, and
protozoans. Allergy is another important cause of conjunctivitis.
The clinical manifestations of acute conjunctivitis include redness
(conjunctival injection or hyperemia), chemosis (conjunctival edema), and
exudation. The exudate in acute purulent bacterial conjunctivitis contains
numerous polymorphonuclear leukocytes (Fig. 5-4). Histologic sections
(obtained incidentally) show edema and infiltration of the conjunctival
epithelium and substantia propria by polys and an exudate composed of a
mixture of polys, fibrin, mucus, and necrotic cellular debris. Clinically, the
presence of copious quantities of pus (hyperacute conjunctivitis) should
suggest the possibility of gonococcal infection.

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 FIG. 5-4. Acute purulent conjunctivitis. A. Copious quantities of purulent
exudate are present. Acute conjunctivitis was caused by Haemophilus influenzae.
B. Polys infiltrate the edematous conjunctival epithelium and are the major
cellular constituent of the purulent exudate. The focus of acute conjunctivitis was
found incidentally in a tumor resection specimen. (B. H&E ×250.)

Inflammatory membranes or pseudomembranes can develop in severely

inflamed eyes. These adhere to the conjunctiva and are composed of fibrin
and inflammatory cells. True membranes generally occur in severe
disorders such as Stevens-Johnson syndrome or bacterial infections by
beta-hemolytic Streptococcus, Neisseria gonorrhoeae, or
Corynebacterium diphtheriae. True conjunctival membranes are firmly
adherent to the epithelium, and bleeding occurs when removal is
attempted.
Conjunctival pseudomembranes are less adherent and can be peeled
without bleeding. Pseudomembranes may complicate infection by
adenovirus 8 (epidemic keratoconjunctivitis or EKC) and adenovirus 3
(pharyngoconjunctival fever or PCF). They also form in patients with
certain severe bacterial infections (Staphylococcus, Streptococcus,
Neisseria meningitidis, Pseudomonas, coliforms) or complicate chemical
burns, foreign bodies, benign mucous membrane pemphigoid, or ligneous
conjunctivitis.
Ligneous conjunctivitis is a rare form of chronic pseudomembranous
conjunctivitis that is marked by a massive accumulation of fibrin that
occurs in patients with type I plasminogen deficiency (Fig. 5-5). The term
ligneous refers to the firm, woody consistency of the large masses of fibrin
that comprise the pseudomembranes. Ligneous conjunctivitis typically
occurs in children but may recur in adults. Treatment is often challenging
because the inflammation is persistent and the pseudomembranes often
recur rapidly after excision. Histopathology shows two components:

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granulation tissue and sheets of intensely eosinophilic acellular amorphous
material, which has been shown to be composed predominantly of fibrin
by immunohistochemical stains (Fig. 5-5B,C). The mass of fibrin also
incorporates other serum components such as immunoglobulin. The
granulation tissue component (like all granulation tissue) is rich in acid
mucopolysaccharide ground substance. Lesions that resemble those found
in the conjunctiva can affect other mucous membranes including the
larynx, vagina, and ear. Some children also develop occlusive
hydrocephalus. Ligneous conjunctivitis is an autosomal recessive trait
caused by mutations in the gene for plasminogen on chromosome 6q26.

FIG. 5-5. Ligneous conjunctivitis. A. Inflammatory mass on upper palpebral

conjunctiva had a firm, woody consistency. It recurred several times and was
composed largely of fibrin. B. Ligneous conjunctivitis is composed of granulation
tissue and sheets of intensely eosinophilic acellular amorphous fibrin. C. Material
is immunoreactive for fibrinogen. Ligneous conjunctivitis has been linked to
mutations in the plasminogen gene. (A. Photo courtesy of Dr. Joseph Calhoun,
Wills Eye Institute; B. H&E ×25, C. IHC for fibrinogen ×200.)

Acute anaphylactic conjunctivitis is marked by the abrupt onset of severe

conjunctival edema (chemosis), mild injection, and itching (Fig. 3-5B).
The latter is an important clinical symptom of ocular allergy. The release
of inflammatory mediators such as histamine and serotonin by mast cells
in the substantia propria causes the signs and symptoms in persons who are
sensitized to antigens such as ragweed pollen or animal dander. Such
atopic individuals produce IgE that is incorporated into the cell membranes
of the mast cells. Mast cell degranulation occurs when the appropriate
antigen is re-encountered. The release of vasoactive substances markedly
increases the permeability of conjunctival vessels, which leads to an
outpouring of fluid that fills the areolar substantia propria of the bulbar
conjunctiva causing chemosis. Contact hypersensitivity to topical
medications can cause severe ocular injection, itching, and eyelid

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erythema in postoperative patients.

CHRONIC CONJUNCTIVITIS
Chronic follicular conjunctivitis and chronic papillary conjunctivitis are
the conjunctiva’s two basic patterns of response to chronic inflammatory
stimuli. Chronic follicular conjunctivitis represents a reactive follicular
hyperplasia of the population of lymphocytes that normally resides in the
substantia propria. This lymphoid hyperplasia can be a reaction to a variety
of stimuli. Conjunctival follicles are evident clinically as gray-white,
round to oval elevations with an avascular center (Fig. 5-6A).
Microscopically, the substantia propria contains an intense basophilic
infiltrate of benign lymphocytes and plasma cells that often contains
follicular centers (Fig. 5-6B). The conjunctival epithelium overlying the
lymphoid follicles is often thinned.

FIG. 5-6. A. Chronic follicular conjunctivitis. Conjunctival follicles are caused

by reactive follicular hyperplasia of the tissue’s normal resident population of
lymphocytes. The round to oval, gray-white elevations are avascular centrally. B.
Conjunctival follicle. The follicle is composed of an avascular sheet of
basophilic lymphocytes. A germinal center is present. The overlying epithelium is
thinned. (B. H&E ×25.)

Conjunctival follicles occur in some types of acute viral conjunctivitis.

They are typically observed in acute adenovirus infections like EKC and
PCF, herpes simplex virus (HSV) conjunctivitis, swimming pool
conjunctivitis (Newcastle virus), and the acute hemorrhagic conjunctivitis
caused by enterovirus 70.
Infectious causes of chronic follicular conjunctivitis include trachoma,
psittacosis, Moraxella, and infectious mononucleosis. Chlamydia, which
are small obligate intracellular parasites that are sensitive to antibiotics,

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cause trachoma, inclusion conjunctivitis, psittacosis, and
lymphogranuloma venereum.
Trachoma, a conjunctival infection, is one of the three most important
causes of blindness in the world. Six million individuals who constitute
15% of the world’s blind have been blinded by the sequelae of trachoma.
Trachoma is caused by serotypes A, B, and C of Chlamydia trachomatis.
In endemic areas, the infection spread by direct contact with infected
ocular secretions. Extreme poverty, poor hygiene, and insect vectors such
as flies contribute to the spread of the disease.
Trachoma is marked by bilateral keratoconjunctivitis, which may be
asymmetric. The initial infection involves the conjunctival epithelial cells
and stimulates epithelial hyperplasia. Conjunctival smears stained with the
Giemsa stain show a mixed inflammatory exudate, which contains both
lymphocytes and polys as well as large macrophages laden with
phagocytized cellular debris called Leber cells. The conjunctival epithelial
cells contain diagnostic basophilic intracytoplasmic inclusions of
Halberstaedter and Prowazek (Fig. 5-7). More specific direct
immunofluorescent tests and a dipstick immunoassay designed for field
testing also are available.

FIG. 5-7. Trachoma, conjunctival smear. Arrow denotes large basophilic

intracytoplasmic inclusion of Halberstaedter and Prowazek in epithelial cell in

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 Giemsa-stained smear. The inflammatory exudate includes both polys and
lymphocytes. (Giemsa ×250.)

An intense infiltration of the substantia propria by chronic inflammatory

cells follows the initial epithelial infection. Numerous lymphoid follicles
occur on the upper tarsus. In florid cases, the follicles develop central areas
of necrosis that can extend superficially forming small ulcerations.
Follicles also occur in the fornix and at the limbus. In the latter stages of
the disease, the remnants of follicles may be evident at the limbus as
saucer-like depressions called Herbert pits. As the disease progresses,
papillary hypertrophy of the conjunctiva supplants the follicular response.
Pannus formation is another characteristic feature of trachoma. The
inflammatory pannus of trachoma is marked by a downgrowth of
subepithelial vessels from the superior limbus that destroys Bowman
membrane. Scarring occurs in the late stages of trachoma. A linear scar
called Arlt line, which extends across the upper tarsus parallel to the lid
margin, is one of the diagnostic criteria for trachoma listed by the World
Health Organization. (Other diagnostic criteria include lymphoid follicles
on the upper tarsus, a vascular pannus, and active limbal follicles or
Herbert pits. Two are diagnostic.)
Blindness in trachoma typically results from sequelae that develop in
the cicatricial stage. Severe conjunctival drying and epidermalization
result from the loss of epithelial goblet cells and obstruction of the ducts of
the main and accessory lacrimal glands. Lid scarring also causes entropion
and trichiasis that predispose to severe corneal scarring as well as corneal
ulceration and secondary bacterial infection.
Serotypes D through K of Chlamydia trachomatis cause inclusion
conjunctivitis or paratrachoma in developed countries. Inclusion
blennorrhea, an infantile form of inclusion conjunctivitis, is an important
cause of acute purulent conjunctivitis or ophthalmia neonatorum in the
newborn. (Other causes include N. gonorrhoeae and a chemical
conjunctivitis caused by Credé silver nitrate prophylaxis against
gonococcal infection.) Infants acquire the disease from an infected mother
during passage through the birth canal. Inclusion conjunctivitis is a
venereal disease in adults. In contrast to the superior conjunctival
involvement found in trachoma, which has superior tarsal involvement, the
follicles in inclusion conjunctivitis occur in the lower fornix.
Chronic follicular conjunctivitis can also be a response to cosmetics,
topical medications such as atropine, eserine or 5-iodo-2'-deoxyuridine,

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viral particles shed by a molluscum contagiosum on the eyelid margin, or
the feces of crab lice infesting the lashes (Phthiriasis palpebrarum). The
lids and lashes should always be carefully (and expeditiously!) examined
when unilateral follicles are encountered during clinical exam.
Papillary hypertrophy is the second relatively nonspecific reaction that
occurs in some patients with chronic conjunctivitis (Figs. 5-8 and 5-9).
Papillary hypertrophy typically develops on the tarsal conjunctiva and is
marked by proliferation of the conjunctival epithelium and hyperplasia of
the substantia propria. Pale avascular valleys that contain deep infoldings
of conjunctival epithelium separate individual papillae, which have a
richly vascular stroma and a central tuft of blood vessels (Fig. 5-9B). This
contrasts with lymphoid follicles, which typically are avascular. Papillae
contain a moderately intense infiltrate composed of a variety of
inflammatory cells. Eosinophils and mast cells usually are present, and the
sheets of lymphocytes and follicular centers found in chronic follicular
conjunctivitis are absent.

FIG. 5-8. Conjunctival papillae. Avascular valleys separate papillae on superior

tarsal conjunctiva. Fine vessels are seen in the center of the papillae. (Photo
courtesy of Dr. Dario Savino-Zari, Caracas, Venezuela.)

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 FIG. 5-9. Vernal conjunctivitis. A. Large cobblestone papillae blanket superior
tarsal conjunctiva. B. Infolding of conjunctival epithelium (at left) extends into
the valley separating two large “cobblestone” papillae. Arrow points to central
vessel in the papilla. Moderately intense inflammatory infiltrate includes chronic
inflammatory cells and eosinophils. (B. H&E ×50.)

Giant papillae, which have been likened to cobblestones, occur on the

superior tarsus in vernal conjunctivitis, a bilateral chronic recurrent disease
that typically afflicts adolescent males who have a history of atopy (Fig. 5-
9). The term vernal reflects the characteristic exacerbation of signs and
symptoms that occurs in the spring. Itching is a characteristic symptom.
Patients have a thick, ropy chewing gum–like mucus rich in eosinophils
and Charcot-Leyden granules. The latter is termed the Maxwell Lyon sign.
Conjunctival smears contain eosinophils and eosinophilic granules. The
large “cobblestone” papillae may abrade the cornea producing painful
shield-like ulcerations of the superior corneal epithelium. A limbal variant
of vernal conjunctivitis marked by papillae at the superior limbus also
occurs. “Limbal vernal” is said to be more common in black patients.
Horner-Trantas dots, which are intra- and subepithelial collections of
eosinophils and cellular debris, occasionally occur near the limbus.
Histopathologically, vernal conjunctivitis is characterized by papillary
hypertrophy of the conjunctiva. The edematous fibrovascular core of the
papillae contains an infiltrate of lymphocytes and plasma cells and
numerous eosinophils.
Giant papillary conjunctivitis occurs in long-term wearers of hard and
soft contact lenses and even ocular prostheses. Probably a cell-mediated
hypersensitivity reaction stimulated by the accumulation of immunogenic
material on the surface of foreign material, giant papillary conjunctivitis
shares similarities with vernal conjunctivitis but usually has fewer
eosinophils.
Phlyctenular keratoconjunctivitis is thought to be a hypersensitivity

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reaction to bacterial proteins. In the past, it classically was associated with
tuberculosis, but now, most cases probably are related to staphylococcal
blepharitis. Phlyctenular conjunctivitis is marked clinically by the presence
of 2- to 3- mm whitish inflammatory nodules on the bulbar conjunctiva. A
zone of dilated vessels surrounds the nodules, and the overlying epithelium
is ulcerated. Microscopically, the nodules are composed of acute and
chronic inflammatory cells.

CHRONIC GRANULOMATOUS
CONJUNCTIVITIS
A chronic inflammatory infiltrate that includes epithelioid histiocytes and
inflammatory giant cells occurs in several conjunctival diseases. Discrete
noncaseating granulomas are found in biopsies from patients with
sarcoidosis (Figs. 3-7B and 5-10B). The granulomas may be evident
clinically as small yellowish-tan nodules in the inferior fornix or epibulbar
surface (Fig. 5-10A). Extensive subepithelial infiltration by sarcoidosis can
stimulate symblepharon formation. The conjunctiva can be biopsied when
sarcoidosis is suspected clinically and a tissue diagnosis is required. About
50% of bilateral conjunctival biopsies performed on patients known to
have sarcoidosis were positive in one study, despite the absence of obvious
nodules or ocular inflammation clinically.

FIG. 5-10. Sarcoidosis. A. Epibulbar nodule has characteristic yellow-pink color.

B. Microscopic examination shows chronic granulomatous infiltrate composed of
epithelioid histiocytes and numerous multinucleated giant cells. Stains for
microorganisms were negative. (B. H&E ×100.)

Granulomatous conjunctivitis with associated regional lymphadenopathy,

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usually a preauricular node, constitutes Parinaud oculoglandular
syndrome. The differential diagnosis of Parinaud oculoglandular syndrome
is rather extensive and includes a number of relatively rare infectious
disorders caused by variety of microorganisms including bacteria,
spirochetes, Chlamydia, Rickettsia, fungi, and viruses.
Cat scratch fever is a relatively common cause of Parinaud
oculoglandular syndrome (Fig. 5-11). The disease is caused by Bartonella
henselae, a recently characterized bacterium that usually is inconspicuous
in routine Gram stains because it is only faintly gram negative. The
infected conjunctiva contains an intense infiltrate of histiocytes with foci
of necrosis. The Warthin-Starry silver stain often reveals masses of
bacteria in the necrotic areas. There usually is a history of a cat scratch that
typically does not involve the eye or face. Conjunctival involvement
results from a bacteremia. A focal angiomatous response to Bartonella
called bacillary angiomatosis has been reported in the conjunctiva of
immunosuppressed patients. Granulomatous conjunctivitis in response to
the irritating hairs or setae of certain species of caterpillars is called
ophthalmia nodosa. The setae occasionally migrate into the anterior
chamber causing severe intraocular inflammation.

FIG. 5-11. Cat scratch disease, conjunctiva. The intense chronic inflammatory
infiltrate contains a focus of necrotic karyorrhectic cells. Silver stain discloses
masses of bacteria (B. henselae) in inset. The patient developed unilateral

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granulomatous conjunctivitis and a preauricular node after being scratched by a
cat. (Main figure, H&E ×100; inset, Warthin-Starry ×250.)

Synthetic fiber granuloma is a foreign body giant cell reaction to a “fuzz

ball” of synthetic fabric fibers lodged in the inferior conjunctival fornix
(Fig. 5-12). Most cases have occurred in infants and young children.
Synthetic fiber granuloma has been confused with ophthalmia nodosa
histopathologically. Particulates of inorganic delustering agent
incorporated into the fibers to opacify them and knife chatter marks on the
ends of sectioned fibers serve to differentiate the synthetic fabric fibers
from hair or caterpillar setae. The condition is also called teddy bear
granuloma after the source of the fibers in some patients.

FIG. 5-12. Synthetic fiber granuloma. A. “Fuzz ball” of synthetic fabric fibers
that stimulated chronic granulomatous inflammatory response in inferior fornix.
B. Foreign body giant cells encompass yellow synthetic fabric fibers, which
contain dark particulates of delustering agent added to opacify the plastic. (B.
H&E ×100.)

Allergic conjunctival granuloma is a bilateral condition marked by the

presence of yellowish nodules on the ocular surface, which is thought to be
response to parasitic infestation, probably by nematodes. Histopathology
discloses granulomatous inflammation and eosinophilia centered around
intensely eosinophilic deposits of antigen–antibody complexes called the
Splendore-Hoeppli phenomenon. Nematode fragments are identified
histologically in less than one fifth of cases.
Parasitic and mycotic infections of the conjunctiva are rare in the
United States. Adult Loa loa worms that have migrated to the
subconjunctival space occasionally are found in visitors from West and
Central Africa (Fig. 5-13A). These worms cause itching, pain, and the
disconcerting sensation of a mobile foreign body. Systemic infestation

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with Trichinella spiralis (trichinosis) causes fever, eosinophilia, periorbital
swelling, edema of the eyelids and conjunctiva, and subconjunctival
hemorrhages and petechiae. Rhinosporidium seeberi, an unusual fungus
with a pathognomonic histologic appearance, causes strawberry-like
papillary conjunctival granulomas that are studded with white
microabscesses (Fig. 5-13B,C). Although rhinosporidiosis has been
reported in the United States, most cases occur in India and Southeast
Asia. Microsporidia and Pneumocystis carinii can cause conjunctivitis in
patients with HIV/AIDS (Fig. 4-17).

FIG. 5-13. A. Loiasis. Nematode (arrow) is seen beneath inferior bulbar

conjunctival in eye of West African student who presented to the Wills Eye
Hospital ER with a severe foreign body sensation. (Photo courtesy of Michael A.
DellaVechia, MD, PhD.) B. Rhinosporidiosis. Infection with rare aquatic fungus
Rhinosporidium seeberi causes a reddish strawberry-like conjunctival papilloma.
The papilloma’s white “seeds” are sporangia. C. Microscopy shows characteristic
sporangia that vary in size. (C. PAS ×100.)

Ocular cicatricial pemphigoid (OCP) is a systemic autoimmune disease

with ocular and systemic manifestations. A type II hypersensitivity
reaction, OCP is thought to occur when environmental factors, probably
viruses, stimulate genetically susceptible individuals to make
autoantibodies (IgG) directed against epithelial basement membrane zone
components including the beta 4 subunit of alpha 6 beta 4 integrin and
laminin 5 (epiligrin) (Fig. 5-14). Similar diseases also occur in some
patients receiving topical medication or as a paraneoplastic effect of
nonocular cancer. Antibody deposition and complement activation cause
chronic inflammation and stimulate fibroblasts to produce collagen
causing abnormal conjunctival scarring. Conjunctival bullae rarely form in
OCP. Progressive cicatrization causes foreshortening of the conjunctival
fornices, symblepharon formation, and drying due to compromise of
lacrimal gland and meibomian gland ductules. The end stage of the disease

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is marked by epidermalization of the cornea and conjunctival epithelium
and adherence of the lids to the globe. Routine conjunctival biopsies are
nondiagnostic; specialized immunohistochemical procedures are required
to show immunoglobulin or complement deposition in the epithelial
basement membrane. These must be performed on fresh frozen-sectioned
tissue.

FIG. 5-14. Ocular cicatricial pemphigoid. Immunofluorescent microscopy

discloses deposition of IgA in conjunctival basement membrane (arrow).
(Immunofluorescence ×250. [Courtesy of Dr. C. Stephen Foster, Boston, MA.])

Severe subepithelial fibrosis, symblepharon formation, severe ocular

drying, and trichiasis complicate Stevens-Johnson syndrome (erythema
multiforme), which is thought to be a type III hypersensitivity reaction to
microbes or drugs characterized by circulating IgA containing immune
complexes and lymphocytic vasculitis. Conjunctival involvement by
pemphigus vulgaris is marked by intraepithelial bulla formation; therefore,
subepithelial scarring and symblepharon formation do not occur. In
pemphigus vulgaris, autoantibodies are directed against desmoglein 3, a
protein component of desmosomes joining epithelial cells.
The normal reparative phase of the inflammatory response is marked
by the production of granulation tissue, which plays an important role in
wound healing. An inappropriate, exuberant proliferation of granulation

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tissue may develop on the surface of the globe or conjunctiva after surgery
or trauma. Ophthalmologists apply the thoroughly ingrained term pyogenic
granuloma to these relatively common inflammatory tumors. Ophthalmic
pathologists diagnose these lesions as “exuberant granulation tissue”
(“pyogenic granuloma”) to distinguish them from an acquired type of
capillary hemangioma called pyogenic granuloma by dermatopathologists.
(The latter lesions usually are relatively devoid of inflammatory cells and
rarely occur on the conjunctiva or eyelid.) The richly vascular mass of
exuberant granulation tissue typically has a smooth, rounded surface and is
red or pink in color (Fig. 5-15). A paler hue may reflect superficial
necrosis or adherent exudate. These lesions often arise quite rapidly, which
serves to differentiate them from true neoplasms.

FIG. 5-15. A. “Pyogenic granuloma.” Round, smooth, red mass of granulation

tissue developed after strabismus surgery. B. Exuberant proliferation of
granulation tissue forms smooth-surfaced pedunculated mass. C. Radially
oriented vessels and inflammatory cells are seen at higher magnification. (A.
H&E ×10, C. H&E ×25.)

The mass of granulation tissue is composed of proliferating capillaries,

activated fibroblasts with contractile properties called myofibroblasts, and
a spectrum of acute and chronic inflammatory cells including
polymorphonuclear leukocytes, lymphocytes, plasma cells, histiocytes, and
occasional eosinophils and mast cells (Fig. 4-20). The inflammatory
infiltrate usually lacks epithelioid histiocytes and inflammatory giant cells
unless it harbors residual lipogranulomatous inflammation from a
previously drained chalazion. The vessels in pyogenic granuloma usually
radiate from the base or stalk of the lesion. This radial vascular pattern and
the prominent inflammatory cell component differentiate pyogenic
granuloma from hemangioma on histopathologic examination.

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DEGENERATIONS
Chronic light exposure damages the stromal connective tissue of the bulbar
conjunctiva exposed in the interpalpebral fissure. This actinic damage is
evident clinically as a yellowish- or gray-white opacification of the
subepithelial tissue. In advanced cases, a raised yellowish mound called a
pinguecula forms near the limbus (Fig. 5-16A). Microscopy discloses an
acellular grayish granular deposit of extracellular matrix material beneath
the limbal epithelium, which usually is elevated and thinned (Fig. 5-16B).
Some pingueculae contain thickened vermiform fibrils of degenerated
collagen; others contain deposits of hyaline material like those found in
chronic actinic keratopathy. The damaged matrix material stains positively
(black) with the Verhoeff-van Gieson stain for elastic tissue (Fig. 5-16C).
Pretreatment with the enzyme elastase does not abolish positive staining
for elastic tissue. Hence, the term elastoid is applied. The degenerative
process actually may involve the production of abnormal elastic tissue
components (elastodysplasia) by light-damaged fibroblasts. Similar foci of
elastotic degeneration often are found in pterygia.

FIG. 5-16. Pinguecula. A. The yellowish mounds near the limbus are caused by
actinic damage to conjunctival stromal connective tissue. B. Grayish deposit of
elastotic degeneration elevates limbal epithelium. Deposit has granular and
hyalinized areas. Inset shows intense positive staining for elastic tissue, which is
not quenched by pretreatment with elastase. (B. H&E ×100, C. Verhoeff-van
Gieson ×125.)

Conjunctival amyloidosis usually is a localized phenomenon that occurs in

healthy adults who do not have systemic amyloidosis (Fig. 5-17). The
degeneration can involve any part of the conjunctiva. The subepithelial
amyloid can form circumscribed polypoid, yellowish, waxy nodules on the
epibulbar surface or may diffusely infiltrate the substantia propria.

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Intralesional hemorrhage is often found. Light microscopy discloses
relatively acellular amorphous deposits of eosinophilic hyaline material.
Special stains, usually Congo red, and polarization microscopy are used to
confirm the diagnosis. Conjunctival amyloidosis is often composed of
immunoglobulin light chains.

FIG. 5-17. Amyloidosis, conjunctiva. A. Bulbar and palpebral conjunctivae are

thickened by an infiltrate of pink translucent material that obscures part of
cornea. B. Paucicellular amorphous eosinophilic material consistent with amyloid
fills substantia propria. C. Amyloid stains with Congo red stain and shows
characteristic apple green birefringence with polarized light (D). E. Focal
infiltrates of plasma cells are present. Plasma cells are immunoreactive for kappa
light chains (G) but do not stain for lambda light chains consistent with
monoclonal infiltrate (F). (B. H&E ×100, C. Congo red ×100, D. Congo red with
crossed polarizers, E. H&E ×250, F. IHC for lambda light chains ×100, G. IHC
for kappa light chains ×100. [Photo courtesy of Irving R. Raber, MD.])

CONJUNCTIVAL CYSTS
Conjunctival cysts occur congenitally or may develop secondarily when
surface epithelium is entrapped or implanted in the stroma during surgery

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or trauma. Conjunctival inclusion cysts are lined by conjunctival
epithelium, which may be attenuated. The lumen appears empty or it may
be filled with mucinous material and/or proteinaceous fluid. Cysts also
form when conjunctival crypts or pseudoglands of Henle become occluded
and dilate. The proteinaceous luminal contents of such cysts occasionally
undergo inspissation and even calcification, forming irritating concretions
that literally feel like “grains of sand” in the eye. Another type of
conjunctival cyst is caused by the blockage of an accessory lacrimal gland
duct. Such cysts are analogous to sweat ductal cysts of eyelid skin. They
have a clear empty lumen and are lined by a dual layer of ductal
epithelium.

CONJUNCTIVAL NEOPLASMS
There are three basic categories of conjunctival neoplasm. The great
majority of benign and malignant tumors of the conjunctiva arise from the
squamous epithelium, associated melanocytes, or the lymphoid cells that
normally reside in the substantia propria.

SQUAMOUS EPITHELIAL LESIONS

Squamous epithelial lesions of the conjunctiva include benign papillomas,
actinic keratoses, and the spectrum of ocular surface squamous neoplasia
(OSSN) that begins as intraepithelial neoplasia and can progress to
invasive squamous cell carcinoma (Figs. 5-18 to 5-23). Rare
keratoacanthomas of the conjunctiva have been reported. Bilateral benign
leukoplakic lesions occur on the conjunctiva and other mucous membranes
in hereditary benign intraepithelial dyskeratosis (Fig. 5-24).

FIG. 5-18. Conjunctival papilloma. A. Vessels in fibrovascular cores of epithelial

fronds are visible as hairpin vascular loops through transparent conjunctival

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epithelium. This benign epithelial tumor occurred in a child. B. Benign
pedunculated tumor is composed of multiple fronds of conjunctival epithelium
that surround cores of fibrovascular tissue. C. Fronds are seen at higher
magnification. (B. H&E ×10, C. H&E ×50.)

FIG. 5-19. Actinic keratosis, conjunctiva. A. Elevated leukoplakic lesion is

located near the limbus in the exposed interpalpebral part of the conjunctiva.
Leukoplakia indicates keratin-producing squamous cell lesion. B. Hyper- and
parakeratosis are present on the surface of thick plaque of epidermoid cells,
which arises abruptly from normal epithelium. The underlying stroma shows
actinic elastosis. (B. H&E ×50.)

FIG. 5-20. Squamous cell lesions, conjunctiva. A. Squamous cell carcinoma is

located near limbus in interpalpebral part of conjunctiva. Limbal tumor is

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leukoplakic indicating keratin production. Peripheral corneal invasion and
prominent feeder vessels are evident. B. Conjunctival intraepithelial neoplasia.
Gelatinous lesion has arisen from exposed interpalpebral conjunctiva at limbus.
Excisional biopsy is required for definitive diagnosis of conjunctival squamous
lesions. C. Conjunctival intraepithelial neoplasia (severe dysplasia). The
thickened epithelium is largely replaced by atypical cells, but a small amount of
surface differentiation persists. The epithelial basement membrane is intact.
Mitotic figures are present within the acanthotic epithelium. D. Conjunctival
intraepithelial neoplasia (carcinoma in situ). The epithelium at left has been
totally replaced by atypical squamous cells and appears hypercellular and
basophilic compared to the segment of normal limbal epithelium at right. Arrow
denotes characteristically abrupt transition characteristically abrupt. The
carcinoma is called in situ because the epithelial basement membrane is intact.
(C. H&E ×200, D. H&E ×100.)

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FIG. 5-21. Squamous cell neoplasms. A. Leukoplakic perilimbal squamous cell
carcinoma in situ is opacified by surface layer of keratin seen in (C). B. Basement
membrane is intact and substantia propria contains foci of chronic inflammatory
cells. Vessels largely hidden by keratin ramify through plaque of atypical
epidermoid squamous cells. D. Typical vascular loops are apparent in gelatinous
translucent sessile papillary squamous cell carcinoma in situ. E. Epithelial
basement membrane is intact. F. An abrupt transition between normal limbal
epithelium and tumor is present. G. Large papillary squamous cell carcinoma in
situ. Vascular fronds that characterize conjunctival squamous lesion are a striking
feature of this large lesion that overhangs the nasal cornea. H. Fronds with central
vessels comprising papillomatous tumor are totally composed of atypical
squamous cells. (B. H&E ×10, C. H&E ×50, E. H&E ×10, F. H&E ×100, H.

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H&E ×100. [Clinical photos courtesy of Jerry and Carol Shields, MD.])

FIG. 5-22. A. Invasive squamous cell carcinoma, conjunctiva. Nests and

islands of squamous cell carcinoma invade the substantia propria at right. The
tumor cells have broken through the epithelial basement membrane. A
characteristically abrupt junction separates the tumor from a segment of normal
limbal conjunctiva at left. B. Papillary squamous cell carcinoma in situ. The
epithelial component of exophytic papillary lesion is totally composed of highly
atypical squamous epithelium consistent with carcinoma in situ. (A. H&E ×50, B.
H&E ×10.)

FIG. 5-23. A. Anterior chamber invasion by conjunctival squamous cell

carcinoma. Tumor lines angle and iris surface and infiltrates iris stroma.
Desquamated keratin fills anterior chamber. B. Mucoepidermoid carcinoma,
conjunctiva. PAS stain highlights focal mucin production by conjunctival
carcinoma. Mucoepidermoid carcinoma of the conjunctiva can behave
aggressively. (A. H&E ×50, B. PAS ×100.)

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 FIG. 5-24. Hereditary benign intraepithelial dyskeratosis, conjunctiva. A. Two
leukoplakic lesions are present. The other eye and buccal mucosa also were
involved. The patient traced her ancestry to Halifax County, North Carolina.
(From Shields CL, Shields JS, Eagle RC. Hereditary benign intraepithelial
dyskeratosis. Arch Ophthalmol 1987;105:422–423. Copyright 1987, American
Medical Association.) B. Hereditary benign intraepithelial dyskeratosis,
conjunctiva. Parakeratin plaque composed of plump dyskeratotic cells covers
acanthotic epithelium. Single dyskeratotic cells are seen in the deeper part of the
benign lesion. The underlying substantia propria contains a heavy infiltrate of
lymphocytes. (B. H&E ×50.)

Most papillomas of the conjunctiva are composed of multiple fronds or

finger-like projections of conjunctival epithelium that enclose cores of
vascularized connective tissue (Fig. 5-18). The vessels in the fronds of the
papilloma are visible through the transparent epithelium as multiple
“hairpin” vascular loops. Conjunctival papillomas tend to be larger and
multiple in children, and they tend to recur after excision. Many are caused
by infection with human papillomavirus (HPV) 6 or 11. Benign papillomas
occasionally contain foci of dysplastic epithelium. Such areas are marked
by thickening of the epithelium, absence of goblet cells, cytologic atypia,
and mitotic figures that are not confined to the basal cell layer. Treatment
usually is surgical excision with supplemental oral Tagamet, an H2 blocker
that stimulates the immune system, or interferon α2b.
The term papilloma signifies a growth pattern. Although conjunctival
papillomas typically are benign, malignant tumors of the squamous
epithelium often grow in a papillomatous fashion. In malignant lesions, the
epithelium comprising the papillomatous growth is thickened and replaced
totally or in part by atypical cells. The former is termed papillary
squamous cell carcinoma in situ (Fig. 5-21G,H).
Squamous cell lesions of the conjunctiva tend to occur in the sun-
exposed part of the conjunctiva near the limbus, where a population of

137
proliferating stem cells resides (Figs. 5-20 and 5-21). Clinically, it is often
impossible to distinguish between actinic keratoses, which recur
infrequently after excision, and the spectrum of conjunctival intraepithelial
neoplasia (CIN; see below), which tends to recur and includes cases of in
situ and invasive squamous cell carcinoma.
Most actinic keratoses are focal leukoplakic lesions that occur on the
surface of pinguecula or pterygia (Fig. 5-19). Histopathology discloses
irregular focal acanthosis of the epithelium by atypical epidermoid cells, a
surface plaque of parakeratosis, and actinic elastosis in the substantia
propria. Excisional biopsy usually is curative.
CIN is a spectrum of squamous epithelial disease, in which part or all
of the conjunctival epithelium is replaced by the proliferation of a new
clone of neoplastic cells spawned by a mutation in the basal germinative
layer. Intraepithelial neoplasia is often called conjunctival dysplasia. The
newer term CIN is derived from terminology applied to an analogous
spectrum of intraepithelial malignancy that involves the uterine cervix.
The term Bowen disease should never be applied to the conjunctiva. CIN
is part of the spectrum of OSSN, which lumps together intraepithelial
neoplasia with invasive squamous cell carcinoma.
Most cases of CIN arise near the limbus in the interpalpebral part of
the conjunctiva (Fig. 5-20). The palpebral conjunctiva is rarely affected.
Patients usually have a history of extensive sun exposure. In many cases,
the abnormal epithelium appears diffusely thickened and has a gelatinous
appearance clinically. Leukoplakia may be present, however. Leukoplakia
(white plaque) signifies keratin production and provides good presumptive
evidence that a lesion is composed of squamous cells. More advanced
lesions form epibulbar tumors that often have a vascularized, exophytic,
papillary configuration. Corneal involvement may be evident as
contiguous areas of grayish epithelial thickening. In rare instances, the
process may be confined to the cornea.
Microscopic examination typically shows an abrupt transition between
the normal conjunctival epithelium and the affected part (Fig. 5-20D).
Compared to normal epithelium, the dysplastic epithelium shows increased
cellularity, poor maturation, and a disorderly arrangement of its cells (Fig.
5-20C,D). Part or all of the epithelium is replaced by the new proliferating
clone of neoplastic cells. The basal part of the epithelium is replaced first
because the mutational event occurs there. The involved epithelium is
often massively thickened or acanthotic, sometimes measuring 8 to 10
times normal thickness. The abnormal cells may have a spindled

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configuration with scant cytoplasm or may show epidermoid
differentiation with copious quantities of eosinophilic cytoplasm. Varying
degrees of atypia are possible. Mitoses are not confined to the basal cell
layer where mitotic activity normally takes place, and may be found
throughout the thickened epithelium.
Depending on the amount of surface differentiation that persists, the
degree of dysplasia is roughly graded as mild, moderate, or severe. If the
entire thickness of the epithelium is replaced and there is no evidence of
maturation or surface differentiation, the process is termed carcinoma in
situ (Fig. 5-20D). The epithelial basement membrane remains intact in
carcinoma in situ. Carcinoma in situ has a good prognosis because the
malignant cells have not gained access to the blood vessels and lymphatics
in the conjunctival stroma.
Intraepithelial carcinoma can progress to invasive squamous cell
carcinoma (Fig. 5-22). This occurs when tumor cells break through the
epithelial basement membrane and invade the conjunctival stroma.
Invasive squamous cell carcinoma does have a potential for metastatic
spread (usually to regional lymph nodes), but the frequency of metastasis
fortunately is low. In many cases, the squamous cell carcinoma tends to be
papillary in configuration and forms an exophytic mass on the surface of
the globe (Figs. 5-21G, 5-22B, and 4-35). In the past, it was suggested that
HPV 16 and 18 were responsible for many cases of OSSN. Recent studies
employing sensitive type-specific PCR assays indicate that HPV probably
does not play a significant role in the pathogenesis of OSSN. HPV 16 was
identified in only 6.5% of OSSN specimens, typically squamous cell
carcinomas in one study from India. Lesions caused by HPV infection may
show koilocytosis. HPV is said to be more common in lesions from the
superior limbus.
Most conjunctival squamous cell carcinomas remain superficial and
rarely invade the eye or orbit. Most are successfully eradicated by local
therapy that usually includes surgery and/or chemotherapy. In recent years,
there has been a trend toward the use of topical chemotherapy
administered as drops or intralesional injections. Mitomycin C, 5-FU, and
interferon α2b have been used to treat OSSN. Interferon is reported to be
effective and has fewer side effects but is relatively expensive and requires
chronic administration. There is some controversy whether a biopsy should
be performed to confirm the diagnosis and exclude invasive squamous cell
carcinoma prior to instituting chemotherapy. Anterior segment optical
coherence tomography (OCT) is used to assess OSSN clinically in some

139
centers.
Invasion of the eye or orbit does occur, however, albeit infrequently,
and enucleation and orbital exenteration occasionally are required (Fig. 5-
23A). Poorly differentiated spindle cell carcinomas or mucoepidermoid
carcinomas of the conjunctiva can behave aggressively, as can tumors that
arise in immunosuppressed patients who have HIV/AIDS or have
undergone organ transplantation. Mucoepidermoid carcinomas contain
pools of mucous and goblet cells (Fig. 5-23B). Positive
immunohistochemical stains for cytokeratin may be necessary to
differentiate spindle cell carcinoma from other spindle cell neoplasms. The
rare clear cell variant of mucoepidermoid carcinoma can be confused
histopathologically with sebaceous carcinoma.
Hereditary benign intraepithelial dyskeratosis (Witkop-Von Sallman
syndrome) is an autosomal dominantly inherited trait characterized by
keratinized plaques of hyperplastic epithelium that occur bilaterally in the
bulbar conjunctiva and are associated with ocular injection (Fig. 5-24).
The disorder can also affect the buccal mucosa. The surface plaque of
keratin is composed of round or oval dyskeratotic cells, which are found
throughout the thickened epithelium (Fig. 4-40). The condition is always
benign. Although cases have been reported elsewhere, most affected
patients belong to a triracial isolate called the Haliwa-Saponi Indians who
live in Halifax and Warren Counties in North Carolina. Visual loss occurs
rarely when the disease affects the corneal epithelium. Affected patients
have a duplication in chromosome 4q35.

PIGMENTED LESIONS OF THE

CONJUNCTIVA
About half of conjunctival lesions in adults are melanocytic. Melanocytic
lesions of the conjunctiva include racial, constitutional, or complexion-
related melanosis, benign freckles and lentigines, several types of nevi,
malignant melanoma, and its clinically important precursor primary
acquired melanosis (PAM). Conjunctival pigmentation unrelated to
melanocytes can develop in certain systemic diseases like Addison disease
and ochronosis (Fig. 5-25A) or may be caused by systemic
(phenothiazines, tetracycline) or topical drugs (epinephrine) or the
deposition of metals like silver (argyrosis) (Fig. 5-25B).

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 FIG. 5-25. A. Ochronosis. Brownish deposit of homogentisic acid discolors
sclera near insertion of medial rectus tendon. A few globules of pigment are seen
in the peripheral cornea. B. Argyrosis, conjunctiva. Chronic administration of
silver-containing eyedrops has caused grayish discoloration of forniceal
conjunctiva. C. Photomicrograph shows deposition of silver granules in
substantia propria. (C. H&E ×250.)

Conjunctival freckles or ephelides are flat patches of pigmentation.

Histopathology shows increased pigmentation of the epithelial basal cell
layer and no melanocytic hyperplasia. An identical picture is seen in racial
or constitutional melanosis and in the early stages of PAM (Fig. 5-26).

FIG. 5-26. Constitutional melanosis. A. Patchy conjunctival pigmentation

occurred in both eyes of darkly complexioned individual. B. Squamous epithelial

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 cells contain melanin pigment. Atypical melanocytic hyperplasia is not present.
C. PAM without atypia. Limbal conjunctiva contains flat patch of pigmentation.
D. (top) Pigmentation is most intense in basal cell layer of conjunctival
epithelium. No atypical melanocytic hyperplasia is noted. D. (bottom)
Immunohistochemical stain for melanocytic marker microphthalmia-associated
transcription factor (MITF) using red chromagen shows that pigment is located
within squamous epithelial cells and confirms absence of melanocytic
hyperplasia. (B. H&E ×250, D. (top) H&E ×100, D. (bottom) IHC for MITF
×100.)

Conjunctival nevi are benign hamartomatous tumors composed of

modified melanocytes called nevus cells, which are derived
embryologically from the neural crest (Figs. 5-27 and 5-28). Conjunctival
nevi typically involve the nasal or temporal bulbar conjunctiva and abut
the limbus. The caruncle and plica semilunaris are involved in 15% and
11% of case, respectively. Nevi rarely involve the tarsal or forniceal
conjunctiva or the cornea. Pigmentation of the latter structures should raise
concern about malignant melanoma or its precursor PAM. About 5% can
be quite large and are termed giant nevi.

FIG. 5-27. Hormone-induced changes in conjunctival nevus. Compound cystic

nevus was photographed at age 11 (left) and age 13 (right). Cytologically benign
lesion appears larger and more intensely pigmented after menarche. The nevus
contains multiple cysts.

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 FIG. 5-28. Compound cystic nevus, conjunctiva. A. Slit beam highlights cysts in
pigmented conjunctival nevus at limbus. B. Lightly pigmented nevus contains
characteristic cystic rests of conjunctival epithelium with goblet cells. Nevus cells
are present at the junctional position and in the substantia propria. (B. H&E ×50.)

Although nevi are considered to be congenital lesions, they often are

detected toward the end of the second decade. Apparent growth and
increased pigmentation of conjunctival nevi is often caused by elevated
levels of hormones during puberty or pregnancy (Fig. 5-27). Most
conjunctival nevi accessioned by the eye pathology laboratory are excised
from children or young adults. Conjunctival nevi are the most common
conjunctival tumor in children and constitute almost two thirds of pediatric
conjunctival lesions. Excisional biopsy is usually performed for cosmetic
reasons or when apparent enlargement or the deepening of pigmentation
raises concern about possible malignant transformation. A large series of
conjunctival nevi published by the Wills Eye Hospital Oncology Service
noted a change in color about 13%. Eight percent of the nevi increased in
size. Quite low, the risk of malignant transformation is actually only 1 in
300. Nevi occasionally become less pigmented with time. This may reflect
the loss of a melanophagic component.
Histopathologically, conjunctival nevi are classified topographically
based on the location of the nevus cells in relation to the epithelium. In
junctional nevi, the nevus cells are located at the epithelial–subepithelial
junction. Nevus cells are confined to the conjunctival stroma in
subepithelial nevi, which are the counterpart of intradermal nevi in the
skin. Most conjunctival nevi are compound nevi that have both junctional
and subepithelial components (Fig. 5-28B). Junctional activity tends to
decrease markedly with age. Junctional nevi are rare in childhood and
almost never occur in adults. Hence, any lesion in an adult that appears to
be a junctional nevus should be considered to be PAM until proven
otherwise. Strictly subepithelial nevi generally are found in older adults.

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 Microscopically, nevus cells often form aggregates called nests.
Polarity of nevus cells may be present, that is, the more superficial cells
tend to be larger, while nevus cells in the deeper stroma tend to be smaller
and may have a lymphocytoid appearance reflecting scanty cytoplasm.
Bland multinucleated nevoid giant cells are seen in some cases.
During histopathologic evaluation, immunohistochemical stains for
melanocytic markers Melan-A and MITF2 readily confirm the melanocytic
nature of nonpigmented lesions and also highlight the junctional
component. Stains for HMB45 can help distinguish conjunctival nevi from
melanoma. Melanomas typically show diffuse, intense staining with
HMB45, while positive immunoreactivity for this marker is restricted to
the junctional zone of nevi. Proliferation marker Ki-67 also helps to
distinguish conjunctival nevi from melanomas, which have a higher
proliferation index (17.9% compared to 1.9% in nevi). Cellular cycling in
inflammatory or conjunctival epithelial cells can make interpretation
difficult, however, unless dual-stained immunohistochemical preparations
are available.
Most compound conjunctival nevi are cystic; the nevus contains cystic
invaginations and occasionally solid rests of conjunctival epithelium (Fig.
5-28B). These intralesional microcysts are readily visible with the slit
lamp in many cases, and this observation can suggest the diagnosis
clinically. The cysts tend to enlarge with age. The pigment content of
conjunctival nevi varies markedly. Most nevi are brown, but 16% are
totally amelanotic and may appear pink if inflamed.
Blue nevi are composed of melanocytes that are located deep to the
epithelium in the stroma or epibulbar tissues. The melanocytes are bland
and are spindle or dendritiform in shape. An extensive deep blue nevus
that typically involves the deep stroma, epibulbar connective tissue, and
adnexal skin occurs in congenital oculodermal melanocytosis or the nevus
of Ota (Fig. 5-29). Patients with Ota nevus typically have congenital
hyperchromic heterochromia iridum (involved eye darker) caused by a
diffuse nevus of the ipsilateral uveal tract. Caucasian patients with
oculodermal melanocytosis are at risk for uveal, orbital, and CNS
malignant melanoma, but not conjunctival melanoma. Blue nevi appear
blue or slate gray in color because the longer wavelengths of light are
absorbed or scattered as the light passes through the epithelium and
connective tissue of the overlying conjunctiva (Fig. 5-29B,C). The
conjunctiva moves freely over the deeply situated pigmented cells. If the
conjunctival pigmentation moves, the pigment or pigmented cells are

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associated with the epithelium.

FIG. 5-29. Congenital ocular melanocytosis. A. Patchy, slate gray pigmentation

is caused by dendritiform melanocytes deep in epibulbar tissues beneath
conjunctiva. (Photograph courtesy of Dr. Jerry A. Shields, Wills Eye Hospital.)
B. Epibulbar pigment on surface of globe (above) appears brown where it is
exposed by defect in conjunctiva. Tyndall effect makes pigment beneath intact
conjunctiva (at right) appear gray. Eye was obtained postmortem from patient
with nevus of Ota who developed leptomeningeal melanoma. C.
Photomicrograph shows dendritic melanocytes in epibulbar tissue. (C. H&E
×100.)

PRIMARY ACQUIRED MELANOSIS

(INTRAEPITHELIAL
MELANOCYTIC PROLIFERATION)
Although conjunctival melanomas occasionally arise de novo or from
preexisting nevi, almost three fourths develop from a form of atypical
intraepithelial melanocytic proliferation that currently is called primary
acquired melanosis or PAM. Clinically, PAM appears as patchy acquired
unilateral pigmentation of the conjunctiva that usually affects middle-aged
or elderly white individuals (Fig. 5-30). The onset is insidious, and the
pigmentation may wax and wane. The acquired and unilateral nature of the
pigmentation serves to distinguish PAM from constitutional or
complexion-related melanosis that occurs bilaterally and symmetrically in
heavily pigmented races. Asymmetrical pigmentation should suggest the
presence of PAM, which can affect black patients, but is exceedingly rare.
Black patients are at greater risk for conjunctival melanoma than uveal
melanoma, probably reflecting the relative paucity of protective
pigmentation in the conjunctiva. The white/black ratio for conjunctival

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melanoma is only 3:1 compared to 17:1 for uveal melanoma.

FIG. 5-30. Primary acquired melanosis. A. Patchy conjunctival pigmentation

developed slowly in a middle-age Caucasian man. The pigment moved with the
conjunctiva. PAM is an important precursor of conjunctival melanoma.
(Photograph courtesy of Dr. Jerry A. Shields, Wills Eye Hospital.) B. PAM with
mild to moderate atypia. Atypical melanocytes are largely confined to basal part
of epithelium. C. PAM with severe atypia. The thickened conjunctival
epithelium is almost totally replaced by nests of atypical pigmented melanocytes
that include epithelioid cells. Some would call this “melanoma in situ.” D. PAM
with severe atypia, sine pigmento. There is extensive replacement of the
epithelium by atypical melanocytes. Little pigment is present. (A. H&E ×250, B.
H&E ×100, C. H&E ×50.)

About 20% of conjunctival lesions evaluated by the Wills Ocular

Oncology Service were classified as PAM. In another report, patches of
conjunctival pigmentation consistent with PAM were found in more than
one third (36%) of 146 Caucasian patients over age 10 examined in a
cornea clinic. Although PAM is relatively common, conjunctiva melanoma
is rare, suggesting that the risk of malignant transformation has been
overestimated in the past. A widely cited study from the Armed Forces
Institute of Pathology (AFIP) reported that nearly one third (31.7%) of
PAM cases progressed to invasive melanoma. However, the authors

146
cautioned that the incidence probably was skewed by referral bias. A
recent clinical study by the Wills Oncology Service found that only 4% of
311 patients with PAM progressed to melanoma. Malignant transformation
occurred in 13% of patients who had histologically diagnosed PAM with
severe atypia. Multivariant analysis showed that the most significant risk
factor for recurrence and progression to melanoma was the extent of the
pigmentation in clock hours. Each clock hour of involvement increased the
relative risk for melanoma by a factor of 1.7.
PAM is classified into benign and malignant variants on the basis of
histopathological examination. Invasive malignant melanomas typically
arise from PAM with severe atypia. PAM is classified as atypical if there
is any degree of atypical melanocytic hyperplasia.
In PAM without atypia, melanin pigment is confined to the
conjunctival epithelial cells and there is no evidence of melanocytic
hyperplasia, or an increased number of benign dendritic melanocytes are
present (Fig. 5-26). A benign lesion, PAM without atypia is
indistinguishable histopathologically from constitutional melanosis or
ephelis or freckle.
Biopsies classified as PAM with mild atypia have atypical
melanocytes that are confined to the basal layer of the epithelium in a
single-cell lentiginous pattern. Patients who have PAM with mild atypia
are at relatively low risk for progression to invasive melanoma.
Atypia is classified as severe if atypical melanocytes are not confined
to the basal cell layer of the epithelium and involve its more superficial
layers or form pagetoid nests (Fig. 5-30). Pagetoid involvement of the
epithelium was associated with a 95% incidence of progression to
melanoma in Folberg’s series from the AFIP. Epithelioid melanocytes are
another criterion for PAM with severe atypia. Folberg reported that
melanoma developed in 75% of cases with epithelioid cells. The term
melanoma in situ has been proposed for extensive or full-thickness
replacement of the epithelium.
In 2008, Damato and Coupland proposed alternative terminology, that
is, conjunctival melanocytic intraepithelial neoplasia (C-MIN) with or
without atypia for this disease spectrum. Analogous to the term CIN used
for squamous lesions of the conjunctiva, the adjective intraepithelial used
in C-MIN emphasizes that the atypical melanocytes are confined to the
conjunctival epithelium by an intact basement membrane. Invasive
melanoma ensues when the epithelial basement membrane is violated and

147
a vertical growth phase into the substantia propria ensues. Damato and
Coupland proposed the term hypermelanosis for cases of conjunctival
pigmentation without melanocytic hyperplasia. Their paper includes a
score sheet to grade C-MIN based on the assessment of a variety of factors
including the pattern of melanocytic involvement of the epithelium (e.g.,
basal/lentiginous location, nesting, etc.), the degree of vertical spread (e.g.,
basal location, less or greater than 50%, etc.), and the degree of
melanocytic atypia. In this schema, the size of nuclei and cytoplasm
compared to normal basal squamous cells and the presence or absence of
nucleoli and mitotic figures are factors used to grade melanocytic atypia.
Working independently and initially unfamiliar with Damato and
Coupland’s important paper in the Australian literature, Jakobiec
developed an alternative diagnostic classification and terminology for
PAM that was published in 2016. Jakobiec recommends that the term
PAM be abandoned because it is “insufficiently specific and
nondescriptive of the underlying cellular events.” Similar to Damato and
Coupland’s classification, Jakobiec’s schema emphasizes the pivotal role
of intraepithelial melanocytic hyperplasia in this disease spectrum.
However, he rejects the term neoplasia because he feels that it is
occasionally impossible to differentiate hyperplasia, a potentially
reversible condition subject to negative feedback, from neoplasia, an
irreversible clonal proliferation of mutated cells.
Immunohistochemical stains for melanocytic markers such as Melan-
A, MITF2 or HMB45 (preferably employing red chromagen) are
recommended to assess pigmented lesions for melanocytic proliferation,
which often is not evident in routine H&E-stained sections. The
immunohistochemical stains readily disclose the number, type, and
location of melanocytes within the epithelium as well as cytologic atypia.
Rejecting Damato and Coupland’s term hypermelanosis, Jakobiec
prefers the term intraepithelial nonproliferative melanocytic pigmentation
for pigmented conjunctival lesions that have a normal number of bland
dendritic melanocytes. The latter include PAM without atypia, ephelis or
freckle, and racial or complexion-associated melanosis. Pigmented lesions
with an increased number of melanocytes fall into two categories:
intraepithelial melanocytic proliferation without atypia and intraepithelial
melanocytic proliferation with atypia.
Cases of intraepithelial melanocytic proliferation without atypia have
an increased number of bland, normal-sized dendritic melanocytes that are
located in their normal position along the epithelial basement membrane

148
but are separated by fewer basal keratinocytes. The melanocytes typically
transfer melanin granules to squamous epithelial cells. The melanocytes in
intraepithelial melanocytic proliferation with atypia are atypical. They
include large bloated cells that have large cell bodies with hyperchromatic
nuclei and swollen dendrites. Not confined to the basal cell layer, the
atypical melanocytes occupy all levels of the epithelium and continue to
manufacture melanin. The atypical melanocytes can also include
polygonal epithelioid cells without dendrites that can involve superficial
layers of the epithelium in a pagetoid fashion. Involvement of the full
thickness of the epithelium by atypical melanocytes is termed melanoma in
situ.
Essentially, when the pathologist evaluates a biopsy of clinically
pigmented conjunctiva, he or she must decide if the pigment is contained
within squamous epithelial cells, if an increased number of melanocytes
are present, and if the melanocytes are atypical. In many instances, this
distinction is difficult using H&E-stained sections alone.
Immunohistochemical stains for melanocytic markers like Melan-
A/MART-1, microphthalmia-associated transcription factor (MITF2), and
melanoma-specific antigen HMB-45 are helpful aids in the assessment and
classification of these difficult and challenging lesions (Fig. 5-26E).
Patients with PAM should be followed closely with photographic
documentation and detailed clinical drawings. Periodic observation is
recommended for lesions of the bulbar conjunctiva <1 clock hour in
extent. Areas of conjunctiva that become thickened and are presumed to be
melanoma should be excised in toto using a careful “no touch technique.”
Multiple map biopsies to determine the extent of the disease are
recommended. Therapy is often challenging. Besides local excision of
nodules, extensive cryotherapy and topical chemotherapy with agents like
mitomycin C have been advocated. Rarely, PAM may be totally
amelanotic and inapparent clinically (Fig. 5-30D). A nodule of invasive
melanoma usually is the presenting sign of PAM sine pigmento.

CONJUNCTIVAL MELANOMA
Conjunctival melanomas are relatively rare tumors: only 200 cases occur
yearly in the United States. The incidence is thought to be increasing,
however (Fig. 5-31). Conjunctival melanoma is about one tenth as
common as uveal melanoma. Although its behavior is unpredictable,
conjunctival melanoma has a better prognosis than uveal melanoma of the

149
ciliary body or choroid. The overall mortality is about 26% compared to
50% for uveal melanoma. Melanomas arising from PAM have the best
outcome; de novo melanomas the poorest. Clinical factors associated with
a good outcome include small tumors <2 mm in thickness and location on
the bulbar conjunctiva near the limbus. Melanomas that are >2 mm in
thickness or involve the fornix, tarsus, or caruncle have the poorest
prognosis.

FIG. 5-31. Malignant melanoma arising from PAM with atypia. A. Several
nodules of recurrent tumor are located inferonasally near the caruncle. Extensive
PAM is present. The patient had a prior incisional biopsy elsewhere. (Photograph
courtesy of Drs. Jerry and Carol Shields, Wills Eye Institute.) B. The conjunctival
epithelium at left is totally replaced by atypical melanocytes. The cells have
broken through the epithelial basement membrane forming an invasive malignant
melanoma. About 75% of conjunctival melanomas appear to arise from PAM
with atypia. (B. H&E ×50.)

Most (75%) conjunctival melanomas appear to arise from PAM with

atypia. Some patients do have a history of an antecedent presumed or
biopsy-confirmed conjunctival nevus. Remnants of a nevus are found
histopathologically in about one fourth of cases. Some conjunctival
melanomas arise de novo.
Conjunctival melanomas do not behave like uveal tumors. Although
they do contain spindle and epithelioid cells, the Callender classification
for uveal melanoma does not apply to conjunctival melanoma. In contrast
to uveal melanoma that metastasizes hematogenously to the liver,
conjunctival melanomas initially spread to regional lymph nodes, usually
the preauricular or intraparotid nodes. The tumor cells then gain access to
blood vessels via anastomoses between vessels and lymphatics in the
nodes. Factors associated with poorer prognosis include extralimbal tumor
location, nasal location, caruncular involvement, involvement of surgical

150
margins, and de novo melanomas without PAM. Several studies have
found that inadequate initial surgical management by nonocular
oncologists including incisional biopsy and incomplete excision increases
risks of local recurrence and metastatic death.
BRAF mutations are found in about 40% of conjunctival melanomas.
They appear to be more common in melanomas that have arisen from nevi
and in amelanotic or partially pigmented tumors. They are less common in
tumors spawned by PAM. BRAF-mutated conjunctival melanomas are
more frequent in younger patients and may have a higher incidence of
distant metastases despite arising in a favorable location.
Wide microsurgical excisional biopsy using the “no touch” technique
and supplemental alcohol corneal epitheliectomy and conjunctival
cryotherapy is advised. Orbital exenteration eventually is required in 15%
to 20% of cases when the conjunctival melanoma recurs and invades the
orbit. Such radical surgical therapy probably does not improve prognosis
for life but may be necessary to debulk the tumor and relieve local
symptoms. Sentinel lymph node biopsy has been recommended for
patients with conjunctival melanoma, but its effect on survival is uncertain.

LYMPHOID NEOPLASMS
Lymphoid neoplasms constitute about 8% of conjunctival tumors in adults.
They include reactive follicular hyperplasias, atypical lymphoid
hyperplasias, and malignant lymphomas.
Conjunctival lymphoid tumors typically present as a salmon-colored
patch or infiltrate in the fornix or on the epibulbar surface of the globe
(Figs. 5-32 to 5-34). About 70% to 80% are extralimbal lesions that
involve the fornix, and about one third involve both eyes. The average age
at presentation is 61 years. The characteristic salmon pink color of
conjunctival lymphoid tumors reflects the lesions’ fine vascularity.
Conjunctival lymphoid tumors typically cause few symptoms because they
lack a connective tissue stroma, are soft and elastic, and mold to the
surrounding tissues (Fig. 4-56). They are covered by an intact layer of
conjunctival epithelium. The epithelium often contains an infiltrate of
lymphocytes (lymphoepithelial lesion) if the tumor is a mucosa-associated
lymphoid tissue (MALT) lymphoma.

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FIG. 5-32. Conjunctival MALT lymphoma. A. Lymphoma appears as diffuse
“salmon patch” covering superior aspect of globe. B. Nodules of translucent
salmon-colored tissue involve nasal conjunctiva. Both tumors were low-grade
non-Hodgkin B-cell lymphomas that were classified as EMZL of MALT. C. The
substantia propria contains a diffuse monomorphic infiltrate of well-differentiated
lymphocytes, seen at higher magnification in (D). Flow cytometric analysis
disclosed a monoclonal proliferation of B lymphocytes that expressed CD20 and
were negative for CD5 and CD10. More than 50% of ocular adnexal lymphomas
are MALT lymphomas. (C. H&E ×50, D. H&E ×400.)

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FIG. 5-33. Benign reactive lymphoid hyperplasia. A. Benign lymphoid lesion in
teenager forms salmon-colored mass involving nasal conjunctiva and plica
semilunaris. B. Low-power microscopy reveals basophilic lymphocytes and large
germinal centers, which are lighter in color. C. Lighter staining germinal centers
have starry sky appearance reflecting the presence of antigen-presenting tingible
body macrophages, seen at higher magnification in (D). E. The bulk of the lesion
including the germinal centers and surrounding mantle zones is immunoreactive
for B-cell marker CD20. F. The B cells are rimmed by a lesser number of CD3-
positive T lymphocytes. G. The germinal centers stain positively for follicular
center cell marker CD10 and are negative for antiapoptotic protein BCL-2,
excluding a follicular lymphoma (H). (B. H&E ×10, C. H&E ×25, D. H&E ×250,
E. IHC for CD20 ×10, F. IHC for CD3 ×10, G. IHC for CD10 ×10, H. IHC for
BCL-2 ×10.)

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FIG. 5-34. Follicular lymphoma. A. Mass in inferolateral fornix has pebbly
follicular aspect. B. Histopathologically, mass has multinodular follicular
appearance but lacks germinal centers and tingible body macrophages. C.
Malignant follicles are strongly immunoreactive for B-cell marker CD20. D. CD3
stain reveals a significantly smaller number of T lymphocytes. E. Follicular cell
marker CD10 is positive consistent with a follicular lymphoma. F. Positive
staining for BCL-2 confirms that follicles are malignant and excludes benign
reactive lymphoid hyperplasia. (B. H&E ×25, C. IHC for CD20 ×75, D. IHC for
CD3 ×75, E. IHC for CD10 ×75, F. IHC for BCL-2 ×75.)

Lymphoid tumors can diffusely infiltrate the substantia propria, or the

154
surface of lesions may be pebbly and multinodular. The latter pattern
typically is seen in reactive follicular hyperplasia or follicular lymphoma
(Fig. 5-34A). In some instances, a conjunctival salmon patch may be the
anterior tip of an orbital lymphoid tumor. Imaging studies to exclude
orbital involvement should be ordered if there is uncertainty whether a
lesion is purely conjunctival, because orbital lesions have a higher
incidence of associated systemic disease.
Histopathologically, follicular lymphoid hyperplasia (often called
benign reactive lymphoid hyperplasia) is a polymorphous infiltrate
composed of mature well-differentiated lymphocytes, often admixed with
plasma cells, that contains benign reactive lymphoid follicles or germinal
centers (Fig. 5-33). The reactive follicles are composed of large, pale,
mitotically active immunoblasts and harbor tingible body macrophages
that contain basophilic bodies of apoptotic nuclear debris. These
macrophages process antigens and present it to helper T cells to initiate the
immune response. Immunohistochemical stains disclose CD20-positive B
lymphocytes in the follicular centers and the surrounding mantle zone.
Antiapoptotic BCL-2 protein normally is absent in the reactive follicles.
CD-3 positive T cells predominate in the interfollicular zone between the
germinal centers. Florid cases of reactive lymphoid hyperplasia
occasionally occur in the conjunctiva of children.
Most lymphomas of the ocular adnexa are diffuse non-Hodgkin B-cell
lymphomas composed largely of a single clone of B lymphocytes that
express either kappa or lambda light chains. Clonality is best assessed by
flow cytometric analysis of fresh tissue because light chains are labile and
usually are destroyed during routine tissue processing. If lymphoma is
suspected clinically and a sufficient quantity of fresh, unfixed tissue is
available, part should be submitted for flow cytometry. Unfortunately, the
amount of tissue excised in many cases of conjunctival lymphoma is
insufficient for flow cytometric analysis. In such cases,
immunohistochemistry performed on routine paraffin sections usually can
establish the diagnosis of lymphoma and classify it as to type (see Figs. 5-
33 and 5-34). A relatively small panel of antibodies directed against
lymphocytic markers CD3, CD5, CD10, CD20, CD23, BCL-2, and BCL-1
(cyclin D-1) usually suffices. In some cases, additional markers and gene
rearrangement studies are necessary.
B-cell lymphoma cells express B-lymphocyte antigen CD20.
Demonstration that a lymphoid infiltrated is composed largely of CD20-
positive B lymphocytes provides circumstantial evidence that it is a

155
lymphoma because chronic inflammatory infiltrates are composed largely
of T lymphocytes, which stain with T-cell markers such as CD-3 and CD-
5.
Most conjunctival lymphomas are low-grade extranodal marginal zone
lymphomas (EMZL) of mucosa-associated lymphoid tissue (often called
MALT lymphomas) (Fig. 5-32). EMZL constituted more than half (51.6
%) of lymphomas in a recent large series of ocular adnexal lymphoid
lesions. The cells of MALT lymphomas are CD20 positive but are
negative for CD3, CD5, CD10, and CD23. Less often, the conjunctiva is
involved by follicular, mantle zone, and diffuse large B-cell lymphomas
and chronic lymphocytic leukemia/small lymphocytic lymphoma. The
latter can be distinguished by morphologic features and characteristic
patterns of immunoreactivity.
Conjunctival lymphoma generally has an excellent prognosis.
Systematized lymphoma rarely presents in the conjunctiva; most cases are
stage IE on presentation. Lymphoma confined to the conjunctiva is
associated with systemic lymphoma (prior, concurrent, or subsequent) in
about 20% of cases. The 31% incidence of associated systemic disease in
117 cases of conjunctival lymphoid lesions in a recent study probably
reflects the inclusion of a significant number (18%) of cases that had
concurrent involvement of the orbit or eyelid in addition to a conjunctival
salmon patch. In that study, systemic lymphoma was more likely if both
conjunctivae were involved (50% vs. 17% incidence at 30 years) or if the
tumor involved an extralimbal location.
Treatment depends on whether the disease is localized to the
conjunctiva or whether systemic lymphoma is present. If a patient has
systemic lymphoma, the conjunctival lesion generally responds to
systemic chemotherapy. Most patients with localized conjunctival disease
are treated with low-dose external beam radiotherapy. Recently,
intralesional interferon and systemic rituximab, which avoid the
complications of radiotherapy, have been used to treat low-grade primary
conjunctival lesions with some success. The role of Helicobacter pylori
and Chlamydia psittaci in the pathogenesis of conjunctival MALT
lymphoma remains controversial.

CARUNCULAR LESIONS
The caruncle is a small nodular island of skin surrounded by conjunctiva
near the medial canthus. It is covered by keratinized epithelium and

156
contains sweat glands, fat, the accessory lacrimal glands of Popoff, and
pilosebaceous units with delicate hairs. Caruncular masses include nevi,
papillomas, senile sebaceous gland hyperplasia, inclusion cysts, and
oncocytomas (Figs. 5-35 and 5-36). The latter comprise modified
glandular epithelial cells with copious amounts of eosinophilic cytoplasm
replete with mitochondria (Fig. 5-36). Rare cases of sebaceous carcinoma
arise from the glands of the pilosebaceous units in the caruncle.

FIG. 5-35. Caruncular lesions. Lesions of the caruncle include A. Senile

sebaceous gland hyperplasia B. Sebaceous gland carcinoma C. Melanocytic
nevus D. Epidermal inclusion cyst. Other lesions include papillomas, malignant
melanomas, and oncocytomas. (A. H&E ×25, B. H&E ×100, C. H&E ×25, D.
H&E ×25.)

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FIG. 5-36. Oncocytoma, caruncle. A. Benign cystadenomatous tumor deep in
stroma of caruncle is composed of tall bland epithelial cells with copious
eosinophilic cytoplasm seen at higher magnification in (B) and (C). Increased
numbers of mitochondria are responsible for granular appearance of cytoplasm in
(C). The epithelium on the apex of the caruncle resembles skin; it is keratinized
and has pilosebaceous units. Located near the medial canthus, the caruncle is an
island of skin surrounded by conjunctiva. (A. H&E ×25, B. H&E ×100, C. H&E
×400.)

BIBLIOGRAPHY
Developmental Lesions
Cunha RP, Cunha MC, Shields JA. Epibulbar tumors in children: a survey of 282
biopsies. J Pediatr Ophthalmol Strabismus 1987;24:249–254.
Dreizen NG, Schachat AP, Shields JA, et al. Epibulbar osseous choristoma. J
Pediatr Ophthalmol Strabismus 1983;20:247–249.
Eijpe AA, Koornneef L, Bras J, et al. Dermolipoma: characteristic CT
appearance. Doc Ophthalmol 1990;74:321–328.
Elsas FJ, Green WR. Epibulbar tumors in childhood. Am J Ophthalmol
1975;79:1001–1007.
Gonnering RS, Fuerste FH, Lemke BN, et al. Epibulbar osseous choristomas with
scleral involvement. Ophthal Plast Reconstr Surg 1988;4:63–66.
Lucarelli MJ, Ceisler EJ, Talamo JH, et al. Complex choristoma. Arch
Ophthalmol 1996;114:498–499.
Melki TS, Zimmerman LE, Chavis RM, et al. A unique epibulbar osseous
choristoma. J Pediatr Ophthalmol Strabismus 1990;27:252–254.
Oakman JH Jr, Lambert SR, Grossniklaus HE. Corneal dermoid: case report and
review of classification. J Pediatr Ophthalmol Strabismus 1993;30:388–391.
Pittke EC, Marquardt R, Mohr W. Cartilage choristoma of the eye. Arch
Ophthalmol 1983;101:1569–1571.
Pokorny KS, Hyman BM, Jakobiec FA, et al. Epibulbar choristomas containing

158
 lacrimal tissue. Clinical distinction from dermoids and histologic evidence of
an origin from the palpebral lobe. Ophthalmology 1987;94:1249–1257.
Roth DB, Shields JA, Shields CL, et al. Lacrimal gland choristoma of the
conjunctiva simulating a squamous cell carcinoma. J Pediatr Ophthalmol
Strabismus 1994;31:62–64.
Shields JA, Eagle RC, Shields CL, et al. Epibulbar osseous choristoma.
Computed tomography and clinicopathologic correlation. Ophthalmic
Practice 1997;15:110–112.
Shields JA, Shields CL, Eagle RC Jr, et al. Ophthalmic features of the organoid
nevus syndrome. Trans Am Ophthalmol Soc 1996;94:65–86.
Sugar HS. The oculoauriculo-vertebral syndrome of Goldenhar. Am J Ophthalmol
1966;62:678–682.

Conjunctivitis
Allansmith MR, Baird RS, Greiner JV. Vernal conjunctivitis and contact lens-
associated giant papillary conjunctivitis compared and contrasted. Am J
Ophthalmol 1979;87:544–555.
Dawson CR, Jones BR, Tarizzo ML. Guide to Trachoma Control. Geneva: World
Health Organization, 1981:7.
Eagle RC Jr, Brooks SJS, Katowitz JA, et al. Fibrin as a major constituent of
ligneous conjunctivitis. (Letter.) Am J Ophthalmol 1986;101:493.
Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy
1995;50:6–9; discussion 34–38.
Hidayat AA, Riddle PJ. Ligneous conjunctivitis. A clinicopathologic study of 17
cases. Ophthalmology 1987;94:949–959.
Leonardi A. Vernal keratoconjunctivitis: pathogenesis and treatment. Prog Retin
Eye Res 2002;21:319–339.
MacCallan AF. The epidemiology of trachoma. Br J Ophthalmol
1931;15:369–411.
Michel CE, Solomon AW, Magbanua JP, et al. Field evaluation of a rapid point-
of-care assay for targeting antibiotic treatment for trachoma control: a
comparative study. Lancet 2006;367(9522): 1585–1590.
Schuster V, Mingers AM, Seidenspinner S, et al. Homozygous mutations in the
plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood
1997;90:958–966.
Trocme SD, Kephart GM, Allansmith MR, et al. Conjunctival deposition of
eosinophil granule major basic protein in vernal keratoconjunctivitis and
contact lens-associated giant papillary conjunctivitis. Am J Ophthalmol
1989;108:57–63.

Granulomatous Conjunctivitis
Bergmans AM, Groothedde JW, Schellekens JF, et al. Etiology of cat scratch

159
 disease: comparison of polymerase chain reaction detection of Bartonella
(formerly Rochalimaea) and Afipia felis DNA with serology and skin tests. J
Infect Dis 1995;171:916–923.
Lee WR, Chawla JC, Reid R. Bacillary angiomatosis of the conjunctiva. Am J
Ophthalmol 1994;118:152–157.
Margo CE, Hamed LM. Ocular syphilis. Surv Ophthalmol 1992;37:203–220.
Nichols CW, Eagle RC Jr, Yanoff M, et al. Conjunctival biopsy as an aid in the
evaluation of the patient with suspected sarcoidosis. Ophthalmology
1980;87:287–291.
Obenauf CD, Shaw HE, Wyndor CF, et al. Sarcoidosis and its ocular
manifestations. Am J Ophthalmol 1978;86:648–655.
Spektor FE, Eagle RC Jr, Nichols CW. Granulomatous conjunctivitis secondary
to Treponema pallidum. Ophthalmology 1981;88: 863–865.
Wear DJ, Raga HM, Zimmerman LE, et al. Cat scratch disease bacilli in the
conjunctiva of patients with Parinaud’s oculoglandular syndrome.
Ophthalmology 1985;92:1282–1287.
Weinberg JC, Eagle RC Jr, Font RL, et al. Conjunctival synthetic fiber
granuloma: a lesion that resembles conjunctivitis nodosa. Ophthalmology
1984;91:867–872.

Parasitic and Mycotic Infections

Ashton N, Cook C. Allergic granulomatous nodules of the eyelid and conjunctiva.
The XXXV Edward Jackson Memorial Lecture. Am J Ophthalmol
1978;87:1–28
Connor DH, Neafie RC, Meyers WM. Loiasis. In: Binford CH, Connor DH, eds.
Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed
Forces Institute of Pathology, 1976.
Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment of microsporidial
keratoconjunctivitis with topical fumagillin. Am J Ophthalmol
1993;115:293–298.
Friedberg DN, Stenson SM, Orenstein JM, et al. Microsporidial
keratoconjunctivitis is acquired immunodeficiency syndrome. Arch
Ophthalmol 1990;108:504–508.
Reidy JJ, Sudesh S, Klafter AB, et al. Infection of the conjunctiva by
Rhinosporidium seeberi. Surv Ophthalmol 1997;41:409–413.
Ruggli GM, Weber R, Messmer EP, et al. Pneumocystis carinii infection of the
conjunctiva in a patient with acquired immune deficiency syndrome.
Ophthalmology 1997;104:1853–1856.

Ocular Cicatricial Pemphigoid

Mondino BJ, Ross AN, Rabin BS. Autoimmune phenomena in ocular cicatricial
pemphigoid. Am J Ophthalmol 1977;83:443–450.

160
Power WJ, Neves RA, Rodriguez A, et al. Increasing the diagnostic yield of
conjunctival biopsy in patients with suspected ocular cicatricial pemphigoid.
Ophthalmology 1995;102:1158–1163.
Rashid KA, Foster CS, Ahmed AR. Identification of epitopes within integrin β4
for binding of auto-antibodies in ocular cicatricial and mucous membrane
pemphigoid: preliminary report. Invest Ophthalmol Vis Sci
2013;54(12):7707–16.
Sacks EH, Jakobiec FA, Wieczorek R, et al. Immunophenotypic analysis of the
inflammatory infiltrate in ocular cicatricial pemphigoid: further evidence for a
T cell-mediated disease. Ophthalmology 1989;96:236–243
Tyagi S, Bhol K, Natarajan K, et al. Ocular cicatricial pemphigoid antigen: partial
sequence and biochemical characterization. Proc Natl Acad Sci U S A
1996;93:14714–14719.

Amyloidosis
Blodi FC, Apple DJ. Localized conjunctival amyloidosis. Am J Ophthalmol
1979;88:346–350.
Demirci H, Shields CL, Eagle RC Jr, et al. Conjunctival amyloidosis: report of six
cases and review of the literature. Surv Ophthalmol 2006;51:419–433.
Knowles DM, Jakobiec FA, Rosen M, et al. Amyloidosis of the orbit and
adnexae. Surv Ophthalmol 1975;19:367–384.
O’Donnell B, Wuebbolt G, Collin R. Amyloidosis of the conjunctiva. Aust N Z J
Ophthalmol 1995;23:207–212.

Conjunctival Tumors
Grossniklaus HE, Green WR, Luckenbach M, et al. Conjunctival lesions in adults.
A clinical and histopathologic review. Cornea 1987;6:78–116.
McLean IW, Burnier MN, Zimmerman LE, et al. Tumors of the Eye and Ocular
Adnexa, Atlas of Tumor Pathology, Third Series, Fascicle 12. Washington,
DC: Armed Forces Institute of Pathology, 1994.
Seitz B, Fischer M, Holbach LM, et al. Differential diagnosis and prognosis of
112 excised epibulbar epithelial tumors. Klin Monbl Augenheilkd
1995;207:239–246.
Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and
nonmelanocytic conjunctival tumors. Ophthalmology 2004;111:1747–1754.
Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol
2004;49:3–24.
Shields CL, Shields JA. Conjunctival tumors in children. Curr Opin Ophthalmol
2007;18:351–360.
Shields JA, Shields CL, De Potter P. Surgical management of conjunctival
tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol
1997;115(6):808–815.

161
Squamous Epithelial Lesions
Brown HH, Glasgow BJ, Holland GN, et al. Keratinizing corneal intraepithelial
neoplasia. Cornea 1989;8:220–224.
Cohen B, Green WR, Iliff N, et al. Spindle cell carcinoma of the conjunctiva.
Arch Ophthalmol 1980;98:1809–1813.
Erie JC, Liesegang TJ, Campbell RJ. Conjunctival and corneal intraepithelial
neoplasia: experience at the Mayo Clinic 1920–1983. Ophthalmology
1986;93:176–183.
Galor A, Garg N, Nanji A, et al. Human papilloma virus infection does not
predict response to interferon therapy in ocular surface squamous neoplasia.
Ophthalmology 2015;122(11):2210–2215.
Gichuhi S, Ohnuma S, Sagoo MS, et al. Pathophysiology of ocular surface
squamous neoplasia. Exp Eye Res 2014;129:172–182.
Illif WF, Marbeck R, Green WR. Invasive squamous cell carcinoma of the
conjunctiva. Arch Ophthalmol 1975;93:119–122.
Kapur R, Sugar J, Edward DP. Conjunctival mucoepidermoid carcinoma: clear
cell variant. Arch Ophthalmol 2005;123:1265–1268.
Lass JH, Grove AS, Papale JJ, et al. Detection of human papillomavirus DNA
sequences in conjunctival papillomas. Am J Ophthalmol 1983;95:670–674.
Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol
1995;39:429–450.
Manderwad GP, Kannabiran C, Honavar SG, et al. Lack of association of high-
risk human papillomavirus in ocular surface squamous neoplasia in India.
Arch Pathol Lab Med 2009;133(8): 1246–1250.
Mauriello JA Jr, Napolitano J, McLean I. Actinic keratosis and dysplasia of the
conjunctiva: a clinicopathological study of 45 cases. Can J Ophthalmol
1995;30:312–316.
McDonnell JM, McDonnell PJ, Sun YY. Human papillomavirus DNA in tissues
and ocular surface swabs of patients with conjunctival epithelial neoplasia.
Invest Ophthalmol Vis Sci 1992;33:184–189.
Nanji AA, Moon CS, Galor A, et al. Surgical versus medical treatment of ocular
surface squamous neoplasia: a comparison of recurrences and complications.
Ophthalmology 2014;121(5):994–1000.
Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface
squamous neoplasia. Curr Opin Ophthalmol 2013;24(4):336–342.
Odrich MG, Jakobiec FA, Lancaster WD, et al. A spectrum of bilateral squamous
conjunctival tumors associated with human papillomavirus type 16.
Ophthalmology 1991;98:628–635.
Pizzarello LD, Jakobiec FA. Bowen’s disease of the conjunctiva: a misnomer. In:
Jakobiec FA, ed. Ocular and Adnexal Tumors. Birmingham, AL: Aesculapius,
1978:553–571.
Rao NA, Font RL. Mucoepidermoid carcinoma of the conjunctiva: a
clinicopathologic study of five cases. Cancer 1976;38:1699–1709.

162
Schubert HD, Farris RL, Green WR. Spindle cell carcinoma of the conjunctiva.
Graefes Arch Clin Exp Ophthalmol 1995;233:52–53.
Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous
neoplasia in 81 cases: outcomes based on the American Joint Committee on
Cancer classification. Cornea 2013;32(3):248–256.
Sjo NC, Heegaard S, Prause JU, et al. Human papillomavirus in conjunctival
papilloma. Br J Ophthalmol 2001;85(7):785–787.
Waring GO, Roth AM, Ekins MB. Clinical and pathologic description of 17 cases
of corneal intraepithelial neoplasia. Am J Ophthalmol 1984;97:547–559.
Woods M, Chow S, Heng B, et al. Detecting human papillomavirus in ocular
surface diseases. Invest Ophthalmol Vis Sci 2013;54(13):8069–8078.

Melanocytic Lesions
Brownstein S, Jakobiec FA, Wilkinson RD, et al. Cryotherapy for precancerous
melanosis (atypical melanocytic hyperplasia) of the conjunctiva. Arch
Ophthalmol 1981;99:1224–1231.
Busam KJ, Chen YT, Old LJ, et al. Expression of melan-A (MART1) in benign
melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg
Pathol 1998;22:976–982.
Busam KJ, Fang Y, Jhanwar SC, et al. Distinction of conjunctival melanocytic
nevi from melanomas by fluorescence in situ hybridization. J Cutan Pathol
2010;37(2):196–203.
Chowers I, Livni N, Solomon A, et al. MIB-1 and PC-10 immunostaining for the
assessment of proliferative activity in primary acquired melanosis without and
with atypia. Br J Ophthalmol 1998;82(11):1316–1319.
Damato B, Coupland SE. Clinical mapping of conjunctival melanomas. Br J
Ophthalmol 2008;92:1545–1549.
Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of
terminology, classification and staging. Clin Experiment Ophthalmol
2008;36:786–795.
Damato B, Coupland SE. An audit of conjunctival melanoma treatment in
Liverpool. Eye (Lond) 2009;23:801–809.
De Potter P, Shields CL, Shields JA, et al. Clinical predictive factors for
development of recurrence and metastasis in conjunctival melanoma: a review
of 68 cases. Br J Ophthalmol 1993;77:624–630.
Dutton JJ, Anderson RL, Schelper RL, et al. Orbital malignant melanoma and
oculodermal melanocytosis. Report of two cases and a review of the literature.
Ophthalmology 1984;91:497–507.
Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic
lesions: clinicopathologic features. Ophthalmology 1989;96:436–461.
Folberg R, Jakobiec FA, McLean IW, et al. Is primary acquired melanosis of the
conjunctiva equivalent to melanoma in situ? Mod Pathol 1992;5:2–5;
discussion 6–8.

163
Folberg R, McLean IW. Primary acquired melanosis and melanoma of the
conjunctiva: terminology, classification, and biologic behavior. Hum Pathol
1986;17(7):652–654.
Folberg R, McLean IW, Zimmerman LE. Conjunctival melanosis and melanoma.
Ophthalmology 1984;91(6):673–678.
Folberg R, McLean IW, Zimmerman LE. Primary acquired melanosis of the
conjunctiva. Hum Pathol 1985;16(2):129–135.
Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the
conjunctiva. Hum Pathol 1985;16(2):136–143.
Furusato E, Hidayat AA, Man YG, et al. WT1 and Bcl2 expression in
melanocytic lesions of the conjunctiva: an immunohistochemical study of 123
cases. Arch Ophthalmol 2009;127(8):964–969.
Jakobiec FA. The ultrastructure of conjunctival melanocytic tumors. Trans Am
Ophthalmol Soc 1984;82:599–752.
Jakobiec FA. Conjunctival primary acquired melanosis: is it time for a new
terminology? Am J Ophthalmol 2016;162:3–19.e1.
Jakobiec FA, Bhat P, Colby KA. Immunohistochemical studies of conjunctival
nevi and melanomas. Arch Ophthalmol 2010;128: 174–183.
Jakobiec FA, Colby K, Bajart AM, et al. Immunohistochemical studies of atypical
conjunctival melanocytic nevi. Arch Ophthalmol 2009;127:970–980.
Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of
premalignant and malignant melanocytic lesions of the conjunctiva.
Ophthalmology 1989;96:147–166.
Jakobiec FA, Rini FJ, Fraunfelder FT, et al. Cryotherapy for conjunctival primary
acquired melanosis and malignant melanoma. Ophthamology
1988;95:1058–1070.
Jay V, Font RL. Conjunctival amelanotic malignant melanoma arising in primary
acquired melanosis sine pigmento. Ophthamology 1998;105(1):191–194.
Larsen AC, Dahmcke CM, Dahl C, et al. A retrospective review of conjunctival
melanoma presentation, treatment, and outcome and an investigation of
features associated with BRAF mutations. JAMA Ophthalmol
2015;133:1295–1303.
Liesegang TJ. Pigmented conjunctival and scleral lesions. Mayo Clin Proc
1994;69:151–161.
Liesegang TJ, Campbell RJ. Mayo Clinic experience with conjunctival
melanomas. Arch Ophthalmol 1980;98:1385–1389.
McDonnell JM, Sun YY, Wagner D. HMB-45 immunohistochemical staining of
conjunctival melanocytic lesions. Ophthalmology 1991;98:453–458.
Mudhar HS, Smith K, Talley P, et al. Fluorescence in situ hybridisation (FISH) in
histologically challenging conjunctival melanocytic lesions. Br J Ophthalmol
2013;97:40–46.
Paridaens AD, McCartney AC, Hungerford JL. Multifocal amelanotic
conjunctival melanoma and acquired melanosis sine pigmento. Br J
Ophthalmol 1992;76:163–165.

164
Paridaens AD, Minassian DC, McCartney AC, et al. Prognostic factors in primary
malignant melanoma of the conjunctiva: a clinicopathological study of 256
cases. Br J Ophthalmol 1994;78:252–259.
Seregard S, Kock E. Conjunctival malignant melanoma in Sweden 1969–91. Acta
Ophthalmol (Copenh) 1992;70(3):289–296.
Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and
nonmelanocytic conjunctival tumors. Ophthalmology 2004;111:1747–1754.
Shields CL, Fasiuddin AF, Mashayekhi A, et al. Conjunctival nevi: clinical
features and natural course in 410 consecutive patients. Arch Ophthalmol
2004;122:167–175.
Shields CL, Kaliki S, Al-Dahmash SA, et al. American Joint Committee on
Cancer (AJCC) clinical classification predicts conjunctival melanoma
outcomes. Ophthal Plast Reconstr Surg 2012;28(5):313–323.
Shields CL, Markowitz JS, Belinsky I, et al. Conjunctival melanoma: outcomes
based on tumor origin in 382 consecutive cases. Ophthalmology
2011;118:389–395.e381–382.
Shields CL, Regillo AC, Mellen PL, et al. Giant conjunctival nevus: clinical
features and natural course in 32 cases. JAMA Ophthalmol
2013;131(7):857–863.
Shields CL, Shields JA. Conjunctival tumors in children. Curr Opin Ophthalmol
2007;18:351–360.
Shields CL, Shields JA. Conjunctival primary acquired melanosis and melanoma:
tales, fairy tales, and facts. Ophthal Plast Reconstr Surg 2009;25:167–172.
Shields CL, Shields JA, Gündüz K, et al. Conjunctival melanoma: risk factors for
recurrence, exenteration, metastasis, and death in 150 consecutive patients.
Arch Ophthalmol 2000;118:1497–1507.
Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the
conjunctiva: risks for progression to melanoma in 311 eyes: the 2006 Lorenz
E. Zimmerman Lecture. Ophthalmology 2007;115:511–519.
Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the
conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz
E. Zimmerman lecture. Ophthalmology 2008;115:511–519.e2.
Sugiura M, Colby KA, Mihm MC Jr, et al. Low-risk and high-risk histologic
features in conjunctival primary acquired melanosis with atypia:
clinicopathologic analysis of 29 cases. Am J Surg Pathol 2007;31:185–192.
Yu GP, Hu DN, McCormick S, et al. Conjunctival melanoma: is it increasing in
the United States? Am J Ophthalmol 2003;135(6):800–806.
Zembowicz A, Mandal RV, Choopong P. Melanocytic lesions of the conjunctiva.
Arch Pathol Lab Med 2010;134(12):1785–1792.

Lymphoid Lesions
Cohen VM, Sweetenham J, Singh AD. Ocular adnexal lymphoma. What is the
evidence for an infectious aetiology? Br J Ophthalmol 2008;92:446–448.

165
Coupland SE, Damato B. Lymphomas involving the eye and the ocular adnexa.
Curr Opin Ophthalmol 2006;17:523–531.
Coupland SE, Krause L, Delecluse HJ, et al. Lymphoproliferative lesions of the
ocular adnexa. Analysis of 112 cases. Ophthalmology 1998;105:1430–1441.
Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study
of 353 cases. Am J Surg Pathol 2007;31:170–184.
Jakobiec FA. Ocular adnexal lymphoid tumors: progress in need of clarification.
Am J Ophthalmol 2008;145:941–950.
Knowles DM, Jakobiec FA, McNally L, et al. Lymphoid hyperplasia and
malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and
eyelids): a prospective multiparametric analysis of 108 cases during 1977 to
1987. Hum Pathol 1990;21:959–973.
Margo CE. Orbital and ocular adnexal lymphoma: evolving concepts. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.
Ophthalmol Clin North America 1995;8:167–177.
Medeiros LJ. Harris NL. Immunohistologic analysis of small lymphocytic
infiltrates of the orbit and conjunctiva. Hum Pathol 1990;21:1126–1131.
Shields CL, Shields JA, Carvalho C, et al. Conjunctival lymphoid tumors: clinical
analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology
2001;108(5):979–984.
Verma V, Shen D, Sieving PC, et al. The role of infectious agents in the etiology
of ocular adnexal neoplasia. Surv Ophthalmol 2008;53(4):312–331.

Miscellaneous Lesions
Kiratli H, Shields CL, Shields JA, et al. Metastatic tumours to the conjunctiva:
report of 10 cases. Br J Ophthalmol 1996;80:5–8.
Margo CE, Grossniklaus HE. Intraepithelial sebaceous neoplasia without
underlying invasive carcinoma. Surv Ophthalmol 1995;39:293–301.

Tumors of the Caruncle

Chang WJ, Nowinski TS, Eagle RC. A large oncocytoma of the caruncle. Arch
Ophthalmol 1995;113:382.
Hirsch C, Holz FG, Tetz M, et al. Clinical aspects and histopathology of
caruncular tumors. Klin Monbl Augenheilkd 1997;210: 153–157.
Massry GG, Holds JB, Kincaid MC, et al. Sebaceous gland hyperplasia of the
caruncle. Ophthal Plast Reconstr Surg 1995;11:32–36.
Rodman RC, Frueh BR, Elner VM. Mucoepidermoid carcinoma of the caruncle.
Am J Ophthalmol 1997;123:564–565.
Shields CL, Shields JA, White D, et al. Survey of lesions of the caruncle. Trans
Pa Acad Ophthalmol Otolaryngol 1986;38:528–534.

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 6 Cornea and Sclera
CORNEAL HISTOLOGY
The cornea is the principal refractive element of the eye (Fig. 1-8). Its
anterior surface is covered by a layer of nonkeratinized stratified squamous
epithelium five or six cells in thickness. The inconspicuous basement
membrane of the epithelium rests on the Bowman membrane, a feltwork of
modified stroma. The bulk of the cornea is composed of paucicellular
collagenous stroma that contains keratocytes and artifactual clefts. The
posterior surface of the cornea is lined by the corneal endothelial cells.
This delicate monolayer of cells rests on a thick PAS-positive basement
membrane called the Descemet membrane, which it secretes.

DEVELOPMENTAL ANOMALIES
The corneal epithelium is derived embryologically from surface ectoderm.
The corneal endothelium and stroma are derived from successive waves of
migrating neural crest cells.
Developmental anomalies of the cornea include microcornea, defined
as <11 mm in greatest diameter, and megalocornea, which is >13 mm.
Cornea plana is a bilateral familial trait (autosomal dominant or recessive)
characterized by corneal flattening and peripheral opacification. The
autosomal recessive variant is caused by mutations in the gene for
keratocan. The cornea in sclerocornea resembles sclera. The epithelium is
thickened, the Bowman membrane is absent, and the anterior third of the
stroma is scarred and vascularized. Solid dermoids and complex
choristomas are discussed in Chapter 5.
The Axenfeld-Rieger syndrome is a spectrum of developmental
anomalies that affects the peripheral cornea, the iris, and the angle and has
associated systemic findings. In the past, the terms angle cleavage
syndrome and mesodermal dysgenesis were commonly applied to this

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disorder. Axenfeld-Rieger syndrome is important because about half of
affected patients develop glaucoma. Prominence and anterior displacement
of the Schwalbe line into clear cornea, which is called posterior
embryotoxon of Axenfeld, occurs in many patients (Fig. 6-1). Processes of
iris stroma often bridge the angle and insert onto the posterior
embryotoxon (Axenfeld anomaly). Patients may have iris stromal
abnormalities including hypoplasia and slit, multiple (polycoria), and false
pupils (pseudocoria). Posterior embryotoxon is a common finding in
Alagille syndrome (Fig. 6-1D,E).

FIG. 6-1. Posterior embryotoxon. A. Prominent, anteriorly displaced line

parallels limbus in clinical photo. B. Posterior embryotoxon is seen as ridge
separating corneal endothelium and trabecular meshwork in scanning electron
micrograph of infant eye. Ruptured iris processes bridge angle to embryotoxon.
C. Large oval mound of connective tissue is interposed between the end of
Descemet membrane (Schwalbe line) and the trabecular meshwork. This infant
had multiple anterior segment anomalies. D. Posterior embryotoxon in seen as a
relucent ridge (arrow) in postmortem eye from a patient with Alagille syndrome.
E. In cross section, embryotoxon appears as collagenous nodule (inset) at
anterior border of trabecular meshwork. (B. SEM ×20, C. H&E ×50, E. H&E
×25, inset ×100.)

Axenfeld/Rieger syndrome is inherited as an autosomal dominant trait.

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Mutations in the FOXC1, PITX2, and RIEG2 genes have been found in the
syndrome. Affected patients can have developmental defects of the face
(maxillary hypoplasia) and teeth (anodontia, oligodontia, microdontia and
peg-like incisors) and redundant periumbilical skin. Shields have
postulated that the ocular abnormalities in Axenfeld-Rieger syndrome are
consistent with a developmental arrest, occurring late in gestation, of
certain anterior ocular structures derived from neural crest.
Congenital corneal opacities occur in Peters anomaly, a developmental
anomaly characterized by a concave defect in the central cornea that
includes posterior stroma, Descemet membrane, and endothelium (Fig. 6-
2). Histopathology shows a central concave defect in the posterior corneal
stroma that often contains abnormal thickened lamellae. The endothelium
and Descemet membrane are absent within the posterior ulcer, and there is
a corresponding area of stromal edema and opacification. The Bowman
layer may be thickened or absent. The crystalline lens adheres to or is
incarcerated within the posterior ulcer in some cases of Peters anomaly
(Fig. 6-2C,D), and iridocorneal adhesions often insert into the periphery of
the posterior corneal defect. Peters anomaly can be caused by mutations in
PAX6, PITX2, CYP1B1, or FOXC1 genes and also occurs in fetal alcohol
syndrome.

FIG. 6-2. Peters anomaly. A. Bands of iris stroma insert into the margin of a

169
 central corneal opacity forming iridocorneal adhesions. The lens was adherent to
the posterior cornea centrally. Both eyes were affected. (Photo courtesy of Dr.
Irving Raber, Wills Eye Hospital.) B. The endothelium and Descemet membrane
are absent in the region of a central “posterior ulcer.” Arrow denotes the
Descemet membrane at margin. The collagenous lamellae of the posterior stroma
are thickened and irregular. The Bowman membrane is absent, and the epithelium
is mildly thickened. A central corneal opacity was present clinically. C.
Keratolenticular adhesion. Lens adheres to large defect in center of cornea. D.
Peters anomaly with keratolenticular adhesion in child with fetal alcohol
syndrome. The cataractous crystalline lens adheres to a posterior ulcer in the
central cornea. The iris also attaches to the margin of the ulcer. (Case courtesy of
Dr. Nongnart Chan, Philadelphia, PA.) (B. H&E ×50, C. H&E ×10, D. H&E
×25.)

This spectrum of developmental anomalies includes the posterior ulcer of

von Hippel and posterior keratoconus. A concave defect in the posterior
cornea is lined by the Descemet membrane and endothelium in posterior
keratoconus. Caused by mutations in the B3GALTL gene, autosomal
recessively inherited Peters plus syndrome includes Peters anomaly plus
short stature, developmental delay, and lip abnormalities.
About 45% of patients with aniridia develop a progressive keratopathy
that has characteristic histopathologic features. Probably related to limbal
stem cell (LSC) deficiency, the keratopathy includes conjunctival
metaplasia of the corneal epithelium with goblet cells and an inflamed
vascularized pannus (Fig. 6-3).

FIG. 6-3. Aniridia keratopathy. A. Periphery of lens in aniridic patient is visible

in red reflex through focally hazy cornea. B. Diffuse subepithelial haze and
vascularization are better seen with direct illumination. C, D. Histopathology of
corneal button shows irregular epithelium and subepithelial vessels consistent
with stem cell deficiency. D. Arrow denotes goblet cell in corneal epithelium. (C.
H&E ×100, D. PAS ×100.)

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CORNEAL INFLAMMATION
Acute Keratitis and Corneal Ulceration
The anterior surface of the cornea is an interface between the eye and the
external environment. Mechanisms that protect the cornea from infection
include the protective barrier of the corneal epithelium, mucous strands
secreted by conjunctival goblet cells that can ensnare microorganisms, and
tears that can wash them away. In addition, the tears contain natural
antimicrobial substances such as lactoferrin, lysozyme, and antibodies.
The latter are made by lymphocytes and plasma cells that are a constant
finding in the stroma of the conjunctiva and the parenchyma of the
lacrimal gland.
Normally, these mechanisms are remarkably effective. Corneal
infection usually develops when these protective mechanisms are
compromised, for example, when a contaminated foreign body perforates
the epithelium and inoculates the corneal stroma, or when the epithelium is
abraded or damaged by chronic bullous keratopathy. Finally, a few
organisms, most notably Neisseria gonorrhoeae, have the ability to invade
through an intact epithelium.
Infiltration of the stroma by polymorphonuclear leukocytes occurs in
acute bacterial keratitis (Fig. 6-4C). The polys collect in the clefts between
adjacent stromal lamellae. Digestive enzymes released by the dying
inflammatory cells cause stromal necrosis, which has a smudged
basophilic appearance in routine H&E sections. Collagenase made by the
corneal epithelium may contribute to dissolution of the stroma. Organisms
such as Pseudomonas also produce potent enzymes that contribute to
corneal destruction. Pseudomonas keratitis is characterized by marked
stromal edema and dissolution and rapid corneal perforation. The infection
can also spread posteriorly into the sclera as a sclerokeratitis (Fig. 6-5).

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FIG. 6-4. Acute keratitis. A. Clinical photo of acute keratitis with ulceration and
hypopyon. B. Anterior chamber deep to corneal ulcer contains hypopyon. Iris is
flattened by neovascular membrane. C. Acute keratitis. Polymorphonuclear
leukocytes and inflammatory debris fill clefts between the stromal lamellae.
Many polys have pyknotic nuclei, and early stromal necrosis is present. D.
Descemetocele, acute keratitis. An intact layer of the Descemet membrane
persists in the bed of deep corneal ulcer. The anterior layers of the cornea have
been destroyed by inflammation. (B. H&E ×25, C. H&E ×100, D. H&E ×50.)

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FIG. 6-5. Pseudomonas sclerokeratitis. Pseudomonas keratitis often extends
posteriorly as an infectious scleritis. The acutely inflamed cornea (at right)
appears blue reflecting necrosis and heavy infiltration by polys. Proteolytic
enzymes released by the gram-negative rods have dissolved the limbal sclera. The
angle is closed. (H&E ×20.)

The epithelium, the Bowman membrane, and the anterior stroma are lost in
corneal ulcer (Fig. 6-4B). Corneal perforation results when the infection
destroys the entire thickness of the stroma. Occasionally, a bulging dome
of intact, elastic membrane called a descemetocele persists in the floor of
the incipient perforation (Fig. 6-4B). Polymorphonuclear leukocytes
collect in the lower part of the anterior chamber as a hypopyon and also
typically adhere to the posterior cornea directly beneath the ulcer. The
endothelium is often damaged. The tissue Gram stain may disclose myriad
microorganisms in the infected cornea or none at all. Bacteria are often
found in relatively noninflamed parts of the stroma bordering the
inflammatory infiltrate. Perforation or impending perforation of the cornea
is an indication for emergent penetrating keratoplasty (corneal
transplantation). Cyanoacrylate tissue adhesive often is used to seal
corneal perforations. Although the “crazy glue” is lost during processing,
its presence is disclosed by a telltale scalloped pattern on the anterior
corneal surface.
Infectious crystalline keratopathy (Fig. 6-6) usually is caused by

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avirulent strains of Streptococci, which proliferate in the relatively
noninflamed stroma forming large interlamellar bacterial colonies that
have a vaguely crystalline configuration on biomicroscopy. This relatively
rare disorder typically occurs in corneal grafts after chronic therapy with
corticosteroids. The bacterial colonies are sequestered by a glycocalyx
whose formation is stimulated by the steroids. Infectious crystalline
keratopathy is also caused by other organisms including the yeast Candida
parapsilosis. Cases of concurrent infectious crystalline keratopathy and
acanthamoebic keratiits have been reported.

FIG. 6-6. Infectious pseudocrystalline keratopathy. A. Macrophoto shows

radiating crystalline appearance of bacterial colony in cornea. B. Large basophilic
colonies of relatively avirulent Streptococci distend interlamellar clefts in
relatively noninflamed part of the corneal stroma. C. Bacteria are gram positive.
(B. H&E ×100, C. Tissue Gram stain ×250.)

Fungal keratitis (Figs. 6-7 and 6-8) is rarer than bacterial keratitis, is more
prevalent in the warm climates, and often complicates corneal injuries by
vegetable matter or steroid therapy in debilitated hosts. Eighty percent of
corneal ulcers in the United States are caused by Fusarium, Aspergillus, or
Candida species. Clinically, fungal ulcers often have a deep crater with
raised edges and may have smaller satellite lesions. The fungal hyphae
readily permeate the stroma and can perforate the Descemet membrane
and invade the anterior chamber placing the patient at risk for fungal
endophthalmitis (Fig. 6-7D,E). Yeast infection can occur in the cleft after
DSEK surgery (Fig. 6-8).

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FIG. 6-7. Fungal keratitis. A. Periodic acid–Schiff stain discloses numerous
hyphae in midstroma, seen at higher magnification in figure B. The corneal
epithelium is absent. A hypopyon adheres to the posterior cornea. C. Deep
hyphae, fungal keratitis. The corneal epithelium and the anterior stroma are
absent in the ulcerated area at left. Arrow points to GMS-stained hyphae in the
deep stroma near the Descemet membrane. Hyphae are seen at higher
magnification in inset. A superficial scraping of the ulcer bed was negative for
fungus. D. PAS-positive septate fungal hypha perforates the Descemet membrane
invades the anterior chamber, which contains polymorphonuclear leukocytes. E.
Scanning electron micrographs show branching fungal hyphae that have invaded
the anterior chamber. (A. PAS ×25, B. PAS ×250, C. Gomori methenamine silver
×50; Inset, GMS ×100, D. PAS ×250, E. SEM ×640.)

FIG. 6-8. Acute keratitis secondary to Candida after DSEK. A. Cleft between
host cornea and detached endothelial graft contains mass of polymorphonuclear

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 leukocytes. Stroma of the cornea and graft are mildly inflamed. B, C. Yeast
forms and pseudomycelia consistent with Candida species are seen in cleft
(above) and inflamed stroma of DSEK graft. (A. H&E ×25, nB, PAS ×100, C.
PAS ×400.)

Fungi may not be detected in superficial smears or scrapings because the

hyphae are often found deep in the bed of the ulcer or in the relatively
viable stroma of the ulcer wall (Fig. 6-7C). Hence, corneal biopsy may be
required to establish the diagnosis. Fungi and yeast are best shown by the
PAS stain or special stains for fungus such as the Gomori methenamine
silver (GMS) impregnation stain. The calcofluor white stain is nonspecific
and currently is no longer available in many centers. Mycobacterium
tuberculosis, M. leprae, and several strains of atypical mycobacteria such
as M. chelonae rarely cause corneal infection. Special stains for acid-fast
organisms and microbiological cultures are used to diagnose mycobacterial
keratitis. The diagnosis is often unsuspected and is frequently delayed.
Numerous microorganisms are often found in atypical mycobacterial
infection.

VIRAL KERATITIS
Herpes simplex virus (HSV) keratitis (Fig. 6-9) is the most common
corneal infection that causes visual loss in the United States and Europe.
Most cases of herpetic keratitis are caused by HSV type I, which causes
infection above the waist. The classic clinical manifestation of early ocular
herpesvirus infection is dendritic keratitis, a superficial ulcerating infection
of the corneal epithelium that has a characteristic branching configuration
(Fig. 6-9A). Viral cultures are positive in 75% of cases, and smears show
Cowdry type A intranuclear viral inclusions in the infected epithelial cells.
The primary epithelial infection tends to be self-limited lasting 7 to 10
days with complete recovery and disappearance of the virus from the
primary site of infection. However, recurrences are quite common because
the virus remains in a latent state in the trigeminal ganglion where its DNA
has been incorporated into the genome of the neurons. Poorly understood
trigger mechanisms reactivate the virus, which travels down the sensory
nerve to cause overt recurrent disease. One in four cases of primary HSV
keratitis recurs. The recurrence rate rises to 50% after an initial recurrence.

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 FIG. 6-9. Herpes simplex keratitis. A. HSV dendritic keratitis. Branching herpes
simplex viral dendrite is full-thickness ulceration with terminal bulbs. Dendrite is
stained with fluorescein dye. B. VZV dendritic keratitis. Dendritiform lesions of
varicella-zoster keratitis are composed of heaped-up epithelium. (Both photos
courtesy of Dr. Peter Laibson, Wills Eye Hospital.) C. Chronic herpetic stromal
keratitis. The stroma is thin, scarred, and chronically inflamed. The inflammatory
infiltrate contains lymphocytes, plasma cells, and epithelioid histiocytes. The
Bowman membrane is largely destroyed and the epithelium is irregularly
thickened. The Descemet membrane is folded. D, E. Giant cell reaction to the
Descemet membrane, chronic HSV keratitis. Although characteristic, this finding
is not pathognomonic for HSV. F. Compensatory epithelial hyperplasia, chronic
HSV keratitis. The epithelium is markedly thickened overlying an area of stroma
loss. The Bowman membrane persists in the area of stromal thinning. (C. H&E
×50, D. H&E ×100, E. H&E ×250, F. H&E ×50.)

A more serious, potentially blinding form of ocular herpesvirus infection

affects the corneal stroma. Although the pathogenesis of herpes stromal
keratitis is not entirely understood, an immunological response to viral
antigens shed from infected corneal epithelial or endothelial cells probably
is basis for nonulcerative HSV disciform keratitis. The necrotizing form of
HSV stromal keratitis actually may involve viral invasion and low-grade
replication in the stroma.
Light microscopy of corneal buttons with chronic herpes stromal
keratitis typically reveals scarring and vascularization of the stroma and

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infiltration by chronic inflammatory cells (Fig. 6-9C). The presence of
lymphocytes, plasma cells, and histiocytes in the inflammatory infiltrate in
many cases provides evidence for an immunological response. The
inflammatory infiltrate frequently includes epithelioid histiocytes. These
can occur anywhere in the stroma, but they characteristically coalesce to
form giant cells near the Descemet membrane (Fig. 6-9D,E). A giant cell
reaction to the Descemet membrane is not pathognomonic for chronic
HSV keratitis, but it is highly suggestive. In many cases, there is thinning
and scarring of the chronically inflamed cornea with loss of the Bowman
membrane and anterior stroma. Progressive stromal loss can lead to
corneal perforation in chronic herpetic keratitis. Compensatory hyperplasia
of the corneal epithelium is often found in areas of extensive stromal loss
(Fig. 6-8F). Viral inclusions are not found light microscopically in the
stroma in herpes stromal keratitis. Virions and viral antigens have been
detected electron microscopically and immunocytochemically, however.
Varicella–zoster virus (VZV), another member of the herpesvirus
family, also causes a dendritic keratitis. Zoster dendrites lack the rounded
terminal bulbs that typically occur at the end of the branches of HSV
dendrites and are not full-thickness epithelial ulcerations as HSV dendrites
are (Fig. 6-8B).
Focal subepithelial infiltrates occur in the corneas of patients who have
epidemic keratoconjunctivitis or EKC, which generally is caused by
adenovirus types 8 and 19. The subepithelial infiltrates develop in the later
noninfectious stage of the disease and are thought to be composed of
lymphocytes attracted by viral antigens. EKC is often a severe, temporarily
incapacitating infection, which is highly contagious. Ophthalmologists
should take care to avoid infecting themselves and other patients. Patients
with EKC usually have preauricular adenopathy.

INTERSTITIAL KERATITIS
In a generic sense, the term interstitial keratitis refers to any nonulcerative
inflammation of the corneal stroma. (HSV disciform keratitis is a form of
interstitial keratitis). Other causes of stromal or interstitial keratitis include
tuberculosis and leprosy; protozoan parasites like Acanthamoeba;
onchocercal microfilaria; systemic disorders like sarcoidosis, Hodgkin
disease, and mycosis fungoides; foreign bodies such as caterpillar setae
and plant material; and drugs including gold and arsenic.
In common parlance, however, the term interstitial keratitis generally

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connotes the severe stromal keratitis that affects patients with congenital
syphilis during the first or second decade. Acute luetic interstitial keratitis
is marked clinically by a “salmon patch” of intense stromal vascularization
and severe photophobia. Lymphocytes infiltrate the edematous stroma.
The late sequelae of old syphilitic interstitial keratitis can be relatively
subtle: they include a faint diffuse nebulous opacification of the stroma
and residual nonperfused ghost vessels located deep in the corneal stroma
(Fig. 6-10A). The ghost vessels are best disclosed by the biomicroscopic
technique of sclerotic scatter.

FIG. 6-10. Chronic luetic interstitial keratitis. A. Clinical photo shows faint
nebulous opacification of the cornea. B. Double arrow denotes vessels deep
within noninflamed corneal stroma. Single arrow points to guttate excrescence on
the irregularly thickened Descemet membrane. C. Arrow in clinical photo denotes
relucent mass of hypertrophic Descemet membrane material on the posterior
cornea. D. Photomicrograph shows thick cylinder of PAS-positive basement
membrane material studded with guttate excrescences on the irregularly
thickened Descemet membrane. (B. PAS ×100, C. Clinical photo courtesy of Dr.
Irving Raber, Wills Eye Hospital, D. PAS ×100.)

Histopathologically, the Bowman membrane usually is absent. The stroma

is free of inflammation, and fine vessels that usually do not contain blood
are seen in the posterior third of the stroma, often just anterior to the
Descemet membrane (Fig. 6-10B). Part of the stroma may have a rarefied
vacuolated appearance and will stain intensely for acid
mucopolysaccharide. The Descemet membrane is often thickened and may
be studded with irregular guttate excrescences. The thickening of the
Descemet membrane may be massive. Relucent strands and networks of
basement membrane material are found on the posterior corneal surface in
exceptional cases (Fig. 6-10C,D).
Luetic interstitial keratitis occasionally develops in acquired syphilis,
in which corneal involvement is typically unilateral and sectoral. The

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association of nonluetic interstitial keratitis and vestibuloauditory
symptoms is called Cogan syndrome. Cogan syndrome is thought to be an
autoimmune disorder.

PARASITIC KERATITIS
Protozoan parasites including microsporidians and the freshwater amoebas
Acanthamoeba castellanii and A. polyphaga cause unusual corneal
infections. Originally reported in patients with HIV/AIDS, microsporidial
keratoconjunctivitis has occurred in immunocompetent individuals as well.
The parasite can infect the epithelium of the cornea and conjunctiva or the
corneal stroma (Fig. 6-11). Extensive interlamellar colonies of
microsporidia with scant inflammation reminiscent of infectious
crystalline keratopathy are found in some cases. The microsporidial spores
are focally birefringent, especially in Gram stains, which helps to
differentiate them from yeast and bacteria (Fig. 6-11C).

FIG. 6-11. Microsporidia keratitis. A. Quiet eye with dense nebulous stromal
opacity in stroma thought to represent scarring from old herpetic keratitis. B.
Microsporidia fill interlamellar clefts. Paucity of inflammation resembles that
seen in infectious pseudocrystalline keratopathy. C. Polarization microscopy
highlights birefringent granules in spores. (A. Photo courtesy of Christopher
Rapuano, MD, Chief, Corneal Service, Wills Eye Hospital. B. H&E ×250 C.
Gram stain with crossed polarizers ×400.)

Acanthamoeba keratitis was initially reported in 1974 and is closely linked

to the development and widespread use of soft contact lenses.
Acanthamoeba keratitis classically afflicts soft contact lens wearers who
use contaminated homemade saline solutions or wear their lenses while
swimming or bathing in hot tubs. The keratitis is usually severely painful.
Although many cases respond to medical therapy, penetrating keratoplasty

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(corneal transplantation) may be necessary. The initial stages of
Acanthamoeba keratitis can be confused with herpetic keratitis if clinical
suspicion is low. A ring or annular infiltrate is a characteristic feature of
Acanthamoeba keratitis, but usually develops in the later stages of the
disease. Radial keratoneuritis also is found in some cases (Fig. 6-12 A,B).

FIG. 6-12. Acanthamoeba keratitis. A. Radial keratoneuritis. B. Ring infiltrate.

E. Inflammed stroma contains acanthamoebic cysts seen at higher magnification
in figures C, D, F, and G. Cysts contain small nucleus with nucleolus (C, G) and
a thick relucent chitinous wall. In sections, the cytoplasm of the amoebas often
retracts from cyst wall (D, G). The cysts are readily visible in sections and
corneal smears or scrapings (H) stained with H&E. Special stains are not
required. (C, D, G, H. H&E, original magnification ×400, E. H&E ×50, F. H&E
×250.)

Microscopically, Acanthamoeba keratitis is often marked by focal

detachment or desquamation of the corneal epithelium. In contrast to
bacterial or fungal keratitis, the anterior stroma in many cases contains
only a relatively sparse infiltrate of inflammatory cells, mainly polys and
macrophages (Fig. 6-12E,F). Stromal necrosis is usually inconspicuous,
and stromal vascularization generally is not observed despite a lengthy
course that may last months prior to keratoplasty. Amoebic cysts in the
stroma and epithelium are readily found in routine hematoxylin and eosin–
stained sections or smears (Fig. 6-12C–H). The chitinous walls of the
Acanthamoeba cysts are round or oval and stain with PAS, GMS, and
Giemsa. The cytoplasm typically retracts from the cyst wall in tissue
sections (Fig. 6-12D,G). The cysts contain a small round nucleus with a
distinct nucleolus. Trophozoites are usually difficult to identify because
they resemble macrophages. Intense stromal keratitis with localized
abscess formation and palisading granulomatous inflammation can be
observed in the late stages of the disease.

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 Acanthamoeba keratitis can be diagnosed using corneal smears,
biopsies, or confocal microscopy. In smears, the organisms are most
readily found within sheets of epithelial cells and are readily detected in
sections stained with hematoxylin and eosin, which has been shown to be
superior to special stains including calcofluor white (Fig. 6-12H).
Previously touted as a diagnostic aid for Acanthamoeba, calcofluor white
currently is unavailable in many hospitals. In addition, it is nonspecific, is
subject to false positives, and requires an ultraviolet fluorescent
microscope. Acanthamoebas are cultured on agar plates overlain with a
layer of Escherichia coli. The amebas produce diagnostic linear tracks on
the surface of the plates as they graze on the bacteria.
Onchocerciasis is a major cause of blindness in parts of Africa and
South and Central America. This infestation by the parasite Onchocerca
volvulus is called river blindness because its vector, the black simulium
fly, breeds in swift-running mountain streams. Pairs of adult Onchocerca
breed in characteristic nodules in the skin of infested individuals. The
female worm releases myriad microfilariae that migrate to all parts of the
body. Necrotic microfilariae incite focal inflammation. Microfilariae are
often found in the corneal stroma where they produce keratitis with a
characteristic nummular (coin-shaped) pattern. Secondary closed-angle
glaucoma caused by anterior uveitis is a major cause of blindness in
endemic areas. Chorioretinal degeneration, also an allergic reaction to the
parasite, is another important cause of blindness. Slit-lamp examination
may disclose microfilariae in the anterior chamber in heavily infested
patients. The tiny worms are photophobic, and they quickly swim behind
the iris when the lamp is turned on. Patients are treated by the surgical
removal of parasitic nodules, the antihelminthic drug ivermectin and
doxycycline. Doxycycline kills Wolbachia bacterial endosymbionts that
are required for the survival of Onchocerca microfilariae and for
embryogenesis.

PERIPHERAL CORNEAL ULCERS

Although bacterial and fungal ulcers usually involve the central cornea, a
variety of ulcerations affect its periphery. Most important are the
peripheral corneal ulcerations that may herald the presence of a systemic
vasculitis such as granulomatosis with polyangiitis (Wegener’s),
periarteritis nodosa, systemic lupus erythematosus, or rheumatoid arthritis.
A rapidly progressive, painful, ulcerative keratitis, Mooren ulcer

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begins peripherally and extends across the cornea. The margin of the ulcer
has a characteristic overhanging configuration (Fig. 6-13). Mooren ulcer
usually is a unilateral disease of elderly patients in the United States. A
severe, bilateral form of the disease affects young individuals in Africa.
Some cases have been linked to chronic hepatitis C infection. An
autoimmune response to calgranulin, a normally hidden antigen expressed
by keratocytes may be involved in the pathogenesis of Mooren ulcer.

FIG. 6-13. Mooren ulcer. Scanning electron micrograph shows characteristic

overhanging margin of ulcer. (SEM ×125.)

Terrien ulcer is a slowly progressive bilateral trough-like thinning of the

stroma that begins as superiorly in males. The epithelium remains intact,
but the Bowman membrane and the superficial stroma are lost.
Vascularization and occasional lymphocytes and plasma cells are found in
the ectatic stroma.
Toxins produced by Staphylococci cause infiltrates and superficial
ulcerations in the peripheral cornea.

PTERYGIUM
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Pterygium (Fig. 6-14) is a degenerative disease of the cornea characterized
by a wedge-shaped ingrowth of conjunctival tissue that slowly invades the
peripheral cornea. The nasal limbus is usually affected, and both eyes are
often involved. The name pterygium reflects the fanciful resemblance of
the vascularized ingrowth to the membranous wing of an insect (pter is the
Greek word for wing). Pterygium initially is a cosmetic blemish, but it can
cause visual loss if it invades the pupillary axis.

FIG. 6-14. Pterygium. A. Wedge-shaped ingrowth of conjunctival tissue invades

the periphery of the nasal cornea. B. Actinic elastosis is seen as grayish material
in substantia propria. (A. Clinical photo courtesy of Dr. Peter Laibson, Wills Eye
Hospital, B. H&E ×100.)

Pterygia occur more often in southern latitudes and are twice as common
in men who work outdoors and typically have greater UV exposure. Other
environmental factors such as wind or dust may play a pathogenic role.
Pterygia probably are caused by damage to LSCs by chronic exposure to
UV light. Focal LSC deficiency is thought to be an important factor in the
transdifferentiation of cornea epithelium into conjunctival-like tissue that
invades the cornea. Pterygia arise from the part of the limbal conjunctiva
exposed to light in the interpalpebral fissure. A phenomenon called
peripheral light focusing may concentrate the UV light on the nasal limbus
where the LSCs reside. Presumably, the chronic UV exposure activates
and/or mutates LSC resulting in clonal expansion, local cell proliferation,
and corneal invasion, or alternatively, the focused UV radiation severely
damages or destroys the repository of LSC allowing the conjunctival
epithelium to invade the cornea. Small clusters of primitive stem-like cells
called Fuchs flecks have been found in the advancing head of some
pterygia. These clusters of primitive cells, which are immunoreactive for
stem cell markers CK15, CK19, and p63A, might be activated to
proliferate, forming an invasive pterygium. As they invade the cornea, the

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cells use matrix metalloproteinases to dissolve Bowman membrane.
Histopathologically, pterygia resemble an ingrowth of benign
conjunctiva onto the periphery of the cornea (Fig. 6-14B). Bowman
membrane is absent, and the stroma shows increased vascularity. Actinic
elastosis of collagen is often present, but may be relatively inconspicuous
or absent in some cases. The epithelium usually resembles conjunctival
epithelium. Epithelial hyperplasia and even dysplasia occur rarely.
Pterygia should be examined histopathologically to exclude the possibility
of an unsuspected neoplasm. In addition to ocular surface squamous
neoplasms, amelanotic melanomas occasionally are misdiagnosed
clinically as pterygia. Definitive therapy is surgical removal, often with
conjunctival autografts or amnionic membrane grafts.

OTHER CORNEAL
DEGENERATIONS
Calcific band keratopathy is a superficial opacity that extends across the
part of the cornea exposed in the interpalpebral fissure (Fig. 6-15). It is
caused by calcification of the Bowman membrane and the anterior stroma.
A clear interval separates the band of superficial calcification from the
limbus, and the opacity usually contains small circular holes. Calcific band
keratopathy can complicate chronic uveitis or long-standing glaucoma and
also complicates systemic disorders of calcium metabolism including
hypercalcemia, vitamin D intoxication, milk-alkali syndrome,
hypophosphatemia, and Fanconi syndrome. Histopathology discloses
basophilic granules in the Bowman membrane and the superficial stroma.
The alizarin red and von Kossa stains for calcium are positive. The
chelating agent EDTA is often used to treat calcific band keratopathy. A
noncalcific form of band keratopathy related to chronic actinic keratopathy
also occurs. The granules are larger and stain positively with the Verhoeff-
van Gieson elastic stain.

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FIG. 6-15. Band keratopathy. A. Clinical photo shows band of superficial
opacification involving the interpalpebral part of the cornea. B. Fine basophilic
granules of calcium stipple Bowman layer. C. Elastic stain highlights larger
granules of actinic elastosis in case with noncalcific component. (B. H&E ×100,
C. Verhoeff-van Gieson elastic stain ×250.)

Chronic actinic keratopathy (Fig. 6-16) and climatic droplet keratopathy

are two of many names applied to a degenerative disorder that is marked
by the deposition of multiple spherules of yellow hyaline material in the
anterior cornea. The disorder is also called spheroidal degeneration and
Labrador keratopathy. The degeneration is particularly prevalent in areas
where intense glare is reflected from ice (Labrador) or sand (the Dahlak
Islands in the Red Sea). Other synonyms such as oleoguttate dystrophy and
degeneratio sphaerularis elaoides stress the resemblance of the corneal
deposits to droplets of olive oil (Fig. 6-16C). In H&E-stained sections the
drop-like deposits of amorphous hyaline material usually are amphophilic
or light gray in color. The material stains intensely with the Verhoeff-van
Gieson elastic stain, and the positive reaction is not abolished by
pretreatment with elastase, a characteristic it shares with the elastotic
degeneration in pinguecula and pterygium. The hyaline deposits
autofluoresce under ultraviolet light and are said to behave similarly when
illuminated with the slit lamp’s cobalt blue filter. In some cases, tiny
globules of hyaline material are concentrated in the Bowman membrane
mimicking calcific band keratopathy. Concurrent corneal scarring can
severely decrease visual acuity in advanced cases.

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 FIG. 6-16. Chronic actinic keratopathy. A. Anterior stroma contains amphophilic
deposits of amorphous hyaline material. B. Material stains shows intensely with
elastic stain. C. Material in scarred cornea resembles droplets of olive oil. (A.
H&E ×100, B. Verhoeff-van Gieson elastic stain ×125.)

Salzmann nodular degeneration was once called Salzmann nodular

dystrophy. It is now recognized that this typically unilateral disorder is not
heritable and is best classified as a secondary degenerative process of
uncertain cause. Clinically, the corneal epithelium is focally elevated by
deposits of dense collagenous connective tissue that appear white
clinically. Salzmann nodular degeneration resembles a massive focal
pannus histopathologically. Mounds of relatively acellular hyaline
connective tissue elevate the corneal epithelium anterior to the plane of the
Bowman membrane, which may be destroyed.
Lipid deposition occurs in the peripheral corneal stroma in arcus
senilis or gerontoxon, a relatively common aging change (Fig. 6-35A). Fat
stains performed on frozen sectioned tissue disclose a concurrent deposit
in the perilimbal sclera, which is inapparent clinically. Similar corneal
deposition in a male less than age forty may signify a hyperlipemic state
that can predispose to cardiovascular disease. Lipid keratopathy is a
secondary phenomenon caused by lipid deposition in a heavily
vascularized stroma.
A corneal keloid is a hypertrophic scar that massively thickens the
corneal stroma. Elevated and exposed, the corneal epithelium on the
surface of the keloid typically undergoes epidermalization and transforms
into opaque skin-like tissue. Large corneal keloids frequently develop in
patients who have corneal staphylomas (Fig. 6-17). In such cases, the
posterior surface of the cornea is lined by atrophic remnants of iris, mainly
iris pigment epithelium. A staphyloma is an ectasia (area of thinning) lined
by uveal tissue. The term uveal is derived from the Latin word uva
meaning grape. Staphyle means a “bunch of grapes” in Greek. The latter

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prefix signifies the involvement of uveal tissue. Corneal staphylomas and
keloids are common sequelae of keratomalacia and measles keratitis in
underdeveloped countries.

FIG. 6-17. Corneal staphyloma. A. The epithelium of protruding, scarred, and

opacified cornea in a Haitian child has undergone epidermalization. The eye was
removed because retinoblastoma was suspected. B. Macrophoto of enucleated
eye shows massively, thickened ectatic cornea lined posteriorly by uveal tissue.
No intraocular tumor was found. A staphyloma is an ectasia lined by uveal tissue.
This staphyloma was complicated by keloid formation.

The tear film functions as the true anterior surface of the cornea, whose
health depends on an adequate supply of properly constituted tears.
Disorders of tear production and composition include deficiencies in the
aqueous component, the mucinous wetting agent produced by the goblet
cells, or abnormalities in the most superficial layer of lipid. Minor degrees
of ocular drying are encountered often in clinical practice. If an eye is
totally dry, the cornea becomes opaque.
Keratoconjunctivitis sicca is marked by corneal drying, superficial
punctate keratopathy (punctate staining), and filamentary keratitis
composed of strands of detached corneal epithelium and mucus.
Keratoconjunctivitis sicca and xerostomia are characteristic features of the
autoimmune disorder Sjögren syndrome. Drying of the mouth and eyes is
caused by infiltration and destruction of the acini of the salivary and the
main and accessory lacrimal glands by T lymphocytes. Myoepithelial
islands persist in the lymphoid infiltrate (lymphoepithelial lesion of
Godwin). About 10% of affected patients develop malignant lymphoma.
Corneal epithelial keratinization and epidermalization occur in severe
vitamin A deficiency. Patients have xerophthalmia and night blindness
caused by deficient rod photopigment. A process of bland corneal melting

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called keratomalacia frequently leads to corneal perforation (Fig. 6-18).
Malnourished children in underdeveloped countries and vitamin A-
deficient alcoholics in the United States are at risk. The Bitot spot, a
clinical marker for xerophthalmia, is an elevated dry area of epithelium
with a foamy appearance.

FIG. 6-18. Keratomalacia secondary to avitaminosis A. Incarcerated iris plugs

sharply margined perforation in center of noninflamed cornea. Avitaminosis A
was caused by dietary deficiency in chronic alcoholic. (H&E ×25.)

A corneal delle (pl. dellen) is a focal area of corneal thinning with

superficial surface ulceration, which is located central to an elevated lesion
at the limbus. Dellen probably are caused by focal dehydration of the
corneal stroma related to deficient focal corneal wetting.
Neurotrophic or neuroparalytic keratopathy is a corneal epitheliopathy
that may complicate 5th nerve lesions or corneal hypesthesia caused by
herpetic eye disease or herpes zoster ophthalmicus. The keratopathy
develops rapidly after surgical sectioning of the trigeminal nerve interrupts
poorly understood trophic factors. Patients with neurotrophic or
neuroparalytic keratopathy can develop sterile corneal ulcers or melts.
Compared to those in infected corneas, the walls and bed of sterile ulcers
contain a paucity of inflammatory cells, and there often is extensive loss of
keratocytes and faint stromal basophilia as well.

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 The term pannus is applied to a flat superficial scar of the anterior
cornea (Fig. 6-19). Two types of pannus are recognized
histopathologically. The paradigmatic inflammatory pannus occurs in
trachoma and is marked by a subepithelial ingrowth of inflamed
fibrovascular tissue from the limbus, which destroys the Bowman
membrane. Degenerative pannus occurs in chronically edematous corneas
with bullous keratopathy. Microscopically, a layer of connective tissue is
found interposed between the base of the epithelium and the Bowman
membrane, which remains intact. In contrast to an inflammatory pannus,
the subepithelial scar of degenerative pannus does not necessarily grow in
from the limbus. Cells, which probably are stromal fibroblasts, migrate
into the space between the Bowman membrane and the detached
epithelium and synthesize collagen. This fibrous scar forms the pannus and
may alleviate the painful bullous keratopathy at the expense of visual
acuity. In rare instances, amyloid is deposited secondarily beneath the
epithelium.

FIG. 6-19. Degenerative pannus, chronic corneal edema. A. Chronically

edematous cornea is opacified by subepithelial fibrosis. B. A thick layer of
relatively acellular connective tissue is interposed between the corneal epithelium
and intact Bowman membrane. (B. H&E ×100.)

KERATOCONUS
Keratoconus is an enigmatic bilateral degenerative disorder characterized
by progressive thinning or ectasia of the central stroma that imparts a
conical configuration to the cornea (Figs. 6-20 and 6-21). Keratoconus
usually presents around puberty with visual loss caused by severe
astigmatism. Most cases of keratoconus do not appear to be inherited, but
there is a positive family history in 10% of cases and the disease is more
prevalent in the first-degree relatives of affected individuals. Most cases

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are sporadic, however, and there is no evidence of a genetic basis for the
disease. Keratoconus can complicate several systemic disorders including
trisomy 21, Ehlers-Danlos syndrome, Leber congenital amaurosis, and
atopic dermatitis. Keratoconus occurs in ~5% of patients with Down
syndrome and frequently is associated with the acute onset of severe
corneal edema called corneal hydrops. Keratoconus in patients with atopic
dermatitis, Down syndrome, and Leber congenital amaurosis, an early-
onset retinal dystrophy, could be related to forceful eye rubbing or the
oculodigital reflex. The latter is a common behavioral pattern seen in
visually and mentally handicapped children who repeatedly strike their
eyes with their thumbs in order to mechanically induce flashes of light or
phosphenes. However, the incidence of keratoconus is much higher in
children blind from Leber congenital amaurosis (29%) compared to other
disorders, suggesting that it might be due to genetic factors.

FIG. 6-20. Keratoconus. A. Clinical photo shows conical shape of the cornea. B.
Sectioned ecstatic cornea has wavy configuration. C. Photomicrograph shows
severe thinning of apical stroma, compensatory hyperplasia of the epithelium, and
multiple dehiscences in the Bowman membrane. D. Arrows point to characteristic
dehiscences in the Bowman membrane. E. Cobalt blue illumination highlights
Fleischer ring surrounding apex of cone. F, G. Iron stain of Fleischer ring shows
focal deposition of iron in corneal epithelium surrounding cone. (B. H&E ×5, C.
H&E ×25, D. H&E ×250, F. Iron stain ×100, G. Iron stain ×250.)

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 FIG. 6-21. Keratoconus, characteristic dehiscences in the Bowman membrane. A.
India ink applied to de-epithelialized cornea highlights radiating pattern of breaks
in the Bowman membrane. Pattern suggests that breaks are caused by progressive
ectasia of the stroma. B. Characteristic defect in Bowman membrane keratoconus
is evident light microscopically as dehiscence with “wiggly” appearance. (A.
Specimen courtesy of Robert Fintelmann, MD. B. H&E ×400.)

The consistency of the cornea in keratoconus is abnormal; the sectioned

cornea almost invariably assumes an irregular wavy configuration on a
microslide, which immediately suggests the diagnosis (Fig. 6-20). Higher
magnification discloses central or apical thinning of the stroma, which can
be reduced to less than one-tenth normal thickness in exceptional cases.
Characteristic dehiscences, which typically have a wavy configuration,
occur in the Bowman membrane. These probably are pathognomic for
keratoconus and serve to confirm the diagnosis histopathologically (Figs.
6-20D and 6-21). Some cases exhibit apical scarring with increased
fibroblastic activity and new collagen production. The corneal epithelium
usually is intact and irregular in caliber with areas of both thinning and
compensatory hyperplasia. The Descemet membrane usually is thin, and
the endothelium is well preserved. A rupture in the Descemet membrane is
found if acute hydrops has occurred. If the hydrops had resolved prior to
corneal transplantation, the gap in Descemet membrane is lined by a thin
layer of new Descemet membrane synthesized by endothelial cells that
have migrated into the defect. Special stains show iron deposition in the
corneal epithelium encircling the cone. This deposit is evident clinically as
a Fleischer ring, one of the several eponymic iron lines of the cornea (Fig.
6-20E-G). Other iron lines unassociated with keratoconus include the
Hudson-Stähli line (across the low third of the cornea), the Stocker line (in
front of a pterygium), and the Ferry line (next to a filtering bleb). The

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basic defect in keratoconus is uncertain but may be related to abnormal
degradation of the corneal extracellular matrix. Abnormal levels of tissue
metalloproteinase inhibitors and alcohol dehydrogenase have been
identified in some cases.
Pellucid degeneration of the cornea resembles keratoconus
histopathologically but is located in the periphery of the cornea

CORNEAL DYSTROPHIES
In classic ophthalmic usage, the term dystrophy usually denotes an
inherited, relatively symmetric bilateral disease that is slowly progressive,
unassociated with vascularization or inflammation in its early stages, and
unrelated to environmental or systemic factors. The pathology is or
appears to be localized to an ocular tissue. Dystrophies usually are not
evident at birth, but become clinically evident later in life. The
etymological derivation of the word dystrophy is outdated because it refers
to poor nutrition. The term usually is applied to hereditary diseases of the
cornea and macula.
Advances in molecular biology have markedly increased our
understanding of these rare, interesting disorders. Several corneal
dystrophies are now known to be caused by allelic mutations in the gene
encoding a single corneal protein. Macular corneal dystrophy (MCD)
appears to be the ocular manifestation of an otherwise innocuous systemic
enzyme deficiency. Meesmann epithelial dystrophy is caused by an
abnormality in the genes for proteins that are only expressed in the corneal
epithelium.
In the past, corneal dystrophies were classified anatomically as
superficial, stromal, and endothelial based on the location of the clinical
and pathologic findings. The second edition of the IC3D Classification of
Corneal Dystrophies, published in 2015, incorporates many aspects of the
traditional definitions of corneal dystrophies with new genetic, clinical,
and pathologic information. This new classification will be continually
upgraded in the future as our understanding of molecular genetics
increases. The IC3D classification contains a wealth of clinical,
pathologic, and genetic information and illustrations and is highly
recommended.
The traditional anatomic classification system was modified slightly in
the second edition of the IC3D classification. Corneal dystrophies are now

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classified as (1) epithelial and subepithelial dystrophies, (2) epithelial–
stromal dystrophies caused by mutations in TGFBI, (3) stromal
dystrophies, and (4) endothelial dystrophies. Category (2) includes the five
corneal dystrophies caused by mutations in the TGFBI gene including
Reis-Bücklers and Thiel-Behnke dystrophies that previously were
classified as Bowman layer dystrophies. The classification also placed
dystrophies into evidence-based categories.

Epithelial and Subepithelial Dystrophies

The category of epithelial and subepithelial dystrophies includes epithelial
basement membrane dystrophy (EBMD), Meesmann corneal dystrophy,
Lisch epithelial corneal dystrophy, gelatinous drop-like corneal dystrophy,
and several rare, less well-characterized dystrophies (Fig. 6-22).

FIG. 6-22. Epithelial dystrophies. A. Meesmann epithelial dystrophy. The

epithelium is thickened and contains small cystoid spaces. The epithelial
basement membrane is markedly thickened. B. Cogan microcystic dystrophy. Slit
lamp discloses intraepithelial deposits of putty-like cellular debris. C.
Photomicrograph of microcystic dystrophy shows devitalized cellular debris
trapped by duplication of the epithelium. D–F. Map-dot-fingerprint dystrophy.
Photomicrographs of corneal scrapings show small intraepithelial cyst and

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 intraepithelial segment of basement membrane (D) and marked thickening of
epithelial basement membrane (E). Folds of thickened basement membrane
protrude into corneal epithelium. (A. PAS ×250, C. PAS ×100, D. PAS ×100, E.
PAS ×100, F. PAS ×250.)

The terms epithelial basement membrane dystrophy, anterior basement

membrane dystrophy, and map-dot-fingerprint dystrophy (Fig. 6-22B–F)
have been applied to a corneal disorder marked by a spectrum of epithelial
abnormalities including reduplication and intraepithelial segments of
corneal epithelial basement membrane, intraepithelial cystoid spaces filled
with devitalized cellular debris, and focal subepithelial scarring. Although
rare familial cases with autosomal dominant inheritance have been
reported, the majority of cases are not inherited and are considered
degenerative in nature or secondary to trauma.
The clinical subtypes of the “dystrophy” often coexist. The
microcystic form of the disorder (called Cogan microcystic dystrophy)
shows multiple intraepithelial cysts filled with white putty-like cellular
debris (Fig. 6-22B,C). The devitalized cells that fill the cystoid spaces are
trapped by duplication of the epithelium, which prevents their
desquamation. Parallel relucent lines seen in the fingerprint subtype may
represent basement membrane material separating sheets of duplicated
epithelium. Irregular, geographically shaped areas of subepithelial scarring
characterize map-like changes. The corneal epithelial basement membrane
is often thickened (Fig. 6-22E,F). Epithelial abnormalities similar to those
found in map-dot-fingerprint dystrophy are found histopathologically in
many chronically edematous corneas. Histopathologic evidence suggests
that detachment of the epithelium and chronic bullous keratopathy are the
primary events that lead subsequently to secondary abnormalities such as
epithelial reduplication and intraepithelial cyst formation. The rare, truly
dystrophic cases of the disease might be caused by defective molecules
involved in corneal epithelial adhesion. Several families with point
mutations in the TGFBI gene have been reported.
Meesmann dystrophy (Fig. 6-22A) is a relatively benign autosomal
dominantly inherited disorder of the corneal epithelium. Meesmann
dystrophy is characterized by the presence of myriad small punctate
vacuoles in the corneal epithelium, which are best seen in
retroillumination. Fluorescein dye typically pools in the vacuoles that have
migrated to the corneal surface. Although recurrent epithelial erosions are
possible, good vision is the rule. Histopathologically, both the epithelium
and its basement membrane are thickened, and the epithelium has a

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disorderly appearance. In addition to small intraepithelial cystoid spaces,
the epithelium contains cells that have a hyalinized appearance. Electron
microscopy has disclosed intracellular aggregates of fibrillogranular
“peculiar substance” composed of mutated cytokeratin. Meesmann corneal
dystrophy is caused by mutations in either of the genes (KRT3 or KRT12)
that encode cornea-specific cytokeratins. The mutations severely impair
cytoskeletal function and cause increased fragility of the corneal
epithelium. The term Stocker-Holt dystrophy has been applied to the
variant caused by mutations in the keratin K12 or KRT12 gene. The latter
affects the entire cornea and has an earlier onset and more severe signs and
symptoms.
Lisch epithelial corneal dystrophy (band-shaped and whorled
microcystic dystrophy of the corneal epithelium) is an X-chromosomal
dominant disorder caused by an unknown gene at Xp22.3. LECD is
characterized by irregular foci of grayish opacities caused by multiple
clear cysts in the corneal epithelium that contain PAS-positive, diastase-
sensitive material consistent with glycogen.
Gelatinous drop-like corneal dystrophy (GDCD) or familial
subepithelial corneal amyloidosis is a rare form of heritable corneal
amyloidosis in which the amyloid accumulates as a band keratopathy or
classically as prominent milky-white gelatinous mulberry-shaped nodules
beneath the corneal epithelium (Fig. 6-23). Stromal opacification or an
orange nodular kumquat-like lesion occurs in the later stages of the
disorder. The amyloid deposits are immunoreactive for the antimicrobial
protein lactoferrin, but are not caused by mutations in the lactoferrin gene.
The autosomal recessively inherited disorder is associated with mutations
in the TACSTD2 gene that encodes tumor-associated calcium signal
transducer 2. The gene was previously called M1S1. The corneal
epithelium in GDCD is extremely hyperpermeable, which allows massive
deposits of amyloid to accumulate beneath the epithelium. Gelatinous
drop-like dystrophy is a severely debilitating disorder that recurs rapidly
after superficial keratectomy.

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 FIG. 6-23. Gelatinous drop-like dystrophy. A. Milky gelatinous nodules of
amyloid elevate the corneal epithelium in case that recurred rapidly after
penetrating keratoplasty. B. Massive subepithelial deposit of amorphous
eosinophilic amyloid elevates irregular epithelium from the Bowman material.
Positive staining with Congo red (C) and characteristic apple-green birefringence
with polarized light (D) confirms that material is amyloid. (B. H&E ×50, C.
Congo red ×100, D. Congo red with crossed polarizers ×100.)

Epithelial–Stromal Dystrophies Caused by

Mutations in TGFBI
Five corneal dystrophies including Reis-Bücklers corneal dystrophy
(RBCD), Thiel-Behnke corneal dystrophy (TBCD), Lattice corneal
dystrophy type I, and granular corneal dystrophy types 1 and 2 are caused
by distinct allelic mutations in the transforming growth factor–induced
(TGFBI) gene on the long arm of chromosome 5 (5q31). The TGFBI gene
previously was called the Big-H3 gene. The TGFBI gene’s protein product
keratoepithelin is expressed by the corneal epithelium and keratocytes as
well as numerous other tissues in the body. The different clinical
manifestations of these dystrophies presumably reflect variations in the
aggregation or precipitation of the several mutant forms of TGFBI protein
in the cornea. All are inherited as autosomal dominant traits.
RBCD and TBCD (Fig. 6-24) are two relatively similar disorders that
primarily affect the epithelium, the Bowman layer, and the anterior stroma
of the cornea. Previously classified as Bowman layer dystrophies, both
present with painful recurrent erosions in the first decade and are
characterized biomicroscopically by diffuse subepithelial scarring that
markedly reduces visual acuity (Fig. 6-24). Histopathologically, the
epithelium in both dystrophies is irregular in caliber and has a saw-toothed
appearance. A thick multilaminar pannus composed of alternating layers of

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collagen and abnormal material that has the same tinctorial characteristics
as the deposits in granular corneal dystrophy elevates the epithelium
anterior to the plane of the Bowman layer, which usually is destroyed (Fig.
6-24B). Like the deposits in granular corneal dystrophy, the abnormal
material is more eosinophilic than normal stromal collagen and stains
intensely red with Masson trichrome (Fig. 6-24C,E). It initially collects
beneath the epithelium and probably predisposes to recurrent erosions by
interfering with epithelial adhesion. The multilaminated pannus probably
results from repeated episodes of synthesis, epithelial detachment, and
scarring. Inherited in an autosomal dominant fashion, these dystrophies are
caused by various mutations involving the 124 and 555 positions in the
TGFBI protein.

FIG. 6-24. A. Reis-Bücklers dystrophy. Slit lamp discloses diffuse subepithelial

scarring. B. Reis-Bücklers dystrophy. The “saw-toothed” epithelium rests on a
thick multilaminar pannus composed of alternating layers of collagen and more
eosinophilic material. Bowman material has been destroyed. Smaller deposits of
eosinophilic material are seen in the stroma. C. Reis-Bücklers dystrophy.
Abnormal material comprising part of multilaminar pannus in Reis-Bücklers
dystrophy stains red with Masson trichrome–like deposits in granular corneal
dystrophy. D. Electron microscopy of Reis-Bücklers dystrophy shows
osmiophilic crystalloids resembling deposits in granular corneal dystrophy E.
Thiel-Behnke dystrophy. Abnormal material in multilaminar pannus stains red
with Masson trichrome. E. TEM shows that abnormal material in Thiel-Behnke

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 dystrophy is composed of “curly filaments.” (A. Clinical photo courtesy of Dr.
Peter Laibson, Wills Eye Hospital, B. H&E ×100, C. Masson trichrome ×250, D.
TEM, E. Masson trichrome ×250, F. TEM.)

Reis-Bücklers dystrophy and Thiel-Behnke dystrophy are distinguished

histologically and electron microscopically by the morphology of the
deposits of abnormal TGFBI protein. Reis-Bücklers dystrophy resembles a
superficial variant of granular corneal dystrophy; the mutant
keratoepithelin forms small, sharply angulated crystalloids that are
intensely Masson trichrome positive and osmophilic on transmission
electron microscopy (Fig. 6-24D). The subepithelial deposits in Thiel-
Behnke dystrophy are less pronounced, more amorphous, and less
intensely acid-fuchsinophilic with Masson trichrome. The deposits are
composed of proteinaceous “curly filaments” electron microscopically
(Fig. 6-24F). In the past, patients with the latter findings were erroneously
reported as having Reis-Bücklers dystrophy in the American literature.
Lattice corneal dystrophy type I (LCDI or Biber-Haab-Dimmer) is an
autosomal dominantly inherited form of amyloidosis that is confined to the
cornea (Fig. 6-25). The amyloid is composed of mutant TGFBI protein.
Lattice corneal dystrophy type I typically begins in the first decade, and
penetrating keratoplasty is indicated in the fourth or fifth decade. Surgery
may be necessary earlier in cases with anterior amyloid deposition
scarring.

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 FIG. 6-25. Lattice corneal dystrophy, type I. A. Slit-lamp photo shows
characteristic lattice work of branching relucent lines in corneal stroma. B.
Corresponding stromal deposits of amyloid are eosinophilic but have more
smudgy margins than deposits in granular dystrophy. C. Deposits stain positively
with Congo red and show characteristic apple-green birefringence (D) and
birefringence (E) with polarized light (D) A. Clinical photo courtesy of Dr. Irving
Raber, Wills Eye Hospital. (B. H&E ×100, C. Congo red ×250, D. Congo red
with crossed polarizers ×250. Congo red with crossed polarizers x250.)

Clinically, the amyloid deposits form a characteristic latticework of

branching relucent lines in the corneal stroma, which once were thought to
be degenerating corneal nerves (Fig. 6-25A). Histopathology reveals
smudgy round or oval deposits of eosinophilic amyloid material in the
stroma, which stain positively with amyloid stains Congo red, crystal
violet, and thioflavine T. The amyloid has a characteristic apple-green
birefringence and dichroism when sections stained with Congo red are
examined with polarization microscopy (Fig. 6-25C–E). The material is
also PAS positive. Diffuse deposits of amyloid occur superficially and
cause recurrent erosions in some cases, which may mimic Reis-Bücklers
dystrophy. Lattice dystrophy recurs in the graft after penetrating
keratoplasty. In the recurrent dystrophy, the amyloid first accumulates
superficially beneath the epithelium and in suture tracts.
Variants of lattice corneal dystrophy are caused by more than two
dozen distinct amyloidogenic mutations in the TGFBI gene. These LCD
variants have varied clinical manifestations and a variety of amyloid
deposits that include thin or thick lines and nonlinear ice chip–like
deposits.
Lattice dystrophy type II (LCDII) is autosomal dominantly inherited
form of systemic amyloidosis caused by mutation in the GSN gene on
chromosome 9q34 that encodes the protein gelsolin involved in actin
metabolism. LCDII is called the Meretoja syndrome or familial
amyloidosis, Finnish, or Meretoja type. The syndrome includes fine
lattice–like deposits in the cornea that are less numerous, more delicate,
and more radially oriented than those in LCDI and usually do not cause
severe visual loss. In addition to the corneal manifestations, affected
patients have a progressive bilateral cranial and peripheral neuropathy with
dry, lax itchy skin and mask-like “hound dog” facies with pendulous ears
and protruding lips. Amyloid deposits also occur in the heart, kidneys,
skin, nerves, and other tissues.
Granular corneal dystrophy type 1 (also known as Groenouw type I) is

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the most benign of the classic corneal stromal dystrophies (Fig. 6-26).
Visual loss develops relatively late in life. Slit-lamp examination shows
multiple white crumb, snowflake or ring-shaped opacities in the central
cornea of both eyes. Most of the opacities are superficial. Visual acuity
usually remains good because the opacities are separated by intervals of
clear corneal stroma. Histologically, the deposits of mutant TGFBI protein
resemble hyaline “rock candy.” The material is more intensely
eosinophilic and less PAS positive than the surrounding normal stroma and
exhibits intense acid fuchsinophilia (red staining) with Masson trichrome
(Fig. 6-26B–D). The granular deposits also stain intensely with the myelin
stain Luxol fast blue, are negative for mucopolysaccharide, and are less
birefringent on polarization microscopy than normal stromal collagen.
Electron microscopy discloses electron dense crystalloids, which may
exhibit a regular periodicity. Granular corneal dystrophy can recur in the
graft after corneal transplantation. When it does, the granular material
typically accumulates in the anterior cornea beneath the epithelium.
Classic granular corneal dystrophy (granular corneal dystrophy type I) is
associated with an Arg555Trp mutation in TGFBI.

FIG. 6-26. Granular corneal dystrophy. A. Multiple white, crumb, or ring-shaped

opacities are present in the central cornea. The stroma is clear between the
opacities. B. Granular corneal dystrophy. Irregular “rock candy” deposits of
mutant TGFBI protein are more intensely eosinophilic than surrounding normal

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 stroma. C. Irregular margins of granular deposits are distinct and angulated. D.
Granular deposits show intense acid fuchsinophilia (red staining) with Masson
trichrome. (B. H&E ×25, C. H&E ×100, D. Masson trichrome ×100.)

Granular corneal dystrophy type II (GCD2) was previously called

combined granular lattice dystrophy or Avellino dystrophy.
Histopathologic examination discloses features of both granular and lattice
corneal dystrophy. The amyloid deposits do not resemble lattice lines,
however, and are found in the posterior stroma deep to the granular
deposits. This disorder originally was called Avellino dystrophy because
the initial patients traced their origin to Avellino district of Italy. GCD2 is
now known to occur worldwide. Most cases are caused by a Arg124His
mutation in TGFBI. Refractive surgical procedures such as LASIK and
photo refractive keratectomy are contraindicated in GCD2 because injury
to the central cornea exacerbates this dystrophy leading to accelerated
corneal opacification (Fig. 6-27).

FIG. 6-27. Granular dystrophy type 2 recurrent in flap after LASIK. A. Slit-lamp
photo shows confluent deposit of granular material at site of prior LASIK. B.
Excised LASIK flap contains linear band of intensely eosinophilic material
consistent with granular corneal dystrophy seen at higher magnification in (C).
Deposit of mutant TGFBI protein have distinct, “crunchy margins” and stain
intensely red with Masson trichrome (D). Cornea trauma exacerbates granular
dystrophy type 2 leading to accelerated corneal opacification. Granular dystrophy
2 was previously called Avellino or combined granular lattice dystrophy. (B.
H&E ×25, C. H&E ×250, D. Masson Trichrome ×250. Photo courtesy of
Theodore Perl, MD.)

Stromal Dystrophies
Granular, lattice, and macular corneal dystrophies are the classic stromal

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dystrophies of the cornea. As noted above, granular and lattice are now
grouped with the TGFBI dystrophies.
MCD is the most severe of the classic corneal stromal dystrophies (Fig
6-28). Although rare in the United States, macular dystrophy is quite
common in Saudi Arabia, India, and Iceland. Unlike the other classic
stromal dystrophies, which are autosomal dominant, MCD is an autosomal
recessive trait caused by a defective enzyme. Most patients develop severe
visual loss by age 20 to 40 years and usually require corneal
transplantation. The term macular refers to grayish opacities with indistinct
borders that are found in the superficial stroma and begin axially (Fig. 6-
28A). The macules are superimposed on a diffuse stromal haze that
extends from limbus to limbus and involves the entire cornea.

FIG. 6-28. Macular corneal dystrophy. A. The entire cornea is diffusely hazy.
Grayish macules with indistinct borders are present axially. The cornea is not
thickened. B. Large subepithelial extracellular deposits of abnormal nonsulfated
keratan correspond to macules seen clinically. The stroma is thin. A few guttae
stud the Descemet membrane. C. Alcian blue stain for acid mucopolysaccharide
stains large subepithelial extracellular deposit of nonsulfated keratan sulfate.
Keratocytes also stain. D. Colloidal iron stain for acid mucopolysaccharide stains
keratocytes and corneal endothelial cells. Note guttate excrescence on the
Descemet membrane. (B. H&E ×50, C. Alcian blue ×100, Colloidal iron ×250.)

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Classified as a localized corneal mucopolysaccharidosis, MCD is caused
by mutations in the CHST6 (N-acetylglucosamine-6-O-sulfotransferase)
gene on chromosome 16q22. Mutations cause defective sulfonation of the
proteoglycan keratan sulfate, a major constituent of the cornea’s ground
substance. The lack of sulfated keratan causes abnormal hydration of the
stroma, which interferes with collagen fibril spacing and destructive
interference, degrading its optical properties. The hazy, poorly hydrated
cornea in macular dystrophy is usually thinner than normal. This contrasts
with the cloudy corneas in systemic mucopolysaccharidoses like Hurler
disease, which usually are thickened. The abnormal nonsulfated keratan is
insoluble and accumulates in the cytoplasm of keratocytes, corneal
endothelial cells, and as large extracellular deposits in the subepithelial
stroma. The latter constitute the macules seen clinically. MCD appears to
be the corneal manifestation of an otherwise innocuous systemic disease.
Patients who have macular dystrophy type I are deficient in corneal
keratan sulfate, and they also lack keratan sulfate in their serum and
cartilage. Deficient keratan sulfate causes corneal opacification, but does
not appear to have adverse consequences elsewhere.
Histopathologically, the cytoplasm of the keratocytes and endothelial
cells has a frothy vacuolated appearance in routine H&E sections, and the
extracellular deposits are composed of vesicular granules that are mildly
basophilic and PAS positive. The histochemical stains of choice for MCD
are the Alcian blue and colloidal iron stains for acid mucopolysaccharide
(glycosaminoglycans) (Fig. 6-28C,D). Some cases of macular dystrophy
have guttate excrescences on the Descemet membrane.
Schnyder corneal dystrophy (SCD) is an autosomal dominantly
inherited disorder caused by mutations in the UBIAD1 gene on the short
arm of chromosome 1 (1p34.1-p36). The dystrophy previously was called
Schnyder crystalline dystrophy, reflecting the characteristic deposition of
polychromatic needle-shaped crystals of cholesterol in the anterior corneal
stroma (Fig. 6-29A). The term crystalline was removed from the
dystrophy’s name in the second edition of the IC3D classification because
crystals actually occur in only half of patients leading to diagnostic
confusion. Diffuse stromal haze and a prominent annulus lipoides senilis
are other characteristic features. Central stromal opacification may
necessitate penetrating keratoplasty in the fifth decade. Some patients have
xanthelasmas and elevated serum lipids. A subtle pattern of stromal
vacuolization is seen histopathologically in routine sections because the
lipid is dissolved during processing (Fig. 6-29B). Stromal lipid deposition

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causes severe diffuse corneal clouding in other rare heritable disorders of
lipid metabolism including lecithin acyl transferase (LCAT) deficiency,
fish eye disease, and Tangier disease. The histopathologic findings are
relatively subtle.

FIG. 6-29. Schnyder corneal dystrophy. A. A deposit of cholesterol crystals is

present in the axial stroma. A prominent arcus senilis is also present. B. Empty
clefts and vacuoles that contained lipid in vivo are concentrated in the anterior
stroma. No vessels or inflammation is present. Only half of cases have crystals.
(H&E ×50.)

Other well-characterized stromal dystrophies include congenital stromal

corneal dystrophy (CSCD) fleck corneal dystrophy (FCD), and posterior
amorphous corneal dystrophy (PACD).
Fleck corneal dystrophy (FCD, François-Neetan fleck corneal
dystrophy, or dystrophie mouchetée) usually is an incidental finding
clinically because visual acuity is unaffected. Patients have minute,
asymptomatic fleck-like opacities in the deep stroma centrally, which have
been likened to fly specks. Ultrastructurally, the keratocytes are swollen
and contain GAGs and lipid. FCD is an autosomal dominantly inherited
trait caused by mutations in the PIKFYVE gene (2q34).
Congenital stromal corneal dystrophy (CSCD) also called congenital
hereditary stromal dystrophy is a stationary, autosomal dominantly
inherited disorder marked by bilateral diffuse clouding of the corneal
stroma with scattered whitish flake-like opacities. Transmission electron
microscopy of the thickened cornea shows lamellae of normal collagen
fibrils separated by layers of thin abnormal collagen filaments (F)
randomly arranged in an electron-lucent ground substance. CSCD is
caused by mutations in the DCN gene for decorin (12q22).
PACD shows deletions of keratocan (KERA), lumican (LUM), decorin

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(DCN), and epiphycan (EPYC). Some have questioned whether it may be
a mesodermal dysgenesis instead of a corneal dystrophy. The central
cloudy dystrophy of François is phenotypically identical to the
degenerative condition posterior crocodile shagreen. One form of pre-
Descemet corneal dystrophy (PDCD) is associated with X-linked
ichthyosis caused by mutations in the steroid sulfatase gene.

CORNEAL EDEMA, BULLOUS

KERATOPATHY, AND THE
ENDOTHELIAL DYSTROPHIES
Corneal edema caused by endothelial damage or disease (endothelial
decompensation) is a major indication for corneal transplantation. In many
cases, the endothelial damage is related to prior intraocular surgery
(aphakic or pseudophakic bullous keratopathy). The edema also may be
caused by primary endothelial disease. The endothelial dystrophies of the
cornea include Fuchs endothelial corneal dystrophy, which is very
common, and congenital hereditary endothelial dystrophy (CHED),
posterior polymorphous dystrophy (PPCD), and X-linked endothelial
corneal dystrophy (XECD), which are rare.
The corneal endothelium is a relatively fragile monolayer of ~400,000
cells that synthesizes and rests upon a thick layer of basement membrane
material called Descemet membrane (Fig. 1-8C, D). In the adult, the
normal density of endothelial cells is 2,400 to 3,200 cells/mm2. The
corneal endothelium is derived embryologically from neural crest, as are
the corneal stroma and most other anterior segment tissues. Mature
endothelial cells do not divide, and the endothelium generally is incapable
of regeneration or repair. Approximately 0.5% of the endothelial cells are
lost yearly with increasing age.
The corneal endothelium plays an extremely important role in the
maintenance of corneal transparency. The transparency and optical
properties of the cornea depend on an exquisitely regular spacing of the
collagen fibrils in the stroma, which is necessary for destructive
interference. This requires the stroma to be in a state of relative
dehydration. The corneal endothelium maintains this state of relative
stromal dehydration by acting as a barrier to aqueous humor and as an ion-
fluid pump. If the endothelium is damaged or depleted, typically during

206
surgery, aqueous humor enters the stroma and the glycosaminoglycan-rich
ground substance swells separating the collagen fibrils, causing edema and
degrading corneal transparency. The spacing of the neighboring collagen
fibrils in the stroma must be <200 nm for there to be transparency.
Histopathologically, an edematous cornea is thickened and may show
partial obliteration of artifactitious interlamellar stromal clefts. The
margins of the lamellae appear somewhat indistinct, and the edematous
stroma is pale and may have a frothy appearance, which has been likened
to cotton candy (Fig. 6-33A). As secondary epithelial edema develops, the
basal cells often have a pale edematous appearance (Fig. 6-30B). Fluid
accumulates in the spaces between cells and beneath the epithelium
forming focal bullous areas of epithelial detachment called bullous
keratopathy (Fig. 6-30A). Bullous keratopathy is painful because the
anterior cornea’s rich supply of sensory nerve endings is exposed when the
epithelial bullae rupture, which they often do. The cornea is also
predisposed to infection because the normally protective epithelial layer
has been compromised. A degenerative pannus (Fig. 6-19) develops in
many corneas with chronic edema and bullous keratopathy. This opaque
layer of connective tissue is interposed between the base of the epithelium
and Bowman layer, which is intact. Secondary epithelial changes similar to
those reported in epithelial basement membrane dystrophy are observed
occasionally.

FIG. 6-30. Corneal edema. A. Pseudophakic bullous keratopathy. The epithelium

has detached from the edematous cornea forming a bulla. The Descemet
membrane is regular in caliber. The endothelium is markedly atrophic. B. Basal
edema, corneal epithelium. Cells constituting edematous basal cell layer of
corneal epithelium have swollen lucent cytoplasm. (A. H&E ×25, B. H&E ×250.)

Fuchs endothelial corneal dystrophy (FECD) is, by far, the most common
corneal dystrophy in the United States. FECD affects 4% of individual

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over age 40 and is more common and severe in women. It typically
presents in the fifth or sixth decade of life with corneal edema and bullous
keratopathy, which are caused by a primary defect in the corneal
endothelium. This primary dystrophy of the corneal endothelium is readily
diagnosed clinically and histopathologically by characteristic changes in
the Descemet membrane.
The Descemet membrane in FECD typically is thickened and studded
with anvil- or mushroom-shaped guttate excrescences of abnormal
basement membrane material made by the dystrophic endothelial cells
(Fig. 6-31). The term cornea guttata (“drop-like cornea”; gutta = drop) is
often applied to FECD and to cases of endothelial dystrophy prior to the
onset of endothelial decompensation and bullous keratopathy. The guttae
(guttata is an adjective) are evident on slit-lamp biomicroscopy as tiny
drop-like relucences on the posterior corneal surface. These appear as
round or oval profiles in flat preparations of DSEK specimens (Figs. 6-
31D and 6-32). Histopathologically, guttae that have been buried by a
newly elaborated posterior layer of the Descemet membrane are often
found, especially in the central cornea (Figs. 6-31B and 6-32B,D).
Thickening and multilamination of the Descemet membrane also is
observed. In rare cases, the Descemet membrane lacks guttate
excrescences and diffusely thickened instead. The endothelium typically is
atrophic, but a significant number of corneal endothelial cells persists in
many cases. The severe endothelial loss that characterizes pseudophakic
bullous keratopathy (Fig. 6-33) is quite unusual in Fuchs dystrophy and, if
present, suggests the superimposition of PBK on a pre-existent dystrophy.
Granules of iris pigment epithelial melanin are often found in the
cytoplasm of the endothelial cells (Fig. 6-31A,D). Observation of this
retrocorneal pigmentation in the fundus red reflex may suggest the
diagnosis during ophthalmoscopy or retinoscopy. Unlike the vertically
oriented Krukenberg spindle of pigmentary glaucoma, the endothelial
pigmentation in Fuchs dystrophy is irregular in shape suggesting that the
pattern of pigmentation is governed by an endothelial abnormality and not
the circulation of aqueous humor.

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FIG. 6-31. Fuchs dystrophy. A. The Descemet membrane is irregular in caliber
and studded with guttate excrescences. Some of the residual endothelial cells
contain melanin granules. B. Fuchs dystrophy, buried guttae. Guttae have been
“buried” by a newly synthesized layer of extracellular matrix material. The
endothelium is markedly atrophic. Buried guttae typically occur in the center of
the cornea. C. Mushroom or anvil-shaped excrescences disclosed by scanning
electron microscopy stud posterior surface of the Descemet membrane. The
specimen is oriented epithelial side down. D. Flat preparation of the Descemet
membrane stripped from patient with Fuchs dystrophy during DSEK procedure.
Many endothelial cells between round pink guttae contain melanin granules. (A.
PAS ×250, B. PAS ×250, SEM ×300, D. Whole mount flat preparation stained
with H&E ×100.)

209
FIG. 6-32. Fuchs dystrophy, flat preparations of DSEK specimens. A. Flat
preparation of Descemet membrane from patient with Fuchs dystrophy obtained
at DSEK procedure shows numerous guttate excrescences. These vary in size and
are confluent in some areas. Residual endothelial cells are seen between guttae.
Some contain granules of iris pigment epithelium melanin. B. Buried guttae, flat
preparation. Many of the guttae are indistinct in this photo because they have
been buried by new extracellular matrix material. Severe endothelial atrophy
corresponds to the area of buried guttae. C. Adjusting microscope condenser
discloses buried guttae. All figures, flat preparations stained with H&E. (A ×250,
B, C×100.)

FIG. 6-33. Pseudophakic bullous keratopathy. A. The Descemet membrane is

regular in caliber and lacks guttate excrescences. The endothelium is severely
atrophic. Edematous stroma has cotton candy appearance and diminished clefts.
B. Scanning electron micrograph of healthy endothelial mosaic in normal cornea.
C. SEM of PBK shows focally denuded Descemet membrane. Residual cells
constituting severely atrophic residual endothelium in PBK specimen are large
and polymorphic. (A. PAS ×250, B. SEM ×320, C. SEM ×160.)

FECD appears to be a complex inherited disorder with variable

expressivity and incomplete penetrance caused by an interaction of genetic
and environmental factors. The family history is negative in most cases. In

210
some instances, FECD appears to be an autosomal dominant disorder with
incomplete penetrance. Mutations in the SLC4A11 or ZEB1 genes are
thought to cause some cases of late-onset Fuchs dystrophy. Mutations in
the COL8A2 gene have been found in rare, early-onset cases.
Pseudophakic bullous keratopathy (PBK) occurs patients who have
undergone cataract surgery with the implantation of a prosthetic
intraocular lens (pseudophakos). Aphakic bullous keratopathy (ABK)
follows cataract surgery without IOL implantation. These iatrogenic forms
of corneal edema result from direct or delayed damage to the corneal
endothelium. In the past, PBK was one of the most common indications
for corneal transplantation, but the incidence has decreased markedly in
recent years as intraocular lens technology and surgical techniques have
improved.
The Descemet membrane in PBK is not thickened and is regular in
caliber without guttate excrescences. The endothelium usually is severely
atrophic and may appear totally absent (Fig. 6-33A). Bullous keratopathy
may be severe; some cases have total epithelial desquamation.
Degenerative pannus formation is encountered less often than in Fuchs
dystrophy, probably because PBK has a more acute course.
An almost identical picture of corneal edema caused by severe
endothelial decompensation occurs in most transplanted corneas that have
failed necessitating repeat penetrating keratoplasty. An eosinophilic
retrocorneal fibrous membrane is found on the posterior surface of the
Descemet membrane in many failed grafts. If a retrocorneal fibrous
membrane is observed microscopically, the periphery of the edematous
cornea should be examined carefully for surgical scars and suture tracts.
Massive corneal edema occurs in infants who have CHED. Autosomal
recessive CHED is caused by mutations in the SLC4A11 gene. Massive
thickening of the Descemet membrane and endothelial atrophy are present
in most cases. However, a relatively normal density of abnormal-appearing
endothelial cells also has been reported. Patients previously reported as
having autosomal dominant CHED are now thought to have a variant of
posterior polymorphous dystrophy. CHED and progressive sensorineural
deafness occur in Harboyan syndrome, an allelic disorder caused by
SLC4A11 mutations.
Posterior polymorphous dystrophy (PPMD) is an autosomal
dominantly inherited disorder characterized by the presence of irregular
blebs or vacuoles at the level of the Descemet membrane in the posterior

211
cornea. These are often surrounded by a grayish area of mild opacification.
The heterogenous spectrum of disease seen in some kindreds also includes
congenital corneal clouding, trough or gutter-shaped lesions of the
posterior cornea, and peripheral anterior synechia formation that resembles
that seen in the ICE syndrome, but is bilateral. The gutters can be confused
with old Descemet tears caused by obstetrical forceps injuries, but they
lack relucent margins.
PPMD is characterized by the metaplasia and overgrowth of corneal
endothelial cells. The corneal endothelial cells in PPMD have many
properties of corneal epithelial cells (Fig. 6-34). They usually grow in a
multilayered fashion, and electron microscopy discloses cytoplasmic
tonofilaments and numerous surface microvilli. In addition, the endothelial
cells express surface epithelial cytokeratins, particularly cytokeratin 7, 8,
18, and 19. Although some autosomal recessive cases have been reported,
most cases of posterior polymorphous dystrophy are inherited as an
autosomal dominant trait. Mutations in the VSX1, COL8A2, and ZEB1
genes have been implicated in PPMD.

FIG. 6-34. Posterior polymorphous dystrophy. A. The corneal endothelium is

hypercellular. B. Multilayered growth, a surface epithelial characteristic, is
present. C. Endothelial cells disclosed by scanning electron microscopy vary
markedly in size and shape. Numerous microvilli are present on the surface of the
cells. (A. H&E ×100, B. H&E ×250, C. SEM ×1,000.)

XECD is characterized by congenital corneal clouding, subepithelial

keratopathy, and moon crater–like endothelial changes. It has been linked
to Xq25.
Corneal edema occurs in some patients who have the iridocorneal
endothelial or ICE syndrome, which is characterized by unilateral
glaucoma and secondary iris abnormalities caused by a proliferation of
abnormal corneal endothelial cells. This disease spectrum includes the

212
Cogan-Reese and Chandler syndromes and essential iris atrophy. The ICE
syndrome is discussed further in Chapter 8.

CORNEAL MANIFESTATIONS OF
SYSTEMIC DISEASE
Copper deposition in the peripheral part of the Descemet membrane is
manifest clinically as a Kayser-Fleischer ring in patients with Wilson
hepatolenticular degeneration (Fig. 6-35B). An analogous deposit of
copper in the anterior lens capsule causes sunflower cataract (Fig. 4-12B).
Corneal copper deposition has been reported in patients with primary
biliary cirrhosis, familial cholestatic cirrhosis, monoclonal gammopathies
associated with multiple myeloma, and pulmonary carcinoma.

FIG. 6-35. Corneal rings. A. Annulus senilis. Peripheral cornea contains annular
deposit of lipid. B. Kayser-Fleischer ring, Wilson disease. Brownish ring in
peripheral corneal is caused by copper deposition in the Descemet membrane.

Deposits of paraprotein in the cornea may herald the presence of protein

dyscrasias such as multiple myeloma or Waldenstrom macroglobulinemia
(Fig. 6-36). The corneal deposition is quite protean in its manifestations.
Deep polymorphic infiltrates occur in some patients; others develop
polychromatic crystals in the corneal epithelium. Electron microscopy can
demonstrate large scroll-like deposits of immunotactoids, immune
complex-like deposits, and randomly arranged fibrils that are
morphologically intermediate between amyloid and immunotactoid
deposits.

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 FIG. 6-36. Immunoglobulin deposits in protein dyscrasias. A. Corneal crystals,
multiple myeloma. Myriad polychromatic crystals in the corneal epithelium were
the presenting manifestation of multiple myeloma. (Photo courtesy of Dario
Savino-Zari, Caracas, Venezuela.) B. Arrows denote square protein crystals in
corneal epithelial cells. A verticillate epithelial deposit was the presenting
manifestation of Waldenstrom macrogloblulinemia. (B. Masson trichrome ×250.)

Other causes of corneal crystals include cystinosis, gout, Bietti crystalline

dystrophy, and injury by the sap of plants such as the tropical aroid
Dieffenbachia that contains crystalline raphides. Cystine crystals dissolve
in water; preservation necessitates fixation of the cornea in absolute
alcohol.
Cysts of the pars plana and pars plicata are quite common in multiple
myeloma. The cysts in affected patients contain myeloma protein or Bence
Jones protein, which is precipitated by fixation causing the cysts to
become milky white (Fig. 9-25C). Pars plana cysts found incidentally in
elderly patients are filled with hyaluronic acid and are not opacified by
fixation.

CORNEAL TRANSPLANTATION
Corneal transplantation or penetrating keratoplasty involves the excision of
a central disk or button of full-thickness cornea and its replacement with a
new transparent tissue obtained postmortem from a donor. Corneal
transplantation does not require systemic immunosuppression because the
cornea is an avascular structure. Diseases with extensive corneal
vascularization tend to do less well.
Corneal edema caused by endothelial damage or dystrophy is the most
common indication for corneal transplantation in the United States. This
category includes Fuchs dystrophy and pseudophakic or aphakic bullous
keratopathy. Most “failed grafts” also are edematous due to endothelial

214
loss. Keratoconus is another very common indication for transplantation.
Other diseases treated by penetrating keratoplasty including interstitial
keratitis, visually disabling scars, corneal dystrophies, and infectious
keratopathies including chronic herpes simplex stromal keratitis and
bacterial or fungal ulcers. Surgery is performed in acute keratitis when
perforation has occurred or is imminent or occasionally when the identity
of the pathogenetic organism is uncertain.
Several types of partial-thickness lamellar keratoplasty currently are
used to treat patients who previously would have undergone full-thickness
penetrating keratoplasty. These include Descemet stripping endothelial
keratoplasty (DSEK or DSAEK), Descemet membrane endothelial
keratoplasty (DMEK), and deep lamellar anterior keratectomy (DALK)
(Fig. 6-37).

FIG. 6-37. Lamellar keratoplasty. A–C. Failed DSEK. Endothelial graft removed
from eye with failed DSEK. B. Graft comprises posterior stroma and the
Descemet membrane. The endothelium is totally absent. C. Strip of the host
Descemet membrane adheres peripherally to anterior surface of graft. Host
Descemet membrane is thickened with guttate excrescences indicating that DSEK
was performed for Fuchs dystrophy. D. Aborted deep anterior lamellar

215
 keratoplasty (DALK) for keratoconus. Empty spaces in stroma are air bubbles
(pneumatic artifact). The Bowman membrane has characteristic dehiscences. E.
DALK for granular corneal dystrophy. Focus of granular dystrophy in anterior
stroma stains red with Masson trichrome. Pneumatic artifact is present. (PAS
×10, B. PAS ×100, C. PAS ×250, D. PAS ×50, E. Masson trichrome ×250.)

DSEK and DMEK are used to treat edematous corneas with endothelial
decompensation such as Fuchs dystrophy or PBK. In this procedure, the
Descemet membrane and its dysfunctional endothelium are stripped from
the posterior corneal surface. In DSEK, a graft of donor cornea tissue
comprising healthy endothelium, Descemet membrane, and posterior
corneal stroma is inserted in the anterior chamber. The graft adheres to
posterior corneal surface without sutures. In DMEK, which is technically
more challenging, the graft comprises only the Descemet membrane and
endothelium. Some use the term endothelial keratoplasty for such
procedures. Patients recover vision faster and have significantly less
astigmatism after DSEK and DMEK compared to penetrating keratoplasty.
DSEK and DMEK specimens can be sectioned routinely or examined as
flat mounts. Specimens from failed DSEK procedures comprise a thin
lamella of posterior cornea stroma lined by the Descemet membrane with
severe endothelial atrophy (Fig. 6-37A–C). Short segments of residual host
Descemet membrane often adhere to the anterior surface of the graft in its
periphery (Fig. 6-37C). The latter may be thickened with guttae if the
DSEK was done for Fuchs dystrophy.
Deep anterior lamellar keratoplasty (DALK) is used to treat
keratoconus and other pathologies confined to the anterior cornea. A thick
lamella of anterior corneal tissue including the epithelium, Bowman
membrane, and most of the stroma is excised and replaced with a new
graft of donor tissue. The Descemet membrane and the endothelium,
which typically are normal in keratoconus, are not affected. During the
procedure, an injection of air is used to form a surgical plane. As a result,
the stroma contains empty vacuoles called pneumatic artifact (Fig. 6-
36D,E). The posterior surface of the anterior lamella is often irregular.
Specimens from aborted DALK procedures include lamellas of both
anterior and posterior corneal tissue. Intraoperative breaks in the posterior
layer usually necessitate conversion to a full-thickness procedure.
The junction between the corneal flap and posterior stroma may be
nearly invisible in corneal grafts after LASIK-refractive surgery. Interface
epithelialization complicates some cases.

216
THE SCLERA
Sclera specimens are relatively uncommon and typically harbor
inflammatory disease. A superficial infiltrate of lymphocytes and plasma
cells is seen in benign episcleritis. A necrotizing zonal pattern of
granulomatous inflammation analogous to that seen in rheumatoid nodules
characterizes the severe scleritis that complicates rheumatoid arthritis (Fig.
6-38). In nodular episcleritis, the granulomatous reaction is limited to the
episcleral tissues. In severe cases of rheumatoid scleritis (scleromalacia
perforans), affected areas appear blue clinically because severe scleral
thinning causes increased visibility of the underlying pigmented uvea.
Patients who have rheumatoid scleritis are susceptible to the development
of fatal cardiac and pulmonary manifestations of their rheumatoid disease.
Posterior scleritis can mimic a primary uveal neoplasm. Scleritis and
peripheral corneal ulceration can complicate systemic lupus
erythematosus, polyarteritis nodosa, granulomatosis with polyangiitis
(Wegener), and relapsing polychondritis.

FIG. 6-38. Rheumatoid scleritis. A. Thinned areas of the sclera appear blue
because there is increased visibility of the underlying uveal tract. B. A zonal
pattern of granulomatous inflammation identical to that found in a rheumatoid
nodule is seen. A palisading granuloma of epithelioid histiocytes surrounds a
sequestrum of residual devitalized scleral collagen. Necrosis is evident as smudgy
basophilic foci along the lower border of the sequestrum. (H&E ×50.)

BIBLIOGRAPHY
Rodrigues MM, Hidayat AA, Choe HS. Advances in corneal pathology. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.
Ophthalmol Clin North Am 1995;8:83–107.
Spencer WH. Cornea. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and
Textbook. Philadelphia, PA: WB Saunders, 1985:229–388.

217
Starck T, Hersh PS, Kenyon KR. Corneal dysgeneses, dystrophies and
degenerations. In: Albert DM, Jakobiec FA, eds. Principles and Practice of
Ophthalmology: Clinical Practice, vol 1. Philadelphia, PA: WB Saunders,
1994:13–77.

Developmental Lesions
Alkemade P. Dysgenesis Mesodermalis of the Iris and the Cornea. Assen,
Netherlands: Charles C Thomas, 1969.
Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J
Ophthalmol 2000;130:107–115.
Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv
Ophthalmol 2000;44(5):415–425.
Dua HS, Miri A, Alomar T, et al. The role of limbal stem cells in corneal
epithelial maintenance: testing the dogma. Ophthalmology
2009;116(5):856–863.
Espinoza HM, Cox CJ, Semina EV, et al. A molecular basis for differential
developmental anomalies in Axenfeld-Rieger syndrome. Hum Mol Genet
2002;11:743–753.
Gomes J, Eagle RJ, Gomes A, et al. Recurrent keratopathy after penetrating
keratoplasty for aniridia. Cornea 1996;15:457–462.
Green JS, Johnson GJ. Congenital cataract with microcornea and Peters’ anomaly
as expressions of one autosomal dominant gene. Ophthalmic Paediatr Genet
1986;7:187–194.
Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found
in heterogeneous anterior segment malformations including Peters’ anomaly.
Nat Genet 1994;6:168–173.
Henkind P, Siegel IM, Carr RE. Mesodermal dysgenesis of the anterior segment:
Rieger’s anomaly. Arch Ophthalmol 1965;73:810–817.
Hennekam RC, Van Schooneveld MJ, Ardinger HH, et al. The Peters’-Plus
syndrome: description of 16 patients and review of the literature. Clin
Dysmorphol 1993;2:283–300.
Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly. The spectrum of
associated ocular and systemic malformations. Ophthalmic Paediatr Genet
1992;13:137–143.
Kanai A, Wood TC, Polack FM, et al. The fine structure of sclerocornea. Invest
Ophthalmol Vis Sci 1971;10:687–694.
Kim T, Cohen EJ, Schnall BM, et al. Ultrasound biomicroscopy and
histopathology of sclerocornea. Cornea 1998;17:443–445.
Lee H, Khan R, O’Keefe M. Aniridia: current pathology and management. Acta
Ophthalmol 2008;86(7):708–715.
Lee HJ, Colby KA. A review of the clinical and genetic aspects of aniridia. Semin
Ophthalmol 2013;28(5–6):306–312.
Lines MA, Kozlowski K, Walter MA. Molecular genetics of Axenfeld-Rieger

218
 malformations. Hum Mol Genet 2002;11:1177–1184.
Maillette de Buy Wenniger-Prick LJ, Hennekam RC. The Peters’ plus syndrome:
a review. Ann Genet 2002;45:97–103.
Mirzayans F, Pearce WG, MacDonald IM, et al. Mutation of the PAX6 gene in
patients with autosomal dominant keratitis. Am J Hum Genet
1995;57:539–548.
Myles WM, Flanders ME, Chitayat D, et al. Peters’ anomaly: a clinicopathologic
study. J Pediatr Ophthalmol Strabismus 1992;29:374–381.
Netland PA, Scott ML, Boyle JW IV, et al. Ocular and systemic findings in a
survey of aniridia subjects. J AAPOS 2011;15(6):562–566.
Pearce WG, Mielke BW, Hassard DT, et al. Autosomal dominant keratitis: a
possible aniridia variant. Can J Ophthalmol 1995;30:131–137.
Ramaesh K, Ramaesh T, Dutton GN, et al. Evolving concepts on the pathogenic
mechanisms of aniridia related keratopathy. Int J Biochem Cell Biol.
2005;37(3):547–557.
Reese A, Ellsworth R. The anterior chamber cleavage syndrome. Arch
Ophthalmol 1966;75:307–318.
Rieger H. Dysgenesis mesodermalis corneae et iridis. Zeitschrift fur Augenheilk
1935;86:333.
Salmon JF, Wallis CE, Murray AD. Variable expressivity of autosomal dominant
microcornea with cataract. Arch Ophthalmol 1988;106:505–510.
Shields MB. Axenfeld-Rieger syndrome: a theory of mechanism and distinctions
from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc
1983;81:736–784.
Shields M, Buckley E, Klintworth G, et al. Axenfeld-Rieger Syndrome: a
spectrum of developmental disorders. Surv Ophthalmol 1985;29:387–409.
Simpson WA, Parsons MA. The ultrastructural pathological features of congenital
microcoria. A case report. Arch Ophthalmol 1989;107:99–102.
Townsend WM, Font RL, Zimmerman LE. Congenital corneal leukomas. 2.
Histopathologic findings in 19 eyes with central defect in Descemet’s
membrane. Am J Ophthalmol 1974;77:192–206.
Townsend WM. Congenital corneal leukomas. 1. Central defect in Descemet’s
membrane. Am J Ophthalmol 1974;77:80–86.
Traboulsi EI, Maumenee IH. Peters’ anomaly and associated congenital
malformations. Arch Ophthalmol 1992;110:1739–1742.
van Schooneveld MJ, Delleman JW, Beemer FA, et al. Peters’-plus: a new
syndrome. Ophthalmic Paediatr Genet 1984;4:141–145.
Vieira V, David G, Roche O, et al. Identification of four new PITX2 gene
mutations in patients with Axenfeld-Rieger syndrome. Mol Vis
2006;12:1448–1460.
Waring GO III, Rodrigues MM, Laibson PR. Anterior chamber cleavage
syndrome. A stepladder classification. Surv Ophthalmol 1975;20:3–27.

Bacterial Keratitis
219
Bullington RH Jr, Lanier JD, Font RL. Nontuberculous mycobacterial keratitis.
Report of two cases and review of the literature. Arch Ophthalmol
1992;110:519–524.
Dugel PU, Holland GN, Brown HH. Mycobacterium fortuitum keratitis. Am J
Ophthalmol 1988;105:661–669.
Elder MJ, Matheson M, Stapleton F, et al. Biofilm formation in infectious
crystalline keratopathy due to Candida albicans. Cornea 1996;15:301–304.
Elder MJ, Stapleton F, Evans E, et al. Biofilm-related infections in
ophthalmology. Eye 1995;9:102–109.
Foroozan R, Eagle RC Jr, Cohen EJ. Fungal keratitis in a soft contact lens wearer.
CLAO J 2000;26:166–168.
Hunts JH, Matoba AY, Osato MS, et al. Infectious crystalline keratopathy. The
role of bacterial exopolysaccharide. Arch Ophthalmol 1993;111:528–530.
Kailasanathan A, Anderson DF. Infectious crystalline keratopathy caused by
Gemella haemolysans. Cornea 2007;26(5):643–644.
Löffler KU, Witschel H. [Whitish crystalloid corneal deposits. Infectious
crystalline keratopathy in amoebic keratitis]. Ophthalmologe
1998;95(8):576–577. German.
Meisler DM, Langston RH, Naab TJ, et al. Infectious crystalline keratopathy. Am
J Ophthalmol 1984;97:337–343.
Rhem MN, Wilhelmus KR, Font RL. Infectious crystalline keratopathy caused by
Candida parapsilosis. Cornea 1996;15(5):543–545.

Herpetic Keratitis
Cook SD, Hill JH. Herpes simplex virus: molecular biology and the possibility of
corneal latency. Surv Ophthalmol 1991;36: 140–148.
Dawson CR, Hanna L, Wood TR, et al. Adenovirus type 8 keratoconjunctivitis in
the United States. III. Epidemiological, clinical and microbiologic features.
Am J Ophthalmol 1970;69:473–480.
Dawson CR, Togni B, Moore TE Jr. Structural changes in chronic herpetic
keratitis studied by light and electron microscopy. Arch Ophthalmol
1968;79:740–747.

Epidemic Keratoconjunctivitis
Font RL. Chronic ulcerative keratitis caused by herpes simplex virus. Arch
Ophthalmol 1973;90:382–385.
Hendricks RL. An immunologist’s view of herpes simplex keratitis: Thygeson
Lecture 1996. Cornea 1997;16:503–506.
Laibson PR, Dhiri S, Oconer J, et al. Corneal infiltrates in epidemic
keratoconjunctivitis: response to double-blind corticosteroid therapy. Arch
Ophthalmol 1970;84:36–40.
Lee SY. Herpes simplex virus ocular infections. Drugs Today (Barc)

220
 1998;34:241–249.
Liesgang TJ. Biology and molecular aspects of herpes simplex and varicella-
zoster virus infections. Ophthalmology 1992;99: 781–799.
Pepose JS. Herpes simplex keratitis: role of viral infection versus immune
response. Surv Ophthalmol 1991;35:345–352.
Piebenga LW, Laibson PR. Dendritic lesions in herpes zoster ophthalmicus. Arch
Ophthalmol 1973;90:268–270.
Wilhelmus KR, Font RL, Lehmann RP, et al. Cytomegalovirus keratitis in
acquired immunodeficiency syndrome. Arch Ophthalmol 1996;114:869–872.
Zhao Z-S, Granucci F, Yeh L, et al. Molecular mimicry by herpes simplex virus-
type I: autoimmune disease after viral infection. Science
1998;279:1344–1347.

Interstitial Keratitis
Char DH, Cogan DG, Sullivan WR. Immunologic study of non-syphilitic
interstitial keratitis with vestibulo-auditory symptoms. Am J Ophthalmol
1975;80:491–494.
Chynn EW, Jakobiec FA. Cogan’s syndrome: ophthalmic, audiovestibular, and
systemic manifestations and therapy. Int Ophthalmol Clin 1996;36:61–72.
Waring GO, Font RL, Rodrigues MM, et al. Alterations of Descemet’s membrane
in interstitial keratitis. Am J Ophthalmol 1976;81:773–785.

Acanthamoeba Keratitis
Auran JD, Starr MB, Jakobiec FA. Acanthamoeba keratitis: a review of the
literature. Cornea 1987;62:2–26.
Clarke DW, Niederkorn JY. The pathophysiology of Acanthamoeba keratitis.
Trends Parasitol 2006;22:175–180.
Davis RM, Schroeder RP, Rowsey JJ, et al. Acanthamoeba keratitis and
infectious crystalline keratopathy. Arch Ophthalmol.
1987;105(11):1524–1527.
Garner A. Pathogenesis of Acanthamoebic Keratitis: hypothesis based on a
histological analysis of 30 cases. Br J Ophthalmol 1993;77:366–370.
Grossniklaus HE, Waring GO IV, Akor C, et al. Evaluation of hematoxylin and
eosin and special stains for the detection of acanthamoeba keratitis in
penetrating keratoplasties. Am J Ophthalmol. 2003;136(3):520–526.
Kremer I, Cohen EJ, Eagle RC Jr, et al. Histopathologic evaluation of stromal
inflammation in Acanthamoeba keratitis. CLAO J 1994;20:45–48.
Marines HC, Osato MS, Font RL. The value of calcofluor white in the diagnosis
of mycotic and Acanthamoeba infections of the eye and ocular adnexa.
Ophthalmology 1987;94:23–26.
Mathers W, Stevens G Jr, Rodrigues M, et al. Immunopathology and electron
microscopy of Acanthamoeba keratitis. Am J Ophthalmol 1987;103:626–635.

221
Mietz H, Font RL. Acanthamoeba keratitis with granulomatous reaction involving
the stroma and anterior chamber. Arch Ophthalmol 1997;115:259–263.
Thebpatiphat N, Hammersmith KM, Rocha FN, et al. Acanthamoeba keratitis: a
parasite on the rise. Cornea 2007;26:701–706.
Tu EY, Joslin CE, Nijm LM, et al. Polymicrobial keratitis: Acanthamoeba and
infectious crystalline keratopathy. Am J Ophthalmol
2009;148(1):13.e2–19.e2.
Vemuganti GK, Pasricha G, Sharma S, et al. Granulomatous inflammation in
Acanthamoeba keratitis: an immunohistochemical study of five cases and
review of literature. Indian J Med Microbiol 2005;23:231–238.

Other Types of Parasitic and Protozoal Keratitis

Chan CC, Ottesen EA, Awadzi K, et al. Immunopathology of ocular
onchocerciasis. I. Inflammatory cells infiltrating the anterior segment. Clin
Exp Immunol 1989;77:367–372.
Font RL, Su GW, Matoba AY. Microsporidial stromal keratitis. Arch Ophthalmol
2003;121:1045–1047.
Hall LR, Pearlman E. Pathogenesis of onchocercal keratitis (River blindness).
Clin Microbiol Rev 1999;12:445–453.
Paul EV, Zimmerman LE. Some observations on the ocular pathology of
onchocerciasis. Hum Pathol 1970;1:581–594.
Pearlman E, Gillette-Ferguson I. Onchocerca volvulus, Wolbachia and river
blindness. Chem Immunol Allergy 2007;92:254–265.
Pearlman E, Hall LR, Higgins AW, et al. The role of eosinophils and neutrophils
in helminth-induced keratitis. Invest Ophthalmol Vis Sci 1998;39:1176–1182.
Tamarozzi F, Halliday A, Gentil K, et al. Onchocerciasis: the role of Wolbachia
bacterial endosymbionts in parasite biology, disease pathogenesis, and
treatment. Clin Microbiol Rev 2011;24(3):459–468.
Tiner JD. Birefringent spores differentiate Encephalitozoon and other
microsporidia from coccidia. Vet Pathol 1988;25(3):227–230.
Walker M, Specht S, Churcher TS, et al. Therapeutic efficacy and
macrofilaricidal activity of doxycycline for the treatment of river blindness.
Clin Infect Dis 2015;60(8):1199–1207.

Peripheral Corneal Ulcerations

Ahmed M, Niffenegger JH, Jakobiec FA, et al. Diagnosis of limited ophthalmic
Wegener granulomatosis: distinctive pathologic features with ANCA test
confirmation. Int Ophthalmol 2008;28:35–46.
Austin P, Green WR, Sallyer DC, et al. Peripheral corneal degeneration and
occlusive vasculitis in Wegener’s granulomatosis. Am J Ophthalmol
1978;85:311–317.
Brown SI. Mooren’s ulcer. Histopathology and proteolytic enzymes of adjacent

222
 conjunctiva. Br J Ophthalmol 1975;59:670–674.
Brown SI, Mondino BJ, Rabin BS. Autoimmune phenomenon in Mooren’s ulcer.
Am J Ophthalmol 1976;82:835–840.
Frayer WC. The histopathology of perilimbal ulceration in Wegener’s
granulomatosis. Arch Ophthalmol 1960;64:88–94.
Gottsch JD, Li Q, Ashraf F, et al. Cytokine-induced calgranulin C expression in
keratocytes. Clin Immunol 1999;91(1):34–40.
Gottsch JD, Liu SH, Minkovitz JB, et al. Autoimmunity to a cornea-associated
stromal antigen in patients with Mooren’s ulcer. Invest Ophthalmol Vis Sci
1995;36(8):1541–1547.
Guyer DR, Barraquer J, McDonnell PJ, et al. Terrien’s marginal degeneration:
clinicopathologic case reports. Graefes Arch Clin Exp Ophthalmol
1987;225:19–27.
Moazami G, Auran JD, Florakis GJ, et al. Interferon treatment of Mooren’s ulcers
associated with hepatitis C. Am J Ophthalmol 1995;119:365–366.

Corneal Degenerations
Austin P, Jakobiec FA, Iwamoto T. Elastodysplasia and elastodystrophy as the
pathologic bases of ocular pterygia and pinguecula. Ophthalmology
1983;90:96–109.
Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism.
Surv Ophthalmol 1991;36:1–22.
Chui J, Coroneo MT, Tat LT, et al. Ophthalmic pterygium: a stem cell disorder
with premalignant features. Am J Pathol 2011;178(2):817–827.
Cogan DG, Albright F, Bartter FC. Hypercalcemia and band keratopathy. Report
of nineteen cases. Arch Ophthalmol 1940;40:624–638.
Cursino JW, Fine BS. A histologic study of calcific and noncalcific band
keratopathy. Am J Ophthalmol 1976;82:395–404.
Detorakis ET, Spandidos DA. Pathogenetic mechanisms and treatment options for
ophthalmic pterygium: trends and perspectives (Review). Int J Mol Med
2009;23(4):439–447.
Dua HS, Miri A, Said DG. Contemporary limbal stem cell transplantation—a
review. Clin Exp Ophthalmol 2010;38:104–117.
Dua HS, Saini JS, Azuara-Blanco A, et al. Limbal stem cell deficiency: concept,
aetiology, clinical presentation, diagnosis and management. Indian J
Ophthalmol 2000;48:83–89.
Dua HS, Shanmuganathan VA, Powell-Richards AO, et al. Limbal epithelial
crypts: a novel anatomical structure and a putative limbal stem cell niche. Br J
Ophthalmol 2005;89:529–532.
Dushku N, Hatcher SL, Albert DM, et al. p53 expression and relation to human
papillomavirus infection in pingueculae, pterygia, and limbal tumors. Arch
Ophthalmol 1999;117(12):1593–1599.
Eagle RC Jr, Dillon EC, Laibson PR. Compensatory epithelial hyperplasia in

223
 human corneal disease. Trans Am Ophthalmol Soc 1992;90:265–273;
discussion 74–76.
Freedman A. Climatic droplet keratopathy. I Clinical aspects. Arch Ophthalmol
1973;89:193–197.
Freedman A. Labrador keratopathy and related diseases. Can J Ophthalmol
1973;8:286–290.
Gray RH, Johnson GJ, Freedman A. Climatic Droplet Keratopathy. Surv
Ophthalmol 1992;36:241–253.
Hida T, Kigasawa K, Tanaka E, et al. Primary band-shaped spheroidal
degeneration of the cornea: three cases from two consanguineous families. Br
J Ophthalmol 1986;70:347–353.
Hogan MJ, Alvarado J. Pterygium and pinguecula: electron microscopic study.
Arch Ophthalmol 1967;78:174–186.
Klintworth GK. Chronic actinic keratopathy—a condition associated with
conjunctival elastosis (pingueculae) and typified by characteristic
extracellular concretions. Am J Pathol 1972;67:327–342.
Nevyas AS, Raber IM, Eagle RC Jr, et al. Acute band keratopathy following
intracameral Viscoat. Arch Ophthalmol 1987;105: 958–964.
Ormerod LD, Dahan E, Hagele JE, et al. Serious occurrences in the natural
history of advanced climatic keratopathy. Ophthalmology 1994;101:448–453.
Rodrigues MM, Laibson PR, Weinreb S. Corneal elastosis. Appearance of band-
like keratopathy and spheroidal degeneration. Arch Ophthalmol
1975;93:111–114.
Secker GA, Daniels JT. Corneal epithelial stem cells: deficiency and regulation.
Stem Cell Rev 2008;4:159–168.
Tsai YY, Chang KC, Lin CL, et al. p53 Expression in pterygium by
immunohistochemical analysis: a series report of 127 cases and review of the
literature. Cornea 2005;24(5):583–586.
Vannas A, Hogan MJ, Wood I. Salzmann’s nodular degeneration of the cornea.
Am J Ophthalmol 1975;79:211–219.

Vitamin A Deficiency
Sjögren H, Bloch K. Keratoconjunctivitis sicca and the Sjögren syndrome. Surv
Ophthalmol 1971;16:145–159.
Smith RS, Farrell T, Bailey T. Keratomalacia. Surv Ophthalmol
1975;20:213–219.
Suan EP, Bedrossian EH Jr, Eagle RC Jr, et al. Corneal perforation in patients
with vitamin A deficiency in the United States. Arch Ophthalmol
1990;108:350–353.
Venkataswamy G. Ocular manifestations of vitamin A deficiency. Br J
Ophthalmol 1967;51:854–859.

Keratoconus
224
Aldave AJ, Yellore VS, Salem AK, et al. No VSX1 gene mutations associated
with keratoconus. Invest Ophthalmol Vis Sci 2006;47:2820–2822.
Barraquer-Somers E, Chan CC, Green WR. Corneal epithelial iron deposition.
Ophthalmology 1983;90:729–734.
Cremona FA, Ghosheh FR, Rapuano CJ, et al. Keratoconus associated with other
corneal dystrophies. Cornea 2009;28:127–135.
Dash DP, George S, O’Prey D, et al. Mutational screening of VSX1 in
keratoconus patients from the European population. Eye (Lond)
2010;24:1085–1092.
Dua HS, Saini JS, Azuara-Blanco A, et al. Limbal stem cell deficiency: concept,
aetiology, clinical presentation, diagnosis and management. Indian J
Ophthalmol 2000;48(2):83–92.
Edwards M, McGhee CN, Dean S. The genetics of keratoconus. Clin Experiment
Ophthalmol 2001;29:345–351.
Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber’s congenital
amaurosis. Age-related findings in 35 patients. Ophthalmology
1992;99:241–245.
Kenney MC, Chwa M, Opbroek AJ, et al. Increased gelatinolytic activity in
keratoconus keratocyte cultures. A correlation to an altered matrix
metalloproteinase-2/tissue inhibitor of metalloproteinase ratio. Cornea
1994;13:114–124.
Kenney MC, Nesburn AB, Burgeson RE, et al. Abnormalities of the extracellular
matrix in keratoconus corneas. Cornea 1997;16:345–351.
Klintworth GK, Damms T. Corneal dystrophies and keratoconus. Curr Opin
Ophthamol 1995;6:44–56.
Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory
corneal thinning disorders. Surv Ophthalmol 1984;28:293–322.
Kremer I, Eagle RC, Rapuano CJ, et al. Histologic evidence of recurrent
keratoconus seven years after keratoplasty. Am J Ophthalmol
1995;119:511–512.
Rabinowitz YS. The genetics of keratoconus. Ophthalmol Clin North Am
2003;16:607–620.
Tyynismaa H, Sistonen P, Tuupanen S, et al. A locus for autosomal dominant
keratoconus: linkage to 16q22.3-q23.1 in Finnish families. Invest Ophthalmol
Vis Sci 2002;43:3160–3164.
Wang Y, Rabinowitz YS, Rotter JI, et al. Genetic epidemiological study of
keratoconus: evidence for major gene determination. Am J Med Genet
2000;93:403–409.
Whitelock RB, Fukuchi T, Zhou L, et al. Cathepsin G, acid phosphatase, and
alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas.
Invest Ophthalmol Vis Sci 1997;38:529–534.
Whitelock RB, Li Y, Zhou LL, et al. Expression of transcription factors in
keratoconus, a cornea-thinning disease. Biochem Biophys Res Commun
1997;235:253–258.

225
Corneal Dystrophies
Afshari NA, Bouchard CS, Colby KA, et al. Corneal dystrophies and ectasias. In:
Weisenthal RW, ed. 2014–2015 Basic and Clinical Science Course, Section
8: External Disease and Cornea. San Francisco, CA: American Academy of
Ophthalmology, 2014:253–287.
Aldave AJ, Han J, Frausto RF. Genetics of the corneal endothelial dystrophies: an
evidence-based review. Clin Genet 2013;84:109–119.
Kannabiran C, Klintworth GK. TGFBI gene mutations in corneal dystrophies.
Hum Mutat 2006;27:615–625.
Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J
Ophthalmol 1999;128:747–754.
Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis 2009;4:7.
Klintworth GK. The molecular genetics of the corneal dystrophies—current
status. Front Biosci 2003;8:d687–d713.
Møller HU. “Corneal dystrophies”. In: Hoyt C, Taylor D, eds. Paediatric
Ophthalmology and Strabismus. 4th ed. Elsevier Science, 2012:323–328.
Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies
—edition 2. Cornea. 2015;34(2):117–159.
Weiss JS, Moller HU, Lisch W, et al. The IC3D classification of the corneal
dystrophies. Cornea 2008;27(suppl 2):S1–S83.

Epithelial and Bowman’s Membrane Dystrophies

Burns RP. Meesmann’s corneal dystrophy. Trans Am Ophthalmol Soc
1968;66:530–635.
Corden L. Molecular genetics of Meesmann’s corneal dystrophy: ancestral and
novel mutations in keratin 12 (K12) and complete sequence of the human
KRT12 gene. Exp Eye Res 2000;70:41–49.
Dota A, Nishida K, Honma Y, et al. Gelatinous drop-like corneal dystrophy is not
one of the beta ig-h3- mutated corneal amyloidoses. Am J Ophthalmol
1998;126:832–833.
Franceschetti A. Hereditaere rezidivierende Erosion der Hornhaut. Z Augenheilk
1928;66:309–316.
Hammar B, Bjöerck E, Lagerstedt K, et al. A new corneal disease with recurrent
erosive episodes and autosomal-dominant inheritance. Acta Ophthalmol
2008;86:758–763.
Hammar B, Bjöerck E, Lind H, et al. Dystrophia Helsinglandica: a new type of
hereditary corneal recurrent erosions with late subepithelial fibrosis. Acta
Ophthalmol 2009;87:659–665.
Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin
K3 or K12 genes cause Meesmann’s corneal dystrophy. Nat Genet
1997;16:184–187.
Klintworth GK, Sommer JR, Obrian G, et al. Familial subepithelial corneal

226
 amyloidosis (gelatinous drop-like corneal dystrophy): exclusion of linkage to
lactoferrin gene. Mol Vis 1998;4:31.
Klintworth GK, Valnickova Z, Kielar RA, et al. Familial subepithelial corneal
amyloidosis—a lactoferrin-related amyloidosis. Invest Ophthalmol Vis Sci
1997;38:2756–2763.
Kuchle M, Green WR, Volcker HE, et al. Reevaluation of corneal dystrophies of
Bowman’s layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke
types): a light and electron microscopic study of eight corneas and a review of
the literature. Cornea 1995;14:333–354.
Kuwabara T, Ciccarelli EC. Meesmann’s corneal dystrophy. A pathological
study. Arch Ophthalmol 1964;71:676–682.
Li S, Edward DP, Ratnakar KS, et al. Clinicohistopathological findings of
gelatinous droplike corneal dystrophy among Asians. Cornea
1996;15:355–362.
Lisch W, Bron AJ, Munier FL, et al. Franceschetti hereditary recurrent corneal
erosion. Am J Ophthalmol 2012;153:1073.e4–1081.e4.
Lisch W, Kivelä T. Individual phenotypic variances in a family with Thiel-
Behnke corneal dystrophy. Cornea 2013;32:e192–e193.
Lohse E, Stock LE, Jones JC, et al. Reis-Büecklers’ corneal dystrophy.
Immunofluorescent and electron microscopic studies. Cornea
1989;8:200–209.
Nakamura H, Li FT, Folterman MO, et al. Individual phenotypic variances in a
family with Thiel-Behnke corneal dystrophy. Cornea2012;31:1217–1222.
Nishida K, Honma Y, Dota A, et al. Isolation and chromosomal localization of a
cornea-specific human keratin 12 gene and detection of four mutations in
Meesmann corneal epithelial dystrophy. Am J Hum Genet
1997;61:1268–1275.
Perry HD, Fine BS, Caldwell DR. Reis-Bücklers dystrophy: a study of eight
cases. Arch Ophthalmol 1979;97:664–670.
Quantock AJ, Nishida K, Kinoshita S. Histopathology of recurrent gelatinous
drop-like corneal dystrophy. Cornea 1998;17:215–221.
Rodrigues MM, Fine BS, Laibson PR, et al. Disorders of the corneal epithelium—
a clinicopathologic study of dot, geographic and fingerprint patterns. Arch
Ophthalmol 1974;92:475–482.
Small KW, Mullen L, Barletta J, et al. Mapping of Reis-Bucklers’ corneal
dystrophy to chromosome 5q. Am J Ophthalmol 1996;121: 384–390.
Sullivan LS, Baylin EB, Font R, et al. A novel mutation of the Keratin 12 gene
responsible for a severe phenotype of Meesmann’s corneal dystrophy. Mol Vis
2007;13:975–980.
Tsujikawa M, Kurahashi H, Tanaka T, et al. Homozygosity mapping of a gene
responsible for gelatinous drop-like corneal dystrophy to chromosome 1p. Am
J Hum Genet 1998;63:1073–1077.
Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of
the epithelium, Bowman’s layer and stroma. Surv Ophthalmol

227
 1978;23:71–122.
Weber FL, Babel J. Gelatinous drop-like dystrophy. A form of primary corneal
amyloidosis. Arch Ophthalmol 1980;98:144–148.
Yee RW, Sullivan LS, Lai HT, et al. Linkage mapping of Thiel-Behnke corneal
dystrophy (CDB2) to chromosome 10q23-q24. Genomics 1997;46:152–154.

Stromal Dystrophies
Aldave AJ, Edward DP, Park AJ, et al. Central discoid corneal dystrophy. Cornea
2002;21:739–744.
Belliveau MJ, Brownstein S, Agapitos P, et al. Ultrastructural features of
posterior crocodile shagreen of the cornea. Surv Ophthalmol
2009;54:569–575.
Bramsen T, Ehlers N, Baggesen LH. Central cloudy corneal dystrophy of
François. Acta Ophthalmol (Copenh) 1976;54:221–226.
Edward DP, Thonar EJ, Srinivasan M, et al. Macular dystrophy of the cornea: a
systemic disorder of keratan sulfate metabolism. Ophthalmology
1990;97:1194–1200.
François J. Une nouvelle dystrophie hérédo-familiale de la cornée. J Genet Hum
1956;5:189–196.
Garner A, Tripathi RC. Hereditary crystalline stromal dystrophy of Schnyder. II.
Histopathology and ultrastructure. Br J Ophthalmol 1972;56:400–408.
Gaynor PM, Zhang WY, Weiss JS, et al. Accumulation of HDL apolipoproteins
accompanies abnormal cholesterol accumulation in Schnyder’s corneal
dystrophy. Arterioscler Thromb Vasc Biol 1996;16:992–999.
Haltia M, Levy E, Meretoja J, et al. Gelsolin gene mutation—at codon 187—in
familial amyloidosis, Finnish: DNA-diagnostic assay. Am J Med Genet
1992;42:357–359.
Hassell JR, Klintworth GK. Serum sulfotransferase levels in patients with
macular corneal dystrophy type I. Arch Ophthalmol 1997;115:1419–1421.
Hirano K, Klintworth GK, Zhan Q et al. Beta ig-h3 is synthesized by corneal
epithelium and perhaps endothelium in Fuchs dystrophic corneas. Curr Eye
Res 1996;15:965–972.
Hogan MJ, Albarado J. Ultrastructure of lattice dystrophy of the cornea. A case
report. Am J Ophthalmol 1967;64:656–660.
Jonasson F, Oshima E, Thonar EJ, et al. Macular corneal dystrophy in Iceland. A
clinical, genealogic, and immunohistochemical study of 28 patients.
Ophthalmology 1996;103:1111–1117.
Jones ST, Zimmerman LE. Histopathologic differentiation of granular, macular,
and lattice dystrophies of the cornea. Am J Ophthalmol 1961;51:394–410.
Karp CL, Scott IU, Green WR, et al. Central cloudy corneal dystrophy of
François. A clinicopathologic study. Arch Ophthalmol 1997;115:1058–1062.
Kivela T, Tarkkanen A, Frangione B, et al. Ocular amyloid deposition in familial
amyloidosis, Finnish: an analysis of native and variant gelsolin in Meretoja’s

228
 syndrome. Invest Ophthalmol Vis Sci 1994;35:3759–3769.
Kivela T, Tarkkanen A, McLean I, et al. Immunohistochemical analysis of lattice
corneal dystrophies types I and II. Br J Ophthalmol 1993;77:799–804.
Klintworth Chang TS, Culbertson WW. Central cloudy corneal dystrophy of
Francois. A clinicopathologic study. Arch Ophthalmol 1997;115:1058–1062.
Klintworth GK, Oshima E, al-Rajhi A, et al. Macular corneal dystrophy in Saudi
Arabia: a study of 56 cases and recognition of a new immunophenotype. Am J
Ophthalmol 1997;124:9–18.
Klintworth GK. Lattice corneal dystrophy. An inherited variety of amyloidosis
restricted to the cornea. Am J Pathol 1967;50: 371–399.
Liu NP, Baldwin J, Lennon F, et al. Coexistence of macular corneal dystrophy
types I and II in a single sibship. Br J Ophthalmol 1998;82:241–244.
Loeffler KU, Edward DP, Tso MO. An immunohistochemical study of gelsolin
immunoreactivity in corneal amyloidosis. Am J Ophthalmol
1992;113:546–554.
Mannis MJ, Krachmer JH, Rodrigues MM, et al. Polymorphic amyloid
degeneration of the cornea. A clinical and histopathologic study. Arch
Ophthalmol 1981;99:1217–1223.
McCarthy M, Innis S, Dubord P, et al. Panstromal Schnyder corneal dystrophy: a
clinical pathologic report with quantitative analysis of corneal lipid
composition. Ophthalmology 1994;101:895–901.
Meretoja J. Familial systemic paramyloidosis with lattice dystrophy of the cornea,
progressive cranial neuropathy, skin changes and various internal symptoms.
A previously unrecognized heritable syndrome. Ann Clin Res
1969;1:314–324.
Meyer JC, Quantock AJ, Thonar EJ, et al. Characterization of a central corneal
cloudiness sharing features of posterior crocodile shagreen and central cloud
dystrophy of Francois. Cornea 1996;15:347–354.
Munier FL, Korvatska E, Djemai A, et al. Kerato-epithelin mutations in four
5q31-linked corneal dystrophies Nat Genet 1997;15:247–251.
Nicholson DH, Green WR, Cross HE, et al. A clinical and histopathological study
of François-Neetens speckled corneal dystrophy. Am J Ophthalmol
1977;83:554–560.
Orr A, Dubé MP, Marcadier J, et al. Mutations in the UBIAD1 gene, encoding a
potential prenyltransferase, are causal for Schnyder crystalline corneal
dystrophy. PLoS One 2007;2:e685.
Purcell JJ Jr, Rodrigues M, Chishti MI, et al. Lattice corneal dystrophy associated
with familial systemic amyloidosis (Meretoja’s syndrome). Ophthalmology
1983;90:1512–1517.
Shearman AM, Hudson TJ, Andresen JM, et al. The gene for schnyder’s
crystalline corneal dystrophy maps to human chromosome 1p34.1-p36. Hum
Mol Genet 1996;5:1667–1672.
Starck T, Kenyon KR, Hanninen LA, et al. Clinical and histopathologic studies of
two families with lattice corneal dystrophy and familial systemic amyloidosis

229
 (Meretoja syndrome). Ophthalmology 1991;98:1197–1206.
Stone EM, Mathers WD, Rossenwasser GOD, et al. Three autosomal dominant
corneal dystrophies map to chromosome 5q. Nat Genet 1994;6:47–51.
Strachan IM. Cloudy central corneal dystrophy of François. Five cases in the
same family. Br J Ophthalmol 1969;53:192–194.
Streeten BW, Qi Y, Klintworth GK, et al. Immunolocalization of beta ig-h3
protein in 5q31-linked corneal dystrophies and normal corneas. Arch
Ophthalmol 1999;117:67–75.
Vance JM, Jonasson F, Lennon F, et al. Linkage of a gene for macular corneal
dystrophy to chromosome 16. Am J Hum Genet 1996;58:757–762.
Varssano D, Cohen EJ, Nelson LB, et al Corneal transplantation in Maroteaux-
Lamy syndrome. Arch Ophthalmol 1997;115:428–429.
Weiss JS, Kruth HS, Kuivaniemi H, et al. Mutations in the UBIAD1 gene on
chromosome short arm 1, region 36 cause Schnyder crystalline corneal
dystrophy. Invest Ophthalmol Vis Sci 2007;48:5007–5012.
Weiss JS, Wiaux C, Yellore V, et al. Reported p.Asp240Asn mutation in
UBIAD1 suggests central discoid corneal dystrophy is a variant of Schnyder
corneal dystrophy. Cornea 2010;29:777–780.
Weiss JS. Schnyder crystalline dystrophy sine crystals. Recommendation for a
revision of nomenclature. Ophthalmology 1996;103:465–473.
Weiss JS. Schnyder’s dystrophy of the cornea. A Swede-Finn connection. Cornea
1992;11:93–101.
Weiss JS. Visual morbidity in 34 families with Schnyder’s crystalline corneal
dystrophy. A clinical pathologic report with quantitative analysis of corneal
lipid composition. Ophthalmology 1994;101:895–901.
Weller RO, Rodger FC. Crystalline stromal dystrophy: histochemistry and
ultrastructure of the cornea. Br J Ophthalmol 1980;64:46–52.
Wilson DJ, Weleber RG, Klein ML, et al. Bietti’s crystalline dystrophy. A
clinicopathologic correlative study. Arch Ophthalmol 1989;107:213–221.

Endothelial Dystrophies
Adamis AP, Filatov V, Tripathi Bj, et al. Fuchs endothelial dystrophy of the
cornea. Surv Ophthalmol 1993;38:149–168.
Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene
encoding the alpha2 chain of type VIII collagen, cause two forms of corneal
endothelial dystrophy. Hum Mol Genet. 2001;10(21):2415–2423.
Chan C, Green WR, Barraquer J. Similarities between posterior polymorphous
and congenital hereditary endothelial dystrophies: a study of 14 buttons in 11
cases. Cornea 1982;1:155–172.
Cibis G, Krachmer J, Phelps C, et al. Iridocorneal adhesions in posterior
polymorphous dystrophy. Trans Am Acad Ophthalmol Otolaryngol
1976;81:770–777.
Cibis G, Krachmer J, Phelps C, et al. The clinical spectrum of posterior

230
 polymorphous dystrophy. Arch Ophthalmol 1977;95:1529–1537.
Desir J, Moya G, Reish O, et al. Borate transporter SLC4A11 mutations cause
both Harboyan syndrome and non-syndromic corneal endothelial dystrophy. J
Med Genet 2007;44(5):322–326.
Ehlers N, Módis L, Møller-Pedersen T. A morphological and functional study of
Congenital Hereditary Endothelial Dystrophy. Acta Ophthalmol Scand
1998;76(3):314–318.
Fuchs E. Dystrophia epithelialis corneae. Arch Ophthalmol 1910;76:478–508.
Hamill CE, Schmedt T, Jurkunas U. Fuchs endothelial cornea dystrophy:a review
of the genetics behind disease development. Semin Ophthalmol
2013;28:281–286.
Hanna C, Fraunfelder FT, McNair JR. An ultrastructure study of posterior
polymorphous dystrophy of the cornea. Ann Ophthalmol 1977;9:1371–1378.
Heon E, Mathers WD, Alward WL, et al. Linkage of posterior polymorphous
corneal dystrophy to 20q11. Hum Mol Genet 1995;4:485–488.
Hirst LW, Bancroft J, Yamauchi K, et al. Immunohistochemical pathology of the
corneal endothelium in iridocorneal endothelial syndrome. Invest Ophthalmol
Vis Sci 1995;36:820–827.
Jirsova K, Merjava S, Martincova R, et al. Immunohistochemical characterization
of cytokeratins in the abnormal corneal endothelium of posterior
polymorphous corneal dystrophy patients. Exp Eye Res 2007;84:680–686.
Kodaganur SG, Kapoor S, Veerappa AM, et al. Mutation analysis of the
SLC4A11 gene in Indian families with congenital hereditary endothelial
dystrophy 2 and a review of the literature. Mol Vis 2013;19:1694–1706. Print
2013. Review.
Krachmer JH, Purcell JJ Jr, Young CW, et al. Corneal endothelial dystrophy. A
study of 64 families. Arch Ophthalmol 1978;96:2036–2039.
Levy SG, Moss J, Noble BA, et al. Early-onset posterior polymorphous
dystrophy. Arch Ophthalmol 1996;114:1265–1268.
Levy SG, Moss J, Sawada H, et al. The composition of wide-spaced collagen in
normal and diseased Descemet membrane. Curr Eye Res 1996;15:45–52.
Lisch W, Buob M, Steuhl KP. [Cornea guttata and Fuchs’ endothelial-epithelial
dystrophy. Clinico- histologic study of 73 patients]. Klin Monatsbl
Augenheilkd 1991;198:83–86.
McCartney AC, Kirkness CM. Comparison between posterior polymorphous
dystrophy and congenital hereditary endothelial dystrophy of the cornea. Eye
1988;2:63–70.
Molia LM, Lanier JD, Font RL. Posterior polymorphous dystrophy associated
with posterior amyloid degeneration of the cornea. Am J Ophthalmol
1999;127:86–88.
Riazuddin SA, Vithana EN, Seet LF, et al. Missense mutations in the sodium
borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy.
Hum Mutat 2010;31(11):1261–1268.
Riazuddin SA, Zaghloul NA, et al. Missense mutations in TCF8 cause late-onset

231
 Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J
Hum Genet 2010;86:45–53.
Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the
pathogenesis of posterior polymorphous dystrophy. Arch Ophthalmol
1995;113:340–345.
Schmid E, Lisch W, Philipp W, et al. A new, X-linked endothelial corneal
dystrophy. Am J Ophthalmol 2006;141:478–487.
Sekundo W, Lee WR, Kirkness CM, et al. An ultrastructural investigation of an
early manifestation of the posterior polymorphous dystrophy of the cornea.
Ophthalmology 1994;101:1422–1431.
Siddiqui S, Zenteno JC, Rice A, et al. Congenital hereditary endothelial dystrophy
caused by SLC4A11 mutations progresses to Harboyan syndrome. Cornea
2014;33(3):247–251.
Soumittra N, Loganathan SK, Madhavan D, et al., Biosynthetic and functional
defects in newly identified SLC4A11 mutants and absence of COL8A2
mutations in Fuchs endothelial corneal dystrophy. J Hum Genet
2014;59(8):444–453.
Toma NM, Ebenezer ND, Inglehearn CF, et al. Linkage of congenital hereditary
endothelial dystrophy to chromosome 20. Hum Mol Genet 1995;4:2395–2398.
Vemuganti GK, Sridhar MS, Edward DP, et al. Subepithelial amyloid deposits in
congenital hereditary endothelial dystrophy: a histopathologic study of five
cases. Cornea 2002;21(5):524–529.
Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies. II. Endothelial
dystrophies. Surv Ophthalmol 1978;23:147–168.

The Cornea in Systemic Disease

Alomar TS, Nubile M, Lowe J, et al. Corneal intraepithelial neoplasia: in vivo
confocal microscopic study with histopathologic correlation. Am J
Ophthalmol 2011;151(2):238–247.
Auran JD, Donn A, Hyman GA. Multiple myeloma presenting as vortex
crystalline keratopathy and complicated by endocapsular hematoma. Cornea
1992;11:584–585.
Ayres BD, Rapuano CJ. Excimer laser phototherapeutic keratectomy. Ocul Surf
2006;4:196–206.
Barr CC, Gelender H, Font RL. Corneal crystalline deposits associated with
dysproteinemia. Report of two cases and review of the literature. Arch
Ophthalmol 1980;98:884–889.
Font RL, Matoba AY, Prabhakaran VC. IgG-kappa immunoglobulin deposits
involving the predescemetic region in a patient with multiple myeloma.
Cornea 2006;25:1237–1239.
Garibaldi DC, Gottsch J, de la Cruz Z, et al. Immunotactoid keratopathy: a
clinicopathologic case report and a review of reports of corneal involvement
in systemic paraproteinemias. Surv Ophthalmol 2005;50(1):61–80.

232
Ghosheh FR, Cremona F, Ayres BD, et al. Indications for penetrating
keratoplasty and associated procedures, 2001-2005. Eye Contact Lens
2008;34:211–214.
Graichen DF, Perez E, Jones DB, et al. kappa-Immunoglobulin corneal deposits
associated with monoclonal gammopathy. Immunohistochemical and electron
microscopic findings. Ger J Ophthalmol 1994;3:54–57.
Gu X, Barrios R, Cartwright J, et al. Light chain crystal deposition as a
manifestation of plasma cell dyscrasias: the role of immunoelectron
microscopy. Hum Pathol 2003;34:270–277.
Lisch W, Saikia P, Pitz S, et al. Chameleon-like appearance of immunotactoid
keratopathy. Cornea 2012;31:55–58.
Liu M, Cohen EJ, Brewer GJ, et al. Kayser-Fleischer ring as the presenting sign
of Wilson disease. Am J Ophthalmol 2002;133:832–834.
Lois N, Kowal VO, Cohen EJ, et al. Indications for penetrating keratoplasty and
associated procedures, 1989-1995. Cornea 1997;16:623–629.
Marcon AS, Cohen EJ, Rapuano CJ, et al. Recurrence of corneal stromal
dystrophies after penetrating keratoplasty. Cornea 2003;22:19–21.
Milman T, Kao AA, Chu D, et al. Paraproteinemic keratopathy: the expanding
diversity of clinical and pathologic manifestations. Ophthalmology
2015;122(9):1748–1756.
Perry HD, Donnenfeld ED, Font RL. Intraepithelial corneal immunoglobulin
crystals in IgG-kappa multiple myeloma. Cornea 1993;12:448–450.
Ramsay AS, Lee WR, Mohammed A. Changing indications for penetrating
keratoplasty in the west of Scotland from 1970 to 1995. Eye 1997;11(Pt
3):357–360.
Stirling JW, Henderson DW, Rozenbilds MA, et al. Crystalloidal paraprotein
deposits in the cornea: an ultrastructural study of two new cases with tubular
crystalloids that contain IgG kappa light chains and IgG gamma heavy chains.
Ultrastruct Pathol 1997;21: 337–344.
Tso MO, Fine BS, Thorpe HE. Kayser-Fleischer ring and associated cataract in
Wilson’s disease. Am J Ophthalmol 1975;79:479–488.
Tzelikis PF, Laibson PR, Ribeiro MP, et al. Ocular copper deposition associated
with monoclonal gammopathy of undetermined significance: case report. Arq
Bras Oftalmol 2005;68:539–541.

Sclera
Arevalo JF, Shields CL, Shields JA. Giant nodular posterior scleritis simulating
choroidal melanoma and birdshot retinochoroidopathy. Ophthalmic Surg
Lasers Imaging 2003;34:403–405.
Benson WE, Shields JS, Tasman W, et al. Posterior scleritis, a cause of diagnostic
confusion. Arch Ophthalmol 1979;97:1482–1486.
Ferry AP. The histopathology of rheumatoid episcleral nodules: an extra-articular
manifestation of rheumatoid arthritis. Arch Ophthalmol 1969;82:77–88.

233
Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients
developing necrotizing scleritis peripheral ulcerative keratitis: effects of
systemic immunosuppression. Ophthalmology 1984;91:1253–1263.
Norn MS. Scleral plaques. I. Incidence and morphology. Acta Ophthalmol
(Copenh) 1974;52:96–106.
Palamar M, Thangappan A, Shields CL, et al. Necrotic choroidal melanoma with
scleritis and choroidal effusion. Cornea 2009;28:354–356.
Rao NA, Marak GE, Hidayat AA. Necrotizing scleritis. A clinicopathologic study
of 41 cases. Ophthalmology 1985;92:1542–1549.
Riono WP, Hidayat AA, Rao NA. Scleritis: a clinicopathologic study of 55 cases.
Ophthalmology 1999;106:1328–3133.
Shields JA, Shields CL. CME review: Sclerochoroidal calcification: the 2001
Harold Gifford Lecture. Retina 2002;22:251–261.
Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol
1976;60:163–191.
Wilhelmus KR, Yen MT, Rice L, et al. Necrobiotic xanthogranuloma with
posterior scleritis. Arch Ophthalmol 2006;124:748.

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 7 The Lens
The embryology and histology of the lens are discussed in Chapter 1.

CONGENITAL ANOMALIES OF THE

LENS
The posterior surface of the lens in an infant’s eye often has a dimpled
configuration called posterior umbilication (Fig. 7-1A). Posterior
umbilication is an artifact caused by fixation and is not present in vivo.

FIG. 7-1. A. Posterior umbilication, infant eye. The concave shape of the
posterior lens is called posterior umbilication. Posterior umbilication is a fixation
artifact that affects the lens in infants. The hyaloid artery persists in this
specimen. B. Posterior lenticonus. Posterior lenticonus appears as “oil droplet”
in retroillumination. Anomaly occurred unilaterally in healthy patient.

The surface of the lens has a conical configuration in lenticonus.

Lenticonus can be anterior or posterior and probably is caused by focal
thinning of the lens capsule. Anterior lenticonus usually is bilateral and
may be associated with Alport syndrome of hereditary hemorrhagic
nephritis and deafness, which is caused by mutations in several genes for
type IV or basement membrane collagen. The lens capsule in Alport
syndrome is thin and has linear dehiscences. The renal disease presumably

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is caused by analogous abnormalities in the glomerular basement
membrane. Many cases of Alport syndrome are caused by mutations in the
COL4A5 gene on the X chromosome (Xq22.3) and show X-linked
inheritance. Patients with Alport syndrome also have a characteristic
retinopathy with macular dots and flecks, a dull macular reflex or
“lozenge,” retinal thinning, and occasional macular holes.
Posterior lenticonus usually is a unilateral sporadic condition that is
not associated with other ocular or systemic disease (Fig. 7-1B). When the
lens is retroilluminated, the lenticonus often appears as an “oil droplet.”
Some cases occur in Lowe syndrome.
Lens coloboma (lens notching) is a secondary phenomenon caused by
a focal absence of zonular fibers in a contiguous coloboma of the ciliary
body. Rarely, lens coloboma can herald the presence of a pediatric ciliary
body neoplasm, usually a medulloepithelioma.
Congenital cataracts are responsible for about 10% of vision loss in
children and are one of the most common treatable causes of decreased
loss and blindness in infancy (Fig. 7-2). Congenial cataracts occur in
isolation or in association with systemic or ocular anomalies.
Approximately one third of congenital cataracts are inherited, one third are
associated with a systemic syndrome or disease, and one third are
idiopathic. Most hereditary cataracts are inherited in an autosomal
dominant fashion with high penetrance. At least 39 loci for isolated or
primary congenital cataracts have been identified. These include genes for
a variety of lens crystallins (CRYA, CRYB, and CRYG), connexin proteins
that form gap junctions (Cx43, Cx46, and Cx50), membrane proteins such
as major intrinsic protein or aquaporin-0, eye lens–specific intermediate
filaments, and development regulators and transcription factors including
PITX3, MAF, and heat shock transcription factor 4 (HSF4). Infectious
causes of congenital cataract include toxoplasmosis, coxsackievirus,
syphilis, varicella-zoster virus, HIV, and Parvovirus B19 as well as
rubella, cytomegalovirus, and HSV-1 and HSV-2.

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 FIG. 7-2. Developmental cataracts. A. Congenital opacity involves embryonic
nucleus of lens, which is delimited by “Y” sutures. B. Anterior pyramidal
cataract. Cone of collagenous connective tissue projects from anterior surface of
lens. Anterior pyramidal cataract is a development variant of ASC.

Developmental cataracts can affect different parts of the lens. Anterior

pyramidal cataract is a congenital form of anterior subcapsular cataract
(ASC) (Fig. 7-2B). The opacity beneath the anterior lens capsule is a white
plaque of dense collagen.
A spectrum of opacities that involve the posterior pole of the lens is
related to faulty resorption of the embryonic hyaloid vascular system that
nourishes the developing lens in utero. An innocuous spot called a
Mittendorf dot marks the site where the hyaloid artery was attached to the
posterior lens capsule. Mittendorf dot is found in about 25% of normal
individuals and is best seen on retroillumination. A patent hyaloid artery
may persist in some adults. Posterior remnants of the hyaloid artery and
Bergmeister papilla may be evident as vascular loops and glial veils on the
optic disk.
The most severe condition related to incomplete resorption of the
embryonic vasculature is persistent fetal vasculature (PFV) or persistent
hyperplastic primary vitreous (PHPV), a congenital anomaly that often is
found in microphthalmic eyes (Fig. 12-20). PFV/PHPV is characterized by
a retrolental plaque of vascularized connective tissue that is thought to
represent a residuum of the embryonic primary vitreous. The tips of the
ciliary processes are attached to the margins of this retrolental plaque. As
the eye enlarges, the ciliary processes are drawn centrally and stretched
and may be seen clinically when the pupil is dilated. PFV/PHPV produces
leukocoria (a white pupil) and is an important lesion in the differential
diagnosis of the childhood retinal malignancy retinoblastoma. This
syndrome previously was called PHPV. Goldberg suggested the term PFV
to emphasize the involvement of other fetal ocular vessels such as iris

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shunts.
Zonular cataracts are marked by the opacification of a single zone of
lens fibers. Lamellar cataract is a form of zonular cataract that results
when a group of lens fibers are opacified at one point during development
and subsequently are buried by the formation of new, healthy clear cortex.
Damage to developing lens fibers during an attack of neonatal tetany is a
classic cause of lamellar cataract. Analogous to tree rings in
chronodendrology, the opacified fibers serve as a clinical marker that
allows one to roughly estimate when an insult occurred during lens
development.
Cataracts occur in patients who have a bewildering number of genetic
syndromes, genetic diseases, and developmental disorders. A search for
cataract on the Online Mendelian Inheritance in Man (OMIM) Web site
retrieved 364 separate items. Rare syndromic associations include
chondrodysplasia punctata and the Hallermann-Streiff, Nance-Horan,
Conradi, Rothmund-Thomson, Marinesco-Sjögren, and hyperferritinemia–
cataract syndromes.
Congenital cataract and glaucoma occur together in patients who have
Lowe syndrome, an X-linked oculocerebrorenal syndrome characterized
by renal rickets and amino aciduria. The lens in Lowe syndrome is small
and discoid in shape and may have lens capsular incresences. Obligate
female carriers of Lowe syndrome may have punctate opacities and
plaque-like posterior subcapsular cataracts. Thirteen percent of patients
with Down syndrome (trisomy 21) have cataracts.
The clinical triad that constitutes Gregg syndrome of rubella
embryopathy includes cataract, deafness, and cardiac anomalies such as
patent ductus arteriosus. Rubella cataracts are typically dense, pearly
white, and nuclear. Lens epithelial nuclei may persist for decades in the
embryonic nucleus of a rubella cataract. Virus has been cultured from
rubella cataracts several years after birth.

CATARACT
The term cataract refers to opacification or optical dysfunction of the
crystalline lens. Cataract is an extremely common and economically
important cause of visual loss. Derived from the Greek word for waterfall,
the term cataract probably refers to the white appearance of some senile
cataracts, which was likened to rapidly flowing “white water.”

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 Cataract is the end stage or final common pathway of lens pathology.
Although lens opacification most often occurs as the result of aging, a host
of other factors can cause cataracts including trauma, drugs, toxins,
radiation, inborn errors of metabolism, and concurrent ocular or systemic
disease.
Cataract is essentially a clinical diagnosis denoting loss of optical
function. Visual function is best determined by the ophthalmologist during
a clinical examination. In most institutions, cataracts are no longer
submitted to pathology. It actually is difficult to diagnose cataract
histopathologically in many cases, especially when modern surgical
techniques of extracapsular lens extraction such as phacoemulsification
have been used. After the contents of the optically dysfunctional lens have
been removed, a prosthetic intraocular lens (IOL) is inserted in the lens
capsular bag. The “IOL” obviates the need for aphakic spectacles
postoperatively (Fig. 7-3).

FIG. 7-3. Pseudophakia. A. Optic of posterior chamber IOL is seen within lens
capsular bag in posterior chamber. Some residual lens cortical material is present.
Eye was enucleated for uveal melanoma. B. Blue haptics of older three-piece
posterior chamber IOL are confined to lens capsular bag. Iris pigment epithelium
and ring of ciliary processes are evident.

Although a bewildering variety of lens opacities have been described

clinically, the pathologist is able to recognize only four basic types of
cataract histopathologically: cortical, nuclear, anterior subcapsular, and
posterior subcapsular cataracts (Fig. 7-4). Each differs in its pathogenesis
and histology.

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 FIG. 7-4. Common types of cataract. A. Anterior subcapsular cataract. ASC
cataract appears as a white plaque of dense collagen beneath folded anterior lens
capsule. Although commonly found in the pathology laboratory, ASCs are seen
infrequently in the clinic because they often are hidden by posterior synechiae
and papillary membranes. B. Posterior subcapsular cataract. Posterior
subcapsular opacity disclosed by retroillumination comprises relucent spherules
consistent with bladder cells. C. Cortical cataract. Advanced cortical cataract
appears white. D. Nuclear sclerotic cataract. Slit lamp reveals yellow
urochrome pigment in sclerotic nucleus of lens.

Some degree of nuclear sclerosis (Fig. 7-5) develops in all individuals as

they age. The inevitability of nuclear sclerotic cataract is inherent in the
lens’ normal pattern of growth and development. The lens is derived from
surface ectoderm, and, like the skin, it grows continuously, albeit slowly,
throughout life. Growth of the lens results from the continuous accretion of
new secondary lens fibers around its circumference. The formation of the
new lens fibers buries the older fibers, which are sequestered centrally in
the lens nucleus. (Mature skin cells are desquamated.) With the passage of
years, the older cells gradually degenerate. This is not surprising because
mature lens cells are anucleate and lack the metabolic machinery for
protein synthesis and repair. Eventually, the highly specialized lens

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proteins called crystallins become denatured, and the cytoplasm of the lens
fibers becomes increasingly dehydrated. The degenerative process is also
marked by the accumulation of a yellow-brown pigment called urochrome
that is probably related to photo-oxidation (Figs. 7-4D and 7-5A).

FIG. 7-5. Nuclear sclerosis. A. Advanced nuclear sclerotic cataract has deep
amber brunescent appearance after sectioning. B. Artifactitious clefts delimit
boundary between the sclerotic lens nucleus and the cortex. The nucleus is more
eosinophilic than the cortex and lacks the artifactitious clefts that normally form
when the lens is sectioned. (B. H&E ×10.)

Histopathologically, nuclear sclerosis is marked by increased eosinophilia

and homogeneity of the lens nucleus and an absence of the artifactitious
cracks that normally occur between lens fibers during microtomy (Fig. 7-
5B). As the nucleus becomes denser, its index of refraction, and hence
refractive power, increases, causing lenticular myopia. The latter has been
called “grandma’s second sight” because presbyopic patients often find
that they are able to read without their reading glasses, as they develop
nuclear sclerosis and become progressively myopic. Nuclear sclerosis also
distorts color vision because the yellow-brown urochrome pigment, which
accumulates in the sclerotic lens, filters out blue wavelengths of light.
After nuclear sclerotic cataracts are removed, patients may complain about
blue vision. In advanced nuclear sclerosis, cataracts may be amber colored
(brunescent) (Fig. 7-5A) or even black (cataracta nigra). Calcium oxalate
crystals occasionally are found in lenses with nuclear sclerosis. These oval
crystals exhibit vivid rainbow-like birefringence during polarization
microscopy (Fig. 7-6).

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 FIG. 7-6. Oxalate crystals, nuclear sclerosis. A. Numerous calcium oxalate
crystals are evident as yellow spherules in nucleus of severely sclerotic,
brunescent cataract. B–D. Polarization microscopy highlights oval birefringent
crystals of calcium oxalate in nuclear sclerotic cataract. The crystal in (D)
exhibits vivid rainbow-like pattern of birefringence. B. H&E with crossed
polarizers ×100, C. H&E with crossed polarizers ×20, D. H&E with crossed
polarizers ×250. (Specimen (A) contributed by Sebastian Heersink, MD.)

Cortical cataract (or soft cataract) is marked by degeneration of the fiber

cells comprising the lens cortex. The incipient stage of cortical cataract is
marked clinically by the development of vacuoles or clefts containing clear
watery fluid (water clefts) (Fig. 7-7A). As the disease progresses, the foci
of degenerated cortical material appear white in direct illumination and are
seen as black shadows in retroillumination. The cortical opacities often
begin near the equator and may involve a wedge-shaped sector of cortex.
Sparkling crystals of cholesterol and insoluble amino acids develop in
some cases. The term Christmas tree cataract has been applied to cataracts
that contain many crystals.

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FIG. 7-7. Cortical cataract. A. Clefts are evident superiorly in cortex of white
cortical cataract. B. Round morgagnian globules fill cleft in peripheral cortex,
which is bordered by fractured lens fibers. C. Cleft contains liquefied cortex and
morgagnian globules. Morgagnian globules are spherules of degenerated lens
protein that have leaked from fragmented lens fibers. D. Scanning electron
micrograph of cortical cataract showing morgagnian globules in cleft. Lens fibers
are seen in foreground. (B. H&E ×50, C. H&E ×250, D. SEM ×320.)

Histopathologically, cortical degeneration is marked by clefts and spaces

in the cortex filled with liquefied cortical material, which oozes from
fractured lens fibers. Spherules of degenerated lens cytoplasm called
morgagnian globules typically are seen (Fig. 7-7B–D). Total cortical
liquefaction occurs in morgagnian cataracts (Fig. 7-8). Morgagnian
cataracts are typically swollen and intumescent because the osmotic effect
of the degenerated cortical material causes the lens to imbibe aqueous
humor. In some patients, the swollen lens may precipitate closed-angle
glaucoma (phacomorphic glaucoma). The sclerotic nucleus typically
resists liquefaction and sinks inferiorly in the capsular bag of liquefied
cortex (Fig. 7-8A). The milky, fluid cortex often contains crystals of
cholesterol. In advanced cases, the denatured lens protein can leak through
the intact lens capsule and stimulate a bland macrophagic response. This

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can produce a variety of secondary open-angle glaucoma called phacolytic
glaucoma, which is caused by obstruction of the trabecular meshwork by
macrophages that have ingested lens material and free high molecular
weight lens protein, as well (Figs. 3-6B and 8-15). Dystrophic calcification
is often found in the degenerated cortex of long-standing cataracts. Blind
painful eyes occasionally contain totally calcified lenses that are rock-hard
and cannot be sectioned without prior decalcification.

FIG. 7-8. Morgagnian cataract. A. Morgagnian cataract results when the lens
cortex undergoes total liquefaction. The densely sclerotic nucleus is resistant to
liquefaction and sinks to the bottom of the bag of liquefied cortex. Calcium
oxalate crystals are evident as lighter spherules in the amber nucleus. (Photo
courtesy of Prof. Dr. med. Wolfgang Lieb, University of Würzburg.) B.
Degenerated lens cortex surrounds the intensely eosinophilic sclerotic nucleus.
Although most of the cortex has liquefied, a few curved disrupted lens fibers are
seen posteriorly. (B. H&E ×10.)

The two other histologic subtypes of cataract, ASC and posterior

subcapsular cataract, are caused by abnormalities in the anterior lens
epithelium. ASC is marked histopathologically by a white plaque of dense
collagenous connective tissue that forms beneath the anterior lens capsule
(Fig. 7-9). Contraction of the fibrous tissue causes characteristic sinuous
folds in the anterior capsule (Fig. 7-9C). The subcapsular collagen is
synthesized by lens epithelial cells. The cells are found within the plaque
surrounded by capsules of basement membrane material that evidence
their lens epithelial lineage (Fig. 7-9D). In some instances, a second,
delicate, new layer of lens capsule is found beneath the anterior
subcapsular fibrous plaque. This is made by lens epithelial cells that have
migrated beneath the plaque. Adhesions between the iris and lens
(posterior synechiae) and/or anterior segment inflammation often
stimulates the proliferation and fibrous transformation of the lens
epithelium. Although ASCs frequently are found in blind painful eyes in

244
the ophthalmic pathology laboratory, they are infrequently observed in the
clinic because they typically are obscured by posterior synechiae and
pupillary membranes. Capsular fibrosis, which causes posterior capsular
opacification and wrinkling after planned extracapsular cataract surgery,
reflects an identical process of lens epithelial proliferation and fibrous
transformation (Fig. 7-10).

FIG. 7-9. Anterior subcapsular cataract. A. ASC appears as white plaque on the
anterior surface of the lens in eye with neovascular glaucoma. Iridocorneal
synechiae and ectropion iridis are present. B. Plaque of collagen comprising ASC
is present beneath anterior lens capsule beneath posterior synechia that stimulated
its formation. C. Contraction of fibrous plaque has caused sinuous folds in
anterior lens capsule. Lens cells that synthesized collagen are seen within plaque.
D. Capsules of PAS-positive basement membrane surround cells indicating that
they are lens epithelium and not fibroblasts. (B. PAS ×100, C. PAS ×250, D.
PAS ×400.)

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 FIG. 7-10. Capsular fibrosis, postextracapsular cataract extraction (post-ECCE).
A. Macrophoto shows white fibrosis and capsular folds near edge of IOL in lens
capsular bag. B. Mass of collagenous connective tissue made by residual lens
epithelial cells, which are enveloped by delicate capsules of basement membrane
material. C. Capsular fibrosis overlying edge of capsulorrhexis. Anterior capsule
is much thicker than posterior capsule. D. Capsular phimosis. Ring of fibrous
tissue (arrow) surrounds capsulorrhexis on surface of IOL. E. Fibrous tissue is
sandwiched between anterior and posterior capsule. (B. PAS ×250, C. H&E
×200, E. PAS ×100.)

In posterior subcapsular cataract, lens epithelial cells migrate posteriorly

beneath the lens capsule behind the lens equator where the monolayer of
anterior lens epithelium normally terminates. Noxae such as inflammation
or ciliary body tumors stimulate the abnormal epithelial migration.
Situated aberrantly at the posterior pole of the lens or sometimes
elsewhere, the lens epithelial cells attempt to form new secondary lens
fibers, but abortive lens fibers called Wedl or bladder cells result (Fig. 7-
11). Filled with lens protein, the Wedl cells are large, round, or oval and
have a single nucleus. Posterior subcapsular cataracts tend to interfere with
near vision early because the opacity is located near the nodal point of the
eye’s visual system. Patients with posterior subcapsular cataract also are
prone to develop severe glare symptoms, especially during night driving.
The nuclei of bladder or Wedl cells serve to distinguish them from
morgagnian globules, which are round anucleate spherules of degenerated
lens protein.

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FIG. 7-11. Bladder cells, posterior subcapsular cataract. A. Aggregate of bladder
cells rests on posterior lens capsule. Posterior migration of lens epithelial cells is
seen on inner surface of capsule. B. Bladder cells are evident as large swollen
aberrant lens fibers in flat preparation of lens material obtained during
lensectomy. (A. H&E ×100, B. H&E ×200.)

Cells analogous to Wedl cells can form on, or within, the lens capsular bag
after planned extracapsular surgery. Large spherical aggregates of these
proliferating cells are called Elschnig pearls. Clinically, the pearls may
resemble a mass of fish eggs (Fig. 7-12).

FIG. 7-12. Elschnig pearls, post-ECCE. A. Relucent spherules derived from

residual lens epithelial cells are seen within lens capsule after extracapsular
cataract extraction. B. Structures resembling bladder cells are present on exposed
surface of posterior lens capsule. Elschnig pearls are analogous to bladder cells
found in PSC cataract. (B. H&E ×400.)

COMPLICATED CATARACTS
Complicated cataracts (cataracta complicata) are caused by concurrent

247
ocular disease. Cataract formation can complicate chronic uveitis in
patients who have sarcoidosis or the pauciarticular, RF-seronegative,
ANA-positive type of juvenile rheumatoid arthritis. Unilateral cataract,
mild asymptomatic uveitis, and depigmentation of the iris stroma are the
classic clinical manifestations of Fuchs heterochromic cyclitis (Fig. 7-13).
There is some evidence linking Fuchs heterochromic cyclitis with rubella
infection.

FIG. 7-13. Fuchs heterochromic cyclitis. A. Normal eye. Affected eye (at right
B.) has developed cataract and hypochromic heterochromia iridum.

Posterior subcapsular cataracts form in nearly 50% of patients who have

retinitis pigmentosa. It is unclear how cataract formation is related to
heritable defects in photopigments such as rhodopsin.
Intraocular tumors, particularly ciliary body malignant melanomas,
should be considered and excluded in patients with unilateral or
asymmetrical cataracts. Ciliary body tumors can directly impinge upon and
deform the periphery of the lens and stimulate posterior migration of lens
epithelium as well.
Cataract also can complicate long-standing glaucoma. In the past,
some cases probably were related to chronic miotic therapy. In the past,
anterior subcapsular vacuoles were reported in patients receiving strong
topical anticholinesterase agents. Filtering surgery for glaucoma
accelerates cataract formation, and cataracts typically occur after
vitrectomy. Scattered focal subcapsular lens opacities called
glaukomflecken are observed in some patients who have had a prior attack
of acute closed-angle glaucoma. These small grayish opacities are thought
to represent focal areas of lens epithelial necrosis and cortical degeneration
and may be caused by hypothetical toxins in the stagnant aqueous humor.

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SUGAR CATARACTS: DIABETES
MELLITUS AND GALACTOSEMIA
The accumulation of sugar alcohol in lens cells is hypothesized to produce
osmotic cataracts in patients who have disorders of sugar metabolism such
as diabetes mellitus. Rarely, patients with previously undiagnosed diabetes
mellitus may present with a characteristic type of diabetic cataract caused
by markedly elevated levels of serum glucose. Such cataracts may resorb
partially when diabetic therapy is instituted. Diabetics are also prone to
develop typical senile nuclear and cortical cataracts at a much earlier age
than does the normal population.
The sugar alcohols that cause osmotic cataracts in patients with
diabetes and galactosemia are formed by the enzyme aldose reductase in
the alternative hexose monophosphate shunt when the normal glycolytic
pathway is overwhelmed by high levels of serum glucose or galactose.
Sorbitol, the sugar alcohol of glucose, accumulates in the lens cells of
diabetics because it is unable to pass through cellular membranes.
Similarly, the sugar alcohol of galactose called galactolol or dulcitol
accumulates in the lens cells of galactosemic infants who are deficient in
the enzyme galactose-1-phosphate uridylyltransferase. Galactosemic
cataracts often have a central oil droplet configuration, may be the first
clinical manifestation of galactosemia, and are partially reversible if
dietary therapy is promptly instituted. Presenile cataracts also occur in
patients who are deficient in galactokinase.

CATARACT AND SYSTEMIC

DISEASE
Patients with myotonic dystrophy develop presenile cataract as well as
myotonia, muscular dystrophy, frontal baldness, and testicular atrophy.
Myotonic cataracts classically have an “iridescent dust” of multiple
polychromatic crystals in the anterior and posterior subcapsular cortex and
a stellate grouping of opacities along suture lines in the posterior cortex,
which develops later.
The sunflower cataract of Wilson disease (hepatolenticular
degeneration) is caused by the deposition of copper in the lens capsule.
The familiar Kayser-Fleischer ring in the periphery of the cornea results

249
from an analogous deposition of copper in Descemet membrane. The
central disk of the “sunflower” corresponds to the diameter of the
undilated pupil, while the large radial ridges on the back of the iris
probably govern the formation of the “petals.” An identical cataract may
occur in patients who have retained intraocular copper foreign bodies
(chalcosis lentis) (Fig. 4-12B). In fact, the similarity between traumatic
chalcosis and Wilson disease led German ophthalmologists to suggest that
copper metabolism was abnormal in Wilson disease.
Posterior spoke-like lens opacities occur in Fabry disease, an X-linked
deficiency of the enzyme alpha-galactosidase A, which causes the storage
of ceramide trihexoside in tissues. A vortex pattern of pigment deposition
called cornea verticillata occurs in affected males.
It is not surprising that cataracts occur in patients who have certain
skin diseases, because both the lens and skin are derived from surface
ectoderm. Most important is the syndermatotic subcapsular cataracts that
occur in atopic dermatitis, an association called Andogsky syndrome.
Complications of surgery for atopic cataract include retinal detachment.

TRAUMATIC CATARACTS
Total opacification of the lens can develop several days after rupture or
laceration of the lens capsule. The entire cortex can undergo liquefaction
in young individuals, in whom total spontaneous resorption of the lens
cortical material occasionally occurs. The iris can seal small lacerations. If
the capsule reforms, only a small focal opacity may result. Severe
contusion injuries can rupture the lens. Less severe contusions often
produce a superficial type of cataract with a distinctly floral appearance
called a petalliform cataract or contusion rosette (Fig. 4-7A). Such
cataracts may cause minimal visual loss, but are an important clinical
marker for prior ocular contusion injury. If a contusion rosette is found
during biomicroscopy, gonioscopy should be performed to rule out
postcontusion angle deformity, which predisposes to glaucoma.
Vossius ring is an annulus of pigment on the anterior lens capsule
caused by a forceful imprint of the iris pigment epithelium during a
contusion injury. Chronically retained intraocular iron foreign bodies can
cause siderosis lentis. Siderotic cataract is marked by scattered foci of rust-
colored material on the anterior surface of the lens and often is associated
with iris heterochromia caused by the deposition of iron pigment in the iris
stroma. Histopathology shows subepithelial plaques of lens epithelial cells

250
that contain large quantities of iron pigment. The siderosis or
hemosiderosis lentis (iron from intraocular hemorrhage) is evident as a
yellowish or yellowish-brown discoloration of the anterior lens epithelium
in routine sections stained with hematoxylin and eosin (H&E). Special iron
stains that employ the Prussian blue reaction are used to confirm the
presence of iron (Fig. 4-7B). Chalcosis lentis is discussed above.
The crystalline lens is very sensitive to relatively low doses of ionizing
radiation. Doses of ionizing radiation as low as 250 cGy can cause
cataract. Hence, the lens should be carefully shielded during radiotherapy.
Soemmerring ring cataract is a donut of residual cortical material that
remains in the equatorial recess of the lens capsular bag after expulsion of
lens nucleus during a perforating corneal or scleral injury. Most eyes that
are examined pathologically after planned extracapsular cataract surgery
have a Soemmerring ring of residual lens cortex (Fig. 7-14). There is some
controversy whether the latter represents cortex that was not removed
during surgery or a consequence of lens epithelial proliferation
postoperatively.

FIG. 7-14. Soemmerring ring cataract, post-ECCE. A, B. Large amounts of

residual lens cortex form Soemmerring ring in equatorial part of lens capsular
bag. The lens in (B) was found in an eye with a uveal melanoma.

Electrical cataracts are caused by lightning strikes or severe electrical

injuries. A thin lamella of anterior or posterior subcapsular cortex usually
is opacified in this rare type of cataract. It is said that lightning typically
opacifies the posterior subcapsular cortex because the electrical current
passes down the neuraxis, while industrial injuries opacify the anterior lens
because the current usually passes down the extremities. The onset of
electrical cataract after injury may be delayed.
The blue wavelengths of the argon blue-green laser are absorbed by

251
the yellow urochrome pigment in nuclear cataract. In the past, lenticular
burns occurred during retinal photocoagulation of patients with advanced
nuclear sclerosis. This complication can be avoided by the use of lasers
with other wavelengths, for example, krypton red. Absorption of laser
energy by the iris pigment epithelium can cause focal thermal opacities in
the underlying lens during transpupillary thermotherapy of posterior
segment tumors.

TOXIC CATARACT
A variety of drugs and toxins can cause cataract. The most important drug-
induced cataract is the posterior subcapsular cataract that develops in
patients receiving chronic therapy with high doses of systemic
corticosteroids. The dose of steroids necessary to produce cataract is
uncertain. One study found that cataracts develop in approximately one
third of patients who receive a chronic daily dose of 10 mg of
prednisolone. Fifteen milligrams of oral prednisone daily for more than 1
year led to cataract formation in 75% of patients. Cataract is also a concern
in patients treated with intraocular steroids. All patients with fluocinolone
acetate intravitreal implants are expected to require cataract surgery within
3-year lifetime of the implant.
Other toxins and drugs that produce cataract include naphthalene,
dinitrophenol, mercury, phenothiazine, anticholinesterase agents,
triparanol, and cigarette smoke.

LENS CAPSULAR ABNORMALITIES

True exfoliation of the lens capsule or capsular delamination is marked by
a split in the lens capsule that leads to the formation of relucent scrolls on
the anterior surface of the lens. True exfoliation is quite rare. Although it
classically is associated with occupational exposure to infrared radiation
(e.g., in glass blowers or steel puddlers), most cases are associated with
aging. True exfoliation does not predispose to glaucoma.
Pseudoexfoliation (PXE) of the lens capsule, or PXE syndrome, is a
relatively common disease that causes a variety of secondary open-angle
glaucoma called capsular glaucoma in about half of affected patients.
Dvorak-Theobald first used the term pseudoexfoliation to differentiate this
disorder from true exfoliation, which does not cause glaucoma. PXE is an
extremely important cause of glaucoma in some populations.

252
 Clinically, PXE is marked by the deposition of a complex mucoprotein
on the anterior lens capsule, as well as the other aqueous-bathed surfaces
of the anterior segment, including the ciliary processes, zonule, vitreous
face, and the posterior iris. On the anterior lens capsule, the PXE material
forms a central disk of granular white material whose diameter
corresponds to that of the undilated pupil (Fig. 7-15A). Surrounding the
central disk is a clear zone wiped clean of PXE by the motion of the pupil.
A granular zone marked by areas of rarefaction that correspond to radial
macroridges on the posterior iridic surface is found peripherally. PXE may
be relatively inconspicuous in a patient with an undilated pupil.
Observation of a few, white, dandruff-like flakes at the pupillary margin
should always prompt a dilated exam.

FIG. 7-15. Pseudoexfoliation of the lens capsule. A. Grayish-white

pseudoexfoliative material forms a “target” on the anterior lens capsule. A PXE-
free zone wiped clean by the iris surrounds the central bull’s eye whose diameter
corresponds to the miotic pupil. The peripheral granular zone contains radial
erosions caused by large radial folds on the posterior iris. Focal outward peeling
of the margin of the peripheral zone is present. B. Eosinophilic bush-like Busacca
deposits of pseudoexfoliation material are seen on the anterior lens capsule. The
appearance of the material has been likened to iron filings on a magnet. C.
Scanning electron microscopy of PXE on anterior lens capsule. (B. H&E ×250,
C. SEM ×320.)

The PXE material on the anterior surface of the lens is synthesized by the
lens epithelium and extruded through the lens capsule forming clumps of
eosinophilic material called Busacca deposits. The light microscopic
appearance of these deposits has been likened to magnetized iron filings
(Fig. 7-15B). Coarser, more irregular clumps of PXE are found on the
zonular fibers, ciliary processes, and iris pigment epithelium (Fig. 7-16C).
Material is also found in the iris stroma, anterior chamber, and the
trabecular meshwork. Secondary open-angle glaucoma is caused by

253
obstruction of the trabecular meshwork. Recent electron microscopic
studies suggest that some of the PXE actually may be synthesized within
the meshwork. PXE has been found in the conjunctiva, orbit, skin, lung,
liver, and heart with electron microscopy. The extraocular material is
always associated with elastic fibers, and it shows immunoreactivity with
antibodies against elastic microfibrils. Such observations suggest that PXE
of the lens capsule may be the ocular manifestation of a presumably
innocuous systemic disorder of elastic tissue.

FIG. 7-16. Pseudoexfoliation syndrome, iris pigment epithelium. Scanning

electron microscopy (A) and light microscopy (B) show coarse “sawtoothed”
appearance of the iris pigment epithelium caused by coalescence of
circumferential ridges. PXE material festoons the ridges. C. Extensive deposits of
PXE are found on the ciliary processes and zonular fibers. (A. SEM ×80, B. H&E
×100, C. H&E ×100.)

Involvement of the zonule by PXE predisposes to dislocation of the lens or

lens capsular bag after extracapsular cataract surgery. Cataract surgery
may also be complicated by poor pupillary dilation and an abnormal
leathery consistency of the iris. Histopathologically, one finds
“sawtoothing” of the iris pigment epithelium caused by coarsening and
coalescence of its circumferential ridges, which are festooned with
pseudoexfoliative material (Fig. 7-16A,B). The iris pigment epithelial
changes often suggest the diagnosis under low magnification microscopy.
Many patients have extensive pigment dispersion, not unlike that found in
pigmentary glaucoma. PXE is associated with mutations in the LOXL-1
(lysyl oxidase-like 1) gene on 15q24.1.
Polychromasia capsulare is a rare autosomal dominantly inherited
disorder characterized by iridescence of the lens capsule that is evident on
slit lamp biomicroscopy (Fig. 7-17). During biomicroscopy, the peripheral
anterior lens capsule displays an extraordinary array of iridescent colors

254
including blue, green, and bronze that vary as the angle of illumination is
changed. Transmission electron microscopy of lens capsule obtained
during cataract surgery disclosed an irregular pattern of polygonal profiles
with a periodicity estimated to be ~400 to 500 nm. Constructive
interference was the presumed mechanism for the iridescence of the lens
capsule.

FIG. 7-17. Polychromasia capsulare. A. Slit lamp photo shows iridescence of

lens capsule in patient with rare heritable disorder. B. Fragment of capsulorrhexis
exhibits spectrum of iridescent color that varied as incidence of illumination
changed. C. Transmission electron microscopy of normal lens capsule. D.
Transmission electron microscopy obtained during cataract surgery discloses an
irregular pattern of polygonal profiles with a periodicity estimated to be ~400 to
500 nm. Constructive interference was the presumed mechanism for the
iridescence of the lens capsule.

ZONULAR FIBERS AND ECTOPIA

LENTIS
The lens is suspended in the posterior chamber by zonular fibers, which
are composed largely of elastic microfibrils. The zonular fibers arise from
the peripheral pars plana and the inner surface of the peripheral retina and
extend anteriorly as a sheet across the pars plana. At the posterior aspect of
the pars plicata, the sheet divides into bundles that pass through the valleys
between the ciliary processes. The zonular fibers are attached to the inner
surface of the pars plicata, which acts as a fulcrum. Two groups of zonular
fibers extend from the ciliary body and insert onto the anterior and
posterior surface of the lens capsule. They enclose a triangular space called
the canal of Hannover.
Trauma, for example, contusion injury, is the most common cause of

255
lens dislocation. Spontaneous dislocation also occurs in patients with
tertiary syphilis. Ectopia lentis also occurs in a variety of heritable diseases
of connective tissue including Marfan syndrome, homocystinuria, and the
Weill-Marchesani syndrome (Fig. 7-18). In most cases, the ectopia lentis
has been linked to mutations in the FBN1 gene for the microfibrillar
glycoprotein fibrillin-1, which is located on the long arm of chromosome
15 (15q21.1), or by other metabolic disorders that affect the structure of
fibrillin secondarily. Fibrillin-1 is a major component of the zonular fibers
and also is involved in the formation of elastic tissue throughout the body.

FIG. 7-18. Ectopia lentis. A. Marfan syndrome. Lens is dislocated superiorly.

Stretched zonular fibers are seen in red reflex. B. Weill-Marchesani syndrome.
Microspherophakic lens has dislocated into anterior chamber causing pupillary
block glaucoma. (Photo courtesy of Dr. Dario Savino-Zari, Caracas, Venezuela.)

Seventy percent of cases of heritable ectopia lentis occur in patients with

Marfan syndrome, which has been linked to more than 50 mutations in the
fibrillin-1 gene. The major manifestations of Marfan syndrome are ocular,
skeletal, and cardiovascular. Bilateral lens dislocation occurs in 50% to
80% of patients and classically is superotemporal in direction (Fig. 7-
18A). Patients are tall and have arachnodactyly (long spidery fingers and
toes), dolichostenomelia, scoliosis, and pectus excavatum or carinatum.
Cardiovascular disease is caused by defective elastic tissue and includes
fatal dissecting aortic aneurysms and aortic valve defects. Other ocular
defects include high myopia, large flat corneas, and a tendency to develop
retinal detachment. Fibrillin-1 defects, which presumably are relatively
innocuous, also have been identified in families that inherit isolated or
simple ectopia lentis as autosomal dominant trait. The autosomal dominant
form of Weill-Marchesani syndrome also has been linked to the FBN1
gene.
The classic manifestations of the Weill-Marchesani syndrome are

256
microspherophakia and brachydactyly. Patients are short and muscular and
have short fingers, broad hands, limited joint mobility, and hearing defects.
The most debilitating aspects of this syndrome are ocular. Patients
typically present with 15 to 20 diopters of lenticular myopia and often
develop axial lens dislocation in their teens (Fig. 7-18B). Lens dislocation
often causes secondary closed-angle glaucoma due to papillary block. The
volume of the small, microspherophakic lens is 20% to 40% less than
normal.
The heritable disorders that cause secondary abnormalities in fibrillin-
1 are caused by defects in the metabolism of sulfur-containing amino
acids. These disorders interfere with the formation of important disulfide
bonds that serve to determine the conformation and aggregation of
fibrillin-1. They include homocystinuria, sulfite oxidase deficiency, and
molybdenum cofactor deficiency.
Many cases of homocystinuria are caused by a recessively inherited
deficiency in cystathionine beta synthase (21q22.3), an enzyme that
catalyzes the condensation of homocysteine with serine to form
cystathionine, an important precursor of cysteine and cystine.
Homocystinuric patients tend to be fair-skinned and blonde and have a tall
marfanoid habitus. About half develop progressive mental retardation, and
nearly 75% die by age 30 from venous and arterial thromboses. The latter
may be related to the endothelial protein thrombomodulin, which also
contains structurally important disulfide bonds. Patients are at increased
risk for thromboembolic complications during general anesthesia. Lens
dislocation occurs in about 90% of patients. The lens usually dislocates
inferiorly, or into the anterior chamber. It never dislocates superiorly as in
Marfan syndrome, a clinical feature that differentiates homocystinuric
patients who are marfanoid. Patients may present with acute pupillary
block glaucoma. High myopia, retinal detachment, and peripheral retinal
pigment epithelium (RPE) degeneration are other ocular manifestations. A
thick layer of periodic acid–Schiff (PAS)-positive zonular material has
been found histopathologically on the surface of the ciliary body.
Sulfite oxidase deficiency usually presents with seizures shortly after
birth in infants who have severe neurological findings. Lens dislocation
occurs in about half and typically is found in older infants. Affected
patients are unable to convert sulfite to sulfate. This leads to an
accumulation of sulfite, which destroys sulfhydryl groups and disulfide
bonds. Most patients with sulfite oxidase deficiency actually have a
deficiency in a molybdenum cofactor that is also shared by xanthine

257
dehydrogenase and aldehyde oxidase. The manifestations of the latter two
enzyme deficiencies are relatively innocuous.
Ectopia lentis occurs rarely in other hereditary disorders including
hyperlysinemia and Ehlers-Danlos syndrome.

BIBLIOGRAPHY
Eagle RC, Spencer WH. The lens. In: Spencer W, ed. Ophthalmic Pathology: An
Atlas and Textbook, 4th ed., vol. 1. Philadelphia, PA: WB Saunders,
1996:372–437.
Hockwin O, Kojima M, Muller-Breitenkamp U, et al. Lens and cataract research
of the 20th century: a review of results, errors and misunderstandings. Dev
Ophthalmol 2002;35:1–11.

Developmental Anomalies
Ahmed F, Kamae KK, Jones DJ, et al. Temporal macular thinning associated with
X-linked Alport syndrome. JAMA Ophthalmol 2013;131:777–782.
Beby F, Morle L, Michon L, et al. The genetics of hereditary cataract. J Fr
Ophtalmol 2003;26:400–408.
Bellows JG. Phakochronology. The study of dating structural changes in the lens.
Br J Ophthalmol 1968;52:540–545.
Brownell RD, Wolter JR. Anterior lenticonus in familial hemorrhagic nephritis.
Arch Ophthalmol 1964;71:481–483.
de Gottrau P, Schlotzer-Schrehardt U, Dorfler S, et al. Congenital zonular
cataract. Clinicopathologic correlation with electron microscopy and review
of the literature. Arch Ophthalmol 1993;111:235–239.
Deng H, Yuan L. Molecular genetics of congenital nuclear cataract. Eur J Med
Genet 2014;57(2–3):113–122.
Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of
signs and symptoms associated with persistent hyperplastic primary vitreous
(PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol
1997;124:587–626.
Graw J. Congenital hereditary cataracts. Int J Dev Biol 2004;48(8–9): 1031–1044.
Huang B, He W. Molecular characteristics of inherited congenital cataracts. Eur J
Med Genet 2010;53:347–357.
Jampol LM, Kass M, Dueker D, et al. Anterior polar cataracts. Am J Ophthalmol
1974;78:95–97.
Khalil M, Saheb N. Posterior lenticonus. Ophthalmology 1984;91:1429–1430,
43A.
Lambert SR, Drack AV. Infantile cataracts. Surv Ophthalmol 1996;40: 427–458.
Leonard A, Bernard P, Hiel AL, et al. Prenatal diagnosis of fetal cataract: case
report and review of the literature. Fetal Diagn Ther 2009;26:61–67.

258
Meisels H, Goldberg M. Vascular anastomoses between the iris and persistent
primary vitreous. Am J Ophthalmol 1979;88:179–185.
Roche O, Beby F, Orssaud C, et al. Congenital cataract: general review. J Fr
Ophtalmol 2006;29:443–455.
Sabates R, Krachmer JH, Weingeist TA. Ocular findings in Alport syndrome.
Ophthalmologia 1983;186:204–210.
Santana A, Waiswo M. The genetic and molecular basis of congenital cataract.
Arq Bras Oftalmol 2011;74:136–142.
Savige J, Liu J, DeBuc DC, et al. Retinal basement membrane abnormalities and
the retinopathy of Alport syndrome. Invest Ophthalmol Vis Sci
2010;51:1621–1627.
Streeten BW, Robinson MR, Wallace RN, et al. Lens capsule abnormalities in
Alport syndrome. Arch Ophthalmol 1987;105:1693–1697.
Yanoff M, Fine BS, Schaffer DB. Histopathology of transient neonatal lens
vacuoles. Am J Ophthalmol 1973;76:363–370.

Rubella Cataract
Boniuk M, Zimmerman LE. Ocular pathology in the rubella syndrome. Arch
Ophthalmol 1967;17:455–473.
Roy FH, Fuste F, Hiatt RL, et al. The congenital rubella syndrome with virus
recovery. Ocular pathology and literature review. Am J Ophthalmol
1966;62:222–232.
Yanoff M, Schaffer DB, Scheie HG. Rubella ocular syndrome. Clinical
significance of viral and pathologic studies. Trans Am Acad Ophthalmol
Otolaryngol 1968;72:896–902.
Zimmerman LE. Histopathologic basis for ocular manifestations of congenital
rubella syndrome. The Eighth William Hamlin Wilder Memorial Lecture. Am
J Ophthalmol 1968;65:837–862.

Cataract in Genetic Syndromes

Cogan DG, Kuwabara T. Pathology of cataracts in mongoloid idiocy: a new
pathogenesis of cataracts of the coronary-cerulean type. Doc Ophthalmol
1962;16:73–80.
Curtin VT, Joyce EE, Ballin N. Ocular pathology in the oculo-cerebro-renal
syndrome of Lowe. Am J Ophthalmol 1967;64(Part II): 533–543.
Robb RM, Marchevsky A. Pathology of the lens in Down’s syndrome. Arch
Ophthalmol 1978;96:1039–1042.
Wadelius C, Fagerholm P, Pettersson U, et al. Lowe oculocerebrorenal syndrome:
DNA-based linkage of the gene to Xq24-q26, using tightly linked flanking
markers and the correlation to lens examination in carrier diagnosis. Am J
Hum Genet 1989;44:241–247.
Wolter JR, Jones DH. Spontaneous cataract absorption in Hallermann-Streiff

259
 syndrome. Ophthalmologica 1965;150:401–408.

Senile Cataract
Benedek GB. Cataract as a protein condensation disease. Invest Ophthalmol Vis
Sci 1997;38:1911–1921.
Boyle DL, Takemoto LJ. Confocal microscopy of human lens membranes in aged
normal and nuclear cataracts. Invest Ophthalmol Vis Sci 1997;38:2826–2832.
Fledelius H. Cataracta ossea and other intraocular ossifications. A case report and
a thirty-year Danish material. Acta Ophthalmol (Copenh) 1975;53:790–797.
Flocks M, Littwin CS, Zimmerman LE. Phacolytic glaucoma: a clinicopathologic
study of 138 cases of glaucoma associated with hypermature cataract. Arch
Ophthalmol 1955;54:37–45.
Font RL, Brownstein S. A light and electron microscopic study of anterior
subcapsular cataracts. Am J Ophthalmol 1974;78:972–984.
Henkind P, Prose P. Anterior polar cataract. Electron-microscopic evidence of
collagen. Am J Ophthalmol 1967;63:768–771.
Jensen OA, Laursen AB. Human senile cataract. Light- and electron-microscopic
studies of the morphology of the anterior lens structures, with special
reference of anterior capsular/subcapsular opacity. Acta Ophthalmol (Copenh)
1980;58:481–495.
Klintworth GK, Garner A. The causes, types, and morphology of cataracts. In:
Garner A, Klintworth GK, eds. Pathobiology of Ocular Disease: a Dynamic
Approach, 2nd ed., Part A. New York, NY: Marcel Dekker, 1994:481–532.
Kluxen G, Wolf E, Kalisch M, et al. Color vision disorders caused by yellow
coloration of lenses. Fortschr Ophthalmol 1984;81:180–182.
Zimmerman LE, Johnson FB. Calcium oxalate crystals within ocular tissues. Arch
Ophthalmol 1958;60:372–383.

Posterior Capsular Opacification

Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv
Ophthalmol 1992;37:73–116.
Green WR, McDonnell PJ. Opacification of the posterior capsule. Trans
Ophthalmol Soc U K 1985;104:727–739.
McDonnell PJ, Zarbin MA, Green WR. Posterior capsular opacification in
pseudophakic eyes. Ophthalmology 1984;90:1548–1553.

Posterior Subcapsular Cataract

Greiner JV, Chylack LT Jr. Posterior subcapsular cataracts: histopathologic study
of steroid-associated cataracts. Arch Ophthalmol 1979;97:135–144.
Streeten BW, Eshaghian J. Human posterior subcapsular cataract: a gross and flat
preparation study. Arch Ophthalmol 1978;96:1653–1658.

260
Cataracts Caused by Ocular Disease (Complicated
Cataracts)
Axelsson U. Glaucoma, miotic therapy and cataract. I. The frequency of anterior
subcapsular vacuoles in glaucoma eyes treated with echothiophate
(Phospholine Iodide), pilocarpine or pilocarpine-eserine, and in
nonglaucomatous untreated eyes with common senile cataract. Acta
Ophthalmol (Copenh) 1968;46:83–98.
de Groot-Mijnes JD, de Visser L, Rothova A, et al. Rubella virus is associated
with fuchs heterochromic iridocyclitis. Am J Ophthalmol 2006;141:212–214.
Fagerholm PP, Philipson BT. Cataract in retinitis pigmentosa. An analysis of
cataract surgery results and pathological lens changes. Acta Ophthalmol
(Copenh) 1985;63:50–58.
Fisher RF. The lens in uveitis. Trans Ophthalmol Soc U K 1981;101: 317–320.
Liu Y, Takusagawa HL, Chen TC, et al. Fuchs heterochromic iridocyclitis and the
rubella virus. Int Ophthalmol Clin 2011;51(4):1–12.
Loewenfeld IE, Thompson HS. Fuchs’s heterochromic cyclitis: a critical review
of the literature. I. Clinical characteristics of the syndrome. Surv Ophthalmol
1973;17:394–457.
Suzuki J, Goto H, Komase K, et al. Rubella virus as a possible etiological agent
of Fuchs heterochromic iridocyclitis. Graefes Arch Clin Exp Ophthalmol
2010;248:1487–1491.

Sugar Cataracts
Beigi B, O’Keefe M, Bowell R, et al. Ophthalmic findings in classical
galactosaemia—prospective study. Br J Ophthalmol 1993;77:162–164.
Bron AJ, Sparrow J, Brown NAP, et al. The lens in diabetes. Eye
1993;7:260–275.
Kinoshita JH. Cataracts in galactosemia. Invest Ophthalmol 1965;4: 786–799.
Stambolian D, Scarpino-Myers V, Eagle RC Jr, et al. Cataracts in patients
heterozygous for galactokinase deficiency. Invest Ophthalmol Vis Sci
1986;27:429–433.

Cataracts Associated with Systemic Disease

Bullock JD, Howard RO. Werner syndrome. Arch Ophthalmol 1973; 90:53–56.
Burns CA. Ocular histopathology of myotonic dystrophy. A clinicopathologic
case report. Am J Ophthalmol 1969;68:416–422.
Chen CC, Huang JL, Yang KD, et al. Atopic cataracts in a child with atopic
dermatitis: a case report and review of the literature. Asian Pac J Allergy
Immunol 2000;18:69–71.
Dark AJ, Streeten BW. Ultrastructural study of cataract in myotonia dystrophica.
Am J Ophthalmol 1977;84:666–674.

261
Eshaghian J, March WF, Goossens W, et al. Ultrastructure of cataract in myotonic
dystrophy. Invest Ophthalmol Vis Sci 1978;17: 289–293.
Fagerholm P, Palmquist BM, Philipson B. Atopic cataract: changes in the lens
epithelium and subcapsular cortex. Graefes Arch Clin Exp Ophthalmol
1984;221:149–152.
Racz P, Kovacs B, Varga L, et al. Bilateral cataract in acrodermatitis
enteropathica. J Pediatr Ophthalmol Strabismus 1979;16:180–182.
Seland JH. The nature of capsular inclusions in lenticular chalcosis. Report of a
case. Acta Ophthalmol (Copenh) 1976;54:99–108.
Spaeth GL, Frost P. Fabry’s disease. Its ocular manifestations. Arch Ophthalmol
1965;74:760–769.
Tso MO, Fine BS, Thorpe HE. Kayser-Fleischer ring and associated cataract in
Wilson’s disease. Am J Ophthalmol 1975;79:479–488.

Traumatic Cataract
Fraunfelder FT, Hanna C. Electric cataracts. I. Sequential changes, unusual and
prognostic findings. Arch Ophthalmol 1972;87: 179–183.
Hanna C, Fraunfelder FT. Electric cataracts. II. Ultrastructural lens changes. Arch
Ophthalmol 1972;87:184–191.
Hanna C, Fraunfelder FT. Lens capsule change after intraocular copper. Ann
Ophthalmol 1973;5:9–12.
Jongebloed WL, Dijk F, Kruis J, et al. Soemmering’s ring, an aspect of secondary
cataract: a morphological description by SEM. Doc Ophthalmol
1988;70:165–174.
Masciulli L, Andersen DR, Charles S. Experimental ocular siderosis in the
squirrel monkey. Am J Ophthalmol 1972;74:638–661.
McCanna P, Chandra SR, Stevens TS, et al. Argon laser induced cataract as a
complication of retinal photocoagulation. Arch Ophthalmol
1982;100:1071–1073.
Rafferty NS, Goossens W, March WF. Ultrastructure of human traumatic
cataract. Am J Ophthalmol 1974;78:985–995.
Reddy SC. Electric cataract: a case report and review of the literature. Eur J
Ophthalmol 1999;9:134–138.
Talamo JH, Topping TM, Maumenee AE, et al. Ultrastructural studies of cornea,
iris and lens in a case of siderosis bulbi. Ophthalmology 1985;92:1675–1680.

Toxic Cataract
Hamming NA, Apple DJ, Goldberg MF. Histopathology and ultrastructure of
busulfan-induced cataract. Albrecht Von Graefes Arch Klin Exp Ophthalmol
1976;200:139–147.
Hiller R, Sperduto RD, Podgor MJ, et al. Cigarette smoking and the risk of
development of lens opacities. The Framingham studies. Arch Ophthalmol

262
 1997;115:1113–1118.
Kirby TJ. Cataracts produced by triparanol. (MER-29). Trans Am Ophthalmol
Soc 1967;65:494–543.
West S, Munoz B, Schein OD, et al. Cigarette smoking and risk for progression of
nuclear opacities. Arch Ophthalmol 1995;113:1377–1380.

True Exfoliation of the Lens Capsule

Anderson IL, van Bockxmeer FM. True exfoliation of the lens capsule. A
clinicopathological report. Aust N Z J Ophthalmol 1985;13: 343–347.
Brodrick JD, Tate GW Jr. Capsular delamination (true exfoliation) of the lens.
Report of a case. Arch Ophthalmol 1979;97:1693–1698.
Burde RM, Bresnick G, Uhrhammer J. True exfoliation of the lens capsule. An
electron microscopic study. Arch Ophthalmol 1969;82: 651–653.
Cashwell LF Jr, Holleman IL, Weaver RG, et al. Idiopathic true exfoliation of the
lens capsule. Ophthalmology 1989;96:348–351.

Pseudoexfoliation of the Lens Capsule

Anastasopoulos E, Founti P, Topouzis F. Update on pseudoexfoliation syndrome
pathogenesis and associations with intraocular pressure, glaucoma and
systemic diseases. Curr Opin Ophthalmol 2015;26:82–89.
Elhawy E, Kamthan G, Dong CQ, et al. Pseudoexfoliation syndrome, a systemic
disorder with ocular manifestations. Hum Genomics 2012;6:22.
Schlötzer-Schrehardt U. Molecular pathology of pseudoexfoliation
syndrome/glaucoma—new insights from LOXL1 gene associations. Exp Eye
Res 2009;88:776–785.
Osher RH, Miller VJ, Eagle RC Jr, et al. Polychromasia capsulare: determining
the cause of multicolored iridescence of the anterior lens capsule. J Cataract
Refract Surg 2016;42(4):631–4.
Schlötzer-Schrehardt U. New pathogenetic insights into pseudoexfoliation
syndrome/glaucoma. Therapeutically relevant?. Ophthalmologe
2012;109:944–951.
Schlötzer-Schrehardt UM, Dorfler S, Naumann GO. Corneal endothelial
involvement in pseudoexfoliation syndrome. Arch Ophthalmol
1993;111:666–674.
Schlötzer-Schrehardt U, Koca M, Naumann G, et al. Pseudoexfoliation syndrome.
Ocular manifestation of a systemic disorder? Arch Ophthalmol
1992;110:1752–1756.
Schlötzer-Schrehardt U, Naumann GO. A histopathologic study of zonular
instability in pseudoexfoliation syndrome. Am J Ophthalmol
1994;118:730–743.
Schlötzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation
syndrome. Am J Ophthalmol 2006;141:921–937.

263
Schlötzer-Schrehardt U, Pasutto F, Sommer P, et al. Genotype-correlated
expression of lysyl oxidase-like 1 in ocular tissues of patients with
pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol
2008;173:1724–1735.
Schlötzer-Schrehardt U, von der Mark K, Sakai LY, et al. Increased extracellular
deposition of fibrillin-containing fibrils in pseudoexfoliation syndrome. Invest
Ophthalmol Vis Sci 1997;38:970–984.
Streeten BW, Dark AJ. Pseudoexfoliation syndrome. In: Garner A, Klintworth
GK, eds. Pathobiology of Ocular Disease: a Dynamic approach, 2nd ed., Part
A. New York, NY: Marcel Dekker, 1994:591–629.
Streeten BW, Li ZY, Wallace RN, et al. Pseudoexfoliative fibrillopathy in
visceral organs of a patient with pseudoexfoliation syndrome. Arch
Ophthalmol 1992;110:1757–1762.
Traboulsi EI, Chung D, Koors JM. Polychromasia capsulare (multicoloured
capsule): report of three families. Trans Am Ophthalmol Soc 2005;103:93–7.

Heritable Lens Dislocation (Ectopia Lentis)

Ahram D, Sato TS, Kohilan A, et al. A homozygous mutation in ADAMTSL4
causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet
2009;84:274–278.
Boileau C, Jondeau G, Mizuguchi T, et al. Molecular genetics of Marfan
syndrome. Curr Opin Cardiol 2005;20:194–200.
Bonetti MI. Microfibrils: a cornerstone of extracellular matrix and a key to
understand Marfan syndrome. Ital J Anat Embryol 2009;114: 201–224.
Chandra A, Charteris D. Molecular pathogenesis and management strategies of
ectopia lentis. Eye (Lond) 2014;28(2):162–168.
Edwards MJ, Challinor CJ, Colley PW, et al. Clinical and linkage study of a large
family with simple ectopia lentis linked to FBN1. Am J Med Genet
1994;53:65–71.
Fujiwara H, Takigawa Y, Ueno S, et al. Histology of the lens in the Weill-
Marchesani syndrome. Br J Ophthalmol 1990;74:631–634.
Greene VB, Stoetzel C, Pelletier V, et al. Confirmation of ADAMTSL4 mutations
for autosomal recessive isolated bilateral ectopia lentis. Ophthalmic Genet
2010;31:47–51.
Hayward C, Brock DJ. Fibrillin-1 mutations in Marfan syndrome and other type-1
fibrillinopathies. Hum Mutat 1997;10:415–423.
Henkind P, Ashton N. Ocular pathology in homocystinuria. Trans Ophthalmol
Soc U K 1965;85:21–38.
Hollister DW, Godfrey M, Sakai LY, et al. Immunohistologic abnormalities of
the microfibrillar-fiber system in the Marfan syndrome. N Engl J Med
1990;323:152–159.
Hubmacher D, Apte SS. ADAMTS proteins as modulators of microfibril
formation and function. Matrix Biol 2015;47:34–43.

264
Lueder GT, Steiner RD. Ophthalmic abnormalities in molybdenum cofactor
deficiency and isolated sulfite oxidase deficiency. J Pediatr Ophthalmol
Strabismus 1995;32:334–337.
Maumenee IH. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc
1981;79:684–733.
Maumenee IH. The Marfan syndrome is caused by a point mutation in the fibrillin
gene. Arch Ophthalmol 1992;110:472–473.
Maumenee IH. The Weill-Marchesani syndrome. In: Beighton P, ed. McCusick’s
Heritable Disorders of Connective Tissue. St. Louis, MO: Mosby,
1993:179–187.
Miraldi Utz V, Coussa RG, Traboulsi EI. Surgical management of lens
subluxation in Marfan syndrome. J AAPOS 2014;18:140–146.
Patel N, Khan AO, Mansour A, et al. Mutations in ASPH cause facial
dysmorphism, lens dislocation, anterior-segment abnormalities, and
spontaneous filtering blebs, or Traboulsi syndrome. Am J Hum Genet
2014;94:755–759.
Pyeritz, RE. Homocystinuria. In: Beighton P, ed. McCusick’s Heritable Disorders
of Connective Tissue. St. Louis, MO: Mosby, 1993:137–178.
Sadiq MA, Vanderveen D. Genetics of ectopia lentis. Semin Ophthalmol
2013;28:313–320.
Schienle HW, Seitz R, Nawroth P, et al. Thrombomodulin and ristocetin cofactor
in homocystinuria: a study in two siblings. Thromb Res 1995;77:79–86.
Shih VE, Abroms IF, Johnson JL, et al. Sulfite oxidase deficiency. Biochemical
and clinical investigations of a hereditary metabolic disorder in sulfur
metabolism. N Engl J Med 1977;297:1022–1028.
Smith TH, Holland MG, Woody NC. Ocular manifestations of familial
hyperlysinemia. Trans Am Acad Ophthalmol Otolaryngol 1971; 75:355–360.
Thomas C, Cordier J, Algan B. Les altérations oculaires de la maladie d’Ehlers-
Danlos. Arch Ophtalmol (Paris) 1954;14:691–697.
Wirtz MK, Samples JR, Kramer PL, et al. Weill-Marchesani syndrome—possible
linkage of the autosomal dominant form to 15q21.1. Am J Med Genet
1996;65:68–75.

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 8 Glaucoma
Visual loss in glaucoma is caused by the death of the retinal ganglion cells
and their axons that constitute the nerve fiber layer of the retina and the
optic nerve (Figs. 8-1 and 8-2). The optic nerve head has a characteristic
cupped or excavated configuration in glaucoma (Figs. 8-2 and 8-3).
Cupping distinguishes glaucomatous optic atrophy from primary optic
atrophy, in which loss of retinal ganglion cells and nerve fibers also
occurs. Cupping of the optic disk suggests that elevated intraocular
pressure is a major risk factor in the pathogenesis of glaucomatous optic
atrophy.

FIG. 8-1. Normal perifoveal retina (A) compared to glaucomatous retinal atrophy
(B). A. Perifoveal retina shows normal lamellar architecture including
characteristic thick layer of ganglion cells. B. In contrast, retina with severe
glaucomatous atrophy shows total loss of ganglion cell and nerve fiber layers.
Persistence of inner plexiform and inner nuclear layers excludes inner ischemic
retinal atrophy. (A. H&E ×250, B. H&E ×250.)

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FIG. 8-2. A. Glaucomatous optic atrophy. Macrophoto of eye with end-stage
glaucoma harbors pale and deeply excavated optic nerve. The macula contains
yellow luteal pigment. B. Optic nerve head of glaucomatous eye is severely
cupped with posterior bowing of the lamina cribrosa. C. Nerve fiber layer
constitutes half of the thickness of normal juxtapapillary retina. D. Thin strand of
gliotic tissue enters margin of deeply cupped optic nerve of eye with severe
glaucomatous atrophy. Peripapillary retina shows loss of ganglion cell and nerve
fiber layers. (B. H&E ×25, C. H&E ×100, D. H&E ×100.)

FIG. 8-3. Glaucomatous optic atrophy, scanning electron micrograph (SEM). A.

Longitudinally sectioned normal nerve shows mild physiologic cupping. Lamina
cribrosa is visible. B. Longitudinal section of nerve with severe glaucomatous

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 cupping. Retina at margin of cup is severely atrophic.

How elevated intraocular pressure kills retinal ganglion cells is not clear.
Experimental evidence suggests that it may be related to ischemia and/or
blockage of axoplasmic flow caused by mechanical compression of axons
in the pores of the lamina cribrosa, which are distorted by high levels of
intraocular pressure. The blockage of axoplasmic flow may deprive cells
of brain-derived neurotrophic factor whose absence triggers programmed
cell death. Glial cell activation, TNF-α, and neuroinflammatory processes
are thought to be important mediators of retinal ganglion cell damage.
Glaucoma has been defined as “a syndrome characterized by an
elevation of intraocular pressure of sufficient degree or chronicity to
produce ocular tissue damage” (Yanoff) or as “an optic neuropathy
associated with a characteristic excavation of the optic disc and a
progressive loss of visual field sensitivity” (Quigley). The first definition
emphasizes that tissue damage, usually nerve fiber atrophy or optic nerve
cupping, is a requisite for the diagnosis. The term syndrome indicates that
there are many mechanisms that can raise intraocular pressure. The first
definition also implies that a single elevated pressure reading is not
glaucoma. The second newer definition does not mention intraocular
pressure because authorities recently have stressed that elevation of
intraocular pressure is only one of the risk factors that are responsible for
neuronal loss in glaucoma. The latter definition includes so-called low-
tension glaucoma that develops in patients whose optic nerves seem to be
especially vulnerable to damage. Most glaucomatous eyes examined in the
ophthalmic pathology laboratory have had elevated intraocular pressure. In
nearly all cases of glaucoma, the elevated intraocular pressure is caused by
obstruction of aqueous outflow.
As noted above (see Chapter 1), intraocular pressure is governed by a
delicate balance between the production of aqueous humor by the
nonpigmented ciliary epithelial cells and its egress or outflow from the eye
via the trabecular meshwork and the canal of Schlemm, which are located
in the anterior chamber angle formed by the cornea and peripheral iris
(Fig. 8-4). Lesser amounts of aqueous humor exit through nontraditional
pathways that include iris vessels and posterior uveoscleral outflow via the
ciliary body and the vortex veins.

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 FIG. 8-4. Iridocorneal angle. A. Gray slit denoted by arrow is canal of Schlemm.
Neighboring trabecular meshwork is lightly pigmented. B. Canal of Schlemm
(CS) and trabecular meshwork (TM) are located in anterior crotch of scleral spur
(SS). Longitudinal ciliary muscle (CM) attaches to posterior aspect of spur. C.
Arrow marks scleral spur in macrophoto of eye with open angle. Thickest part of
trabecular meshwork is seen as pigmented band immediately anterior to scleral
spur. D. Laboratory “goniophoto” of eye with angle pigmentation. Band of
pigment marks thickest part of trabecular meshwork (TM) adjoining scleral spur
(SS). A second finer band of pigment forms Sampaolesi (SL) line at termination
of Descemet membrane.

The trabecular meshwork is a sieve-like structure that is nestled in the

anterior crotch of the scleral spur (Figs. 8-4 and 8-5). It is composed of an
interconnected network of small collagenous beams or trabeculae
enveloped by trabecular endothelial cells. A thin layer of extracellular
matrix material called the juxtacanalicular connective tissue (JCT) is
interposed between the interstices of the meshwork and the lumen of
Schlemm canal, which is lined by a continuous layer of endothelial cells.
A modified vein, Schlemm canal runs circumferentially around the
chamber angle, giving off branches or collector channels that traverse the
sclera and discharge their contents into the epibulbar veins via the aqueous

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veins of Ascher.

FIG. 8-5. A. Schlemm canal and JCT. Aqueous outflow obstruction in POAG
probably resides in the JCT, which borders the inner wall of Schlemm canal.
Alvarado has shown that the area of the trabecular cul-de-sacs is markedly
reduced in POAG. These trabecular cul-de-sacs, which abut the JCT, are
responsible for a major proportion of normal outflow resistance. (From Alvarado
JA, Murphy CG. Outflow obstruction in pigmentary and primary open angle
glaucoma. Arch Ophthalmol 1992;110:1769–1778. Copyright 1992 American
Medical Association.) B. Trabecular meshwork, POAG. Trabeculectomy
specimen from patient with POAG shows decreased cellularity of trabecular
endothelium and fusion of beams in inner meshwork. These changes may be
artifactitious. PAS ×250.

CLASSIFICATION OF THE
GLAUCOMAS
The glaucomas are classified into developmental, primary, or idiopathic
and secondary types. Primary and secondary glaucomas are subclassified
into open-angle and closed-angle variants depending on whether the angle
is open or closed (Fig. 8-6). Angle-closure glaucoma is marked by the
apposition or adherence of the peripheral iris to the trabecular meshwork
(Fig. 8-6B,D). Developmental glaucomas present in infancy or childhood
and may be inherited or are associated with other ocular anomalies or
systemic disorders.

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FIG. 8-6. Open and closed anterior chamber angles. Normal anterior chamber
angle (A and C) contrasts with closed angle in eyes with secondary angle-closure
glaucoma (B and D). B. Peripheral iris adheres to and blocks trabecular
meshwork in eye with peripheral anterior synechiae and angle-closure glaucoma
due to NVI. Transparent neovascular membrane flattens anterior surface of iris.
D. Narrow peripheral anterior synechia in photomicrograph covers most of the
trabecular meshwork. (C. H&E ×50, D. H&E ×50.)

DEVELOPMENTAL GLAUCOMA
Developmental glaucomas are caused by developmental abnormalities or
dysembryogenesis of the aqueous outflow pathways. Primary congenital
glaucoma is a bilateral disorder that is often inherited as an autosomal
recessive trait. Autosomal recessively inherited congenital glaucoma is
caused by mutations in the cytochrome P4501B1 gene (CYP1B1) on
chromosome 2 (2p22-p21). Forty percent of cases are present at birth, and
86% become evident during the first year of life. Affected infants often
have light sensitivity (photophobia), blepharospasm, and tearing and may
be misdiagnosed as having nasolacrimal duct obstruction. Ocular
enlargement (buphthalmos or “ox eye”) is the clinical hallmark of
congenital glaucoma. Elevation of intraocular pressure only causes ocular

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enlargement during childhood when the sclera is relatively thin and elastic.
Corneal enlargement and ectasia of limbal tissues is especially striking
(Fig. 8-7A). As the cornea stretches, the Descemet membrane may rupture
spontaneously causing corneal edema and opacification. Old healed
ruptures in Descemet membrane in patients with congenital glaucoma are
called Haab striae (Fig. 8-7B). Haab striae usually are oriented
horizontally or concentric to the limbus in the peripheral cornea. This
distinguishes them from traumatic ruptures caused by obstetrical forceps,
which usually are oriented obliquely.

FIG. 8-7. Congenital glaucoma. A. Ridges on back of cornea denoted by arrows

are healed ruptures in Descemet membrane (Haab striae). The cornea is large, the
anterior chamber is deep, and the limbal tissues are somewhat ectatic.
Depigmentation of ciliary body was caused by a prior cyclodestructive procedure.
B. Haab stria, congenital glaucoma. A thickened ridge of hypertrophic coiled
Descemet membrane has formed at the site of a rupture caused by corneal
enlargement. Intrinsically elastic, Descemet membrane often coils up when
lacerated or ruptured. PAS ×100.

Hypothetical mechanisms involved in the pathogenesis of congenital

glaucoma include an imperforate mesodermal sheet covering the trabecular
meshwork called Barkan membrane, congenital absence of Schlemm
canal, and persistence of a fetal angle configuration. Histopathologically,
the fetal angle is characterized by anterior insertion of the iris root and
ciliary processes, the presence of mesenchymal tissue in the angle, and
continuity of ciliary muscle fibers with trabecular beams. The anterior
chamber usually is quite deep in eyes with congenital glaucoma. The angle
is open gonioscopically, and there is a high insertion of the iris root.
Developmental glaucoma occasionally occurs in association with other
ocular abnormalities or congenital syndromes including aniridia, the
Axenfeld-Rieger syndrome, and Peters anomaly. Glaucoma also

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complicates von Recklinghausen neurofibromatosis (NF-1) and Sturge-
Weber syndrome, particularly if the upper eyelid is involved by the
hamartomatous process, a plexiform or diffuse neurofibroma in NF-1 (Fig.
2-8), or a nevus flammeus in Sturge-Weber syndrome (Fig. 2-11).
Hamartomatous infiltration of the angle may produce a distinctive
gonioscopic appearance in NF-1. The angle is blanketed by a uniform
layer of tan tissue, which obscures normal trabecular landmarks.
Glaucoma and cataract occur concurrently in Lowe syndrome. Other
syndromes that may have congenital glaucoma include Gregg congenital
rubella syndrome, Stickler syndrome, Hallermann-Streiff syndrome,
Hurler syndrome, Turner syndrome, and trisomies 21 and 13.

PRIMARY OPEN-ANGLE
GLAUCOMA
Primary or idiopathic open-angle glaucoma (POAG) is the most common
type of glaucoma, and affects an estimated 1% to 3% of the population.
POAG is an insidious disease that causes asymptomatic painless visual
loss. By definition, the angle is open on gonioscopic examination. POAG
usually is a bilateral disease, and affected patients frequently have a
positive family history. The genetics of POAG are complex; the disorder
has been linked to 14 genes, most notably the myocilin (MYOC) gene on
chromosome 1. Mutations in myocilin are found in 3% to 5% of patients
with adult-onset POAG.
The cause of aqueous outflow obstruction in POAG remains uncertain,
but the area of obstruction may be located in the JCT in the deepest part of
the trabecular meshwork bordering Schlemm canal. Several pathogenetic
theories involve obstruction of the meshwork or JCT by
glycosaminoglycans or other abnormal extracellular matrix material. Loss
of trabecular endothelial cells could lead to fusion of trabecular beams and
decreased porosity of the meshwork (Fig. 8-5B). Electron microscopy has
shown that the density of trabecular endothelial cells is decreased in
patients with POAG. Trabecular endothelial cell death in patients with
mutations in the MYOC gene may be related to the intracellular
accumulation of abnormal myocilin. Another study showed that the area of
the trabecular cul-de-sacs, which provide a major proportion of normal
outflow resistance, is markedly reduced in POAG (Fig. 8-5A). Other
hypothetical pathogenetic mechanisms include abnormalities in the
formation of giant vacuoles in the endothelial lining of Schlemm canal, or

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age-related sclerosis in the scleral spur that impedes posterior uveoscleral
outflow.

PRIMARY CLOSED-ANGLE
GLAUCOMA
Primary closed-angle glaucoma (acute angle-closure glaucoma or acute
congestive glaucoma) is caused by functional apposition or blockage of the
trabecular meshwork by the peripheral iris. The resultant acute rise in
intraocular pressure produces major symptoms including severe ocular
pain, headache, and gastrointestinal symptoms (nausea and vomiting)
caused by a vagal oculogastric reflex. During an acute attack of closed-
angle glaucoma, the involved eye is injected and classically has a fixed,
dilated pupil. The vision often is diminished by corneal epithelial edema
evident clinically as “bedewing” or possibly by posterior segment
ischemia. Primary closed-angle glaucoma usually is unilateral and
classically occurs in hyperopic (“far-sighted”) patients whose small eyes
have shallow, crowded anterior chambers. Primary closed-angle glaucoma
is extremely rare in myopes (near-sighted individuals) and younger
patients less than age 40. Progressive growth of the lens or development of
an intumescent cataract can precipitate an acute attack of closed-angle
glaucoma in elderly patients (phacomorphic glaucoma). Acute angle-
closure glaucoma is more prevalent in certain racial groups (e.g., Asians
and Inuits) and often occurs in nanophthalmic eyes, which are markedly
hyperopic and prone to develop exudative ciliochoroidal detachment. Most
patients with angle closure have an asymptomatic course and do not suffer
acute attacks. Quigley has hypothesized that disturbed physiological
mechanisms contribute to angle closure and angle-closure glaucoma in
many cases. Such factors include diminished loss of iris volume during
pupillary dilation and expansion of choroidal volume.
Functional pupillary block is involved in the pathogenesis of primary
closed-angle glaucoma. When the pupil is mid-dilated, the iris pigment
epithelium near the pupil is pressed firmly against the anterior surface of
the lens, impeding the flow of aqueous humor into the anterior chamber.
The pupillary block is functional because actual adhesions between the iris
and lens called posterior synechiae have not formed. Continual production
of aqueous humor behind the iris produces a pressure gradient that bows
the peripheral part of the iris forward obstructing the trabecular meshwork.
If this functional papillary block is not relieved expeditiously, permanent

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adhesions between peripheral iris and trabecular meshwork called
peripheral anterior synechiae eventually develop. Acute closed-angle
glaucoma is cured by making a full-thickness hole in the iris. This
equalizes the pressure in the anterior and posterior chambers and allows
the iris to fall back into its normal position. The iridotomy usually is
performed with a surgical laser.
High levels of intraocular pressure during an attack of acute closed-
angle glaucoma can cause permanent damage to anterior segment
structures. Ischemic in nature, these changes persist as stigmata of a prior
“acute attack” and include permanent dilation and unreactivity of the pupil
caused by necrosis of the sphincter muscle, patchy atrophy of the iris
stroma, and small grayish anterior subcapsular lens opacities called
glaukomflecken. Glaukomflecken probably represent focal areas of lens
epithelial necrosis and cortical degeneration.

SECONDARY CLOSED-ANGLE
GLAUCOMA
Secondary glaucomas are caused by concurrent ocular or systemic disease.
Both closed-angle and open-angle varieties of secondary glaucoma occur.
Many blind glaucomatous eyes examined in the ophthalmic pathology
laboratory have secondary closed-angle glaucoma. Secondary closed-angle
glaucoma is characterized by the formation of permanent adhesions
between iris and trabecular meshwork called peripheral anterior synechiae
(Figs. 8-6D, 8-11A and 8-12A). There are many causes of secondary
closed-angle glaucoma. Permanent peripheral anterior synechiae can form
in untreated primary closed-angle glaucoma and often develop in the late
stages of retinopathy of prematurity or persistent fetal vasculature (PFV).
Posterior segment tumors usually cause secondary closed-angle glaucoma
by stimulating iris neovascularization (NVI) or by a pupillary block
mechanism.

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FIG. 8-11. Neovascular glaucoma. A. Arrow denotes compressed trabecular
meshwork deep to broad peripheral anterior synechia in eye with NVG secondary
to central retinal vein occlusion. The anterior surface of the iris is flattened. B.
Iris neovascularization. Arrows point to new vessels on iris beneath surface sheet
of myofibroblasts. (From John TJ, Sassani JW, Eagle RC Jr. The myofibroblastic
component of rubeosis iridis. Ophthalmology 1983;90:721–728. Courtesy of
Ophthalmology.) (A. SEM ×20, B. SEM ×640.)

FIG. 8-12. Neovascular glaucoma. A. A broad peripheral anterior synechia is

present. The free surface of the iris is flattened by a florid neovascular membrane
that is causing ectropion of the iris pigment epithelium and sphincter muscle. B.
Ectropion iridis, NVG. SEM discloses a florid fibrovascular membrane that
flattens the anterior surface of the iris, which normally is an avascular site.
Traction has pulled the iris pigment epithelium and sphincter muscle onto the
front of the iris. (A. H&E ×10, B. SEM ×80.)

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The role of functional pupillary block in primary closed-angle glaucoma is
discussed above. Pupillary block also is important in several types of
secondary closed-angle glaucoma. Inflammatory adhesions between the
pupillary part of the iris and the anterior lens capsule called posterior
synechiae readily form in the sticky, fibrin-rich milieu of iritis or
iridocyclitis. The entire circumference of the pupil may become firmly
bound to the lens (seclusio pupillae), totally blocking the flow of aqueous
humor into the anterior chamber. The elevated pressure in the posterior
chamber bows the peripheral part of the iris forward (iris bombe) and
blocks the trabecular meshwork secondarily (Fig. 8-8). Cycloplegic
medications such as atropine or scopolamine relieve the pain of pupillary
and ciliary spasm in uveitis and help to prevent posterior synechiae by
dilating the pupil. The lens or vitreous can also block the pupil. Anterior
displacement of a microspherophakic lens in Weill-Marchesani syndrome
readily occludes the pupil causing pupillary block glaucoma (Fig. 7-18B).
Pupillary block glaucoma also occurs in patients with traumatic or
heritable lens dislocation. Prophylactic peripheral iridectomies were
performed routinely during intracapsular cataract surgery to prevent
postoperative blockage of the pupil by the anterior face of the vitreous.
Pupillary block caused by anterior movement of the lens–iris diaphragm is
a common cause of secondary closed-angle glaucoma in eyes that have
large posterior segment tumors or extensive bullous retinal detachments.

FIG. 8-8. Iris bombe. Pupil is secluded by 360-degree posterior synechiae.

Peripheral iris is bowed anteriorly forming broad secondary peripheral anterior
synechiae.

Several clinically important types of secondary closed-angle glaucoma are

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caused by the proliferation of cells on anterior chamber structures. These
secondary proliferative glaucomas include epithelial downgrowth or
ingrowth caused by proliferation of ocular surface epithelium after surgical
or nonsurgical trauma (Fig. 8-9), the iridocorneal endothelial or ICE
syndrome caused by proliferation of abnormal corneal endothelial cells
(Figs. 8-13 and 8-14), and neovascular glaucoma (NVG) caused by NVI
(Figs. 8-10 to 8-12). Epithelial downgrowth is discussed in Chapter 4.

FIG. 8-9. Epithelial downgrowth. A. Slit lamp discloses sheet of corneal

epithelium on posterior corneal surface superiorly. B. SEM shows sheet of
surface epithelium introduced by trauma lining the posterior cornea, trabecular
meshwork, and anterior surface of the iris. The epithelial membrane flattens the
anterior surface of the iris. SEM ×80.

FIG. 8-13. A. ICE syndrome, essential iris atrophy variant. Distorted pupil is
drawn toward synechia in inferior angle. Arrow points to full-thickness iris hole.
Multiple iris nodules are seen in flattened endothelialized zone of iris bordering
synechia and ectropion iridis. (From Eagle RC Jr. Congenital, developmental and
degenerative disorders of the iris and ciliary body. In: Albert DM, Jakobiec FA,
eds. Principles and Practice of Ophthalmology. Clinical Practice, vol. 1.
Philadelphia, PA: Saunders, 1993:368–389.) B.ICE syndrome, essential iris
atrophy variant. Rodlets and tubules of new Descemet membrane material are
seen within area of synechia closure at margin of tractional iris hole. Location of

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abnormal matrix material within synechia excludes secondary reactive
endothelialization. Thick layer of ectopic Descemet membrane lines anterior
surface of severely stretched and ectatic iris at right. (B. PAS ×100.)

FIG. 8-14. ICE syndrome, Cogan-Reese variant. A. Photo of initial patient

reported by Cogan and Reese shows flattening and effacement of anterior iridic
surface, multiple pigmented iris nodules, and ectropion iridis. Patient had
unilateral glaucoma and was thought to have an iris melanoma. B. Pigmented iris
nodule and thick layer of ectopic Descemet membrane are seen on anterior
surface of iris. Basement membrane material is also interposed between iris and
cornea in area of synechial closure, excluding reactive endothelialization. C.
Scanning electron microscopy shows sheet of ectopic corneal endothelial cells on
anterior surface of iris in similar case. Endothelium encircles groups of iris cells
forming nodules. D.Similar nodule of iris stromal cells encircled by ectopic
endothelium in case of essential iris atrophy. (B. H&E ×100, C. SEM ×160, SEM
×640.)

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 FIG. 8-10. Neovascular glaucoma. A. Scanning electron microscopy of normal
iris shows collarette, crypts, and contraction furrows. B. Neovascular glaucoma.
Neovascular membrane flattens and effaces normal architecture of anterior iridic
surface. A peripheral iridectomy is present. Peripheral ridge (arrow) marks site of
ruptured anterior synechia. (A. SEM ×10, B. SEM ×10.)

NEOVASCULAR GLAUCOMA
Many blind painful eyes accessioned by ophthalmic pathology laboratories
have NVG (Figs. 8-10 to 8-12). Peripheral anterior synechia formation in
NVG is caused by the proliferation of fibrovascular tissue on the anterior
surface of the iris and angle. Angiogenic factors such as vascular
endothelial growth factor (VEGF) produced by ischemic parts of the retina
or intraocular tumor cells stimulate the NVI. VEGF levels in the aqueous
humor are significantly increased in NVG. Clinically, conditions most
commonly associated with NVG include retinal vein and artery occlusions,
proliferative diabetic retinopathy, and intraocular tumors, particularly
retinoblastoma.
Severe NVI (rubeosis iridis) flattens the anterior surface of the iris,
effacing normal architectural details like contraction furrows (Fig. 8-10B).

280
The anterior border layer of the iris normally is a totally avascular site.
Any vessels found here during histopathologic examination are abnormal.
The new vessels have thin walls and lack the thick mantle of collagen
fibers that normally envelops iris stromal vessels. The new vessels are
located deep to a flat, delicate sheet of contractile myofibroblasts, which is
transparent clinically (Fig. 8-11B). The surface layer of myofibroblasts
may provide the motive force for synechial closure of the angle and
formation of pigment epithelial ectropion (ectropion iridis). In ectropion
iridis, the iris pigment epithelium is dragged around the pupillary margin
onto the anterior surface of the iris by the contracting sheet of neovascular
tissue (Fig. 8-12). An associated ectropion of the pupillary sphincter
muscle is often present.
Fewer eyes with NVG are being enucleated and submitted to
ophthalmic pathology laboratories in recent years. This reflects the
availability of effective new therapies such as panretinal photocoagulation
(PRP) that prevent the development of proliferative retinopathy and NVI
in patients who have diabetes and other ischemic retinopathies. PRP uses
hundred of laser burns to kill outer retinal cells. Hypothetically, this
diminishes the production of angiogenic factors by decreasing the demand
for oxygen and nutrients or increases the supply of metabolites by
disrupting the outer part of the blood retinal barrier. PRP does not reverse
synechiae after they have formed. Specialized filtering operations using
plastic setons or tube shunts or transscleral cycloablation procedures that
use intense cold or laser energy to reduce aqueous production can be used
to treat established cases of NVG. VEGF inhibitors ranibizumab and
bevacizumab currently are being evaluated as an adjunctive therapy for
NVI.

THE IRIDOCORNEAL
ENDOTHELIAL (ICE) SYNDROME
Proliferation of abnormal corneal endothelial cells, possibly transformed
by viral infection, causes unilateral closed-angle glaucoma and a
characteristic spectrum of iris abnormalities in patients who have the ICE
syndrome (Figs. 8-13 and 8-14). The iris abnormalities include distortion
of the pupil, which typically is drawn toward a synechia that develops in
the otherwise open angle, marked degrees of iris pigment epithelial
ectropion, flattening and effacement of the anterior iridic surface with
multiple pigmented iris nodules (Fig. 8-14), and the formation of full-

281
thickness tractional iris holes (Fig. 8-13A). The name iridocorneal
endothelial or ICE syndrome stresses the role of endothelial proliferative
in the pathogenesis of the iris abnormalities. Several conditions that
comprise the ICE syndrome are distinguished by the nature of their iris
abnormalities. Full-thickness iris holes are a characteristic feature of
essential iris atrophy, but typically do not develop in the Cogan-Reese or
iris nevus syndrome, in which the iris is covered by endothelium and
flattened by ectopic Descemet membrane studded with pigmented nodules.
Corneal edema overshadows iris abnormalities in the variant of essential
iris atrophy described by Chandler (Chandler syndrome).
Normal corneal endothelium does not proliferate during adult life, but
the abnormal endothelial cells in the ICE syndrome are able to multiply
and extend across the trabecular meshwork onto the iris where they
elaborate large quantities of extracellular matrix material including new
Descemet membrane (Figs. 8-13B and 8-14B). The matrix material
thickens trabecular beams and welds the flattened iris to the posterior
cornea. The iris nodules that characterize Cogan-Reese syndrome and
some cases of essential iris atrophy are formed when the sheets of
migrating endothelial cells encircle and “pinch off” of knuckles of iris
stroma (Fig. 8-14C,D). Endothelialization and descemetization of fistulas
and filtering blebs leads to failure of glaucoma surgery.
Corneal endothelial abnormalities often are evident on clinical
specular microscopy as “dark-light” reversal and the presence of two
sharply demarcated populations of endothelial cells that vary in size and
shape. What causes the corneal endothelium to transform into a new
species of cells capable of proliferation is unclear. Theories include viral
transformation of cells, an endothelial neoplasm, or abnormalities in
terminal differentiation of neural crest cells.

SECONDARY OPEN-ANGLE
GLAUCOMA
The angle appears open on gonioscopic examination in patients who have
secondary open-angle glaucoma. Causes of secondary open-angle
glaucoma include obstruction of the trabecular meshwork by cells,
pigment, debris or other material, damage or scarring of outflow pathways,
or systemic or local conditions that elevate episcleral venous pressure.
Substances that can obstruct the trabecular meshwork include blood

282
and blood-breakdown products, inflammatory cells, particles of lens
material, melanin pigment, and an abnormal form of extracellular matrix
material called pseudoexfoliation (PXE), which is found in some elderly
patients. Glaucoma complicates large anterior chamber hemorrhages
caused by contusion injuries (“eight-ball” or “black ball” hyphemas).
Patients with sickle hemoglobinopathy who develop hyphemas are at
particular risk for glaucoma because their erythrocytes sickle in the low-
oxygen environment and the sickled cells, which are less pliable, become
trapped in the trabecular meshwork.
Infiltration of the trabecular meshwork by inflammatory cells
(“trabeculitis”) occasionally causes elevated intraocular pressure in eyes
with iridocyclitis. Frequently, however, disruption of the blood-aqueous
barrier by the inflammation leads to “shutdown” of aqueous production by
the ciliary body.
Several rare types of secondary glaucoma are caused by physical
obstruction of the trabecular meshwork by macrophages. Phacolytic
glaucoma (Fig. 8-15) is caused by macrophages that have ingested
degenerated lens material that has leaked through the capsule of a mature
cortical cataract. Free high molecular weight lens protein also contributes
to trabecular meshwork blockage. Patients who have phacolytic glaucoma
often have undergone successful cataract surgery in their fellow eye and
have forgone additional surgery because they are satisfied with uniocular
vision. Many eyes with phacolytic glaucoma were enucleated in the past
before the condition was widely recognized. Now most cases respond to
lens extraction and anterior chamber lavage.

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 FIG. 8-15. Phacolytic glaucoma. A. Eye with phacolytic glaucoma has mature
cortical cataract and milky aqueous humor. B. Asterisk labels lens protein-rich
fluid in open angle. Arrow points to empty lens capsule. Postcontusion angle
recession is present. C. Aggregate of macrophages laden with lens material
adheres to anterior surface of iris. D. Specimen from lensectomy procedure used
to treat phacolytic glaucoma contains degenerated lens fibers and macrophages
laden with degenerated lens material. (B. H&E × 50, C. H&E × 250, D. H&E
×100.)

The trabecular meshwork in hemolytic glaucoma is obstructed by

macrophages laden with blood-breakdown products including globules of
the golden-brown pigment hemosiderin and erythrocyte ghost cells (Fig. 8-
16D). Hemolytic glaucoma usually occurs in patients who have chronic
vitreous hemorrhage. Microscopic examination of the khaki or yellow
ochre-colored vitreous blood discloses small eosinophilic hemoglobin
spherules, macrophages laden with hemosiderin and other blood-
breakdown products and erythrocyte ghost cells. Ghost cells or
erythroclasts are red blood cells that have lost their hemoglobin. The inner
surface of the empty cell membranes is studded with dots called Heinz
bodies. All of these blood-breakdown products occasionally are able to
enter the anterior segment through defects in the vitreous face or zonule. A

284
relatively pure population of ghost cells blocks the meshwork in the
variant of hemolytic glaucoma called ghost cell glaucoma. The clinical
findings in ghost cell glaucoma may be quite subtle; the ghost cells usually
form a faint, inconspicuous khaki-colored layer in the inferior chamber
angle.

FIG. 8-16. A. Melanocytomalytic glaucoma. Macrophoto shows melanophages

in anterior chamber angle and ciliary sulcus. B. Macrophages laden with melanin
pigment dispersed by necrotic melanocytoma fill peripheral anterior chamber and
infiltrate trabecular meshwork. C. SEM shows melanophages obstructing
trabecular meshwork in eye with melanocytomalytic glaucoma. D. Hemolytic
glaucoma. Blood-breakdown products including hemosiderin-laden macrophages
and erythrocyte ghost cells (arrow) are seen on trabecular meshwork. (A. H&E
×100, B. SEM ×160, D. H&E ×250.)

Macrophages that have ingested melanin pigment released from necrotic

pigmented tumors cause melanomalytic glaucoma and melanocytomalytic
glaucoma (Fig. 8-16). Magnocellular nevi called melanocytomas are
particularly prone to undergo spontaneous necrosis. Several cases of
melanocytomalytic glaucoma caused by necrosis of iris melanocytomas
have been reported. Gonioscopy discloses heavy pigmentation of the

285
trabecular meshwork.
Particles of degenerated lens material dispersed by lens injuries or
surgery can cause secondary open-angle glaucoma (lens particle
glaucoma). Rare cases of alpha chymotrypsin glaucoma were reported in
the era of intracapsular cataract surgery. The enzymatic zonulysis released
zonular fragments and debris causing temporary obstruction of the
trabecular meshwork. Secondary trabecular obstruction by photoreceptor
outer segments in eyes with chronic rhegmatogenous retinal detachments
is called the Schwartz-Matsuo syndrome.
A relatively common type of secondary open-angle glaucoma called
glaucoma capsulare occurs in elderly patients who have PXE of the lens
capsule (see Chapter 7, Figs. 7-15 and 7-16). PXE dispersed by the
aqueous physically blocks the trabecular meshwork, and additional
material actually may be synthesized within the meshwork by the
trabecular endothelial cells. Iris pigment epithelial abnormalities also lead
to dispersal of iris pigment epithelial melanin throughout the anterior
segment.
Granules of melanin pigment released from the iris pigment epithelium
accumulate in the trabecular meshwork and interfere with aqueous outflow
in pigmentary glaucoma (Figs. 8-17 and 8-18). Pigmentary glaucoma is
particularly common in young to middle-aged males who are myopic and
have a deep anterior chamber and a tremulous iris (iridodonesis).
Campbell proposed that abrasion by bundles of zonular fibers causes
release of melanin from the iris pigment epithelium (Fig. 8-18A,B). An
inverse pupillary block mechanism appears to bow the peripheral iris
against the zonules in some patients. The zonular abrasions cause defects
in the pigment epithelium that are evident during transillumination as
characteristic radially oriented areas of increased light transmission (Fig.
8-17A). Biomicroscopy discloses pigment-laden macrophages (clump cells
of Koganei type I) in the superficial iris stroma overlying the defects (Fig.
8-17B). Iris pigment phagocytized by the corneal endothelium is seen
clinically as a vertically oriented Krukenberg spindle. The orientation of
the spindle is governed by convection currents in the aqueous humor. The
trabecular meshwork is heavily pigmented (Fig. 8-18C). Large round
melanin granules consistent with iris pigment epithelial origin are found
within the cytoplasm of the trabecular endothelial cells (Fig. 8-18D).
Chronic pigmentation is thought to induce trabecular scarring. Only about
half of patients with pigment dispersion actually develop glaucoma.

286
FIG. 8-17. Pigmentary glaucoma-iris transillumination. A. Radial
transillumination defects in peripheral iris of patient with pigment dispersion
syndrome. B. Melanophages on anterior surface of iris are clinical markers for
pigment epithelial erosion. (Photos courtesy of Ocular Oncology Service, Wills
Eye Hospital.)

FIG. 8-18. Pigmentary glaucoma. A. Depigmented foci on posterior surface of

iris correspond to erosions in iris pigment epithelium caused by zonular bundles,
which pass through valleys between ciliary processes. (Macrophoto courtesy of
Dr. Myron Yanoff.) B. Arrow in SEM points to defect in iris pigment epithelium
that lines up with valley (V). C. Trabecular meshwork of open angle is heavily
pigmented. D. Cytoplasm of trabecular endothelial cells is replete with large
round oval granules of iris pigment epithelial melanin. (B. SEM ×40, C. SEM
×1250.)

Malignant tumors, particularly malignant melanomas of the ciliary body

and/or iris, can cause secondary open-angle glaucoma by diffusely seeding
the trabecular meshwork with tumor cells, or by proliferating
circumferentially around the angle as a “ring melanoma” (Fig. 8-19).
Anterior segment tumors generally cause secondary open-angle glaucoma.
Posterior tumors, especially large choroidal melanomas or exophytic
retinoblastomas with extensive bullous retinal detachments, cause
secondary closed-angle glaucoma (Fig. 8-20). Angiogenesis factors like

287
VEGF produced by tumors can also cause NVG.

FIG. 8-19. Ring melanoma. A. Heavily pigmented melanoma has grown

circumferentially around the angle obstructing the trabecular meshwork. B. SEM
show melanoma cells obstructing trabecular meshwork. Oval cells are epithelioid
melanoma cells. Bipolar spindle cells also are present. Patient had unilateral
glaucoma. C. Nodules of lightly pigmented melanoma cells fill angle and block
trabecular meshwork. Patient presented with iris heterochromia and unilateral
glaucoma. D. Mass of melanoma cells rests on inner surface of trabecular
meshwork. Cells also infiltrate meshwork and Schlemm canal. (B. SEM ×160, D.
H&E ×100.)

FIG. 8-20. Secondary closed-angle glaucoma in eyes with choroidal melanomas

288
 and total retinal detachments. A. Anterior displacement of lens–iris diaphragm
has caused secondary closed-angle glaucoma. Inset shows large melanoma in
posterior choroid and total retinal detachment. B. Another eye with posterior
melanoma, high bullous total retinal detachment, and secondary closed-angle
glaucoma caused by anterior displacement of lens–iris diaphragm. A tumor must
be excluded in any eye with glaucoma and a total retinal detachment.

Glaucoma often occurs in eyes that have diffuse iris melanomas that
typically are composed of poorly cohesive epithelioid cells. Aqueous
dispersion of tumor cells throughout the anterior chamber may cause a
progressive darkening of the involved iris (hyperchromic heterochromia
iridum). Unilateral glaucoma and a subtle change in the color of the iris
may be the only indication that a patient harbors a diffuse iris melanoma
(Fig. 8-21).

FIG. 8-21. A. Hyperchromatic heterochromia iridum caused by high-grade

diffuse iris melanoma. Patient had uncontrolled unilateral glaucoma. B. Tumor
cells dispersed by aqueous humor blanket anterior surface of left iris. Epithelioid
cells were present. The iris was blue prior to development of unilateral glaucoma.

Ocular trauma is another cause of secondary open-angle glaucoma.

Chronic inflammation or repeated anterior chamber hemorrhage can cause
scarring of the trabecular meshwork. Iron released from retained iron
intraocular foreign bodies (siderosis) or recurrent intraocular hemorrhages
(hemosiderosis) can have toxic effects on the trabecular endothelial cells
as well as on the retinal photoreceptors. Postcontusion angle recession, a
well-recognized cause of unilateral glaucoma, is discussed in Chapter 4
(Fig. 4-9).
An important factor that determines the outflow of aqueous humor
from the eye is the difference between the intraocular pressure and the
pressure in the episcleral veins (episcleral venous pressure). Diseases that
cause venous obstruction such as cavernous sinus thromboses or

289
mediastinal syndromes can cause glaucoma by elevating episcleral venous
pressure. Arterialization of episcleral veins markedly elevates episcleral
venous pressure in some patients with carotid cavernous fistulas. The
resultant glaucoma is difficult to manage.
Orbital pathology, for example, orbital tumors or the enlarged
extraocular muscles of thyroid ophthalmopathy, can raise intraocular
pressure by directly compressing the globe.

OCULAR TISSUE CHANGES IN

GLAUCOMATOUS EYES
The histopathologic diagnosis of glaucoma requires the demonstration of
ocular tissue damage, typically glaucomatous retinal and optic atrophy.
Glaucomatous retinal atrophy is characterized by atrophy of the retinal
ganglion and nerve fiber layers, which is composed of the axons of the
ganglion cells (Fig. 8-1). The atrophic nerve fiber layer is often gliotic.
Involvement of the inner plexiform layer and the inner part of the inner
nuclear layer distinguish inner ischemic retinal atrophy that follows retinal
artery occlusion from glaucomatous retinal atrophy. Gliosis typically is
absent in ischemic atrophy, and the inner retinal layers may have a
hyalinized appearance.
Cupping of the optic disk is the characteristic feature of glaucomatous
optic atrophy (Figs. 8-2 and 8-3). There is posterior bowing and distortion
of the collagenous lamina cribrosa, and loss of nerve tissue anterior to the
lamina. The pia and pial septa and subarachnoid space are widened.
Schnabel cavernous optic atrophy occasionally occurs in eyes with severe
glaucoma. Clear cavernous spaces filled with hyaluronic acid are found in
the retrolaminar part of the nerve (Fig. 15-5).
Focal areas of scleral thinning may develop in eyes with chronically
elevated intraocular pressure. These scleral ectasias are called staphylomas
if they are lined by uveal tissue (staphylo and uva mean grape in Greek
and Latin, respectively). Corneal changes found in eyes with chronic
glaucoma include calcific band keratopathy, vascularization, corneal
edema, bullous keratopathy, and degenerative pannus formation.
Chronically edematous corneas are at risk for infection. Perforation of
corneal ulcers in hypertensive eyes can cause spontaneous expulsive
choroidal hemorrhage.

290
BIBLIOGRAPHY
Spencer WH. Glaucoma. In: Spencer W, ed. Ophthalmic Pathology: An Atlas and
Textbook, 4th ed, vol. 1. Philadelphia, PA: WB Saunder, 1996:438–512.

Genetics and Pathogenesis

Anderson DR. Glaucoma: the damage caused by pressure. XLVI Edward Jackson
memorial lecture. Am J Ophthalmol 1989;108:485–495.
Doucette LP, Rasnitsyn A, Seifi M, et al. The interactions of genes, age, and
environment in glaucoma pathogenesis. Surv Ophthalmol 2015;60:310–326.
Kerrigan LA, Zack DJ, Quigley HA, et al. TUNEL-positive ganglion cells in
human primary open-angle glaucoma. Arch Ophthalmol
1997;115:1031–1035.
Liu Y, Allingham RR. Molecular genetics in glaucoma. Exp Eye Res
2011;93:331–339.
Mackey DA. Gillies lecture: dissecting glaucoma: understanding the molecular
risk factors. Clin Experiment Ophthalmol 2008;36(5):403–409.
Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve damage in
human glaucoma. II. The site of injury and susceptibility to damage. Arch
Ophthalmol 1981;99:635–649.
Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma.
III. Quantitative correlation of nerve fiber loss and visual field defect in
glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch
Ophthalmol 1982;100:135–146.
Quigley HA, Green WR. The histology of human glaucoma and nerve damage:
clinicopathologic correlation in 21 eyes. Ophthalmology 1979;86:1803–1827.
Tripathi RC, Tripathi BJ. Functional anatomy of the anterior chamber angle. In:
Jakobiec FA, ed. Ocular Anatomy, Embryology and Teratology. Philadelphia,
PA: Harper & Row, 1982:197–284.
Wang R, Wiggs JL. Common and rare genetic risk factors for glaucoma. Cold
Spring Harb Perspect Med 2014;4(12):a017244.
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of
glaucoma: a review. JAMA 2014;311:1901–1911.
Wiggs JL. Glaucoma genes and mechanisms. Prog Mol Biol Transl Sci
2015;134:315–342.

Developmental Glaucoma
Abdolrahimzadeh S, Fameli V, Mollo R, et al. Rare diseases leading to childhood
glaucoma: epidemiology, pathophysiogenesis, and management. Biomed Res
Int 2015;2015:781294.
Alzuhairy S, Abu-Amero KK, Al-Shahwan S, et al. A novel CYP1B1 mutation
with congenital glaucoma and total aniridia. Ophthalmic Genet

291
 2015;36:89–91.
Anderson DR. The development of the trabecular meshwork and its abnormality
in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981;79:458–485.
Boniuk M. Glaucoma in the congenital rubella syndrome. Int Ophthalmol Clin
1972;12:121–136.
Broughton WL, Fine B, Zimmerman LE. A histologic study of congenital
glaucoma associated with a chromosome defect. Arch Ophthalmol
1981;99:481–486.
Chen TC, Chen PP, Francis BA, et al. Pediatric glaucoma surgery: a report by the
American Academy of Ophthalmology. Ophthalmology
2014;121(11):2107–2115.
Curtin VT, Joyce EE, Ballin N. Ocular pathology in the oculo-cerebro-renal
syndrome of Lowe. Am J Ophthalmol 1967;64 (Part II):533–543.
François J, Hanssens M. Syndrome oculo-cerebro-renal de Lowe: examen
histopathogique oculaire. Bull Soc Belge Ophtalmol 1963;135:412–431.
Furuyoshi N, Furuyoshi M, Futa R, et al. Ultrastructural changes in the trabecular
meshwork of juvenile glaucoma. Ophthalmologica 1997;211:140–146.
Grant WM, Walton DS. Distinctive gonioscopic findings in glaucoma due to
neurofibromatosis. Arch Ophthalmol 1968;79:127–134.
Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia,
with development of glaucoma. Trans Am Ophthalmol Soc 1974;72:207–228.
Honig MA, Barraquer J, Perry HD, et al. Forceps and vacuum injuries to the
cornea: histopathologic features of twelve cases and review of the literature.
Cornea 1996;15:463–472.
Jain A, Gupta S, James MK, et al. Aniridic Glaucoma: Long-term Visual
Outcomes and Phenotypic Associations. J Glaucoma 2015;24:539–542.
Lichter PR. Genetic clues to glaucoma’s secrets: The L. Edward Jackson
Memorial Lecture. Part 2. Am J Ophthalmol 1994;117:706–727.
Maul E, Strozzi L, Munro C, et al. The outflow pathway in congenital glaucoma.
Am J Ophthalmol 1980;89:667–675.
Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Trans
Am Ophthalmol Soc 1958;56:507–570.
Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Trans Am
Acad Ophthalmol Otolaryngol 1978;85:276–286.
Sarfarazi M. Recent advances in molecular genetics of glaucomas. Hum Mol
Genet 1997;6:1667–1677.
Shaffer RN. Pathogenesis of congenital glaucoma: Gonioscopic and microscopic
anatomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:297–300.
Shields B. Axenfeld-Rieger syndrome: a theory of mechanism and distinctions
from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc
1983;81:736–784.
Stoilova D, Child A, Brice G, et al. Identification of a new ‘TIGR’ mutation in a
family with juvenile-onset primary open angle glaucoma. Ophthalmic Genet
1997;18:109–118.

292
Traboulsi E, Maumenee IH. Peters’ anomaly and associated congenital
malformations. Arch Ophthalmol 1992;110:1739–1742.
Wiggs JL, Del Bono EA, Schuman JS, et al. Clinical features of five pedigrees
genetically linked to the juvenile glaucoma locus on chromosome 1q21-q31.
Ophthalmology 1995;102:1782–1789.

Primary Open Angle Glaucoma

Alvarado J, Murphy C, Polansky J, et al. Age-related changes in trabecular
meshwork cellularity. Invest Ophthalmol Vis Sci 1981;21: 714–727.
Alvarado JA, Murphy CG, Juster R. Trabecular meshwork cellularity in primary
open-angle glaucoma and nonglaucomatous normals. Ophthalmology
1984;91:564–579.
Alvarado JA, Murphy CG. Outflow obstruction in pigmentary and primary open
angle glaucoma. Arch Ophthalmol 1992;110:1769–1778.
Alvarado JA, Yun AJ, Murphy CG. Juxtacanalicular tissue in primary open angle
glaucoma and in nonglaucomatous normals. Arch Ophthalmol
1986;104:1517–1528.
Murphy CG, Johnson M, Alvarado JA. Juxtacanalicular tissue in pigmentary and
open angle glaucoma: the hydrodynamic role of pigment and other
constituents. Arch Ophthalmol 1992;110:1779–1785.
Vranka JA, Kelley MJ, Acott TS, et al. Extracellular matrix in the trabecular
meshwork: intraocular pressure regulation and dysregulation in glaucoma.
Exp Eye Res 2015;133:112–125.

Angle Closure Glaucoma

Emanuel ME, Parrish RK II, Gedde SJ. Evidence-based management of primary
angle closure glaucoma. Curr Opin Ophthalmol 2014; 25:89–92.
Friedman DS, Foster PJ, Aung T, et al. Angle closure and angle-closure
glaucoma: what we are doing now and what we will be doing in the future.
Clin Experiment Ophthalmol 2012;40:381–387.
Ng WT, Morgan W. Mechanisms and treatment of primary angle closure: a
review. Clin Experiment Ophthalmol 2012;40:e218–e228.
Quigley HA. Angle-closure glaucoma-simpler answers to complex mechanisms:
LXVI Edward Jackson Memorial Lecture. Am J Ophthalmol
2009;148(5):657–669.

Neovascular Glaucoma
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in
ocular fluid of patients with diabetic retinopathy and other retinal disorders. N
Engl J Med 1994;331:1519–1520.
Colosi NJ, Yanoff M. Reactive corneal endothelialization. Am J Ophthalmol
1977;83:219–224.

293
John TJ, Sassani JW, Eagle RC Jr. The myofibroblastic component of rubeosis
iridis. Ophthalmology 1983;90:721–728.
Madsen PH. Rubeosis of the iris and hemorrhagic glaucoma in patients with
proliferative diabetic retinopathy. Br J Ophthalmol 1971;55:368–371.

The Iridocorneal Endothelial Syndrome

Alvarado JA, Murphy CG, Juster RP, et al. Pathogenesis of Chandler’s syndrome,
essential iris atrophy and the Cogan-Reese syndrome. II. Estimated age at
disease onset. Invest Ophthalmol Vis Sci 1986;27: 873–882.
Alvarado JA, Underwood JL, Green WR, et al. Detection of herpes simplex viral
DNA in the iridocorneal endothelial syndrome. Arch Ophthalmol
1994;112:1601–1609.
Bourne W, Brubaker R. Decreased endothelial permeability in the iridocorneal
endothelial syndrome. Ophthalmology 1982;89: 591–595.
Bourne WM, Brubaker RF. Progression and regression of partial corneal
involvement in the iridocorneal endothelial syndrome. Am J Ophthalmol
1992;114:171–181.
Campbell DG, Shields BM, Smith TR. The corneal endothelium and the spectrum
of essential iris atrophy. Am J Ophthalmol 1978;86:317–324.
Chandler P. Atrophy of the stroma of the iris, endothelial dystrophy, corneal
edema and glaucoma. Am J Ophthalmol 1956;41:607–615.
Cogan D, Reese A. A syndrome of iris nodules, ectopic Descemet’s membrane
and unilateral glaucoma. Doc Ophthalmol 1969;26: 424–433.
Eagle RC Jr, Font RL, Yanoff M, et al. Proliferative endotheliopathy with iris
abnormalities. The iridocorneal endothelial syndrome. Arch Ophthalmol
1979;97:2104–2111.
Eagle RJ, Font R, Yanoff M, et al. The iris naevus (Cogan-Reese) syndrome: light
and electron microscopic observations. Br J Ophthalmol 1980;64:446–452.
Eagle RJ, Shields J. Iridocorneal endothelial syndrome with contralateral guttate
endothelial dystrophy. Ophthalmology 1987;94:862–870.
Hirst L, Quigley H, Stark W, et al. Specular microscopy of iridocorneal
endothelial syndrome. Am J Ophthalmol 1980;89:11–21.
Hirst LW, Bancroft J, Yamauchi K, et al. Immunohistochemical pathology of the
corneal endothelium in iridocorneal endothelial syndrome. Invest Ophthalmol
Vis Sci 1995;36:820–827.
Kramer TR, Grossniklaus HE, Vigneswaran N, et al. Cytokeratin expression in
corneal endothelium in the iridocorneal endothelial syndrome. Invest
Ophthalmol Vis Sci 1992;33:3581–3585.
Lee WR, Marshall GE, Kirkness CM. Corneal endothelial cell abnormalities in an
early stage of the iridocorneal endothelial syndrome. Br J Ophthalmol
1994;78:624–631.
Levy SG, McCartney AC, Baghai MH, et al. Pathology of the iridocorneal-
endothelial syndrome. The ICE-cell. Invest Ophthalmol Vis Sci

294
 1995;36:2592–2601.
Neubauer L, Lund O, Leibowitz H. Specular microscopic appearance of the
corneal endothelium in the iridocorneal endothelial syndrome. Arch
Ophthalmol 1983;101:916–916.
Scheie H, Yanoff M. Iris nevus (Cogan-Reese) syndrome. A cause of unilateral
glaucoma. Arch Ophthalmol 1975;93:963–970.
Shields CL, Shields MV, Viloria V, et al. Iridocorneal endothelial syndrome
masquerading as iris melanoma in 71 cases. Arch Ophthalmol
2011;129(8):1023–1029.
Shields M, Campbell D, Simmons R. The essential iris atrophies. Am J
Ophthalmol 1978;85:749–759.
Shields M. Progressive essential iris atrophy, Chandler’s syndrome, and the iris
nevus (Cogan-Reese) syndrome. A spectrum of disease. Surv Ophthalmol
1979;24:3–20.
Yanoff M. Iridocorneal endothelial syndrome. Unification of a disease spectrum.
Surv Ophthalmol 1979;24:1–2.

Phacolytic Glaucoma
Flocks M, Littwin CS, Zimmerman LE. Phacolytic glaucoma: a clinicopathologic
study of 138 cases of glaucoma associated with hypermature cataract. Am J
Ophthalmol 1955;54:37–45.
Rosenbaum JT, Samples JR, Seymour B, et al. Chemotactic activity of lens
proteins and the pathogenesis of phacolytic glaucoma. Arch Ophthalmol
1987;105:1582–1584.
Smith ME, Zimmerman LE. Contusive angle recession in phacolytic glaucoma.
Arch Ophthalmol 1965;74:799–804.
Volcker HE, Naumann G. Clinical findings in phakolytic glaucoma. Klin
Monatsbl Augenheilkd 1975;166:613–618.
Yanoff M, Scheie HG. Cytology of human lens aspirate. Its relationship to
phacolytic glaucoma and phacoanaphylactic endophthalmitis. Arch
Ophthalmol 1968;80:166–170.

Pigmentary Glaucoma
Campbell DG. Pigmentary dispersion and glaucoma: a new theory. Arch
Ophthalmol 1979;97:1667–1672.
Farrar SM, Shields MB. Current concepts in pigmentary glaucoma. Surv
Ophthalmol 1993;37:233–252.
Fine B, Yanoff M, Scheie H. Pigmentary “glaucoma”: a histologic study. Trans
Am Acad Ophthalmol Otolaryngol 1978;78:314–325.
Potash S, Tello C, Liebmann J, et al. Ultrasound biomicroscopy in pigment
dispersion syndrome. Ophthalmology 1994;101: 332–339.
Scheie HG, Cameron JD. Pigment dispersion syndrome: a clinical study. Br J

295
 Ophthalmol 1981;65:264–269.
Siddiqui Y, Ten Hulzen RD, Cameron JD, et al. What is the risk of developing
pigmentary glaucoma from pigment dispersion syndrome? Am J Ophthalmol
2003;135:794–799.

Pseudoexfoliation Syndrome
Schlotzer-Schrehardt U, Koca M, Naumann G, et al. Pseudoexfoliation syndrome.
Ocular manifestation of a systemic disorder? Arch Ophthalmol
1992;110:1752–1756.
Schlotzer-Schrehardt U, Naumann GO. Trabecular meshwork in
pseudoexfoliation syndrome with and without open-angle glaucoma. A
morphometric, ultrastructural study. Invest Ophthalmol Vis Sci
1995;36:1750–1764.
Schlotzer-Schrehardt U, Pasutto F, Sommer P, et al. Genotype-correlated
expression of lysyl oxidase-like 1 in ocular tissues of patients with
pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol
2008;173:1724–1735.
Streeten BW, Dark AJ. Pseudoexfoliation syndrome. In: Garner A, Klintworth
GK, eds. Pathobiology of Ocular Disease: A Dynamic Approach, 2nd ed, Part
A. New York, NY: Marcel Dekker, 1994:591–629.
Streeten BW, Li Zy, Wallace RN, et al. Pseudoexfoliative fibrillopathy in visceral
organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol
1992;110:1757–1762.

Other Secondary Glaucomas

Campbell DG, Simmons RJ, Grant WM. Ghost cells as a cause of glaucoma. Am
J Ophthalmol 1976;81:441–450.
Campbell DG. Ghost cell glaucoma following trauma. Ophthalmology
1981;88:1151–1158.
Fenton RH, Zimmerman LE. Hemolytic glaucoma: an unusual case of acute,
open-angle secondary glaucoma. Arch Ophthalmol 1963;70:236–239.
Knox, DL. Glaucoma following syphilitic interstitial keratitis. Arch Ophthalmol
1961;66:18–25.
Lichter PR, Shaffer RN. Interstitial keratitis and glaucoma. Am J Ophthalmol
1969;68:241–248.
Matsuo T. Photoreceptor outer segments in aqueous humor: key to understanding
a new syndrome. Surv Ophthalmol 1994;39: 211–233.
Pesin SR, Katz LJ, Augsburger JJ, et al. Acute angle-closure glaucoma from
spontaneous massive hemorrhagic retinal or choroidal detachment. An
updated diagnostic and therapeutic approach. Ophthalmology 1990;97:76–84.

Tumors and Glaucoma

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Fineman MS, Eagle RC Jr, Shields JA, et al. Melanocytomalytic glaucoma in
eyes with necrotic iris melanocytoma. Ophthalmology 1998;105:492–496.
Shields CL, Shields JA, Shields MB, et al. Prevalence and mechanisms of
secondary intraocular pressure elevation in eyes with intraocular tumors.
Ophthalmology 1987;94:839–846.
Teekhasaenee C, Ritch R, Rutnin U, et al. Glaucoma in oculodermal
melanocytosis. Ophthalmology 1990;97:562–570.
Yanoff M, Scheie HG. Melanomalytic glaucoma. Arch Ophthalmol
1970;84:471–473.
Yanoff M. Glaucoma mechanisms in ocular malignant melanomas. Am J
Ophthalmol 1970;70:898–904.

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 9 Retina
An outpost of the central nervous system, the retina is a colony of brain
cells that is located in the periphery of the body where it is able to interact
with and detect the rather narrow spectrum of electromagnetic radiation
called visible light. Death, destruction, or loss of all or part of the retina
renders the eye sightless. Visual loss due to the death of retinal cells is
permanent and irrevocable, because, like brain cells, the cells of the retina
are incapable of repair or regeneration. Retinal anatomy is discussed in
detail in Chapter 1.

DEVELOPMENTAL ANOMALIES
Dysplasia of the retina is a characteristic manifestation of trisomy 13 and
also occurs in the Walker-Warburg syndrome. Congenital nonattachment
of the retina is a rare anomaly caused by faulty invagination of the optic
vesicle. Congenital detachment of the retina causes leukocoria in male
infants with X-linked Norrie disease, who also are deaf and mentally
retarded. The retina lining a choroidal coloboma may be absent,
hypoplastic, or dysplastic (Fig. 2-1C).
Aplasia of the fovea occurs in aniridia and albinism. Albinos also have
a lightly pigmented albinotic fundus. Variants of oculocutaneous albinism
are caused by recessively inherited mutations in four genes. Patients with
OCA1a, the classic form of so-called tyrosinase-negative oculocutaneous
albinism, have white hair, pink eyes, and pink irides that transilluminate
vividly. OAC1a is caused by mutations in the tyrosinase gene on
chromosome 11 (11q14-q21) that cause complete absence of tyrosinase
enzyme activity. Some patients with less deleterious tyrosinase mutations
(OCA1b) initially were classified as tyrosinase-positive albinos because
they have some pigmentation. Temperature-sensitive tyrosinase mutations
analogous to those responsible for the pigmented ears and limbs of
Siamese cats cause peripheral pigmentation in some human albinos.
Oculocutaneous albinism type 2 (OCA2) is another variant of tyrosinase-

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positive albinism that is very common in some African populations such as
the Ibo of Nigeria, in whom the prevalence is 1/1,100. Affected patients
have yellow hair and hazel irides. OCA2 is caused by mutations in the
OCA2 or P gene on chromosome 15 (15q11.2-q12). OCA3 and OCA4 are
caused by mutations in the genes for tyrosinase-related protein-1 (TYRP1)
9p23 and membrane-associated transporter protein (MATP), respectively.
The Hermansky-Pudlak syndrome is common in Puerto Ricans who also
have a bleeding diathesis and bruise easily. Parents of affected children
have been wrongfully accused of child abuse. Albinos with the rare
autosomal recessively inherited Chédiak-Higashi syndrome are subject to
bacterial and fungal infection and a peculiar form of lymphoproliferation.
They have abnormal leukocytes with giant lysosomes and
macromelanosomes. The syndrome is caused by mutations in the
lysosomal trafficking regulator gene (LYST) on chromosome 1 (1q42.1-
q42.2).
Albinism may affect both the skin and eyes (oculocutaneous albinism)
or affect the eyes primarily (ocular albinism). Ocular albinos typically
present with decreased vision and nystagmus caused by foveal aplasia. Iris
transillumination serves to identify ocular albinos, who have normal skin
pigmentation and may have dark hair. Macromelanosomes are found in the
RPE and skin in X-linked ocular albinism (Fig. 9-1B). Skin biopsy
occasionally is used to confirm the diagnosis. Although white female
carriers of X-linked ocular albinism have normal vision, iris
transillumination is present and ophthalmoscopy may disclose a “mud-
spattered” appearance of the fundus caused by patchy depigmentation of
the peripheral RPE that results from lyonization. Most common, the X-
linked or Nettleship-Falls type of ocular albinism is caused by mutations in
the GPR143 gene G protein-coupled receptor 143 gene (GPR143) on the X
chromosome (Xp22.2).

FIG. 9-1. Albinism. A. Transillumination of the iris discloses periphery of the

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 lens and ciliary processes. B. X-linked ocular albinism. The RPE in postmortem
eye contains large spherical macromelanosomes. (B. H&E ×250 [Microslide
courtesy of Dr. W.R. Green, From Eagle RC Jr. Congenital, developmental and
degenerative disorders of the iris and ciliary body. In: Albert DM, Jakobiec FA,
eds. Principles and Practice of Ophthalmology. Clinical Practice, vol. 1.
Philadelphia, PA: Saunders, 1993:367–389.])

Congenital hypertrophy of the RPE (CHRPE) (Fig. 11-32A,B) and

congenital grouped pigmentation of the RPE are characterized by
increased pigmentation and hypertrophy of RPE cells (Fig. 11-32C,D) (see
Chapter 11).
Myelinated nerve fibers occur in about 1% of the population.
Myelination of optic nerve axons normally terminates at the posterior
margin of the lamina cribrosa. The patches of aberrant myelination of the
nerve fiber layer may or may not be contiguous with the optic disc.
Myelination usually occurs within the temporal vascular arcade and is
caused by displacement of oligodendroglia into the eye.
Myelinated nerve fibers produce a focal scotoma.
Congenital vascular abnormalities of the retina include retinal
arteriovenous communication, cavernous hemangioma of the retina (Fig.
2-12), Leber miliary retinal aneurysms, Coats disease (Figs. 12-21 and 12-
22) and parafoveal telangiectasis. Retinal hemangioblastomas may occur
sporadically or in association with von Hippel-Lindau disease (Fig. 2-10).
A peripheral retinal fold called Lange fold occurs at the ora serrata in
infant eyes. Lange fold does not occur in vivo; it is a fixation artifact
caused by vitreous traction.

RETINAL HEMORRHAGES AND

EXUDATES
The retinopathies that occur in a variety of systemic and ocular diseases
actually are composed of six types of retinal hemorrhages and two types of
retinal exudates that occur in varying constellations.
The clinical appearance of retinal hemorrhages is determined by the
location of the blood in the retina (Fig. 9-2). Retinal hemorrhages are
categorized as superficial (flame or splinter shaped), deep (blot and dot),
sub-RPE, sub-ILM (internal limiting membrane), subhyaloid, and vitreous.

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 FIG. 9-2. Retinal hemorrhages. A. Flame or splinter hemorrhages are located in
the inner nerve fiber layer of the retina. Blot and dot hemorrhages are located in
the deeper retinal layers. B. Subhyaloid hemorrhage, proliferative diabetic
retinopathy. The blood is located between the ILM and the posterior surface of
the detached vitreous. (A. H&E ×100, B. H&E ×25.)

Splinter- or flame-shaped hemorrhages are located superficially in the

inner nerve fiber layer of the retina. The configuration and feathery margin
of these hemorrhages are caused by tracking of the erythrocytes along the
axons of the ganglion cells as they arch above and below the fovea. The
pattern of hemorrhages can graphically highlight the arcuate distribution of
the nerve fibers in patients who have numerous superficial hemorrhages,
for instance, after a branch retinal vein occlusion.
Blot and dot hemorrhages occur in the deeper retinal layers where the
axons are oriented perpendicular to the plane of the Bruch membrane.
Here, the extravasations of blood have a discrete localized configuration
because the erythrocytes are corralled or fenced in by the surrounding
axons.
Scaphoid or boat-shaped hemorrhages are preretinal hemorrhages that
have a fluid level caused by settling-out of the red cells. Two types of
scaphoid hemorrhage are recognized histopathologically: sub-ILM and
subhyaloid hemorrhages. True subhyaloid hemorrhages are common in
patients with proliferative diabetic retinopathy, in whom the blood collects
between the ILM and the posterior face of the detached vitreous humor,
which may be lined by a sheet of neovascularization. The term hyaloid
refers to the hyaloid body, another name for the vitreous humor. Sub-ILM
hemorrhages actually are hemorrhagic detachments of the ILM. The blood
is located between the nerve fiber layer and the outer aspect of the ILM,
the retina’s single true basement membrane, which is secreted by the
Müller cells (Fig. 9-3C). Occasionally, sub-ILM hemorrhages may be
distinguished by the ophthalmoscopic observation of focal relucences

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called Gunn dots on their inner surface. The latter correspond to focal
concavities on the outer surface of the basement membrane that conform
to the footplates of the Müller cells.

FIG. 9-3. Abusive head trauma (shaken baby syndrome). A. Sectioned

postmortem eye from abused infant shows posterior perifoveal retinal fold and
multiple retinal hemorrhages that extend to ora serrata. B. Round convex
hemorrhagic detachments of the internal limiting membrane called cherry
hemorrhages are a characteristic finding in many cases. C. Photomicrograph
shows hemorrhagic ILM detachment (at left), deep and superficial retinal
hemorrhages, and subretinal blood. D, E. Vitreoretinal traction, which has

302
detached ILM, extends from apex of perifoveal retinal folds in macrophoto (D)
and photomicrograph (E). F. Extensive hemorrhage within sheath causes bluish
discoloration of retrolaminar optic nerve. G. Transversely sectioned optic nerve is
ringed by blood. H. Blood is present in subdural and subarachnoid spaces of
retrolaminar optic nerve sheath and in juxtapapillary sclera. (C. H&E ×50, E.
H&E ×50, H. H&E ×10.)

Sub-ILM hemorrhages, which some have called cherry hemorrhages, are

quite common in the severe hemorrhagic retinopathy found in infants with
abusive head trauma (AHT or shaken baby syndrome) (Fig. 9-3). The
retinal hemorrhages may be too numerous to count and typically extend to
the ora serrata. They include deep and superficial hemorrhages, sub-ILM
hemorrhages and full-thickness retinal hemorrhages in severe cases. Other
ocular findings of abusive head trauma include a characteristic perifoveal
ridge or fold related to vitreoretinal traction (Fig. 9-3A,D,E), which
encircles the macula, and extensive detachment of the ILM of the posterior
retina. Although the latter has been termed retinoschisis, it does not
resemble the disorder of the peripheral retina. Subretinal hemorrhage
occurs in some cases. Optic nerve sheath hemorrhage is another
characteristic finding of AHT (Fig. 9-3F–H). Blood may be present in the
subarachnoid or subdural spaces or may infiltrate the dura mater of the
optic nerve. More blood typically is found in the optic nerve sheath
directly behind the globe. Blood also is found in the orbital fat in some
cases, and hemorrhages have been reported in the juxtapapillary sclera.
The findings in AHT may be asymmetric, and some cases may have only
retinal or optic nerve sheath hemorrhage.
Hemorrhagic detachment of the RPE often occurs in patients who have
sub-RPE neovascular membranes. Sub-RPE hemorrhage is an important
stage in the evolution of many disciform scars in age-related macular
degeneration. Sub-RPE hemorrhages typically appear quite dark because
the blood is located beneath a layer of pigmented cells. As a result, they
can be confused clinically with uveal malignant melanoma. However, in
contrast to melanomas, sub-RPE hemorrhages block choroidal
fluorescence and appear dark during intravenous fluorescein angiography.
Vitreous hemorrhage occurs when blood breaks through the hyaloid
membrane into the substance of the formed vitreous. Blood in the formed
vitreous can be quite persistent but gradually undergoes degeneration and
assumes a characteristic yellow-ochre color. Nonresorbing vitreous
hemorrhage is a common indication for vitrectomy, especially in patients
with diabetes mellitus.

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 Retinal exudates and edema that occur in diabetes, hypertensive
retinopathy, and other retinal vascular disorders reflect a breakdown in the
blood–retinal barrier (Fig. 9-4A). The term blood–retinal barrier refers to
structural modifications that protect the retina’s delicate neural tissues
from fluid overload and osmotic stress. The blood–retinal barrier is
analogous to the blood–brain barrier in the CNS. The inner or intraretinal
part of the blood–retinal barrier is composed of tight junctions that join
together the endothelial cells that line the retinal vessels. During
fluorescein angiography, these impermeable intercellular junctions confine
the fluorescein dye within the lumens of healthy retinal vessels. The girdle
of terminal bars that join the RPE cells near their apices forms the outer
part of the blood–retinal barrier. The choriocapillaris, which supplies the
avascular outer third of the retina, is composed of fenestrated capillaries
that leak fluorescein dye profusely. The RPE serves as the barrier that
protects the outer retina from an influx of fluid.

FIG. 9-4. Retinal exudates. A. Blood retinal barrier, human eye. Tight junctions
joining retinal vascular endothelial cells constitute the inner part of the blood–
retinal barrier, which confines fluorescein dye within lumina of retinal vessels.
Occluding junctions joining apices of RPE cells form outer part of barrier.
Choriocapillaris is composed of leaky fenestrated capillaries. Arrow denotes
yellow band of autofluorescent lipofuscin in RPE. B. Retinal hard exudates.
Classic hard exudates are pools of eosinophilic protein-rich fluid in the outer

304
 plexiform layer. Hard exudates typically occur in the OPL because that layer is
the watershed zone between the retina’s two blood supplies. C. Inset shows
clinical appearance of hard exudates. C. Retinal exudates composed of lipidized
histiocytes in subretinal space and outer retina. Macrophoto of eye discloses
yellow spherules in outer retina and subretinal space. Extensive areas of retinal
exudation were noted clinically. D. Histopathology reveals infiltrate of lipidized
histiocytes with foamy vacuolated cytoplasm in outer retinal layers and subretinal
space. A. Freeze-dried preparation, fluorescent microscopy ×100. (From Eagle
RC. Mechanisms of maculopathy. Ophthalmology 1984;91:613–625, Courtesy of
Ophthalmology) (B. H&E ×100, B. H&E ×150, E. H&E ×250.)

Incompetence of either the inner or outer part of the blood–retinal barrier

gives lipid- and protein-rich fluid access to the retinal parenchyma leading
to edema and exudate formation (Fig. 9-4B). Hard, yellow, waxy exudates
appear histopathologically as pools of eosinophilic proteinaceous fluid
(Fig. 9-4B). Hard exudates usually are located in the outer plexiform layer,
the watershed zone between the retina’s dual blood supplies. In chronic
cases, the exudates may be phagocytized by foamy macrophages called
gitter cells. Lipidized histiocytes in the subretinal space or outer retina may
also appear as hard exudates (Fig. 9-4C,D).
Hard exudates in the perifoveal retina are often arranged in a stellate
pattern (macular star figure) (Fig. 9-5). This pattern of exudation is
governed by the radial orientation of the photoreceptor axons (Henle
fibers) in the outer plexiform layer on each side of the fovea.

FIG. 9-5. Macular star figure. A. Radiating pattern of hard exudates in

periofoveal retina is evident clinically as “macular star.” B. Stellate pattern
reflects pools of proteinaceous fluid within obliquely oriented Henle fibers of
perifoveal outer plexiform layer. (B. H&E ×250.)

Soft exudates or cotton-wool spots (Fig. 9-6) actually are not exudates in
the true sense of the word. Cotton-wool spots represent focal areas in the

305
nerve fiber layer where the normal flow of axoplasm is blocked. This focal
blockage of axoplasmic flow is thought to be a response to focal retinal
ischemia and probably is caused by thrombosis of a precapillary arteriole.
Cotton-wool spots are a helpful clinical marker for retinal ischemia. They
develop in the preproliferative phase of diabetic retinopathy and also are
found in ischemic retinal vein occlusions and severe hypertensive
retinopathy. Cotton-wool spots occur in relative isolation in patients who
have HIV/AIDS or collagen vascular diseases such as systemic lupus
erythematosus as a manifestation of intravascular immune complex
deposition.

FIG. 9-6. Cotton-wool spots. A. Cotton-wool spots represent focal areas of

axoplasmic flow blockage in the nerve fiber layer. They are a clinical marker for
retinal ischemia. B. Histopathology of cotton-wool spot shows focus of dilated
nerve fiber layer axons filled with eosinophilic axoplasm. Cytoid bodies with
prominent eosinophilic nucleoids are evident. C. Cytoid body, cotton-wool spot.
Eosinophilic staining distinguishes the nucleoid in the cytoid body from an actual
nucleus. Arrow denotes axon entering the cytoid body. Cytoid bodies resemble
cells but actually are focal areas of axonal swelling. (B. H&E ×100, C. H&E
×250.)

Histopathologic examination of a cotton-wool spot shows focal swelling of

the nerve fiber layer and cytoid bodies (Fig. 9-6B,C). Cytoid bodies are
eosinophilic segments of ganglion cell axons ballooned by stagnant
axoplasm. They are called cytoid because they superficially resemble cells.
Some have a nucleoid composed of aggregated organelles that mimics a
cellular nucleus but is eosinophilic rather than basophilic.

ANGIOID STREAKS
Angioid streaks are linear structures seen on ophthalmoscopy that radiate
from the optic disc in an angioid or vessel-like fashion (Fig. 9-7A).

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Histopathology has shown that angioid streaks correspond to breaks in the
Bruch membrane (Fig. 9-7B). Angioid streaks tend to develop in patients
who have certain systemic disorders that cause calcification of the Bruch
membrane. Such diseases include pseudoxanthoma elasticum, Paget
disease of bone, and some cases of sickle hemoglobinopathy. Calcification
may impart an eggshell-like fragility to Bruch membrane predisposing to
fracture. The RPE usually is intact overlying the breaks in Bruch
membrane. Sub-RPE neovascularization can complicate angioid streaks
and actually is a major cause of visual loss in affected patients.
Unfortunately, when sub-RPE membranes develop, they generally involve
the region of the macula for reasons unknown. This fact implies that the
development of subretinal neovascularization requires more than a break
in Bruch membrane.

FIG. 9-7. Angioid streaks. A. The gray linear structures radiating the optic disk
in an angioid or vessel-like pattern are angioid streaks. They occur in several
systemic disorders marked by massive calcification of Bruch membrane. B.
Arrows denote margins of break in Bruch membrane. Heavily calcified Bruch
membrane appears as a thick dark band beneath the RPE. The RPE is intact
overlying the break in Bruch membrane. The patient had sickle cell anemia.
Toluidine blue ×150. (From Jampol LM, Acheson R, Eagle RC Jr, et al.
Calcification of Bruch’s membrane in angioid streaks with homozygous sickle
cell disease. Arch Ophthalmol 1987;105:93–98, Copyright 1987 American
Medical Association.)

RETINAL ARTERY AND

ARTERIOLAR OCCLUSIONS
Interruption of the vascular supply to the inner two thirds of the retina
causes ischemic infarction and coagulative necrosis of its cells. The
sequelae of central or branch retinal artery occlusion are evident

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histopathologically as inner ischemic retinal atrophy (Fig. 9-8). All of the
cells nourished by capillaries derived from the central retinal artery are
affected in inner ischemic retinal atrophy, including the nerve fiber and
ganglion cell layers, the inner plexiform layer, and most of the inner
nuclear layer. The outer part of the inner nuclear layer usually persists
because its cells are sustained by diffusion from the choriocapillaris. In a
long-standing case, the inner retinal layers are paucicellular and have a
glassy, hyalinized appearance. Gliosis of the nerve fiber layer is not
observed because the fibrous astrocytes and other accessory glial cells that
cause NFL gliosis in chronic glaucoma perish in the retinal ictus. The
additional involvement of the IPL and the inner part of the INL serve to
differentiate inner ischemic retinal atrophy from glaucomatous retinal
atrophy. Only the retinal ganglion cells and their axons that constitute the
NFL and optic nerve are atrophic in glaucomatous retinal atrophy.

FIG. 9-8. A. Branch retinal artery occlusion, fovea. The fovea is seen
centrally. The layers of the perfused parafoveal retina at left are well preserved.
The retina supplied by the obstructed arteriole (at right) shows marked inner
ischemic atrophy. The ganglion cell layer is absent, and the inner nuclear layer is
reduced in caliber. Photoreceptor atrophy was caused by a shallow detachment of
the macula. B. Inner ischemic retinal atrophy, CRAO. All of the inner layers
of the retina supplied by the central retinal artery are atrophic including the inner
plexiform and nuclear layers, which are spared in glaucomatous atrophy. A few
nuclei persist in the outer part of the inner nuclear layer. (A. H&E ×50, B. H&E
×100.)

In the acute stages of central retinal artery occlusion (CRAO), the retina
shows edema, cellular dissolution, and nuclear fragmentation or pyknosis.
Clinically, the normally transparent retina is marked by milky-white
opacification (Fig. 9-9). A macular cherry-red spot is present because the
cells composing the floor of the foveola remain viable, and therefore
transparent, because they are supplied by the choriocapillaris. Although

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the foveal photoreceptors persist, central vision is lost because the other
cells in the neural pathway are destroyed. Retinal hemorrhages usually are
not seen. In the acute phase, SD-OCT discloses thickening and
hyperreflectivity of the inner retinal layers supplied by the central retinal
artery and marked retinal thinning in chronic cases.

FIG. 9-9. Retinal opacification. A. The retina of freshly enucleated unfixed eye
(above) is transparent. B. Fixation causes retinal opacification (below). Cellular
death caused by ischemic causes similar retinal opacification after CRAO. C.
Central retinal artery occlusion. Foveola appears as cherry-red spot in opacified,
infarcted retina.

Occlusion of the central retinal artery produces a “ministroke” of the entire

retina. Only part of the retina is infarcted in hemiretinal or branch retinal
arteriolar occlusions (Fig. 9-8A). Most branch artery occlusions are caused
by emboli that lodge at the bifurcation of an arteriole.
CRAO is usually a disease of elderly individuals who are often
atherosclerotic, hypertensive, and diabetic. Central or branch retinal artery
occlusion in a young individual should suggest the possibility of a primary
cardiac tumor such as a myxoma, vasculitis, or the presence of
anticardiolipin (lupus anticoagulant) antibodies. Most CRAOs result from
thrombosis or embolization. Thrombosis usually occurs within the optic
nerve head and is related to atherosclerosis at this site. Atherosclerosis
does not develop in retinal arterioles because those vessels lack a distinct
muscularis.
About 60% of retinal emboli are glistening crystals of cholesterol
called Hollenhorst plaques, and about 11% are aggregates of platelets and
fibrin. Most are shed from the surface of ulcerating atherosclerotic plaques
in the internal carotid artery. Calcific emboli originating in the heart are
less common.

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 Giant cell arteritis is an important treatable condition that must be
ruled out in any elderly patient who has retinal artery occlusion or
ischemic optic neuropathy. The erythrocyte sedimentation rate is typically
elevated in affected individuals, who also may have thrombocytosis and
elevated levels of C-reactive protein. Expedient temporal artery biopsy is
performed to confirm the diagnosis. Patients who have giant cell arteritis
classically have a history of malaise, weight loss, and muscle aches
(polymyalgia rheumatica) and may complain of headache and painful
mastication due to jaw claudication. Severely inflamed temporal arteries
may be elevated, tender, and cord-like. Biopsy surgery may be relatively
bloodless if the arteritis is severe.
An affected segment of artery appears firm, thickened, and opacified
grossly. Histopathology discloses compromise or even occlusion of the
vascular lumen and chronic inflammation within the thickened arterial
wall (Fig. 9-10). The chronic granulomatous inflammatory infiltrate should
contain epithelioid histiocytes, but giant cells are not particularly common
in most positive biopsies and are unnecessary for the diagnosis.
Inflammation can affect all layers of the artery but classically is
concentrated in the vicinity of the internal elastic lamina, which almost
invariably shows severe dissolution and segmental loss. Granulomatous
inflammation rims the outer surface of the muscularis in some cases.
Fibrosis and scarring often are seen in the adventitial connective tissue.
Signs of old or “healed” giant cell arteritis, for example, in a patient who
has received chronic corticosteroid therapy, include focal atrophy or
destruction of the muscularis, extensive segmental destruction of the
internal elastic lamina, and perivascular scarring. “Skip lesions”
(uninflamed segments in a positive biopsy) do occur but are relatively rare.
Hence, the biopsied segment of artery should be at least 2 cm long.
Bilateral biopsy may be considered if the initial biopsy is negative and
clinical suspicion is high, but the yield is quite low.

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 FIG. 9-10. Giant cell arteritis, temporal artery biopsy. A. The lumina of the
chronically inflamed artery is largely occluded. No skip lesions are present. B.
Arrows denote giant cells within chronic inflammatory infiltrate that includes
epithelioid histiocytes and lymphocytes. There is extensive destruction of the
lamina and the muscularis and fibrosis of the adventitia. Giant cell arteritis is an
important cause of artery occlusion and ischemic optic neuropathy in elderly
patients. (A. H&E ×10, B. H&E ×25.)

Prompt diagnosis of giant cell arteritis is critical because bilateral

blindness can develop rapidly in untreated cases. High-dose systemic
corticosteroid therapy should be instituted immediately if giant cell
arteritis is suspected. The temporal artery is biopsied to confirm the
diagnosis histopathologically because systemic steroids can have severe
side effects in elderly patients.
Small ischemic lesions localized to the middle layers of the retina at
the level of the inner nuclear layer recently have been disclosed by SD-
OCT. Termed paracentral acute middle maculopathy, these lesions are
thought to be caused by ischemia involving the intermediate and deep
plexi of retinal capillaries.

RETINAL VENOUS OCCLUSION

Occlusion of the central retinal vein or one of its major branches produces
hemorrhagic infarction of the retina. The terms “blood and thunder
fundus” or “squashed tomato sign” that have been applied clinically to this
retinopathy reflect the plethora of deep and superficial retinal hemorrhages
that develop after venous occlusion (Fig. 9-11A).

FIG. 9-11. Central retinal vein occlusion. A. Many deep and superficial
hemorrhages are present. Retinal veins are dilated and tortuous. Cotton-wool
spots surrounding swollen optic nerve indicate ischemia. B. Central retinal artery

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 and vein. Common adventitial sheath (yellow) surrounds central retinal artery
(red) and vein (blue) in transverse section of optic nerve. Sclerosis of the artery is
a factor in the pathogenesis of many cases of CRVO. (B. False-colorized SEM
×320.)

Most retinal venous occlusions involve branches of the central retinal vein,
typically (70%) the superotemporal branch vein. Venous occlusions tend
to occur in men who are older than age 50 years and have diabetes
mellitus, hypertension, and arteriosclerosis. Local intraocular conditions
that predispose to venous occlusion include elevated intraocular pressure,
papilledema, and large drusen of the optic disc. Many central retinal vein
occlusions are thought to be related to arteriosclerosis of the central retinal
artery, which shares a common adventitial sheath with the central retinal
vein within the lamina cribrosa of the optic nerve (Fig. 9-11B). The
sclerotic arteriole compresses the vein within the adventitial sheath
causing turbulence in the lumen of the vein that damages the vascular
endothelium and predisposes to venous thrombosis.
The early stages of a retinal venous occlusion are characterized
histopathologically by diffuse and cystoid edema of the macula. The
hemorrhagic retina contains numerous deep, superficial, and full-thickness
retinal hemorrhages. Preretinal hemorrhages are found in some cases, and
in rare instances, blood may extend into the subretinal space causing
hemorrhagic retinal detachment. Other findings include shallow serous
retinal detachment and papilledema. If severe ischemia and capillary
nonperfusion are present, focal retinal necrosis and cotton-wool spots are
noted. Cotton-wool spots are an important clinical marker for the ischemic
variant of CRVO.
In chronic retinal venous occlusive disease, histopathology discloses
disorganization of retinal architecture and marked gliosis. The retina often
contains macrophages laden with golden brown hemosiderin pigment from
blood breakdown, and the retina and other epithelial structures may stain
positively for iron (hemosiderosis). Inner ischemic retinal atrophy may be
present if the venous occlusion was ischemic. Most eyes requiring
enucleation have painful neovascular glaucoma (NVG).
Secondary closed-angle glaucoma caused by iris neovascularization
(rubeosis iridis) develops in about 20% of untreated patients who have
ischemic CRVOs. Profound visual loss, cotton-wool spots, and severe
nonperfusion of the retinal capillary bed disclosed by fluorescein
angiography are clinical signs of ischemic vein occlusion. This type of

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NVG has been called “90-day glaucoma,” reflecting its fairly rapid onset.
In the past, most of these blind, painful glaucomatous eyes were
enucleated. Today, modern therapies including panretinal
photocoagulation and tube shunts have dramatically diminished the
number of eyes enucleated after CRVO. NVG also develops in about 12%
to 16% of patients after CRAO.

HYPERTENSIVE RETINOPATHY
The retinopathy that develops in patients with severe systemic
hypertension is caused by vascular incompetence and breakdown of the
blood–retinal barrier. Acute severe elevation of the blood pressure causes
retinal arteriolar narrowing and focal vasospasm. If elevated blood
pressure levels and vasospasm persist chronically, the muscular and
endothelial coats of the vessels eventually become necrotic.
Histopathologic studies have revealed changes in the endothelial lining,
necrosis of the smooth muscle, and insudation of fibrin-rich plasma in the
vessel wall. The endothelial damage causes vascular incompetence with
resultant retinal edema, exudation, and occasionally even serous retinal
detachment. Small exudates called edema residues may form a stellate
pattern around the fovea (macular star figure) reflecting the radial
orientation of the Henle fibers in the perifoveal OPL (Fig. 9-5). In the
early days of ophthalmoscopy, severe hypertensive retinopathy with a
macular star figure was often called hyperalbuminuric retinitis, reflecting
the common association between severe hypertension and renal failure.
Retinal hemorrhages and papilledema are additional manifestations of
hypertensive retinopathy. Retinal hemorrhages are relatively common and
occur in the disorder’s early stages. Optic disc edema marks the fourth and
final stage of hypertensive retinopathy, is an important clinical marker for
malignant hypertension and potential encephalopathy, and is an indication
for aggressive antihypertensive therapy as well. Clinicians should always
remember to check the blood pressure in patients with optic disc edema.
Fibrinoid necrosis caused by the insudation and accumulation of plasma
proteins in vessel walls can affect retinal and choroidal vessels. Occlusion
of small damaged vessels also occurs, causing microinfarctions of the NFL
(cotton-wool spots) and, occasionally, infarctions of larger areas of retina.
Focal choroidal infarction with pigmentary change may be evident
clinically as Elschnig spots and Siegrist streaks. These were considered to
be grave prognostic signs before effective antihypertensive therapy
became available. Retinal macroaneurysms occasionally develop in

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hypertensive patients (Fig. 9-22).

RETINAL ARTERIOSCLEROSIS
Chronic low-grade hypertension induces fibrosis in the walls of retinal
arterioles, a process called retinal arteriolar sclerosis (Fig. 9-12).
Histopathologically, the sclerotic retinal vessels are enveloped by a thick
mantle of collagenous connective tissue. The term “onion skin” often is
applied to this change.

FIG. 9-12. Retinal arteriolar sclerosis. A. Fundus photo shows copper-hued

sclerotic arterioles and A-V crossing defects. B. Thick mantle of collagenous
connective tissue surrounds sclerotic vessel. Blue staining with Masson trichrome
(below) confirms presence of collagen. (B. Masson trichrome ×100.)

Like the surrounding neurosensory retina, the walls of healthy retinal

vessels normally are transparent. What one observes ophthalmoscopically
as retinal vessels actually are the columns of pigmented erythrocytes
filling the lumina of the vessels. The progressive accumulation of
connective tissue in the vessel walls of patients with retinal arteriolar
sclerosis gradually obscures the blood column, widening the light reflex
and imparting an orange or coppery hue to the arterioles. Eventually, if the
process is prolonged and severe, perivascular fibrosis may totally hide the
blood column, and the vessels will appear as white lines or silver wires.
Arteriovenous crossing defects (A-V nicking) result when the opaque
walls of thickened arterioles obscure part of the underlying venules. In
advanced cases, there may be deflection or banking of the retinal vein.

CYSTOID MACULAR EDEMA

Cystoid macular edema (CME) is characterized by the accumulation of

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serous fluid in cystoid spaces in the parenchyma of the perifoveal retina
(Fig. 9-13). The intraretinal cysts have a characteristic petaloid appearance
on intravenous fluorescein angiopathy and are disclosed by optical
coherence tomography (OCT) (Fig. 9-13B). The petaloid pattern
undoubtedly reflects the radial orientation of the Henle fibers in the
perifoveal outer plexiform layer. Fine has suggested that CME initially
may begin as intracellular edema in Müller cells. Cystoid spaces
presumably form as a consequence of cellular death in the milieu of
chronic edema. Histopathologically, the cystoid spaces appear relatively
empty or contain scant amounts of granular or fibrinous material. The
latter serves to distinguish them from hard exudates, which are usually
pools of eosinophilic hyaline material.

FIG. 9-13. Cystoid macular edema. A. IVFA discloses petaloid pattern of

intraretinal cystoid spaces. B. Macrophoto of enucleated eye with CME sectioned
through fovea shows spaces in outer layers of thickened perifoveal retina. C. SD-
OCT of CME in eye with large peripheral RPE tumor. There is a suggestion of
vitreoretinal traction. D. Corresponding histopathology of enucleated eye shows
large cystoid spaces containing scant proteinaceous fluid in outer plexiform layer
and smaller spaces in inner nuclear layer. The retina is artifactitiously detached.
(D. H&E ×100.)

Inflammatory mediators such as prostaglandins that are made in the

anterior segment are responsible for some cases of CME. The dramatic
response of CME to anti-VEGF therapy indicates that VEGF plays an
important pathogenetic role as well. Vitreous traction on the macula has
been incriminated in other instances. Visual loss due to CME may be the
presenting clinical manifestation of peripheral lesions including tumors or
peripheral uveitis (pars planitis). CME is an important complication of
ocular surgery. The association of CME with cataract surgery is called the

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Irvine-Gass syndrome. A relatively high incidence of CME occurred in
patients who had iris-supported intraocular lenses implanted after
intracapsular cataract surgery. The IOL probably stimulated prostaglandin
production by the iris, and complete removal of the lens allowed the
inflammatory mediator to readily diffuse to the posterior segment. CME
can complicate any severe chronic ocular inflammatory disorder. Visual
loss may respond to medical therapy in early cases.

MACULAR HOLES
Idiopathic macular holes are caused by shrinkage of the prefoveal cortical
vitreous that exerts tangential traction on the perifoveal retina. The traction
initially causes a localized foveal detachment that progresses to a full-
thickness hole in about 50% of cases. Vitrectomy surgery relieves the
traction leading to hole closure and resorption of subretinal fluid. Patients
can have substantial recovery of vision after surgery. A partial-thickness
defect in the neurosensory retina is called a lamellar macular hole. Macular
pseudoholes can be confused with full-thickness macular holes clinically.
They are produced by perifoveal epiretinal membranes with a round or
oval configuration.

AGE-RELATED MACULOPATHY
(AMD; AGE-RELATED MACULAR
DEGENERATION, ARMD)
Age-related maculopathy (AMD) or age-related macular degeneration is
the leading cause of irreversible blindness in people 50 years of age or
older in the developed world. (Legal blindness generally is defined as a
best-corrected visual acuity of 20/200 or 6/60.) AMD causes loss of central
vision because it involves the fovea, the specialized part of the retina used
for high-resolution color vision (Fig. 9-14). Although affected patients
have trouble reading and recognizing faces, they retain their peripheral
vision and are able to ambulate. Anxious patients may be assured that they
will never go totally blind. (This is not entirely true, however, since
patients with neovascular AMD receiving anticoagulant therapy
occasionally develop massive hemorrhagic retinal detachment and acute
closed-angle glaucoma.)

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 FIG. 9-14. A. The “macula.” The foveola is located in the center of the 1.5-mm-
wide fovea or pit. The area centralis is delimited by the temporal vascular
arcades. The imprecise term macula (from macula lutea, “yellow spot”) is often
applied clinically to this region. B, C. Normal macula. Direct correlation between
SD-OCT and histology. B. SD-OCT of normal fovea of eye with ciliary body
melanoma. C. Correlative histopathology of same eye after enucleation. Retinal
layers disclosed by SD-OCT do not correspond exactly with histology. Thick
dark outer band in OCT includes outer nuclear layer and outer part of outer
plexiform layer. (C. H&E montage ×50.)

There are atrophic or dry and exudative or wet forms of AMD (Figs. 9-15
and 9-16). The simultaneous or sequential development of dry and wet
changes in a single patient suggests that both are variants of a clinical and
pathological spectrum. Dry or atrophic macular degeneration is
characterized by atrophy and death of subfoveal RPE, which leads to
photoreceptor degeneration and outer retinal atrophy.

FIG 9-15. Atrophic form of age-related macular degeneration. A. Extensive area

of RPE atrophy involves posterior pole in eye removed from nonagenarian with
long history of blindness who underwent enucleation for invasive
mucoepidermoid carcinoma. Window defect reveals choroidal vessels. B.
Corresponding histopathology shows total loss of RPE, photoreceptors, and outer

317
nuclear layer. Outer retina is fused to Bruch membrane, which is thickened and
PAS positive. The choriocapillaris has undergone involution. (B. PAS ×50.)

FIG 9-16. Exudative form of age-related macular degeneration. A. Large

confluent soft drusen blanket posterior retina. B. Subretinal neovascular
membrane. A thin layer of fibrous tissue containing capillaries elevates the
atrophic RPE from the inner surface of the Bruch membrane. The atrophic outer
retina shows extensive photoreceptor loss. The Bruch membrane is fractured and
focally calcified. The choroid contains an incidental focus of chronic
inflammatory cells. C. The RPE is detached by blood and vascularized
connective tissue. A collagenous disciform scar is forming on the inner surface of
the Bruch membrane as the hemorrhagic RPE detachment undergoes
organization. D. Disciform scar. Mound of collagen incorporating RPE and
vessels elevates fovea. Severe photoreceptor atrophy is present. (B. H&E ×100,
C. H&E ×25, D. H&E ×25.)

Yellowish-white subretinal deposits called drusen are clinical hallmarks

for AMD. Drusen are focal deposits of extracellular debris located
between the basal lamina of the retinal pigment epithelium (RPE) and the
inner collagenous layer of Bruch membrane. The composition of drusen is
complex. Constituents are numerous and include neutral lipids,
unesterified cholesterol, carbohydrates, vitronectin, C-reactive protein,
apolipoprotein E, and variety of proteins involved with inflammation such
as amyloid-beta, immunoglobulin light chains, factor X, complement

318
factor H (CFH), C5, and the C5b complex.
Several varieties of drusen are recognized clinically and a number of
somewhat confusing and occasionally conflicting classification schemes
based on histopathologic and ultrastructural features have been proposed.
Hard or cuticular drusen are most abundant and are found throughout the
retina. They are discrete, round, or globular mounds of homogeneous,
deeply PAS-positive hyaline material (Fig. 9-17A,B). Soft drusen are
found only in the region of the macula and are strongly associated with
AMD. Soft drusen typically comprise loose amorphous material called
membranous debris. Their contents may be liquefied and often are lost
during histologic processing. Soft drusen are often associated with diffuse
deposits of extracellular matrix material called basal laminar deposits.
Basal laminar deposits play an extremely important role in the
pathogenesis of AMD, especially the severe exudative type, which is
complicated by the formation of subretinal neovascular membranes and
disciform scar formation.

FIG. 9-17. Drusen. A. Hard drusen. Hard drusen are excrescences of

homogeneous hyaline material on the inner surface of the Bruch membrane that
focally detach the RPE. B. Many hard drusen are intensely PAS positive. C.
Basal laminar deposit (diffuse soft drusen). A thick band of abnormal basement
membrane material elevates the RPE off the inner surface of the Bruch
membrane. Part of the deposit has detached artifactitiously from the Bruch
membrane (arrow). The RPE cells are flattened and atrophic. Basal laminar
deposits predispose to RPE detachment and age-related macular degeneration.
(A. H&E ×250, B. PAS ×250, C. H&E ×250.)

Basal laminar deposits appear light microscopically as extensive plaques

or layers of “soft” granular eosinophilic material that elevate the atrophic
RPE from the inner surface of Bruch membrane (Fig. 9-17C).
Transmission electron microscopy has shown that such deposits are

319
located between the plasma membrane and the basement membrane of the
RPE and are composed of extracellular matrix material rich in “curly
collagen” or 1,000 Å-banded basement membrane material. Basal laminar
deposits adhere loosely to Bruch membrane, predisposing to RPE
detachments and tears. The deposits theoretically could interfere with
biochemical modulation of the choriocapillaris by the RPE and also could
provide a plane for sub-RPE neovascular invasion. A second less
important variety of diffuse soft drusen called a basal linear deposit has
been identified electron microscopically. Basal linear deposits are located
within Bruch membrane external to the RPE basement membrane and are
composed of multivesicular particles of lipoprotein, which are also the
primary constituent of soft drusen. It is impossible to distinguish these two
varieties of diffuse soft drusen with routine light microscopy.
Subretinal neovascular membranes characterize the exudative type of
AMD. Angiogenic factors, most notably vascular endothelial growth factor
(VEGF), stimulate the proliferation of the new vessels (Fig. 9-16B).
Clinically, patients typically present with decreased visual acuity or
distorted vision (“metamorphopsia”). Membranes appear as grayish
patches on ophthalmoscopy, frequently with associated hemorrhage and
overlying subretinal fluid. Intravenous fluorescein angiography is used to
confirm the presence of neovascularization. Spectral domain optical
coherence tomography (SD-OCT) also can disclose the neovascular
membranes but is used primarily to evaluate retinal thickness and cystoid
edema and gauge response to anti-VEGF therapy. In the past, laser
photocoagulation was used to obliterate the vessels. In recent years,
however, laser therapy has been largely supplanted by the intravitreal
injection of monoclonal antibodies or antibody fragments such as
bevacizumab, ranibizumab, or aflibercept that target VEGF. Such agents
are highly efficacious in many cases, but they must be administered
repeatedly by intravitreal injection at relatively frequent intervals.
Neovascularization and its complications recur if therapy is stopped. Anti-
VEGF therapy halts the progression of neovascular AMD and improves
vision in many patients but does not address the underlying causes of the
disease and has no effect on the atrophic form of the disease. Clinical trials
of drugs designed to target other molecules involved in neovascularization
such as platelet-derived growth factor currently are under way, as are tests
of novel long-term delivery systems designed to decrease the burden of
monthly intravitreal injections. Treatment modalities to treat dry AMD
also are under investigation. These include stem cells and drugs targeting
the alternative complement pathway.

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 In untreated cases, the new vessels leak or bleed forming serous and/or
hemorrhagic detachments of the RPE (Fig. 9-16C). When the RPE
detaches, the plane of the detachment usually is between the inner surface
of Bruch membrane and a basal laminar deposit, which detaches with the
RPE. If new vessels have invaded a basal laminar deposit, they are apt to
be sheared off during detachment causing hemorrhagic detachment of the
RPE. Fibrous disciform scar formation, the end stage of exudative AMD,
may result from the organization of hemorrhagic RPE detachment.
Histopathologically, mature scars are composed of mounds of dense
collagenous connective tissue on the inner surface of Bruch membrane
(Fig. 9-16D). The collagenous scar usually contains vessels and aggregates
of RPE cells. The outer part of the overlying retina undergoes degeneration
because the disciform scar is a solid retinal detachment that separates the
photoreceptors from their usual source of nourishment. The collagenous
part of the scar is derived in part from the fibroblastic component of the
granulation tissue that invades and organizes the sub-RPE hemorrhage.
Fibrous metaplasia of the RPE also contributes to scar formation. RPE
cells are able to produce large quantities of extracellular matrix material
including drusenoid basement membrane material, collagen, and even
bone.
Heredity plays a role in the susceptibility to AMD, but development of
the disorder appears to depend on a complex interplay of genetic and
environmental factors. Environmental risk factors include a history of
smoking, white ethnicity, obesity, high dietary intake of vegetable fat, and
low dietary intake of antioxidants and zinc. Other contributing factors
appear to be photooxidative damage, the accumulation of lipofuscin and
chromophores that accumulate within and damage RPE cells,
accumulation of lipid in Bruch membrane that impedes its conductivity, as
well as hypoxia caused by involution of the choriocapillaris.
There is recent evidence that suggests that chronic inflammation may
play an important role in the pathogenesis of AMD. Cellular remnants and
debris from damaged RPE cells trapped between the RPE and Bruch
membrane are thought to trigger local up-regulation of cytokines, acute
phase reactants such as C-reactive protein, and inflammatory mediators
causing activation of the complement cascade. The debris also may attract
choroidal dendritic cells that function as antigen-presenting cells.
Immunohistochemical studies have disclosed complement components C5
and complement attack complex C5b-9 in drusen and damaged RPE cells.
This observation is quite important because patients who have a

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characteristic polymorphism in the gene for CFH are at significantly
greater risk for AMD. CFH encodes the major inhibitor of the alternative
complement pathway.
Subretinal neovascular membranes also complicate other conditions
such as angioid streaks. Idiopathic subretinal membranes occasionally
occur in relatively young individuals without antecedent cause. Ocular
histoplasmosis syndrome (OHS) typically affects patients from the Ohio
Valley or other areas where histoplasmosis is endemic.
Histopathologically, the disciform scars found in patients with OHS
resemble those seen in AMD but typically have a prominent infiltrate of
lymphocytes in the underlying choroid (Fig. 9-18B). In addition to
disciform macular scars, patients with OHS have peripapillary
chorioretinal atrophy and multiple white “punched-out” chorioretinal scars
(Fig. 9-18A). The latter also contain chronic inflammatory cells.

FIG. 9-18. Ocular histoplasmosis syndrome. A. Fundus photo shows triad of

hemorrhagic disciform macular scar, peripapillary chorioretinal atrophy, and
“punched-out” chorioretinal scars. B. Disciform scar, OHS. A mound of
connective tissue containing vessels and RPE cells rests on the Bruch membrane
and focally detaches the retina. The photoreceptors are atrophic. Chronic
inflammation is seen in the underlying choroid. (H&E ×100.)

Readers interested in the details of the histopathology of age-related

macular degeneration are encouraged to visit Curcio’s monumental Project
Macula Web site (http://projectmacula.cis.uab.edu/), which contains a
wealth of information including more than 100 interactive digitized
microslides of macular degeneration.

THE RETINAL PIGMENT

EPITHELIUM
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The RPE is vital to the health and survival of the overlying retina (Figs. 1-
3A,C and 1-4). Responsible for most of the characteristic reddish brown
color of the human fundus, the RPE absorbs excess light and prevents
intraocular light scattering like the black coating on the inside of a camera.
The RPE is also involved in the transport of fluid, nutrients, and vital
metabolites to and from the outer retina and the regeneration of the visual
pigment rhodopsin. It also appears to play a major active role in retinal
adherence by actively pumping fluid from the subretinal space. Finally, the
RPE phagocytizes and digests the tips of millions of damaged and
discarded photoreceptor outer segments every day.

STARGARDT DISEASE (FUNDUS

FLAVIMACULATUS)
Striking RPE abnormalities occur in several inherited human retinal
diseases that include Stargardt disease or fundus flavimaculatus (Fig. 9-
19). Affected patients lose vision in their teens from an atrophic type of
macular degeneration caused by the death of the subfoveal RPE. The term
fundus flavimaculatus, applied to this disorder by Franceschetti, literally
means “yellow-spotted fundus” and refers to characteristic yellow
pisciform spots at the level of the RPE disclosed by ophthalmoscopy. The
fundus may have a vermilion hue, and a striking clinical abnormality
called the dark choroid or the sign of choroidal silence is evident on
intravenous fluorescein angiography. This obscuration of the normal
choroidal pattern is caused by the massive accumulation of an abnormal
lipofuscin-like lipopigment in the cytoplasm of the RPE cells. The surfeit
of pigment absorbs excitatory blue wavelengths during angiography and
makes the RPE intensely PAS positive (Fig. 9-19B,C). The RPE cells are
taller than normal, and their nuclei are often displaced toward the apex of
the cell. Scanning electron microscopy has revealed markedly enlarged
RPE cells, which are more numerous in the posterior part of the fundus
(Fig. 9-19A). Groups of abnormal enlarged RPE cells surrounded by
smaller relatively normal cells may be responsible for the yellow flecked
appearance of the fundus. All of the RPE cells contain yellow-brown
lipopigment, but the lipofuscin is hidden by a relatively normal
complement of apical melanin in the smaller, more normal cells. The
pisciform aggregates of larger cells appear yellow because these grossly
abnormal cells are relatively amelanotic. Macrophages or detached,
lipopigment-laden RPE cells in the subretinal space might also contribute

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to the flecked retinal appearance. The massive accumulation of pigment
probably contributes to RPE dysfunction and death. The death of
subfoveal RPE cells in turn leads to photoreceptor degeneration and
atrophic macular degeneration.

FIG. 9-19. Stargardt disease (fundus flavimaculatus). A. RPE abnormalities.

False-colorized scanning electron micrograph shows aggregates of markedly
enlarged RPE cells in posterior part of eye obtained postmortem from a patient
with autosomal recessive fundus flavimaculatus. Hypothetically, the groups of
larger cells may appear as yellow spots clinically because they have less apical
melanin pigment than the surrounding smaller, more normal cells. B. RPE cells
are packed with granules of PAS-positive material consistent with an abnormal
form of lipofuscin. Nuclei in small peripheral RPE cells are displaced apically. C.
Posterior RPE cells contain more lipofuscin cells and are abnormally large,
amelanotic, and focally detached. The abnormal pigment in the RPE blocks
normal choroidal fluorescence during intravenous fluorescein angiography,
producing a dark choroid. The massive accumulation of lipofuscin is caused by a
toxic vitamin A derivative contained in ingested photoreceptor outer segments.
The ABCA4 gene is expressed only in rod outer segments. (A. False-colorized
SEM ×120 [From Eagle RC, Lucier AC, Bernardino VB, et al. Retinal pigment
epithelial abnormalities in fundus flavimaculatus: a light and electron
microscopic study. Ophthalmology 1980;87:1189–1200. Courtesy of
Ophthalmology]. B. PAS ×250, C. PAS ×250.)

Although Stargardt disease was long considered to be a classic disorder of

the RPE, the striking retinal pigment epithelial abnormalities described
above actually are secondary. Autosomal recessively inherited Stargardt
disease is caused by mutations in the ABCA4 gene (1p22.1), which is
expressed exclusively in the outer segments of rod photoreceptors. The
gene encodes a transmembrane protein that is involved in the clearance of
all-trans-retinal aldehyde from the outer segment discs. ABCA4 mutations
cause the accumulation of the toxic vitamin A derivate A2-E in the outer

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segments, which are phagocytized by the RPE. A2-E poisons the
lysosomes in the RPEs phagolysosomal system, leading to the
accumulation of large quantities of poorly digested ROS material as
lipofuscin, which in turn causes dysfunction and “terminal constipation” of
the cells. Teens who have homozygous mutations in the ABCA4 gene
develop fundus flavimaculatus. Heterozygous mutations have been found
in a small percentage of adults with the atrophic form of age-related
macular degeneration, and the gene also has been implicated in a few cases
of retinitis pigmentosa (RP) and cone–rod dystrophy.
Lipopigment accumulation appears to be a relatively stereotypical
response of the RPE, because excessive amounts of RPE lipopigment have
been found in several other disorders. One of these hereditary disorders is
Best disease. This autosomal dominant macular dystrophy is also called
vitelliform dystrophy because a yellowish plaque resembling an egg yolk
is observed in the macula in the early stages of the disorder. Visual loss
develops when the egg “scrambles” and chorioretinal scarring develops.
Although the early stage of Best disease has not been examined
histopathologically, the egg yolk probably is composed of lipopigment. An
abnormal EOG (electro-oculogram) incriminates the RPE in Best disease.
Best disease is caused by mutations in the bestrophin gene (BEST1) on
chromosome 11q (11q13), which encodes a calcium-activated chloride
channel. Some cases of adult-onset foveomacular vitelliform dystrophy
have been linked to defects in the RDS or peripherin gene (PRPH2), which
also causes a form of RP as well as patterned dystrophy.

RETINITIS PIGMENTOSA
RP includes a large, complex, and diverse group of inherited retinal
disorders that have similar characteristic clinical features. Patients with RP
usually present with nyctalopia (night blindness) early in life. The
electroretinogram (ERG) typically reveals a marked diminution or total
extinction of the retina’s electrical responses. A ring-shaped area of
blindness called a ring scotoma develops in the patient’s equatorial visual
field. As the disease progresses, this annular zone of blindness moves
posteriorly, progressively encroaching on central vision and producing
“tunnel vision.”
Ophthalmoscopy discloses RPE atrophy and a characteristic segmental
pattern of black intraretinal “bone spicule” pigmentation arranged along
retinal vessels (Fig. 9-20A). The retinal vessels are usually markedly

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narrowed, presumably reflecting the atrophic retina’s diminished
nutritional needs. Although the optic nerve classically displays “waxy
pallor,” the nerve does not appear to be especially atrophic
histopathologically, and this clinical appearance probably is related to
decreased vascularity. Macular edema, preretinal membrane formation,
and optic disc drusen are also encountered. Patients frequently develop
posterior subcapsular cataracts.

FIG. 9-20. Retinitis pigmentosa. A. Optic disk is pale, and retinal vessels are
severely attenuated and sheathed. Bone spicule pigmentation ensheathes atrophic
vessels in peripheral retina. B. Autosomal dominant retinitis pigmentosa. Only an
interrupted monolayer of cone nuclei persists as the outer nuclear layer in the
posterior part of the retina. The inner segments of the residual cones are grossly
abnormal and outer segments are not seen. The RPE and the inner retinal layers
are well preserved. C. Retinitis pigmentosa, intraretinal pigmentation. Focus of
bone spicule pigmentation comprises intraretinal perivascular proliferation of
RPE cells. Inset shows macromelanosomes in hyperplastic RPE. (B. H&E ×100
[case presented by Dr. David. G. Cogan, Verhoeff Society, 1989], C. H&E ×100,
inset. H&E ×250.)

Histopathology shows variable degrees of photoreceptor degeneration that

initially affects the rods and ultimately the cones (Fig. 9-20B). The outer

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nuclear layer comprising the photoreceptor cell nuclei also becomes
atrophic. The extent of involvement depends on both the variant and stage
of the disease. The RPE is usually relatively spared compared to the
photoreceptors. Presumably, since it is no longer constrained by
photoreceptor cell contact inhibition, the RPE proliferates and invades the
atrophic retina and grows in the space around retinal vessels forming
perivascular cuffs of intensely pigmented, polarized cells, which are
evident clinically as bone spicule pigmentation (Fig. 9-20C). Electron
microscopy has shown that the vascular endothelial cells adjacent to the
translocated RPE cells are thin and fenestrated, resembling the
choriocapillaris, and are separated from the RPE by an organized layer of
extracellular matrix resembling Bruch membrane. The intense black
pigmentation of the bone spicules is caused by numerous large round
granules of intracytoplasmic melanin that include macromelanosomes.
This pattern of intraretinal pigmentation is not specific for RP; identical
findings including macromelanosomes are found in eyes with secondary
pigmentary retinopathies related to long-standing retinal detachment. In
the latter instance, photoreceptor atrophy caused by chronic retinal
detachment presumably facilitates retinal invasion by the RPE.
The retina’s response to a wide variety of molecular or enzymatic
defects appears to be relatively limited and stereotyped. More than 3,000
mutations in over 57 different genes cause nonsyndromic RP. Rhodopsin
(RHO 3q22.1), the first gene linked to RP, was identified by Dryja and
coworkers in 1990. RHO mutations cause 15% to 20% of dominantly
inherited cases of nonsydromic RP. Most are single amino acid (missense)
mutations in the opsin part of the molecule. The most common rhodopsin
mutation is the substitution of histidine for the normal proline at position
23. This amino acid substitution is caused by a single nucleotide
transversion (C to A) in the triplet of nucleotides in the patient’s DNA that
codes for amino acid 23. Detailed marker studies suggest that all families
who have Pro-23-His AD RP are descended from a single individual.
Additional RP genes encode other proteins involved in rod
phototransduction including the alpha and beta subunits of rod
phosphodiesterase, the alpha and beta subunits of rod cGMP-gated
channel, arrestin, and guanylate cyclase–activating protein. Others encode
cytoskeletal proteins such as peripherin/RDS or proteins involved in
cellular trafficking including RPGR. Mutations in RPGR (retinitis
pigmentosa GTPase regulator) account for 13% of cases of RP. Other RP
genes are involved in photoreceptor differentiation, mRNA splicing,

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extracellular matrix composition, and other metabolic pathways. Although
most RP genes are expressed in rod photoreceptors, a few are expressed in
the RPE where they are involved in retinol metabolism or the phagocytosis
of photoreceptor outer segments. Some RP genes have been implicated in
other retinal dystrophies and degenerations. For example, autosomal
dominantly inherited mutations in rhodopsin cause some cases of retinitis
punctata albescens.
Almost 40% of RP occurs sporadically in patients who have a negative
family history. About 37% are autosomal recessively inherited, 20% are
autosomal dominantly inherited, and 4% are X linked. The disease tends to
be more severe and have an earlier onset in patients with X-linked RP.
Autosomal dominantly inherited cases tend to have the most benign
course. However, the severity of the disease measured by objective clinical
and electrophysiological criteria in a given kindred of AD RP appears to
correlate well with the specific amino acid substitution found in that
family, that is, whether the substituted amino acid occurs in the intradiscal,
transmembrane, or cytoplasmic region of the rod outer segment.
The online database Online Mendelian Inheritance in Man includes
433 articles dealing with different subtypes of nonsyndromic RP, genes
and proteins incriminated in the pathogenesis of RP, as well as a variety of
syndromes whose clinical manifestations include RP. Common syndromic
variants of RP include Usher syndrome, in which typical RP is associated
with neurosensory deafness, and Bardet-Biedl syndrome, which comprises
polydactyly, truncal obesity, hypogenitalism, and renal failure and is
caused by mutations in at least 14 genes thought to play critical roles in
cilia. Severe RP also accompanies renal failure in Senior-Loken syndrome,
another rare ciliopathy caused by mutations in one of at least five genes.
RP also occurs in certain dysmorphic syndromes and metabolic and
neurological diseases. Metabolic associations include abetalipoproteinemia
or Bassen-Kornzweig syndrome, Bietti corneoretinal crystalline dystrophy,
cystinosis, mucopolysaccharidoses, and Refsum disease. Bietti dystrophy
has microcrystalline deposits in the fundus and cornea and is caused by
mutations in the CYP4V2 gene encoding cytochrome P450. Neurological
diseases with RP include neuronal ceroid lipofuscinosis or Batten disease,
Joubert syndrome, autosomal dominant cerebellar ataxia type II, and
neurodegeneration with brain iron accumulation.
Leber congenital amaurosis (LCA) is the designation for a
heterogenous group of autosomal recessive retinal dystrophies that cause
congenital visual impairment in infants and children. LCA is caused by

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mutations in at least 18 genes including CEP290, which is responsible for
about one fifth of cases. Gene therapy has been used to successively treat
briard dogs and humans with LCA2 caused by mutations in RPE65, a
retinal pigment epithelial-specific isomerase involved in the regeneration
of light-altered vitamin A molecules.

OTHER HERITABLE DISORDERS OF

THE RETINA
In recent years, specific genetic defects have been discovered in a variety
of retinal and vitreous disorders using the tools of molecular genetics.
Ironically, few of these disorders have been examined histopathologically
or show relatively nonspecific findings. They include Oguchi disease
(mutation in the arrestin or rhodopsin kinase genes involved in the shutoff
of phototransduction), Sorsby pseudoinflammatory fundus dystrophy
(mutation in gene on chromosome 22 encoding tissue inhibitor of
metalloproteinase-3 [TIMP3]), pattern or butterfly dystrophy (mutations in
the RDS or photoreceptor peripherin gene [PRPH2] cause pattern
dystrophy in some patients; others have RP-like picture), choroideremia
(X-linked defect in the CHM gene, which encodes for Rab escort protein-1
[REP1], which is involved in membrane trafficking), Norrie disease and
X-linked variants of familial exudative vitreoretinopathy (defects in NDP
gene encoding norrin), gyrate atrophy (autosomal recessive ornithine
delta-aminotransferase deficiency), Stickler syndrome (autosomal
dominant mutation in COL2A1 for type II collagen), Kearns-Sayre and
MERRF and MELAS syndromes (defects in mitochondrial DNA), and
Stargardt disease (mutations in outer segment ABCA4 gene; see above).
Autosomal dominant familial exudative vitreoretinopathy is caused by
mutations in the frizzled-4 gene (FZD4) on chromosome 11q14 that
encodes receptors for Wnt signaling proteins.
The retina and RPE are involved in a wide variety of heritable
metabolic storage diseases including the systemic mucopolysaccharidoses,
sphingolipidoses, mucolipidoses, neuronal ceroid lipofuscinoses, and
disorders of glycoprotein degradation. Retinal pigmentary degeneration
resembling RP occurs in patients with Hurler (MPS I-H), Scheie (MPS I-
S), Hunter (MPS II), Sanfilippo (MPS III), and Morquio (MPS IV)
syndromes. Accumulation of GM2 ganglioside in retinal ganglion cells
opacifies the ganglion cell–rich perifoveal retina in infants with Tay-Sachs
disease (GM2 gangliosidosis type I) who are deficient in hexosaminidase

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A (Fig. 9-21). This is evident clinically as a macular cherry-red spot
because ganglion cells are absent in the floor of the fovea (foveola), which
remains transparent. Electron microscopy discloses multimembranous
inclusions called zebra bodies within lysosomes. Macular cherry-red spots
also occur in Sandhoff disease and the Niemann-Pick group of diseases.

FIG. 9-21. Tay-Sachs disease. A. Foveal cherry-red spot is caused by

opacification of perifoveal retinal ganglion cells by GM-2 ganglioside. B. PAS-
positive GM-2 ganglioside fills cytoplasm of retinal ganglion cells. (B. PAS
×250.)

TOXIC RETINOPATHIES
The chronic administration of certain drugs can cause irreversible visual
loss. Some of these chemical compounds are toxic to the RPE.
Chloroquine and its hydroxy derivative Plaquenil, antimalarial drugs used
in the treatment of rheumatoid arthritis and lupus erythematosus, can cause
a toxic maculopathy that has a characteristic “bull’s-eye” appearance.
These drugs have an affinity for melanin and are concentrated in the RPE.
The macular degeneration appears to be dose related, and severe visual
loss usually develops after patients have received many grams of the drug.
The chronic administration of high doses of phenothiazines,
particularly thioridazine or Mellaril can cause extensive irreversible
damage to the RPE and photoreceptors as well as severe cardiac
arrhythmias. NP27, a phenothiazine derivative, has been used
experimentally as an RPE toxin.
Experimental studies suggest that high levels of the amino acid
ornithine are toxic to the RPE. This toxicity appears to be the basis for the
widespread chorioretinal atrophy that occurs in patients who have gyrate
atrophy. At the molecular level, this rare autosomal recessively inherited

330
disorder is caused by the absence or dysfunction of the mitochondrial
matrix enzyme ornithine-delta-aminotransferase, which normally converts
ornithine to glutamate. The gene is located on chromosome 10. Serum
levels of ornithine are elevated 10- to 20-fold in patients with gyrate
atrophy. Clinically, gyrate atrophy is characterized by widespread
chorioretinal atrophy that blinds most patients by age 40 or 50 years.

PERIPHERAL RETINAL
DEGENERATIONS
Peripheral chorioretinal degeneration (commonly called cobblestone or
paving stone degeneration) occurs in more than one fourth of individuals
over age 20 years and is more common in myopes. The lesions appear as
yellow-white patches of chorioretinal atrophy that have scalloped, sharply
demarcated borders that often are pigmented (Fig. 9-22). Cobblestone
degeneration occurs most often in the inferotemporal retina and is
separated from the ora serrata by a zone of normal retina. The patches
appear white because the overlying sclera is bared by the severe atrophy of
the RPE and choriocapillaris. Large choroidal vessels often persist,
however. The pigmented border surrounding many lesions reflects
hyperplasia of the adjacent RPE.

FIG. 9-22. Peripheral retinal degenerations. A. Peripheral chorioretinal atrophy

(cobblestone or paving stone degeneration). Macrophoto (A) shows yellow-white
patches of chorioretinal atrophy with scalloped, sharply demarcated borders. B.
Atrophic outer retina is bound to denuded segment of Bruch membrane by firm
chorioretinal adhesion. The peripheral retina is thin and atrophic. C, D. Lattice
degeneration of the retina. The involved part of the retina (at left) is diffusely
atrophic and disorganized. A sclerotic vessel is seen in (C) and an intraretinal
focus of pigment in (D). Arrows denote vitreous strands attached to the margin of
both lesions. Tractional retinal breaks caused by vitreoretinal traction predispose

331
 to retinal detachment in patients with lattice degeneration. Pools of liquefied
vitreous typically are found overlying lattice lesions, and the internal limiting
membrane of the retina is focally absent. (A. H&E ×50, B. H&E ×50, C. H&E
×50.)

Histopathologically, the outer retina is welded to the inner surface of

Bruch membrane, which is devoid of RPE. Replaced by gliosis, the rods
and cones are absent in the area of chorioretinal adhesion and the
underlying choriocapillaris is atrophic as well. Unlike lattice degeneration
(see below), cobblestone degeneration does not predispose to retinal
detachment. In fact, these peripheral chorioretinal scars are quite similar
histopathologically to mature laser burns or cryotherapy scars used to treat
retinal disorders. Both therapeutic modalities use thermal effects to induce
chorioretinal scarring that firmly binds the outer retina to the denuded
inner surface of Bruch membrane. One sees the typical pattern of outer
ischemic retinal atrophy with loss of choriocapillaris, RPE, and outer
retina. Retinal breaks do not form because there is no associated
vitreoretinal traction. Markedly asymmetric involvement in patients with
unilateral ocular ischemia suggests that cobblestone degeneration might be
caused by choroidal vascular insufficiency.
Peripheral microcystoid degeneration is a ubiquitous, generally
innocuous degeneration of the peripheral retina found in all adults older
than 20 years. The condition is bilaterally symmetrical and most prominent
temporally. Clinically or macroscopically, one sees a stippled pattern that
corresponds to an array of interconnecting channels or lacunae in the
peripheral retina just posterior to the ora serrata (Fig. 9-23A).
Microscopically, the outer plexiform layer contains multiple cystoid
spaces called Blessig-Iwanoff cysts that are filled with hyaluronic acid and
are separated by residual pillars of Müller cells (Fig. 9-23B). Zonular
traction on the peripheral retina during accommodation may be a cause of
peripheral microcystoid degeneration.

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 FIG. 9-23. Peripheral microcystoid degeneration. A. Array of interconnecting
cystoid channels is evident grossly as stippled pattern in the peripheral retina
bordering the ora serrata. Peripheral microcystoid degeneration is almost a
universal finding in the peripheral retina after age 8 years. B. Cystoid spaces
called Blessing-Iwanoff cysts are located in the midretina. The cysts contain acid
mucosaccharide disclosed by colloidal iron stain. C. Pretreatment with
hyaluronidase abolishes staining, confirming that material in cysts is hyaluronic
acid. (B. Colloidal iron for AMP ×50, C. Colloidal iron for AMP after
hyaluronidase digestion ×50.)

Typical degenerative retinoschisis, a split centered in the outer plexiform

layer of the retina, is caused by coalescence of the cystoid spaces in
peripheral microcystoid degeneration. Degenerative or senile retinoschisis
occurs in 1% of adults and usually is located inferotemporally. Although
degenerative retinoschisis produces a localized scotoma (a focal area of
blindness), the retinal split rarely progresses posteriorly and usually
remains confined to the pre-equatorial retina. Rarely, retinal detachment
can complicate retinoschisis, if large holes develop in the outer layer of the
retina.
A rarer variant of peripheral microcystoid degeneration called reticular
cystoid degeneration is said to occur in about 18% of adults and is bilateral
in 41%. Evident as a polygonal patch of delicate tunnels with a finely
stippled appearance, reticular cystoid degeneration typically is located
posterior to a patch of typical cystoid degeneration. The cysts are located
in the nerve fiber layer of the retina (Fig. 9-24A). Reticular cystoid
degeneration may spawn a corresponding type of retinoschisis called
reticular retinoschisis. The split in the retina occurs in the nerve fiber layer.

333
 FIG. 9-24. A. Reticular cystoid degeneration. The cystoid spaces are located in
the nerve fiber layer of the retina. Reticular cystoid degeneration always occurs
posterior to a focus of typical peripheral microcystoid degeneration. It can evolve
into reticular retinoschisis. B. Juvenile X-linked retinoschisis. The retinal split
in this rare X-linked hereditary disorder is located in the nerve fiber layer. Many
affected patients have a pattern of stellate folds in the macula. (A. H&E ×50, B.
H&E ×50.)

Juvenile X-linked retinoschisis is an inherited disorder caused by

mutations in the RS1 gene on the X chromosome (Xp22.2-p22.1).
When affected males present with decreased visual acuity in the first
decade, ophthalmoscopy often discloses a curious stellate pattern of foveal
schisis seen as a cartwheel pattern of radiating lines or folds surrounding
the fovea. SD-OCT shows that the cysts involve multiple layers of the
inner retina, but they do not leak on fluorescein angiography. Peripheral
retinoschisis typically occurs in the inferotemporal retina and can become
quite extensive. The split develops in the superficial layers of the retina
(Fig. 9-24B). Retinoschisin protein produced by the RS1 gene is believed
to function in cellular adhesion in the development and maintenance of
retinal architecture. In one study, electron microscopy disclosed an
accumulation of amorphous PAS-positive material in the retina adjoining
schisis cavities. The authors postulated that juvenile x-linked retinoschisis
might be a disorder of Müller cells.
Lattice degeneration is a fairly common degenerative condition found
in 6% to 11% of the population. Lattice degeneration is important because
it predisposes to the development of rhegmatogenous retinal detachment,
particularly in myopic patients. The vitreoretinal degeneration is
characterized by the presence of oval areas of retinal thinning, which are
sharply demarcated, circumferentially oriented, and located anterior to the
equator in the vertical meridians of the eye. The term lattice degeneration
is derived from a lattice-like pattern of crisscrossing white lines (sclerotic

334
vessels) that occurs in relatively few (12%) lesions.
Histopathologically, lattice degeneration appears as a focal area of
retinal thinning (Fig. 9-22C,D). The inner retinal layers are atrophic and
the internal limiting membrane is absent. A pocket of liquefied vitreous
overlies the discontinuity in the ILM. Firm vitreoretinal condensations,
occasionally fortified by glial cell proliferation, adhere to the margins of
the lattice lesions. Thick-walled vessels, which correlate with the white
lattice lines seen clinically, are present. Hypertrophy, hyperplasia, and
intraretinal RPE migration are seen in some cases. The retinal capillary
bed is focally occluded.
The firm vitreoretinal adhesions to the margins of the patches of thin
atrophic retina predispose to the development of tractional retinal breaks
and rhegmatogenous retinal detachment. The tractional breaks typically
develop at the posterior or lateral margins of the lesions, and patches of
lattice degeneration are often found in the flaps of horseshoe breaks or
within small opercula extracted by vitreoretinal traction.
Pars plana cysts usually are innocuous, acquired degenerative lesions
that occur in about one third of normal individuals over age 70 years (Fig.
9-25). Most are found incidentally during pathologic examination. Pars
plana cysts are formed by detachment of the inner nonpigmented layer of
ciliary epithelium from the outer pigmented layer. In normal individuals,
the cysts contain an acidic glycosaminoglycan presumed to be hyaluronic
acid because it is sensitive to digestion with the enzyme hyaluronidase
(Fig. 9-25D–F). Multiple pars plana cysts occur in patients with multiple
myeloma or other dysproteinemic or hyperproteinemic disorders.
Myeloma cysts contain Bence Jones or myeloma protein, which is
precipitated by fixation and causes milky-white opacification of the cysts
(Fig. 9-25B,C).

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FIG. 9-25. Pars plana cysts. A. Cysts of the pars plana filled with hyaluronic acid
occasionally are found in eyes from elderly patients. D. The inner nonpigmented
layer of the ciliary epithelium has detached from the outer pigmented layer,
which remains attached to the pars plana. E. Cyst contents stain blue with
colloidal iron stain for acid mucopolysaccharide. F. Colloidal iron staining is
abolished by pretreatment with hyaluronidase, confirming presence of hyaluronic
acid. B. Pars plana cysts, multiple myeloma. Multiple pars plana cysts in eye
obtained postmortem from patient with multiple myeloma are seen before (B) and
after fixation (C). The cysts are clear in vivo. Fixation has precipitated the
myeloma protein filling the cysts causing milky-white opacification (C). (D.
H&E ×10, E. Colloidal iron for AMP ×10, F. Colloidal iron for AMP after
hyaluronidase digestion ×10.)

The temporal ora serrata is relatively smooth, while the nasal ora is
marked by prominent dentate processes and oral bays. Small, yellow
transparent jewel-like nodules of calcification called ora pearls
occasionally are found intraretinally within dentate processes. A
meridional complex is an elongated dentate process that bridges the pars
plana and attaches to a ciliary process anteriorly.

RETINAL DETACHMENT
Retinal detachment is a physical separation of the neurosensory retina
from the RPE (the two layers derived respectively from the inner and outer
layers of the embryonic neuroectodermal optic cup) (Fig. 9-26C).
Although these two layers normally are closely apposed, they are not

336
joined by intercellular connections, and a potential space called the
subretinal space exists between the two. Fluid collects in this potential
space in retinal detachment. The fluid prevents reapproximation and
reattachment of the retina unless it resorbs or is drained. The physical
separation deprives the outer, avascular part of the retina of its normal
supply of oxygen and nutrients from the choroid and also precludes vital
interactions between the energy-intensive photoreceptors and the RPE.
These factors can lead rapidly to permanent visual loss from irreversible
degeneration and atrophy of the rods and cones. Hence, vision may remain
poor after a seemingly successful reattachment operation, that is, surgery
can be a technical success but a functional failure.

FIG. 9-26. Retinal holes. A. Atrophic retina surrounds retinal hole. B. This
tractional break developed within a patch of perivascular lattice degeneration. C.
Chronic retinal detachment. Eosinophilic proteinaceous fluid fills the subretinal
space. The photoreceptors are totally absent and the outer nuclear layer is mildly
atrophic. The RPE shows focal budding. The subretinal fluid contains cholesterol
clefts. (H&E ×100.)

There are three basic categories of retinal detachment: rhegmatogenous,

exudative, and tractional. Rhegmatogenous retinal detachments are caused
by holes or breaks (rhegma = break) in the neurosensory retina that
provide fluid (usually liquid vitreous) access to the subretinal space (Fig.
9-26A,B). Most retinal holes found in eyes with rhegmatogenous retinal
detachment are tears caused by vitreoretinal traction. The vitreous humor’s
framework of type II collagen fibers is adherent to the internal limiting
membrane of the retina. Particularly firm vitreoretinal adhesions occur at
the vitreous base, which straddles the ora serrata, the circumference of the
optic disc, around the fovea and along major retinal vessels.
The framework of vitreous humor frequently detaches from the
posterior retina in elderly patients or in individuals who have diabetes or

337
other retinal pathology. Anterior displacement of the posteriorly detached
vitreous caused by eye movements can exert traction on areas where the
vitreous and retina remain firmly adherent causing tears in the retina (that
release the traction). Rhegmatogenous retinal detachment was a relatively
common complication of intracapsular cataract extraction, in which the
entire lens is removed within its capsule. Aphakic (no lens) retinal
detachment after intracapsular surgery typically is caused by small
horseshoe tears located at the posterior vitreous base. Hole formation is
related to increased mobility of the posteriorly detached vitreous, which
has been deprived of support anteriorly. The apices of horseshoe tears
always point posteriorly, that is, the horse always walks toward the optic
nerve. Posterior vitreous detachment and the mechanics of vitreoretinal
traction are responsible for this characteristic orientation.
Rhegmatogenous retinal detachment is also relatively common in
patients who are myopic and/or who have lattice degeneration of the
retina. Several factors probably contribute to the development of retinal
detachment in high myopia. Vitreous degeneration or syneresis is
extremely common in myopic eyes. This is evident clinically to most
affected persons as vitreous floaters. Most cases of myopia are caused by
enlargement of the eye, which usually occurs as the refractive disorder
develops toward the end of the first decade. Presumably, the vitreous
framework degenerates as the sclera and retina “outgrow” the vitreous.
Retinal stretching and attenuation in high myopes also contribute to retinal
hole formation. Subretinal neovascularization, macular hemorrhage, and
disciform scar formation can complicate pathologic high myopia.
Stretching of Bruch membrane causes splits or ruptures, which are evident
clinically as “lacquer cracks” or lightning figures. A central, circular, dark
spot called a Förster-Fuchs spot may develop in the macula during the
fourth or fifth decade in association with lacquer cracks. Blood pigment
from choroidal hemorrhage and RPE proliferation probably contribute to
this spot.
Trauma is another cause of rhegmatogenous retinal detachment. The
retina can be torn by severe distortion of the globe during contusion
injuries. Lengthy rips in the retina called giant tears can result. Giant tears
are typically oriented parallel to the limbus and generally extend for 90
degrees or more. Contusion injuries also can avulse or physically disinsert
the retina from its attachment to the ora serrata. The large peripheral gaps
that result are called retinal dialyses. Most retinal dialyses affect the
inferotemporal quadrant and occur in young emmetropes.

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 Tractional retinal detachments are caused by fibrous or fibrovascular
vitreoretinal membranes that contract and mechanically pull off the retina
(Fig. 9-27). Tractional detachment of the posterior retina, which
unfortunately often involves the macula, is a major complication of
proliferative diabetic retinopathy. Vitreoretinal traction in diabetics is
caused by the contraction of fibrovascular membranes. The neovascular
component of such membranes originates within the retina and proliferates
on the face of the posteriorly detached vitreous (Fig 9-28). The
organization of vitreous hemorrhage also contributes to vitreoretinal
membrane formation and traction. In the past, severe fibroplasia and
organization of the vitreous in diabetics was termed retinitis proliferans.
Tractional retinal detachment caused by vitreoretinal neovascularization
also complicates sickle cell retinopathy and the retinopathy of prematurity.

FIG. 9-27. Tractional retinal detachments, proliferative diabetic retinopathy. A.

New vessels bridge the subretinal space and arborize on posterior face of the
detached vitreous. The organized vitreous is exerting A–P traction on retina
causing focal retinal detachment. B. Fibrosis accentuates the posterior face of the
organized and partially detached vitreous (arrow), which remains focally
adherent to the retina. A–P traction lines are evident. Blood fills the subhyaloid
space where the organized posterior hyaloid face bridges the retina. The formed
vitreous contains blood. Gelatinous subretinal fluid detaches the posterior retina.
The glistening white particles in the subretinal fluid are lipid histiocytes.

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 FIG. 9-28. Chronic retinal detachment. A. Long-standing retinal detachments
typically have a funnel or morning glory configuration caused by PVR. Retinal
macrocysts and large pedunculated drusen are an indicator of chronicity. B, C.
Large pedunculated drusen-like structures found in eye with long-standing retinal
detachment are capped by plump RPE cells. Most of the RPE is flattened and
atrophic. These curious structures were composed of soft drusenoid matrix
material. (B. SEM ×160, C. SEM ×640.)

Tractional retinal detachment can also follow severe trauma, especially

perforating injuries of the globe. The retinal traction is caused by
vitreoretinal bands formed by ingrowth of fibrous scar tissue from the
wound or by the organization of tracks of hemorrhage in the vitreous.
Removal of vitreous hemorrhage after severe injury can help to reduce the
incidence of this complication.
Severe inflammatory and infectious conditions that stimulate
organization of the vitreous are additional causes of tractional retinal
detachment. A relatively high incidence of detachment complicates ocular
toxocariasis, particularly the peripheral form of the disease. Retinal
detachment is also a major problem in patients who have necrotizing
retinitides such as CMV retinitis or acute retinal necrosis (ARN) (see
Chapter 2).
Exudative retinal detachment is caused by the accumulation of fluid in
the subretinal space. The subretinal fluid may derive from “leaky” vascular
lesions in the retina but more typically is caused by choroidal infiltration
by tumor or inflammation. Exudative retinal detachments are
nonrhegmatogenous; careful clinical examination fails to disclose a hole in
the neurosensory retina.
Exudative retinal detachments caused by leaky retinal lesions occur in
patients who have Coats disease or retinal hemangioblastomas. Coats
disease is discussed in Chapter 12. Retinal hemangioblastomas (commonly
called retinal capillary hemangiomas) occur in isolation or may be a

340
manifestation of autosomal dominantly inherited von Hippel-Lindau
disease (see Chapter 2).
Most primary or secondary choroidal tumors usually have some degree
of associated exudative retinal detachment. Exudative detachment occurs
in most patients who have choroidal malignant melanomas and is often the
presenting manifestation of the tumor. Initially, fluid percolates into the
space at the margins of the “solid detachment” formed by “tenting-up” and
anterior displacement of the retina by the tumor. Degeneration or
destruction of the RPE and choriocapillaris overlying the tumor may be
additional contributory factors. Extensive exudative retinal detachment
typically is found in eyes with carcinoma metastatic to the uvea. The
location of the bulk of the subretinal fluid may shift with eye movements
(shifting fluid). Exudative retinal detachment is a major cause of visual
loss in eyes with choroidal hemangiomas and ultimately can lead to loss of
the eye if painful pupillary block glaucoma results. Treatment of these
benign vascular tumors is often warranted to prevent this complication.
Exudative retinal detachment also complicates choroidal inflammatory
disease, particularly disorders marked by extensive choroidal infiltration
such as sympathetic uveitis or Vogt-Koyanagi-Harada disease. Exudative
retinal detachment also complicates toxemia of pregnancy and oxygen
toxicity.

TRUE AND ARTIFACTITIOUS

RETINAL DETACHMENTS
Nearly all intact eyes that are fixed routinely by immersion in neutral
buffered formaldehyde have an artifactitious detachment of the retina.
Several features serve to differentiate true and artifactitious retinal
detachments histopathologically. True retinal detachments are
characterized by eosinophilic proteinaceous fluid in the subretinal space
(this is not present in all cases) and degeneration and atrophy of the
photoreceptors, which can involve the outer nuclear layer in long-standing
cases (Fig. 9-26C). On the other hand, if the retinal detachment is
artifactual, the subretinal space is empty, the photoreceptors are well
preserved, and ellipsoidal granules of RPE pigment remain attached to the
tips of the outer segments.

SIGNS OF CHRONIC RETINAL

341
DETACHMENT
Findings that indicate that a retinal detachment has persisted for a long
time include budding and papillary and pseudoadenomatous proliferation
of the RPE. The RPE has a great capacity for reactive proliferation and
migration, which, under normal circumstances, presumably is held in
check by contact inhibition by healthy retinal photoreceptors. Retinal
detachment removes this inhibition.
The RPE cells are capable of elaborating enormous quantities of
extracellular matrix material including drusenoid basement membrane
material, collagen, and even bone. Curious, large drusen-like structures
with a central core of soft granular extracellular matrix material enveloped
by RPE cells occasionally are found in eyes with long-standing retinal
detachments (Fig. 9-28C,D). Osseous metaplasia of the RPE is almost
invariably found in blind phthisical eyes with chronic retinal detachment
(Fig. 3-23C). The intraocular bone always is located on the inner surface
of the Bruch membrane and typically occurs at sites of traction near the
ora serrata or the optic disc. The bone is mature lamellar bone and it often
contains fatty marrow.
Chronically detached retinas found in blind painful eyes typically have
a funnel or “morning glory” configuration (Fig. 9-28A). This configuration
reflects the end stage of proliferative vitreoretinopathy (PVR). It is caused
by the growth of cells on both the inner and outer surfaces of the detached
retina and on the posterior surface of the detached vitreous, which remains
firmly attached to the vitreous base. The cellular constituents include RPE
cells, glial cells, and myofibroblasts that migrate, proliferate, and elaborate
extracellular matrix material and form fibrocellular membranes.
Organization of the vitreous and contraction of this scar tissue exerts
traction on the inner part of the peripheral retina drawing it centrally and
permanently welding the retina into this floral configuration. Organization
of the vitreous also forms cyclitic membranes, which bridge the vitreous
cavity behind the lens. The cyclitic membranes exert traction on the
vitreous base and detach the ciliary body. PVR is a major cause of
inoperable retinal detachment or recurrent detachment after reattachment
surgery. Fibrocellular membranes on its inner and outer surfaces bind
adjacent parts of the retina together, forming fixed folds. Other findings in
long-standing retinal detachment include gliosis and micro- and
macrocystic retinal degeneration.

342
THE OCULAR PATHOLOGY OF
DIABETES MELLITUS
The ocular complications of diabetes mellitus are an important cause of
acquired visual disability and blindness. In the United States, diabetic
retinopathy is the leading cause of new cases of legal blindness between
the ages of 20 and 74. Diabetic retinopathy occurs in patients with either
type I (insulin-dependent or juvenile-onset) or type II (maturity-onset)
diabetes mellitus. The prevalence of retinopathy is higher in patients with
type I diabetes. Patients with insulin-dependent diabetes also are at greater
risk for developing proliferative retinopathy, probably because they
generally have more severe hyperglycemia. Overall, however, a significant
proportion of the disorder’s blinding complications actually develop in
patients with type II diabetes because adult-onset diabetes is more
common. The prevalence of retinopathy in both groups is related to the
duration of the disease. Retinopathy occurs in about 50% of patients who
have had insulin-dependent diabetes mellitus for 15 years. Strict control of
blood sugar and glycosylated hemoglobin A1c appears to slow progression
of the disease.
Background, preproliferative, and proliferative forms of diabetic
retinopathy are recognized clinically. The initial stage of diabetic
retinopathy called background retinopathy is marked by retinal edema,
hemorrhages, and exudates (see above) and capillary microaneurysms
(Fig. 9-29). The onset of many soft exudates or cotton-wool spots heralds
progressive retinal ischemia as diabetic retinopathy enters the
preproliferative phase. Retinal and vitreoretinal neovascularization occur
in proliferative diabetic retinopathy (Fig. 9-30). Neovascularization
predisposes to the blinding complications vitreous hemorrhage and
tractional retinal detachment.

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FIG. 9-29. A. Background diabetic retinopathy. Retinal hemorrhages, hard
yellow waxy exudates, cotton-wool spots, and retinal edema are present. B.
Diabetic microaneurysms, trypsin retinal digestion. C. Normal retinal capillaries,
trypsin retinal digestion. Normal retinal capillaries are composed of
approximately equal numbers of endothelial cells and pericytes. The nuclei of the
endothelial cells are cigar shaped. The pericyte nuclei are round. The pericytes
are embedded in the basement membrane of the capillary wall. D. Retinal
capillaries in diabetes mellitus, trypsin retinal digestion. A preferential loss of
pericytes occurs in the early stages of diabetic retinopathy, disturbing the normal
1:1 ratio between pericytes and endothelial cells. Arrows denote pericyte ghosts
in the capillary in the capillary basement membrane. Diabetic thickening of the
basement membrane causes intense staining with PAS stain. (B. PAS ×100, C.
PAS ×250, D. PAS ×250.)

FIG. 9-30. A. Proliferative diabetic retinopathy. Arrow points to large frond of

vitreoretinal neovascularization above flat-topped subhyaloid hemorrhage. IVFA

344
 disclosed extensive retinal capillary nonperfusion. B. Retinal neovascularization,
PDR. Feeder vessel passes through the ILM and enters base of neovascular frond.
The new vessels are encompassed by collagen. C. Arrow denotes sheet of
neovascularization growing on posterior surface of detached vitreous. Subhyaloid
hemorrhage and vitreous hemorrhages are present. (B. H&E ×200, C. H&E
×100)

Diabetic retinopathy is the retinal manifestation of the generalized

microangiopathy that occurs throughout the body in diabetes mellitus (Fig.
9-29C,D). Breakdown of the blood–retinal barrier is one of the earliest
functional lesions in diabetic eyes and contributes to the development of
hemorrhages, exudates, and retinal edema. Retinal edema is an extremely
important cause of visual loss in diabetic patients. The characteristic
retinal vascular abnormalities of diabetic retinopathy can be demonstrated
by the trypsin retinal digestion technique. Normal retinal capillaries are
composed of endothelial cells, which form the lining of the capillary, and
pericytes or mural cells, which reside in capsules in the perivascular
basement membrane (Fig. 9-29C). Pericytes have contractile properties
that regulate capillary caliber and the flow within the retinal
microcirculation. Normally, endothelial cells and pericytes occur in a one-
to-one ratio. Pericytes are lost preferentially in the early stages of diabetic
retinopathy (Fig. 9-29D). Pericyte loss appears to be directly related to
hyperglycemia, which induces apoptosis.
Trypsin digestion of diabetic retinas also discloses capillary
microaneurysms and generalized thickening of the capillary basement
membranes evident as increased PAS-positive staining. Totally acellular
areas of the retinal capillary bed devoid of both endothelial cells and
pericytes also are found. The latter correspond to areas of capillary
nonperfusion seen on fluorescein angiography. Histopathologic
examination of zones of capillary nonperfusion shows inner ischemic
retinal atrophy.
Retinal capillary microaneurysms (Fig. 9-29B) are grape-like or
spindle-shaped dilatations of retinal capillaries. Many microaneurysms
appear quite cellular suggesting that capillary endothelial cell proliferation
may be involved in their formation. Weakening of the capillary wall
secondary to focal pericyte loss may also contribute.
Retinal capillary pericyte loss has several important consequences.
Retinal capillaries lose the ability to autoregulate, leading to changes in
retinal blood flow. In addition, pericytes appear to have an inhibitory

345
effect on vascular endothelial cell proliferation, which is mediated by
TGF-β. Loss of this inhibitory effect may stimulate endothelial cell
proliferation and neovascularization.
Neovascularization occurs in proliferative diabetic retinopathy and is a
major factor in the pathogenesis of blinding complications such as vitreous
hemorrhage and tractional retinal detachment (Figs. 9-27B, 9-30, and 9-
31). Neovascularization is stimulated by angiogenic factors produced by
the ischemic retina such as VEGF. VEGF is a potent angiogenic factor and
endothelial cell–specific mitogen whose synthesis is regulated by the level
of oxygen in the cellular microenvironment. VEGF has been identified in
ocular fluid from patients with active retinal and anterior segment
neovascularization associated with several ocular diseases with retinal
ischemia.

FIG. 9-31. Proliferative diabetic retinopathy. A. Eye obtained postmortem from

patient with chronic insulin-dependent diabetes mellitus has tractional
detachment of posterior retina caused by vitreoretinal neovascularization.
Detachment is seen at higher magnification in Fig. 9-25A. B. Scanning electron
microscopy discloses new vessels proliferating on scaffold of posteriorly
detached vitreous. (B. SEM ×40.)

Neovascularization begins in the retina where it is evident clinically as

IRMA (intraretinal microvascular abnormalities). The new vessels break
through the internal limiting membrane and grow on the inner surface of
the retina (Fig. 9-30). Neovascularization cannot invade the formed
vitreous, but it readily grows on the posterior face of the detached vitreous
(Fig. 9-30C, 9-31). Neovascularization that originates on the optic disc

346
typically grows into the conical posterior opening of Cloquet canal called
the area of Martegiani. The neovascularization stimulates fibroplasia and
vitreous fibrosis. Contraction of vitreoretinal membranes and progression
of posterior vitreous detachment frequently tears the delicate new vessels
causing subhyaloid and vitreous hemorrhage. Organization of hemorrhage,
in turn, engenders a vicious cycle of additional fibrosis, traction, and
hemorrhage. Localized tractional detachment of the macula often occurs
because the vitreous typically remains adherent to the temporal arcades of
the major retinal vessels. The vascularized bridge of detached vitreous
contracts, causing retinal–retinal traction (Fig. 9-27B). Anteroposterior
traction also contributes to the retinal detachment (Fig. 9-27A).
Eyes with proliferative diabetic retinopathy also are prone to develop
neovascularization of the iris (NVI) and NVG (Fig. 8-12). NVI is caused
by the anterior diffusion of VEGF. NVI (initially called rubeosis iridis
diabetica) may develop or progress markedly after intracapsular cataract
extraction, which presumably removes a barrier to diffusion. Iris
neovascularization usually starts near the pupillary border and in the angle.
The normal architecture of the iris is flattened and effaced by the
fibrovascular membrane on its normally avascular anterior surface.
Secondary closed-angle glaucoma results when the formation of adhesions
between the peripheral iris and the trabecular meshwork called peripheral
anterior synechiae blocks aqueous outflow.
A rarer, more innocuous form of diabetic iridopathy called lacy
vacuolization of the iris pigment epithelium occurs in some patients (Fig.
9-32B–D). Lacy vacuolization is marked by an accumulation of glycogen
in cystoid spaces within the iris pigment epithelium. The focal
glycogenosis of the iris pigment epithelium is thought to be related to
chronically elevated levels of blood glucose and may be analogous to an
accumulation of glycogen in the renal tubules called Armanni-Ebstein
glycogen nephropathy. Transient pigmentation of aqueous humor observed
intraoperatively in some diabetics may reflect pigment epithelial damage
caused by lacy vacuolization. Lacy vacuolization may be evident during
slit-lamp biomicroscopy as a faint moth-eaten pattern of iris
transillumination.

347
 FIG. 9-32. A. Thickening of pigmented ciliary epithelial basement
membrane, diabetes mellitus. Periodic acid–Schiff stain accentuates massive
thickening of the basement membrane of pigmented pars plicata ciliary
epithelium in eye from relatively young diabetic patient. B. Diabetic iridopathy.
A fibrovascular membrane flattens the anterior iridic surface. Multiple vacuoles
impart a lacy appearance to the thickened iris pigment epithelium. C. The
vacuoles are filled with PAS-positive granules of glycogen. D. Diastase digestion
abolishes PAS staining confirming that material is glycogen. (A. PAS ×100, B.
H&E ×50, C. PAS ×250, D. PAS after diastase digestion ×250.)

Basement membrane thickening occurs throughout the body in diabetic

patients. Thickening of the basement membrane of the pigmented ciliary
epithelium occurs in many diabetic eyes and is a helpful histologic marker
for the disease (Fig. 9-32A). An analogous thickening of the glomerular
basement membrane is found in the Kimmelstiel-Wilson form of diabetic
nephropathy. Thickening of the corneal epithelial basement membrane can
predispose to sheet-like desquamation of corneal epithelium during
vitreoretinal surgery.
Cataracts also complicate diabetes mellitus. A specific form of diabetic
cataract may be the presenting manifestation of the disease. Relatively
rare, such cataracts probably are caused by the osmotic effect of sorbitol
accumulation in the lens. Such opacities may be partially reversible if
blood sugar levels are normalized. Diabetics also develop typical senile
cataracts at an earlier age. Variable refractive errors in diabetics reflect
changes in lens hydration caused by hyperglycemia. Patients usually
become more myopic when their blood sugar is elevated.
Diabetics also are at increased risk for infection. One of the most
serious infections that can complicate diabetes is mucormycosis. Poorly
controlled diabetics who are acidotic are particularly at risk for infection
by normally saprophytic fungi in the order Mucorales. The fungal
infection begins in the paranasal sinuses and then invades the orbital

348
tissues secondarily. Usually evident in routine sections stained with H&E,
the large nonseptate fungal hyphae typically invade vessels producing
thrombosis and necrosis (Fig. 14-5). Neural invasion is also common. In
rare instances, diabetes mellitus may present with unilateral or even
bilateral CRAO caused by mucormycosis.

SICKLE HEMOGLOBINOPATHY
Vitreoretinal neovascularization is a characteristic finding in patients who
have sickle hemoglobinopathy, particularly hemoglobin SC disease.
Occlusion of peripheral retinal vessels by sickled erythrocytes causes
extensive capillary nonperfusion and inner ischemic atrophy of the
peripheral retina, particularly the longer arc of the temporal retina.
Neovascularization develops within the retina just behind the
characteristically abrupt junction between its peripheral ischemic
nonperfused and posterior perfused parts and then extends into the
vitreous. The appearance of the neovascular fronds has been likened to the
sessile colonial soft coral Gorgonia flabellum, the sea fan. The sea fans
bleed causing vitreous hemorrhage. Vitreoretinal traction caused by
organization of the vitreous blood produces holes in the retina that cause
rhegmatogenous retinal detachment. Neovascularization is more likely to
occur in patients with Hb SC disease because they are less anemic than
patients with Hb SS disease, and vascular occlusion is more apt to occur
when the hematocrit is higher. Pigmented scars called black sunburst signs
caused by chorioretinal hemorrhage are more common in patients with Hb
SS disease. The partial resorption of hemorrhages in these patients is
evident clinically as salmon patches. Angioid streaks also occur in a small
number of patients with sickle hemoglobinopathy. It has been postulated
that the deposition of iron in Bruch membrane somehow predisposes to
massive calcification of Bruch membrane.

NEW RETINAL IMAGING

TECHNIQUES
A relatively limited spectrum of retinal pathology typically is evaluated in
most ophthalmic pathology laboratories unless they process a large
number of postmortem eyes. Categories of retinal pathology that typically
are seen are limited to abnormalities found in eyes that have been
enucleated for blindness and pain or intraocular tumors. Many of these

349
eyes have chronic retinal detachments. The best source for detailed
information on retinal pathology is the late W. Richard Green’s
monumental chapter in Spencer’s Ophthalmic Pathology: An Atlas and
Textbook. Dr. Green’s laboratory at Johns Hopkins’ Wilmer Eye Institute
evaluated numerous postmortem eyes with retinal disease.
A significant number of retinal diseases have never been examined
histopathologically. In recent years, the availability of new imaging
techniques such as SD-OCT, scanning laser ophthalmoscopy, and fundus
autofluorescence are providing new clues about the cause, pathogenesis,
and anatomic basis of retinal disorders that have not, and possibly never
will be, examined in the eye pathology lab. SD-OCT is a noncontact
medical imaging technique that uses low-coherence interferometry to
produce detailed cross-sectional and 3-D images of the retina. It is used
extensively in the evaluation and treatment of a variety of retinal disorders,
particularly age-related macular degeneration, and is also used to assess
the optic nerve and nerve fiber layer in glaucoma.
Generated by mathematical algorithms, the layers of the retina
disclosed by SD-OCT do not correspond exactly to the retinal layers seen
histopathologically. The cellular layers of the retina generally appear in
SD-OCT images as dark bands and the plexiform layers as lighter bands.
However, the prominent dark band in the outer part of the outer retina
disclosed by OCT comprises both the outer nuclear layer and the outer part
of the outer plexiform layer (Fig. 9-14B,C). The latter is composed of that
part of the OPL that is located external to the zone of synapses comprising
the middle limiting membrane and the inner plexiform portion composed
of photoreceptor axons. Four outer retinal hyperreflective bands disclosed
by SD-OCT to this layer are extremely important landmarks that are used
in the clinical assessment of the health of the retina and the status of its
photoreceptors (Fig. 9-33). The anatomic correlates to these SD-OCT
bands recently have been reevaluated and standardized nomenclature
established by an international consensus panel. Four lines are now
thought to represent the external limiting membrane of the retina, the
ellipsoid zone of the photoreceptors, the interdigitation zone, and the
RPE/Bruch membrane complex. The ellipsoid zone previously was called
the photoreceptor inner segment–outer segment junction.

350
 FIG. 9-33. SD-OCT of outer retinal layers. A. SD-OCT of normal posterior
retina with characteristic bright outer bands. B. Histology of same area in
enucleated eye. Thick ganglion cell layer indicates location within arcades. C, D.
Histology of photoreceptors, RPE, and inner choroid and corresponding bright
bands on SD-OCT. Inner segments of photoreceptors comprise inner myoid and
larger outer ellipsoid zones. Bright inner band on OCT is thought to correspond
to mitochondria-rich ellipsoid layer. Other bands include external limiting
membrane, outer segment contact cylinder region, and RPE choriocapillary
complex. Distinct ellipsoid layer serves as a clinical marker for healthy
photoreceptors. (B. H&E ×100, C. H&E original magnification ×400.)

The external limiting membrane is a series of intercellular connections that

join the apices of the Müller cells and the photoreceptor cells. The inner
and outer segments of the photoreceptors project through this belt
desmosome into the subretinal space. The inner segments of the
photoreceptors have two components, the myoid, which is closest to the
XLM, and the ellipsoid. The ellipsoid part of the inner segments is packed
with mitochondria, which are thought to be responsible for this bright band
on SD-OCT. The interdigitation zone denotes that area where processes on
the apical surfaces of the RPE cells envelop the tips of the photoreceptor
outer segments. RPE, Bruch membrane, and the choriocapillaris probably
contribute to the outer band. The histology of the outer retina and the four
bands are seen in figure blank 9–33.
Attenuation, discontinuity, and disruption of the external enemy
membrane, ellipsoid zone, and interdigitation zones disclosed by SD-OCT
are hallmarks of photoreceptor dysfunction or damage in a variety of
retinal diseases (Fig. 9-34).

351
FIG. 9-34. Foveal detachment: SD-OCT and correlative histopathology. A.
Bright ellipsoid band area of normal attached retina in SD-OCT at left becomes
indistinct in area of foveal detachment. B, C. Correlative light microscopy of
same region of attached retina shows orderly array of rods and cones with normal
inner and outer segments. Curvature of photoreceptors may be an artifact. D.
Ellipsoids of detached fovea persist but appear swollen and poorly aligned. (B.
H&E ×100, C. H&E ×400, D. H&E ×400.)

Bibliography
Green W. Pathology of the retina. In: Spencer W, ed. Ophthalmic Pathology: An
Atlas and Textbook. vol 2. Philadelphia, PA: WB Saunders, 1996:667–1331.

Albinism and Other Developmental Anomalies

Bergsma D, Kaiser-Kupfer M. A new form of albinism. Am J Ophthalmol
1974;77:837–844.
Blume R, Wolff S. The Chediak-Higashi syndrome: studies in four patients and a
review of the literature. Medicine 1972;51:247–280.
Dessinioti C, Stratigos AJ, Rigopoulos D, et al. A review of genetic disorders of
hypopigmentation: lessons learned from the biology of melanocytes. Exp
Dermatol 2009;18:741–749.
Di Pietro SM, Dell’Angelica EC. The cell biology of Hermansky-Pudlak
syndrome: recent advances. Traffic 2005;6:525–533.
Falls H. Sex-linked ocular albinism displaying typical fundus changes in the
female heterozygote. Am J Ophthalmol 1951;34:41–50.
Garrod A. Inborn Errors of Metabolism. London, UK: Frowde, 1909.
Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J
Rare Dis 2007;2:43.
Hornyak TJ. The developmental biology of melanocytes and its application to
understanding human congenital disorders of pigmentation. Adv Dermatol
2006;22:201–218.
Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and Chediak-

352
 Higashi syndrome: disorders of vesicle formation and trafficking. Thromb
Haemost 2001;86:233–245.
King R, Creel D, Cervenka J, et al. Albinism in Nigeria with delineation of a new
recessive oculocutaneous type. Clin Genet 1980;17:259–270.
Kirkwood BJ. Albinism and its implications with vision. Insight 2009;34:13–16.
Messmer E, Font RL, Laqua H, et al. Cavernous hemangioma of the retina.
Immunohistochemical and ultrastructural observations. Arch Ophthalmol
1984;102:413–418.
Mietz H, Green WR, Wolff SM, et al. Foveal hypoplasia in complete
oculocutaneous albinism. A histopathologic study. Retina 1992;12:254–260.
Naumann GOH, Lerche W, Schroeder W. Foveola-Aplasie bei Tyrosinase-
positivem oculocutanem Albinismus. Graefes Arch Clin Exp Ophthalmol
1976;200:39–50.
O’Donnell FE Jr, Green WR, Fleischman JA, et al. X-linked ocular albinism in
Blacks. Ocular albinism cum pigmento. Arch Ophthalmol
1978;96:1189–1192.
O’Donnell FJ, Hambrick GJ, Green W, et al. X-linked ocular albinism: an
oculocutaneous macromelanosomal disorder. Arch Ophthalmol
1976;94:1883–1892.
O’Donnell FJ, King R, WR G, et al. Autosomal recessively inherited ocular
albinism: a new form of ocular albinism affecting women as severely as men.
Arch Ophthalmol 1978;96:1621–1625.
Oetting WS, Fryer JP, Shriram S, et al. Oculocutaneous albinism type 1: the last
100 years. Pigment Cell Res 2003;16:307–311.
Ray K, Chaki M, Sengupta M. Tyrosinase and ocular diseases: some novel
thoughts on the molecular basis of oculocutaneous albinism type 1. Prog
Retin Eye Res 2007;26:323–358.
Read AP, Newton VE. Waardenburg syndrome. J Med Genet 1997;34:656–665.
Russell-Eggitt I. Albinism. Ophthalmol Clin North Am 2001;14: 533–546.
Scheinfeld NS. Syndromic albinism: a review of genetics and phenotypes.
Dermatol Online J 2003;9:5.
Shiflett SL, Kaplan J, Ward DM. Chediak-Higashi Syndrome: a rare disorder of
lysosomes and lysosome related organelles. Pigment Cell Res
2002;15:251–257.
Straatsma BR, Foos RY, Heckenlively JR, et al. Myelinated retinal nerve fibers
associated with ipsilateral myopia, amblyopia and nystagmus. Am J
Ophthalmol 1979;88:506–510.
Straatsma BR, Foos RY, Heckenlively JR, et al. Myelinated retinal nerve fibers.
Am J Ophthalmol 1981;91:25–38.
Tran T, Kaufman LM. The child’s eye in systemic diseases. Pediatr Clin North
Am 2003;50:241–258.
Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and
organelle function. Pigment Cell Res 2006;19:19–42.
Wong L, O’Donnell FE Jr, Green WR. Giant pigment granules in the retinal

353
 pigment epithelium of a fetus with X-linked ocular albinism. Ophthalmic
Paediatr Genet 1983;2:47–65.

Retinal Hemorrhages and Exudates

Ashton N. Pathological and ultrastructural aspect of the cotton-wool spots. Proc R
Soc Med 1969;62:1271–1276.
Ashton N. Pathophysiology of retinal cotton-wool spots. Br Med Bull
1970;26:143–150.
Ashton N, Harry J. The pathology of cotton-wool spots and cytoid bodies in
hypertensive retinopathy and other diseases. Trans Ophthalmol Soc UK
1963;83:91–114.
Breazzano MP, Unkrich KH, Barker-Griffith AE. Clinicopathological findings in
abusive head trauma: analysis of 110 infant autopsy eyes. Am J Ophthalmol
2014;158(6):1146–1154.
Cunha-Vaz JG. The blood-retinal barriers. Doc Ophthalmol 1976;41:287–327.
Duane TD, Osher RH, Green WR. White centered hemorrhages: their
significance. Ophthalmology 1980;87:66–69.
Morad Y, Wygnansky-Jaffe T, Levin AV. Retinal haemorrhage in abusive head
trauma. Clin Exp Ophthamol 2010;38:514–520.
Wolter JR. Pathology of a cotton-wool spot. Am J Ophthalmol 1959;48:473–485.
Wolter JR. Axonal enlargements in the nerve-fiber layer of the human retina. Am
J Ophthalmol 1968;65:1–12.

Angioid Streaks
Dreyer R, Green WR. Pathology of angioid streaks. Trans Pa Acad Ophthalmol
Otolaryngol 1978;31:158–167.
Jampol LM, Acheson R, Eagle RC Jr, et al. Calcification of Bruch’s membrane in
angioid streaks with homozygous sickle cell disease. Arch Ophthalmol
1987;105:93–98.

Retinal Vascular Occlusion

Arruga J, Sanders MD. Ophthalmologic findings in 70 patients with evidence of
retinal embolism. Ophthalmology 1982;89:1336–1347.
Ball CJ. Atheromatous embolism to the brain, retina, and choroid. Arch
Ophthalmol 1966;76:690–695.
Bonini Filho MA, Adhi M, de Carlo TE, et al. Optical coherence tomography
angiography in retinal artery occlusion. Retina 2015;35:2339–2346.
Brownstein S, Font RL, Alper MG. Atheromatous plaques of the retinal blood
vessels. Arch Ophthalmol 1973;90:49–52.
Dahrling BE. The histopathology of early central retinal artery occlusion. Arch
Ophthalmol 1965;73:506–510.
Fineman MS, Savino PJ, Federman JL, et al. Branch retinal artery occlusion as

354
 the initial sign of giant cell arteritis. Am J Ophthalmol 1996;122:428–430.
Frangieh GT, Green WR, Barraquer-Somer E, et al. Histopathologic study of nine
branch retinal vein occlusions in eight eyes of seven patients. Arch
Ophthalmol 1982;100:1132–1140.
Green WR, Chan CC, Hutchins GM, et al. Central retinal vein occlusion: a
prospective histopathologic study of 29 eyes of 28 patients. Trans Am
Ophthalmol Soc 1981;79:371–422.
Hayreh SS. Pathogenesis of occlusion of the central retinal vessels. Am J
Ophthalmol 1971;72:998–1011.
Jampol LM, Setogawa T, Rednam KR, et al. Talc retinopathy in primates. A
model of ischemic retinopathy: I. Clinical studies. Arch Ophthalmol
1981;99:1273–1280.
Jampol LM, Wong AS, Albert DM. Atrial myxoma and central retinal artery
occlusion. Am J Ophthalmol 1973;75:242–249.
Levine SR, Crofts JW, Lesser GR, et al. Visual symptoms associated with the
presence of a lupus anticoagulant. Ophthalmology 1988;95:686–692.
Mason JO III, Patel SA, Feist RM, et al. Ocular neovascularization in eyes with a
central retinal artery occlusion or a branch retinal artery occlusion. Clin
Ophthalmol 2015;5:995–1000.
McDonnell PJ, Moore GW, Miller NR, et al. Temporal arteritis. A
clinicopathologic study. Ophthalmology 1986;93:518–530.
Mckibbin DW, Gott VL, Hutchins GM. Fatal cerebral atheromatous embolization
after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1976;71:741–745.
Penner R, Font RL. Retinal embolism from calcified vegetations of aortic valve.
Spontaneous complications of rheumatic heart disease. Arch Ophthalmol
1969;81:565–568.
Pfaffenbach DD, Hollenhorst RW. Morbidity and survivorship of patients with
embolic cholesterol crystals in the ocular fundus. Trans Am Ophthalmol Soc
1972;70:337–349.
Pulido JS, Ward LM, Fishman GA, et al. Antiphospholipid antibodies associated
with retinal vascular disease. Retina 1987;7:215–218.
Rahimy E, Sarraf D. Paracentral acute middle maculopathy spectral-domain
optical coherence tomography feature of deep capillary ischemia. Curr Opin
Ophthalmol. 2014;25(3):207–212.
Rothstein T. Bilateral retinal vein closure as the initial manifestation of
polycythemia. Am J Ophthalmol 1972;74:256–260.
Wang FM, Henkind P. Visual system involvement in giant cell (temporal)
arteritis. Surv Ophthalmol 1979;23:264–271.
Weyand CM. The Dunlop-Dottridge Lecture: the pathogenesis of giant cell
arteritis. J Rheumatol 2000;27:517–522.
Weyand CM, Goronzy JJ. Pathogenic principles in giant cell arteritis. Int J
Cardiol 2000;75(suppl 1):S9–S15; discussion S17–S19.
Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann
Intern Med 2003;139:505–515.

355
Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med
2003;349:160–169.
Yu S, Pang CE, Gong Y, et al. The spectrum of superficial and deep capillary
ischemia in retinal artery occlusion. Am J Ophthalmol 2015;159:53.e1-
2–63.e1-2.

Hypertensive Retinopathy
Garner A, Ashton N. Pathogenesis of hypertensive retinopathy: a review. J R Soc
Med 1979;72:362–365.
Garner A, Ashton N, Tripathi R, et al. Pathogenesis of hypertensive retinopathy.
An experimental study in the monkey. Br J Ophthalmol 1975;59:3–44.
Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignant hypertension. VI.
Hypertensive choroidopathy. Ophthalmology 1986;93:1383–1400.
Tso MO, Jampol LM. Pathophysiology of hypertensive retinopathy.
Ophthalmology 1982;89:1132–1145.
Walsh JB. Hypertensive retinopathy. Description, classification, and prognosis.
Ophthalmology 1982;89:1127–1131.

Age-Related Maculopathy
Allikmets R, Shroyer NF, Singh N, et al. Mutation of the Stargardt disease gene
(ABCR) in age-related macular degeneration. Science 1997;277:1805–1807.
Alten F, Eter N. Current knowledge on reticular pseudodrusen in age-related
macular degeneration. Br J Ophthalmol 2015;99(6):717–722.
Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in
the formation of drusen in the aging eye. Am J Ophthalmol
2002;134:411–431.
Boon CJ, van de Ven JP, Hoyng CB, et al. Cuticular drusen: stars in the sky. Prog
Retin Eye Res 2013;37:90–113.
Boozalis GT, Schachat AP, Green WR. Subretinal neovascularization from the
retina in radiation retinopathy. Retina 1987;7:156–161.
Bressler NM, Silva JC, Bressler SB, et al. Clinicopathological correlation of
drusen and retinal pigment epithelial abnormalities in age-related macular
degeneration. Retina 1994;14:130–142.
Bressler SB, Bressler NM, Sarks SH, et al. Age-related macular degeneration:
nonneovascular early AMD, intermediate AMD, and geographic atrophy. In:
Ryan SJ, ed. Retina. St. Louis, MO: Mosby, 2006:1041–1074.
Bressler SB, Silva JC, Bressler NM, et al. Clinicopathologic correlation of occult
choroidal neovascularization in age-related macular degeneration. Arch
Ophthalmol 1992;110:827–832.
Bynoe LA, Chang TS, Funata M, et al. Histopathologic examination of vascular
patterns in subfoveal neovascular membranes. Ophthalmology
1994;101:1112–1117.

356
Cohen SY, Dubois L, Tadayoni R, et al. Prevalence of reticular pseudodrusen in
age-related macular degeneration with newly diagnosed choroidal
neovascularisation. Br J Ophthalmol 2007;91:354–359.
Curcio CA, Johnson M, Huang JD, et al. Aging, age-related macular
degeneration, and the response-to-retention of apolipoprotein B-containing
lipoproteins. Prog Retin Eye Res 2009;28:393–422.
Curcio CA, Millican CL. Basal linear deposit and large drusen are specific for
early age-related maculopathy. Arch Ophthalmol 1999;117:329–339.
Dastgheib K, Green WR. Granulomatous reaction to Bruch’s membrane in age-
related macular degeneration. Arch Ophthalmol 1994;112:813–818.
el Baba F, Jarrett WH, Harbin TS Jr, et al. Massive hemorrhage complicating age-
related macular degeneration. Clinicopathologic correlation and role of
anticoagulants. Ophthalmology 1986;93:1581–2592.
Gehrs KM, Anderson DH, Johnson LV, et al. Age-related macular degeneration
—emerging pathogenetic and therapeutic concepts. Ann Med
2006;38:450–471.
Gorin MB, Breitner JC, De Jong PT, et al. The genetics of age-related macular
degeneration. Mol Vis 1999;5:29.
Green WR. Clinicopathologic studies of treated choroidal neovascular
membranes. A review and report of two cases. Retina 1991;11:328–356.
Green WR, Enger C. Age-related macular degeneration histopathologic studies.
The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology
1993;100:1519–1535.
Green WR, McDonnell PJ, Yeo JH. Pathologic features of senile macular
degeneration. Ophthalmology 1985;92:615–627.
Grossniklaus HE, Green WR. Pathologic findings in pathologic myopia. Retina
1992;12:127–133.
Grossniklaus HE, Hutchinson AK, Capone A Jr, et al. Clinicopathologic features
of surgically excised choroidal neovascular membranes. Ophthalmology
1994;101:1099–1111.
Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the
complement regulatory gene factor H (HF1/CFH) predisposes individuals to
age-related macular degeneration. Proc Natl Acad Sci U S A
2005;102:7227–7232.
Hageman GS, Mullins RF. Molecular composition of drusen as related to
substructural phenotype. Mol Vis 1999;5:28.
Haimovici R, Gantz DL, Rumelt S, et al. The lipid composition of drusen,
Bruch’s membrane, and sclera by hot stage polarizing microscopy. Invest
Ophthalmol Vis Sci 2001;42:1592–1599.
Hanus J, Zhao F, Wang S. Current therapeutic developments in atrophic age-
related macular degeneration. Br J Ophthalmol 2016;100:122–127.
Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J
Med 2008;358:2606–2617.
Johnson LV, Anderson DH. Age-related macular degeneration and the

357
 extracellular matrix. N Engl J Med 2004;351:320–322.
Johnson LV, Leitner WP, Staples MK, et al. Complement activation and
inflammatory processes in Drusen formation and age related macular
degeneration. Exp Eye Res 2001;73:887–896.
Johnson LV, Ozaki S, Staples MK, et al. A potential role for immune complex
pathogenesis in drusen formation. Exp Eye Res 2000;70:441–449.
Johnson PT, Betts KE, Radeke MJ, et al. Individuals homozygous for the age-
related macular degeneration risk-conferring variant of complement factor H
have elevated levels of CRP in the choroid. Proc Natl Acad Sci U S A
2006;103:17456–17461.
Johnson PT, Lewis GP, Talaga KC, et al. Drusen-associated degeneration in the
retina. Invest Ophthalmol Vis Sci 2003;44:4481–4488.
Kenyon KR, Maumenee AE, Ryan SJ, et al. Diffuse drusen and associated
complications. Am J Ophthalmol 1985;100:119–128.
Khanifar AA, Koreishi AF, Izatt JA, et al. Drusen ultrastructure imaging with
spectral domain optical coherence tomography in age-related macular
degeneration. Ophthalmology 2008;115:1883–1890.
Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy.
Ophthalmology 1992;99:933–943.
Mullins RF, Russell SR, Anderson DH, et al. Drusen associated with aging and
age-related macular degeneration contain proteins common to extracellular
deposits associated with atherosclerosis, elastosis, amyloidosis, and dense
deposit disease. FASEB J 2000;14:835–846.
Rudolf M, Clark ME, Chimento M, et al. Prevalence and morphology of druse
types in the macula and periphery of eyes with age-related maculopathy.
Invest Ophthalmol Vis Sci 2008;49:1200–1209.
Rudolf M, Malek G, Messinger JD, et al. Sub-retinal drusenoid deposits in human
retina: organization and composition. Exp Eye Res 2008;87:402–408.
Russell SR, Mullins RF, Schneider BL, et al. Location, substructure, and
composition of basal laminar drusen compared with drusen associated with
aging and age-related macular degeneration. Am J Ophthalmol
2000;129:205–214.
Sarks S, Cherepanoff S, Killingsworth M, et al. Relationship of basal laminar
deposit and membranous debris to the clinical presentation of early age-
related macular degeneration. Invest Ophthalmol Vis Sci 2007;48:968–977.
Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the
retinal pigment epithelium. Eye 1988;2:552–577.
Sarks JP, Sarks SH, Killingsworth MC. Evolution of soft drusen in age-related
macular degeneration. Eye 1994;8:269–283.
Saxe SJ, Grossniklaus HE, Lopez PF, et al. Ultrastructural features of surgically
excised subretinal neovascular membranes in the ocular histoplasmosis
syndrome. Arch Ophthalmol 1993;111:88–95.
Schramm EC, Clark SJ, Triebwasser MP, et al. Genetic variants in the
complement system predisposing to age-related macular degeneration: a

358
 review. Mol Immunol 2014;61:118–125.
Spraul CW, Grossniklaus HE. Characteristics of Drusen and Bruch's membrane in
postmortem eyes with age-related macular degeneration. Arch Ophthalmol
1997;115:267–273.
Spraul CW, Lang GE, Grossniklaus HE. Morphometric analysis of the choroid,
Bruch’s membrane, and retinal pigment epithelium in eyes with age-related
macular degeneration [see comments]. Invest Ophthalmol Vis Sci
1996;37:2724–2735.
Wang L, Clark ME, Crossman DK, et al. Abundant lipid and protein components
of drusen. PLoS One 2010;5:e10329.
Zweifel SA, Imamura Y, Spaide TC, et al. Prevalence and significance of
subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular
degeneration. Ophthalmology 2010;117(9):1775–1781.
Zweifel SA, Spaide RF, Curcio CA, et al. Reticular pseudodrusen are subretinal
drusenoid deposits. Ophthalmology 2010;117: 303.e.1–312.e.1.

Toxic Maculopathies
Bernstein HN. Some iatrogenic ocular diseases from systemically administered
drugs. Int Ophthalmol Clin 1970;10:553–587.
Henkind P, Rothfield NF. Ocular abnormalities in patients treated with synthetic
antimalarial drugs. N Engl J Med 1963;269:433–439.
Ramsey MS, Fine BS. Chloroquine toxicity in the human eye: histopathologic
observations by electron microscopy. Am J Ophthalmol 1972;73:229–235.
Rosenthal AR, Kolb H, Bergsma D, et al. Chloroquine retinopathy in the rhesus
monkey. Invest Ophthalmol Vis Sci 1978;17:1158–1175.
Smith RS, Berson EL. Acute toxic effects of chloroquine on the cat retina:
ultrastructural changes. Invest Ophthalmol Vis Sci 1971;10:237–246.
Wetterholm DH, Winter FC. Histopathology of chloroquine retinal toxicity. Arch
Ophthalmol 1964;71:82–87.

Hereditary Maculopathies
Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding
transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.
Nat Genet 1997;15:236–246.
Armstrong JD, Meyer D, Xu S, et al. Long-term follow-up of Stargardt's disease
and fundus flavimaculatus. Ophthalmology 1998;105:448–457; discussion
457–448.
Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes
caused by mutations in the BEST1 gene. Prog Retin Eye Res
2009;28:187–205.
Boon CJ, Theelen T, Hoefsloot EH, et al. Clinical and molecular genetic analysis
of best vitelliform macular dystrophy. Retina 2009;29:835–847.

359
Chong NH, Alexander RA, Gin T, et al. TIMP-3, collagen, and elastin
immunohistochemistry and histopathology of Sorsby's fundus dystrophy.
Invest Ophthalmol Vis Sci 2000;41:898–902.
Cremers FP, van den Hurk JA, den Hollander AI. Molecular genetics of Leber
congenital amaurosis. Hum Mol Genet 2002;11:1169–1176.
Davidson AE, Millar ID, Urquhart JE, et al. Missense mutations in a retinal
pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J
Hum Genet 2009;85:581–592.
Demirci FY, Gupta N, Radak AL, et al. Histopathologic study of X-linked cone-
rod dystrophy (CORDX1) caused by a mutation in the RPGR exon ORF15.
Am J Ophthalmol 2005;139:386–388.
Eagle RC, Lucier AC, Bernardino VB, et al. Retinal pigment epithelial
abnormalities in fundus flavimaculatus: a light and electron microscopic
study. Ophthalmology 1980;87:1189–1200.
Frangieh GT, Green WR, Fine SL. A histopathologic study of Best’s macular
dystrophy. Arch Ophthalmol 1982;100:1115–1121.
Guziewicz KE, Zangerl B, Lindauer SJ, et al. Bestrophin gene mutations cause
canine multifocal retinopathy: a novel animal model for best disease. Invest
Ophthalmol Vis Sci 2007;48:1959–1967.
Haji Abdollahi S, Hirose T. Stargardt-Fundus flavimaculatus: recent
advancements and treatment. Semin Ophthalmol 2013;28:372–376.
Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis 2007;2:7.
Klevering BJ, Deutman AF, Maugeri A, et al. The spectrum of retinal phenotypes
caused by mutations in the ABCA4 gene. Graefes Arch Clin Exp Ophthalmol
2005;243:90–100.
Koenekoop RK. The gene for Stargardt disease, ABCA4, is a major retinal gene:
a mini-review. Ophthalmic Genet 2003;24:75–80.
Lois N, Halfyard AS, Bird AC, et al. Fundus autofluorescence in Stargardt
macular dystrophy-fundus flavimaculatus. Am J Ophthalmol 2004;138:55–63.
Lois N, Holder GE, Bunce C, et al. Phenotypic subtypes of Stargardt macular
dystrophy-fundus flavimaculatus. Arch Ophthalmol 2001;119:359–369.
Lopez PF, Maumenee IH, de la Cruz Z, et al. Autosomal-dominant fundus
flavimaculatus. Clinicopathologic correlation. Ophthalmology
1990;97:798–809.
Moradi P, Moore AT. Molecular genetics of infantile-onset retinal dystrophies.
Eye (Lond) 2007;21(10):1344–1351.
Nichols BE, Drack AV, Vandenburgh K, et al. A 2 base pair deletion in the RDS
gene associated with butterfly-shaped pigment dystrophy of the fovea. Hum
Mol Genet 1993;2:601–603.
O’Gorman S, Flaherty WA, Fishman GA, et al. Histopathologic findings in Best's
vitelliform macular dystrophy. Arch Ophthalmol 1988;106:1261–1268.
Pasquay C, Wang LF, Lorenz B, et al. Bestrophin 1--Phenotypes and Functional
Aspects in Bestrophinopathies. Ophthalmic Genet 2015;36:193–212.
Querques G, Regenbogen M, Quijano C, et al. High-definition optical coherence

360
 tomography features in vitelliform macular dystrophy. Am J Ophthalmol
2008;146:501–507.
Ronquillo CC, Bernstein PS, Baehr W. Senior-Loken syndrome: a syndromic
form of retinal dystrophy associated with nephronophthisis. Vision Res
2012;75:88–97.
Spaide RF, Noble K, Morgan A, et al. Vitelliform macular dystrophy.
Ophthalmology. 2006;113(8):1392–1400.
Weber BH. Recent advances in the molecular genetics of hereditary retinal
dystrophies with primary involvement of the macula. Acta Anat (Basel)
1998;162:65–74.
Weingeist TA, Kobrin JL, Watzke RC. Histopathology of Best's macular
dystrophy. Arch Ophthalmol 1982;100:1108–1114.
Zhang K, Nguyen TH, Crandall A, et al. Genetic and molecular studies of
macular dystrophies: recent developments. Surv Ophthalmol 1995;40:51–61.

Gyrate Atrophy
Kaiser-Kupfer MI, Valle D, Del Valle LA. A specific enzyme defect in gyrate
atrophy. Am J Ophthalmol 1978;85:200–204.
Kuwabara T, Ishikawa Y, Kaiser-Kupfer MI. Experimental model of gyrate
atrophy in animals. Ophthalmology 1981;88:331–334.
Wilson DJ, Weleber RG, Green WR. Ocular clinicopathologic study of gyrate
atrophy. Am J Ophthalmol 1991;111:24–33.

Retinitis Pigmentosa
Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis
pigmentosa. Clin Genet 2013;84:132–141.
Drack AV, Traboulsi EI. Systemic associations of pigmentary retinopathy. Int
Ophthalmol Clin 1991;31:35–59.
Dryja TP. Doyne Lecture. Rhodopsin and autosomal dominant retinitis
pigmentosa. Eye 1992;6:1–10.
Dryja TP. Gene-based approach to human gene-phenotype correlations. Proc Natl
Acad Sci U S A 1997;94:12117–12121.
Dryja TP, Hahn LB, Kajiwara K, et al. Dominant and digenic mutations in the
peripherin/RDS and ROM1 genes in retinitis pigmentosa. Invest Ophthalmol
Vis Sci 1997;38:1972–1982.
Dryja TP, Li T. Molecular genetics of retinitis pigmentosa. Hum Mol Genet
1995;4:1739–1743.
Dryja TP, McGee TL, Hahn LB, et al. Mutations within the rhodopsin gene in
patients with autosomal dominant retinitis pigmentosa. N Engl J Med
1990;323:1302–1307.
Fingert JH, Oh K, Chung M, et al. Association of a novel mutation in the retinol
dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis

361
 pigmentosa. Arch Ophthalmol 2008;126:1301–1307.
Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet
2006;368:1795–1809.
Huang SH, Pittler SJ, Huang X, et al. Autosomal recessive retinitis pigmentosa
caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nat
Genet 1995;11:468–471.
Li ZY, Possin DE, Milam AH. Histopathology of bone spicule pigmentation in
retinitis pigmentosa. Ophthalmology 1995;102:805–816.
Luckenbach MW, Green WR, Miller NR, et al. Ocular clinicopathologic
correlation of Hallervorden-Spatz syndrome with acanthocytosis and
pigmentary retinopathy. Am J Ophthalmol 1983;95:369–382
Milam AH, Li ZY, Fariss RN. Histopathology of the human retina in retinitis
pigmentosa. Prog Retin Eye Res 1998;17(2):175–205.
Rivolta C, Sharon D, DeAngelis MM, et al. Retinitis pigmentosa and allied
diseases: numerous diseases, genes, and inheritance patterns. Hum Mol Genet
2002;11(10):1219–1227.
Sahel JA, Marazova K, Audo I. Clinical characteristics and current therapies for
inherited retinal degenerations. Cold Spring Harb Perspect Med
2014;5:a017111.
Sandberg MA, Weigel-DiFranco C, Dryja TP, et al. Clinical expression correlates
with location of rhodopsin mutation in dominant retinitis pigmentosa. Invest
Ophthalmol Vis Sci 1995;36:1934–1942.
Sippel KC, DeStefano JD, Berson EL, et al. Evaluation of the human arrestin
gene in patients with retinitis pigmentosa and stationary night blindness.
Invest Ophthalmol Vis Sci 1998;39:665–670.
Triolo G, Pierro L, Parodi MB, et al. Spectral domain optical coherence
tomography findings in patients with retinitis pigmentosa. Ophthalmic Res
2013;50(3):160–164.
van Soest S, Westerveld A, de Jong PT, et al. Retinitis pigmentosa: defined from
a molecular point of view. Surv Ophthalmol 1999;43:321–334.
Witkin AI, Ko TH, Fujimoto JG, et al. Ultra-high resolution optical coherence
tomography assessment of photoreceptors in retinitis pigmentosa and related
diseases. Am J Ophthalmol 2006;142:945–952.

Choroideremia
Cameron JD, Fine BS, Shapiro I. Histopathologic observations in choroideremia
with emphasis on vascular changes of the uveal tract. Ophthalmology
1987;94:187–196.
MacDonald IM, Chen MH, Addison DJ, et al. Histopathology of the retinal
pigment epithelium of a female carrier of choroideremia. Can J Ophthalmol
1997;32:329–333.
Rodrigues MM, Ballintine EJ, Wiggert BN, et al. Choroideremia: a clinical,
electron microscopic, and biochemical report. Ophthalmology

362
 1984;91:873–883.
Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia:
deficiency of rab geranylgeranyl transferase. Science 1993;259:377–381.

Other Heritable Retinal Disorders

Bensaoula T, Shibuya H, Katz ML, et al. Histopathologic and
immunocytochemical analysis of the retina and ocular tissues in Batten
disease. Ophthalmology 2000;107:1746–1753.
Bergsma DR Jr, Chen CJ. The Mizuo phenomenon in Oguchi disease. Arch
Ophthalmol 1997;115:560–561.
Carrero-Valenzuela RD, Klein ML, Weleber RG, et al. Sorsby fundus dystrophy.
A family with the Ser181Cys mutation of the tissue inhibitor of
metalloproteinases 3. Arch Ophthalmol 1996;114:737–738.
Dryja TP. Molecular genetics of Oguchi disease, fundus albipunctatus, and other
forms of stationary night blindness: LVII Edward Jackson Memorial Lecture.
Am J Ophthalmol 2000;130:547–563.
Edwards AO. Clinical features of the congenital vitreoretinopathies. Eye (Lond)
2008;22:1233–1242.
Fishman GA, Roberts MF, Derlacki DJ, et al. Novel mutations in the cellular
retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata
albescens: evidence of interfamilial genetic heterogeneity and fundus changes
in heterozygotes. Arch Ophthalmol 2004;122:70–75.
Jacobson SG, Aleman TS, Cideciyan AV, et al. Identifying photoreceptors in
blind eyes caused by RPE65 mutations: prerequisite for human gene therapy
success. Proc Natl Acad Sci U S A 2005;102:6177–6182.
Jacobson SG, Cideciyan AV, Aleman TS, et al. Leber congenital amaurosis
caused by an RPGRIP1 mutation shows treatment potential. Ophthalmology
2007;114:895–898.
Nakazawa M, Wada Y, Fuchs S, et al. Oguchi disease: phenotypic characteristics
of patients with the frequent 1147delA mutation in the arrestin gene. Retina
1997;17:17–22.
Shastry BS, Hejtmancik JF, Trese MT. Identification of novel missense mutations
in the Norrie disease gene associated with one X-linked and four sporadic
cases of familial exudative vitreoretinopathy. Hum Mutat 1997;9:396–401.
Sieving PA, Boskovich S, Bingham E, et al. Sorsby’s fundus dystrophy in a
family with a Ser-181-CVS mutation in the TIMP-3 gene: poor outcome after
laser photocoagulation. Trans Am Ophthalmol Soc 1996;94:275–294.
Wong F, Goldberg MF, Hao Y. Identification of a nonsense mutation at Codon
128 of the Norrie’s disease gene in a male infant. Arch Ophthalmol
1993;111:1553–1557.

Peripheral Retinal Degenerations

363
Foos RY. Senile retinoschisis: relationship to cystoid degeneration. Trans Am
Acad Ophthalmol Otolaryngol 1970;74:33–51.
Foos RY, Feman SS. Reticular cystoid degeneration of the peripheral retina. Am J
Ophthalmol 1970;69:392–403.
O’Malley PF, Allen RA. Peripheral cystoid degeneration of the retina: Incidence
and distribution in 1,000 autopsy eyes. Arch Ophthalmol 1967;77:769–776.
O’Malley PF, Allen RA, Straatsma BR, et al. Pavingstone degeneration of the
retina. Arch Ophthalmol 1965;73:169–182.
Straatsma BR, Foos RY. Typical and reticular degenerative retinoschisis. XXVI
Francis I. Proctor memorial lecture. Am J Ophthalmol 1973;75:551–575.
Zimmerman LE, Spencer WH. The pathologic anatomy of retinoschisis: with a
report of two cases diagnosed clinically as malignant melanoma. Arch
Ophthalmol 1960;63:10–19.

Juvenile Retinoschisis
Condon GP, Brownstein S, Wang NS, et al. Congenital hereditary (juvenile X-
linked) retinoschisis. Histopathologic and ultrastructural findings in three
eyes. Arch Ophthalmol 1986;104:576–583.
Harris GS, Yeung J. Maculopathy of sex-linked juvenile retinoschisis. Can J
Ophthalmol 1976;11:1–10.
Manschot WA. Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol
1972;88:131–138.
Yanoff M, Kertesz Rahn E, Zimmerman LE. Histopathology of juvenile
retinoschisis. Arch Ophthalmol 1968;79:49–53.

Lattice Degeneration
Straatsma BR, Allen RA. Lattice degeneration of the retina. Trans Am Acad
Ophthalmol Otolaryngol 1962;66:600–613.
Straatsma BR, Zeegan PD, Foos RY, et al. Lattice degeneration of the retina.
Trans Am Acad Ophthalmol Otolaryngol 1974;78:87–113.
Streeten BW, Bert M. The retina surface in lattice degeneration of the retina. Am J
Ophthalmol 1972;74:1201–1209.

Pars Plana Cysts

Baker T, Spencer W. Ocular findings in multiple myeloma. Arch Ophthalmol
1974;91:110–113.
Gärtner J. Fine structure of pars plana cysts. Am J Ophthalmol 1972;73:971–984.
Johnson B. Proteinaceous cysts of the ciliary epithelium. II. Their occurrence in
nonmyelomatous hypergammaglobulinemic conditions. Arch Ophthalmol
1970;84:171–175.
Johnson B, Storey J. Proteinaceous cysts of the ciliary epithelium. I. Their clear
nature and immunoelectrophoretic analysis in a case of multiple myeloma.

364
 Arch Ophthalmol 1970;84:166–170.
Zimmerman L, Fine B. Production of hyaluronic acid by cysts and tumors of the
ciliary body. Arch Ophthalmol 1964;72:365–379.

Diabetic Retinopathy
Aiello LP. Vascular endothelial growth factor. 20th-century mechanisms, 21st-
century therapies. Invest Ophthalmol Vis Sci 1997;38:1647–1652.
Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in
ocular fluid of patients with diabetic retinopathy and other retinal disorders. N
Engl J Med 1994;331:1480–1487.
Cogan DG, Toussaint D, Kuwabara T. Retinal vascular patterns: IV. Diabetic
retinopathy. Arch Ophthalmol 1961;66:366–378.
D’Amore PA. Mechanisms of retinal and choroidal neovascularization. Invest
Ophthalmol Vis Sci 1994;35:3974–3979.
DCCT Research Group. The effect of intensive treatment of diabetes in the
development and progression of long-term complications in insulin-dependent
diabetes. N Engl J Med 1993;329:977–986.
Engerman RL, Kern TS. Experimental galactosemia produces diabetic-like
retinopathy. Diabetes 1984;33:97–100.
Fine BS, Berkow JW, Helfgott JA. Diabetic lacy vacuolization of the iris pigment
epithelium. Am J Ophthalmol 1970;69:197–200.
Gabbay KH. The sorbitol pathway and the complications of diabetes mellitus. N
Engl J Med 1973;288:831–836.
Jampol LM, Ebroon DA, Goldbaum MH. Peripheral proliferative retinopathies:
an update on angiogenesis, etiologies and management. Surv Ophthalmol
1994;38:519–540.
Kador PF, Akagi Y, Takahashi Y, et al. Prevention of retinal vessel changes
associated with diabetic retinopathy in galactose-fed dogs by aldose reductase
inhibitors. Arch Ophthalmol 1990;108:1301–1309.
Klein R, Klein BEK, Moss SE, et al. The Wisconsin epidemiologic study of
diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age
of diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527–532.
Kuwabara T, Cogan DG. Studies of retinal vascular patterns: I. Normal
architecture. Arch Ophthalmol 1960;64:904–911.
Yanoff M, Fine BS, Berkow JW. Diabetic lacy vacuolization of iris pigment
epithelium. Am J Ophthalmol 1970;69:201–210.
Yanoff M. Diabetic retinopathy. N Engl J Med 1966;274:1344–1349.

Sickle Retinopathy
Eagle RC Jr, Yanoff M, Fine BS. Hemoglobin SC retinopathy and fat emboli to
the eye: a light and electron microscopical study. Arch Ophthalmol
1974;92:28–32.

365
Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy.
Am J Ophthalmol 1971;71:649–665.
Romayananda N, Goldberg MF, Green WR. Histopathology of sickle cell
retinopathy. Trans Am Acad Ophthalmol Otolaryngol 1973;77:652–676.

Macular Holes
Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction
Study Group classification of vitreomacular adhesion, traction, and macular
hole. Ophthalmology 2013;120:2611–2619.
Frangieh GT, Green WR, Engel HM. A histopathologic study of macular cysts
and holes. Retina 1981;1:311–336.
Gass JD. Idiopathic senile macular hole. Its early stages and pathogenesis. Arch
Ophthalmol 1988;106:629–639.
Gass JD. Reappraisal of biomicroscopic classification of stages of development of
a macular hole. Am J Ophthalmol 1995;119:752–759.
Yooh HS, Brooks HL Jr, Capone A Jr, et al. Ultrastructural features of tissue
removed during idiopathic macular hole. Am J Ophthalmol 1996;122:67–75.

Retinal Detachment and Proliferative

Vitreoretinopathy
Aaberg TM. Management of anterior and posterior proliferative vitreoretinopathy.
XLV. Edward Jackson memorial lecture. Am J Ophthalmol
1988;106:519–532.
Elner SG, Elner VM, Diaz-Rohena R, et al. Anterior proliferative
vitreoretinopathy. Clinicopathologic, light microscopic, and ultrastructural
findings. Ophthalmology 1988;95:1349–1357.
Elner SG, Elner VM, Freeman HM, et al. The pathology of anterior (peripheral)
proliferative vitreoretinopathy. Trans Am Ophthalmol Soc 1988;86:330–353.
Lean JS, Stern WH, Irvine AR, et al. Classification of proliferative
vitreoretinopathy used in the silicone study. The Silicone Study Group.
Ophthalmology 1989;96:765–771.
Lewis H, Aaberg TM, Abrams GW, et al. Subretinal membranes in proliferative
vitreoretinopathy. Ophthalmology 1989;96:1403–1414.
Lewis H, Burke JM, Abrams GW, et al. Perisilicone proliferation after vitrectomy
for proliferative vitreoretinopathy. Ophthalmology 1988;95:583–591.
Lopez PF, Grossniklaus HE, Aaberg TM, et al. Pathogenetic mechanisms in
anterior proliferative vitreoretinopathy. Am J Ophthalmol 1992;114:257–279.
Machemer R. Proliferative vitreoretinopathy (PVR): a personal account of its
pathogenesis and treatment. Proctor lecture. Invest Ophthalmol Vis Sci
1988;29:1771–1783.
Machemer R, Aaberg TM, Freeman HM, et al. An updated classification of
retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol

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 1991;112:159–165.
Mazure A, Grierson I. In vitro studies of the contractility of cell types involved in
proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci
1992;33:3407–3416.
Schwartz D, de la Cruz ZC, Green WR, et al. Proliferative vitreoretinopathy.
Ultrastructural study of 20 retroretinal membranes removed by vitreous
surgery. Retina 1988;8:275–281.
Wiedemann P, Weller M. The pathophysiology of proliferative vitreoretinopathy.
Acta Ophthalmol Suppl 1988;189:3–15.
Wilkes SR, Mansour AM, Green WR. Proliferative vitreoretinopathy.
Histopathology of retroretinal membranes. Retina 1987;7: 94–101.

Retinal Imaging
Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina
by optical coherence tomography: literature review and model. Retina
2011;31:1609–1619.
Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by
fluorescein angiography and optical coherence tomography angiography.
JAMA Ophthalmol 2015;133:45–50.
Staurenghi G, Sadda S, Chakravarthy U, et al.; International Nomenclature for
Optical Coherence Tomography (IN-OCT) Panel. Proposed lexicon for
anatomic landmarks in normal posterior segment spectral-domain optical
coherence tomography: the IN-OCT consensus. Ophthalmology
2014;121:1572–1578.

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 10 Vitreous
The transparent gelatinous vitreous humor fills most of the interior of the
eye. The most delicate connective tissue in the body, the vitreous humor is
composed of a framework of thin, randomly oriented, unbranched fibrils of
type II collagen and is rich in hyaluronic acid, an extremely large,
negatively charged, hydrophilic polysaccharide. Hyaluronic acid is named
after the hyaloid body, an older term for the vitreous humor. (Both hyaloid
and vitreous mean glassy.)
The collagenous framework of the vitreous humor adheres to the
internal limiting membrane (ILM) of the retina, the periphery of the optic
disc and most firmly to the 2-mm wide vitreous base that straddles the ora
serrata. The anterior attachment of the vitreous is particularly firm.
Relatively severe trauma that typically disrupts the ciliary epithelium is
required to detach or avulse the vitreous from the vitreous base. In
contrast, the posterior attachments of the vitreous are tenuous. Posterior
vitreous detachment affects many individuals after age 55 years and is
found in more than 60% of the population in the eighth decade (Fig. 10-
1A). Patients usually complain of the abrupt onset of floaters and
occasionally light flashes that signify vitreoretinal traction. The
peripapillary condensation of the vitreous framework may be evident
clinically or macroscopically after detachment as a Weiss ring (Fig. 10-
1B).

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 FIG. 10-1. Posterior vitreous detachment. A. Mild opacification by protein
accentuates the vitreous. The vitreous framework has detached from the inner
retina posteriorly. It remains attached to the anterior vitreous base, which
straddles the ora serrata. The attachment there is very strong. The anterior
chamber is flat and part of the retina is shallowly detached by gelatinous exudate
rich in lipid. B. Weiss ring, posterior vitreous detachment. The white ring
represents the peripapillary condensation of the vitreous framework, which has
separated from the optic disc during a posterior vitreous detachment.

The vitreous humor contributes to visual loss in two basic ways. First, the
vitreous framework serves as a growth scaffold for cellular proliferation,
and resultant vitreoretinal traction plays an important role in the
pathogenesis of many retinal detachments. Secondly, under pathologic
conditions, the transparent medium may be opacified by the accumulation
of a variety of materials including blood, acute or chronic inflammatory
cells, tumor cells, iridescent particles, and amyloid.
Vitreoretinal adhesions and traction cause retinal holes or breaks that
predispose to rhegmatogenous retinal detachment. New blood vessels,
cells, and fibrous tissue also proliferate on exposed surfaces of the vitreous
framework. Tractional retinal detachment is caused by subsequent
organization and contraction of the vitreous. The organization of vitreous
hemorrhage or inflammation also stimulates vitreous traction.
Detachment of the vitreous and retina exposes new surfaces that can
serve as a substrate for cellular growth. The contraction of delicate glial
membranes on the inner retinal surface (epiretinal gliosis) causes sinuous
folds in the ILM (surface wrinkling or cellophane retinopathy) that distort
vision (Fig. 10-2A). Proliferation of myofibroblasts, retinal pigment
epithelial (RPE) cells, and glial cells forms fibrocellular membranes on
retinal surfaces exposed by retinal detachment. These membranes can bind
the detached retina into a folded mass that may be impossible to reattach
surgically. Analogous cellular proliferation also can occur on the detached
posterior face of the vitreous inducing fibrosis. Somewhat analogous to “in
vivo tissue culture,” this process is called proliferative vitreoretinopathy
(PVR) or massive periretinal proliferation (MPP). PVR is an important
cause of inoperable retinal detachment or recurrent detachment after
reattachment surgery (Fig. 10-3).

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FIG. 10-2. Epiretinal gliosis (surface wrinkling retinopathy). A. Arrow denotes
delicate membrane of glial cells on inner retinal surface after posterior vitreous
detachment. Contraction of the membrane has caused folds in the ILM. B.
Scanning electron microscopy (SEM) shows folds in ILM. Glial membrane has
partially detached. C. Vitreoretinal membrane in vitrectomy specimen. Presumed
glial cells form a subconfluent membrane on the surface of a condensed sheet of
vitreous. The cells have bland spindled nuclei. The indication for vitrectomy was
macular pucker. (A. H&E ×100, B. SEM ×640, C. Millipore filter preparation,
H&E ×50.)

FIG. 10-3. Anterior variant of proliferative vitreoretinopathy (PVR). A. Chronic

retinal detachment with macrocysts persists after vitrectomy surgery. PVR
membrane extends anterior from inner retinal surface to cover the ciliary body
and iris. Traction draws iris posteriorly. B. Fibrosis of residual vitreous overlying
ciliary body exerts traction on the retina and produces anterior loop retinal
detachment. Iris is drawn posteriorly. (B. H&E ×10.)

Blood is the substance that opacifies the vitreous most frequently.

Common sources of vitreous hemorrhage include trauma, proliferative
diabetic retinopathy, and other disorders with vitreoretinal
neovascularization, tractional retinal tears, and posterior vitreous
detachment. Rarer causes include intraocular tumors, exudative age-related
maculopathy, and subarachnoid hemorrhage (Terson syndrome).

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 Persistent vitreous hemorrhage is a major indication for vitreous
surgery. Blood and other opacities in the vitreous are removed using a
surgical procedure called vitrectomy that employs miniaturized cutting and
aspiration instruments, intraocular illuminators, and laser
photocoagulators, which are inserted through small incisions in the pars
plana. The excised vitreous is replaced with saline, which is introduced
through an infusion port. In some instances, silicone oil is instilled to
tamponade the retina.
Vitrectomy specimens can be processed using a variety of cytological
techniques including cytocentrifugation, liquid-based monolayer cytology,
or Millipore filtration. If particulates are numerous, the fluid can be
centrifuged and the pellet embedded in paraffin as a cell block for
histology. The latter is particularly helpful if evaluation of the specimen
requires immunohistochemistry or special stains for microorganisms.
Microscopic examination of vitrectomy specimens from patients with
chronic vitreous hemorrhage discloses blood and blood-breakdown
products including erythroclasts or erythrocyte ghost cells, hemoglobin
spherules and macrophages laden with ghost cells, and golden-brown
granules of the blood pigment hemosiderin (Fig. 10-4). In very chronic
cases, the blood-breakdown products occasionally stimulate a
granulomatous inflammatory foreign body response. Hemoglobin
spherules may be quite large if the vitreous blood originates from the
choroid. Clinically and macroscopically, chronic vitreous hemorrhage
typically is yellow-ochre in color and may appear as an “ochre membrane”
(Fig. 4-1C). If the anterior face of the vitreous is ruptured, ghost cells and
hemosiderin-laden macrophages may enter the anterior chamber and block
the trabecular meshwork causing secondary open-angle glaucoma (ghost
cell or hemolytic glaucoma).

FIG. 10-4. Chronic vitreous hemorrhage. A. Numerous erythrocyte ghost cells or

erythroclasts are seen below. Ghost cells are the empty cell membranes of

371
 erythrocytes that have lost their hemoglobin-rich cytoplasm. The eosinophilic
bodies above are hemoglobin spherules. Macrophages that have ingested ghost
cells and other blood-breakdown products also are present. B. Hemosiderin-laden
macrophages, chronic vitreous hemorrhage. The yellow-brown pigment in the
macrophages is the blood-breakdown product hemosiderin. C. The pigment in
some of macrophages in this chronic vitreous hemorrhage stains positively (blue)
for iron. Many large hemoglobin spherules are present. (A. H&E ×250, B. H&E
×250, C. Perl stain for iron, ×250.)

The vitreous is rapidly opacified by an intense influx of

polymorphonuclear leukocytes and macrophages in acute purulent
endophthalmitis (Figs. 3-12 and 3-14). A vitreous abscess composed of
polys forms in neglected cases or virulent infections. Some of the
inflammatory cells in a vitreous abscess may be arranged in a linear
fashion, reflecting the alignment of the cells along the fibrils of the
vitreous’ collagenous framework. A large solitary vitreous abscess
characterizes bacterial endophthalmitis. Fungal endophthalmitis, which
generally is a more indolent infection, typically is marked by the presence
of multiple smaller vitreous microabscesses (Fig. 3-13). Digestive
enzymes released from degenerating polys in a vitreous abscess often
cause extensive necrosis of intraocular tissues including retinal
destruction. Vitrectomy is used to surgically “drain” the vitreous abscess
in some patients with endophthalmitis. If vitrectomy is not performed, the
vitreous abscess may be organized by an ingrowth of granulation tissue
from the ciliary body and choroid. Eventually, a dense collagenous scar
elaborated by fibroblasts and metaplastic RPE cells fills the vitreous
cavity.
Remnants of the embryonic hyaloid vascular system are seen by
patients as innocuous vitreous opacities called floaters or muscae
volitantes (“flying flies”). Patients frequently complain that they see a spot
like a moving insect in their peripheral visual field that darts away when
they move their eyes. Floaters are especially prevalent in myopes and are
caused by syneresis or degeneration of the vitreous framework in the
enlarging myopic eye. When light flashes accompany floaters, vitreoretinal
traction is present and retinal holes must be excluded by a careful and
expedient ophthalmoscopic examination.
Iridescent particles accumulate in the vitreous humor in two disorders:
asteroid hyalosis (AH) and synchysis scintillans. AH (Benson disease,
scintillatio nivea) is relatively common, occurring in about 0.8% to 2.0%
of the adult population (Fig. 10-5). Asteroid hyalosis was once called

372
asteroid hyalitis, but the name was changed when it became apparent that
the disorder is degenerative and not inflammatory in nature. Ironically,
histopathologic examination occasionally discloses asteroid bodies
enveloped by foreign body giant cells.

FIG. 10-5. Asteroid hyalosis. A. Numerous calcified spherules impart a starry

sky appearance to posteriorly detached vitreous. The AH was an incidental
finding in an eye enucleated for uveal melanoma. B. Asteroid bodies appear as
grayish blue spherules in routine H&E sections. They are attached to the vitreous
framework. C. Intact asteroid bodies in vitrectomy specimen show characteristic
Maltese cross pattern of birefringence during polarization microscopy. D. SEM
shows attachment of asteroid bodies to vitreous fibrils. (A. H&E ×250, B.
Millipore filter preparation, H&E with crossed polarizers ×250, D. SEM ×640.)

Clinical examination with the slit-lamp biomicroscope or ophthalmoscope

discloses a starry array of white iridescent particles in the vitreous (Fig.
10-5A). The asteroid bodies are firmly attached to the vitreous framework;
they move with the vitreous and do not sink to the bottom of the eye (Fig.
10-5D). The iridescent particles are tiny spherules of calcium
hydroxyapatite and are not calcium soap as was previously reported. The
spherules stain gray with H&E, are moderately PAS positive, and show a
positive histochemical reaction for calcium (Fig. 10-5C). They typically
display a vivid “Maltese cross” pattern of birefringence on polarization

373
microscopy (Fig. 10-5C). How and why the spherules form is uncertain. A
large autopsy cohort study of AH and its systemic associations found no
statistically significant correlation between AH and diabetes mellitus or
other systemic diseases. AH was strongly correlated with age and
inversely correlated with posterior vitreous detachment.
Synchysis scintillans is an exceedingly rare disorder marked by the
accumulation of sparkling crystals of cholesterol in the vitreous (Fig. 10-
6). Synchysis scintillans is said to occur bilaterally in young patients, who
are blind from a chronic degenerative disorder. Although intraocular
cholesterol (cholesterolosis bulbi) is not that uncommon, involvement of
the vitreous is quite unusual. Cholesterol crystals typically are found in the
subretinal fluid of chronic exudative detachments caused by retinal
vascular abnormalities (e.g., Coats disease, diabetes, or radiation
retinopathy) or less often in the anterior chamber. Blood breakdown is a
major source of intraocular cholesterol. Erythrocyte cell membranes are an
excellent source of the lipid. The cholesterol crystals in synchysis
scintillans are not attached to the vitreous framework, and they sink to a
dependent position when the eye is at rest.

FIG. 10-6. Synchysis scintillans. Vitreous in blind aphakic eye contains blood
and glistening polychromatic crystals of cholesterol.

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The first therapeutic vitrectomy was performed for vitreous amyloidosis
(Fig. 10-7). This rare form of vitreous opacification occurs in patients who
have several types of transthyretin-related hereditary amyloidosis (familial
amyloidotic polyneuropathy) caused by autosomal recessively inherited
allelic missense mutations in the TTR gene (18q12.1) encoding
transthyretin, a plasma transport protein for thyroxine and retinol (vitamin
A). Many patients who present with vitreous involvement are elderly
women who have the Portuguese or Andrade variant of hereditary
amyloidosis caused by substitution of methionine for valine at codon 30.
The family history is typically negative, and vitreous amyloidosis is often
the initial manifestation of the disease. Vitreous involvement has an earlier
onset in the more severe Indiana variant of hereditary amyloidosis.

FIG. 10-7. Vitreous amyloidosis. A. Amyloid composed of mutant transport

protein transthyretin opacifies the vitreous in eye obtained postmortem from a
patient with the Indiana (SER 84) type of hereditary amyloidosis. A vitrectomy
has been performed previously. B. Amyloid in detached vitreous shows apple
green birefringence during polarization microscopy. Amyloid also lines the inner
retinal surface. (A. Specimen submitted by Dr. Merrill Benson, Indianapolis,
Indiana, B. Congo red with crossed polarizers ×25.)

PRIMARY INTRAOCULAR
LYMPHOMA
Tumor cells can infiltrate or seed the vitreous humor. Primary intraocular
lymphoma (PIO) characteristically involves the vitreous and presents with
vitreous floaters or visual loss due to vitreous cells. This rare subtype of
primary CNS lymphoma should be suspected in elderly patients who have
chronic vitritis that does not respond to therapy. Although most cases
affect elderly patients, the disease also occurs in younger individuals who
are immunosuppressed. Vitreous lymphoma is bilateral in 60% to 90% of

375
cases but may be quite asymmetric or seemingly unilateral at onset.
Approximately 80% of patients with primary vitreous lymphoma develop
CNS lymphoma and most die from CNS disease. Hence, imaging studies
and spinal fluid examination are mandatory to exclude CNS involvement.
The eye is involved before the CNS in 50% to 80% of cases. Many CNS
lesions occur in the frontal lobe and cause behavior changes or dementia.
Most cases of vitreous lymphoma are high-grade, aggressive B-cell non-
Hodgkin lymphomas (NHL) that have a poor prognosis. These are
subtyped as diffuse large B-cell lymphomas and probably are derived from
early postgerminal center B cells.
In addition to the vitreous, the lymphoma cells infiltrate the retina and
typically collect between Bruch membrane and the retinal pigment
epithelium, forming solid yellowish RPE detachments. Cytologic
examination of diagnostic vitrectomy specimens typically reveals a highly
cellular and extensively necrotic infiltrate that contains atypical
lymphocytes with prominent nucleoli and protrusions of the nuclear
membrane, as well as cells that are totally necrotic or undergoing apoptosis
(Fig. 10-8). Immunophenotypic analysis by flow cytometry or
immunohistochemistry can help to confirm the diagnosis when cytologic
findings are subtle. ELISA assays of interleukin (IL) levels in ocular fluids
also can support the diagnosis. Malignant B cells often express high levels
of IL-10 compared to inflammatory cells that produce higher levels of IL-
6. A ratio of IL-10 to IL-6 >1.0 suggests that a patient has a B-cell
lymphoma.

FIG. 10-8. Primary vitreous lymphoma. A. Infiltrate obtained during diagnostic

vitrectomy contains large atypical lymphocytes, necrotic lymphoid cells, and
nuclear debris. B. Large lymphoma cells have prominent nucleoli and folds and
protrusions of nuclear membrane. C. Positive immunoreactivity of cells for CD20
confirms B-cell lineage of lymphoma cells. D. Patients with vitreous lymphoma
may have large keratic precipitates. (A. Millipore filter, H&E ×250, B. H&E

376
×400, C. IHC for CD20 ×100.)

The vitreous usually is spared when the eye is involved secondarily by

disseminated, non-CNS, visceral lymphoma. Such systemic lymphomas
usually involve the uvea. Many patients who undergo diagnostic
vitrectomy to exclude primary vireous lymphoma actually are found to
have a form of granulomatous vitritis termed idiopathic senile vitritis.
Cytologically, the latter lacks necrosis and contains a mixture of small
well-differentiated lymphocytes and epithelioid histiocytes that have a
spindled or dendritiform configuration where they adhere to the vitreous
framework. Careful cytologic screening and follow-up are warranted in
such cases, however, because vitreous lymphoma occasionally presents
with chronic inflammation.
Involvement of the vitreous by tumor cells also occurs in eyes with
retinoblastoma (Fig. 10-9A–C). Vitreous seeding typically develops in
eyes with tumors that have an endophytic or diffuse infiltrative growth
pattern. Vitreous seeding is a major factor in the failure of eye-sparing
therapy. In recent years, eyes with intravitreal seeds of retinoblastoma
destined for enucleation have been salvaged with intravitreal injections of
melphalan. Vitreous metastasis is a characteristic feature of metastatic
cutaneous melanoma to the eye (Fig. 10-9D,E). Only the vitreous is
involved in many cases, which lack choroidal metastases. The metastatic
cutaneous melanoma may be pigmented or amelanotic.

FIG. 10-9. Vitreous involvement by tumor cells. A. Retinoblastoma, vitreous

seeds. The white spheres in the anterior vitreous are seeds of retinoblastoma shed
by an endophytic tumor in the posterior segment. B. Some seeds have a white
center reflecting central necrosis. C. Histopathology of seed shows central focus
of necrotic cells enveloped by viable retinoblastoma. D. Vitreous involvement by
metastatic cutaneous melanoma. Sheets and nodules of pigment infiltrate
vitreous. E. Posterior vitreous contains aggregates of melanoma cells. (C. H&E
×100, E. H&E ×100.)

377
Uveitis and vitritis occur rarely in patients with Whipple disease, who may
also have CNS signs. PAS-positive macrophages filled with bacterial cell
walls and degenerating Tropheryma whippelii bacteria comprise the retinal
and vitreal infiltrate in Whipple disease (Fig. 10-10).

FIG. 10-10. Whipple disease. PAS-positive macrophages that have phagocytized

Tropheryma whippelii bacteria infiltrate the inner retina and cortical vitreous.
(Courtesy of Dr. Ramon L. Font, Houston, TX.) (PAS ×250.)

Bibliography
Brucker AJ, Michels RG, Green WR. Pars plana vitrectomy in the management of
blood-induced glaucoma with vitreous hemorrhage. Ann Ophthalmol
1978;10:1427–1437.
Chess J, Sebag J, Tolentino FI, et al. Pathologic processing of vitrectomy
specimens: a comparison of findings with celloidin bag and cytocentrifugation
of 102 vitrectomy specimens. Ophthalmology 1983;90:1560–1564.
Eagle RC Jr. Specimen handling in the ophthalmic pathology laboratory. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.
Ophthalmol Clin North America 1995;8:1–15.
Eagle RC Jr. The pathology of vitrectomy specimens. In: Cohen EJ, ed. The Year
Book of Ophthalmology. St. Louis: Mosby, 1996:353–368.
Engel H, de la Cruz ZC, Jiminiz-Abalihin LD, et al. Cytopreparatory techniques

378
 for eye fluid specimens obtained by vitrectomy. Acta Cytol 1982;26:551–560.
Engel HM, Green WR, Michels RG, et al. Diagnostic vitrectomy. Retina
1981;1:121–149.
Foos RY. Posterior vitreous detachment. Trans Am Acad Ophthalmol Otolaryngol
1972;76:480–497.
Foos RY, Kreiger AE, Forsythe AB, et al. Posterior vitreous detachment in
diabetic subjects. Ophthalmology 1980;87:122–128.
Foos RY, Wheeler NC. Vitreoretinal juncture synchysis senilis and posterior
vitreous detachment. Ophthalmology 1982;89:1502–1512.
Green WR. Diagnostic cytopathology of ocular fluid specimens. Ophthalmology
1984;91:726–749.
Linder B. Acute posterior vitreous detachment and its retinal complications. A
clinical biomicroscopic study. Acta Ophthalmol Suppl 1966;87:1–108.
Spencer WH. The vitreous. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas
and Textbook, 3rd ed. Philadelphia, PA: WB Saunders, 1985:548–588.
Streeten BAW, Wilson DJ. Disorders of the vitreous. In: Garner A, Klintworth
GK, eds. Pathobiology Of Ocular Disease: A Dynamic Approach, 2nd ed,
Part A. New York, NY: Marcel Dekker, 1994:701–742.

Posterior Vitreous Detachment

Clarkson JG, Green WR, Massof D. A histopathologic review of 168 cases of
preretinal membrane. Am J Ophthalmol 1977;84:1–17.
Elner SG, Elner VM, Diaz-Rohena R, et al. Anterior proliferative
vitreoretinopathy. Clinicopathologic, light microscopic, and ultrastructural
findings. Ophthalmology 1988;95:1349–1357.
Elner SG, Elner VM, Freeman HM, et al. The pathology of anterior (peripheral)
proliferative vitreoretinopathy. Trans Am Ophthalmol Soc 1988;86:330–353.
Kampik A, Kenyon KR, Michels RG, et al. Epiretinal and vitreous membranes: a
comparative study of 56 cases. Arch Ophthalmol 1981;99:1445–1453.
Lopez PF, Grossniklaus HE, Aaberg TM, et al. Pathogenetic mechanisms in
anterior proliferative vitreoretinopathy. Am J Ophthalmol 1992;114:257–279.
Machemer R, Aaberg TM, Freeman HM, et al. An updated classification of
retinal detachment with proliferative vitreoretinopathy. Am J Ophthalmol
1991;112:159–165.
Michels RG. A clinical and histopathologic study of epiretinal membranes
affecting the macula and removed by vitreous surgery. Trans Am Ophthalmol
Soc 1980;80:580–656.
Peczon BD, Wolfe JK, Gipson IK, et al. Characterization of membranes removed
during open-sky vitrectomy. Invest Ophthalmol Vis Sci 1983;24:1382–1389.
Schwartz D, de la Cruz ZC, Green WR, et al. Proliferative vitreoretinopathy.
Ultrastructural study of 20 retroretinal membranes removed by vitreous
surgery. Retina 1988;8:275–281.

379
Vitreoretinal Membranes and Proliferative
Vitreoretinopathy
Wilkes SR, Mansour AM, Green WR. Proliferative vitreoretinopathy.
Histopathology of retroretinal membranes. Retina 1987;7:94–101.

Vitreous Hemorrhage
Campbell DG. Ghost cell glaucoma following trauma. Ophthalmology
1981;88:1151–1158.
Campbell DG, Simmons RJ, Grant WM. Ghost cells as a cause of glaucoma. Am
J Ophthalmol 1976;81:441–450.
Grossniklaus HE, Frank E, Fahri DC, et al. Hemoglobin spherulosis in the
vitreous cavity. Arch Ophthalmol 1988;106:961–962.
Meredith TA, Gordon PA. Pars plana vitrectomy for severe penetrating injury
with posterior segment involvement. Am J Ophthalmol 1987;103:549–554.
Ryan SJ. Penetrating ocular trauma and pars plana vitrectomy. Trans New
Orleans Acad Ophthalmol 1983;31:129–136.
Spraul CW, Grossniklaus HE. Vitreous hemorrhage. Surv Ophthalmol
1997;42:3–39.

Asteroid Hyalosis
Bergren RL, Brown GC, Duker JS. Prevalence and association of asteroid
hyalosis with systemic diseases. Am J Ophthalmol 1991;111:289–293.
Eagle RC, Yanoff M. Cholesterolosis of the anterior chamber. Albrecht von
Graefe’s Arch Ophthalmol 1975;193:121–134.
Fawzi AA, Vo B, Kriwanek R, et al. Asteroid hyalosis in an autopsy population:
the University of California at Los Angeles (UCLA) experience. Arch
Ophthalmol 2005;123:486–490.
Miller H, Miller B, Rabinowitz H, et al. Asteroid bodies—an ultrastructural study.
Invest Ophthalmol Vis Sci 1983;24:133–136.
Renaldo DP. Pars plana vitrectomy for asteroid hyalosis. Retina 1981;1:252–254.
Streeten BW. Vitreous asteroid bodies. Ultrastructural characteristics and
composition. Arch Ophthalmol 1982;100:969–975.
Topilow HW, Kenyon KR, Takahashi M, et al. Asteroid hyalosis. Biomicroscopy,
ultrastructure, and composition. Arch Ophthalmol 1982;100:964–968.

Vitreous Amyloidosis
Benson MD. Hereditary amyloidosis—disease entity and clinical model. Hosp
Pract 1988;23:165–172, 177, 181.
Ciulla TA, Tolentino F, Morrow JF, et al. Vitreous amyloidosis in familial
amyloidotic polyneuropathy. Report of a case with the Val30Met transthyretin

380
 mutation. Surv Ophthalmol 1995;40:197–206.
Doft BH, Machemer R, Skinner M, et al. Pars plana vitrectomy for vitreous
amyloidosis. Ophthalmology 1987;94:607–611.
Sandgren O, Holmgren G, Lundgren E. Vitreous amyloidosis associated with
homozygosity for the transthyretin methionine-30 gene. Arch Ophthalmol
1990;108:1584–1586.

Vitreous Lymphoma
Barr CC, Green WR, Payne JW, et al. Intraocular reticulum cell sarcoma. Clinical
pathological study of 4 cases and review of the literature. Surv Ophthalmol
1975;19:224–239.
Carroll DM, Franklin RM. Vitreous biopsy in uveitis of unknown cause. Retina
1981;1:245–251.
Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am
Ophthalmol Soc 2003;101:275–292.
Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin
Ophthalmol 2002;13:411–418.
Chan CC, Wallace DJ. Intraocular lymphoma: update on diagnosis and
management. Cancer Control 2004;11:285–295.
Chan CC, Whitcup SM, Solomon D, et al. Interleukin-10 in the vitreous of
patients with primary intraocular lymphoma. Am J Ophthalmol
1995;120:671–673.
Char DH, Ljung B-M, Miller T, et al. Primary intraocular lymphoma (ocular
reticulum cell sarcoma), diagnosis and management. Ophthalmology
1988;95:625–630.
Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment
Ophthalmol 2008;36:564–578.
Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: a
review of the clinical, histopathological and molecular biological features.
Graefes Arch Clin Exp Ophthalmol 2004;242:901–913.
Dean JM, Novak MA, Chan CC, et al. Tumor detachments of the retinal pigment
epithelium in ocular/central nervous system lymphoma. Retina
1996;16:47–56.
Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory
investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology
1987;94:1631–1639.
Rankin GA, Jakobiec FA, Hidayat AA. Intraocular lymphoproliferations
simulating uveitis. In: Albert DM, Jakobiec FA, eds. Principles and Practice
of Ophthalmology: Clinical Practice, vol. 1. Philadelphia, PA: WB Saunders,
1994:524–548.
Vogel MH, Font RL, Zimmerman LE, et al. Reticulum cell sarcoma of the retina
and uvea. Report of six cases and review of the literature. Am J Ophthalmol
1968;66:205–215.

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Whitcup SM, de Smet MD, Rubin BI, et al. Intraocular lymphoma: clinical and
histopathologic diagnosis. Ophthalmology 1993;100:1399–1406.

Whipple Disease
Avila MP, Jalkh AE, Feldman E, et al. Manifestations of Whipple’s disease in the
posterior segment of the eye. Arch Ophthalmol 1984;102:384–390.
Durant WJ, Flood T, Goldberg MF, et al. Vitrectomy and Whipple’s disease.
Arch Ophthalmol 1984;102:848–851.
Font RL, Rao NA, Issarescu S, et al. Ocular involvement in Whipple’s disease:
light and electron microscopic observations. Arch Ophthalmol
1978;96:1431–1436.
Knox DL, Green WR, Troncoso JC, et al. Cerebral ocular Whipple’s disease: a
62-year odyssey from death to diagnosis. Neurology 1995;45:617–625.
Rickman LS, Freeman WR, Green WR, et al. Uveitis caused by Tropheryma
whippelii (Whipple’s bacillus). N Engl J Med 1995;332:390–392.
Selsky EJ, Knox DL, Maumenee AE, et al. Ocular involvement in Whipple’s
disease. Retina 1984;4:103–106.

Vitreous Involvement by Other Tumors

Francis JH, Abramson DH, Gaillard MC, et al. The classification of vitreous
seeds in retinoblastoma and response to intravitreal melphalan.
Ophthalmology 2015;122:1173–1179.
Gunduz K, Shields JA, Shields CL, et al. Cutaneous melanoma metastatic to the
vitreous cavity. Ophthalmology 1998;105:600–605.
Gupta S, Blair MP, Lin AY, et al. Cutaneous melanoma metastatic to the vitreous
cavity. Retin Cases Brief Rep 2011;5(3):197–200.
Lawson BM, Saktanasate J, Say EA, et al. Intravitreal chemotherapy provides
control for massive vitreous seeding from retinoblastoma. J Pediatr
Ophthalmol Strabismus 2014;51:e92–e94.
Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous
disease in retinoblastoma revisited: from prohibition to conditional
indications. Br J Ophthalmol 2012;96(8):1078–1083.
Solomon JD, Shields CL, Shields JA, et al. Posterior capsule opacity as initial
manifestation of metastatic cutaneous melanoma. Graefes Arch Clin Exp
Ophthalmol 2011;249:127–131.
Zografos L, Mirimanoff RO, Angeletti CA, et al. Systemic melanoma metastatic
to the retina and vitreous. Ophthalmologica 2004;218:424–433.

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 13 Eyelid
INTRODUCTION
The eyelids are flaps of modified skin with highly modified epidermal
appendages that cover and protect the eye (Fig. 13-1). The eyelids form a
moist chamber lined by mucous membrane (conjunctiva) that is absolutely
essential for the maintenance of corneal transparency. The importance of
the eyelids in the maintenance of corneal health and transparency becomes
evident when facial paralysis or stupor prevents normal eyelid closure and
produces corneal exposure or lagophthalmos (rabbit eye). If congenital
defects in the eyelid called colobomas (coloboma—“a defect”) are not
corrected expeditiously, corneal ulceration and/or opacification caused by
epidermalization invariably result. The corneal epithelium literally turns to
skin if it is not continuously moistened.

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FIG. 13-1. A. Upper eyelid. The upper eyelid is roughly rectangular compared to
the lower lid, which is much shorter and triangular in shape. The anterior surface
of the lid is covered by skin. A row of cilia (eyelashes) arises near the lid margin
(at right) and curves away from the globe. The white foci seen below are the
lobules of the meibomian gland in the tarsal plate, the eyelid’s fibrous skeleton.
The palpebral conjunctiva is tightly adherent to the back surface of the tarsal
plate. B. Lower eyelid. The lower eyelid is roughly triangular and has a much
shorter tarsal plate and fewer meibomian glands. C. Histology, lower eyelid. The
anterior surface of the eyelid is covered by a delicate layer of skin. The posterior
surface is covered by the palpebral conjunctiva, which is firmly adherent to the
tarsal plate. The tarsal plate contains large sebaceous glands called the
meibomian glands. Eosinophilic bundles of orbicularis muscle are seen in cross
section in the connective tissue anterior to the tarsus. The tarsal plate of the lower
lid is much shorter. The lower lid is roughly triangular in shape. D. Eyelid skin.
The skin of the eyelid is extremely delicate and lacks rete pegs. The layers of the
epidermis include the basal cell layer, the malpighian or prickle cell layer, the

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 granular cell layer, and the superficial keratin layer.E. Meibomian gland lobule,
eyelid. Each meibomian gland is composed of multiple sebaceous gland lobules
arranged along a central duct, which is oriented perpendicular to the lid margin.
Sebaceous glands are holocrine glands; lipidized cells shed into the duct
constitute the secretory product. Cellular division occurs in the basal cell layer in
the periphery of the lobules. The nuclei become increasingly pyknotic as the cells
mature and become lipidized. A flap-like valve of ductal epithelium covers the
opening of this lobule. F. Glands of Moll. The dilated lumina of these apocrine
sweat glands are lined by tall eosinophilic cells capped with the apical snouts that
characterize apocrine decapitation secretion. (C. H&E ×10, D. H&E ×50, E.
H&E ×50, F. H&E ×100.)

TERMS USED IN SKIN PATHOLOGY

The external surface of the eyelid is covered by one of the thinnest and
most delicate layers of skin in the body (Fig. 13-1D). The epidermis of the
eyelid skin is generally only five or six cells in thickness and is covered by
a thin layer of surface keratinization. Unlike skin elsewhere, eyelid
epidermis lacks rete ridges. The basal cell or germinative layer of the
epidermis, where cellular division normally occurs, rests on a delicate
basement membrane. Compared to the squamous cells of the overlying
epidermis, the basal cells have relatively little cytoplasm. Hence, lesions
composed of basal cells such as basal cell carcinoma appear blue or
basophilic on low-power microscopy. Most of the epidermis is composed
of the prickle cells of the stratum spinosum or malpighian layer. These
cells are polygonal in shape and are joined by bundles of tonofilaments
evident in light microscopy as intercellular bridges. Squamous cell lesions
appear pink or eosinophilic under low-power microscopy because the cells
have abundant eosinophilic cytoplasm.
Thickening of the prickle cell layer is termed acanthosis (from Gk,
akantha, thorn). As basal cells mature and approach the surface of the skin,
they become flattened and squamoid. The nuclei undergo apoptosis as the
cells near the surface, releasing intensely basophilic granules of
nucleoprotein that form the granular cell layer. The dead, desiccated,
anucleate cellular remnants form a thin horny layer of keratin called the
stratum corneum (from Latin, cornu, a horn). Abnormal thickening of this
normally thin surface layer of keratin is called hyperkeratosis (Fig. 13-2A).
Hyperkeratosis is commonly found on the surface of benign squamous
papillomas and is responsible for the greasy or scaly character of
seborrheic keratoses. Colonies of yeast or bacteria frequently are found in

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the thick layer of keratin.

FIG. 13-2. A. Hyperkeratosis. The superficial layer of eosinophilic keratin is

markedly thickened. The dead cells coonstituting the mass of keratin lack nuclei.
A granular cell layer is present beneath the keratin. The epidermis in this
specimen is mildly thickened. B. Parakeratosis, actinic keratosis. The keratin
layer retains flattened nuclei, and no granular cell layer is present. Parakeratosis
is typically found in actinic keratosis. In this example, the epidermis is composed
of mildly atypical squamous cells. (A. H&E ×50, B. H&E ×100.)

Retention of nuclei in the stratum corneum is termed parakeratosis (Fig.

13-2B). Parakeratosis generally occurs in pathologic states when the
epidermis is rapidly proliferating. When parakeratosis is present, there is
no granular cell layer in the underlying epidermis. Parakeratosis is
relatively rare and should alert one that he/she may be dealing with a
premalignant lesion such as actinic keratosis.
Dyskeratosis refers to the keratinization of single cells within the
prickle cell layer. Dyskeratotic cells are round and intensely eosinophilic
and have pyknotic nuclei. Dyskeratosis is particularly striking in the
conjunctival lesions of hereditary benign intraepithelial dyskeratosis (Fig.
5-24).

Congenital and Developmental Lesions

Developmental anomalies of the eyelid include ablepharon,
cryptophthalmos, colobomas, microblepharon, ankyloblepharon,
euryblepharon, blepharophimosis, congenital ectropion, epicanthal folds,
and dystopia canthorum. An intact sheet of skin covers the eye in
cryptophthalmos. Affected patients may have Fraser syndrome, which also
includes syndactyly, renal agenesis, and aural and genital malformations.
Colobomas are partial or full-thickness defects in the lid that affect the lid

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margin. Lid colobomas are common in facial microsomia syndrome
(Goldenhar syndrome) and mandibulofacial dysostosis. Isolated strands of
skin bridge the palpebral fissure in ankyloblepharon filiforme adnatum.
These are related to the fusion of the upper and lower lids that normally
occurs in utero. Dystopia canthorum, iris heterochromia, a white forelock,
synophrys, and deafness constitute Waardenburg syndrome. An accessory
row of eyelashes arises from the meibomian glands in distichiasis.
Phakomatous choristoma or Zimmerman tumor is a rare congenital
neoplasm that involves the lower medial eyelid or anterior orbit. The
ultimate choristoma, Zimmerman tumor, is composed of extraocular eye
lens tissue including lens epithelium, neoplastic lens capsule, and bladder
cells like those found in posterior subcapsular cataract (Fig. 13-3). An
even rarer eyelid lesion called odontogenic choristoma contains an ectopic
tooth. This curious lesion also occurs in the inferomedial eyelid and is
thought to arise from displaced buccal epithelium.

FIG. 13-3. Zimmerman’s tumor (phakomatous choristoma). A. Phakomatous

choristoma is a rare congenital tumor of lenticular anlage that always occurs in
the lower medial eyelid or anterior orbit. B. The tumor is composed of neoplastic
lens epithelial cells. Arrow denotes cell resembling bladder or Wedl cell found in
posterior subcapsular cataract. C. Lens epithelial cells rest on thick PAS-positive
basement membrane that mimics lens capsule. D. Cells are immunoreactive for
lens crystallin. (B. H&E ×50, C. PAS ×250, D. IHC for beta crystalline ×100.)

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AGING CHANGES
Aging produces atrophy and laxity of eyelid skin (dermatochalasis), loss of
orbital fat and subcutaneous tissue, and relaxation of eyelid ligaments.
Folds of redundant skin overhang the upper lid margin, and the orbital fat
protrudes through the attenuated orbital septum, producing bags under the
eyes. Chronic light damage (senile or actinic elastosis) is evident
histologically as basophilic degeneration of dermal collagen.
Laxity of eyelid tissues predisposes to senile entropion or ectropion.
Entropion occurs when the preseptal part of the orbicularis muscle
overrides the pretarsal part. The lateral canthal tendon is lax in senile
ectropion, and the exposed conjunctiva becomes inflamed and undergoes
epidermalization. The floppy eyelid syndrome occurs in obese men who
have eyelids with a rubbery tarsus that are easily everted. Spontaneous
eversion of the eyelids or loss of eyelid contact occurs during sleep,
causing chronic papillary conjunctivitis. Patients with floppy eyelid
syndrome should be evaluated for obstructive sleep apnea, a potentially
fatal condition.

COMMON INFLAMMATORY
LESIONS OF THE EYELID
Hordeolums or styes and chalazia are common inflammatory lesions of the
eyelid. Hordeolums are acute infections of eyelash follicles (external
hordeolums) or meibomian glands (internal hordeolums) that usually are
caused by Staphylococci. Internal hordeolums are more painful because
the inflammation is localized within a confined space. Hordeolums usually
respond to conservative therapy, for example, hot compresses, and
therefore are rarely examined histopathologically.
Chalazia typically appear as mildly tender nodules, or areas of
localized nodular thickening on the eyelid (Fig. 13-4). Inflammatory signs
such as pain and redness are not especially prominent because chalazia are
chronic inflammatory lesions. Chalazia are chronic lipogranulomas, that is,
“endogenous foreign body reactions” to the lipid-rich secretions of the
meibomian and Zeis glands. When sebum escapes from its normal
confines in these sebaceous glands, it is extremely irritating and stimulates
chronic granulomatous inflammation. Histopathology discloses epithelioid
histiocytes and inflammatory giant cells that typically surround empty

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spaces (lipid vacuoles) (Fig. 13-4B,D). In vivo, the vacuoles contained
lipid. During tissue processing, solvents such as alcohol and xylene
dissolve out the lipid. Other chronic inflammatory cells such as
lymphocytes and plasma cells contribute to the chronic inflammatory
infiltrate in chalazion specimens. If the chalazion has ruptured
spontaneously, or if prior incision and drainage has been performed,
granulation tissue is often found. Although granulation tissue typically is
nongranulomatous, the granulation tissue associated with chalazion may
contain epithelioid cells or giant cells, which are residua of the
lipogranulomatous response. Chalazion curettings often include fragments
of tarsal plate.

FIG. 13-4. Chalazion. A. The focal area of nodular thickening in the upper eyelid
represents a chronic granulomatous inflammatory response to irritating lipid
material that has escaped from its normal compartment in the lid. Chalazia
usually are only mildly tender and inflamed. Recurrent or atypical “chalazia”
should be examined pathologically to exclude simulating lesions such as
sebaceous carcinoma. B. Pink epithelioid histiocytes and giant cells indicative of
chronic granulomatous inflammation surround an empty lipid vacuole. The lipid
was dissolved by fat solvents during processing. Empty lipid vacuoles are
required for the diagnosis of lipogranulomatous inflammation. The inflammatory
infiltrate also contains many plasma cells and lymphocytes. C. Chalazion, lower

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 eyelid. Inflammatory focus with empty lipid vacuole abuts meibomian glands in
tarsal plate. D. Polys and granulomatous inflammation surround vacuole that
contained lipid in vivo. (B. H&E ×100, C. H&E ×10, D. H&E ×50.)

Sebaceous carcinoma, which also arises in Zeis and meibomian glands,

can be confused with chronic chalazia clinically. It is imperative that
recurrent or atypical chalazia be submitted for histopathologic examination
to exclude the possibility of this potentially fatal eyelid malignancy. The
author personally has seen several cases of sebaceous carcinoma that were
initially misdiagnosed as chalazia. These lesions were treated with incision
and drainage and were not examined histopathologically. When the correct
diagnosis was finally made, extensive pagetoid involvement of the
conjunctiva by tumor cells necessitated orbital exenteration. Other unusual
neoplasms such as sweat gland carcinomas, Merkel cell tumors, and
carcinoma metastatic to the eyelid have been misdiagnosed clinically as
chalazia.

VIRAL LESIONS
Verruca vulgaris, a benign papillomatous skin lesion caused by human
papillomavirus type 2 (HPV-2), a DNA papovavirus, occasionally occurs
on the eyelid. These viral papillomas are distinguished by elongated spire-
shaped papillary fronds and rete ridges that bend inwardly toward the
center of the lesion (Fig. 13-5A). Vertical tiers of parakeratosis occur on
the crests of papillomatous elevations and overlie foci of vacuolated cells
that contain eosinophilic intranuclear and intracytoplasmic viral inclusions.
The viral inclusions, which are necessary for definitive diagnosis, are only
found in early lesions (Fig. 13-5B). Verruca vulgaris is diagnosed
infrequently in the ophthalmic pathology laboratory.

FIG. 13-5. Viral lesions. A. Verruca vulgaris. Viral papilloma is composed of

spire-shaped fronds of hyperkeratotic epidermis. B. Parakeratosis and vacuolated

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 cells containing viral inclusions are seen on crest of frond. C. Herpes simplex
infection of the skin. Serous fluid and inflammatory cells fill herpetic vesicle
that has formed within the acantholytic epidermis. The underlying dermis is
intensely inflamed. D. Multinucleated giant cells with Cowdry type A
intranuclear inclusions are present. (A. H&E ×25, B. H&E ×250, C. H&E ×25,
D. H&E ×250.)

Molluscum contagiosum is a fairly common viral tumor with a distinctive

histopathologic appearance. Caused by a pox virus, molluscum
contagiosum often is associated with poor hygiene, and lesions may occur
in crops on the face and eyelids of children as the result of autoinoculation.
Massive involvement of eyelids and adnexal skin has been reported in
patients with HIV/AIDS. Clinically, molluscum contagiosum appears as
either an elevated smooth nodule with central umbilication or a larger pore
enclosing multiple flattened papillae. Histopathologically, molluscum
contagiosum typically has an elevated cup or crateriform configuration and
is composed of lobules of markedly acanthotic benign epithelium (Fig. 13-
6A). The epithelial cells contain large intracytoplasmic inclusion bodies
called Henderson-Patterson corpuscles (Fig. 13-6B). The inclusions are
eosinophilic near the base of the epithelium where they form, and they
become denser and more basophilic as they mature and migrate toward the
surface where they discharge virus particles. The individual virus particles
are quite large and can be resolved with the oil immersion objective of the
light microscope in one-micron-thick plastic-embedded sections.
Molluscum contagiosum on the eyelid margin can incite unilateral chronic
follicular conjunctivitis by dispersing viral particles into the conjunctival
sac. The lids of any patient who has chronic follicular conjunctivitis should
be inspected carefully for molluscum contagiosum (or the presence of
pubic or “crab” lice whose waste can incite a similar reaction) (Fig. 13-
7C–E).

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FIG. 13-6. Molluscum contagiosum. A. This viral tumor has a typical crateriform
configuration. Inclusions of pox virus shed by the infected acanthotic epithelium
fill the crater. B. Henderson-Patterson corpuscles. The pox virus infection
causes lobular acanthosis of the epidermis. The thickened epidermis contains
large oval intracytoplasmic viral inclusions called Henderson-Patterson
corpuscles. The inclusions become increasingly basophilic as they mature. (A.
H&E ×10, B. H&E ×100.)

FIG. 13-7. Ectoparasites, eyelids. A. Demodex folliculorum. Multiple mites

392
 crowd follicles in eyelid biopsy. Mites were an incidental finding. B. Single
demodex mite found after eyelash epilation. Head and eight legs are seen at right.
Tapering tail has ribbed cuticle. C. Phthiriasis palpebrarum. Oval eggs or nits
on lashes. D. Adult pubic louse grasping eyelash. E. SEM discloses claws of
“crab.” (A. H&E ×100, E. Scanning electron micrograph ×20.)

Molluscum contagiosum is one of three cup-shaped or crateriform lesions

commonly found on eyelid skin. Basal cell carcinoma and
keratoacanthoma also are often umbilicated or have a central area of
ulceration. Both tend to be larger than molluscum contagiosum.
Other viral lesions that affect eyelid skin include the vesicular
eruptions caused by the herpes simplex and varicella–zoster viruses.
Herpes simplex infection causes fluid-filled intraepidermal vesicles
marked by profound epidermal degeneration and acantholysis (Fig. 13-
5C,D). Round acantholytic balloon cells and multinucleated giant cells that
contain eosinophilic intranuclear viral inclusions are found.
Demodex mites (Demodex folliculorum) are ubiquitous ectoparasites
that inhabit follicles in facial skin and the ear canals. They are frequently
found in eyelid biopsies, which may harbor multiple mites in a single
follicle (Fig. 13-7A). Demodex typically infest eyelash follicles and are
especially numerous in patients who have seborrheic blepharitis whose
lashes have basal cuffs. These acarine mites are 0.1 to 0.4 mm in length
and have eight legs and a ribbed cuticle. Demodex brevis, a second smaller
species, lives within sebaceous glands where it grazes on the sebum.
Demodex DNA has been found on the facial skin of 100% of humans over
18 years of age suggesting that this infestation is universal. There is some
controversy about the possible pathogenic role of these mites in corneal
disease.

Benign Cystic Lesions

Eyelid cysts are commonly accessioned by ocular pathology laboratories.
Most are epidermal inclusion cysts or sweat ductal cysts.
Epidermal inclusion cysts are round or oval and unilocular (have a
single lumen) and are filled with cheesy, foul-smelling keratin debris.
They are lined by keratinizing stratified squamous epithelium that
resembles normal epidermis (Fig. 13-8B). By definition, the epithelial
lining has no epidermal appendages such as pilosebaceous units or sweat
glands. (If epidermal appendages are present, and hair shafts are found

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mixed with the keratin filling the lumen, the cyst probably should be
classified as a cystic dermoid, a developmental lesion caused by
entrapment of epidermis in bony sutures.) Many epidermal inclusion cysts
are caused by the cystic dilatation of hair follicles by keratin debris.
Essentially, they result from the cystic dilatation of a single epidermal
appendage. Follicular cyst, infundibular type is the dermatopathological
term applied to this type of cyst. In such cases, the lining of the cyst may
communicate with the skin through a pore (Fig. 13-8A). Clinically,
epidermal inclusion cysts are often called sebaceous cysts, an
inappropriate term since they have nothing to do with sebaceous glands or
sebum.

FIG. 13-8. Epidermal inclusion cyst. A. Epithelial lining of cyst derived from
hair follicle communicates with eyelid skin via a pore. B. Cyst is lined by
keratinized stratified squamous epithelium without epidermal appendages and is
filled with laminated keratin debris. Follicular cyst, infundibular type is an
alternate name for epidermal inclusion cyst. The common term “sebaceous cyst”
is totally inappropriate because they totally lack sebaceous features. (A. H&E
×25, B. H&E ×250.)

Sweat ductal cysts, sudoriferous cysts, or hidrocystomas are caused by the

blockage of a sweat duct. These cysts are soft, smooth, and fluctuant and
are filled with watery fluid. Some are transparent or translucent, and they
readily transilluminate. Some patients have multiple cysts that often
involve the skin of both medial and lateral canthi (Fig. 13-9A).

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 FIG. 13-9. Eccrine hidrocystoma. A. Cysts caused by the blockage of eccrine
sweat glands often involve the canthal skin. Multiple cysts occur in some
patients. They are filled with watery fluid. Eccrine hidrocystomas also are called
sweat ductal or sudoriferous cysts. B. The eccrine hidrocystoma is lined by a dual
layer of epithelial cells (arrow) resembling the epithelium of an eccrine sweat
gland duct. The lumen is filled with eosinophilic granular material consistent with
serous fluid. The lumen is often branching and multilocular. (B. H&E ×100.)

Histopathologically, sweat ductal cysts are often multilocular, and their

lumens appear empty, or contain scant amounts of granular eosinophilic
material consistent with serous fluid. The epithelial lining, which is often
attenuated, is composed of a dual layer of cells that resembles the normal
lining of an eccrine sweat duct (Fig. 13-9B). Although most sudoriferous
cysts are eccrine hidrocystomas, the epithelial lining occasionally shows
apocrine differentiation. Apocrine hidrocystomas are recognized by their
epithelial lining, which is composed of tall cells with eosinophilic
cytoplasm and apical snouts of decapitation secretion (Fig. 13-10D). The
cytoplasm of the apocrine cells may contain golden-brown granules of
lipofuscin pigment that are periodic acid–Schiff (PAS) positive. Apocrine
hidrocystomas often contain brown fluid stained by this pigment and may
be misdiagnosed preoperatively as primary melanocytic lesions (Fig. 13-
10A,B).

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 FIG. 13-10. Apocrine hidrocystoma. A. Bluish lesion near lid margin was
thought to be pigmented melanocytic nevus preoperatively. B. Macrophoto of
another case shows brownish fluid filling lumen of cyst. C. Branching lumen of
multilocular Moll gland cyst appears empty. D. The cells coonstituting the
epithelial lining are tall and show apical snouts of decapitation secretion
indicative of apocrine differentiation. (C. H&E ×25, D. H&E ×100.)

Benign Epidermal Lesions

Benign tumors that arise from the epidermis generally are located anterior
to the plane of the surrounding normal skin because they are composed of
cells that are unable to invade or infiltrate the dermis or deeper structures
of the lid as malignant lesions can (Figs. 13-11 to 13-13). The redundant
epidermis formed by the proliferation of these benign cells typically forms
a branching tree-shaped lesion composed of fronds or finger-like
projections that have cores of fibrovascular tissue analogous to dermis. A
lesion that exhibits this growth pattern is called a papilloma (Figs. 13-11
and 13-12). Papillomas can be elevated and exophytic or relatively squat
and sessile. A variety of lesions show a papillomatous growth pattern
including some malignant tumors, for example, papillary squamous cell
carcinoma of the conjunctiva (Fig. 5-21G).

FIG. 13-11. Benign papillomatous lesions. The term papilloma refers to an

epithelial tumor that grows exophytically and typically forms finger-like fronds.
A. Typical pedunculated squamous papilloma or fibroepithelial polyp. B.
Seborrheic keratosis is a sessile papilloma. Pseudohorn cysts filled with keratin
are present. The contents of one “pseudocyst” communicates with the surface of
the lesion (arrow). (A. H&E ×50, B. H&E ×50.)

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FIG. 13-12. Squamous papillomas. A. Squamous papillomas are very common
benign epidermal tumors of the eyelid. They are branching tree-shaped lesions
composed of multiple fronds of benign epidermis. A large papilloma is present on
upper eyelid. B. Smaller pedunculated papillomas are called skin tags,
acrochordons, or fibroepithelial polyps. C. Multiple fronds or finger-like
projections of epidermis constitute the benign epidermal tumor. The epidermal
fronds contain a central core of fibrovascular tissue. Hyperkeratosis is present on
the surface of this lesion. (C. H&E ×25.)

FIG. 13-13. Seborrheic keratosis. A. Dermatosis papulosa nigra. Multiple

seborrheic keratoses are seen on the face of this elderly African American
woman. B. Benign sessile papilloma is situated anterior to the plane of the
surrounding skin. Lesion contains many characteristic pseudohorn cysts. C. Thick
layer of hyperkeratosis covers sessile papilloma. Characteristic pseudohorn cysts
filled with keratin are present. D. Seborrheic keratosis, adenoid type. The

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 dermis contains interweaving bands of benign epithelial cells. Several keratin-
filled pseudohorn cysts are present. (B. H&E ×10, C. H&E ×25, D. H&E ×50.)

Benign papillomatous lesions of eyelid skin such as seborrheic keratoses

and squamous cell papillomas frequently are submitted for histopathologic
evaluation. In most instances, the correct diagnosis is suspected
preoperatively, and cosmesis is a major indication for excisional biopsy.
Seborrheic keratoses usually occur in elderly patients. They are
sharply demarcated, superficial lesions that sit anterior to the plane of
surrounding epidermis like a button on the surface of the skin (Fig. 13-13).
They typically have a greasy or scaly appearance caused by hyperkeratosis
and are often pigmented. Approximately one third of black adults have
multiple, small, pigmented seborrheic keratoses on their facial skin, a
condition called dermatosis papulosa nigra (Fig. 13-13A).
Seborrheic keratoses are an upward papillomatous proliferation of
basaloid cells that resemble normal epidermal basal cells. Therefore, under
low magnification, seborrheic keratoses often appear “blue” and are
situated “above” the plane of the surrounding skin (signifying a benign
lesion of basal cells) (Fig. 13-13B). In contrast to “garden variety”
squamous papillomas, acrochordons, or skin tags, which are often
exophytic and pedunculated, seborrheic keratoses are often sessile. A thick
surface layer of keratin usually is present, and circular spaces filled with
keratin called pseudohorn cysts are found within the acanthotic epithelium
(Fig. 13-13B). The latter represent invaginations filled with surface keratin
(Fig. 13-11B).
Interweaving bands composed of benign cells are found in the dermis
in the adenoid variant of seborrheic keratosis (Fig. 13-13D), which should
not be confused with the highly infiltrative morpheaform variant of basal
cell carcinoma. Inverted follicular keratosis (IFK) is considered by some to
be an irritated form of seborrheic keratosis. IFK typically has an inverted
cup-shaped configuration and surface invaginations that have been
interpreted as hair follicles (Fig. 13-14). Other characteristic
histopathologic features include acantholysis (widening of intercellular
spaces between squamous cells) and small foci of squamous differentiation
called squamous eddies.

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FIG. 13-14. Inverted follicular keratosis. A. IFK is thought to be an irritated
variant of seborrheic keratosis. Acantholysis and circular foci of squamous cells
(squamous eddies) are characteristic histologic features. B. Several oval foci of
squamous differentiation called squamous cells are seen at right. The smaller
basaloid cells show mild acantholysis. (A. H&E ×25, B. H&E ×100.)

Many benign eyelid papillomas do not fulfill all of the diagnostic criteria
for seborrheic keratosis. Such lesions tend to be small and pedunculated,
and their epidermal component is not particularly basaloid and resembles
normal or only slightly acanthotic skin with minimal hyperkeratosis (Figs.
13-11A and 13-12). The dermal component often contains a sparse to
moderate infiltrate of chronic inflammatory cells. Such lesions usually are
diagnosed as squamous papillomas and are also called skin tags,
acrochordons, or fibroepithelial polyps. Some may be viral in origin.

Keratoacanthoma
Keratoacanthoma is a crater-shaped squamous cell lesion that classically
arises rapidly in elderly patients and then undergoes spontaneous
involution (Fig. 13-15). Although keratoacanthoma was classified as a
benign pseudoepitheliomatous hyperplasia in the past, some authorities
now believe that it actually may be a “deficient squamous cell carcinoma”
that tends to involute spontaneously. Rare cases invade deeply like
squamous cell carcinomas.

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 FIG. 13-15. Keratoacanthoma. A. Keratin fills irregular crater in large biopsy-
confirmed keratoacanthoma of the lower eyelid. The tumor developed rapidly.
Some authorities now believe that keratoacanthoma is a “deficient squamous cell
carcinoma” that tends to involute spontaneously. B. A mass of keratin fills the
crater-shaped tumor, which is composed of squamous cells with eosinophilic
cytoplasm. A lateral buttress of normal skin is seen at right. The base of the
lesion has a smooth “pushing” margin. The general configuration of the lesion is
important in histopathologic diagnosis. It usually is impossible to distinguish
keratoacanthoma from squamous cell carcinoma in a small incisional biopsy. (B.
H&E ×5.)

Histopathology discloses a central crater filled with a mass of keratin that

is enclosed by markedly acanthotic squamous epithelium that typically
extends like a lip or buttress over the side of the crater (Fig. 13-15B). The
base of a well-developed lesion appears regular and well demarcated, and
the margin is relatively smooth and “pushing” rather than infiltrative. An
intense band of inflammation usually is present in the underlying dermis.
The overall configuration of the lesion is quite important from a diagnostic
standpoint. It is usually impossible to differentiate keratoacanthoma from
squamous cell carcinoma in a small incisional biopsy because
keratoacanthoma frequently harbors atypical cells and mitotic figures.
Keratoacanthomas should be totally excised.

MALIGNANT TUMORS OF THE

EYELID
Basal Cell Carcinoma
Basal cell carcinoma is the most common malignant tumor affecting the
periocular skin. The incidence of basal cell carcinoma varies markedly

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with locale and skin pigmentation. The incidence is highest in fair-skinned
adults of European descent in whom it affects one in three of adults, but
the tumor is quite rare in African Americans. In parts of Asia, basal cell
carcinoma is less common than squamous cell and sebaceous carcinoma.
Basal cell carcinomas occasionally occur in younger persons. They arise in
sun-exposed skin and are thought to be caused by actinic damage (Figs.
13-16 and 13-17).

FIG. 13-16. Basal cell carcinoma. A. Noduloulcerative basal cell carcinoma of

lower lid has pearly elevated margins. B. Basal cell carcinoma of lower eyelid
appears “blue and below.” Its cells are basophilic and are located deep to the
plane of the epidermis. C. The surface of this tumor is ulcerated. Basophilic
lobules invade dermis. D. Well-differentiated basal cell carcinoma is composed
of nests of basaloid cells that show peripheral palisading of nuclei. Retraction
artifact is not present. No connection with epidermis is evident in this field. (B.
H&E ×5, C. H&E ×25, D. H&E ×100.)

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 FIG. 13-17. Morpheaform basal cell carcinoma. A. Neglected morpheaform
basal cell carcinoma has produced ghastly facial disfigurement. B. Morpheaform
basal cell carcinoma is a poorly differentiated variant of basal cell carcinoma that
is composed of slender infiltrating tendrils of tumor cells similar to those found in
scirrhous breast carcinoma. The margins of morpheaform basal cell carcinoma
are often indistinct clinically, and the tumor tends to infiltrate deeply. (B. H&E
×25.)

Several variants of basal cell carcinoma are recognized clinically.

Noduloulcerative basal cell carcinomas are firm, elevated, pearly nodules
whose surface initially may be marked by telangiectatic vessels (Fig. 13-
16A). Ulceration often develops centrally as the nodules increase in size.
More advanced lesions appear as slowly enlarging ulcers with prominent
rolled pearly borders. Noduloulcerative basal cell carcinomas usually have
relatively distinct margins.
In contrast, the sclerosing or morpheaform variant of basal cell
carcinoma frequently has relatively indistinct margins and does not tend to
ulcerate until late. (The term morpheaform alludes to the lesion’s
similarity to morphea, a circumscribed type of scleroderma.) Widespread
superficial multicentric involvement occurs in some patients. Extensive
areas of ulceration called “rodent ulcers” are found in neglected cases.
Patients who are cancerphobic, are afraid of doctors, or manifest excessive
denial may present late in the course of the disease with ghastly disfiguring
facial destruction (Fig. 13-17).
In the United States, basal cell carcinoma occurs 15 to 40 times more
often than does squamous cell carcinoma on the eyelids. The tumor arises
most frequently in the lower eyelid, followed by the inner canthus, upper
lid, and outer canthus. Considering its frequency, it is fortunate that basal
cell carcinoma rarely metastasizes. The unusual cases that do metastasize
usually are of the metatypical or basosquamous type. Rare fatalities can

402
result, however, when deeply infiltrative, ulcerative lesions invade the
orbital bones and meninges and cause secondary meningitis.
Basal cell carcinoma appears “blue” and “below” on low-power light
microscopy. The neoplastic basaloid cells of basal cell carcinoma typically
form large masses or fields, or smaller nests, islands, or cords (Fig. 13-16).
Peripheral palisading of nuclei and contraction artifact are seen at the
periphery of the tumor lobules (Fig. 13-18A). Peripheral palisading refers
to the perpendicular arrangement of the nuclei at the periphery of a tumor
lobule to its margin, which has been likened to the row of logs constituting
a wooden fort or palisade. Shrinkage of the mucin-rich stroma during
processing causes retraction artifact, an empty space or cleft between the
tumor lobule and the surrounding stroma.

FIG. 13-18. Basal and squamous cell carcinoma. A. Invasive basal cell
carcinoma (at left) appears basophilic because tumor cells have scant cytoplasm.
Peripheral palisading and retraction artifact are present. B. Invasive squamous
cell carcinoma is composed of cells with eosinophilic cytoplasm. The surface is
keratinized. (A. H&E ×25, B. H&E ×50.)

The fibrous stroma that separates the lobules of neoplastic epithelial cells
in basal cell carcinoma is generally more fibrotic and much denser than the
adjacent normal dermis. The stimulation of fibrosis by the tumor is called
desmoplasia.

403
 Several histopathological variants of basal cell carcinoma are
recognized. In these variants, the tumor appears to be undergoing
differentiation toward various epidermal appendages. Mucin production is
evident as intralobular pools of foamy, lucent, slightly basophilic material
in the adenoid variant of basal cell carcinoma. Keratotic basal cell
carcinomas contain small keratinized horn cysts that may represent
abortive pilar differentiation. Sebaceous differentiation is quite rare and
should raise concern about an internal malignancy (see Muir-Torre
syndrome below). Pigmented basal cell carcinomas contain melanin
pigment and may be confused clinically with malignant melanomas or
nevi. Pigmented basal cell carcinoma is quite common in Asia.
Pseudocystic basal cell carcinomas are formed by necrobiosis in the center
of a large mass of tumor cells, which is somewhat analogous to holocrine
secretion. Morpheaform basal cell carcinomas are composed of slender
cords or tendrils of tumor cells embedded in a densely fibrotic stroma (Fig.
13-17B,C). Morpheaform tumors can widely and deeply infiltrate the
tissues of the eyelid and orbit and have indistinct margins. Excision may
be incomplete unless frozen section control of margins or MOHS surgery
is performed.
Optimally, basal cell carcinomas of the eyelid and periocular skin
should be excised with frozen section control of surgical margins. Frozen
sections probably are unnecessary for some smaller noduloulcerative
lesions that have clinically distinct margins. The time-consuming modified
MOHS technique is best suited for extensive and deeply infiltrative lesions
arising in areas like the inner canthus where the danger of orbital invasion
is great. Basal cell carcinoma does not invariably recur after incomplete
excision. We frequently find no residual basal cell carcinoma
histopathologically when tumors that were reported as having been
incompletely removed are reexcised. The initial trauma of surgery or
postoperative inflammation may destroy the residual tumor in such cases.
About 0.5% of basal cell carcinomas occur in patients who have the
Gorlin-Goltz or basal cell nevus syndrome. Young patients who have this
autosomal dominantly inherited syndrome develop multiple basal cell
carcinomas that can affect parts of the skin that are not subject to actinic
damage. The syndrome also includes odontogenic keratocysts of the jaw,
palmar and plantar pits, frontal bossing, skeletal anomalies including bifid
ribs, and calcification of the falx cerebri. Patients also have been reported
to have bilateral epiretinal membranes and myelinated nerve fibers.
Gorlin-Goltz syndrome is caused by mutations in the patched gene PTCH1

404
(9q22) and PTCH2 (1p36) in the sonic hedgehog pathway, which play an
important role in the pathogenesis of basal cell carcinoma. UV signature
mutations in the PTCH1 gene have been found in up to 70% of sporadic
basal cell carcinomas. Vismodegib, a cyclopamine-competitive antagonist
of the smoothened receptor in the sonic hedgehog pathway, has been
approved for the treatment of advanced and metastatic basal cell
carcinoma.

Actinic Keratosis and Squamous Cell

Carcinoma
Actinic keratosis is a premalignant lesion of squamous cells that develops
on the sun-exposed skin of fair-skinned middle-aged individuals.
Clinically, these keratoses appear as scaly, keratotic, flat-topped lesions, or
erythematous nodules. Microscopy reveals thickened epidermis that is
partially replaced by atypical squamous cells (Fig. 13-19). Parakeratosis
usually is present, and the granular cell layer is absent. Irregular buds of
atypical keratinocytes extend into the papillary dermis at the base of some
lesions. The disease spares the openings of the pilosebaceous units. The
underlying dermis characteristically shows solar elastosis (elastotic
degeneration) similar to that seen in pinguecula and pterygium. The
elastotic degeneration stains positively with the Verhoeff-van Gieson stain
for elastic tissue. If severe atypia is present, but invasion is not present, the
diagnosis of squamous cell carcinoma in situ is warranted.

FIG. 13-19. A. Actinic keratosis. A surface plaque of parakeratosis covers a

thickened segment of epidermis that is replaced by atypical squamous cells.
Irregular buds of atypical keratinocytes extend into the papillary dermis at the
base of some lesions. The dermis shows actinic elastosis. Normal epidermis is
seen at right. B. Squamous cell carcinoma arising from actinic keratosis.
Atypical squamous cells remain confined by the basement membrane of the

405
markedly acanthotic epithelium at left. Eosinophilic squamous cell carcinoma
invades the dermis at right. The tumor has incited a chronic inflammatory
response. (A. H&E ×100, B. H&E ×10.)

Squamous cell carcinoma of the eyelid is relatively rare compared to basal

cell carcinoma in the United States. Squamous cell carcinoma typically
affects elderly, fair-skinned individuals. Although the lower lid margin is
typically involved, squamous cell carcinoma is said to be more common
than basal cell carcinoma in the upper lid and outer canthus.
Histopathologically, squamous cell carcinomas are composed of nests,
cords, and islands of malignant squamous cells that have abundant
eosinophilic cytoplasm and appear “pink” under low power (Figs. 13-18B
and 13-20). Reflecting the tumor’s invasive malignant potential, tumor
cells are seen deep to the plane of the epidermis. More differentiated
tumors produce keratin. Squamous cell carcinomas of the eyelid rarely
metastasize. Metastatic disease is particularly uncommon if the squamous
cell carcinoma has arisen from a preexisting actinic keratosis (Fig. 13-
19B). Approximately 12% of patients who had actinic keratosis in one
series developed a nonaggressive form of squamous cell carcinoma that
had an excellent prognosis compared to squamous cell carcinoma that
arose de novo. The incidence of metastatic disease was only 0.5%. A
larger study from Australia found a much lower incidence (0.1%) of
progression to squamous cell carcinoma. Many actinic keratoses in that
series underwent spontaneous regression.

FIG. 13-20. Squamous cell carcinoma. A. Eosinophilic nests of squamous cell

carcinoma infiltrate the eyelid margin. A thick layer of surface keratinization is
present. B. Infiltrating nests of squamous cell carcinoma are composed of
neoplastic squamous cells with abundant eosinophilic cytoplasm. (A. H&E ×10,
B. H&E ×100.)

406
Sebaceous Carcinoma and Other Sebaceous
Tumors
In the United States, sebaceous carcinoma of the eyelid is about as
common as squamous cell carcinoma. Rarely encountered before age
forty, sebaceous carcinoma typically occurs in elderly patients and is also
more common in women and Asians. It is the most common eyelid tumor
in India. Sebaceous carcinoma has a definite predilection for the sebaceous
glands of the eyelid, but is quite rare elsewhere in the body. It can arise
from the meibomian glands in the tarsal plate, the glands of Zeis that
accompany the lashes, or rarely the sebaceous glands in the caruncle (Figs.
13-21 to 13-23).

FIG. 13-21. Sebaceous carcinoma. A. Tumor of upper eyelid has yellow color

407
that indicates presence of lipid. Madarosis is present. B. Tumor is composed of
lobules of cells with foamy vacuolated cytoplasm. Numerous mitoses are present.
Peripheral palisading is not seen. C. Large lobule of sebaceous carcinoma stained
with oil red O shows central necrosis (comedocarcinoma pattern) mimicking
holocrine secretion. D. Oil red O stain performed on frozen sectioned material
confirms the presence of lipid in cytoplasmic vacuoles. E. Immunohistochemical
stain for adipophilin can be performed on routine paraffin sections. F. Pagetoid
invasion of eyelid skin by sebaceous carcinoma. Individual tumor cells with
vacuolated cytoplasm from an underlying sebaceous carcinoma infiltrate the
epidermis in a fashion analogous to Paget disease of the breast. G. Tarsal
conjunctiva shows intraepithelial sebaceous carcinoma. Lobules of tumor are
present in tarsal plate. H. Intraepithelial sebaceous carcinoma, conjunctiva.
Atypical cells with large, hyperchromatic nuclei and cytoplasmic vacuoles
replace basal half of conjunctival epithelium. (B. H&E ×100, C. Oil red O ×50,
D. Oil red O ×250, E. IHC for adipophilin ×250, H&E ×100, F. H&E ×250, G.
H&E ×100, H. H&E ×250.)

FIG. 13-22. A. Senile sebaceous gland hyperplasia. Lobules of mature benign

hyperplastic sebaceous glands form a nodule in the dermis. These show typical
arrangement around central duct. The nodule was misdiagnosed as basal cell
carcinoma preoperatively. B. Sebaceous adenoma. Incompletely lipidized cells
comprising low-grade sebaceous neoplasm form disorderly lobules. Differential
diagnosis included sebaceous adenoma or low-grade sebaceous carcinoma.
Sebaceous adenomas serve as a clinical marker for systemic malignancy in
patients with the MTS. (A. H&E ×10, B. H&E ×100.)

408
 FIG. 13-23. Low-grade sebaceous neoplasm with somatic mutations in MMR
genes. A. Yellow papillomatous tumor on palpebral conjunctiva. Tumor also
involves meibomian gland orifice above. B. Tumor protrudes from posterior
aspect of tarsal plate. C. Low-grade sebaceous neoplasm is composed of basaloid
and paler lipidized cells. Cytology is quite bland compared to typical sebaceous
carcinoma. D, E. Tumor cells show normal positive nuclear staining for MMR
gene MLH1. Tumor cell nuclei do not stain with MSH2 (F) or MSH6 (G), but
adjacent meibomian glands show normal nuclear staining. Elderly patient had no
personal or family history of colon carcinoma or other manifestations of MTS
and is presumed to have somatic mutations in MSH2 and MSH6. Genetic testing
must be done to confirm that diagnosis. (B. H&E ×10, C. H&E ×250, D. IHC for
MLH1 ×250, E. IHC for MLH1 ×50, F. IHC for MSH2 ×50, G. IHC for MSH6
×50.)

Sebaceous carcinoma is an important tumor that can confound both

ophthalmologists and pathologists. Lesions that arise deep in the substance
of the lid, for example, meibomian carcinomas, typically cause no
abnormalities in the overlying skin until late in the course of the disease.
Meibomian gland carcinomas can be confused with chalazia, which
typically arise within the tarsal plate. Recurrent or atypical chalazia should
be submitted for histopathologic examination.
Rarely, sebaceous carcinoma presents as a chronic unilateral
keratoconjunctivitis that is unresponsive to therapy. This “masquerade
syndrome” is caused by the intraepithelial spread of tumor that replaces
the conjunctival epithelium in a pagetoid or bowenoid fashion. Any elderly
patient who has unilateral chronic keratoconjunctivitis that does not
respond to treatment should be biopsied.
Two thirds of sebaceous carcinomas arise in the upper eyelid,
undoubtedly reflecting the greater mass of meibomian gland tissue in the
upper lid (Figs. 13-21A and 13-23A). Sebaceous carcinoma grows forming

409
lobules and sheets whose size and shape are somewhat reminiscent of
normal sebaceous glands (Fig. 13-21B,C). Meibomian glands in the tarsus
are often completely replaced by tumor. The tumor lobules lack peripheral
palisading, and the cells have nuclei that tend to be larger and more
pleomorphic, hyperchromatic, and atypical than those in basal cell
carcinoma. Mitotic figures are common and may be abnormal. In well-
differentiated cases, the cytoplasm of the tumor cells has a frothy or foamy
appearance caused by lipid vacuoles.
Large lobules of sebaceous carcinoma frequently are necrotic
centrally, a feature called the comedocarcinoma pattern, which
recapitulates the necrobiosis that occurs during normal holocrine secretion
(Fig. 13-21C). Another characteristic and extremely important feature of
sebaceous carcinoma is the tumor’s ability to invade and replace eyelid
skin and conjunctival epithelium in a pagetoid fashion (Fig. 13-21F). The
term pagetoid derives from the similarity of this process to Paget disease
of the nipple that is marked by replacement of the epidermis by breast
carcinoma cells. The observation of pagetoid involvement of the skin or
conjunctiva helps to confirm the diagnosis of sebaceous carcinoma. The
ability to invade and replace the conjunctival epithelium is one of the
tumor’s most insidious features. A relatively small eyelid tumor can give
rise to extensive intraepithelial spread. Histopathologically, the affected
segments of conjunctival epithelium are thickened and often are totally
replaced by tumor cells. The infiltrated epithelium is often poorly adherent
and may be lost or desquamated leading to nondiagnostic biopsies.
Surgeons who suspect sebaceous carcinoma clinically should always
inform the pathologist so wet tissue can be reserved for possible fat stains.
Fat stains such as oil red O help to confirm the diagnosis by
demonstrating the presence of intracytoplasmic lipid. They must be
performed on frozen sections, however, because the solvents used in
normal tissue processing and paraffin embedding dissolve fat (Fig. 13-
21C,D). In practice, experienced ocular pathologists perform fat stains
infrequently, reserving it for exceptional cases with equivocal sebaceous
differentiation. However, pathologists who are less familiar with the tumor
may wish to confirm the presence of lipid. Recently, the availability of a
new immunohistochemical stain for fat called adipophilin has lessened the
need for frozen sections. Adipophilin stains protein associated with fat and
can be used on routine paraffin sections (Fig. 13-21E). Adipophilin
staining is present in 100% of sebaceous carcinomas and compared to
other carcinomas, is more intensely expressed, and occurs in large

410
intracytoplasmic vacuoles (>1.5 μm). Stains for androgen receptors (AR)
also are recommended. Other immunohistochemical strategies for
diagnosing sebaceous carcinoma are not entirely satisfactory as they tend
to work best on well-differentiated cases that are easily diagnosed using
routine sections. One protocol recommends the use of epithelial membrane
antigen (EMA), CAM 5.2, and breast marker BRST-1. Sebaceous
carcinoma often stains with EMA and shows focal immunoreactivity with
BRST-1. P-16 readily highlights pagetoid cells within the epidermis and
conjunctival epithelium. Stains for AR also are recommended and are said
to be more effective than adipophilin in demonstrating intraepithelial
involvement. BerEP4 is negative in sebaceous carcinoma but stains basal
cell carcinoma.
Sebaceous carcinoma can spread by direct extension and can
metastasize to regional lymph nodes and distant sites such as lung, liver,
brain, and skull. Tumor mortality was estimated to be about 15% in a large
series by Rao et al. from the Armed Forces Institute of Pathology that
included many advanced lesions. Factors associated with poor prognosis
include origin from the upper eyelid, tumor diameter >10 mm, origin from
meibomian glands, duration of symptoms before diagnosis >6 months, an
infiltrative growth pattern, poor sebaceous differentiation, extensive
pagetoid invasion, and invasion of lymphatics, vessels, and the orbit.
Early diagnosis and treatment are important. Few fatal tumors were
reported in recent series, reflecting increased awareness of sebaceous
carcinoma by ophthalmologists. Wide local excision with frozen section
control of surgical margins should be performed. Radiation should be
reserved only for palliation of advanced cases that refuse or cannot tolerate
radical surgery. Orbital exenteration is performed in many institutions if
there is orbital invasion or extensive pagetoid replacement of the
conjunctiva. Some have questioned whether exenteration is excessive
therapy for the latter, which essentially is an in situ disease process.
Cryotherapy of conjunctival disease has been advocated to treat this
diffuse, yet relatively localized form of the disease. Topical chemotherapy
with mitomycin C has been used in treating intraepithelial sebaceous
carcinoma in some instances.
Senile sebaceous gland hyperplasia, sebaceous adenomas, and
sebaceomas are other sebaceous lesions that occur on facial and eyelid
skin (Fig. 13-22). Relatively common, senile sebaceous gland hyperplasia
appears as a nodule that may be umbilicated and often is misdiagnosed as
basal cell carcinoma. Histopathology shows mature sebaceous gland

411
lobules surrounding a central dilated duct (Fig. 13-22A).
Sebaceous adenomas are rare tumors composed of irregular lobules of
incompletely differentiated sebaceous glands composed of foamy
sebaceous cells with an outer rim of nonlipidized basaloid germinal cells
thicker than that seen in a normal gland (Fig. 13-22B). The lobules are not
arranged around a duct.
Previously called sebaceous epitheliomas, sebaceomas lack the more
highly organized lobular arrangement found in sebaceous adenomas and
are composed largely of undifferentiated basaloid cells with randomly
scattered sebaceous cells without nuclear atypia and squamoid elements
with interspersed microcystic ductules.
A variety of sebaceous neoplasms and keratoacanthomas are
associated with an internal malignancy, especially colon carcinoma, in
patients with Muir-Torre syndrome (MTS), a rare variant of the Lynch
syndrome of nonpolyposis colonic carcinoma. This autosomal dominant
syndrome is caused by germline mutations in DNA mismatch repair
(MMR) genes hMLH1, hHSH2, hHSH6, and PMS2. Tumors, which show
microsatellite instability, arise from a second “hit” or gene inactivation.
There is a greater association of MTS with nonocular sebaceous gland
carcinomas. Lower-grade sebaceous carcinomas or adenomas of the ocular
adnexa, especially those with an exophytic or papillary growth pattern, are
more likely to harbor MMR defects than “garden variety” malignant
sebaceous carcinomas (Fig. 13-23A). MMR status can be evaluated using
immunohistochemical stains; nuclear staining of tumor cells is lost when
mutations are present (Fig. 13-23F,G). Abnormal immunohistochemical
staining for MMR can occur in sporadic tumors in patients who do not
have the MTS syndrome. Hence, confirmatory molecular testing for
germline mutations is mandatory. One study of sebaceous neoplasms
found that 57% had abnormal immunohistochemistry (IHC) for MMR, yet
only 14% were shown to have MTS by genetic testing or clinical criteria.

Melanocytic Lesions
Melanocytic nevi are relatively common eyelid lesions. They are often
misdiagnosed preoperatively when they are amelanotic or papillary in
configuration. Nevi are classified as junctional, intradermal, or compound.
Junctional nevi are flat, pigmented, and relatively rare. The nevus cells in
junctional nevi are confined to the junction between the epidermis and the
dermis. Junctional activity is much more common in younger patients. As

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we age, nevus cells tend to leave the epidermal–dermal junction and
migrate into the underlying dermis. Most nevi submitted to ophthalmic
pathology laboratories are intradermal (or dermal) nevi (Fig. 13-24A).
They are often papillomatous, pedunculated, or dome shaped; bear hairs;
and are frequently amelanotic or only slightly pigmented. Because a
junctional component is absent, malignant transformation almost never
occurs. Microscopy shows infiltration of the dermis by nevus cells
arranged in nests. A cell-free collagenous grenz zone (grenz, German for
border) separates the nevus cells in the dermis from the epidermis. The
nevus cells in intradermal nevi typically show polarity, that is, the cellular
morphology changes with location. Large type A nevus cells are found in
the upper dermis. Type B cells found in the middermis are smaller and are
often lymphocytoid (i.e., they superficially resemble lymphocytes). Type
C cells in the lower dermis have little or no melanin and tend to appear
fibroblastic with spindled nuclei. In elderly individuals, the deeper cells
may have a distinctly neural appearance. Benign nevi can infiltrate the
deeper structures in the lid and occasionally may contain multinucleated
giant cells. If one observes mitotic figures, atypical cells with prominent
nucleoli, or an intense infiltrate of inflammatory cells in a nevus, or finds
“junctional activity” or epithelial involvement in an older patient, the
diagnosis may be malignant melanoma.

FIG. 13-24. A. Intradermal nevus. Nests of benign nevus cells infiltrate the
dermis. An acellular “grenz” zone separates the nevus cells from the epidermis.
No junctional activity persists. Some of the cells are lightly pigmented. B.
Malignant melanoma, eyelid. Lobules of frankly malignant melanocytes
including epithelioid cells invade the dermis. The basal half of the overlying
epidermis is replaced by atypical melanocytic hyperplasia. (A. H&E ×25, B.
H&E ×50.)

Compound nevi usually are slightly elevated, papillomatous, and

pigmented. The term compound indicates that nevus cells occur both at the

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junction and in the dermis. Other forms of nevi occasionally are
encountered. Blue nevi are composed of heavily pigmented spindled or
dendritic melanocytes that are located in the deeper tissues. The gray-blue
skin pigmentation in the nevus of Ota (congenital oculodermal
melanocytosis) is caused by an extensive blue nevus. Cellular blue nevi
can undergo malignant transformation into melanoma.
Malignant melanomas of eyelid skin (Fig. 13-24B) are relatively rare
tumors that constitute <1% of eyelid malignancies. A detailed description
of the histopathology of cutaneous melanoma is beyond the scope of this
textbook. Essentially, the prognosis of skin melanoma depends on the type
of tumor and its thickness and depth of invasion. The depth of tumor
invasion is a very important prognostic indicator. Breslow’s original tumor
invasion depth criteria recently have been supplanted by AJCC depth
guidelines that use 1, 2, and 4 mm to divide patients into prognostic stages.
Lentigo maligna melanoma, which has the best prognosis, develops in
light-damaged facial skin of elderly individuals who have lentigo maligna
or Hutchinson melanotic freckle, which typically is seen as a large, slowly
growing patch of discolored skin. Lentigo maligna is characterized
histopathologically by a confluent layer of single melanocytes at the
epidermal–dermal junction that typically spreads down the epidermal
appendages. Lentigo maligna melanoma (Fig. 13-25) is present when the
atypical melanocytes, often spindled in shape, invade the dermis. A similar
histopathologic picture can develop when atypical melanocytic hyperplasia
in the conjunctiva (primary acquired melanosis with atypia or melanoma in
situ) spreads to involve the neighboring epidermis of the eyelid. Patients
with nodular melanoma tend to do poorly, while the prognosis of
superficial spreading melanoma is intermediate.

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FIG. 13-25. Lentigo maligna melanoma. A. Patient has large patch of discolored,
pigmented skin with focal nodularity. B. Prominent nests of atypical melanocytes
are present in the basal epithelium. Focal invasion of the dermis is present.
Lentigo maligna or the “melanotic freckle of Hutchinson” is an in situ form of
melanoma. The atypical melanocytes remain confined to the epidermis and
invasion of the dermis is not present. (B. H&E ×100.)

Adnexal Tumors
A variety of eyelid neoplasms are derived from adnexal structures such as
sweat glands and hair follicles. Most are quite rare. Syringomas are
relatively common benign tumors of eccrine sweat glands that occur as
multiple flesh-colored nodules on the faces of young women.
Histopathology discloses small cysts and/or comma or tadpole-shaped
ductules lined by a dual layer of eccrine ductal epithelium embedded in a
dense fibrous stroma (Fig. 13-26). Primary cutaneous mucinous carcinoma
can occur on the eyelid of elderly women (Fig. 13-27B). Diagnosis
requires exclusion of a metastasis from a primary mucinous carcinoma of
the breast or GI tract. Exclusion of a primary breast carcinoma can require
imaging and clinical assessment because some sweat gland tumors of the
eyelid express breast markers including gross cystic disease protein
(BRST-2) and estrogen and progesterone receptors (ER and PR). The
incidence of distant metastases is quite low.

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FIG. 13-26. Syringoma. Syringomas are benign sweat gland tumors. Oval and
comma- or tadpole-shaped epithelial ductules are found amid dense fibrous
stroma. The ducts mimic the straight dermal duct of eccrine sweat glands.
Syringomas often occur as multiple elevated papules on the facial skin of young
women. (Inset) (H&E ×50.)

FIG. 13-27. A. Syringocystadenoma papilliferum. A papillary proliferation of

benign apocrine sweat glandular epithelium lines and partially fills cystic spaces
in the dermis. Plasma cells infiltrate the stroma. The overlying epidermis was
acanthotic. B. Primary mucin-secreting sweat gland carcinoma. Pools of
mucin surround cords of malignant sweat gland epithelium. C. Mucin stains
intensely with colloidal iron stain for acid mucopolysaccharide. Primary sweat
gland carcinomas can metastasize, but fortunately are quite rare. A metastasis to
the lid from a distant primary carcinoma must be excluded clinically. (A. H&E

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×50, B. H&E ×80, C. colloidal iron ×100.)

Endocrine mucin-producing sweat gland carcinoma is a newly described,

underrecognized low-grade carcinoma with a predilection for the eyelids.
It is part of the spectrum of mucinous carcinoma and may be a precursor
for invasive mucinous carcinoma. Its cells express neuroendocrine
markers, for example, synaptophysin and/or chromogranin and are positive
for ER and PR as well as low-weight cytokeratins CK7 and CAM5.2 and
EMA (Fig. 13-28). Some eccrine adenocarcinomas are composed of signet
ring cells. A malignant variant of syringoma called microcystic carcinoma
can present with enophthalmos, like scirrhous breast carcinoma.
Microcystic carcinoma has little metastatic potential, but it deeply
infiltrates the lid and orbit, causing stromal desmoplasia. Apocrine tumors
of the eyelid include syringocystadenoma papilliferum (Fig. 13-27A) and
rare adenomas and adenocarcinomas of the glands of Moll.

FIG. 13-28. Endocrine mucin-producing sweat gland carcinoma. A. Multinodular

tumor involves lid margin producing madarosis. Dark area is an intralesional
hemorrhage. B. Circumscribed tumor lobules have papillary configuration. C.
Tumor cells show suggestion of apocrine differentiation. D. Mucicarmine stain
highlights intralesion mucin. IHC is positive for gross cystic disease

417
protein/BRST1 (E), estrogen receptors (F), and synaptophysin (G). (B. H&E
×25, C. H&E ×250, D. Mucicarmine ×80, E. IHC for BRST1 ×100, F. IHC for
ER ×100, G. IHC for synaptophysin ×100.)

Tumors of hair follicle origin include trichofolliculomas, trichoadenomas,

trichoepitheliomas, trichilemmomas, and pilomatrixomas. Most of these
“tricky” tumors are rare and are a diagnostic challenge to
dermatopathologists. Pilomatrixoma (or pilomatricoma) often presents as a
reddish nodule on the upper lid or brow of young patients and is relatively
common (Fig. 13-29A). Both its eponymic designation (the calcifying
epithelioma of Malherbe) and its histopathologic features are memorable.
Pilomatrixoma contains sheets of bland, uniform, basophilic cells (hair
matrix cells) that readily undergo necrosis forming eosinophilic shadow
cells with ghostly nuclei (Fig. 13-29B). Dystrophic calcification
characteristically develops in the necrotic areas, and a prominent foreign
body giant cell response to the sheets of dead cells typically is observed.

FIG. 13-29. Pilomatrixoma (calcifying epithelioma of Malherbe). A. Tumor

beneath brow in child appears clinically as slightly erythematous subepidermal
nodule. B. Tumor is composed of viable hair matrix cells, which are basophilic,
and sheets of nonviable eosinophilic shadow cells. Arrow denotes focus of
dystrophic calcification in necrotic area. (B. H&E ×50.)

Other Lesions
Xanthelasmas are soft, flat or slightly elevated, yellowish plaques that
typically occur near the inner canthi (Fig. 13-30). Cosmesis often is an
indication for removal. Xanthelasmas are predominantly dermal lesions.
Histopathologic examination reveals sheets of foamy, lipid-laden
histiocytes (xanthoma cells) that tend to aggregate around vessels in the
dermis. The epidermis is normal. Although xanthelasmas occasionally
signify hyperlipidemia, two thirds of patients have normal lipids.

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 FIG. 13-30. Xanthelasma. A. Elevated yellowish plaque involves inner canthal
skin of upper lid. B. The dermis contains an infiltrate of xanthoma cells (lipid-
laden histiocytes). The epidermis is normal. (B. H&E ×50.)

Indurated, atypical xanthelasma-like lesions are eyelid markers for several

xanthogranulomatous disorders including Erdheim-Chester disease,
necrobiotic xanthogranuloma, and orbital xanthogranuloma with adult-
onset asthma (Fig. 13-31A). The xanthogranulomatous infiltrates in the
latter disorders are deeper and more extensive than that seen in
xanthelasma and typically contain Touton giant cells (Fig. 13-31C).
Bilateral orbital infiltration, retroperitoneal fibrosis, and characteristic
bone lesions occur in Erdheim-Chester disease, a rare and potentially fatal
systemic disorder. The xanthogranulomatous infiltrate in patients with
adult-onset asthma usually contains foci of follicular lymphoid hyperplasia
(Fig. 13-31B).

FIG. 13-31. Atypical xanthelasma in patient with orbital xanthogranuloma with

adult-onset asthma. A. Periorbital skin is swollen and yellow in color. B. Biopsy
shows typical admixture of follicular lymphoid hyperplasia and
xanthogranulomatous inflammation, rich in lipidized histiocytes and Touton giant
cells (C). (B. H&E ×50, C. H&E ×400.)

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Multiple waxy beaded papules on the eyelid margins and hoarseness
caused by laryngeal infiltration occur in patients with autosomal
recessively inherited lipoid proteinosis or Urbach-Wiethe disease.
Mutations in the ECM1 extracellular matrix protein-1 gene on 1q21.3
cause the deposition of an acellular eosinophilic hyaline glycoprotein in
the tissues.
Patients who have primary systemic amyloidosis may develop multiple
confluent waxy purpuric papules on the eyelid skin that hemorrhage
spontaneously, or after minor trauma. The AI amyloid deposits are
composed of immunoglobulin light chains. Slightly elevated or
umbilicated papules, which may be partially depigmented in blacks, are an
eyelid manifestation of sarcoidosis. Histopathology shows noncaseating
granulomas. Multiple eyelid nodules and severe mutilating arthritis occur
in patients with multicentric reticulohistiocytosis.

Eyelid Markers for Systemic Malignancy

Rare eyelid tumors serve as clinical markers for internal malignancy in
patients with several hereditary syndromes. Trichilemmomas of the eyelid
have been reported in Cowden multiple hamartoma–neoplasia syndrome,
which predisposes to the development of breast cancer in one third of
affected women. Sebaceous adenomas, other sebaceous neoplasms, and
keratoacanthomas occur in MTS, a variant of the Lynch or hereditary
nonpolyposis colorectal cancer syndrome (see above). Myxomas of the
eyelid (Fig. 13-32A,B) and spotty lentiginous pigmentation of the lids and
conjunctiva, which often involves the caruncle and semilunar fold, are
ocular markers for cardiac myxomas, endocrine abnormalities, and rare
testicular tumors in autosomal dominantly inherited Carney complex,
caused by mutations in the PRKAR1A gene on chromosome 17q. Atypical
xanthelasma-like lesions that contain xanthoma cells, Touton giant cells,
cholesterol clefts, and foci of necrobiosis are found in patients with
necrobiotic xanthogranuloma who may have systemic monoclonal
gammopathies and plasma cell dyscrasias. Patients with the Brooke-
Spiegler syndrome develop multiple skin appendage tumors of the head
and neck including cylindromas, trichoepitheliomas, and spiradenomas.

420
FIG. 13-32. Eyelid myxoma, Carney complex. A. Lucent pools of relatively
acellular mucin are present deep in the dermis. B. The alcian blue stain confirms
the presence of acid mucopolysaccharide. The patient had Carney complex an
autosomal dominantly inherited syndrome that includes multiple myxomas,
spotty mucocutaneous pigmentation, and endocrine abnormalities. C. Merkel cell
tumor. Primary neuroendocrine tumor of eyelid skin infiltrates orbicularis
muscle. D. Lobules of poorly differentiated basophilic cells lack peripheral
palisading. Tumor was immunoreactive for keratin, neuron-specific enolase, and
chromogranin. (A. H&E ×50, B. Alcian blue ×100, C. H&E ×25, D. H&E ×100.)

Other rare malignant eyelid tumors include metastases from distant

primary cancers and Merkel cell carcinoma, a rare and aggressive
neoplasm that occurs in older individuals (Fig. 13-32B,C). A cutaneous
APUDoma, Merkel cell carcinoma typically presents as a violaceous or
reddish-blue nodule. The tumor is a neuroendocrine neoplasm of the skin
that has a carcinoid-like histology. Electron microscopy shows dense core
neurosecretory granules, and IHC typically shows the dual expression of
epithelial markers and neural markers chromogranin and neuron-specific
enolase. Dot-like staining for cytokeratin 20 (CK20) distinguishes Merkel
cell tumor from metastatic small cell carcinoma. The fatality rate is 20%.
Most cases of Merkel cell carcinoma probably are caused by Merkel cell
polyomavirus, a human oncovirus that is integrated into the DNA of the
tumor cells. Merkel cell carcinoma should be locally resected with frozen
section control of surgical margins.

Lacrimal Drainage System

Tears are drained into the nose through the nasolacrimal drainage system,
which is located nasally and is composed of the puncta, canaliculi,
lacrimal sac, and nasolacrimal duct. The puncta are the openings of the
canaliculi. They are located in upper and lower eyelids near the inner
canthus. The canaliculi are small tubules lined with epithelium that run

421
from the puncta to the lacrimal sac. The lacrimal sac is located in the
lacrimal fossa in anteromedial wall of the orbit. A downward extension of
the lacrimal sac called the nasolacrimal duct enters the nasal cavity on the
lateral wall of the inferior nasal meatus. The nasolacrimal duct is enclosed
in a bony canal about 12 mm long.
Congenital obstruction of the nasal lacrimal duct is a relatively
common cause of tearing (epiphora) in infants. This usually is caused by
incomplete canalization of the duct near its lower end. Chronic
dacryocystitis is the most common cause of nasolacrimal duct obstruction
or stenosis in adults. Surgical specimens obtained at
dacryocystorhinostomy typically contain an infiltrate of lymphocytes and
plasma cells in the wall of the lacrimal sac (Fig. 13-33A). Concretions or
casts occasionally are found within the lumina of the canaliculi or sac.
These include masses of the gram-positive filamentous fungus
Actinomyces (Fig. 13-33B) and dacryoliths composed of laminated
inspissated protein that may contain fungal elements. Chronic nasolacrimal
duct obstruction can predispose to acute bacterial infection of the lacrimal
sac (acute dacryocystitis).

FIG. 13-33. A. Chronic nongranulomatous dacryocystitis. Infiltrate of

lymphocytes and plasma cells is present in stroma beneath respiratory epithelial
lining of lacrimal sac. B. Actinomycotic lacrimal cast. Mass of gram-positive
filamentous fungi removed from canaliculus has laminated appearance. (A. H&E
×100, B. Gram stain ×100.)

Neoplasms of the lacrimal sac are a rare cause of nasolacrimal duct

obstruction and recurrent dacryocystitis. In addition to tearing, patients
present with a mass in the inner canthal region that is situated below the
medial canthal tendon. Hemorrhage (bloody discharge or epistaxis) and
pain are signs suggestive of a malignant neoplasm.
Most lacrimal sac tumors are papillomatous neoplasms that arise from

422
the epithelial lining of the sac (Fig. 13-34). They include exophytic and
inverted papillomas composed of squamous cells, transitional cells, or a
mixture of both. The papillomas may be benign, show focal atypia, or
progress to invasive carcinoma. Invasive carcinoma typically arises from
papillomas that have an inverted growth pattern. Less than one third of
lacrimal gland tumors are nonepithelial. Lymphomas, malignant
melanomas, fibrous histiocytomas, hemangiopericytomas,
neurilemmomas, and angiosarcomas occasionally occur in this site.

FIG. 13-34. Papillary squamous carcinoma, lacrimal sac. A. Exophytic papillary

epithelial tumor partially fills lumen of the lacrimal sac. Foci of squamous
differentiation are present. B. Papilloma, lacrimal sac with exophytic and inverted
components. Acanthotic fronds of transitional epithelium invade stroma in
inverted region. C. Inverted papilloma lacrimal sac. Inverted growth pattern is
more prominent in this tumor. Most lacrimal gland carcinomas arise from
inverted papillomas. D. In situ carcinoma, transitional epithelium. Full-thickness
epithelium is replaced by atypical cells. (A. H&E ×10, B. H&E ×25, C. H&E
×25, D. H&E ×400.)

BIBLIOGRAPHY
Eagle RC Jr. Specimen handling in the ophthalmic pathology laboratory. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.

423
 Ophthalmol Clin North America. Philadelphia, PA: WB Saunders, 1995;8:1–
15.
Font RL. Eyelids and lacrimal drainage system. In: Spencer W, ed. Ophthalmic
Pathology: An Atlas and Textbook, 4th ed., vol. 2. Philadelphia, PA: WB
Saunders, 1996:2218–2437.
Lever WF, Schaumburg-Lever G. Histopathology of the Skin, 7th ed.
Philadelphia, PA: JB Lippincott, 1990.

Developmental Lesions
Boyd PA, Keeling JW, Lindenbaum RH. Fraser syndrome (cryptophthalmos-
syndactyly syndrome): a review of eleven cases with postmortem findings.
Am J Med Genet 1988;31:159–168.
Culbertson WW, Ostler HB. The floppy eyelid syndrome. Am J Ophthalmol
1981;92:568–575.
Ellis FJ, Eagle RC Jr, Shields JA. Phakomatous choristoma (Zimmerman’s
tumor): immunohistochemical confirmation of lens-specific proteins.
Ophthalmology 1993;100:955–960.
Kidwell ED, Tenzel RR. Repair of congenital colobomas of the lids. Arch
Ophthalmol 1979;97:1931–1932.
Mansour AM, Wang F, Henkind P, et al. Ocular findings in the
facioauriculovertebral sequence (Goldenhar-Gorlin syndrome). Am J
Ophthalmol 1985;100:555–559.
Pe’er J, BenEzra D, Sela M, et al. Cryptophthalmos syndrome. Clinical and
histopathological findings. Ophthalmic Paediatr Genet 1987;8:177–182.
Schauer GM, Dunn LK, Godmilow L, et al. Prenatal diagnosis of Fraser
syndrome at 18.5 weeks gestation, with autopsy findings at 19 weeks. Am J
Med Genet 1990;37:583–591.
Schwartz LK, Gelender H, Forster RK. Chronic conjunctivitis associated with
‘floppy eyelids’. Arch Ophthalmol 1983;101:1884–1888.
Stefanyszyn MA, Hidayat AA, Flanagan JC. The histopathology of involutional
ectropion. Ophthalmology 1985;92:120–127.
Waardenburg P. A new syndrome combining developmental anomalies of the
eyelids, eyebrows and nose root with pigmentary defects of the iris and head
hair with congenital deafness. Am J Hum Genet 1951;3:195–253.
Whitaker LA, Katowitz JA, Jacobs WE. Ocular adnexal problems in craniofacial
deformities. J Maxillofac Surg 1979;7:55–60.

Benign Lesions
al-Hazzaa SA, Hidayat AA. Molluscum contagiosum of the eyelid and
infraorbital margin—a clinicopathologic study with light and electron
microscopic observations. J Pediatr Ophthalmol Strabismus 1993;30:58–59.
Averbuch D, Jaouni T, Pe’er J, et al. Confluent molluscum contagiosum covering

424
 the eyelids of an HIV-positive child. Clin Experiment Ophthalmol
2009;37:525–527.
Boniuk M, Zimmerman LE. Eyelid tumors with reference to lesions confused
with squamous cell carcinoma. II. Inverted follicular keratosis. Arch
Ophthalmol 1963;69:698–707.
Henderer JD, Tanenbaum M. Excision of multiple eyelid apocrine hidrocystomas
via an en-bloc lower eyelid blepharoplasty incision. Ophthalmic Surg Lasers
2000;31:157–161.
Kwitko ML, Boniuk M, Zimmerman LE. Eyelid tumors with reference to lesions
confused with squamous cell carcinoma. I. Incidence and errors in diagnosis.
Arch Ophthalmol 1963;69:693–697.
Leahey AB, Shane JJ, Listhaus A, et al. Molluscum contagiosum eyelid lesions as
the initial manifestation of acquired immunodeficiency syndrome. Am J
Ophthalmol 1997;124:240–241.
Luque Aranda R, Baquero Aranda I, Salido Hidalgo C, et al. Molluscum
contagiosum in a patient with no risk factors. Eur J Ophthalmol
2006;16:621–623.
Mencia-Gutierrez E, Gutierrez-Diaz E, Redondo-Marcos I, et al. Cutaneous horns
of the eyelid: a clinicopathological study of 48 cases. J Cutan Pathol
2004;31:539–543.
Mulugeta A. Giant molluscum contagiosum presenting as a tumour in an HIV-
infected patient: case report. Ethiop Med J 2000;38:125–130.
Perez-Blazquez E, Villafruela I, Madero S. Eyelid molluscum contagiosum in
patients with human immunodeficiency virus infection. Orbit 1999;18:75–81.
Robinson MR, Udell IJ, Garber PF, et al. Molluscum contagiosum of the eyelids
in patients with acquired immune deficiency syndrome. Ophthalmology
1992;99:1745–1747.
Sassani JW, Yanoff M. Inverted follicular keratosis. Am J Ophthalmol
1979;87:810–813.
Shields JA, Eagle RC Jr, Shields CL, et al. Apocrine hidrocystoma of the eyelid.
Arch Ophthalmol 1993;111:866–867.

Keratoacanthoma
Boniuk M, Zimmerman LE. Eyelid tumors with reference to lesions confused
with squamous cell carcinoma. III. Keratoacanthoma. Arch Ophthalmol
1967;77:29–40.
Cribier B. Keratoacanthoma? Better to say “squamous cell carcinoma,
keratoacanthoma type”. Ann Dermatol Venereol 2008;135:541–546.
Grossniklaus HE, Wojno TH, Yanoff M, Font RL. Invasive keratoacanthoma of
the eyelid and ocular adnexa. Ophthalmology 1996;103:937–941.
Hodak E, Jones RE, Ackerman AB. Solitary keratoacanthoma is a squamous-cell
carcinoma: three examples with metastases. Am J Dermatopathol
1993;15:332–342.

425
Mandrell JC, Santa Cruz D. Keratoacanthoma: hyperplasia, benign neoplasm, or a
type of squamous cell carcinoma? Semin Diagn Pathol 2009;26:150–163.
Requena L, Romero E, Sanchez M, et al. Aggressive keratoacanthoma of the
eyelid: “malignant” keratoacanthoma or squamous cell carcinoma? J
Dermatol Surg Oncol 1990;16:564–568.
Tan KB, Lee YS. Immunoexpression of Bcl-x in squamous cell carcinoma and
keratoacanthoma: differences in pattern and correlation with pathobiology.
Histopathology 2009;55:338–345.

Basal Cell Carcinoma

Doxanas MT, Green WR, Iliff CE. Factors in the successful surgical management
of basal cell carcinoma of the eyelid. Am J Ophthalmol 1981;91:726–736.
Einaugler RB, Henkind P. Basal cell carcinoma of the eyelid: apparent
incomplete removal. Am J Ophthalmol 1969;67:413–417.
Honavar SG, Shields JA, Shields CL, et al. Basal cell carcinoma of the eyelid
associated with Gorlin-Goltz syndrome. Ophthalmology
2001;108:1115–1123.
Jakobiec FA, Hanna E, Townsend DJ. Basal cell carcinoma of the eyelid with
exceptional histomorphologic expressions. Ophthal Plast Reconstr Surg
2009;25:232–234.
Kim GK, Del Rosso JQ, Bellew S. Skin cancer in Asians: Part 1: nonmelanoma
skin cancer. J Clin Aesthet Dermatol 2009;2(8):39–42.
Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105
persons with nevoid basal cell carcinoma syndrome. Am J Med Genet
1997;69:299–308.
Kimonis VE, Mehta SG, Digiovanna JJ, et al. Radiological features in 82 patients
with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med
2004;6:495–502.
Margo CE, Waltz K. Basal cell carcinoma of the eyelid and periocular skin. Surv
Ophthalmol 1993;38:169–192.
Milman T, McCormick SA. The molecular genetics of eyelid tumors: recent
advances and future directions. Graefes Arch Clin Exp Ophthalmol
2013;251(2):419–433.
Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med
2005;353(21):2262–2269.
Shields CL. Basal cell carcinoma of the eyelids. Int Ophthalmol Clin
1993;33:1–4.

Squamous Cell Carcinoma and Predisposing

Lesions
Caya JG, Hidayat AA, Weiner JM. A clinicopathologic study of 21 cases of
adenoid squamous cell carcinoma of the eyelid and periorbital region. Am J

426
 Ophthalmol 1985;99:291–297.
Dailey JR, Kennedy RH, Flaharty PM, et al. Squamous cell carcinoma of the
eyelid. Ophthal Plast Reconstr Surg 1994;10:153–159.
Faustina M, Diba R, Ahmadi MA, et al. Patterns of regional and distant
metastasis in patients with eyelid and periocular squamous cell carcinoma.
Ophthalmology 2004;111:1930–1932.
Gaasterland DE, Rodrigues MM, Moshell AN. Ocular involvement in xeroderma
pigmentosa. Ophthalmology 1982;89:980–986.
Hadi U, Tohmeh H, Maalouf R. Squamous cell carcinoma of the lower lid in a
19-month-old girl with xeroderma pigmentosum. Eur Arch Otorhinolaryngol
2000;257:77–79.
Lopez-Tizon E, Mencia-Gutierrez E, Garrido-Ruiz M, et al. Clinicopathological
study of 21 cases of eyelid actinic keratosis. Int Ophthalmol
2009;29:379–384.
Lund HZ. How often does squamous cell carcinoma of the eyelid metastasize.
Arch Dermatol 1965;92:635–637.
Marks R, Foley P, Goodman G, et al. Spontaneous remission of solar keratoses:
the case for conservative management. Br J Dermatol 1986;115:649–655.
Proia AD, Selim MA, Reutter JC, et al. Basal cell-signet-ring squamous cell
carcinoma of the eyelid. Arch Pathol Lab Med 2006;130: 393–396.
Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid. Surv
Ophthalmol 1986;30:349–365.
Scott KR, Kronish JW. Premalignant lesions and squamous cell carcinoma. In:
Albert DM, Jakobiec FA, eds, Principles and Practice of Ophthalmology:
Clinical Practice, vol. 3. Philadelphia, PA: WB Saunders, 1994:1733–1744.
Sullivan TJ. Squamous cell carcinoma of eyelid, periocular, and periorbital skin.
Int Ophthalmol Clin 2009;49:17–24.
Sullivan TJ, Boulton JE, Whitehead KJ. Intraepidermal carcinoma of the eyelid.
Clin Experiment Ophthalmol 2002;30:23–27.

Sebaceous Tumors
Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms as markers of Muir-
Torre syndrome: a diagnostic algorithm. J Cutan Pathol 2009;36:613–619.
Asadi-Amoli F, Khoshnevis F, Haeri H, et al. Comparative examination of
androgen receptor reactivity for differential diagnosis of sebaceous carcinoma
from squamous cell and basal cell carcinoma. Am J Clin Pathol
2010;134(1):22–26.
Demirci H, Nelson CC, Shields CL, et al. Eyelid sebaceous carcinoma associated
with Muir-Torre syndrome in two cases. Ophthal Plast Reconstr Surg
2007;23:77–79.
Dores GM, Curtis RE, Toro JR, et al. Incidence of cutaneous sebaceous
carcinoma and risk of associated neoplasms: insight into Muir-Torre
syndrome. Cancer 2008;113:3372–3381.

427
Doxanas MT, Green WR. Sebaceous gland carcinoma. Review of 40 cases. Arch
Ophthalmol 1984;102:245–249.
Eisen DB, Michael DJ. Sebaceous lesions and their associated syndromes: parts I
& II. J Am Acad Dermatol 2009;61:549–578.
Font RL, Rishi K. Sebaceous gland adenoma of the tarsal conjunctiva in a patient
with Muir-Torre syndrome. Ophthalmology 2003;110:1833–1836.
Hidayat AA, Font RL. Sebaceous carcinoma of the eyelids and caruncle of eyelid
and eyebrow: a clinicopathologic study of 31 cases. Arch Ophthalmol
1980;98:844–847.
Honavar SG, Shields CL, Maus M, et al. Primary intraepithelial sebaceous gland
carcinoma of the palpebral conjunctiva. Arch Ophthalmol 2001;119:764–767.
Jakobiec FA. Sebaceous adenoma of the eyelid and visceral malignancy. Am J
Ophthalmol 1974;78:952–960.
Jakobiec FA. Sebaceous tumors of the ocular adnexa. In: Albert DM, Jakobiec
FA, eds. Principles and Practice of Ophthalmology: Clinical Practice, vol. 3.
Philadelphia, PA: WB Saunders, 1994:1745–1770
Jakobiec FA, Werdich X. Androgen receptor identification in the diagnosis of
eyelid sebaceous carcinomas. Am J Ophthalmol 2014;157(3):687–696..e1–2.
Jakobiec FA, Zimmerman LE, La Piana F, et al. Unusual eyelid tumors with
sebaceous differentiation in the Muir-Torre syndrome. Rapid clinical
regrowth and frank squamous transformation after biopsy. Ophthalmology
1988;95:1543–1548.
Margo CE, Grossniklaus HE. Intraepithelial sebaceous neoplasia without
underlying invasive carcinoma. Surv Ophthalmol 1995;39:293–301.
Milman T, Schear MJ, Eagle RC Jr. Diagnostic utility of adipophilin immunostain
in periocular carcinomas. Ophthalmology 2014;121(4):964–971.
Mulay K, Shah SJ, Aggarwal E, et al. Periocular sebaceous gland carcinoma: do
androgen receptor (NR3C4) and nuclear survivin (BIRC5) have a prognostic
significance? Acta Ophthalmol 2014;92(8):e681–e687.
Mulay K, White VA, Shah SJ, et al. Sebaceous carcinoma: clinicopathologic
features and diagnostic role of immunohistochemistry (including androgen
receptor). Can J Ophthalmol 2014;49(4):326–332.
Pettey AA, Walsh JS. Muir-Torre syndrome: a case report and review of the
literature. Cutis 2005;75:149–155.
Plaza JA, Mackinnon A, Carrillo L, et al. Role of immunohistochemistry in the
diagnosis of sebaceous carcinoma: a clinicopathological and
immunohistochemical study. Am J Dermatopathol 2015;37(11):809–821.
Rao NA, Hidayat AA, McLean IW, et al. Sebaceous gland carcinoma of the
ocular adnexa: a clinicopathologic study of 104 cases with five year follow-up
data. Hum Pathol 1982;13:113–122.
Rishi K, Font RL. Sebaceous gland adenoma of the tarsal conjunctiva in a patient
with Muir–Torre syndrome. Ophthalmology 2003;110:1833–1836.
Rishi K, Font RL. Sebaceous gland tumors of the eyelids and conjunctiva in
patients with the Muir–Torre syndrome. A clinicopathological study of five

428
 cases and literature review. Ophthal Plast Reconstr Surg 2004;20(1):31–36.
Roberts ME, Riegert-Johnson DL, Thomas BC, et al. Screening for Muir-Torre
syndrome using mismatch repair protein immunohistochemistry of sebaceous
neoplasms. J Genet Couns 2013;22(3):393–405.
Shalin SC, Lyle S, Calonje E, et al. Sebaceous neoplasms and the Muir-Torre
syndrome: important connections with clinical implications. Histopathology
2010:56:133–147.
Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the eyelids:
personal experience with 60 cases. Ophthalmology 2004;111:2151–2157.
Shields JA, Demirci H, Marr BP, et al. Conjunctival epithelial involvement by
eyelid sebaceous carcinoma. The 2003 J. Howard Stokes lecture. Ophthal
Plast Reconstr Surg 2005;21:92–96.
Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region:
a review. Surv Ophthalmol 2005;50:103–122.
Sinard JH. Immunohistochemical distinction of ocular sebaceous carcinoma from
basal cell and squamous cell carcinoma. Arch Ophthalmol 1999;117:776–783.
Singh RS, Grayson W, Redston M, et al. Site and tumor type predicts DNA
mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol
2008;32(6):936–942.
Singh AD, Mudhar HS, Bhola R, et al. Sebaceous adenoma of the eyelid in Muir-
Torre syndrome. Arch Ophthalmol 2005;123:562–565.
Wolfe JT III, Yeatts RP, Wick MR, et al. Sebaceous carcinoma of the eyelid:
Errors in clinical and pathological diagnosis. Am J Surg Pathol
1984;8:597–606.
Yonekawa Y, Jakobiec FA, Zakka FR, et al. Sebaceoma of the eyelid.
Ophthalmology 2012;119(12):2645.e1–2645.e14.

Melanocytic Lesions
Chan FM, O’Donnell BA, Whitehead K, et al. Treatment and outcomes of
malignant melanoma of the eyelid: a review of 29 cases in Australia.
Ophthalmology 2007;114:187–192.
Esmaeli B, Youssef A, Naderi A, et al. Margins of excision for cutaneous
melanoma of the eyelid skin: the Collaborative Eyelid Skin Melanoma Group
Report. Ophthal Plast Reconstr Surg 2003;19:96–101.
Margo C. Pigmented Lesions of the Eyelid. In: Albert D.M., Jakobiec FA, eds.
Principles and Practice of Ophthalmology: Clinical Practice, vol. 3.
Philadelphia, PA: WB Saunders, 1994:1797–1812.
Naidoff MA, Bernardino VB Jr, Clark WH. Melanocytic lesions of the eyelid
skin. Am J Ophthalmol 1976;82:371–382.
Putterman AM. Intradermal nevi of the eyelid. Ophthalmic Surg
1980;11:584–587.
Rodriguez-Sains RS, Jakobiec FA, Iwamoto T. Lentigo maligna of the lateral
canthal skin. Ophthalmology 1981;88:1186–1192.

429
Sanchez R, Ivan D, Esmaeli B. Eyelid and periorbital cutaneous malignant
melanoma. Int Ophthalmol Clin 2009;49:25–43.
Tahery DP, Goldberg R, Moy RL. Malignant melanoma of the eyelid. A report of
eight cases and a review of the literature. J Am Acad Dermatol
1992;27:17–21.
Vaziri M, Buffam FV, Martinka M, et al. Clinicopathologic features and behavior
of cutaneous eyelid melanoma. Ophthalmology 2002;109:901–908.
Wang Q, Prieto V, Esmaeli B, et al. Cellular blue nevi of the eyelid: a possible
diagnostic pitfall. J Am Acad Dermatol 2008;58:257–260.

Adnexal Tumors
Aurora AL, Luxenberg MN. Case report of adenocarcinoma of the glands of
Moll. Am J Ophthalmol 1970;70:984–990.
Auw-Haedrich C, Boehm N, Weissenberger C. Signet ring carcinoma of the
eccrine sweat gland in the eyelid, treated by radiotherapy alone. Br J
Ophthalmol 2001;85:112–113.
Barker-Griffith AE, Streeten BW, Charles NC. Moll gland neoplasms of the
eyelid: a clinical and pathological spectrum in 5 cases. Arch Ophthalmol
2006;124:1645–1649.
Buchi ER, Peng Y, Eng AM, et al. Eccrine acrospiroma of the eyelid with
oncocytic, apocrine and sebaceous differentiation. Further evidence for
pluripotentiality of the adnexal epithelia. Eur J Ophthalmol 1991;1:187–193.
Hidayat AA, Font RL. Trichilemmoma of eyelid and eyebrow. A
clinicopathologic study of 31 cases. Arch Ophthalmol 1980;98:844–847.
Katowitz WR, Shields CL, Shields JA, et al. Pilomatrixoma of the eyelid
simulating a chalazion. J Pediatr Ophthalmol Strabismus 2003;40:247–248.
Khalil M, Brownstein S, Codere F, et al. Eccrine sweat gland carcinoma of the
eyelid with orbital involvement. Arch Ophthalmol 1980;98:2210–2214.
Kramer TR, Grossniklaus HE, McLean IW, et al. Histiocytoid variant of eccrine
sweat gland carcinoma of the eyelid and orbit: report of five cases.
Ophthalmology 2002;109:553–559.
Lahav M, Albert DM, Bahr R, et al. Eyelid tumors of sweat gland origin. Albrecht
von Graefes Arch Klin Ophthalmol 1981;216:301–311.
Levy J, Ilsar M, Deckel Y, et al. Eyelid pilomatrixoma: a description of 16 cases
and a review of the literature. Surv Ophthalmol 2008;53:526–535.
Mehta S, Thiagalingam S, Zembowicz A, et al. Endocrine mucin-producing sweat
gland carcinoma of the eyelid. Ophthal Plast Reconstr Surg
2008;24:164–165.
Netland PA, Townsend DJ, Albert DM, et al. Hidradenoma papilliferum of the
upper eyelid arising from the apocrine gland of Moll. Ophthalmology
1990;97:1593–1598.
Perez RC, Nicholson DH. Malherbe’s calcifying epithelioma (pilomatrixoma) of
the eyelid. Clinical features. Arch Ophthalmol 1979;97:314–315.

430
Shields JA, Shields CL, Eagle RC Jr, et al. Pilomatrixoma of the eyelid. J Pediatr
Ophthalmol Strabismus 1995;32:260–261.
Shintaku M, Tsuta K, Yoshida H, et al. Apocrine adenocarcinoma of the eyelid
with aggressive biological behavior: report of a case. Pathol Int
2002;52:169–173.
Shuster AR, Maskin SL, Leone CR Jr. Primary mucinous sweat gland carcinoma
of the eyelid. Ophthalmic Surg 1989;20:808–810.
Thomas JW, Fu YS, Levine MR. Primary mucinous sweat gland carcinoma of the
eyelid simulating metastatic carcinoma. Am J Ophthalmol 1979;87:29–33.
Tong JT, Flanagan JC, Eagle RC Jr, et al. Benign mixed tumor arising from an
accessory lacrimal gland of Wolfring. Ophthal Plast Reconstr Surg
1995;11:136–368.
Topping NC, Chakrabarty A, Edrich C, et al. Desmoplastic trichilemmoma of the
upper eyelid. Eye (Lond) 1999;13(Pt 4):593–594.
Wright JD, Font RL. Mucinous sweat gland carcinoma of the eyelid. A
clinicopathologic study of 21 cases with histochemical and electron
microscopic observations. Cancer 1979;44:1757–1768.
Yap EY, Hohberger GG, Bartley GB. Pilomatrixoma of the eyelids and eyebrows
in children and adolescents. Ophthal Plast Reconstr Surg 1999;15:185–189.
Zembowicz A, Garcia CF, Tannous ZS, et al. Endocrine mucin-producing sweat
gland carcinoma: twelve new cases suggest that it is a precursor of some
invasive mucinous carcinomas. Am J Surg Pathol 2005;29(10):1330–1339.

Eyelid Markers for Systemic Disease

Bardenstein DS, McLean IW, Nerney J, et al. Cowden’s Disease. Ophthalmology
1988;95:1038–1041.
Bianciotto C, Demirci H, Shields CL, et al. Metastatic tumors to the eyelid: report
of 20 cases and review of the literature. Arch Ophthalmol
2009;127:999–1005.
Bianciotto CG, Demirci HY, Shields CL, et al. Simultaneous eyelid and choroidal
metastases 36 years after diagnosis of medullary thyroid carcinoma. Ophthal
Plast Reconstr Surg 2008;24:62–63.
Carney JA. Carney complex: the complex of myxomas, spotty pigmentation,
endocrine overactivity, and schwannomas. Semin Dermatol 1995;14:90–98.
Jonsson A. Sigfusson N. Significance of xanthelasma palpebrarum in the normal
population. Lancet 1976;1(7955):372.
Kennedy RH, Flanagan JC, Eagle RC Jr, et al. The Carney complex with ocular
signs suggestive of cardiac myxoma. Am J Ophthalmol 1991;111:699–702.
Mansour AH, Hidayat AA. Metastatic eyelid disease. Ophthalmology
1987;94:667–670.
Ozdol S, Sahin S, Tokgozoglu L. Xanthelasma palpebrarum and its relation to
atherosclerotic risk factors and lipoprotein (a). Int J Dermatol
2008;47:785–789.

431
Robertson DM, Winkelmann RK. Ophthalmic features of necrobiotic
xanthogranuloma with paraproteinemia. Am J Ophthalmol 1984;97:173–183.
Rohrich RJ, Janis JE, Pownell PH. Xanthelasma palpebrarum: a review and
current management principles. Plast Reconstr Surg 2002;110:1310–1314.
Shields JA, Eagle RC Jr, Gausas RE, et al. Retrograde metastasis of cutaneous
melanoma to conjunctival lymphatics. Arch Ophthalmol
2009;127:1222–1224.
Tsilou ET, Chan CC, Sandrini F, et al. Eyelid myxoma in Carney complex
without PRKAR1A allelic loss. Am J Med Genet A 2004;130A:395–397.

Merkel Cell Carcinoma

Chan JK, Suster S, Wenig BM, et al. Cytokeratin 20 immunoreactivity
distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and
salivary gland small cell carcinomas from small cell carcinomas of various
sites. Am J Surg Pathol 1997;21: 226–234.
Cummings HL, Green WR. Merkel cell carcinoma of the eyelid: a report of two
new cases and a review of the literature. Md Med J 1992;41:149–153.
D’Agostino M, Cinelli C, Willard R, et al. Epidermotropic Merkel cell
carcinoma: a case series with histopathologic examination. J Am Acad
Dermatol 2010;62:463–468.
Kivela T, Tarkkanen A. The Merkel cell and associated neoplasms in the eyelids
and periocular region. Surv Ophthalmol 1990;35: 171–187.
Rubsamen PE, Tanenbaum M, Grove AS, et al. Merkel cell carcinoma of the
eyelid and periocular tissues. Am J Ophthalmol 1992;113:674–680.
Samimi M, Gardair C, Nicol JT, et al. Merkel cell polyomavirus in merkel cell
carcinoma: clinical and therapeutic perspectives. Semin Oncol
2015;42(2):347–358.
Santos-Juanes J, Fernández-Vega I, Fuentes N, et al. Merkel cell carcinoma and
Merkel cell polyomavirus: a systematic review and meta-analysis. Br J
Dermatol 2015;173(1):42–49.

Miscellaneous Lesions
Alper MG, Zimmerman LE, LaPiana FG. Orbital manifestations of Erdheim-
Chester disease. Trans Am Ophthalmol Soc 1983;81: 64–85.
Coston TO. Demodex folliculorum blepharitis. Trans Am Ophthalmol Soc
1967;65:361–392.
Eagle RC Jr, Penne RA, Hneleski IS Jr. Eyelid involvement in multicentric
reticulohistiocytosis. Ophthalmology 1995;102:426–430.
Feiler-Ofry V, Lewy A, Regenbogen L, et al. Lipoid proteinosis (Urbach-Wiethe
syndrome). Br J Ophthalmol 1979;63:694–698.
Ferry AP. Subcutaneous granuloma annulare (“pseudorheumatoid nodule”) of the
eyebrow. J Pediatr Ophthalmol 1977;14:154–157.

432
Floyd BB, Brown B, Isaacs H, et al. Pseudorheumatoid nodule involving the
orbit. Arch Ophthalmol 1982;100:1478–1480.
Game JA, Davies R. Mycosis fungoides causing severe lower eyelid ulceration.
Clin Experiment Ophthalmol 2002;30:369–371.
Girard C, Johnson WC, Graham JH. Cutaneous angiosarcomas. Cancer
1970;26:868–883.
Hamada T, McLean WH, Ramsay M, et al. Lipoid proteinosis maps to 1q21 and
is caused by mutations in the extracellular matrix protein 1 gene (ECM1).
Hum Mol Genet 2002;11(7):833–840.
Kheirkhah A, Casas V, Li W, et al. Corneal manifestations of ocular demodex
infestation. Am J Ophthalmol 2007;143(5):743–749.
Rosenthal G, Lifshitz T, Monos T, et al. Carbon dioxide laser treatment for lipoid
proteinosis (Urbach-Wiethe syndrome) involving the eyelids [letter]. Br J
Ophthalmol 1997;81:253.
Sanka RK, Eagle R Jr, Wojno TH, et al. Spectrum of CD30+ lymphoid
proliferations in the eyelid lymphomatoid papulosis, cutaneous anaplastic
large cell lymphoma, and anaplastic large cell lymphoma. Ophthalmology
2009;117:343–351.
Scupham RK, Fretzin DF. Necrobiotic xanthogranuloma with paraproteinemia.
Arch Pathol Lab Med 1989;113:1389–1391.
Valentine EA, Friedman HD, Zamkoff KW, et al. Necrobiotic xanthogranuloma
with IgA multiple myeloma: a case report and literature review. Am J
Hematol 1990;35:283–285.

Lacrimal Sac
Gupta A, Prabhakaran VC, Dodd T, et al. Characterization of lacrimal sac
histology: an immunohistochemical study. Clin Experiment Ophthalmol
2012;40(9):869–873.
Hardy AW, Dwivedi RC, Masterson L, et al. Inverted papilloma of lacrimal sac
invading into the orbit: case report and review of literature. J Cancer Res Ther
2015;11(1):238–240.
Pe’er JJ, Stefanyszyn M, Hidayat AA. Nonepithelial tumors of the lacrimal sac.
Am J Ophthalmol 1994;118:650–658.
Ryan SJ, Font RL. Primary epithelial neoplasms of the lacrimal sac. Am J
Ophthalmol 1973;76:73–88.
Stefanyszyn MA, Hidayat AA, Pe’er JJ, et al. Lacrimal sac tumors. Ophthal Plast
Reconstr Surg 1994;10:169–184.
Tanweer F, Mahkamova K, Harkness P. Nasolacrimal duct tumours in the era of
endoscopic dacryocystorhinostomy: literature review. J Laryngol Otol
2013;127(7):670–675.

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 14 Orbit
INTRODUCTION
Orbital disease is relatively uncommon, but quite diverse in nature.
Inflammatory diseases, such as infectious cellulitis, and the immunological
disorders thyroid ophthalmopathy and idiopathic orbital inflammation or
“pseudotumor” are encountered most often in general clinical practice.
However, the soft tissues of the orbit occasionally give rise to a relatively
broad spectrum of primary neoplasms, and the orbit can be involved
secondarily by systemic lymphoma, metastases from distant primary
cancers, or by tumors that arise in neighboring tissues such as conjunctiva,
eyelid, paranasal sinuses, or even the intracranial cavity (Fig. 14-1).

FIG. 14-1. Orbital contents. The orbital contents include the eye, optic nerve,
smooth and striated muscle, vessels, nerves, fatty and fibrous connective tissue,

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 and the lacrimal gland. They are delimited anteriorly by a fibrous tissue septum
and protected by the eyelids.

The essential clinical manifestation of orbital disease is ocular proptosis or

exophthalmos (Fig. 14-2A). The eye usually is pushed forward because the
orbit is a semiconfined space bounded by bony walls, and most orbital
diseases are space occupying. The proptotic eye may be pushed directly
forward (axial proptosis) or in other directions (i.e., down and in) that are
determined by and serve to indicate the location of the orbital lesion. For
example, tumors of the lacrimal gland, which is located in the
superotemporal orbit, typically push the eye inferomedially as well as
forward, while mucoceles of the ethmoid sinus in the medial orbital wall
cause lateral displacement. Retraction of the eye or enophthalmos occurs
occasionally. Causes of enophthalmos include traumatic blow-out fractures
of the orbital floor and sclerosing tumors such as metastatic scirrhous
breast carcinoma. Other symptoms and signs of orbital disease include
pain, loss of vision, and ocular motility disturbances, which may or may
not be conspicuous depending on the underlying cause; some orbital
tumors, that is, lymphomas, tend to be well tolerated. Others, that is,
metastatic carcinoma, are more likely to be symptomatic.

FIG. 14-2. A. Thyroid ophthalmopathy (Graves disease). The patient has

bilateral exophthalmos and a characteristic stare. Vertical extraocular muscle

435
 imbalance (right hypotropia) reflects fibrosis of right inferior oblique muscle. B.
CT shows massive enlargement of extraocular muscles. C. Postmortem
exenteration specimen from a patient with thyroid optic neuropathy shows
massive enlargement of extraocular muscles. D. Extraocular muscle from case
seen grossly in (C) contains patchy foci of chronic inflammatory cells composed
largely of lymphocytes. The myofibers are separated by fibrosis. The
inflammation in Graves disease characteristically spares the tendons of the
extraocular muscles and the orbital fat, features that serve to distinguish the
disorder histopathologically from idiopathic orbital inflammatory pseudotumor.
(C. Photo by the author. From
Hufnagel TJ, Hickey WF, Cobbs WH, et al. Immunohistochemical and ultrastructural studies on the exenterated
orbital tissues of a patient with Graves’ disease. Ophthalmology 1984;91:1411–1419. Courtesy of
Ophthalmology, D. H&E ×50.)

ORBITAL INFLAMMATORY
DISEASE
Most orbital disease encountered by the ophthalmologist in general
practice is inflammatory in nature. The most common inflammatory
diseases of the orbit include infectious orbital cellulitides, noninfectious
idiopathic orbital inflammation (inflammatory orbital pseudotumor), and
Graves disease or thyroid orbitopathy.
Orbital cellulitis usually is caused by the extension of a primary sinus
infection into adjacent soft tissues of the orbit (Fig. 14-3). Abscesses can
form beneath the periosteum (subperiosteal abscess) or in the orbital soft
tissues. Patients with orbital cellulitis have signs of acute inflammation
including erythema and pain as well as proptosis. Although most orbital
cellulitis is caused by bacteria, fungi such as Aspergillus or Mucor
occasionally invade the orbit from primary foci in the sinuses.
Haemophilus influenzae is an important cause of orbital cellulitis in
children but is becoming rarer due to immunization. Rarely, a clinical
picture resembling orbital cellulitis may be caused by an extensively
necrotic intraocular retinoblastoma or melanoma. Orbital involvement has
been reported in allergic fungal sinusitis (Fig. 14-4).

436
FIG. 14-3. Orbital cellulitis. A. CT scan of patient with orbital cellulitis shows
opacification of adjacent infected sinus. Orbital cellulitis often is caused by
extension of a primary sinus infection into orbital soft tissues. B. Orbital
abscess. An abscess is a focal collection of polymorphonuclear leukocytes. Many
of the polys infiltrating the orbital fat are degenerated. Basophilia reflects
necrosis. (A. Photo courtesy of Jurij Bilyk, MD, Wills Eye Institute, B. H&E
×100.)

FIG. 14-4. Allergic fungal sinusitis. A. CT scan shows massive involvement and
expansion of sinuses by allergic mucin. B. Allergic mucin contains clumps of
eosinophils and Charcot-Leyden crystals (arrow). C. GMS stain discloses hyphae
of noninvasive fungus within mucin. (B. H&E ×250, C. Gomori methenamine
silver ×250.)

Mucormycosis is a potentially lethal opportunistic infection by saprophytic

fungi that usually occurs in acidotic persons such as those with poorly
controlled diabetes. The fungus is vasotropic and invades orbital vessels
causing thrombosis and necrosis (Fig. 14-5). Histopathology shows both
acute and chronic granulomatous inflammation and necrotic tissue. The
hyphae are large and nonseptate and are easily identified in standard
hematoxylin and eosin (H&E)-stained sections. Lives occasionally can be
saved if an expedient diagnosis is made and antifungal therapy is
instituted.

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 FIG. 14-5. Mucormycosis. A. Necrotic orbital fat contains large branching
hyphae. The hyphae are readily seen in routine H&E sections. B. Fungus
infiltrates wall and lumen of thrombosed vessel. (A. H&E ×250, B. H&E ×100.)

Thyroid eye disease (thyroid ophthalmopathy, Graves orbitopathy) is the

most common cause of unilateral or bilateral exophthalmos (Fig. 14-2A).
Affected patients have an underlying immunological disorder, which is
complex and still poorly understood, that affects both the thyroid gland
and orbital structures, especially the extraocular muscles. The
exophthalmos is caused by enlargement of the extraocular muscles (Fig.
14-2B,C). The enlarged muscles contain foci of chronic nongranulomatous
inflammation and increased quantities of glycosaminoglycans and show
endomysial fibrosis (Fig. 14-2D). The tendon of the extraocular muscle
and the orbital fat characteristically are noninflamed, a feature that serves
to differentiate thyroid ophthalmopathy from idiopathic orbital
inflammation (pseudotumor). Visual loss due to compressive optic
neuropathy occurs in some patients when the swollen muscle bellies press
on the optic nerve in the crowded orbital apex. Corneal complications
caused by exposure can also cause visual loss. Graves ophthalmopathy can
occur in patients whose thyroid function tests are high, low, or even
normal. Most cases are readily diagnosed by the demonstration of enlarged
extraocular muscles on computed tomography (CT) or MRI scans. Very
few cases are biopsied.
Idiopathic orbital inflammation or pseudotumor is relatively common
(Fig. 14-6A,B). Although orbital pseudotumor undoubtedly is an
immunological disorder, the details of its immunopathology and the
identity of the antigens responsible for inciting the inflammation are still
unclear. Idiopathic orbital inflammatory pseudotumor is a diagnosis of
exclusion, from both the clinical and histopathological standpoint. The
presence of fungi, bacteria, and acid-fast organisms, foreign substances,
and other specific inflammatory diseases such as granulomatosis with

438
polyangiitis (GPA; Wegener) or sarcoidosis must be excluded with special
stains or appropriate tests.

FIG. 14-6. A. Idiopathic orbital inflammation, orbital fat (idiopathic

inflammatory pseudotumor). The orbital fat contains patchy foci of chronic
inflammatory cells. The polymorphous inflammatory infiltrate was composed
largely of lymphocytes and plasma cells. B. Idiopathic orbital inflammation
with fibrosis, lacrimal gland (sclerosing idiopathic inflammatory
pseudotumor). A few residual ductules persist in the eosinophilic, chronically
inflamed scar tissue that has replaced the lacrimal gland. Patchy foci of chronic
inflammatory cells are present. Higher magnification disclosed a polymorphous
inflammatory infiltrate composed largely of lymphocytes and plasma cells. C.
Sarcoidosis. Atrophic parenchyma of lacrimal gland contains multiple discrete
noncaseating granulomas consistent with sarcoidosis. D. Granulomatosis with
polyangiitis (Wegener). Granulomatous vasculitis involves orbital vessel. Foci
of necrosis were present. (A. H&E ×25, B. H&E ×25, C. H&E ×50, D. H&E
×50.)

Idiopathic orbital inflammation can affect both adults and children who
may have either unilateral or bilateral disease. Although occasional cases
are relatively asymptomatic and indolent in their course, idiopathic orbital
inflammation classically presents explosively with the acute onset of pain,
ocular proptosis, muscle paresis, and sometimes visual loss. The
inflammation may be localized to single orbital structures such as the

439
extraocular muscles (orbital myositis), the lacrimal gland (chronic
dacryoadenitis), or the sclera or episclera (scleritis or episcleritis). A
diagnostic trial of systemic corticosteroids may be administered to patients
suspected of having idiopathic orbital inflammation, because the disorder
is exquisitely sensitive to steroids.
Biopsy is often performed on patients with orbital inflammatory
pseudotumor. Microscopy typically discloses a polymorphous infiltrate of
inflammatory cells that may contain lymphocytes, plasma cells,
eosinophils, macrophages, and occasionally epithelioid histiocytes (Fig.
14-6A,B). Although vessels ringed or cuffed by chronic inflammation can
be seen, this reflects diapedesis of lymphocytes, not true vasculitis.
Lymphoid follicles and germinal centers occur in some cases, and fibrosis
is often extensive. If the lacrimal gland is involved, its acini are destroyed
by the inflammatory process and fibrosis replaces the parenchyma. The
fibrosis is responsible for the typically eosinophilic appearance of
specimens under low magnification light microscopy (Fig. 14-6B). This
eosinophilia usually distinguishes “pseudotumor” from lymphoid tumors,
which are composed of sheets of basophilic cells. Follicular lymphoid
hyperplasia is considered to be an orbital lymphoid tumor by ophthalmic
pathologists; it should not be called an inflammatory pseudotumor.
The sclerosing type of orbital pseudotumor may be a subset of IgG4-
related disease (Fig. 14-7). It has been estimated that 40% of patients with
idiopathic orbital inflammation have IgG4-related disease. The topic of
IgG4-related disease is somewhat confusing, and criteria for diagnosis are
not clear-cut. Classic diagnostic criteria in tissue biopsies include an
intense lymphoplasmacytic infiltrate with lymphoid follicles, obliterative
phlebitis, and often eosinophilia. Storiform fibrosis and obliterative
phlebitis are said to be rare in orbital disease, however. There also are
conflicting statements about the number of IgG4 plasma cells that are
required for diagnosis. Demonstration of IgG4-positive plasma cells
requires immunohistochemical stains for IgG4 and IgG (Fig. 14-7D). It is
often stated that the ratio of IgG4/IgG plasma cells should be at least 40%.
The actual intensity of the IgG4-positive plasma cell infiltrate is less clear.
Ten or more IgG4-positive plasma cells per high-power field is a
frequently stated criterion. However, some authors require much higher
counts, that is, 100/HPF for lacrimal gland involvement. The issue is
complicated further by the observation that IgG4-positive plasma cells are
common in orbital tissue from patients with variety of other inflammatory
disorders including sarcoidosis and GPA. Patients found to have IgG4-

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related disease in the orbit should be investigated for involvement of other
organs, because early treatment may prevent destructive changes.

FIG. 14-7. IgG4-related disease, orbit. A. Orbital biopsy comprises intense

follicular lymphoid hyperplasia and area of fibrosis at right. B. Area of storiform
fibrosis contains numerous plasma cells and eosinophils, shown at higher
magnification in (C). D. Many of the plasma cells (>100/HPF) are
immunoreactive for IgG4. (A. H&E ×10, B. H&E ×50, C. H&E ×400, D. IHC for
IgG4 ×250.)

If true vasculitis, granulomatous inflammation, and focal necrosis are

observed, the patient may have GPA, formerly called Wegener
granulomatosis (Fig. 14-6D). About one third of patients with GPA have
ophthalmic manifestations during the course of their disease, and they may
present with ocular findings such as orbital infiltration or peripheral
corneal ulceration. Clinical suspicion is important because the classic
histopathologic features of GPA are found in few orbital biopsies. Most
patients have concurrent sinus disease. The cytoplasmic antineutrophilic
cytoplasmic antibody (c-ANCA) test is a helpful diagnostic adjunct but
may be negative in the early stages of the disease.
Lacrimal gland biopsy typically discloses discrete noncaseating

441
granulomas composed of epithelioid histiocytes and giant cells in
sarcoidosis, which is another diagnosis of exclusion (Fig. 3-10A).
Lacrimal gland biopsy occasionally is performed to confirm the diagnosis
of sarcoidosis histopathologically.
Unusual inflammatory reactions related to the iatrogenic use or
instillation of various materials occasionally are encountered in the
eyelids, conjunctiva, or orbit. These substances include proprietary
formulations of collagen or hyaluronic acid used as dermal fillers in
cosmetic surgery and silicone oil used to tamponade the retina during
vitreoretinal surgery. Leaking silicone oil stimulates lipogranulomatous
inflammation that contains large vacuoles of oil and vacuolated histiocytes
(Fig. 14-8).

FIG. 14-8. Orbital silicone oil granuloma after vitreoretinal surgery. A. Excised
orbital tissue contains large vacuoles of silicone oil. B. Single encapsulated
vacuole. C. Orbital tissue contains large empty vacuoles with intervening
infiltrate of macrophages that have ingested oil, seen at higher magnification in
(D). (C. H&E ×250, D. H&E ×250.)

ORBITAL TUMORS
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A wide variety of benign and malignant primary neoplasms are spawned
by the tissues of the orbit. Most of these tumors are relatively rare.
Secondary involvement of the orbit by blood-borne metastases, systemic
lymphoproliferative disorders, or direct invasion from contiguous
structures also occurs. Children and adults are affected by different spectra
of orbital tumors.

Orbital Tumors in Adults

Primary orbital tumors that are encountered fairly often in adults include
cavernous hemangioma or malformation; schwannoma; solitary fibrous
tumor (SFT), which includes tumors previously diagnosed as fibrous
histiocytoma (FH) or hemangiopericytoma; epithelial tumors of the
lacrimal gland; and lymphoid tumors. Cavernous hemangioma and
lymphoid tumors are encountered most often.

LYMPHOID TUMORS
Orbital lymphoid tumors constitute a spectrum that includes polyclonal
reactive lymphoid hyperplasias and malignant lymphomas composed of
clonal proliferations of lymphoid cells (Figs. 14-9 and 14-10).
Immunophenotypic analysis has shown that most lesions previously
classified light microscopically as atypical lymphoid hyperplasias are low-
grade lymphomas. Lymphoma is also discussed in Chapter 5.

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FIG. 14-9. Lymphoid tumors. A. Cut surface of soft orbital lymphoma has
uniform salmon-yellow color. B. Follicular lymphoid hyperplasia. Small well-
differentiated lymphocytes surround a germinal center. The lighter cells in the
germinal center are tingible body macrophages, which are antigen-presenting
cells. Mitoses normally are found in germinal centers. The germinal center and
adjacent mantle zone are composed largely of B lymphocytes. C. Diffuse non-
Hodgkin lymphoma, well-differentiated lymphocytic type. Infiltrate is
composed of monotonous monomorphic sheet of small well-differentiated
lymphocytes. Immunophenotypic studies disclosed a monoclonal population of B
lymphocytes. D. Diffuse large cell lymphoma. This obviously malignant tumor
is composed of large, atypical immunoblastic B cells that have prominent
nucleoli. Apoptotic cells and mitoses are present. (B. H&E ×100, C. H&E ×250,
D. H&E ×250.)

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FIG. 14-10. A. Extranodal marginal zone lymphoma of MALT lymphoma.
Lymphoma is composed of diffuse infiltrate of small, well-differentiated B
lymphocytes. Immunohistochemical panel at the right shows that neoplastic B
cells express B cell marker CD20 but are negative for CD3, CD5, and CD10.
More than half of ocular adnexal lymphomas are MALT lymphomas. B. Mantle
cell lymphoma. The neoplastic B cells constituting mantle cell lymphoma
usually have irregular cleaved nuclei. The CD20-positive B cells coexpress T-cell
marker CD5 but are negative for CD3. Positive immunoreactivity for BCL-1
(cyclin D1) confirms the diagnosis. Mantle cell lymphoma has a poor prognosis.
(A. Main figure: H&E ×250, insets: IHC for CD20, CD3, CD5, and CD10, all
×100; B. Main figure: H&E ×250, insets: IHC for CD20, CD3, CD5, and BCL-
1, all ×100.)

Orbital lymphoma usually is a disorder of older patients that is diagnosed

on average at age 60 years. The onset of orbital lymphoma is usually
insidious. Orbital lymphoid tumors typically present with painless, well-
tolerated proptosis, because the tumor has no fibrous stroma, is soft and
pliable, and molds to the globe and other orbital structures. Some patients
may present with a conjunctival mass or patch of salmon-colored tissue on
the epibulbar surface or fornix (Figs. 5-32A,B and 14-9A). The tumor’s
characteristic salmon hue reflects the presence of many fine capillaries.
The lymphoid infiltrate is often delimited sharply by tissue planes. The
latter are evident on imaging studies as linear margins. Lymphomas

445
diffusely infiltrate and thicken the lacrimal gland, which drapes around the
globe assuming an appearance that Jakobiec has facetiously termed a
“pregnant pancake.” The latter contrasts with epithelial neoplasms of the
lacrimal gland, which typically are rounded. Ninety percent of orbital
lymphomas involve the superior part of the orbit behind the orbital septum.
More than 40% involve the lacrimal gland and often affect its palpebral
lobe. Bone destruction is very rare except in multiple myeloma. When
extraocular muscles are involved, usually a single muscle is affected.
Motility remains normal because the lymphoma does not stimulate
fibrosis.
Ocular lymphomas are extranodal by definition because the orbit lacks
lymphatics and lymph nodes, and most are diffuse, as well. About two
thirds of ocular adnexal lymphoid tumors are malignant non-Hodgkin
lymphomas (NHL) composed of a monoclonal proliferation of B
lymphocytes, and most of these are low-grade lesions composed of well-
differentiated lymphocytes. In recent years, pathologists have used the
WHO classification to classify lymphomas. Types of NHL in the WHO
classification that typically affect the ocular adnexa include extranodal
marginal zone lymphoma of mucosa-associated lymphoid tissue (often
called MALT lymphoma), follicular lymphoma, mantle cell lymphoma,
diffuse large cell lymphoma, and small lymphocytic lymphoma (SLL)
(Fig. 14-9C,D).
More than half of ocular adnexal lymphomas are MALT lymphomas.
About 23% are follicular lymphomas, 5% mantle cell, and 4% small
lymphocytic lymphoma (SLL/CLL). These four entities are very difficult
to differentiate using routine light microscopy alone, but distinguishing
them is important clinically because they differ greatly in prognosis and
the proper choice of therapy requires accurate classification. The cells of
extranodal marginal zone or MALT lymphoma are CD20 positive but are
negative for CD3, CD5, and CD10 (Fig. 14-10A). Mantle cell lymphoma
is usually widely disseminated on presentation and has a poor prognosis.
Its CD20-positive B cells coexpress T-cell marker CD5 and BCL-1 (also
called cyclin D1) (Fig. 14-10B). The cells constituting the neoplastic
follicles of follicular lymphoma stain with CD20, CD10, and BCL-2 (Fig.
5-34). About one third of patients who have orbital lymphomas have a past
history of, or will develop, systemic lymphoma. All patients with ocular
adnexal lymphoid tumors need to be evaluated by a hematologist–
oncologist. Some patients with polyclonal lymphoid proliferations are a
risk for systemic lymphoma.

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 Lymphoid tumors of the orbit and ocular adnexa are treated with
external beam radiotherapy, chemotherapy, and immunotherapy with
agents such as rituximab, a monoclonal antibody directed against B
lymphocytes. External beam radiotherapy with appropriate eye shielding
can be used if there is no evidence of systemic disease. Chemotherapy or
immunotherapy should be used if extraocular systemic lymphoma is
present. This may be supplemented with adjuvant radiotherapy if ocular
regression is subtotal.

VASCULAR LESIONS
Cavernous hemangioma or malformation is probably the most common
primary orbital tumor (Fig. 14-11). These lesions recently have been
categorized as nondistensible venous malformations. Cavernous
hemangiomas typically occur in middle-aged women. They cause low-
grade proptosis and usually are well tolerated, sparing vision and ocular
motility. Some cases are discovered incidentally when imaging is
performed for headache or other indications. These benign vascular tumors
are well-circumscribed, encapsulated lesions with a pebbly surface that
appear dusky red or purplish-blue grossly (Fig. 14-11B). They are
composed of large round or oval vascular spaces lined by endothelium,
which are separated by thick septa of fibrous tissue that may contain
smooth muscle (Fig. 14-11C,D). Cavernous hemangiomas show little
contrast enhancement on imaging studies because their circulation is
relatively stagnant. Other vascular lesions that affect the orbit include
varices and arteriovenous malformations. Patients with orbital varices
often show variable proptosis that depends on head position and is
increased by a Valsalva maneuver. Histopathology shows a markedly
dilated vein that may contain a thrombus (Fig. 14-12D). Intravascular
papillary endothelial hyperplasia may develop in the thrombosed varix.
Tumors previously diagnosed as hemangiopericytomas are now considered
to be SFTs. Lymphangioma and capillary hemangioma are discussed in the
“Pediatric Orbital Tumors” section below (Fig. 14-12).

447
FIG. 14-11. Cavernous hemangioma (malformation), orbit. A. CT scan shows
characteristically well-circumscribed oval mass within muscle cone. The
differential diagnosis of a well-circumscribed orbital tumor also includes
schwannoma, hemangiopericytoma, and SFT. B. After fixation, the well-
circumscribed, encapsulated tumor appears bluish-purple in color and has a
pebbly surface. C. The benign encapsulated tumor is composed of large blood-
filled vascular channels separated by fibrous septa that are evident grossly. D.
The large vascular channels constituting the benign vascular tumor are lined by a
single layer of endothelial cells. The fibrous septa separating the vessels often
contain smooth muscle. (D. H&E ×25.)

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FIG. 14-12. Vascular lesions. A. Lymphangioma with secondary hemorrhage.
Blood-filled chocolate cysts caused by secondary hemorrhage into lymphangioma
are evident in this gross specimen. Many lymphangiomas contain blood.
Lymphangiomas typically are unencapsulated and show an infiltrative growth
pattern. B. Lymphangioma, orbit. Lymphoid channels constituting
lymphangioma vary markedly in size and shape. They appear empty or contain
serous fluid if intralesional hemorrhage has not occurred. Lymphoid foci in
intervascular septa help to differentiate a lymphangioma with secondary
hemorrhage from a cavernous hemangioma. Lymphangiomas typically are
unencapsulated and have an infiltrative growth pattern. C. Capillary
hemangioma. Mature capillary hemangioma is composed of a plexus of capillary
caliber vessels. Early lesions often are composed predominantly of a solid sheet
of endothelial cells. Vascular lumina develop and become progressively ectatic at
the lesion matures. D. Thrombosed varix, orbit. A varix is a dilated or ectatic
vein. An organized thrombus adheres to the wall of this orbital varix. (B. H&E
×10, C. H&E ×100, D. H&E ×5.)

Neurogenic Tumors
Neurogenic tumors of the orbit include schwannomas, neurofibromas,
amputation neuromas, and malignant peripheral nerve sheath tumors.
Schwannoma or neurilemmoma (Fig. 14-13) is a well-circumscribed,
encapsulated orbital tumor of adults composed of a neoplastic proliferation

449
of Schwann cells, the perineural cells that form the myelin sheaths around
axons in peripheral nerves. Many orbital schwannomas arise from sensory
branches of the ophthalmic division of the trigeminal nerve and may be
painful. Histopathology shows an encapsulated spindle cell neoplasm
composed of cells with eosinophilic cytoplasm that have indistinct cellular
borders and bland elongated oval nuclei. Two growth patterns are
recognized. Tumors with the solid Antoni A pattern show bands of nuclear
palisading and structures called Verocay bodies (Fig. 14-13C). The Antoni
B pattern is marked by a loose myxomatous background. Schwannomas
are immunoreactive with neural markers such as S100 protein and CD57
(Fig. 14-13D).

FIG. 14-13. Schwannoma (neurilemoma). A. Benign peripheral nerve sheath

tumor appears grossly as piriform encapsulated mass. B. Cut surface has yellow-
white translucent appearance with vascular foci. C. Antoni A portion (above) is
composed of fascicles of bland spindle cells that show nuclear palisading and
enclose tangles of fibrillary processes called Verocay bodies. A small focus of
looser myxoid tumor (Antoni B pattern) is seen below. D. The tumor shows
positive immunoreactivity for S100 protein. Schwannomas are well-
circumscribed, encapsulated tumors that are associated with a peripheral nerve.
(C. H&E ×100, D. IHC for S100 protein.)

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Isolated neurofibromas cause diffuse enlargement of the affected nerve
and contain axons. They are pseudoencapsulated. Schwannomas and
neurofibromas are often grouped together under the designation peripheral
nerve sheath tumor. Schwannomas and isolated neurofibromas are more
prevalent in patients who have neurofibromatosis. Plexiform
neurofibromas and diffuse neurofibromas are characteristic manifestations
of neurofibromatosis type 1 (NF1). Malignant peripheral nerve sheath
tumors are encountered rarely.

Solitary Fibrous Tumor (SFT), Fibrous

Histiocytoma, and Hemangiopericytoma
SFTs are fairly common spindle cell neoplasms that can affect the orbit
(Fig. 14-14). Many orbital lesions that previously were diagnosed as FH
and hemangiopericytoma prior to the ready availability of
immunohistochemical diagnosis now are diagnosed as SFT. Essentially,
there has been a change in terminology; prior clinical observations about
FH and hemangiopericytoma of the orbit remain valid. All three of these
lesions tend to be well-circumscribed orbital tumors.

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FIG. 14-14. Solitary fibrous tumor, orbit. A. SFT is encapsulated. B. Cellular
tumor exhibits hemangiopericytomatous vascular pattern with vascular sinusoids.
C. Spindle cells in this tumor are arranged in a “patternless pattern” and are
separated by thick bands of collagen. D. Arrangement of tumor cells in this field
resembles FH. E.Tumor cells are immunoreactive for CD34. A vascular sinusoid
is present. F. Tumor cell nuclei stain for STAT6. (B. H&E ×50, C. H&E ×250,
D. H&E ×250, E. IHC for CD34 ×100, F. IHC for STAT6 ×250.)

SFT was initially diagnosed in the pleura. It often is composed of spindle

cells that are arranged in a patternless pattern and are separated by thick
bands of collagen. Diagnosis is confirmed by positive immunoreactivity

452
for CD34 and STAT6 (Fig. 14-14E,F). Many tumors also stain for CD99
and BCL-2. SFTs have a characteristic gene fusion of the NAB2 and
STAT6 genes.
Relatively rare orbital lesions, hemangiopericytomas originally were
classified as vasculogenic soft tissue tumors that were thought to arise
from pericytes in the walls of capillaries. Large sinusoidal vessels with a
branching “staghorn” configuration are a classic histopathologic feature,
and the reticulin stain shows that its constituent cells are totally enveloped
by basement membrane. About 15% of patients with orbital lesions
classified as hemangiopericytoma reported in 1982 by Croxatto and Font
at the Armed Forces Institute of Pathology developed distant metastases.
The histologic appearance of the tumor did not always predict metastatic
potential, as metastatic disease occasionally developed in patients with
benign-appearing tumors. In recent years, authorities have stressed that
SFT may show a branching staghorn hemangiopericytomatous vascular
pattern (Fig. 14-14B,E). Some authorities have questioned whether
hemangiopericytoma actually exists. The diagnosis is no longer included
in the WHO classification of soft tissue tumors.
Decades ago, FH was said to be the most common mesenchymal
tumor of the orbit in adults. Currently, most of these tumors would be
classified as SFT based on their immunoreactivity. Such lesions typically
are well circumscribed but nonencapsulated, and their constituent spindle
cells are said to be arranged in a characteristic whirling, pinwheel, or
storiform pattern. Benign, locally aggressive, and rare malignant variants
of FH were recognized, as is also the case with SFT. Although tumors
classified as benign and locally aggressive cannot metastasize, total
excision is recommended to prevent recurrence.
A variety of rare mesenchymal tumors of fibrous, fibro-osseous,
smooth muscle, adipose tissue or cartilaginous derivation occur in the
orbit. Other extremely rare primary orbital tumors include endodermal
sinus tumor, alveolar soft part sarcoma, granular cell tumor,
paraganglioma, primary orbital carcinoid, primary orbital melanoma,
retinal anlage tumor, neuroepithelioma, ectomesenchymal tumor,
malignant rhabdoid tumor, and primitive neuroectodermal tumor.
Common fibro-osseous lesions of the orbital bones include fibrous
dysplasia, juvenile psammomatoid ossifying fibroma, and ivory osteoma.
Ivory osteoma is the most common bony lesion in adults. Fibrous
dysplasia generally occurs in the first two decades and may spread across
suture lines to involve multiple orbital bones. The affected bones have a

453
“ground-glass” appearance in CT bone windows (Fig. 14-15A). Fibrous
dysplasia is composed of irregular trabeculae of immature woven bone
surrounded by fibrous stroma (Fig. 14-15B–D). The bony trabeculae are
not rimmed by osteoblasts and are often shaped like Chinese characters.

FIG. 14-15. Fibro-osseous lesions. A. Fibrous dysplasia. Lesion of nasal bones

has “ground-glass” appearance on CT scan. Fibrous dysplasia may spread across
suture lines to involve multiple orbital bones. B. Fibrous dysplasia. Fibrous
stroma contains irregular trabeculae of immature woven bone, which are not
rimmed by osteoclasts. Fibrous dysplasia represents an arrest in the maturation of
bone. C. Polarization microscopy of fibrous dysplasia discloses an irregular
interweaving pattern of collagenous matrix that resembles the fibers in woven
cloth. D. In contrast, collagen fibers disclosed by polarization in mature lamellar
bone form highly regular, parallel lamellae. E. Psammomatoid ossifying
fibroma. The cellular stroma contains spindle cells and small spicules of bone
called ossicles that can be confused with the psammoma bodies of meningioma.
This benign lesion found in young individuals has an expansile growth pattern
and behaves more aggressively than fibrous dysplasia. It usually does not cross
suture lines and is restricted to a single orbital bone. (B. H&E ×25, C. H&E with
crossed polarizers ×50, D. H&E with crossed polarizers ×50, E. H&E ×100.)

Juvenile ossifying fibroma is a more aggressive expansile lesion that

usually is restricted to a single bone. Radiographically, it has a sclerotic
margin and a less radiodense center. The cellular fibrous stroma of the

454
psammomatoid variant of juvenile ossifying fibroma contains bony
spicules that can be confused with psammoma bodies and lead to the
misdiagnosis of meningioma (Fig. 14-15E).
The orbital bones occasionally are affected by a perplexing group of
rare osseous lesions that contain giant cells including aneurysmal bone
cyst, giant cell reparative granuloma, giant cell tumor, the brown tumor of
hyperparathyroidism, and eosinophilic granuloma (see below). Osteogenic
sarcoma and other soft tissue sarcomas can arise after radiotherapy for
retinoblastoma.

THE LACRIMAL GLAND

The lacrimal gland is a minor salivary gland that is located in a bony fossa
behind the superotemporal orbital rim (Fig. 14-16). Lacrimal gland tumors
constitute only 10% to 15% of orbital lesions. Most lacrimal gland lesions
encountered in nonreferral clinical practice are inflammatory or lymphoid
tumors, which are at least five times more prevalent than primary epithelial
tumors. Epithelial neoplasms of the lacrimal gland are quite rare, but they
are important because about half are highly malignant tumors that are
potentially lethal.

FIG. 14-16. Lacrimal gland. A. Fibrofatty stroma separates multiple lobules

composed of glandular acini. Patchy foci of chronic inflammation are present. B.
Lacrimal gland, acini. Inner layer of tall columnar secretory cells and a
relatively inconspicuous discontinuous outer layer of contractile myoepithelial
cells comprise acini of lacrimal gland. Large intensely eosinophilic secretory
granules called zymogen granules are found in the apical cytoplasm of the
secretory cells. (A. H&E ×10, B. H&E ×250.)

Granulomatous dacryoadenitis can cause bilateral lacrimal gland

enlargement and a characteristic “s”-shaped lid fissure in patients with

455
sarcoidosis (Fig. 14-6C). Keratoconjunctivitis sicca develops in patients
with Sjögren syndrome when intense lymphocytic infiltration replaces the
parenchyma of the lacrimal gland. Damaged ducts and epimyoepithelial
islands persist in the resultant benign lymphoepithelial lesion, and patients
are at risk for lymphoma. Cystic dilation of lacrimal gland ducts
(dacryops) may simulate a primary lacrimal gland tumor. Concretions or
stones (dacryolithiasis) occasionally form in the ducts of the lacrimal
gland.

Epithelial Tumors of the Lacrimal Gland

Compared to other salivary glands, the lacrimal gland gives rise to a
relatively limited spectrum of primary epithelial neoplasms (Figs. 14-17 to
14-19). About one half of epithelial tumors of the lacrimal gland are
pleomorphic adenomas or benign mixed tumors, and half are malignant.
Lacrimal gland malignancies include adenoid cystic carcinomas (ACC),
malignant mixed tumors derived from pleomorphic adenomas, and
adenocarcinomas that have arisen de novo. Mucoepidermoid carcinoma is
quite rare in the lacrimal gland and acinic cell (Fig. 14-19C), and Warthin
tumors are almost nonexistent. The lacrimal gland gives rise to a greater
proportion of malignant tumors than the parotid gland.

FIG. 14-19. Rare malignant tumors of lacrimal gland. A. Mucoepidermoid

456
carcinoma, lacrimal gland. Tumor is composed of sheets of eosinophilic
squamous cells with a “paving stone” arrangement and mucus-producing goblet
cells. Mucoepidermoid carcinoma is an extremely rare lacrimal gland tumor that
behaves less aggressively than do other lacrimal gland malignancies. B.
Malignant mixed tumor, lacrimal gland. The epithelial tubules constituting this
field are composed of frankly malignant cells. Most malignant mixed tumors
result from the malignant degeneration of a benign mixed tumor. C. Acinic cell
carcinoma, lacrimal gland. Acinic cell carcinomas of the lacrimal gland are
very rare. D. Ductal adenocarcinoma, lacrimal gland. Malignant cells within
ducts are arranged in cribriform pattern. This rare variant of lacrimal gland
adenocarcinoma resembles ductal carcinoma of the breast. (A. H&E ×100, B.
H&E ×50, C. H&E ×50, D. H&E ×25.)

FIG. 14-17. Pleomorphic adenoma (benign mixed tumor), lacrimal gland. A.

Sagittal and coronal CT scans of right orbit disclose well-circumscribed tumor in
superotemporal orbit that has produced accentuation of lacrimal fossa. B. Convex
bosselations are present on surface of well-circumscribed, pseudoencapsulated
tumor. C. Tumor is composed of neoplastic ductules of epithelial cells set in a
fibromyxoid stroma. The term mixed tumor refers to this mixture of epithelial
and mesenchymal elements. D. The epithelial ductules are composed of two
layers of cells. Myoepithelial cells from the outer layer spindle off into the
surrounding stroma where they may undergo metaplasia into myxoid tissue,
cartilage, or rarely bone. (C. H&E ×25, D. H&E ×100.)

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FIG. 14-18. ACC, lacrimal gland. A. Tumor disclosed by CT scan has irregular
margins and has produced scalloped fossa in orbital bone. The tumor developed
rapidly and was painful. B. ACC, lacrimal gland (cribriform pattern). Multiple
pools of mucin impart a “Swiss cheese” appearance to the basophilic lobules of
cells constituting the cribriform pattern of ACC. The tumor cells are relatively
uniform and have a deceptively bland appearance. ACC has a dismal prognosis.
C. ACC, lacrimal gland, perineural invasion. Infiltrative ACC surrounds a
large orbital nerve. This highly malignant tumor has a propensity for neural and
perineural invasion. Patients may present with pain. D. ACC, lacrimal gland
(basaloid pattern). Poorly differentiated tumor is composed of solid lobules of
deeply basophilic cells with scanty cytoplasm. Absence of peripheral palisading
serves to differentiate basaloid ACC from invasive basal cell carcinoma. ACC
with a basaloid component has a poor prognosis. (B. H&E ×25, C. H&E ×150, D.
H&E ×100.)

Epithelial tumors of the lacrimal gland typically arise in relatively young

individuals whose average age at diagnosis is about forty. Several signs
and symptoms are very important in the clinical evaluation of patients with
lacrimal gland tumors. These include the duration of symptoms, the
presence of pain, and the status of the orbital bones on imaging studies. A
tumor is probably malignant if it is has been present for <6 months, the
patient complains of pain, and there is radiographic evidence of bony
erosion. Benign pleomorphic adenomas produce a regular, well-corticated
fossa in the bone, not bone erosion.

458
 Pleomorphic adenoma or benign mixed tumor has a slight male
predominance. The patient typically presents with painless proptosis that
has been present for a year or more (Fig. 14-17). The eye is displaced
inferonasally. Imaging studies disclose a rounded or oval mass that usually
involves the gland’s orbital lobe. As noted above, the pressure of the
slowly enlarging lesion does not destroy bone; rather it accentuates the
lacrimal fossa (Fig. 14-17A). Macroscopically, the tumor is well
circumscribed and pseudoencapsulated, and its surface is marked by
convex bosselations (Fig. 14-17B). Sectioning may disclose mucinous or
myxomatous areas and hemorrhage. The term mixed tumor reflects the
biphasic mixture of epithelial and mesenchymal elements seen
histopathologically (Fig. 14-17C,D). The epithelial components include
ducts composed of an inner layer of cuboidal or columnar cells and an
outer layer of flattened or spindled myoepithelial cells. The myoepithelial
cells typically spindle off into the stroma where they may maintain a
spindled configuration, or undergo metaplasia forming the mesenchymal
part of the tumor including myxoid tissue, cartilage, or rarely fat or bone.
Electron microscopic studies suggest that pleomorphic adenomas probably
are derived from the duct cells of the lacrimal gland. Pleomorphic
adenomas have specific gene fusions that involve the PLAG1 and HMGA2
oncogenes, and the diagnosis can be confirmed using
immunohistochemical stains for PLAG1.
If pleomorphic adenoma of the lacrimal gland is suspected clinically,
the tumor should be totally excised within an intact capsule. Benign mixed
tumors should never be biopsied. An orbital recurrence will develop in
about one third of patients after incisional biopsy is performed. Recurrent
benign mixed tumor can infiltrate orbital soft tissues and even bone and
brain, and the recurrences also are prone to malignant degeneration. The
rate of malignant degeneration in recurrent benign mixed tumor is 10%
and 20%, respectively, at 20 and 30 years.
ACC (Fig. 14-18) is the second most common epithelial neoplasm of
the lacrimal gland, constituting 25% to 30% of cases. About 60% of cases
occur in women. Although the average age at presentation is 40 years,
ACC has a biphasic age distribution and tumors occasionally develop in
children. Patients with ACC typically have had symptoms for a relatively
short period of time. The tumor has a propensity for perineural invasion
(Fig. 14-18C) and can present with pain and/or numbness, blepharoptosis,
and ocular motility deficits. Unfortunately, it may have already extended
out of the orbit via nerves before becoming symptomatic.

459
 ACC tends to be rounded or globular in imaging studies like
pleomorphic adenoma, but the margin of the tumor is often irregular or
serrated and it may extend into the medial or posterior orbit (Fig. 14-18A).
Bone destruction is seen in 80% of cases. Five histologic patterns of ACC
are recognized: the cribriform or “Swiss cheese,” the basaloid or solid
pattern, a sclerosing pattern, a tubular pattern with true duct formation, and
a comedocarcinoma pattern marked by tumor lobules with central necrosis.
A thick basement membrane surrounds the epithelial elements in the
cylindromatous variant. The cribriform pattern is characterized by
smoothly rounded biomorphic sheets of deceptively bland-appearing
basaloid cells that contain round pools of mucin that mimic glands (Fig.
14-18B). The term adenoid means “gland-like.” About half of ACC have a
balanced translocation between the genes for MYB and NFIB transcription
factors. Strong immunostaining for MYB is very specific for ACC but is
not present in all cases.
The prognosis of ACC of the lacrimal gland is dismal; only 20% of
patients survive 10 years. Many fatal tumors invade the middle cranial
fossa through the superior orbital fissure. Late pulmonary metastases also
occur. Survival correlates with tumor histology; the poorly differentiated
basaloid pattern is particularly ominous (Fig. 14-18D). If foci of basaloid
tumor are found, the 5-year survival is 21% and the median survival is 3
years. If no basaloid tumor is found, the 5-year survival increases to 71%
and the median survival to 8 years.
The management of ACC of the lacrimal gland is controversial. An
incisional biopsy should be performed if the diagnosis is suspected on
clinical grounds. Orbital exenteration should be performed after the
diagnosis is confirmed by review of permanent sections. The decision to
perform a mutilating operation such as orbital exenteration should never be
based on frozen section diagnosis. Some authorities recommend en bloc
resection of the tumor and contiguous bone or radical orbitectomy
including the roof and lateral walls of the orbit. Improved survival has
been reported in patients treated with neoadjuvant intra-arterial
cytoreductive chemotherapy followed by orbital exenteration and
intravenous chemotherapy.
Malignant mixed tumor (pleomorphic adenocarcinoma) usually results
from the malignant transformation of benign mixed tumor (Fig. 14-19B).
Patients with malignant mixed tumors generally are older than patients
who have benign mixed tumors. In most cases, the tumor contains a clone
of poorly differentiated adenocarcinoma that may show squamous, acinar,

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or sebaceous differentiation. Patients usually succumb within 3 years with
lung and lymphatic node metastases. The prognosis of adenocarcinoma de
novo is equally poor. Most of these poorly differentiated tumors occur in
older men. Mucoepidermoid carcinoma of the lacrimal gland has a better
prognosis than other epithelial malignancies, but is quite rare.
Histopathologically, the tumor contains paving stone-like squamous
elements and mucous-secreting goblet cells (Fig. 14-19A). Many
mucoepidermoid carcinomas have a MECT1–MAML2 translocation.
Treatment includes exenteration or wide local excision. Rare examples of
primary ductal adenocarcinoma (Fig. 14-19D), acinic cell carcinoma
(Fig.14-19C), basal cell adenocarcinoma, lymphoepithelial carcinoma,
epithelial–myoepithelial carcinoma, and cystadenocarcinoma have been
reported in the lacrimal gland.

Secondary Orbital Tumors

Secondary orbital neoplasms in adults include metastases from distant
primary tumors and tumors that have invaded the orbit from contiguous
structures. Breast carcinoma, especially the lobular variant, metastasizes to
the orbit most frequently, constituting 42% of 195 orbital metastases in a
combined series (Fig. 14-20A). Other common sources of orbital
metastases include lung (12.8%), prostate (6.7%), and gastrointestinal
carcinomas (4.1%). The primary tumor was unknown in 11.3% of cases.

FIG. 14-20. Secondary orbital lesions. A. Metastatic breast carcinoma, orbit. The
carcinoma cells are arranged in a linear “Indian file” fashion. Inset shows signet
ring cells with prominent cytoplasmic vacuoles of mucin. B. Mucocele. The
mucocele is lined by ciliated respiratory epithelium. It arose in the ethmoid sinus.
(A. H&E ×100, inset H&E ×250, B. H&E ×100.)

Tumors that directly invade the orbit include basal cell, squamous cell, and

461
sebaceous gland carcinomas of the eyelid and malignant melanomas and
squamous cell and mucoepidermoid carcinomas of the conjunctiva.
Secondary orbital tumors also result from the extraocular extension of
intraocular tumors, most notably retinoblastoma and uveal melanoma. In
underdeveloped countries, retinoblastoma frequently presents as an orbital
tumor that requires exenteration (Fig. 12-2). Sinus carcinomas and
lacrimal sac tumors can also invade the orbit. Benign cystic lesions lined
by respiratory epithelium called mucoceles occasionally erode through
orbital bones and impinge on the orbital contents (Fig. 14-20B). Most
occur in patients who have chronic sinusitis. Secondary orbital invasion by
intracranial meningioma actually is more common than primary optic
nerve meningioma.

Pediatric Orbital Tumors

Congenital teratomas of the orbit may present at birth with hideously
deforming proptosis (Fig. 14-21A). The dermoid cyst or cystic dermoid is
the most common orbital lesion found in infants and children. Caused by
entrapment of surface ectoderm in bony sutures during development, these
choristomatous lesions typically are located in the superotemporal
quadrant. Cystic dermoids resemble epidermal inclusion cysts
histopathologically, but the keratinized stratified squamous epithelial
lining also has epidermal appendages such as pilosebaceous units and
sweat glands (Fig. 14-22). Hairs are often found mixed with the cheesy,
keratinous material filling the lumen. Polarization microscopy helps to
highlight the hair shafts during examination. Epidermal inclusion cysts
lack epidermal appendages in their epithelial lining because they actually
result from the cystic dilatation of a single epidermal appendage, that is, a
hair follicle. An alternate dermatopathologic term is follicular cysts,
infundibular type. The epithelial lining of a dermoid cyst may be partially
replaced by a layer of foreign body giant cells. A rare variant of dermoid
cyst, which has been termed a “conjunctivoid,” occasionally is found in
the nasal orbit. These unusual dermoids are lined by nonkeratinized
epithelium with goblet cells that resembles conjunctiva, but has epidermal
appendages.

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FIG. 14-21. Pediatric orbital lesions. A. Congenital orbital teratoma.
Congenital orbital tumor produces hideous proptosis. (Case presented by Dr.
Harry Brown, 1993 meeting of the Verhoeff Society, Coral Gables, FL.) B.
Granulocytic (myeloid) sarcoma. Positive (red) Leder naphthol AS-D
chloroacetate esterase stain confirms the presence of granulocytic differentiation.
This use of this stain has largely been supplanted by more specific
immunohistochemical stains. Granulocytic or myeloid sarcoma must be excluded
in when an apparent “lymphoma” is encountered in the orbit of a child. (B. Leder
stain ×250.)

FIG. 14-22. Dermoid cyst. A. Cheesy keratin debris with hair shafts fills lumen
of sectioned cyst. B. The cyst is filled with laminated keratin. It is lined with
keratinized stratified squamous epithelium that resembles skin and has
pilosebaceous units and other epidermal appendages. A few hair shafts are mixed
with the keratin (arrow). (B. H&E ×50.)

Capillary hemangiomas (infantile hemangioma) and lymphangiomas are

the most common vascular tumors of the orbit in children. Involvement of
eyelid skin by a capillary hemangiomas is readily apparent as a bright red
strawberry nevus. Infantile hemangiomas confined to the orbit are more
subtle and may present with proptosis and bluish discoloration of the skin.
Poorly circumscribed and unencapsulated, these benign vascular tumors
are composed of lobules of capillary caliber vessels or sheets of capillary

463
endothelial cells (Fig. 14-12C). The hemangiomas in very young infants
tend to be quite cellular; capillary lumens appear and enlarge as the lesions
mature. Although infantile hemangiomas eventually involute
spontaneously, they may be a major cosmetic blemish and often produce
potentially reversible visual loss (amblyopia) by causing corneal
astigmatism or by occluding the pupil. In recent years, systemic
administration of the beta-blocker propranolol has replaced interferon and
the interlesional injection of steroids as a first-line treatment for infantile
hemangioma. Infantile hemangiomas show specific immunoreactivity for
GLUT1.
Lymphangiomas or orbital venous–lymphatic malformations are part
of a spectrum of low-flow orbital vascular malformations that includes
orbital varices. Although most contain a mixture of lymphatic and venous
channels, some lesions are composed primarily of lymphatic channels.
Their lymphatic nature is confirmed by positive immunoreactivity with
D2-40 or podoplanin, an immunohistochemical marker for lymphatic
endothelial cells.
Lymphangiomas are poorly circumscribed choristomatous lesions
composed of large endothelial-lined channels filled with lymph or
serosanguineous fluid (Fig. 14-12B,C). Focal lymphoid infiltrates in the
contiguous stroma, which may contain germinal centers, serve to
differentiate lymphangioma from cavernous hemangioma, particularly in
cases where there has been secondary hemorrhage into the lymphatic
vessels. Acute enlargement of lymphangioma is often caused by
intralesional hemorrhage, which can produce a blood-filled “chocolate
cyst.” Lymphangiomas also may enlarge during upper respiratory
infections, presumably because their lymphoid component undergoes
hyperplasia. Lymphangiomas are usually quite infiltrative in their growth
pattern, and they do not undergo spontaneous involution. Surgical removal
may be quite difficult.
Childhood neural tumors include plexiform neurofibroma found in von
Recklinghausen NF1 and juvenile pilocytic astrocytoma (optic nerve
glioma), which also complicates neurofibromatosis. Plexiform
neurofibroma feels like a “bag of worms” when palpated because the
malformation is composed of an interweaving plexus of nerves that are
markedly enlarged by a proliferation of Schwann cells and mucoid
material (Fig. 2-8). The upper eyelid fissure often has an “S” configuration
on the side of the plexiform neurofibroma.
Rhabdomyosarcoma is the most common malignant orbital tumor of

464
childhood (Fig. 14-23). The tumor presents on average at age 7 and is
more common in boys. The possibility of rhabdomyosarcoma should be
considered in any child with orbital disease. Orbital rhabdomyosarcoma
often grows rapidly and can cause fulminant proptosis. Occasionally,
progression is so rapid that the tumor can be confused with inflammatory
disease. Orbital rhabdomyosarcoma affects the superior orbit most
commonly and may appear deceptively well circumscribed on imaging
studies. About 60% of cases erode through the ethmoidal lamina
papyracea in the medial orbital wall. Infrequently, rhabdomyosarcoma
arises in the paranasal sinuses and invades the orbit secondarily.
Macroscopically, fresh tumor usually is fleshy or yellow in color and may
be focally hemorrhagic.

FIG. 14-23. Orbital rhabdomyosarcoma. A. Embryonal rhabdomyosarcoma,

orbit. Spindled mesenchymal cells in a loose myxoid stroma constitute poorly
differentiated embryonal tumor. Most orbital rhabdomyosarcomas are classified
as embryonal. B. Orbital rhabdomyosarcoma with cross striations and
rhabdomyoblasts. Arrow points to eosinophilic strap cell with cross striations.
Rhabdomyoblast above has eosinophilic cytoplasm. Many embryonal
rhabdomyosarcomas lack cross striations. IHC is used to demonstrate striated
muscle differentiation. C. Alveolar rhabdomyosarcoma. Round, poorly
cohesive tumor cells are compartmentalized by fibrous septa that resemble
pulmonary alveoli D. Large polygonal tumor cells in alveolar rhabdomyosarcoma
have eosinophilic cytoplasm. E. Rhabdomyosarcoma, immunohistochemical

465
 diagnosis. Cells in embryonal tumor show positive nuclear staining for myogenin,
a transcription factor specific for striated muscle. The tumor was also
immunoreactive for MyoD, desmin, and muscle-specific actin. (A. H&E ×150, B.
H&E ×250, C. H&E ×50, D. H&E ×250, E. IHC for myogenin ×100.)

Histologically, rhabdomyosarcoma is nonencapsulated and its growth

pattern is usually infiltrative, although “pushing” margins occasionally are
encountered. Several histological variants of orbital rhabdomyosarcoma
are recognized. Most orbital tumors are embryonal rhabdomyosarcomas,
which are poorly differentiated neoplasms composed of spindle and strap
cells arranged haphazardly in a loose, myxomatous stroma (Fig. 14-23A).
Cross striations (Fig. 14-23B) are found in <60% of cases, but
rhabdomyoblasts, which appear as globoid cells with abundant
eosinophilic cytoplasm, may be present. Immunohistochemistry (IHC) is
used to confirm the diagnosis in most cases (see below). In some instances,
special studies including IHC or electron microscopy fail to reveal
evidence of striated muscle differentiation. Such tumors are called
embryonic sarcomas. Botryoid rhabdomyosarcoma is a variant of
embryonal rhabdomyosarcoma that is associated with a mucous membrane
like the conjunctiva. Botryoid rhabdomyosarcomas have a multinodular
grape-like appearance clinically. Alveolar rhabdomyosarcoma is less
common, often occurs in the inferior orbit, and tends to have a poorer
prognosis. Approximately 75% of alveolar rhabdomyosarcomas have
characteristic chromosomal translocations t(2;13) or t(1;13) that result in
fusion of the PAX3 or PAX7 genes with the FKHR or FOXO1A gene on
chromosome 13. Tumors with the PAX3-FKHR translocation have a
poorer prognosis. The latter can be detected with molecular genetic
techniques. The tumor cells in alveolar rhabdomyosarcoma are enclosed
by fibrous tissue septa that resemble alveoli in the lungs (Fig. 14-23C,D).
The large polygonal tumor cells have abundant eosinophilic cytoplasm.
Pleomorphic or differentiated rhabdomyosarcomas are rare in the orbit and
occur in adults.
Orbital rhabdomyosarcomas are thought to arise from pluripotential
mesenchymal cells and are not derived from the dedifferentiation of an
extraocular muscle. The diagnosis can be rapidly confirmed with
immunohistochemical stains for cytoplasmic muscle markers desmin and
muscle-specific actin or preferably with nuclear stains for transcription
factors myogenin and MyoD, which are more specific (Fig. 14-23E).
Diagnostic transmission electron microscopy can also disclose sarcomeric
units and 150 Å myosin filaments, but is rarely performed. After orbital

466
rhabdomyosarcoma is diagnosed by expedient biopsy, the tumor usually is
treated with a combination of radiation and adjuvant chemotherapy.
Orbital exenteration is rarely necessary. The prognosis of orbital
rhabdomyosarcoma is relatively good. The Intergroup Rhabdomyosarcoma
Study-IV found that the 3-year failure free survival rate was 91%.
Lymphomas are rare in childhood. If an apparent “lymphoma” is
encountered in the orbit of a child, an infiltrate of leukemic cells called a
granulocytic or myeloid sarcoma must be excluded. The Leder esterase
stain can be used to confirm granulocytic differentiation, but has largely
been supplanted by immunohistochemical stains for a variety of markers
including myeloperoxidase (MPO) and hematopoietic stem cell markers
CD34 and CD117 or by flow cytometry (Fig. 14-21B). In the past,
granulocytic sarcomas were called chloromas, reflecting a greenish hue
caused by MPO in some tumors. Infiltration of the orbital tissues by
leukemic cells may antedate peripheral leukemia or even bone marrow
involvement by several months.
Orbital involvement can occur in Langerhans cell histiocytosis (LHC,
previously called histiocytosis X), especially the eosinophilic granuloma
variant, which typically causes a cystic or erosive lesion in the
superotemporal orbital bone. Biopsy shows a mixture of histiocytes with
folded nuclei, eosinophils, and small round osteoclast-like giant cells (Fig.
14-24A). The histiocytes stain positively for Langerhans cell markers
CD1a, langerin (CD207) and S100 protein. Electron microscopy shows
rod or tennis racket-shaped Birbeck granules in the cytoplasm of the
Langerhans cells. LHC currently is thought to arise from langerin-positive
dendritic cells in the bone marrow, not dermal Langerhans cells. Sinus
histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) can
involve the orbit. The histiocytes are S100 protein positive and show
emperipolesis (Fig. 14-24B).

FIG. 14-24. A. Eosinophilic granuloma, orbit. Infiltrate is composed of

467
eosinophils, large mononuclear histiocytes with folded nuclei, and small round
osteoclast-like giant cells. B. Higher magnification shows folds in histiocytic
nuclei. Eosinophilic granuloma is a localized form of Langerhans cell
histiocytosis that characteristically forms a lytic lesion in the superotemporal
orbital bone. The cells stain positively for CD1A and S100 protein and contain
racket-shaped Birbeck granules disclosed by electron microscopy. C. Sinus
histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Large
histiocytes in orbital infiltrate have phagocytized lymphocytes (arrows) a process
called emperipolesis. The histiocytes are S100 positive. (A. H&E ×100, B. H&E
×250, C. H&E ×250.)

Most orbital metastases in children stem from neuroblastoma or Ewing

sarcoma. Metastatic orbital neuroblastoma occurs in the late stages of the
disease in children who are known to have the tumor. Metastases from
neuroblastoma are often hemorrhagic and cause periocular ecchymoses, an
appearance termed “raccoon eyes.”

BIBLIOGRAPHY
General References
Henderson JW; (in Collaboration with Campbell RJ, Farrow GM, Garrity JA).
Orbital Tumors, 3rd ed. New York, NY: Raven Press, 1994.
Jakobiec FA, Bilyk JR, Font RL. Orbit. In: Spencer W, ed. Ophthalmic
Pathology: an Atlas and Textbook. 4th ed., vol. 2, Philadelphia, PA: WB
Saunders, 1996:2438–2933.
Rootman J. Diseases of the Orbit. Philadelphia, PA: JB Lippincott, 1988.
Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with orbital tumors
and simulating lesions: the 2002 Montgomery Lecture, part 1. Ophthalmology
2004;111:997–1008.
Shields JA. Diagnosis and Management of Orbital Tumors. Philadelphia, PA:
WB Saunders, 1989.

Orbital Cellulitis
Bilyk JR. Periocular infection. Curr Opin Ophthalmol 2007;18:414–423.
Hornblass A, Herschorn BJ, Stern K, et al. Orbital abscess. Surv Ophthalmol
1984;29:169–179.
Macy HI, Mandelbaum SH, Minckler DA. Orbital cellulitis. Ophthalmology
1980;87:1309–1314.
Shields JA, Shields CL, Suvarnamani C, et al. Retinoblastoma manifesting as
orbital cellulitis. Am J Ophthalmol 1991;112:442–449.
Watters EC, Wallar PH, Hiles DA, et al. Acute orbital cellulitis. Arch Ophthalmol

468
 1976;94:785–788.
Weiss A, Friendly D, Eglin K, et al. Bacterial periorbital and orbital cellulitis in
childhood. Ophthalmology 1983;90:195–203.
Youssef OH, Stefanyszyn MA, Bilyk JR. Odontogenic orbital cellulitis. Ophthal
Plast Reconstr Surg 2008;24:29–35.

Fungal Infection
Houle T, Ellis P. Aspergillosis of the orbit with immunosuppressive therapy. Surv
Ophthalmol 1975;20:35–41.
Green WR, Font RL, Zimmerman LE. Aspergillosis of the orbit: report of ten
cases and review of the literature. Arch Ophthalmol 1969;82:302–312.
Ferry AP, Abedi S. Diagnosis and management of rhino-orbitocerebral
mucormycosis (phycomycosis). Ophthalmology 1983;90:1096–1104.
Yohai RA, Bullock JD, Aziz AA, et al. Survival factors in rhino-orbital-cerebral
mucormycosis. Surv Ophthalmol 1994;39:3–22.
DeJuan E, Green WR, Iliff NT. Allergic periorbital mucopyocele in children. Am
J Ophthalmol 1983;96:299–303.
Chang WJ, Shields CL, Shields JA, et al. Bilateral orbital involvement with
massive allergic fungal sinusitis [letter]. Arch Ophthalmol 1996;114:767–768.
Klapper SR, Lee AG, Patrinely JR, et al. Orbital involvement in allergic fungal
sinusitis. Ophthalmology 1997;104:2094–2100.

Thyroid Ophthalmology
Bahn RS. Clinical review 157: pathophysiology of Graves’ ophthalmopathy: the
cycle of disease. J Clin Endocrinol Metab 2003;88:1939–1946.
Char DH. The ophthalmopathy of Graves’ disease. Med Clin North Am
1991;70:97–119.
Goldstein SM, Katowitz WR, Moshang T, et al. Pediatric thyroid-associated
orbitopathy: the Children’s Hospital of Philadelphia experience and literature
review. Thyroid 2008;18:997–999.
Heufelder AE. Involvement of the orbital fibroblast and TSH receptor in the
pathogenesis of Graves’ ophthalmopathy. Thyroid 1995;5:331–340.
Hufnagel TJ, Hickey WF, Cobbs WH, et al. Immunohistochemical and
ultrastructural studies on the exenterated orbital tissues of a patient with
Graves’ disease. Ophthalmology 1984;91:1411–1419.
Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease:
review and update on molecular mechanisms. Br J Ophthalmol
2016;100(1):142–150.
Netland PA, Dallow RL. Thyroid ophthalmology. In: Albert DM, Jakobiec FA,
eds. Principles and Practice of Ophthalmology: Clinical Practice, vol. 5.
Philadelphia, PA: WB Saunders, 1994:2937–2955.
Rosenbaum JT, Choi D, Wong A, et al. The role of the immune response in the

469
 pathogenesis of thyroid eye disease: a reassessment. PLoS One
2015;10(9):e0137654.
Sergott RC, Glaser JS. Graves’ ophthalmopathy. A clinical and immunologic
review. Surv Ophthalmol 1981;26:1–21.
van der Gaag R, Vernimmen R, Fiebelkorn N, et al. Graves’ ophthalmopathy:
what is the evidence for extraocular muscle specific autoantibodies. Int
Ophthalmol 1990;14:25–30.
Wall JR, Bernard N, Boucher A, et al. Pathogenesis of thyroid-associated
ophthalmopathy: an autoimmune disorder of the eye muscle associated with
Graves’ hyperthyroidism and Hashimoto’s thyroiditis. Clin Immunol
Immunopathol 1993;68:1–8.
Weetman AP, McGregor AM, Hall R. Ocular manifestations of Graves’ disease: a
review. J R Soc Med 1984;77:936–942.
Werner WC. Modification of the classification of the eye changes of Graves’
disease. Am J Ophthalmol 1977;83:725–727.
Abramovitz JN, Kasdon DL, Satala F, et al. Sclerosing orbital pseudotumor.
Neurosurgery 1983;12:463–468.
Andrew NH, Sladden N, Kearney DJ, et al. An analysis of IgG4-related disease
(IgG4-RD) among idiopathic orbital inflammations and benign lymphoid
hyperplasias using two consensus-based diagnostic criteria for IgG4-RD. Br J
Ophthalmol 2015;99(3):376–381.
Brannan PA. A review of sclerosing idiopathic orbital inflammation. Curr Opin
Ophthalmol 2007;18:402–404.
Chavis RM, Garner A, Wright JE. Inflammatory orbital pseudotumor. A
clinicopathologic study. Arch Ophthalmol 1978;96:1817–1822.
El-Khalawany M, Fawzy S, Saied A, et al. Dermal filler complications: a
clinicopathologic study with a spectrum of histologic reaction patterns. Ann
Diagn Pathol 2015;19(1):10–15.
Gordon LK. Orbital inflammatory disease: a diagnostic and therapeutic challenge.
Eye (Lond) 2006;20:1196–1206.
Hara Y, Ohnishi Y. Orbital inflammatory pseudotumor: clinicopathologic study
of 22 cases. Jpn J Ophthalmol 1983;27:80–89.

Idiopathic Orbital Inflammation (Pseudotumor)

Andrew N, Kearney D, Selva D. IgG4-related orbital disease: a meta-analysis and
review. Acta Ophthalmol 2013;91(8):694–700.
Andrew NH, Sladden N, Kearney DJ, et al. An analysis of IgG4-related disease
(IgG4-RD) among idiopathic orbital inflammations and benign lymphoid
hyperplasias using two consensus-based diagnostic criteria for IgG4-RD. Br J
Ophthalmol 2015;99(3):376–381.
Kennerdell JS, Dresner SC. The nonspecific orbital inflammatory syndromes.
Surv Ophthalmol 1984;29:93–103.
McCarthy JM, White VA, Harris G, et al. Idiopathic sclerosing inflammation of

470
 the orbit: immunohistologic analysis and comparison with retroperitoneal
fibrosis. Mod Pathol 1993;6:581–587.
McKelvie P, McNab AA, Hardy T, et al. Comparative study of clinical
pathological, radiological, and genetic features of patients with adult ocular
adnexal xanthogranulomatous disease, Erdheim-Chester Disease, and IgG4-
related disease of the orbit/ocular adnexa. Ophthal Plast Reconstr Surg
2016;12. [Epub ahead of print]
Mehta M, Frederick Jakobiec FA, et al. Idiopathic fibroinflammatory disease of
the face, eyelids, and periorbital membrane with immunoglobulin G4–positive
plasma cells. Arch Pathol Lab Med 2009;133:1251–1255.
Mombaerts I, Goldschmeding R, Schlingemann RO, et al. What is orbital
pseudotumor? Surv Ophthalmol 1996;41:66–78.
Mottow-Lippa L, Jakobiec FA. Idiopathic inflammatory orbital pseudotumor in
childhood. Arch Ophthalmol 1978;96:1410–1417.
Mulay K, Wick MR. Ophthalmic immunoglobulin G4-related disease IgG4-RD
current concepts. Semin Diagn Pathol 2016;33(3): 148–55.
Owosho AA, Bilodeau EA, Vu J, et al. Orofacial dermal fillers: foreign body
reactions, histopathologic features, and spectrometric studies. Oral Surg Oral
Med Oral Pathol Oral Radiol 2014;117(5):617–625.
Rootman J, McCarthy M, White V, et al. Idiopathic sclerosing inflammation of
the orbit. A distinct clinicopathologic entity. Ophthalmology
1994;101:570–584.
Rosenbaum JT, Choi D, Wilson DJ, et al. Fibrosis, gene expression and orbital
inflammatory disease. Br J Ophthalmol 2015;99(10): 1424–1429.
Rosenbaum JT, Choi D, Wilson DJ, et al. Molecular diagnosis of orbital
inflammatory disease. Exp Mol Pathol 2015;98(2):225–229.
Rosenbaum JT, Choi D, Wilson DJ, et al. Parallel gene expression changes in
sarcoidosis involving the lacrimal gland, orbital tissue, or blood. JAMA
Ophthalmol 2015;133(7):770–777.
Sa HS, Lee JH, Woo KI, et al. IgG4-related disease in idiopathic sclerosing
orbital inflammation. Br J Ophthalmol 2015;99(11):1493–1497.
Uy HS, Nguyen QD, Arbour J, et al. Sclerosing inflammatory pseudotumor of the
eye. Arch Ophthalmol 2001;119:603–607.
Wong AJ, Planck SR, Choi D, et al. IgG4 immunostaining and its implications in
orbital inflammatory disease. PLoS One 2014;9(10):e109847.

Granulomatosis with Polyangiitis (Wegener, GPA)

Bullen CL, Liesegang TJ, McDonald TJ. Ocular complications of Wegener’s
granulomatosis. Ophthalmology 1983;90:279–290.
Kalina PH, Lie JT, Campbell RJ, et al. Diagnostic value and limitations of orbital
biopsy in Wegener’s granulomatosis. Ophthalmology 1994;99:120–124.
Koyama T, Matsuo N, Watanabe Y, et al. Wegener’s granulomatosis with
destructive ocular manifestations. Am J Ophthalmol 1984;98:736–740.

471
Perry SR, Rootman J, White VA. The clinical and pathologic constellation of
Wegener granulomatosis of the orbit. Ophthalmology 1997;104:683–694.
Rosenbaum JT, Choi D, Wilson DJ, et al. Orbital pseudotumor can be a localized
form of granulomatosis with polyangiitis as revealed by gene expression
profiling. Exp Mol Pathol 2015;99(2):271–278.
Trocme SD, Bartley GB, Campbell RJ, et al. Eosinophil and neutrophil
degranulation in ophthalmic lesions of Wegener’s granulomatosis. Arch
Ophthalmol 1991;109:1585–1589.

Orbital Xanthogranuloma
Hammond MD, Niemi EW, Ward TP, et al. Adult orbital xanthogranuloma with
associated adult-onset asthma. Ophthal Plast Reconstr Surg
2004;20:329–332.
Karcioglu ZA, Sharara N, Boles TL, et al. Orbital xanthogranuloma: clinical and
morphologic features in eight patients. Ophthal Plast Reconstr Surg
2003;19:372–381.
Miszkiel KA, Sohaib SA, Rose GE, et al. Radiological and clinicopathological
features of orbital xanthogranuloma. Br J Ophthalmol 2000;84:251–258.
Sheu SY, Wenzel RR, Kersting C, et al. Erdheim-Chester disease: case report
with multisystemic manifestations including testes, thyroid, and lymph nodes,
and a review of literature. J Clin Pathol 2004;57:1225–1228.
Sivak-Callcott JA, Rootman J, Rasmussen SL, et al. Adult xanthogranulomatous
disease of the orbit and ocular adnexa: new immunohistochemical findings
and clinical review. Br J Ophthalmol 2006;90:602–608.

Lymphoid Tumors
Adkins JW, Shields JA, Shields CL, et al. Plasmacytoma of the eye and orbit. Int
Ophthalmol 1996;20:339–343.
Chan JK. The new World Health Organization classification of lymphomas: the
past, the present and the future. Hematol Oncol 2001;19:129–150.
Coupland SE, Damato B. Lymphomas involving the eye and the ocular adnexa.
Curr Opin Ophthalmol 2006;17:523–531.
Coupland SE, Hummel M, Stein H. Ocular adnexal lymphomas: five case
presentations and a review of the literature. Surv Ophthalmol
2002;47:470–490.
Coupland SE, Krause L, Delecluse HJ, et al. Lymphoproliferative lesions of the
ocular adnexa. Analysis of 112 cases. Ophthalmology 1998;105:1430–1441.
Craig FE. Flow cytometric evaluation of B-cell lymphoid neoplasms. Clin Lab
Med 2007;27:487–512.
Demirci H, Shields CL, Karatza EC, et al. Orbital lymphoproliferative tumors:
analysis of clinical features and systemic involvement in 160 cases.
Ophthalmology 2008;115:1626–1631.

472
Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study
of 353 cases. Am J Surg Pathol 2007;31:170–184.
Graue GF, Finger PT, Maher E, et al. Ocular adnexal lymphoma staging and
treatment: American Joint Committee on Cancer versus Ann Arbor. Eur J
Ophthalmol 2013;23(3):344–355.
Kaleem Z. Flow cytometric analysis of lymphomas: current status and usefulness.
Arch Pathol Lab Med 2006;130:1850–1858.
Knowles DM, Jakobiec FA, McNally L, et al. Lymphoid hyperplasia and
malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and
eyelids): a prospective multiparametric analysis of 108 case during 1977 to
1987. Hum Pathol 1990;21:959–973.
Looi A, Gascoyne RD, Chhanabhai M, et al. Mantle cell lymphoma in the ocular
adnexal region. Ophthalmology 2005;112:114–119.
Margo CE. Orbital and ocular adnexal lymphoma: evolving concepts. In:
Grossniklaus HE, Margo CE, eds. Advances in Ophthalmic Pathology.
Ophthalmol Clin North Am 1995;8:167–177.
Medeiros LJ. Harris NL. Immunohistologic analysis of small lymphocytic
infiltrates of the orbit and conjunctiva. Hum Pathol 1990;21:1126–1131.
Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours
of Haemopoietic and Lymphoid Tissues, 4th ed. Lyon, France: World Health
Organization, 2008.
White WL, Ferry JA, Harris NL, et al. Ocular adnexal lymphoma. A
clinicopathologic study with identification of lymphomas of mucosa-
associated lymphoid tissue type. Ophthalmology 1995;102:1994–2006.

Vascular Tumors
Croxatto JO, Font RL. Hemangiopericytoma of the orbit: a clinicopathologic
study of 30 cases. Hum Pathol 1982;13:210–218.
Font RL, Wheeler TM, Boniuk M. Intravascular papillary endothelial hyperplasia
of the orbit and ocular adnexa. A report of five cases. Arch Ophthalmol
1983;101:1731–1736.
Harris GJ, Jakobiec FA. Cavernous hemangioma of the orbit: an analysis of 66
cases. J Neurosurg 1979;51:219–228.
Henderson JW, Farrow GM. Primary orbital hemangiopericytoma: an aggressive
and potentially malignant neoplasm. Arch Ophthalmol 1978;96:666–673.
Iwamoto T, Jakobiec FA. Ultrastructural comparison of capillary and cavernous
hemangiomas of the orbit. Arch Ophthalmol 1979;97:1144–1153.
Keller RG, Patel KG. Evidence-based medicine in the treatment of infantile
hemangiomas. Facial Plast Surg Clin North Am 2015;23(3):373–392.
Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized,
controlled trial of oral propranolol in infantile hemangioma. N Engl J Med
2015;372:735–746.
Selva D, Strianese D, Bonavolonta G, et al. Orbital venous-lymphatic

473
 malformations (lymphangiomas) mimicking cavernous hemangiomas. Am J
Ophthalmol 2001;131(3):364–370.
Moodley ST, Hudson DA, Adams S, et al. Shouldn’t propranolol be used to treat
all haemangiomas? Aesthetic Plast Surg 2015; 39(6):963–967.
Nassiri N, Rootman J, Rootman DB, et al. Orbital lymphaticovenous
malformations: current and future treatments. Surv Ophthalmol
2015;60(5):383–405.
Ni N, Guo S, Langer P. Current concepts in the management of periocular
infantile (capillary) hemangioma. Curr Opin Ophthalmol
2011;22(5):419–425.
Rootman J, Heran MK, Graeb DA. Vascular malformations of the orbit:
classification and the role of imaging in diagnosis and treatment strategies.
Ophthal Plast Reconstr Surg 2014;30(2):91–104.
Rootman J. Vascular malformations of the orbit: hemodynamic concepts. Orbit
2003;22(2):103–120.
Ruchman MC, Flanagan J. Cavernous hemangiomas of the orbit. Ophthalmology
1983;90:1328–1336.
Shields JA, Shields CL, Eagle RC Jr. Cavernous hemangioma of the orbit. Arch
Ophthalmol 1987;105:853.
Werner MS, Hornblass A, Reifler DM, et al. Intravascular papillary endothelial
hyperplasia: collection of four cases and a review of the literature. Ophthal
Plast Reconstr Surg 1997;13:48–56.

Neural Tumors
Blodi FC. Amputation neuroma in the orbit. Am J Ophthalmol 1949;32:929–932.
Coleman DJ, Jack RL, Franzen LA. Neurogenic tumors of the orbit. Arch
Ophthalmol 1972;88:380–384.
Krohel GB, Rosenberg MD, Wright JE Jr, et al. Localized orbital neurofibromas.
Am J Ophthalmol 1985;100:458–464.
Rootman J, Goldberg C, Robertson W. Primary orbital schwannomas. Br J
Ophthalmol 1982;66:194–204.

Mesenchymal Tumors
Bernardini FP, de Conciliis C, Schneider S, et al. Solitary fibrous tumor of the
orbit: is it rare? Report of a case series and review of the literature.
Ophthalmology 2003;110(7):1442–1448.
Cheah AL, Billings SD, Goldblum JR, et al. STAT6 rabbit monoclonal antibody
is a robust diagnostic tool for the distinction of solitary fibrous tumour from
its mimics. Pathology 2014;46(5): 389–395.
Dorfman DM, To K, Dickersin GR, et al. Solitary fibrous tumor of the orbit. Am J
Surg Pathol 1994;18:281–287.
Folberg R, Cleasby G, Flanagan JA, et al. Orbital leiomyosarcoma after radiation

474
 therapy for bilateral retinoblastoma. Arch Ophthalmol 1983;101:1562–1565.
Font RL, Hidayat AA. Fibrous histiocytoma of the orbit: a clinicopathologic
study of 150 cases. Hum Pathol 1982;13:199–209.
Font RL, Jurco S III, Brechner RJ. Postradiation leiomyosarcoma of the orbit
complicating bilateral retinoblastoma. Arch Ophthalmol
1983;101:1557–1561.
Bartley GB, Yeatts RP, Garrity JA, et al. Spindle cell lipoma of the orbit. Am J
Ophthalmol 1985;100:605–609.
Furusato E, Valenzuela IA, Fanburg-Smith JC, et al. Orbital solitary fibrous
tumor: encompassing terminology for hemangiopericytoma, giant cell
angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases.
Hum Pathol 2011;42(1):120–128.
Goldsmith JD, van de Rijn M, Syed N. Orbital hemangiopericytoma and solitary
fibrous tumor: a morphologic continuum. Int J Surg Pathol
2001;9(4):295–302.
Guccion J, Font RL, Enzinger FM, et al. Extraskeletal mesenchymal
chondrosarcoma. Arch Pathol 1973;95:336–340.
Hidayat AA, Font RL. Juvenile fibromatosis of the periorbital region and eyelid.
A clinicopathologic study of six cases. Arch Ophthalmol 1980;98:280–285.
Holland MG, Allen JH, Ichinose H. Chondrosarcoma of the orbit. Trans Am Acad
Ophthalmol Otolaryngol 1961;65:898–905.
Jakobiec FA, Rini F, Char D, et al. Primary liposarcoma of the orbit. Problems in
the diagnosis and management of five cases. Ophthalmology
1989;96:180–191.
Krishnakumar S, Subramanian N, Mohan ER, et al. Solitary fibrous tumor of the
orbit: a clinicopathologic study of six cases with review of the literature. Surv
Ophthalmol 2003;48:544–554.
Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent
NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative
sequencing. Nat Genet 2013;45(2):180–185.
Sanborn GE, Valenzuela RE, Green WR. Leiomyoma of the orbit. Am J
Ophthalmol 1979;87:371–375.
Weiner JM, Hidayat AA. Juvenile fibrosarcoma of the orbit and eyelid. Arch
Ophthalmol 1983;101:253–259.

Rare Orbital Tumors

Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic
diversity in Ewing family tumors: a study of 66 genetically confirmed cases.
Am J Surg Pathol 2005;29:1025–1033.
Font RL, Jurco S III, Zimmerman LE. Alveolar soft-part sarcoma of the orbit.
Hum Pathol 1982;13:569–579.
Goldstein BG, Font RL, Alper MG. Granular cell tumor of the orbit: a case report
including electron microscopic observation. Ann Ophthalmol

475
 1982;14:231–238.
Gunduz K, Shields JA, Eagle RC Jr, et al. Malignant rhabdoid tumor of the orbit.
Arch Ophthalmol 1998;116:243–246.
Jakobiec FA, Ellsworth R, Tannenbaum M. Primary orbital melanoma. Am J
Ophthalmol 1974;78:24–39.
Lamping KA, Albert DM, Lack E, et al. Melanotic neuroectodermal tumor of
infancy (retinal anlage tumor). Ophthalmology 1985;92:143–147.
Margo CE, Folberg R, Zimmerman LE, et al. Endodermal sinus tumor (yolk sac
tumor) of the orbit. Ophthalmology 1983;90:1426–1432.
Rootman J, DamJi KF, Dimmick JE. Malignant rhabdoid tumor of the orbit.
Ophthalmology 1989;96:1650–1604.
Singh AD, Husson M, Shields CL, et al. Primitive neuroectodermal tumor of the
orbit. Arch Ophthalmol 1994;112:217–221.
Tellada M, Specht CS, McLean IW, et al. Primary orbital melanomas.
Ophthalmology 1996;103:929–932.
Zimmerman LE, Stangl R, Riddle PJ. Primary carcinoid tumor of the orbit. Arch
Ophthalmol 1983;101:1395–1398.

Osseous and Fibro-osseous Lesions

Blodi, FC. Pathology of orbital bones. Am J Ophthalmol 1976;81:1–26.
Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses,
and nasopharynx: a clinicopathological study. II. Osseous and fibro-osseous
lesions, including osteoma, fibrous dysplasia, ossifying fibroma,
osteoblastoma, giant cell tumor and osteosarcoma. Cancer
1974;33:1289–1305.
Hoopes PC, Anderson RL, Blodi FC. Giant cell (reparative) granuloma of the
orbit. Ophthalmology 1981;88:1361–1366.
Klepach GL, Ho REM, Kelly JK. Aneurysmal bone cyst of the orbit. J Clin
Neuro-Ophthalmol 1984;4:49–52.
Margo CE, Ragsdale B, Purman K, et al. Psammomatoid (juvenile) ossifying
fibroma of the orbit. Ophthalmology 1985;92:150–159.
Moore AT, Buncic R. Fibrous dysplasia of the orbit in childhood: clinical features
and management. Ophthalmology 1985;92: 12–20.
Naiman J, Green WR, D’Heurle D, et al. Brown tumor of the orbit associated
with primary hyperparathyroidism. Am J Ophthalmol 1980;90:565–571.
Spraul CW, Wojno TH, Grossniklaus HE, et al. Reparative giant cell granuloma
with orbital involvement. Klin Monatsbl Augenheilkd 1997;211:133–134.

Lacrimal Gland Tumors

Ahmad SM, Esmaeli B, Williams M, et al. American Joint Committee on Cancer
classification predicts outcome of patients with lacrimal gland adenoid cystic
carcinoma. Ophthalmology 2009;116:1210–1215.

476
Bartley GB, Harris GJ. Adenoid cystic carcinoma of the lacrimal gland: is there a
cure…yet? Ophthal Plast Reconstr Surg 2002;18:315–318.
Bell D, El-Naggar AK. Molecular heterogeneity in mucoepidermoid carcinoma:
conceptual and practical implications. Head Neck Pathol 2013;7(1):23–27.
Biggs SL, Font RL. Oncocytic lesions of the lacrimal gland. Arch Ophthalmol
1977;95:474–478.
Bonavolonta G, Tranfa F, Staibano S, et al. Warthin tumor of the lacrimal gland.
Am J Ophthalmol 1997;124:857–858.
Brill LB II, Kanner WA, Fehr A, et al. Analysis of MYB expression and MYB-
NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms.
Mod Pathol 2011;24(9):1169–1176.
Briscoe D, Mahmood S, Bonshek R, et al. Primary sebaceous carcinoma of the
lacrimal gland. Br J Ophthalmol 2001;85:625–626.
Brownstein S, Belin MW, Krohel GB, et al. Orbital dacryops. Ophthalmology
1984;91:1424–1428.
Chan WM, Liu DT, Lam LY, et al. Primary epithelial-myoepithelial carcinoma of
the lacrimal gland. Arch Ophthalmol 2004;122:1714–1717.
Chang CJ, Lin TK, Wei LC, et al. Carcinoma ex pleomorphic adenoma of the
lacrimal gland: a case report. Ann Ophthalmol (Skokie) 2006;38:141–144.
Cunningham RD. Lacrimal gland tumors. In: Fraunfelder FT, Roy FH, eds.
Current Ocular Therapy 4. Philadelphia, PA: WB Saunders, 1995:693–695.
Eviatar JA, Hornblass A. Mucoepidermoid carcinoma of the lacrimal gland: 25
cases and a review and update of the literature. Ophthal Plast Reconstr Surg
1993;9:170–181.
Fenton S, Srinivasan S, Harnett A, et al. Primary squamous cell carcinoma of the
lacrimal gland. Eye (Lond) 2003;17:424–425.
Font RL, Gamel JW. Adenoid cystic carcinoma of the lacrimal gland: a
clinicopathological study of 79 cases. In: Nicholson DH, ed. Ocular
Pathology Update. New York, NY: Masson Publishing USA, 1980:277–283.
Font RL, Gamel JW. Epithelial tumors of the lacrimal gland: an analysis of 256
cases. In: Jakobiec FA, ed. Ocular and Adnexal Tumors. Birmingham, AL:
Aesculapius, 1978:787–805.
Font RL, Yanoff M, Zimmerman LE. Benign lymphoepithelial lesion of the
lacrimal gland and its relationship to Sjogren’s syndrome. Am J Clin Pathol
1967;48:365–376.
Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and
treatment approaches. Clin Cosmet Investig Dermatol 2013;6:295–316.
Gamel JW, Font RL. Adenoid cystic carcinoma of the lacrimal gland: the clinical
significance of a basaloid histologic pattern. Hum Pathol 1982;13:219–225.
Gibson A, Mavrikakis I, Rootman J, et al. Lacrimal gland pleomorphic adenomas
with low-density zones resembling cystic change on computed tomography.
Ophthal Plast Reconstr Surg 2007;23:234–235.
Grossniklaus HE, Wojno TH, Wilson MW, et al. Myoepithelioma of the lacrimal
gland. Arch Ophthalmol 1997;115:1588–1590.

477
Henderson JW. Adenoid cystic carcinoma of the lacrimal gland, is there a cure?
Trans Am Ophthalmol Soc 1987;85:312–319.
Hotta K, Arisawa T, Mito H, et al. Primary squamous cell carcinoma of the
lacrimal gland. Clin Experiment Ophthalmol 2005;33: 534–536.
Ishida M, Hotta M, Kushima R, et al. Case of ductal adenocarcinoma ex
pleomorphic adenoma of the lacrimal gland. Rinsho Byori 2009;57:746–751.
Iwamota T, Jakobiec FA. A comparative ultrastructural study of the normal
lacrimal gland and its epithelial tumors. Hum Pathol 1982;13:236–262.
Jang J, Kie JH, Lee SY, et al. Acinic cell carcinoma of the lacrimal gland with
intracranial extension: a case report. Ophthal Plast Reconstr Surg
2001;17:454–457.
Katz SE, Rootman J, Dolman PJ, et al, Primary ductal adenocarcinoma of the
lacrimal gland. Ophthalmology 1996;103(1): 157–162.
Khalil M, Arthurs B. Basal cell adenocarcinoma of the lacrimal gland.
Ophthalmology 2000;107:164–168.
Lee DA, Campbell RJ, Waller RR, et al. A clinicopathologic study of primary
adenoid cystic carcinoma of the lacrimal gland. Ophthalmology
1985;92:128–134.
Lee YJ, Oh YH. Primary ductal adenocarcinoma of the lacrimal gland. Jpn J
Ophthalmol 2009;53:268–270.
Lin SC, Kau HC, Yang CF, et al. Adenoid cystic carcinoma arising in the inferior
orbit without evidence of lacrimal gland involvement. Ophthal Plast Reconstr
Surg 2008;24:74–76.
Malhotra GS, Paul SD, Batra DV. Mucoepidermoid carcinoma of the lacrimal
gland. Ophthalmologica 1967;153:184–190.
Matsuyama A, Hisaoka M, Nagao, et al. Aberrant PLAG1 expression in
pleomorphic adenomas of the salivary gland: a molecular genetic and
immunohistochemical study. Virchows Arch 2011;458(5): 583–592.
Milman T, Shields JA, Husson M, et al. Primary ductal adenocarcinoma of the
lacrimal gland. Ophthalmology 2005;112:2048–2051.
Ostrowski ML, Font RL, Halpern J, et al. Clear cell epithelial-myoepithelial
carcinoma arising in pleomorphic adenoma of the lacrimal gland.
Ophthalmology 1994;101:925–930.
Persson M, Andrén Y, Mark J, et al. Recurrent fusion of MYB and NFIB
transcription factor genes in carcinomas of the breast and head and neck. Proc
Natl Acad Sci U S A 2009;106(44):18740–18744.
Perzin K, Jakobiec FA, LiVolsi V, et al. Malignant mixed tumors of the lacrimal
gland. Cancer 1980;45:2593–2606.
Rao NA, Kaiser E, Quiros PA, et al. Lymphoepithelial carcinoma of the lacrimal
gland. Arch Ophthalmol 2002;120:1745–1748.
Rootman J, White VA. Changes in the 7th edition of the AJCC TNM
classification and recommendations for pathologic analysis of lacrimal gland
tumors. Arch Pathol Lab Med 2009;133(8):1268–1271.
Rose GE. Wright JE. Pleomorphic adenoma of the lacrimal gland. Br J

478
 Ophthalmol 1992;76:395–400.
Rosenbaum PS, Mahadevia PS, Goodman LA, et al. Acinic cell carcinoma of the
lacrimal gland. Arch Ophthalmol 1995;113:781–785.
Selva D, Davis GJ, Dodd T, et al. Polymorphous low-grade adenocarcinoma of
the lacrimal gland. Arch Ophthalmol 2004;122:915–917.
Shields CL, Shields JA, Eagle RC, et al. Clinicopathologic review of 142 cases of
lacrimal gland lesions. Ophthalmology 1989;96:431–435.
Shields JA, Shields CL, Eagle RC Jr, et al. Adenoid cystic carcinoma developing
in the nasal orbit. Am J Ophthalmol 1997;123:398–389.
Shields JA, Shields CL, Epstein JA, et al. Review: primary epithelial
malignancies of the lacrimal gland: the 2003 Ramon L. Font lecture. Ophthal
Plast Reconstr Surg 2004;20:10–21.
Sofinski SJ, Brown BZ, Rao N, et al. Mucoepidermoid carcinoma of the lacrimal
gland. Case report and review of the literature. Ophthal Plast Reconstr Surg
1986;2:147–151.
Stenman G. Fusion oncogenes and tumor type specificity—insights from salivary
gland tumors. Semin Cancer Biol 2005;15(3):224–235.
Su GW, Patipa M, Font RL. Primary squamous cell carcinoma arising from an
epithelium-lined cyst of the lacrimal gland. Ophthal Plast Reconstr Surg
2005;21:383–385.
Takahira M, Minato H, Takahashi M, et al. Cystic carcinoma ex pleomorphic
adenoma of the lacrimal gland. Ophthal Plast Reconstr Surg
2007;23:407–409.
Tellado MV, McLean IW, Specht CS, et al. Adenoid cystic carcinomas of the
lacrimal gland in childhood and adolescence. Ophthalmology
1997;104:1622–1625.
Tse DT, Kossler AL, Feuer WJ, et al. Long-term outcomes of neoadjuvant intra-
arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic
carcinoma. Ophthalmology 2013;120(7): 1313–1323.
Vangveeravong S, Katz SE, Rootman J, et al. Tumors arising in the palpebral
lobe of the lacrimal gland. Ophthalmology 1996;103: 1606–1612.
Wagoner MD, Chuo N, Gonder JR. Mucoepidermoid carcinoma of the lacrimal
gland. Ann Ophthalmol 1982;14:383–386.
Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic
classification and current understanding. Arch Ophthalmol
2009;127(8):1016–1028.
White VA. Update on lacrimal gland neoplasms: molecular pathology of interest.
Saudi J Ophthalmol 2012;26(2):133–135.
Wiwatwongwana D, Berean KW, Dolman PJ, et al. Unusual carcinomas of the
lacrimal gland: epithelial-myoepithelial carcinoma and myoepithelial
carcinoma. Arch Ophthalmol 2009;127(8):1054–1056.
Wright JE, Rose GE, Garner A. Primary malignant neoplasms of the lacrimal
gland. Br J Ophthalmol 1992;76:401–407.
Yamamoto N, Mizoe JE, Hasegawa A, et al. Primary sebaceous carcinoma of the

479
 lacrimal gland treated by carbon ion radiotherapy. Int J Clin Oncol
2003;8:386–390.

Orbital Metastasis
Ahmad SM, Esmaeli B. Metastatic tumors of the orbit and ocular adnexa. Curr
Opin Ophthalmol 2007;18:405–413.
Cline RA, Rootman J. Enophthalmos: a clinical review. Ophthalmology
1984;91:229–237.
Font RL, Ferry AP. Carcinoma metastatic to the eye and orbit. III. A
clinicopathologic study of 28 cases metastatic to the orbit. Cancer
1976;38:1326–1335.
Goldberg RA, Rootman J, Cline RA. Tumors metastatic to the orbit: a changing
picture. Surv Ophthalmol 1990;35:1–24.
Holland D, Maune S, Kovacs G, et al. Metastatic tumors of the orbit: a
retrospective study. Orbit 2003;22:15–24.
Sabatini P, Ducic Y. Bilateral lacrimal gland masses: unusual case of metastatic
renal cell carcinoma. J Otolaryngol Head Neck Surg 2009;38:E1–E2.
Shields CL, Shields JA, Peggs M. Tumors metastatic to the orbit. Ophthal Plast
Reconstr Surg 1988;4:73–80.
Shields JA, Shields CL, Brotman HK, et al. Cancer metastatic to the orbit: the
2000 Robert M. Curts Lecture. Ophthal Plast Reconstr Surg
2001;17:346–354.
Watkins LM, Rubin PA. Metastatic tumors of the eye and orbit. Int Ophthalmol
Clin 1998;38:117–128.
Zografos L, Ducrey N, Beati D, et al. Metastatic melanoma in the eye and orbit.
Ophthalmology 2003;110:2245–2256.

Mucocele
Alberti PWRM, Marshall HF, Black HIM. Frontoethmoidal mucocoele as a cause
of unilateral proptosis. Br J Ophthalmol 1968;52: 833–838.
Avery G, Tang RA, Close LG. Ophthalmic manifestations of mucoceles. Ann
Ophthalmol 1983;15:734–737.
Iliff CE. Mucoceles in the orbit. Arch Ophthalmol 1973;89:392–395.

Dermoid Cysts
Dutton JJ, Fowler AM, Proia AD. Dermoid cyst of conjunctival origin. Ophthal
Plast Reconstr Surg 2006;22:137–139.
Emerick GT, Shields CL, Shields JA, et al. Chewing-induced visual impairment
from a dumbbell dermoid cyst. Ophthal Plast Reconstr Surg 1997;13:57–61.
Jakobiec FA, Bonanno PA. Conjunctival adnexal cysts and dermoids. Arch
Ophthalmol 1978;96:1040–1049.
Shields JA, Kaden IH, Eagle RC Jr, et al. Orbital dermoid cysts: clinicopathologic

480
 correlations, classification and management. The 1997 Josephine E. Schueler
Lecture. Ophthal Plast Reconstr Surg 1997;13:265–276.

Rhabdomyosarcoma
Abramson DH, Ellsworth RM, Tretter P, et al. The treatment of orbital
rhabdomyosarcoma with irradiation and chemotherapy. Ophthalmology
1979;86:1330–1335.
Arnold MA, Anderson JR, Gastier-Foster JM, et al. Histology, fusion status, and
outcome in alveolar rhabdomyosarcoma with low-risk clinical features: a
report from the Children’s Oncology Group. Pediatr Blood Cancer
2016;63(4):634–639.
Ashton N. Embryonal sarcoma and embryonal rhabdomyosarcoma of the orbit. J
Clin Pathol 1965;18:699–714.
Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV:
results for patients with nonmetastatic disease. J Clin Oncol
2001;19:3091–3102.
Donaldson SS, Meza J, Breneman JC, et al. Results from the IRS-IV randomized
trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma—
a report from the IRSG. Int J Radiat Oncol Biol Phys 2001;51:718–728.
Jakobiec FA, Font RL. Ocular and orbital tumors. In: Johanessen JV, ed. The
Nervous System, Sensory Organs and Respiratory Tract. Electron Microscopy
in Human Diseases, vol. VI. New York, NY: McGraw-Hill Book Co.,
1979:346–368.
Karcioglu ZA, Hadjistilianou D, Rozans M, et al. Orbital rhabdomyosarcoma.
Cancer Control 2004;11:328–333.
Knowles DM II, Jakobiec FA, Potter G, et al. Ophthalmic striated muscle
neoplasms. Surv Ophthalmol 1976;21:219–261.
Newton WA, Soule EH, Hamoudi AB, et al. Histopathology of childhood
sarcomas, intergroup rhabdomyosarcoma studies I and II: clinicopathologic
correlation. J Clin Oncol 1988;6:67–75.
Porterfield JF, Zimmerman LE. Rhabdomyosarcoma of the orbit: a
clinicopathologic study of 55 cases. Virchows Arch [A] 1962;335: 329–344.
Raney RB, Anderson JR, Barr FG, et al. Rhabdomyosarcoma and undifferentiated
sarcoma in the first two decades of life: a selective review of intergroup
rhabdomyosarcoma study group experience and rationale for Intergroup
Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 2001;23:215–220.
Raney RB, Anderson JR, Kollath J, et al. Late effects of therapy in 94 patients
with localized rhabdomyosarcoma of the orbit: report from the Intergroup
Rhabdomyosarcoma Study (IRS)-III, 1984–1991. Med Pediatr Oncol
2000;34:413–420.
Raney RB, Maurer HM, Anderson JR, et al. The Intergroup Rhabdomyosarcoma
Study Group (IRSG): major lessons from the IRS-I through IRS-IV studies as
background for the current IRS-V treatment protocols. Sarcoma 2001;5:9–15.

481
Shields CL, Shields JA, Honavar SG, et al. Clinical spectrum of primary
ophthalmic rhabdomyosarcoma. Ophthalmology 2001;108: 2284–2292.
Shields CL, Shields JA, Honavar SG, et al. Primary ophthalmic
rhabdomyosarcoma in 33 patients. Trans Am Ophthalmol Soc 2001;99:
133–142; discussion 142–133.
Shields JA, Shields CL. Rhabdomyosarcoma: review for the ophthalmologist.
Surv Ophthalmol 2003;48:39–57.

Other Pediatric Orbital Tumors

Barnes CM, Christison-Lagay EA, Folkman J. The placenta theory and the origin
of infantile hemangioma. Lymphat Res Biol 2007;5:245–255.
Barnes CM, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a
placental origin of infantile hemangioma. Proc Natl Acad Sci U S A
2005;102:19097–19102.
Ellis FJ, Eagle RC Jr, Shields JA. Phakomatous choristoma (Zimmerman’s
tumor): immunohistochemical confirmation of lens-specific proteins.
Ophthalmology 1993;100:955–960.
Fay A, Nguyen J, Jakobiec FA, et al. Propranolol for isolated orbital infantile
hemangioma. Arch Ophthalmol 2010;128:256–258.
Ferry AP, Font AP. The phakomatoses. Int Ophthalmol Clin 1972; 12:1–50.
Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic
diversity in Ewing family tumors: a study of 66 genetically confirmed cases.
Am J Surg Pathol 2005;29:1025–1033.
Galambos C, Nodit L. Identification of lymphatic endothelium in pediatric
vascular tumors and malformations. Pediatr Dev Pathol 2005;8:181–189.
Gausas RE, Daly T, Fogt F. D2-40 expression demonstrates lymphatic vessel
characteristics in the dural portion of the optic nerve sheath. Ophthal Plast
Reconstr Surg 2007;23:32–36.
Haik BG, Karcioglu ZA, Gordon RA, et al. Capillary hemangioma (infantile
periocular hemangioma). Surv Ophthalmol 1994;38:399–426.
Hidayat AA, Cameron JD, Font RL, et al. Angiolymphoid hyperplasia with
eosinophilia (Kimura’s disease) of the orbit and ocular adnexa. Am J
Ophthalmol 1983;96:176–189.
Illif WJ, Green WR. Orbital lymphangiomas. Ophthalmology 1979;86:914–929.
Kivela T, Tarkkanen A. Orbital germ cell tumors revisited: a clinicopathological
approach to classification. Surv Ophthalmol 1994;38:541–554.
Kobrin JL, Blodi FC, Weingeist TA. Ocular and orbital manifestations of
neurofibromatosis. Surv Ophthalmol 1979;24:45–51.
Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe
hemangiomas of infancy. N Engl J Med 2008;358(24):2649–2651.
Lo K, Mihm M, Fay A. Current theories on the pathogenesis of infantile
hemangioma. Semin Ophthalmol 2009;24:172–177.
McEachren TM, Brownstein S, Jordan DR, et al. Epithelioid hemangioma of the

482
 orbit. Ophthalmology 2000;107:806–810.
North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered
immunohistochemical marker for juvenile hemangiomas. Hum Pathol
2000;31(1):11–22.
Ramchandani PL, Sabesan T, Hussein K. Angiolymphoid hyperplasia with
eosinophilia masquerading as Kimura disease. Br J Oral Maxillofac Surg
2005;43:249–252.
Sartelet H, Grossi L, Pasquier D, et al. Detection of N-myc amplification by FISH
in immature areas of fixed neuroblastomas: more efficient than Southern
blot/PCR. J Pathol 2002;198:83–91.
Shields JA, Bakewell B, Augsburger JJ, et al. Space-occupying orbital masses in
children: a review of 250 consecutive biopsies. Ophthalmology
1986;93:379–384.
Singh AD, Husson M, Shields CL, et al. Primitive neuroectodermal tumor of the
orbit. Arch Ophthalmol 1994;112:217–221.
Sun ZY, Yi CG, Zhao H, et al. Infantile hemangioma is originated from placental
trophoblast, fact or fiction? Med Hypotheses 2008;71:444–448.
Tajiri T, Shono K, Fujii Y, et al. Highly sensitive analysis for N-myc
amplification in neuroblastoma based on fluorescence in situ hybridization. J
Pediatr Surg 1999;34:1615–1619.
Wilson DJ, Dailey RA, Griffeth MT, et al. Primary Ewing sarcoma of the orbit.
Ophthal Plast Reconstr Surg 2001;17:300–303.
Woog JJ, Albert DM, Solt LC, et al. Neurofibromatosis of the eyeball and orbit.
Int Ophthalmol Clin 1982;22:157–187.

Leukemic and Histiocytic Disorders

Davis JL, Parke DW II, Font RL. Granulocytic sarcoma of the orbit: a
clinicopathologic study. Ophthalmology 1985;92:1758–1762.
Emile JF, Wechsler J, Brousse N, et al. Langerhans’ cell histiocytosis. Definitive
diagnosis with the use of monoclonal antibody O10 on routinely paraffin-
embedded samples. Am J Surg Pathol 1995;19:636–641.
Feldman RB, Moore DM, Hood CI, et al. Solitary eosinophilic granuloma of the
lateral orbital wall. Am J Ophthalmol 1985;100: 318–323.
Foucar E, Rosai J, Dorfman RF. The ophthalmologic manifestations of sinus
histiocytosis with massive lymphadenopathy. Am J Ophthalmol
1979;87:354–367.
Friendly DS, Font RL, Rao NA. Orbital involvement in “sinus” histiocytosis: a
report of four cases. Arch Ophthalmol 1977;95:2006–2011.
Gunduz K, Palamar M, Parmak N, et al. Eosinophilic granuloma of the orbit:
report of two cases. J AAPOS 2007;11:506–508.
Hidayat AA, Mafee MF, Laver NV, et al. Langerhans’ cell histiocytosis and
juvenile xanthogranuloma of the orbit. Clinicopathologic, CT, and MR
imaging features. Radiol Clin North Am 1998;36:1229–1240.

483
Khan R, Moriarty P, Kennedy S. Rosai Dorfman disease or sinus histiocytosis
with massive lymphadenopathy of the orbit. Br J Ophthalmol 2003;87:1054.
Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv
Ophthalmol 1983;27:211–232.
Kramer TR, Noecker RJ, Miller JM, et al. Langerhans cell histiocytosis with
orbital involvement. Am J Ophthalmol 1997;124:814–824.
Paulli M, Rosso R, Kindl S, et al. Immunophenotypic characterization of the cell
infiltrate in five cases of sinus histiocytosis with massive lymphadenopathy
(Rosai-Dorfman disease). Hum Pathol 1992;23:647–654.
Puri P, Grover AK. Granulocytic sarcoma of orbit preceding acute myeloid
leukaemia: a case report. Eur J Cancer Care (Engl) 1999;8: 113–115.
Vemuganti GK, Naik MN, Honavar SG. Rosai dorfman disease of the orbit. J
Hematol Oncol 2008;1:7.
Willman CL, Busque L, Griffith BB, et al. Langerhans’-cell histiocytosis
(histiocytosis X)—a clonal proliferative disease. N Engl J Med
1994;331:191–193.

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 15 Optic Nerve
Developmental anomalies of the optic nerve include optic nerve aplasia
and hypoplasia, optic pits, optic nerve colobomas, and the morning glory
disc anomaly (MGDA). Bilateral hypoplasia is often associated with
congenital syndromes such as de Morsier syndrome of septo-optic
dysplasia, which includes bilateral hypoplastic nerves, pituitary
dysfunction, and midline abnormalities of the brain, including absence of
the corpus callosum and septum pellucidum and Aicardi syndrome.
Aicardi syndrome includes peripapillary chorioretinal lacunae, ectopic
RPE, agenesis of the corpus callosum, infantile spasms, and mental
retardation. It is an X-linked dominant disorder caused by mutations in the
AIC gene on Xp22.
Colobomas of the optic nerve (Fig. 15-1) are caused by incomplete
closure of the posterior portion of the fetal fissure. Eyes with extensive
optic nerve colobomas may be microophthalmic and have a cystic
outpouching of the posterior sclera (microphthalmos with cyst) (Fig. 2-2).
The cyst typically is lined by dysplastic neuroectodermal tissue, which
communicates with the retina via the coloboma. Optic nerve colobomas
occasionally are associated with choristomatous malformations that
contain smooth muscle and heterotopic fat.

FIG. 15-1. A, B. Optic nerve coloboma. Optic nerve colobomas are caused by
incomplete closure of the fetal fissure. (B. H&E ×10.)

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Optic pits are small crater-like holes that usually occur unilaterally at the
temporal margin of the optic disc. Pathogenesis probably is related to
anomalous closure of the superior margin of the embryonic fissure. Optic
pits frequently are complicated by serous macular detachment and
retinoschisis. Studies suggest that the vitreous probably is the source of the
subretinal and intraretinal fluid.
The MGDA or morning glory syndrome is a congenital optic nerve
anomaly characterized by a funnel-shaped excavation in the optic nerve
head that appears to contain a central tuft of glial tissue believed to be
residual Bergmeister papilla. Cilioretinal vessels radiate from the margin
of the disc, which is surrounded by an elevated annulus of disturbed
chorioretinal pigment and may lack a central retinal artery. About one half
of cases of MGDA have cerebrovascular disease including bilateral carotid
stenosis and moyamoya disease that predispose to stroke. Patients with
MGDA should have neuroimaging to detect vascular and structural brain
anomalies.
Optic disc drusen are globular aggregates of concentrically laminated,
calcified material, probably calcium phosphate, that are located in the
prelaminar optic nerve head within the scleral ring (Fig. 15-2). Optic disc
drusen appear ophthalmoscopically as tan, yellow, or straw-colored
glistening or refractile spheric structures. They typically are found in a
small, crowded optic disc that has a small or absent cup. Optic disc drusen
are unrelated to drusen of the RPE or the heavily calcified epipapillary
astrocytomas called giant drusen of the optic disc that occur in some
patients with tuberous sclerosis complex. Optic disc drusen are important
clinically because they may be misdiagnosed as papilledema and prompt
an unnecessary neurological evaluation. The pathogenesis of optic disc
drusen may be related to blockage of axoplasmic flow in ganglion cell
axons within a narrow crowded scleral canal. Tso suggested that calcified
mitochondria dispersed from prelaminar corpora amylacea may provide a
nidus for further calcium deposition. Optic disc drusen occur sporadically
or may be inherited as an irregular autosomal dominant trait. Disc drusen
also occur in some patients with retinitis pigmentosa or pseudoxanthoma
elasticum with angioid streaks.

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 FIG. 15-2. Optic disc drusen. A. Anterior substance of optic disc contains yellow
spherical refractile bodies. Optic disc drusen may be misdiagnosed clinically as
papilledema. B. A conglomeration of calcareous deposits is present in the optic
nerve anterior to the lamina cribrosa. The drusen have fractured during
sectioning. They were unsuspected, and the specimen was not decalcified. (A.
Photo courtesy of Dr. Peter Savino, B. H&E ×25).

OPTIC DISC EDEMA

(PAPILLEDEMA)
Although optic disc edema (papilledema) classically is associated with
elevated intracranial pressure and space-occupying intracranial lesions,
swollen optic discs also occur in eyes with acute glaucoma, ocular
hypotony, central retinal vein occlusion, juxtapapillary tumors, and severe
hypertensive retinopathy. Optic disc edema does not result from an
accumulation of fluid in the extracellular spaces of the disc. Rather, the
increase in the volume of the nerve head reflects the intracytoplasmic
swelling and distension of ganglion cell axons caused by blockage of
axoplasmic flow in the distorted lamina cribrosa (Fig. 15-3D). The pores
of the lamina cribrosa are distorted by a pressure gradient between the
intraocular pressure and pressure in the retrolaminar optic nerve. A
pressure gradient can form if the intracranial pressure is elevated (classic
papilledema), the intraocular pressure is low (hypotony), or the intraocular
pressure is acutely elevated (acute glaucoma) (Fig. 15-3).

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 FIG. 15-3. Optic disc edema. A. The optic nerve is massively swollen and
injected and has blurred margins. Concentric folds and exudates are present in the
adjacent retina. B. Optic disc edema, secondary to juxtapapillary melanoma.
Small choroidal tumor has invaded the optic nerve sheath, severely compressing
the nerve and blocking axoplasmic flow. The nerve head is massively swollen
and the photoreceptors are displaced laterally. C. The photoreceptors of the
swollen optic nerve are displaced laterally. Paton’s folds and exudates are noted
in the outer retina. D. Dilated axonal profiles in prelaminar optic nerve are filled
with blocked axoplasm. (B. H&E ×25, C. H&E ×100, D. H&E ×400.)

Histopathologically, the nerve head is swollen and the physiological cup is

narrowed (Fig. 15-3). The increase in the volume of nerve head tissue
displaces the photoreceptors laterally from the margin of the disc (Fig. 15-
3C). This lateral displacement of photoreceptors and an accompanying
shallow peripapillary collection of serous subretinal fluid are responsible
for enlargement of the blind spot on visual field testing. Paton folds are
also found in the outer retinal layers. Extensive gliosis and axonal loss
occur in chronic papilledema.

OPTIC ATROPHY
488
Optic nerve atrophy is characterized pathologically by shrinkage of the
parenchyma of the optic nerve caused by loss of ganglion cell axons (Fig.
15-4). The subarachnoid space around the shrunken nerve becomes
widened, and the dura appears redundant and folded. Light microscopy
discloses loss of axons and thickening of the pia mater and pial septa.
Gliosis may or may not become prominent depending on the cause of the
atrophy.

FIG. 15-4. Optic atrophy. A. The optic nerve is atrophic and the subarachnoid
space is widened. The severity of the optic atrophy makes the meninges appear
redundant. B. The pia and pial septa are markedly thickened, and the substance of
the nerve is severely atrophic. C. Transverse section shows that most of the
parenchyma of the severely atrophic optic nerve has been replaced by blue-
staining collagenous connective tissue. The pia and pial septa are markedly
widened. (B. H&E ×10, C. Masson trichrome ×25.)

By convention, the terms primary or descending optic atrophy are applied

to atrophy of the nerve caused by lesions in the central nervous system or
orbit. Primary optic atrophy generally is not associated with an
ophthalmoscopically visible glial or mesenchymal reaction. Causes of
primary optic atrophy include optic nerve trauma, compression by
neoplasms or enlarged extraocular muscles in thyroid ophthalmopathy,
neurosyphilis, demyelinating diseases including multiple sclerosis,
heritable leukodystrophies, and toxic and nutritional optic neuropathies.
Inflammatory, neoplastic, or vascular lesions located in the retina or
the vicinity of the optic disc cause secondary or ascending optic atrophy,
which is often marked by pronounced alterations in the glial and
mesenchymal tissues of the nerve head. Common retinal causes of optic
atrophy include chorioretinitis, retinitis pigmentosa, and trauma.
Leber hereditary optic neuropathy (LHON) is caused by mutations in
mitochondrial DNA. Three-point mutations in the ND4, ND1, and ND6

489
subunit genes of complex I that code for the NADH dehydrogenase protein
in the mitochondrial oxidative phosphorylation chain are responsible for
most cases, and 70% of Northern European and 90% of Asian cases harbor
the ND4 G11778A “Wallace mutation.” The retinal ganglion cells,
especially those in the maculopapillary bundle, are primarily affected and
undergo apoptosis and degeneration.
LHON is maternally inherited because the mother’s egg cells are the
developing embryo’s sole source of mitochondria and mitochondrial DNA.
LHON usually presents with subacute progressive bilateral central visual
loss in males between ages 18 and 30 years. Some patients have optic disc
swelling and telangiectatic peripapillary vessels. Although retinal ganglion
cells and axons are lost in both primary and glaucomatous optic atrophies,
cupping of the disc generally occurs in glaucomatous optic atrophy and is
not prominent in primary optic atrophy.
Schnabel cavernous optic atrophy is a relatively rare type of optic
atrophy characterized by the presence of large spaces filled with
hyaluronic acid in the retrolaminar part of the nerve (Fig. 15-5).

FIG. 15-5. Schnabel cavernous optic atrophy. A. Diameter of transversely

sectioned optic nerve is markedly widening. Small cystoid spaces replace
myelinated parenchyma. B. Retrolaminar optic nerve contains pools of clear
mucoid material. C. Clear spaces in retrolaminar optic nerve stain intensely for
acid mucopolysaccharide. D. Positive staining is abolished by pretreatment with
hyaluronidase indicating that the substance is hyaluronic acid. (B. H&E ×10, C.
colloidal iron for AMP ×10, D. colloidal iron after hyaluronidase digestion ×10.)

Schnabel cavernous optic atrophy classically was associated with an acute

elevation of intraocular pressure, but a large postmortem study found
many cases in elderly women who had systemic vascular disease and no
evidence of glaucoma. Hypothetical sources of the mucopolysaccharide
include the vitreous in glaucomatous eyes or in situ production within

490
areas of optic nerve infarction. No gliosis or histiocytic reaction typically
is seen. Intraocular silicone oil instilled during vitreoretinal surgery
occasionally infiltrates the optic nerve in glaucomatous eyes producing
pseudo-Schnabel cavernous atrophy (Fig. 15-6). In rare instances, the
silicone oil can migrate to the brain.

FIG. 15-6. Pseudo-Schnabel cavernous atrophy. A. Vacuoles of silicone oil are

present in retrolaminar part of deeply cupped optic nerve. Clumps of
macrophages that have ingested emulsified oil are present on the inner surface of
the retina and glaucoma cup. B. Large silicone oil vacuoles in transversely
sectioned nerve. (A. H&E ×10, B. H&E ×50.)

OPTIC NEURITIS
The term optic neuritis refers to involvement of any part of the optic nerve
by an inflammatory disease process. The process is called retrobulbar
neuritis clinically when the inflammation involves the retrobulbar part of
the optic nerve, and ophthalmoscopy initially reveals no abnormalities.
Multiple sclerosis is a relatively common cause of retrobulbar neuritis. The
term papillitis is used when the optic disc is affected, and the process is
called neuroretinitis if the peripapillary retina is involved by edema,
hemorrhage, and inflammation. Optic neuritis is classified topographically
as perineuritis, periaxial neuritis, axial neuritis, and transverse neuritis. It
can be caused by bacterial, mycobacterial, viral, mycotic, and parasitic
infection as well as by granulomatous disorders such as sarcoidosis and
granulomatosis with polyangiitis (Wegener) (Fig. 15-7). Large granulomas
occur on the surface of the optic disc in some patients with sarcoidosis.

491
 FIG. 15-7. Sarcoid optic neuropathy. A. The parenchyma of the optic nerve
contains several foci of chronic granulomatous inflammation. B, C. Epithelioid
histiocytes and giant cells form characteristic discrete noncaseating granulomas.
D. Granulomas are immunoreactive for CD68. (A. H&E ×10, B. H&E ×50, C.
H&E ×250, D. IHC for histocytic marker CD68 ×150.)

OPTIC NERVE NEOPLASMS

Most primary tumors of the optic nerve are optic nerve gliomas (ONGs)
and meningiomas. Although melanocytoma (magnocellular nevus) can
occur anywhere in the uveal tract, it typically affects the optic nerve head
(Fig. 11-3). Large epipapillary astrocytomas occur in some patients with
tuberous sclerosis complex, and the optic nerve head can be affected by
hemangioblastoma in von Hippel-Lindau syndrome. Rare
medulloepitheliomas of the optic nerve have been reported. Combined
hamartoma of the RPE and retina may affect the optic disc and has been
reported in association with neurofibromatosis type 2 (NF2).
ONG is the most common primary tumor the optic nerve. ONGs
previously were called juvenile pilocytic astrocytomas, but the preferred
term is now pilocytic astrocytoma WHO grade 1. ONG usually presents

492
between ages 2 and 6 years with axial proptosis and unilateral visual loss.
Ophthalmoscopy may disclose either optic atrophy or papilledema.
Strabismus, an afferent pupillary defect and enlargement of the ipsilateral
optic canal, may be present. There is a strong association with NF1 (10%
to 50%). ONGs cause a fusiform swelling of the optic nerve. The tumor
does not invade the orbital tissues because it typically remains confined by
the intact dura (Fig. 15-8C). Most ONGs in children are low-grade (WHO
grade 1) pilocytic astrocytomas, which are composed of spindly cells that
have long, delicate, hair-like processes (Fig. 15-8E). The term pilocytic
reflects that feature. Eosinophilic clumps of fibrils called Rosenthal fibers
are a prominent finding in some tumors (Fig. 15-8F). ONGs associated
with NF1 often break through the pia and proliferate in the subarachnoid
space within the intact dura (arachnoidal gliomatosis) (Fig. 15-8D). In
such cases, the central remnant of the optic nerve may be evident on
imaging studies. Arachnoidal gliomatosis may be confused with
meningioma in a superficial biopsy. The proliferation index disclosed by
Ki-67 immunostaining typically is low (<1%). A higher index (2% to 3%)
may be a sign of more aggressive behavior. Molecular genetic studies
show that both copies of the NF1 gene are inactivated in ONGs from
patients with neurofibromatosis. Many sporadic cases harbor mutations in
the BRAF gene including duplications involving 17q34 or the V600E
point mutation.

493
FIG. 15-8. Optic nerve glioma. Magnetic resonance scans shows fusiform
swelling of optic nerve. A. T1-weighted image. B. T2-weighted image. C.
Meninges of markedly swollen nerve are intact. D. Glial cells infiltrate arachnoid
above (arachnoidal gliomatosis). E.Cells constituting low-grade pilocytic
astrocytoma of the optic nerve have bland nuclei and slender cellular processes.
F. This tumor contains many periodic acid–Schiff (PAS)-positive Rosenthal
fibers. (C. H&E ×2, D. H&E ×25, E. H&E ×100, F. Periodic acid-Schiff ×100.)

The treatment of ONG is somewhat controversial and includes

observation, surgery, radiation, and chemotherapy. At the present time,
many ONGs are followed conservatively. Both radiation and
chemotherapy can stabilize the growth of ONGs. Chemotherapy has been
advocated as first-line treatment for younger patients with progressive
lesions because it has fewer side effects than does radiation. Surgical
excision, usually sparing the eye, may be indicated for high degrees of
cosmetically unacceptable proptosis or when the tumor threatens to extend
intracranially and involve the chiasm.
High-grade malignant gliomas of chiasm or optic nerve consistent with
glioblastoma multiforme occur rarely in adults and have a dismal
prognosis (Fig. 15-9).

FIG. 15-9. Malignant glioma, optic nerve. A. Hypercellular tumor is composed

of highly atypical glial cells with hyperchromatic pleomorphic nuclei seen at
higher magnification in B. Malignant gliomas of the optic nerve are quite rare and
have a poor prognosis. (A. H&E ×100, B. H&E ×250.)

Primary meningiomas of the optic nerve can occur in either adults or

children. They may behave aggressively in children. Clinically, optic nerve
meningiomas compress the optic nerve causing optic atrophy and visual
loss (Fig. 15-10). Ophthalmoscopy may reveal opticociliary
(retinochoroidal) venous shunt vessels on the optic disc. Primary orbital
meningiomas arise from the meninges of the optic nerve or rarely from

494
ectopic rests of arachnoidal tissue. Primary intracranial meningiomas also
invade the orbit secondarily. Most primary meningiomas of the orbit are
either meningothelial or transitional. The tumor cells typically are arranged
in whorls or paving stone clusters and may have intranuclear vacuoles of
herniated cytoplasm. Calcified psammoma bodies may be present (Fig. 15-
10D). Meningiomas typically stain for vimentin, epithelial membrane
antigen (EMA), and cytokeratin. Unlike ONGs, optic nerve meningiomas
frequently erode through the meninges and invade the soft tissue of the
orbit. Fractionated external beam radiotherapy improves or stabilizes
visual acuity in many patients and has been recommended as initial
therapy.

FIG. 15-10. Meningioma of the optic nerve. A. Involved optic nerve is thickened.
B. Tumor compressing the optic nerve contains many psammoma bodies. The
patient had neurofibromatosis. C. Meningothelial meningioma, optic nerve.
Whorls of bland meningothelial cells constitute this tumor. Psammoma bodies are
not present. D. Meningothelial meningioma with psammoma bodies. Most
meningiomas cannot metastasize but are locally infiltrative. Orbital meningiomas
arise primarily from the optic nerve sheath or invade the orbit secondarily from
the intracranial meninges. Rare ectopic meningiomas derived from extradural
meningothelial rests have been reported. (B. H&E ×10, C. H&E ×100, D. H&E
×100.)

495
Leukemia can infiltrate the optic nerve (Fig. 15-11).

FIG. 15-11. Leukemic optic neuropathy. A. Leukemia cells, seen under higher
magnification in (B), infiltrate pia and peripheral pial septa of optic nerve.
Specimen was obtained postmortem after fatal relapse. (A. H&E ×25, B. H&E
×250.)

BIBLIOGRAPHY
Developmental Lesions
Brockhurst RJ. Optic pits and posterior retinal detachment. Trans Am Ophthalmol
Soc 1975;73:264–291.
Brodsky MC, Parsa CF. The moyamoya optic disc. JAMA Ophthalmol
2015;133:164.
Brown GC, Shields JA, Patty BE, et al. Congenital pits of the optic nerve head. I.
Experimental studies in collie dogs. Arch Ophthalmol 1979;97:1341–1344.
Christoforidis JB, Terrell W, Davidorf FH. Histopathology of optic nerve pit-
associated maculopathy. Clin Ophthalmol (Auckland, NZ) 2012;6:1169–1174.
Ehlers JP, Kernstine K, Farsiu S, et al. Analysis of pars plana vitrectomy for optic
pit–related maculopathy with intraoperative optical coherence tomography: a
possible connection with the vitreous cavity. Arch Ophthalmol
2011;129:1483–1486.
Eustis HS, Sanders MR, Zimmerman T. Morning glory syndrome in children:
association with endocrine and central nervous system anomalies. Arch
Ophthalmol 1994;112:204–207.
Font RL, Zimmerman LE. Intrascleral smooth muscle in coloboma of the optic
disc: electron microscopic verification. Am J Ophthalmol 1971;72:452–457.
Fruhman G, Eble TN, Gambhir N, et al. Ophthalmologic findings in Aicardi
syndrome. J AAPOS 2012;16:238–241.
Gass JDM. Serous detachment of the macula secondary to congenital pit of the
optic nerve head. Am J Ophthalmol 1969;67:821–841.

496
Hoyt CS, Billson FA, Ouvrier R, et al. Ocular features of Aicardi’s syndrome.
Arch Ophthalmol 1978;96:291–295.
Imamura Y, Zweifel SA, Fujiwara T, et al. High-resolution optical coherence
tomography findings in optic pit maculopathy. Retina 2010;30:1104–1112.
Jensen PE, Kalina RE. Congenital anomalies of the optic disk. Am J Ophthalmol
1976;82:27–31.
Katome T, Mitamura Y, Hotta F, et al. Swept-source optical coherence
tomography identifies connection between vitreous cavity and retrobulbar
subarachnoid space in patient with optic disc pit. Eye 2013;27:1325–1326.
Kindler P. Morning glory syndrome: unusual congenital optic disk anomaly. Am J
Ophthalmol 1970;69:376–384.
Lenhart PD, Lambert SR, Newman NJ, et al. Intracranial vascular anomalies in
patients with morning glory disc anomaly. Am J Ophthalmol
2006;142:644–650.
Lieb W, Rochels R, Gronemeyer U. Microphthalmos with colobomatous orbital
cyst: clinical, histological, immunohistological, and electron microscopic
findings. Br J Ophthalmol 1990;74:59–62.
Lincoff H, Lopez R, Kreissig I, et al. Retinoschisis associated with optic nerve
pits. Arch Ophthalmol 1988;106:61–67.
Mafee MF, Jampol LM, Langer BG, et al. Computed tomography of optic nerve
colobomas, morning glory anomaly, and colobomatous cyst. Radiol Clin
North Am 1987;25:693–699.
Martel JN, Rutar T, Lujan BJ, et al. Chorioretinal architecture in Aicardi
syndrome: an optical coherence tomography and fluorescein angiography
study. J AAPOS 2011;15:308–310.
Pagon RA. Ocular coloboma. Surv Ophthalmol 1981;25:223–223.
Pollock S. The morning glory disc anomaly: contractile movement, classification,
and embryogenesis. Doc Ophthalmol 1987;65:439–460.
Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J
Med 2009;360:1226–1237.
Slamovits TL, Kimball GP, Friberg TR, et al. Bilateral optic disc colobomas with
orbital cysts and hypoplastic optic nerves and chiasm. J Clin
Neuroophthalmol 1989;9:172–177.
Waring GO, Roth AM, Rodrigues MM. Clinicopathologic correlation of
microphthalmos with cyst. Am J Ophthalmol 1976;82:714–721.
Weiss A, Martinez C, Greenwald M. Microphthalmos with cyst: clinical
presentations and computed tomographic findings. J Pediatr Ophthalmol
Strabismus 1985;22:6–12.
Wiggins RE, von Noorden GK, Boniuk M. Optic nerve coloboma with cyst: a
case report and review. J Pediatr Ophthalmol Strabismus 1991;28:274–277.
Zeki SM, Dutton GN. Optic nerve hypoplasia in children: mini review. Br J
Ophthalmol 1990;74:300–304.

Leber Hereditary Optic Neuropathy

497
Brown MD, Voljavec AS, Lott MT, et al. Leber’s hereditary optic neuropathy: a
model for mitochondrial neurodegenerative diseases. FASEB J
1992;6:2791–2799.
Howell N. Leber hereditary optic neuropathy: how do mitochondrial DNA
mutations cause degeneration of the optic nerve? J Bioenerg Biomembr
1997;29:165–173.
Kerrison JB, Newman NJ. Clinical spectrum of Leber’s hereditary optic
neuropathy. Clin Neurosci 1997;4:295–301.
Morris MA. Mitochondrial mutations in neuro-ophthalmological diseases. A
review. J Clin Neuroophthalmol 1990;10:159–166.
Phillips CI, Gosden CM. Leber’s hereditary optic neuropathy and Kearns-Sayre
syndrome: mitochondrial DNA mutations. Surv Ophthalmol
1991;35:463–472.
Riordan-Eva P, Wood NW. Mitochondrial disorders in neuro-ophthalmology.
Curr Opin Neurol 1996;9:1–4.
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated
with Leber’s hereditary optic neuropathy. Science
1988;242(4884):1427–1430.

Optic Disk Edema

Galbraith JEK, Sullivan JH. Decompression of the perioptic meninges for relief
of papilledema. Am J Ophthalmol 1973;76:687–692.
Tso MOM, Fine BS. Electron microscopic study of papilledema in man. Am J
Ophthalmol 1976;82:424–434.
Tso MOM, Hayreh SS. Optic disc edema in raised intracranial pressure. III. A
pathologic study of experimental papilledema. Arch Ophthalmol
1977;95:1458–1462.

Optic Disk Drusen

Kapur R, Pulido JS, Abraham JL, et al. Histologic findings after surgical excision
of optic nerve head drusen. Retina 2008;28(1):143–146.
Spencer WH. Drusen of the optic nerve (XXXIV Edward Jackson Memorial
Lecture). Am J Ophthalmol 1978;85:1–12.
Tso MOM. Pathology and pathogenesis of drusen of the optic nerve head.
Ophthalmology 1981;188:1066–1080.

Schnabel Cavernous Degeneration of the Optic

Nerve
Giarelli L, Falconieri G, Cameron JD. Schnabel cavernous degeneration: a
vascular change of the aging eye. Arch Pathol Lab Med
2003;127(10):1314–1319.

498
Gong H, Ye W, Freddo TF, et al. Hyaluronic acid in the normal and
glaucomatous optic nerve. Exp Eye Res 1997;64:587–595.
Kalvin NH, Hamasaki DI, Gass JDM. Experimental glaucoma in monkeys. I.
Relationship between intraocular pressure and cupping of the optic disc and
cavernous atrophy of the optic nerve. Arch Ophthalmol 1966;76:82–93.
Zimmerman LE, deVenecia G, Hamasaki DI. Pathology of the optic nerve in
experimental acute glaucoma. Invest Ophthalmol 1967;6:109–125.

Pseudo-Schnabel Cavernous Degeneration of the

Optic Nerve
Eller AW, Friberg TR, Mah F. Migration of silicone oil into the brain: a
complication of intraocular silicone oil for retinal tamponade. Am J
Ophthalmol 2000;129:685–688.
Fangtian D, Rongping D, Lin Z, et al. Migration of intraocular silicone oil into the
cerebral ventricles. Am J Ophthalmol 2005;140:156–158.
Grzybowski A, Pieczynski J, Ascaso FJ. Neuronal complications of intravitreal
silicone oil: an updated review. Acta Ophthalmol 2014;92(3):201–204.
Jabbour P, Hanna A, Rosenwasser R. Migration of silicone oil in the cerebral
intraventricular system. Neurologist 2011;17:109–110.
Shields CL, Eagle RC Jr. Pseudo-Schnabel’s cavernous degeneration of the optic
nerve secondary to intraocular silicone oil. Arch Ophthalmol
1989;107:714–717.
Williams RL, Beatty RL, Kanal E, et al. MR imaging of intraventricular silicone:
case report. Radiology 1999;212(1):151–154.

Optic Neuritis and Optic Atrophy

Andersen DR. Ascending and descending optic atrophy produced experimentally
in squirrel monkeys. Am J Ophthalmol 1973;76:693–711.
Laties AM, Scheie HG. Sarcoid granuloma of the optic disk: evolution of multiple
small tumors. Trans Am Ophthalmol Soc 1970;689:219–233.
Miller NR. The optic nerve. Curr Opin Neurol 1996;9:5–15.
Newman NJ. Neuro–ophthalmology: the afferent visual system. Curr Opin
Neurol 1993;6:738–746.
Newman NJ. Optic neuropathy. Neurology 1996;46:315–322.
Warner J, Lessell S. Neuro–ophthalmology of multiple sclerosis. Clin Neurosci
1994;2:180–188.

Optic Nerve Gliomas

Bar EE, Lin A, Tihan T, Burger PC, et al. Frequent gains at chromosome 7q34
involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol
2008;67:878–887.

499
Borit A, Richardson EP Jr. The biological and clinical behavior of pilocytic
astrocytomas of the optic pathways. Brain 1982;105:161–187.
Cameron JD, Rodriguez FJ, Rushing E, et al. An 80-year experience with optic
nerve glioma cases at the Armed Forces Institute of Pathology: evolution from
museum to molecular evaluation suggests possible interventions in the
cellular senescence and microglial pathways (an American Ophthalmological
Society thesis). Trans Am Ophthalmol Soc 2014;112:11–25.
Cummings TJ, Provenzale JM, Hunter SB, et al. Gliomas of the optic nerve:
histological, immunohistochemical (MIB-1 and p53), and MRI analysis. Acta
Neuropathol 2000;99:563–570.
Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol
1994;38:427–452.
Lewis RA, Gerson LP, Axelson KA, et al. Von Recklinghausen’s
neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology
1984;91:929–935.
Miller NR, Illif WJ, Green WR. Evaluation and management of gliomas of the
anterior visual pathways. Brain 1974;97:743–754.
Miller NR. Primary tumours of the optic nerve and its sheath. Eye (Lond)
2004;18(11):1026–1037. Review. PubMed PMID: 15534587.
Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a
mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin
Invest 2008;118:1739–1749.
Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, et al. BRAF duplications and
MAPK pathway activation are frequent in gliomas of the optic nerve proper. J
Neuropathol Exp Neurol 2012;71(9):789–794.
Rush JA, Younge BR, Campbell RJ, et al. Optic glioma. Long-term follow-up of
85 histopathologically verified cases. Ophthalmology 1982;89:1213–1219.
Sadun F, Hinton DR, Sadun AA. Rapid growth of an optic nerve ganglioglioma in
a patient with neurofibromatosis 1. Ophthalmology 1996;103:794–799.
Review.
Spoor TC, Kennerdell JS, Martinez AJ, et al. Malignant gliomas of the optic
nerve pathways. Am J Ophthalmol 1980;89:284–292.
Stern J, Jakobiec FA, Housepian E. The architecture of optic nerve gliomas with
and without neurofibromatosis. Arch Ophthalmol 1980;98:505–511.
Tibbetts KM, Emnett RJ, Gao F, et al. Histopathologic predictors of pilocytic
astrocytoma event-free survival. Acta Neuropathol 2009;117:657–665.
Weiss L, Sagerman RH, King GA, et al. Controversy in the management of optic
nerve glioma. Cancer 1987;59:1000–1004.
Yu J, Deshmukh H, Gutmann RJ, et al. Alterations of BRAF and HIPK2 loci
predominate in sporadic pilocytic astrocytoma. Neurology
2009;73:1526–1531.

Optic Nerve Meningiomas

500
Dutton JJ. Optic nerve gliomas and meningiomas. Neurol Clin 1991;9:163–177.
Dutton JJ. Optic nerve sheath meningiomas. Surv Ophthalmol 1992;37:167–183.
Grant EA, Trzupek KM, Reiss J, et al. Combined retinal hamartomas leading to
the diagnosis of neurofibromatosis type 2. Ophthalmic Genet
2008;29:133–138.
Karp LA, Zimmerman LE, Borit A, et al. Primary intraorbital meningiomas. Arch
Ophthalmol 1974;91:24–28.
Marquardt MD, Zimmerman LE. Histopathology of meningiomas and gliomas of
the optic nerve. Hum Pathol 1982;13:226–235.
Pravdenkova S, Al-Mefty O, Sawyer J, et al. Progesterone and estrogen receptors:
opposing prognostic indicators in meningiomas. J Neurosurg
2006;105:163–173.

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 16 Laboratory
Techniques and Special
Stains

SPECIMEN HANDLING IN THE

OPHTHALMIC PATHOLOGY
LABORATORY
This chapter discusses the basic principles of practical ocular
histopathology and summarizes techniques used in the handling, gross
dissection, and submission of enucleated eyes and other ocular specimens
for routine histopathologic examination. Special histochemical and
immunohistochemical stains also are discussed.

Fixation
Enucleated eyes are routinely fixed for at least 24 hours by total immersion
in a relatively large volume (50 to 100 mL) of 10% neutral buffered
formalin. The large volume of fixative is necessary because the solution
must penetrate through the sclera. Bouin solution (bright yellow in color)
should not be used because it hardens the sclera, making eyes extremely
difficult to section. Alcohol-based fixatives are also unsatisfactory because
they precipitate protein in the vitreous and interfere with gross
examination. Enucleated eyeballs should be briefly rinsed in running tap
water to remove excess fixative prior to handling.

Specimen Orientation

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Determination of laterality (right or left eye) is a prerequisite for proper
specimen orientation. The laterality of an eye is determined by identifying
key anatomic landmarks (Fig. 16-1). These include the long posterior
ciliary vessels, which appear as blue lines on the posterior sclera on either
side of the optic nerve in the horizontal plane; the cornea, whose
horizontal diameter is usually a millimeter longer than its vertical
diameter; and the insertions of the inferior and superior oblique muscles.
The inferior oblique muscle lacks a tendon; its muscular fibers insert
directly into the sclera in the inferotemporal quadrant. The nasal end of the
muscular inferior oblique insertion lies close to the fovea. The shiny
tendinous insertion of the superior oblique muscle is located superiorly and
temporally and is marked by parallel white bands. It is an excellent
landmark for the superior pole of the eye. After the horizontal meridian
and the superior pole have been located, the nasal and temporal sides of
the eye are readily identified. It is important to remember that both oblique
muscles insert on the temporal side of the eye, and their fibers run nasally.
The temporal arc of the posterior sclera is longer than the nasal arc
because the optic nerve enters the eye 15 degrees nasal to the posterior
pole. The angulation of the optic nerve stump cannot be relied upon to
determine laterality, however, because it often bends temporally after
fixation.

FIG. 16-1. Orientation of globe, posterior landmarks. The temporal insertions of

the oblique muscles are helpful landmarks. The inferior oblique lacks a tendon,
and its muscular fibers insert inferonasally near the fovea. The tendinous
insertion of the superior oblique muscle is located superotemporally. The long
posterior ciliary vessels are often evident as blue lines on either side of the optic
nerve in the horizontal plane.

Measurement

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After orientation, the eye is measured using caliper or a millimeter ruler.
Standard measurements include the anteroposterior, horizontal, and
vertical diameters of the eye; the length of the segment of optic nerve
attached; the horizontal and vertical diameters of the cornea; and the
diameter of the pupil (Fig. 16-2A). Measurements should be made and
recorded in a standardized sequence, that is, AP, horizontal, and vertical.
Important pathologic features such as wounds, lacerations, and tumors
should also be measured and their location noted. Most normal human
eyes are slightly <1 inch in diameter (24 to 25 mm), and the normal cornea
is ~1 cm in diameter (11×10 mm).

FIG. 16-2. A. Ocular measurements. Standard measurements include the A-P,

horizontal and vertical diameters of the eye, the length of the optic nerve
segment, the horizontal and vertical diameters of the cornea, and the size of the
pupil. B. Transillumination of globe. Transillumination is used to localize
ciliochoroidal melanoma in enucleated eye. Arrow points to round shadow cast
by choroidal part of pigmented tumor. The pupil glows brightly.

It is easier to section an eye after the attached segment of optic nerve is

removed. The nerve should sectioned a millimeter or two posterior to the
sclera to avoid “buttonholing” a deeply cupped nerve head in a severely
glaucomatous eye. A transverse section of the optic nerve should always
be submitted if the nerve has not been cut flush with the globe. The
surgical margin should be marked with an indelible colored pencil or India
ink before the nerve is removed. The optic nerve segment should always
be removed before the globe is opened to preclude potential contamination
of the surgical margin with intraocular tumor. This is especially important
if the eye contains retinoblastoma, which tends to invade the optic nerve.
Surgeons occasionally submit the optic nerve in a separate container.
Blood staining and crushing serve to identify the true surgical margin of
such specimens.

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INSPECTION AND DESCRIPTION
The general character and consistency of the eye are noted. Descriptive
terms that commonly are used include normal, soft, collapsed, ruptured,
lacerated, hard, rubbery, phthisical, etc. Before it is opened, the external
surface of the eye should be carefully and systematically examined with a
dissecting microscope, starting anteriorly. The cornea is usually slightly
hazy in fixed or postmortem specimens. The presence of corneal opacities,
scars, vascularization, ulcers, band keratopathy, wounds, incisions, and
sutures should be described and measured when appropriate. The shape
and size of the pupil, the color of the iris, and the presence and location of
iridectomies, surgical iris colobomas, and ectropion of the iris pigment
epithelium should be recorded. If the cornea is hazy, iris defects are readily
disclosed by transillumination.
The rest of the globe should be carefully inspected with the dissecting
microscope looking for signs of surgical or nonsurgical trauma or
extraocular tumor extension. The presence, type, location, and size of
wounds, scars, vitrectomy ports, sutures, and prosthetic devices such as
retinal implants, explants, and encircling bands and tube shunts should be
precisely noted. The use of “clock hours,” for example, “between 1 and 3
o’clock” is helpful in the description of wounds and other important
lesions. Drawing a diagram of the findings on the pathology protocol
facilitates description and permits reconstruction of the gross description if
the dictation is lost.

TRANSILLUMINATION
Eyes are transilluminated before they are opened to disclose occult
pathology that may not be evident on external examination.
Transillumination is performed by holding the eye directly on the surface
of a bright light in a darkened chamber. Transillumination is especially
helpful during the orientation of eyes that contain intraocular tumors,
particularly uveal malignant melanomas (Fig. 16-2B). Pigmented
melanomas usually cast a dark shadow on the sclera, which should be
localized and measured. When clinical data are absent, transillumination
may disclose signs of previous surgery, for example, an iridectomy, that
may be an indication for vertical sectioning. Eyes that are filled with blood
or contain dense gelatinous exudate often transmit light poorly, as do
specimens from heavily pigmented individuals. Staphylomas and

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cyclodestructive procedures cause increased light transmission.

DISSECTION
Microscopic sections are cut from a paraffin block that contains a short
cylindrical segment of the eyeball called the pupil–optic nerve or P-O
segment. The P-O segment includes most of the cornea, iris, and pupil
anteriorly and the optic nerve posteriorly (Fig.16-3B).

FIG. 16-3. A. Sectioning technique for globe. Globe is sectioned with a razor
blade. It is positioned corneal side down during initial cut. B. P-O segment and
calottes. The central P-O segment, which is submitted for sectioning includes the
pupil and optic nerve.

When tissue is submitted for histopathological examination, care must be

taken to ensure that the microscopic sections will include important lesions
such as tumors, lacerations, or incisions that must be described and
diagnosed. The presence and location of the ocular pathology determines
how the eye is opened. As routine practice, eyes are opened horizontally if
they do not contain wounds or lesions located in other quadrants. In
addition to the pupil and optic nerve, horizontal P-O sections include the
macula, as well as the pupil and optic nerve. In the past, many eyes that
had prior surgery were opened vertically to include wounds that typically
were located at the superior limbus. This category still includes eyes that
have had filtering procedures for glaucoma. Surgical techniques have
changed, however, and many cataract wounds now are located
horizontally. These will be included in routine horizontal P-O sections. If
an eye with a small superior incision is opened horizontally, the
microscopic sections will not include the wound and the pathologist will
be unable to document its presence. Eyes that have had tubes shunts for
glaucoma should be opened perpendicular to the insertion of the tube into

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the anterior chamber. The epibulbar reservoir of the shunt must be
carefully dissected and removed from the eye prior to sectioning the eye.
Traumatic lacerations and intraocular tumors can occur anywhere.
Such eyes are opened along the meridian that includes the main part of the
lesion. The localization of intraocular tumors by transillumination greatly
aids sectioning. If the eye does not permit transillumination, the location of
tumor sometimes can be determined by careful palpation

SECTIONING TECHNIQUE
I currently section eyes using one half of a standard double-edged razor
blade that has been snapped in half within its protective wrapper (Fig. 16-
3A). The two ends of the blade are held between the apposed surfaces of
the thumb and forefinger, and a gentle sawing and pushing motion is used.
During the initial cut, the eye is positioned cornea side down on the cutting
block and steadied with the nondominant hand. Guidelines drawn on the
eye with colored pencil facilitate sectioning and assure that the eye
maintains proper orientation. The initial cut is begun just external to the
dural sheath of the optic nerve and should enter the periphery of the
anterior chamber anteriorly. The two dome-shaped caps of tissue that are
removed are called calottes (French for visorless cap). Ideally, the first
calotte should include about one fourth to one fifth of the peripheral
anterior chamber. The central P-O segment should be about 8 to 10 mm
thick. During removal of the second calotte, the globe is placed cut-
surface-down on the cutting board. Eye protection (glasses, goggles, or
face shield) should be worn during the initial cut to protect against
occasional squirts or splashes of fixative and intraocular contents that can
occur if the intraocular pressure is high or the eye is grasped too firmly.
Any material that flows from the eye during sectioning (blood,
crystals, pigment-tinged fluid, or silicone oil) should be described. Gritty,
hard, or even impenetrable intraocular material may be encountered. When
this happens, possibilities include intraocular bone, a calcified cataractous
lens, or some older types of prosthetic intraocular lenses. Intraocular bone
is an extremely common finding in phthisical eyes. Eyes that contain bone
must be decalcified before they are submitted. In some cases, so much
bone is present that calcification is a prerequisite for sectioning.
Every specimen should be examined carefully and systematically with
the dissecting microscope and macrophotography performed if indicated.
Disturbing light reflexes can be minimized by immersing the specimen in

507
60% “grossing” alcohol during gross examination and macrophotography.
Placing the flat-bottomed cylindrical dish on a plate of dark blue Plexiglas
provides an aesthetic background for the gross photographs, which is
enhanced if bottom of the dish is coupled to the plastic with a thin layer of
alcohol. The calottes usually are retained in alcohol as “wet tissue” and
may be retrieved if additional sections or studies are necessary. Both
calottes are “bread-loafed” and submitted entirely, if the eye contains
retinoblastoma to disclose possible choroidal invasion by tumor.

ROUTINE HISTOPATHOLOGY:
DEHYDRATION, EMBEDDING, AND
MICROTOMY
The P-O segment is embedded in a block of paraffin wax to facilitate the
cutting of microscopic sections. Because water and wax are not miscible,
the aqueous fixative and the water in the tissue must be removed before
the specimen can be embedded. This process is called dehydration. Tissue
is dehydrated by passing it through increasing concentrations of ethanol
(“graded alcohols”) until absolute ethanol is reached. The dehydrated
tissue is then transferred to xylene, which is miscible with both absolute
alcohol and paraffin and then infiltrated with molten paraffin under
vacuum. After infiltration, the specimen is placed in a plastic mold that is
filled with molten paraffin. The paraffin is cooled and hardens into a
block, which fits into the chuck of a rotary microtome. The support
provided by the surrounding paraffin matrix allows the tissue to be
sectioned thinly (5 to 8 µm). The thin slices of paraffin and tissue are then
floated onto the surface of a heated water bath, which causes the paraffin
to expand. The tissue sections are then mounted on glass slides, which are
heated in an oven to promote tissue adherence.

STAINING
Most human tissues are relatively transparent unless they contain
endogenous pigment (Fig. 16-4A). To facilitate examination, microscopic
slides are stained with dyes such as hematoxylin and eosin (H&E) that
color certain tissue components. Because aqueous solutions of these stains
usually are used, the tissue sections must be deparaffinized and rehydrated
before they can be stained. This is done by immersing the slides in

508
successive baths of xylene, absolute alcohol, and then decreasing
concentrations of alcohol and water. After staining, the tissue subsequently
is dehydrated and coverslipped.

FIG. 16-4. Staining, H&E stain. A. Unstained section. Presence of endogenous

pigment allows identification of RPE and choroidal melanocytes. B.
Hematoxylin-stained section (same area as A). Basic dye stains DNA in cellular
nuclei, highlighting retinal nuclear layers and inflammatory cells in choroid. C.
Eosin-stained section (same area as A). Acidic dye stains cytoplasm,
erythrocytes in choroidal vessels and proteinaceous subretinal fluid. D. H&E-
stained section (same area as A). A shallow retinal detachment and chronic
nongranulomatous choroiditis are present. Photoreceptor atrophy denotes chronic
process. (A. Unstained section ×100, B. Hematoxylin ×100, C. Eosin ×100, D.
H&E ×100.)

In most laboratories, histopathologic sections routinely are stained with

H&E (Fig. 16-4D). Hematoxylin is a basic dye that binds to acidic
materials including the DNA in the nuclei of cells (Fig. 16-4B). Eosin
(tetrabromofluorescein) is acidic and stains basic substances such as
proteins pink (Fig. 16-4C).
H&E staining provides helpful diagnostic color cues. Lesions

509
composed of cells with scanty cytoplasm tend to look blue or basophilic in
microscopic sections. Examples of basophilic lesions include infiltrates of
lymphoid and inflammatory cells, retinoblastoma, and basal cell
carcinoma. Necrosis, calcification, and DNA deposition in eyes with
retinoblastoma also appear blue. In contrast, cells that have abundant
cytoplasm (e.g., squamous cells or epithelioid histiocytes) appear pink.
Squamous cell carcinomas usually are eosinophilic. Normal ocular
structures composed largely of connective tissue such as the cornea and
sclera appear eosinophilic in H&E sections. Protein-rich subretinal fluid,
lens material, amyloid, and exfoliation material also are eosinophilic.
The periodic acid–Schiff (PAS) stain is used routinely in most
ophthalmic pathology laboratories because it vividly highlights the thick
basement membranes of the eye (lens capsule and Descemet membrane).
PAS stains materials that contain unsubstituted vicinal glycol groups
(CHOH-CHOH). The vicinal glycol groups are oxidized to dialdehydes
(CHO-CHO) by periodic acid, and the Schiff reagent (leucofuchsin) reacts
with the dialdehydes forming complexes that range in color from red to
magenta. In addition to basement membranes and aggregates of basement
membrane material such as guttae and cuticular drusen, PAS stains
glycogen, some mucins (e.g., conjunctival goblet cells), and many but not
all yeast and fungal hyphae (Fig. 16-5D).

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 FIG. 16-5. Special stains for microorganisms. A. Tissue Gram stain. Tissue
Gram stain discloses myriad gram-positive cocci in exudate from eye with
endophthalmitis. B. Acid-fast stain. Stain discloses large colony of atypical
mycobacteria within vacuole in granulomatous inflammation. Patient developed
infection after blepharoplasty. C. GMS stain for fungus. Branching septate
Aspergillus hyphae in choroid of patient with endogenous endophthalmitis are
stained black by silver impregnation. D. Periodic acid–Schiff. Yeast stains
intensely with PAS, which is another excellent stain for fungus. PAS is a routine
stain in ophthalmic pathology that is used to disclose Descemet membrane and
the lens capsule. (A. Brown and Hopps ×400, B. Ziehl-Neelsen ×400, C. GMS
×250, D. PAS ×400.)

SPECIAL HISTOCHEMICAL STAINS

A variety of special histochemical stains occasionally are ordered in the
ophthalmic pathology laboratory to demonstrate the presence of
microorganisms and highlight special structures and materials in histologic
sections. Standard histochemical stains rely on chemical reactions to
demonstrate the presence of substances. All special stains must be used in
conjunction with positive control slides that contain the sought-for
organisms or materials. These control slides confirm that the special stains
are working.
Special stains for microorganisms are ordered most often. These
include modifications of the Gram stain for bacteria (Brown and Hopps or
Brown and Brenn stains) (Fig.16-5A), the Gomori methenamine-silver
(GMS) stain for fungi (Fig. 16-5C), and several acid-fast stains for
mycobacteria. The Dieterle and Warthin-Starry silver impregnation
techniques for spirochetes, Bartonella, and Legionella occasionally are
ordered (Fig. 5-11). Fungi and yeast are impregnated with silver and
appear black against a green counterstain in the GMS stain. The Ziehl-
Neelsen and Fite-Faraco acid-fast stains are used to demonstrate the acid-
fast organisms that cause tuberculosis, leprosy, and nocardiosis. The
organisms appear red (“red snappers”) against a blue background (Fig. 16-
5B).
Several histochemical stains are used to demonstrate the presence of
metals in tissue. These include the Perls Prussian blue reaction for iron and
the von Kossa and Alizarin red stains for calcium. The iron stain is used to
demonstrate the deposition of iron in ocular epithelial structures in
hemosiderosis and siderosis (Fig. 4-11B) and in corneal iron lines (Fig. 6-
20F,G). The iron deposits are blue. The von Kossa stain for calcium

511
actually stains the anionic material that binds with calcium (Fig. 12-6D).
This silver stain stains calcium deposits black. The Alizarin red stain forms
complexes with calcium, which appear red against a green counterstain.
The ruthenium red stain and rhodanine stains for copper are relatively
nonspecific and are used infrequently.
The Masson trichrome stain stains collagen blue and cellular tissue
red. It is used to demonstrate the presence of fibrosis (Figs. 9-10B and 15-
4C). Masson trichrome also is the histochemical stain of choice for
granular corneal dystrophy (Fig. 6-21D). Stains for acid
mucopolysaccharides (AMP) include alcian blue, Hales colloid iron for
AMP, and mucicarmine. The first two stain mucin blue because the
histochemical reaction is based partially on the iron stain. AMP stains are
used to demonstrate mucin production in tumors and in the assessment of
corneal dystrophies. They are the stains of choice for macular corneal
dystrophy (Fig. 6-28C,D). The Verhoeff-van Gieson stain for elastic tissue
demonstrates the internal elastic lamina in arteries (e.g., temporal artery
biopsies) and the excessive production of elastic components (elastotic
degeneration) in pterygium and pinguecula (Fig. 5-16C). In the latter, the
elastotic degeneration stains black, but the reaction is not quenched by
pretreatment with elastase. The reticulin stain occasionally is used in the
assessment of certain neoplasms such as hemangiopericytoma and
lymphomas.
Although amyloid can be stained with the metachromatic stain crystal
violet and the fluorescent stain thioflavin T, the Congo red stain is
generally used in clinical practice. The amyloid deposits stain light orange
and show apple green birefringence and dichroism during polarization
microscopy. Congo red is the stain of choice for lattice corneal dystrophy
(Figs. 5-17C,D and 6-25C–E).
Other histochemical stains that occasionally are ordered include the
Fontana-Masson stain for melanin, the Luxol fast blue stain for myelin, the
Bodian stain for axons, and the Oil red O (ORO) stain for lipid (Fig. 13-
21C,D). ORO must be used on frozen-sectioned tissue because the
solvents used during normal tissue processing dissolves the fat in tissue.

IMMUNOHISTOCHEMISTRY
Immunohistochemistry (IHC) is a powerful technique that has
revolutionized histopathologic diagnosis in the past several decades. IHC
employs antibodies to identify antigens or epitopes whose expression is

512
limited to certain types of cells. This technique has markedly improved
diagnostic accuracy. Using IHC, pathologists are now able to diagnose
many poorly differentiated neoplasms that were not classifiable by routine
light microscopy in the past. Carcinomas, amelanotic melanomas, and
high-grade lymphomas are identified by the expression of characteristic
antigens that serve as cellular markers. These include cytokeratins and
other epithelial markers that are expressed by and serve to identify
carcinomas, melanocytic markers such as S-100, HMB-45, Melan-A,
MITF2, and SOX10 expressed by melanoma, and leukocyte common
antigen CD45, which is expressed by most neoplastic B and T
lymphocytes.
Many antibodies employed in diagnostic IHC work well in sections
prepared from routinely processed, paraffin-embedded tissue. Tissue
sections for IHC are cut, placed on polylysine-coated “plus” slides that
promote tissue adherence, and are deparaffinized and hydrated. A battery
of primary antibodies that are directed against a series of potential antigens
are then applied and allowed to react with the tissue (Fig. 16-6A). The
choice of antibodies depends on the histopathologic differential diagnosis.

FIG. 16-6. Immunohistochemistry. A. Step 1. Binding of primary antibody to

tissue antigen. B. Step 2. Binding of biotinylated secondary antibody to primary
antibody. C. Step 3. Avidin–biotin–peroxidase complex and chromogen forms

513
 colored reaction product that permanently marks site of antigen. D. Solitary
fibrous tumor stained with battery of immunohistochemical stains. Sectioned
tumor in microslides shows positive brown staining for CD34, vimentin, and
smooth muscle actin and negative staining for S100 and cytokeratin AE1/AE3.

A second antibody of a different class (made in another species), which is

directed against the first class of antibody, is then applied (Fig. 16-6B).
Binding of the second antibody occurs if the primary antibody has reacted
with its complementary antigen. Although techniques and reagents vary,
the second, or occasionally third, antibody are labeled with an enzyme
(usually peroxidase) that reacts with a substrate called a chromogen to
produce a colored reaction product (Fig. 16-6C,D). Often brown, the
reaction product is deposited in the tissue and serves as a permanent
marker for the presence and location of the antigen. Appropriate negative
and positive controls are mandatory to ensure that results are accurate and
meaningful. The use of a red chromogen is extremely useful in the
assessment of pigmented lesion whose endogenous pigment masks the
brown reaction product. Dual-staining techniques are also used to
determine the lineage of staining cells in certain situations. For example,
dual staining can be used to determine if the positively staining cells
disclosed by the Ki-67 marker in a conjunctival nevus are melanocytic and
not benign admixed corneal epithelium or inflammatory cells that often
show significant cellular cycling.
The prudent practice of diagnostic IHC employs a battery of antibodies
directed against a number of potential tissue markers, not a single stain or
two. The final diagnosis is based on the tumor’s pattern of positive and
negative immunoreactivity. For example, both malignant melanoma and
schwannoma typically stain for S100 protein, but only the melanoma
should react with more specific melanocytic markers such as HMB-45,
Melan-A, or MITF. Furthermore, a melanoma should not stain for neural
markers neurofilament protein or CD57. In contrast, a schwannoma should
be immunoreactive for neural markers and stain negatively for
melanocytic markers.
In addition to facilitating diagnosis, IHC increasingly is being used to
assess prognosis and guide therapy. For example, metastatic breast
carcinoma typically is evaluated for the presence of estrogen and
progesterone receptors and the expression of HER2/neu (Fig. 16-7C,D).
Estrogen receptor–positive breast cancers are treated with selective
estrogen receptor modulator drugs like tamoxifen or aromatase inhibitors
that decrease estrogen production by the adrenal glands in postmenopausal

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women. About 15% to 20% of breast carcinomas overexpress HER2/neu,
which is targeted by therapeutic monoclonal antibody trastuzumab
(Herceptin).

FIG. 16-7. IHC in breast carcinoma. A. Choroidal metastasis found in woman

with remote history of breast carcinoma. B. Positive immunoreactivity with
BRST-2 confirms that tumor is breast carcinoma. C. Estrogen receptors. Black
staining of tumor cell nuclei indicates presence of estrogen receptors. D.
HER2/neu-positive breast carcinoma. Tumor cells show intense continuous
immunostaining of cell membranes for HER2/neu protein, indicating that patient
is a candidate for trastuzumab therapy. (A. H&E ×100, B. IHC for BRST-2, C.
IHC for estrogen receptors ×150, D. IHC for HER2/neu ×200.)

In the ophthalmic pathology lab at the Wills Eye Hospital IHC is

frequently used to classify lymphoid lesions, assess melanocytic lesions of
the conjunctiva, and investigate tumors that have metastasized to the uvea
or orbit. These uses have been discussed above in Chapters 5, 11, and 14.
In some instances, IHC can identify the nature of an occult primary tumor
that spawned an ocular metastasis (Fig. 16-7). IHC is also invaluable in the
classification of many spindle cell and so-called small round blue cell
tumors of the orbit.
Immunohistochemical markers that are commonly used in the
diagnostic ophthalmic pathology are listed in Tables 16-1 and 16-2.

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Table 16-1 Immunohistochemical Markers Commonly Used in Ophthalmic
Pathology

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CLL/SLL, small lymphocytic lymphoma; IHC, immunohistochemistry;
JXG, juvenile xanthogranuloma; MEN2B, multiple endocrine neoplasia
syndrome 2B; PNET, primitive neuroectodermal tumor; PPMD, posterior
polymorphous dystrophy.
Modified from Eagle RC Jr. Immunohistochemistry in diagnostic ophthalmic pathology: a review. Clin Exp
Ophthalmol 2008;36(7):675–688 [review].

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 Table 16-2 Immunoprofiles of Various Ocular Lesions

Modified from Eagle RC Jr. Immunohistochemistry in diagnostic ophthalmic pathology: a review. Clin Exp
Ophthalmol 2008;36(7):675–688 [review].

Other Ocular Specimens

Other tissue specimens processed by ophthalmic pathology laboratories
include eyelid, conjunctival and orbital biopsies, corneal specimens, ocular
evisceration and orbital exenteration specimens, intraocular biopsies
including intraocular tumors that have been locally resected, fine needle
aspiration biopsies (FNABs), and vitreous fluid and particulates from
diagnostic vitrectomies.
Unoriented biopsies of soft tissue with no obvious epithelial lining are
measured and described. The description should include the color and
consistency of the tissue and any distinguishing characteristics. Larger
specimens should be sectioned before submitting, typically by “bread-
loafing.”
Skin lesions and other specimens with an epithelium must be
embedded on their side so that the resultant sections include a cross section
of the epithelium. Benign skin lesions (papillomas, cysts) usually are
excised with a surrounding ellipse of the skin. Larger ellipses should be
bisected and the two new cut surfaces marked with India ink or blue pencil
as a guide for embedding. If the specimen has been oriented by the
surgeon (using sutures and/or diagrams), the margins should be examined.
This usually is done be submitting a number of designated tissue segments
in separate cassettes.

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 Full-thickness eyelid resection usually is performed to remove
malignant tumors such as basal cell, squamous, or sebaceous carcinomas.
Separate nasal and temporal margins are submitted to determine if the
tumor has been totally excised (Fig. 16-8A). The true surgical margin is
marked with ink or colored pencil before the specimen is dissected. The
central part of the resection (main specimen) is sectioned perpendicular to
the lid margin in a bread-loaf fashion and totally submitted. The nasal and
temporal margins of an eyelid resection can be readily determined if the
laterality (OD vs. OS) and location (upper or lower lid) of the specimen
are known. The upper eyelid can be distinguished by the length of the
tarsal plate and its roughly rectangular configuration. The lower lid is
roughly triangular in shape.

FIG. 16-8. A. Sectioning technique for full-thickness eyelid resection of

malignant tumor. B. Conjunctival lesions like this nevus should be spread on thin
cardboard prior to fixation to minimize distortion.

Many malignant tumors of the eyelid are excised with frozen section
control of surgical margins. After the frozen sections are prepared, the
marginal tissue samples are fixed in formaldehyde and submitted for
permanent control sections. It is unnecessary to reexamine the margins of
the main fixed tissue specimen because the true surgical margins already
have been examined the with frozen sections.
Corneal buttons obtained at penetrating keratoplasty usually are
bisected before submission. The halves are wrapped in tissue to avoid
specimen loss. Specimens from lamellar keratoplasty procedures also are
commonly accessioned. These include thick lamellas of anterior cornea
from DALK procedures, diaphanous sheets of Descemet membrane from
DSEK procedures, and thin lamellas of posterior stroma and Descemet
membrane from “failed” DSEK procedures. Our laboratory currently

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examines the stripped sheets of Descemet membrane from DSEK
procedures as flat mounts. These can be resubmitted and sectioned if
necessary.
Conjunctival biopsies tend to roll or ball-up in fixative making
assessment of surgical margins nearly impossible. Conjunctival biopsies
should be gently spread-out stromal side-down on heavy paper or the thin
cardboard used to package sutures before they are immersed in fixative
(Fig. 16-8B). If this is done, the specimen is fixed as a flat sheet, which is
much easier to manipulate and section.
Ocular evisceration involves excision of the cornea and a rim of
surrounding sclera and removal of the intraocular contents including uvea,
retina, and vitreous. The scleral shell is left behind in the orbit. Some
oculoplastic surgeons prefer to eviscerate eyes because postoperative
ocular motility is said to be superior. However, evisceration does not
totally prevent the development of sympathetic uveitis and blind painful
eyes occasionally harbor unsuspected malignant neoplasms (see Fig. 11-6).
A malignant tumor should be excluded with imaging, preferably B-scan
ultrasonography, prior to eviscerating a blind painful eye. The large
corneoscleral button and the intraocular contents are bisected and entirely
submitted.
Orbital exenteration involves removal of the eye and all of the orbital
contents. Orbital exenteration usually is performed when the orbit contains
an unresectable primary tumor or has been invaded by an eyelid or
conjunctival malignancy. Exenteration specimens are large, and multiple
surgical margins must be submitted. Orientation must be maintained
during dissection. Before dissection, the surgical margin (external aspect
of the specimen) is marked by coating the specimen with India ink.
Immersing the ink-coated specimen in Bouin fixative binds the ink to the
tissue.
Temporal artery biopsy is performed to rule out giant cell arteritis (Fig.
9-10). To avoid skip lesions, an adequate biopsy should be at least 2 cm
long. After fixation, the artery is divided into a series of transverse
segments, which are embedded cut-surface down. It is much easier to
interpret transverse sections. Arteries that are positive for giant cell
arteritis may appear thickened and opacified on gross examination. My
technician prefers to transversely section temporal arteries after tissue
processing because the paraffin-infiltrated segments are easier to embed.

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Frozen Section Diagnosis
Frozen sections are cut from a block of fresh unfixed tissue that is flash
frozen in liquid nitrogen or refrigerated isopentane. The frozen tissue is
sectioned with a refrigerated microtome called a cryostat and is stained
with a rapid H&E technique. Sections usually are ready for interpretation
in 10 minutes or less.
The most common indication for frozen section diagnosis in
ophthalmic pathology is the intraoperative assessment of surgical margins
during excision of malignant eyelid tumors. In orbital surgery, frozen
sections are used to determine if the tissue obtained is representative or
adequate for diagnosis. The decision to exenterate an orbit should always
be based on examination of the permanent sections.
Rapid diagnosis is the main advantage of frozen section diagnosis, but
speed has its price. The technical quality of frozen sections is always
substantially inferior to routine sections prepared from paraffin-embedded
tissue. The quality of frozen sections usually is sufficient to determine if a
basal cell carcinoma or some other common eyelid tumor has been totally
excised, although sebaceous and melanocytic lesions may be problematic.
In many instances, the final diagnosis of orbital lesions must be deferred to
permanent sections. One should remember that frozen section diagnosis
consumes valuable tissue that might be better utilized if it were fixed in
formaldehyde and processed routinely for light microscopy. Lesions that
are difficult to diagnose in paraffin sections may be impossible to diagnose
in frozen sections.

Lymphoid Tumors
Lymphoid tumors are discussed in the conjunctival and orbital chapters. If
lymphoma is suspected clinically, fresh unfixed tissue should be submitted
for immunophenotypic assessment by flow cytometry. Flow cytometry is
superior to IHC performed on sections of paraffin-embedded tissue,
because flow cytometry can determine clonality by assessing
immunoglobulin light chains and quantifies the different types of
lymphocytes as well. An adequate sample of fresh tissue is necessary for
flow cytometry, however. Optimally, the sample should be at least as large
as a pea, which excludes many conjunctival lesions. Specimens for flow
cytometry should be forwarded expeditiously to the lab in a closed, moist
container that contains a piece of gauze moistened with saline to prevent

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drying. The specimen should not be immersed in saline.

Other Diagnostic Tools

Transmission (TEM) and scanning electron microscopy (SEM)
occasionally are used as adjuncts to routine histology in diagnostic
pathology laboratories and are tools in ocular research. TEM is still used
occasionally for the diagnosis of tumors and unusual lesions, but it has
been largely supplanted by IHC, which is cheaper, faster, and less labor
intensive. SEM shows the three-dimensional shape of objects at high
magnification and resolution and can reveal patterns of disease that are not
immediately obvious in sectioned material (Fig. 9-19A). Specially
equipped scanning electron microscopes can rapidly determine the
elemental composition of materials such as foreign bodies using energy
dispersive x-ray spectroscopy.
As noted above, flow cytometry is used primarily to assess the
immunophenotype of adnexal lymphoid lesions in ophthalmic pathology.
A suspension of fresh, unfixed cells is prepared, and aliquots are reacted
with a variety of antibodies directed against selected lymphocytic markers.
Suspended in fluid, the cells flow rapidly through a thin tube past detectors
that are able to detect and accurately quantify them. Flow cytometry has
been used to measure the DNA content of tumor cells and assess the
ploidy of neoplasms. This has not proved to be especially beneficial in the
evaluation of ocular tumors.
In situ hybridization employs nucleic acid probes whose sequences are
complementary to a specific sought-for sequence of DNA or RNA in
tissue. In situ hybridization is used to detect the presence of pathogens
such as bacteria or viruses in tissue sections. Fluorescent in situ
hybridization (FISH) is used to detect chromosomal deletions and
translocations. Examples include the evaluation of uveal melanoma for
monosomy 3 and the assessment of rhabdomyosarcoma for the
characteristic translocations found in the alveolar form of the tumor.
The polymerase chain reaction (PCR) is used to detect the presence of
organisms by amplifying species-specific parts of their genetic material.
The technique uses two single-stranded DNA primers that are
complementary to segments of the target organism’s DNA. DNA synthesis
is catalyzed by a heat-resistant form of DNA polymerase obtained from
Thermus aquaticus, a bacteria isolated from a hot spring in Yellowstone
National Park. Repeated cycles of thermal denaturation, annealing, and

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synthesis amplifies the sought-after segment of DNA a million fold,
producing quantities that are large enough to detect. Southern blot analysis
is used to identify the DNA.
Gene expression profiling is a research tool that employs DNA
microarray technology to measure the activity of thousands of genes.
Microarray analysis of uveal malignant melanoma has identified two
classes of tumors that differ markedly in their risk of metastasis (Fig. 11-
18J).
Molecular genetic tests are being used increasingly to diagnose or
classify lesions by detecting mutations, translocations, and chromosomal
abnormalities. Genetic testing is done routinely in retinoblastoma to
determine if the mutations responsible for the tumor are somatic or germ
line.

The Ophthalmologist and the Pathology

Laboratory
Effective and accurate communication is the most important element in the
relationship between the practicing ophthalmologist and the pathology
laboratory. Pathologists are consultants who require accurate clinical data
to provide their clinical colleagues with optimum service. Few physicians
would refer a patient to a consultant without a clinical summary or letter of
introduction, yet specimens constantly arrive in pathology labs with little
or no clinical data.
Ophthalmologists usually communicate with the pathology laboratory
in writing using the pathology slip or transmittal form. Information on the
slip should include the age, date of birth, sex, and race (if pertinent) of the
patient; the laterality and location of the lesion; the operation performed;
the clinical impression (preoperative diagnosis); the postoperative
diagnosis if different; and any other appropriate clinical information. If the
specimen is a globe, the visual acuity and intraocular pressure also should
be listed. Many surgeons do not realize that satisfactory completion of
pathology slips is a requirement of hospital and laboratory accrediting
organizations like the Joint Commission and the College of American
Pathologists.
The patient’s age, birth date, and sex should always be listed. Age is
an extremely important factor in the interpretation of melanocytic lesions
of the conjunctiva. Junctional nevi of the conjunctive do occur rarely in

523
children, but a “junctional nevus” in a middle-aged or elderly patient is
almost always primary acquired melanosis, a precursor of conjunctival
malignant melanoma. The sex of the patient is important in the assessment
of metastatic disease. Breast carcinoma is the most common source of
ocular metastases in women but is quite rare in men. The patient’s race or
ethnic background should be noted if it is pertinent and important from a
clinical standpoint, political correctness notwithstanding. Certain tumors
such as uveal melanoma occur infrequently in patients of African ancestry,
while sarcoidosis is common.
“Lesion” is not a particularly helpful or informative preoperative
diagnosis. Always list the suspected diagnosis if you are fairly certain what
the “lesion” is or at least indicate important entities that you would like to
rule out. Your clinical impression is important because it may influence
how your specimen is processed. For example, if the pathologist knows
that you are concerned about sebaceous carcinoma, she/he may reserve
some “wet tissue” for possible fat stains, which may be necessary to
confirm the diagnosis in a poorly differentiated cases. Fat stains cannot be
done if the entire specimen has been embedded in paraffin because the fat
is dissolved-out by the solvents used in processing. Although routine tissue
processing precludes staining for fat, fixation does not. Fresh unfixed
tissue is easier to cut, but frozen sections still can be prepared from
formalin-fixed tissue. At the present time, fat staining requiring frozen
tissue is being supplanted by the immunohistochemical stain adipophilin
that can be performed on routine sections of paraffin-embedded tissue.
Direct personal communication with your pathologist is advised if
your case is unusual or important, you are concerned about the diagnosis,
or have questions about proper specimen handling. Call your pathologist if
you have questions or concerns. Personal contact is the fastest, most
efficient (and most confidential) means of conveying important clinical
data. Furthermore, it decreases the likelihood that your specimen will be
mishandled and may give your pathologist additional insight that can
contribute to an accurate diagnosis. Your pathologist is your best guide to
laboratory services and may be able to suggest additional tests, techniques,
or methods of tissue processing that can facilitate diagnosis. She/he can
also inform you about special fixation or processing requirements (e.g.,
fresh tissue for flow cytometric analysis of lymphoid tumors).
Personal communication is always best if you think your specimen
may need special stains or special procedures like electron microscopy.
Ordering the pathologist to do a certain stain on the pathology slip without

524
discussing the case beforehand is tantamount to the pathologist instructing
the surgeon what operation to perform and what instruments to use. The
pathologist usually knows what stains and procedures are indicated and
should be ordered (assuming that he or she is aware of your problem and
has been supplied with adequate clinical data). You should also speak to
the pathologist directly if you need photographs for presentation or
publication. Most cases are not photographed routinely, and the cost of
photography is not reimbursed. You are asking the pathologist to expend
his/her time and resources to do you a favor.
If possible, you should consider personally hand-delivering your
important specimens to the laboratory. This assures that your specimen
will arrive expeditiously and will not be misplaced in the operating room
or lost in transit. It also evidences your interest and concern.
Batching and submitting multiple specimens excised from different
locations in a single container is dangerous. This occasionally is done by
ophthalmologists who believe that they are excising multiple benign cysts
or papillomas. If one of the lesions proves to be an unexpected malignancy
(e.g., an incompletely excised basal cell carcinoma), its location will be
unknown.
All ophthalmologists are encouraged to visit the pathology laboratory
and review their cases with the pathologist under the microscope. Always
review the histopathology with your pathologist if your clinical impression
and the pathologic diagnosis are discordant, and question diagnoses that
are unexpected or make no sense. If you remain unsatisfied, request a
consultation with an experienced ophthalmic pathologist. Finally, always
forward rare or unusual ocular lesions to ophthalmic pathology
laboratories that appreciate their significance and have the experience and
expertise to process and evaluate them.

BIBLIOGRAPHY
Boenisch T. Handbook on Immunohistochemical Staining Methods, 3rd ed.
Carpinteria, CA: Dako Corporation, 2001.
DeLellis RA, Resnick M, Frable WJ. General and special techniques in surgical
pathology and cytopathology. In: Silverberg SG, DeLellis RA, Frable WJ, et
al., eds. Silverberg’s Principles and Practice of Surgical Pathology and
Cytopathology. Philadelphia, PA: Churchhill Livingstone/Elsevier,
2006:25–54.
Eagle RC Jr. Specimen handling in the ophthalmic pathology laboratory.
Ophthalmol Clin North Am 1995;8:1–15.

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Eagle RC Jr. Photographic tips for the ophthalmic pathology laboratory. In:
Wilson R, ed. The Year Book of Ophthalmology. St. Louis, MO: Mosby,
1997:341–354.
Eagle RC Jr. Immunohistochemistry in diagnostic ophthalmic pathology: a
review. Clin Experiment Ophthalmol 2008;36:675–688.
Eagle RC Jr. The Dissection and Processing of Human Eyes (Instructional Video)
www.youtube.com/watch?v=FgGtw6oyHl8
Guesdon Jl, Ternynck T, Avrameas S. The uses of avidin-biotin interaction in
immunoenzymatic techniques. J Histochem Cytochem 1979;27:1131–1139.
Hsu S-M, Raine L. Protein A, avidin and biotin in immunocytochemistry. J
Histochem Cytochem 1981;29:1349–1353.
Hsu S-M, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (abc) in
immunoperoxidase techniques: a comparison between abc and unlabeled
antibody (pap) procedures. J Histochem Cytochem 1981;29:577–580.
Ramos-Vara JA. Technical aspects of immunohistochemistry. Vet Pathol
2005;42:405–426.
Shi SR, Key ME, Kalra KL. Antigen retrieval in formalin-fixed, paraffin-
embedded tissues: an enhancement method for immunohistochemical staining
based on microwave oven heating of tissue sections. J Histochem Cytochem
1991;39:741–748.

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 11 Intraocular Tumors in
Adults

MELANOCYTIC TUMORS OF THE

UVEAL TRACT
Introduction
In adults, most intraocular tumors arise from, or involve the uveal tract, the
eye’s middle coat composed of the stroma of the iris, ciliary body, and
choroid. The uvea tract is highly vascular and pigmented. The pigment is
contained within the cytoplasm of dendritic uveal melanocytes, which are
derived embryologically from the neural crest (Fig. 11-1). A similar
number of uveal melanocytes are present in lightly and heavily pigmented
eyes. Increasing intensity of uveal pigmentation (and eye color) is caused
by a corresponding increase in the size and number of melanin pigment
granules or melanosomes in the cytoplasm of the melanocytes. The
pigment may protect against the development of uveal tumors, because
uveal malignant melanoma occurs most often in patients with blue eyes
and is rare in heavily pigmented individuals.

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FIG. 11-1. A. Choroid. The choroid is the posterior part of the uveal tract. Its
stroma contains dendritiform melanocytes and vessels. The latter include the
choriocapillaris, which is located directly beneath the Bruch membrane and
Sattler and Haller layers composed of progressively larger vessels. B. Scanning
electron micrograph shows dendritic configuration of a choroidal melanocyte. (A.
H&E × 100, B. SEM ×1250.)

The choroidal vessels occasionally undergo hamartomatous proliferation

forming hemangiomas, and the rich vascular supply of the posterior
choroid explains that region’s predilection for blood-borne metastases.

NEVI
Uveal nevi are benign melanocytic neoplasms that are incapable of
metastasis. Nevi, which occur in 5% of adults, are the most common
intraocular tumor. Most choroidal nevi typically appear as flat or
minimally elevated patches of increased choroidal pigmentation that
measure 1 to 2 mm in diameter and are <2 mm in thickness (Fig. 11-2A).
They may be pigmented or amelanotic, and they often have an irregular or
feathery border. Drusen often develop on the surface of nevi with time and
are one of the factors that serve to distinguish them from small
melanomas. Although they are considered stationary lesions, about one
third show slight enlargement when followed for many years. About 8% of
nevi are classified as giant, measuring more than 10 mm in diameter. Signs
of chronicity such as drusen serve to distinguish them from melanomas.
Halo nevi are a variant that have a brown center and a yellow halo. Nevi
occasionally undergo malignant transformation into malignant melanoma;
the rate of malignant transformation is estimated to be only 1/10,000 to
15,000 per year.

FIG. 11-2. Choroidal nevus. A. Small pigmented lesion presumed to be nevus

remained stable on follow-up. B. Choroidal nevus. Choroid contains infiltrate of

528
 pigmented spindle cells with bland nuclei. The RPE and choriocapillaris are
intact and the overlying retina remains attached. (B. H&E ×100.)

It may be difficult to differentiate between a choroidal nevus and a small

malignant melanoma clinically. Detecting melanomas when they are small
is important because it has been reported that each millimeter increase in
the thickness of a melanoma results in approximately a 5% increased risk
for metastatic disease at 10 years. The observation of tumor growth may
be the only clinical criterion that is helpful in this regard. Dr. Carol Shields
and her team on the Oncology Service at the Wills Eye Hospital identified
certain clinical tumor parameters that suggest that pigmented lesion will
grow and probably is a melanoma that should be treated. The mnemonic
“To Find Small Ocular Melanoma Using Helpful Hints Daily” includes
these parameters. The initial “T” denotes thickness greater than 2 mm, “F”
the presence of subretinal fluid, “S” symptoms, “O” orange pigment on the
surface of the tumor and “M” the location of the posterior margin of the
tumor less than 3 mm from the optic disc. The remainder of the mnemonic
refers to an acoustically hollow appearance on B scan ultrasonography and
the absence of a halo and drusen. A small melanocytic lesion of the
choroid with none of these factors has a 3% risk of growth into melanoma
at 5 years and most likely represents a choroidal nevus. Tumors that
display one factor have a 38% risk of growth, and those with two or more
factors show growth in over 50% of cases. Most tumors with two or more
risk factors probably represent small choroidal melanomas, and early
treatment generally is indicated.
New diagnostic techniques that facilitate tumor assessment are now
available. Spectral domain optical coherence tomography (SD-OCT) aids
the detection of subretinal fluid, while fundus autofluorescence (FAF)
imaging helps to disclose and confirm the presence of orange pigment. The
latter comprises fluorescent lipofuscin pigment within macrophages
released from disrupted retinal pigment epithelial (RPE) cells on the
surface of an actively growing tumor. More recently, enhanced depth
imaging OCT (EDI-OCT) has shown promise in the differential diagnosis
of choroidal lesions. EDI-OCT of choroidal nevi typically shows a lesion
with a smooth domed surface with chronic RPE changes and photoreceptor
atrophy. Nevi lack subretinal fluid and so-called shaggy photoreceptors,
which are present in many melanomas.
Uveal nevi are bland spindle cell tumors that comprise the benign end
of the biological spectrum of melanocytic neoplasms. Histopathologically,

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a compact infiltrate of slender pigmented or nonpigmented spindle cells
typically replaces the choroidal stroma (Fig. 11-2B). The nevus cells have
bland oval or cigar-shaped nuclei that lack nucleoli or nuclear folds and
have finely dispersed chromatin. Mitotic activity is absent. In some cases,
the nevus cells are plump and dendritic in shape. Intranuclear cytoplasmic
inclusions are common in some cases. Foamy balloon cells that appear to
be undergoing lipoidal degeneration are found in 4% of nevi. Maximally
pigmented, plump, polyhedral nevus cells comprise the magnocellular
variant of nevus called melanocytoma (see below).

MELANOCYTOMA
(MAGNOCELLULAR NEVUS)
A melanocytoma is a characteristic type of uveal nevus composed of
plump polyhedral nevus cells filled with copious quantities of maximally
pigmented cytoplasm. Melanocytomas have been called magnocellular
nevi. In contrast to most nevi, melanocytoma may be relatively large and
may be difficult to distinguish clinically from melanoma (Figs. 11-3 and
11-4).

FIG. 11-3. Melanocytoma. A. Large, intensely pigmented melanocytoma of optic

disk in African American woman was enucleated because patient complained of

530
intractable pain and there was concern about malignant transformation. B.
Pigmented mass protrudes from the optic disk. C. Intensely pigmented tumor
replaces parenchyma of the optic disk. D. Bleached sections revealed no evidence
of malignant transformation. (C. H&E ×25, D. Bleach ×25.)

FIG. 11-4. Melanocytoma. A. Copious quantities of melanin pigment obscure

nuclear details. B. Bleaching of melanin pigment discloses bland nuclei and low
nuclear/cytoplasmic ratio consistent with benign magnocellular nevus. (A. H&E
×250, B. Bleach ×250.)

Melanocytomas classically involve the optic disk but can arise from any
part of the uveal tract including the iris, choroid, or ciliary body.
Clinically, they are intensely pigmented and often occur in young patients.
Unlike melanoma, they do not have a predilection for Caucasians; 37% to
50% of optic disc melanocytomas have been reported in African
Americans.
Melanocytomas are so intensely pigmented that they appear black on
routine microscopy. The copious cytoplasmic pigmentation typically
obscures the nuclei of the melanocytoma cells requiring bleached sections
for proper evaluation (Figs. 11-3D and 11-4). When bleached sections are
examined, the tumor cells are found to have a low nuclear/cytoplasmic
ratio and bland nuclei. Nucleoli usually are inconspicuous, but there are
exceptions to the rule. Melanocytomas often undergo spontaneous necrosis
and typically contain pigment-laden macrophages. Extensive tumor
necrosis typically is observed more often in a melanocytoma than a
melanoma of comparable size, and totally necrotic melanocytomas
occasionally are encountered. Melanophages released by partially necrotic
iris melanocytomas can cause secondary melanocytomalytic glaucoma by
physically obstructing the trabecular meshwork (Fig. 8-16).
Transformation into malignant melanoma occurs rarely (1% to 2%).

531
UVEAL MALIGNANT MELANOMA
Clinical Features
Uveal melanoma is the most common primary malignant intraocular
neoplasm in adults in Europe and the United States. On a worldwide basis,
retinoblastoma actually is the most common primary intraocular tumor.
Kivelä has estimated that there are ~8,000 cases of retinoblastoma yearly
in the world compared to 7,000 cases of melanoma. Uveal melanoma is a
tumor with a definite predilection for fair-skinned, blue-eyed Europeans.
Approximately two third of uveal melanomas arise in Caucasians of
European descent who comprise ~13% of the world’s population. In
contrast, Han Chinese and Bengalis comprise one fourth of the world’s
population, yet have only 8% of the uveal melanomas. Uveal melanomas
are relatively rare; about 1,800 tumors occur yearly in the United States.
The annual age-adjusted incidence in the United States is about 6 cases per
1 million population.
Uveal melanomas arise from the dendritic melanocytes of the uvea, the
middle pigmented and vascularized coat of the eye, which includes the iris,
ciliary body, and the choroid (Fig. 11-1B). Choroidal melanomas are most
common. More than 90% are choroidal tumors. Uveal melanoma affects
both sexes equally. Although pediatric and even rare congenital cases have
been reported, uveal melanoma generally occurs in older persons. The
mean age of patients eligible for treatment in the Collaborative Ocular
Melanoma Study (COMS) was 59 years. Less than 0.8% of cases occur in
patients less than age 20 years. Older patients tend to have larger tumors
and are more likely to die from their tumors after enucleation.
As noted above, race is an important predisposing factor for uveal
melanoma. In the United States, the incidence of uveal melanoma in White
patients is 8.5 times greater than the incidence in African Americans. The
tumor is also relatively uncommon in Latin America and Asia. The
incidence of uveal melanoma in the United States is 25 times greater than
that in Taiwan, that is, 0.28 per million versus 7 per million.
Caucasian patients who have congenital ocular or oculodermal
melanocytosis (nevus of Ota) (Fig. 5-29) are especially at risk to develop
uveal malignant melanoma. The tumor is spawned by a diffuse nevus of
the uvea, which is evident clinically as hyperchromic heterochromia
iridum. Affected patients often have slate-gray epibulbar pigmentation and

532
a bluish discoloration of adnexal skin as well. It has been estimated that
about 1 in 400 white patients with oculodermal melanocytosis will develop
uveal melanoma in their lifetime. This risk is about 25 times greater than
the risk in unaffected patients. Patients with uveal melanoma associated
with oculodermal melanocytosis have double the risk for metastasis
compared to those without melanocytosis. Melanomas have developed in
young patients with Ota nevus. Ocular and oculodermal melanocytosis are
relatively common in Asians but do not appear to predispose them to
melanoma. Melanoma also can arise in patients who have the combination
of ocular melanocytosis and nevus flammeus called phacomatosis
pigmentovascularis.
Uveal melanomas occasionally arise from localized uveal nevi, but the
estimated incidence of malignant transformation is quite low. Uveal
melanoma has been reported in patients with neurofibromatosis type I, the
dysplastic nevus or familial atypical mole melanoma syndrome, and the
BAP1 cancer syndrome. Uveal melanoma can arise in patients who have a
rare paraneoplastic syndrome called benign diffuse uveal melanocytic
proliferation or BDUMP syndrome. The tumor’s propensity for blue-eyed
individuals and the inferior exposed part of the iris suggests that exposure
to ultraviolet light could be a predisposing factor.
The clinical signs and symptoms of uveal malignant melanoma depend
largely on the location of the tumor and the extent of the disease when the
patient initially seeks medical attention. Most posterior uveal melanomas
present with painless visual loss. Visual symptoms are caused most often
by serous and/or solid detachment of the retina. Other mechanisms of
visual loss include physical obscuration of the fovea by overhanging
tumor, cystoid macular edema, cataracts caused by expanding ciliary body
tumors, and rarely vitreous hemorrhage, which usually develops when
tumors erode through the retina. Melanomas occasionally are found in
asymptomatic patients during routine ophthalmologic examinations. Iris
melanomas may present as an enlarging pigmented blemish or a change in
eye color (heterochromia iridum) (Fig. 8-21). Other tumors present with
unilateral glaucoma. Anterior segment melanomas cause secondary
glaucoma by directly seeding or infiltrating the aqueous outflow pathways.
Posterior segment tumors usually cause secondary closed-angle glaucoma
through a pupillary block mechanism or by stimulating iris
neovascularization. Infarcted or extensively necrotic tumors can cause
prominent inflammatory signs that can mimic orbital cellulitis (Fig. 11-5).
Advanced cases with extrascleral tumor extension into the orbit may

533
present with ocular proptosis. Unsuspected melanomas occasionally are
found when blind painful glaucomatous eyes with opaque media are
examined pathologically. Before the advent of ultrasonography, as many
as 10% of blind painful eyes were said to harbor previously undiagnosed
tumors. Care should be taken to exclude the presence of an occult tumor
preoperatively if ocular evisceration is planned (Fig. 11-6). Distant
metastases usually are not evident when the tumor is first detected and
treated.

FIG. 11-5. Necrotic melanoma presenting as aseptic orbital cellulitis. A. Swollen

and erythematous eyelids and chemotic conjunctiva suggest orbital cellulitis in
patient found to have necrotic melanoma. B. MRI disclosed large ciliochoroidal
melanoma in mildly proptotic eye. C. Totally necrotic melanoma cells have lost
their basophilic DNA. Nuclear profiles serve to identify epithelioid cells. (C.
H&E ×400.)

FIG. 11-6. Inadvertently eviscerated choroidal melanoma. A. Large pigmented

mushroom-shaped choroidal melanoma is evident in macrophoto of evisceration
specimen removed from the blind painful eye of a young Hispanic woman in her
mid-20s. B. The tumor contains spindle B, intermediate, and rare epithelioid
melanoma cells. The case was referred to an oculoplastic surgeon who did not

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perform preoperative imaging. He did not suspect a tumor due to the patient’s
young age and ethnicity. (B. H&E ×400.)

Diagnosis
Many posterior uveal melanomas are diagnosed by direct ophthalmoscopic
visualization of the tumor by experienced clinicians (Fig. 11-7).
Adjunctive studies including A and B scan ultrasonography, intravenous
fluorescein angiography (IVFA), enhanced depth imaging OCT, fundus
autofluorescence and computed tomography or magnetic resonance
imaging frequently are used to confirm the clinical impression and may be
particularly helpful if the ocular media are opacified. Transvitreal fine
needle aspiration biopsy (FNAB) performed under direct ophthalmoscopic
visualization occasionally is performed if the diagnosis remains uncertain
after routine tests, and choice of therapy requires an accurate diagnosis.
Examples where FNAB might be used include a patient who has a history
of breast cancer who presents with a solitary amelanotic choroidal tumor
that could be a second primary amelanotic melanoma, a patient who is
thought to have a choroidal metastasis but has no history of cancer, or
patient who demands a tissue diagnosis prior to therapy. FNAB also is
used to obtain tissue for molecular genetic studies from eyes with tumors
being treated by plaque brachytherapy. EDI-OCT of small choroidal
melanoma typically discloses a mass with a smooth, moderately dome-
shaped topography, often with shallow overlying subretinal fluid and
“shaggy” photoreceptors. The results in larger melanomas usually are
unsatisfactory.

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FIG. 11-7. Choroidal melanoma. A. Fundus photograph shows mushrooming
head of pigmented choroidal tumor elevating inferotemporal retina. B. Tumor
seen in wide-angle photograph has broken through the Bruch membrane and
assumed characteristic mushroom or collar button configuration. C. Lightly
pigmented mushrooming head of choroidal melanoma arises from pigmented
base. D. IVFA highlights vascular congestion in tumor apex caused by
compressive cinch-like effect of the Bruch membrane on the waist of the tumor.

Gross Pathology
Melanomas initially arise in the uveal stroma. In early cases of choroidal
melanoma, the profile of the sectioned tumor is oval or almond shaped,
and its tissue usually appears relatively cohesive after fixation (Fig. 11-
8A). Although some melanomas diffusely infiltrate the uvea, most uveal
melanomas are relatively well-circumscribed tumors with distinct margins.
In many cases, the growing melanoma perforates the Bruch membrane and
enters the subretinal space where its apical portion typically assumes a
spherical shape that often is likened to a mushroom or collar button (Figs.
11-7, 11-8B,D and 11-9). If a choroidal tumor has a mushroom
configuration, one can be reasonably certain that it is a uveal melanoma.
There are exceptions to this rule, but they are exceedingly rare. Dilated
blood vessels typically are found in the mushrooming head of the tumor

536
(Figs. 11-7D and 11-9). The ruptured ends of the Bruch membrane exert a
compressive cinch-like effect on the waist of the tumor causing vascular
congestion in its apex. Rupture of the Bruch membrane was present in
87.7% of 1,527 large- or medium-sized melanomas examined in the
COMS. Retinal invasion was present in nearly half (49.1%), and tumor
cells were found in the vitreous body in one fourth. About 3% of
melanomas diffusely thicken the choroid without forming an elevated
mass. These diffuse melanomas usually are of mixed cell type are more
likely to infiltrate the sclera and invade the optic nerve or orbit (Figs. 11-
10 and 11-11E). Delayed diagnosis or misdiagnosis is common.

FIG. 11-8. Gross pathology, uveal melanoma. A. Small choroidal tumor has oval
or almond configuration. The Bruch membrane is intact. B. Heavily pigmented
melanoma has arisen from the equatorial choroid and ruptured through the Bruch
membrane. The tumor has a characteristic mushroom or collar button
configuration. Infiltration of the retina is seen at the tumor’s apex. Posterior to the
tumor, the retina is detached by serous fluid. C. Ciliary body melanoma. Heavily
pigmented ciliary body tumor deforms and displaces lens. D. Large choroidal
melanoma. Large, heavily pigmented mushroom-shaped melanoma has produced
a total retinal detachment and secondary glaucoma.

537
FIG. 11-9. Mushroom-shaped choroidal melanoma. A. Dilated vessels are
present in mushrooming head of choroidal melanoma, which has ruptured
through the Bruch membrane. Scleral infiltration is present at the base of the
tumor. The adjacent retina is detached and the retina on the tumor’s apex is
severely atrophic. B. Arrows point to the edge of rupture in the Bruch membrane.
Dilated vessels in mushrooming head of tumor are caused by the compressive
cinch-like effect of the ends of the Bruch membrane on the waist of the tumor.
The retina is detached by serous fluid. (B. H&E ×5.)

FIG. 11-10. Diffuse ciliochoroidal melanoma. A. Arrows denote thin choroidal

infiltrate of melanoma cells on both sides of the globe. B. Parts of uveal
melanoma were <200 μm in thickness. C. Spindle cells predominate in this area.
Epithelioid cells are found elsewhere. A significant number of lymphocytes
infiltrate the tumor. The case initially was diagnosed as uveitis. Diffuse uveal
melanoma has a poor prognosis; the patient died several months after enucleation.
(B. H&E, ×10, C. H&E ×100.)

538
FIG. 11-11. Extraocular extension, uveal melanoma. A. Vortex vein invasion by
uveal melanoma. The vortex vein in the macrophoto at the left is massively
distended by heavily pigmented tumor. B. Photomicrograph shows melanoma in
the lumen of the vessel. C. Massive posterior extrascleral extension. Posterior
choroidal melanoma has extended extrasclerally forming large pigmented orbital
mass that dwarfs the intraocular tumor. Optic nerve invasion is present. The
patient presented with ocular proptosis. D. Anterior extraocular extension.
Ciliary body melanoma exited globe via anterior emissarial canals. E. Diffuse
choroidal melanoma. Melanoma diffusely thickens choroid. Highly aggressive
tumor has invaded optic nerve and grown through posterior emissarial canal–
forming juxtapapillary epibulbar mass. (B. H&E ×100, E. H&E ×25.)

In the COMS, choroidal melanomas were classified as small, medium, and

large based on the tumor’s largest basal diameter (LTD). Small choroidal
melanomas measure <10 mm in LTD and appear as a focal discoid or oval
area of choroidal thickening. Medium-sized melanomas measure 11 to 15
mm, and large tumors are more than 15 mm in largest basal tumor
diameter. Size is an important prognostic feature in uveal melanoma.
Choroidal melanomas typically cause an exudative serous detachment
of the overlying and adjacent retina. Large tumors may cause total retinal
detachment (Figs. 11-8B,D and 11-9). The detached retina typically shows
photoreceptor atrophy and microcystoid retinal degeneration. The RPE on
the surface of the tumor undergoes atrophy and proliferation forming

539
drusenoid material and occasionally a plaque of metaplastic fibrous tissue.
Many tumors infiltrate the overlying retina. The melanoma may perforate
the retina in exceptional cases, causing vitreous hemorrhage and tumor
seeding of the vitreous and the inner retinal surface. Large tumors may
totally fill the globe. Eventually, some melanomas extend extraocularly
through the sclera and invade the orbit (Fig. 11-11C,E). Secondary
glaucoma is often present in eyes with advanced or neglected tumors.
Uveal melanomas vary markedly in their pigment content. Some tumors
are totally amelanotic. Other maximally pigmented tumors appear jet black
grossly and must be bleached before they can be interpreted
histopathologically. Varying degrees of pigmentation typically are found
within a single tumor. The cut surface of some tumors has a marbleized
appearance. Clumps of orange pigment are found on the surface of many
melanomas (Fig. 11-12). The orange pigment comprises either aggregates
of macrophages that have ingested lipofuscin pigment and melanin from
the damaged RPE or detached RPE cells termed RPE macrophages (Fig.
11-12C,D). The pigment generally is thought to be a clinical marker for an
actively growing tumor and can be highlighted with FAF.

FIG. 11-12. Orange pigment. A. The presence of orange pigment is one of the
factors that predicts that a pigmented choroidal lesion will grow and probably is a
melanoma. B. Clumps of orange pigment adhere to posterior surface of detached
retina overlying actively growing melanoma. C. Orange pigment is composed of

540
 aggregates of macrophages that have phagocytized lipofuscin and melanin
pigment released by RPE cells that have been disrupted by an actively growing
tumor. D. Macrophages that have ingested lipofuscin pigment are PAS positive.
(C. H&E ×250, D. PAS ×100.)

Ciliary body melanomas are less common than choroidal tumors and tend
to have a more spherical shape (Fig. 11-8C). Ciliary body tumors may be
larger when they are first detected because they remain hidden behind the
iris and often remain asymptomatic because they cause late retinal
detachment. Ciliary body melanomas can deform the crystalline lens and
cause unilateral cataract. Occasionally, they can invade the anterior
chamber and present with iris heterochromia and secondary glaucoma. The
glaucoma is caused by seeding of the trabecular meshwork by tumor cells
or by circumferential tumor growth around the angle (ring melanoma).
Patients with ciliary body involvement have a poorer prognosis.

Histopathology
The biologic spectrum of uveal melanoma cells comprises bland spindle A
melanoma cells at one end and wildly anaplastic epithelioid cells at the
other (Fig. 11-13). The term spindle cell is derived from the fusiform or
spindled configuration of the cells’ cytoplasmic outline. Spindle cells are
bipolar in shape, and many have long tapering processes that occasionally
are visible when individual pigmented cells are seen in a largely
amelanotic tumor. Spindle cells grow in a syncytial fashion and form
interweaving fascicles of parallel oriented cells (Fig. 11-14A,B). The cells
can be pigmented or nonpigmented.

541
FIG. 11-13. The biological spectrum of uveal melanoma. Melanocytic lesions of
the uveal tract comprise a biologic spectrum; tumor cells become progressively
less differentiated as mutations accumulate. The benign end of the spectrum
includes spindle nevus cells (A), low-grade spindle melanoma cells (B), and
spindle B cells (C). Intermediate cells (D) are spindle shaped but have nuclear
characteristics intermediate between spindle B and epithelioid. The malignant end
of the spectrum comprises epithelioid cells (E–I) that have distinct cytoplasmic
margins and prominent nucleoli. They include wildly anaplastic tumor giant cells
(G–I). (All figures, H&E, original magnification ×400.)

542
FIG. 11-14. Uveal melanoma cells. A. Spindle A melanoma cells. Many of the
cells in the photo have spindle A nuclear characteristics. The nuclei are bland,
slender, and cigar shaped and have finely dispersed chromatin and indistinct
nucleoli. Longitudinal folds in the nuclear membrane are apparent
microscopically as a chromatin stripe or line. The spindle cells form a syncytium
with indistinct cytoplasmic borders. B. Spindle B melanoma cells. Most of the
cells in this field are spindle B melanoma cells. They have oval nuclei and an
obvious nucleolus. Compared to spindle A cells, their chromatin is more coarsely
clumped. The spindle cells form a syncytium. C. Epithelioid melanoma cells.
The cytoplasmic margins of these large, poorly cohesive epithelioid melanoma
cells are easily discernible. Epithelioid cell nuclei are typically round and have
peripheral margination of coarsely clumped chromatin. Epithelioid cells usually
have prominent reddish-purple nucleoli. They typically are polyhedral in shape
and have copious amounts of cytoplasm. D. Uveal melanoma, mixed cell type.
Mixed cell melanomas are composed of a mixture of spindle (above) and
epithelioid cells (below). (All figures H&E ×250.)

There are two types of spindle cells, spindle A and spindle B, which are
distinguished by their nuclear characteristics. Spindle A nuclei are cigar-
shaped and have finely dispersed chromatin (Fig. 11-14A). Many spindle
A cells have a longitudinally oriented chromatin stripe caused by a fold in
the nuclear membrane. If a nucleolus is present, it usually is

543
inconspicuous. The nuclei of spindle B cells tend to be plumper and more
oval in shape and have coarser chromatin and distinct nucleoli (Fig. 11-
14B).
Epithelioid melanoma cells comprise the poorly differentiated end of
the cytologic spectrum. Uveal melanomas that contain epithelioid cells
have a poorer prognosis. The term epithelioid, which means “epithelial-
like,” reflects the superficial resemblance of the tumor cells to simple
epithelial cells. Epithelioid cells have abundant cytoplasm and are often
polygonal in shape (Fig. 11-14C). They have distinct cytoplasmic margins,
are poorly cohesive, and do not grow as a syncytium. The nuclei of
epithelioid cells typically are round or oval in shape, and they often appear
vesicular due to margination or clumping of chromatin along the inner side
of the nuclear membrane. Epithelioid melanoma cells also have prominent
nucleoli that are often large and reddish-purple in color. The large nucleoli
are often visible at lower magnification. Variants of epithelioid cells
include wildly anaplastic tumor giant cells (Figs. 11-13G–I and 11-15) and
relatively uniform small epithelioid cells (Fig. 11-16A).

FIG. 11-15. Tumor giant cells, uveal melanoma. Tumor giant cells are highly
anaplastic epithelioid cells. They are relatively rare, and their prognostic
significance is uncertain. (A. H&E ×50, B. H&E ×100.)

544
 FIG. 11-16. A. Small epithelioid cells. Although these cells are relatively small,
they definitely are epithelioid in character. They are polyhedral in shape and have
distinct cytoplasmic outlines and round or oval nuclei with prominent nucleoli.
Clones of small epithelioid cells are encountered occasionally in uveal
melanoma. B. Fascicular melanoma. The fascicular category of uveal melanoma
was deleted from the revised Callender classification because cellular
arrangement does not appear to affect prognosis. This amelanotic melanoma has a
striking fascicular appearance. The nuclei of its constituent spindle cells form
rows that resemble the Antoni A pattern of Schwannoma. (A. H&E ×400, B.
H&E ×50.)

During histopathologic assessment, melanoma cells are classified by their

nuclear characteristics. Spindle-shaped cells that have epithelioid nuclei
occasionally are encountered; such cells are classified as epithelioid. In
recent years, the term intermediate cell has been used more and more.
Intermediate cells have nuclear characteristics that are intermediate
between spindle B and epithelioid. For example, one might apply the term
intermediate cell to a spindle B cell that has a nucleus that is somewhat
large and has a fairly prominent nucleolus.
Occasionally, spindle cells in a uveal melanoma are arranged radially
around vessels or perpendicular to fibrovascular septa (vasocentric
pattern), or their nuclei form rows that resemble the Verocay bodies or the
Antoni A pattern seen in schwannoma (Verocay pattern). Melanomas are
called fascicular if these patterns dominate (Fig. 11-16B). Fascicular
melanoma was a separate category in the Callender initial classification
that was dropped from McLean’s 1983 modification.
Varying degrees of necrosis may be found (Fig. 11-5C). Necrosis
tends to be more prominent in rapidly growing high-grade tumors, or
tumors that have had prior brachytherapy, and may produce inflammatory
signs clinically. The necrosis may be patchy and focal, or may involve
extensive parts, or even all of the tumor. Aggregates of melanophages
typically are found in the necrotic areas. Total infarction of the tumor (and
other intraocular structures) may occur in eyes with severe secondary
closed-angle glaucoma. As mentioned above, melanocytoma is especially
prone to spontaneous necrosis. The latter diagnosis should always be
considered when a totally necrotic, heavily pigmented tumor is found.
Choroidal melanomas produce abnormalities in the overlying RPE
including atrophy, hyperplasia, and the formation of drusen and drusenoid
material. The overlying retina often shows photoreceptor loss and may
develop cystoid edema. The latter tends to be more common over slower

545
growing lesions, especially choroidal hemangiomas. After the Bruch
membrane has ruptured, the vessels located in the mushrooming head of
the tumor are often quite prominent, reflecting vascular stagnation caused
by the compression at the waist of the tumor (Fig. 11-9). Aggregates of
macrophages that have ingested PAS-positive lipofuscin pigment and
melanin from the damaged RPE or perhaps detached RPE cells can be
found in the subretinal fluid (Fig. 11-12). These are evident
ophthalmoscopically as clumps of orange pigment that serve as a clinical
marker for an actively growing neoplasm.
Uveal melanomas are placed into four categories based on their
cytology. Tumors composed entirely of spindle A cells or even blander
nevus cells are classified as spindle cell nevi. Tumors composed of a
mixture of malignant spindle A and spindle B cells are called spindle
melanomas. Melanomas of mixed cell type contain a mixture of spindle
and epithelioid melanoma cells (Fig. 11-14D). Some laboratories specify
the predominant cell type found in a mixed cell melanoma, for example,
reporting mixed cell, predominantly spindle if only a few epithelioid cells
are present. Epithelioid melanomas are composed predominantly of
epithelioid cells. They are relatively rare and have the poorest prognosis.
Most medium- and large-sized melanomas contain a mixture of spindle
and epithelioid cells. Eighty-six percent of the posterior melanomas in the
COMS histopathology study were classified as mixed cell type; 8% were
of spindle cell type and 5% were epithelioid. The association between
cytology and mortality is known as the Callender classification (see
section on “Prognostic Factors” below).

Prognostic Factors
About one half of patients with choroidal and ciliochoroidal malignant
melanomas eventually die from their tumors. Because the eye and orbit
lack lymphatics, uveal melanoma spreads via the bloodstream.
Hematogenous metastasis to the liver occurs most often; more than 90% of
cases with metastatic melanoma have liver metastases, and they are the
first metastases detected in 80% (Fig. 11-17B). For this reason, liver
enzymes and hepatic imaging are used clinically to monitor patients for
recurrence. Other common sites of metastatic uveal melanoma include the
lung (24%) and bone (16%). Multiple sites are found in 87%.
Micrometastases in the liver are not evident clinically and may remain
dormant for many years.

546
FIG. 11-17. A. Dr. Lorenz E. Zimmerman conducting ophthalmic pathology
conference at the Armed Forces Institute of Pathology in Washington, DC circa
1978. A short time later, “Zimm” formulated his hypothesis concerning the effect
of enucleation on the dissemination of uveal melanoma. B. Liver metastases,
uveal melanoma. Postmortem examination of patient who died from metastatic
uveal melanoma shows massive replacement of liver by tumor. (A. Photo by the
author, B. Slide courtesy of Dr. Daniel M. Albert.)

FIG. 11-18. Prognostic features in uveal melanoma. Prognostic features evident

on clinical examination include large tumor size (A) and the presence of ciliary
body involvement (B) and extraocular extension (C). These are the major factors
included in the AJCC tumor classification. In addition to the above, prognostic
factors evident on routine histopathologic examination include a cell type with

547
epithelioid cells (D), mitotic activity (E), the presence of vascular mimicry
patterns (F), tumor-infiltrating lymphocytes (G) and tumor-infiltrating
macrophages (H). Powerful factors that require special testing include assessment
for nonrandom chromosomal abnormalities such as monosomy 3 (I) and the
tumor’s gene expression profile. Melanomas with class 2 GEP have a
significantly poorer prognosis. (D. H&E ×400, E. H&E ×400, F. PAS ×50, G.
H&E ×400, H. H&E ×250, I. FISH). (Figure J courtesy of J. William Harbour
MD.)

Grossniklaus examined biopsies of liver tissue from patients dying from

metastatic uveal melanoma and found that they contained three stages of
metastases. Stage I metastases, which were most common, comprised
small clusters of tumor cells measuring <50 μm in diameter that were
present in the sinusoids of the liver. Based on size, stage II and III
metastases were defined as 51 to 500 μm and >500 μm, respectively. The
architecture of stage II metastases mimicked the surrounded hepatic
parenchyma, while stage III metastases showed either a lobular or portal
growth pattern. The mean vascular density and mitotic index of the
metastases increased with increasing size. Stage I metastases were not
vascularized and showed little mitotic activity, consistent with small,
apparently dormant micrometastases.
It is now generally believed that metastasis already has occurred in
many cases before the melanoma is diagnosed and treated. Unfortunately,
once distant metastases are manifest clinically, therapy generally is
ineffective. More than 50% of patients who have metastatic uveal
melanoma die within 1 year. In recent years, there has been an effort to
identify prognostic factors that could identify patients at high risk for
metastatic disease who hopefully might benefit from prophylactic chemo-
or immunotherapy (Fig. 11-18). These include factors evident on routine
clinical examination, factors disclosed by routine histopathologic
evaluation, and powerful new factors that require special testing.
Prognostic factors evident on clinical examination include the size of the
tumor and the presence or absence of ciliary body involvement and
extraocular extension. These three clinical factors are used to
prognostically stratify uveal melanomas in the American Joint Committee
on Cancer (AJCC) Cancer Staging Manual. Tumor size is particularly
important. In the seventh edition of the AJCC Cancer Staging Manual,
melanomas are divided into four size categories based on their largest
basal diameter and thickness in millimeters. Tumors >18 mm in diameter
are class 4. Tumors that involve the ciliary body have a poor prognosis, as

548
do tumors that have extended out of the eye.
Other aspects of tumor size that typically are measured and recorded
by ophthalmic pathologists include the size of the melanoma’s
transillumination shadow and the dimensions of the tumor on the cut
surface of the globe. Both are measured during gross dissection of the eye.
In addition, the tumor’s largest basal diameter and height are measured on
the glass slide at the time of microscopic evaluation.
In addition to tumor size, ciliary body involvement, and extraocular
extension, prognostic factors evident on routine histopathologic
examination include the cytologic characteristics of the tumor cells (cell
type or Callender classification) discussed above, mitotic activity, and the
presence of vascular mimicry patterns (i.e., vascular loops and networks)
and tumor-infiltrating lymphocytes and macrophages.
Cell type or the Callender classification refers to the relationship
between mortality and the characteristic of the melanoma’s cells. This
association initially was reported in 1931 by Major George Russel
Callender who examined a series of cases on file in the Registry of
Ophthalmic Pathology at the Army Medical Museum in Washington, DC.
Callender observed that melanomas were composed of two types of
spindle cells that he designated spindle A and B and less differentiated
epithelioid cells. He found that tumors that contained epithelioid cells had
a poorer prognosis. Ian McLean and his coworkers at the Armed Forces
Institute of Pathology modified the Callender original classification in
1978.
In actuality, uveal melanoma represents a biological spectrum (Fig.
11-13). The appearance of morphology of the melanoma cells evolves as
mutations accumulate, and the cells become progressively less
differentiated. The Callender classification is an attempt to pigeonhole this
biologic spectrum.
The presence or absence of epithelioid cells is an extremely important
prognostic factor in uveal melanoma. McLean reviewed a series of 3,432
cases of malignant melanoma of the choroid and ciliary body on file in the
AFIP’s Registry of Ophthalmic Pathology and found that 56% were mixed
cell tumors composed of a mixture of spindle and epithelioid cells. The 15-
year mortality of patients with melanomas of mixed cell type was three
times that of patients whose tumors were composed solely of spindle cells.
Tumor size, measured as the largest tumor diameter (LTD), was also
highly correlated with mortality.

549
 The modified Callender classification remains an important and
reliable prognosticator of mortality from uveal melanoma. Tumor
mortality is greater if uveal melanomas contain epithelioid cells
(epithelioid melanomas or mixed epithelioid/spindle cell type). The 5-year
mortality of uveal melanomas that contain epithelioid cells is 42%. At 15
years, death from metastatic melanoma increases to 63%. The prognosis of
spindle cell tumors is much better; 90% survive 5 years and 72% survive
15 years. Although rare fatal spindle A melanomas have been reported,
most tumors composed entirely of spindle A cells are thought to be benign
spindle cell nevi.
Cell type remains one of prognostic mainstays of surgical pathologists
because assessment is relatively rapid and requires no special stains or
equipment. However, determination of cell type is highly subjective, and
diagnostic accuracy can vary with the expertise and experience of the
pathologist. A masked study showed that even experienced ophthalmic
pathologists disagree about their classification of individual tumor cells.
Secondly, uveal melanoma’s biological spectrum, which includes
extremely bland spindle A melanoma cells at one end and highly
anaplastic epithelioid cells at the other, includes only three diagnostic
categories, spindle, mixed, or epithelioid, and tumors in a single category,
for example, mixed cell type, can vary significantly in their apparent
degree of differentiation.
The limitations of the Callender classification prompted a search for
more objective and reliable criteria for the histopathological assessment of
the malignant potential of uveal melanomas. Gamel and coworkers showed
that certain nucleolar parameters, most notably the inverse of the standard
deviation of the area of the nucleolus and a second simpler objective
method of nucleolar assessment based on the measurement of the 10
largest nucleoli (MTLN), were useful predictors of death from metastatic
melanoma. Although these techniques more accurately predicted survival
after enucleation using morphological data contained within routine
histologic slides, they were not widely adopted because they were labor
intensive and relatively time consuming and required special expertise and
equipment.
Other attempts to make the assessment of cell type more objective and
quantitative include counting the number of epithelioid cells and
intermediate cells in 40 high-power fields (HPFs). (The mitotic activity of
uveal melanoma is routinely assessed by counting the number of mitotic
figures in 40 HPFs.)

550
 As noted above, tumor size is an important prognostic factor. Large
melanomas have a poorer prognosis than medium- and small-sized
melanomas. Tumor size generally is recorded as the largest tumor diameter
or LTD measured at the base. The 5-year survival of small (<10 mm),
medium (10 to 15 mm), and large (>15 mm) melanomas are 86%, 66%,
and 56%, respectively. These survival rates drop to 76%, 51%, and 41% at
10 years and 70%, 43%, and 35% at 15 years. Smaller melanomas are
more likely to be spindle cell tumors. Furthermore, they are more likely to
have disomy of chromosome 3 and a more favorable class I gene
expression profile.
Certain extracellular matrix patterns within uveal melanomas that
initially were termed microvascular patterns have been shown to be
prognostic indicators for death from metastatic melanoma. The so-called
vascular loops and networks composed of back-to-back loops encircling
microdomains of tumor are the vascular mimicry patterns that are strongly
associated with death from metastatic melanoma (Fig. 11-18F). The term
vasculogenic mimicry looping matrix patterns has been applied to these
patterns in recent publications.
Other prognostic factors, which have been shown by multivariant
statistical analysis to be less important, include mitotic activity,
extraocular tumor extension, necrosis, pigmentation, anterior location, and
lymphocytic infiltration. Paradoxically, the prognosis of heavily
pigmented tumors may be slightly poorer.
Ocular pathologists routinely assess the mitotic activity of uveal
melanoma by counting the number of mitotic figures in 40 high-power
(“high dry”) microscopic fields. Forty fields are counted because most
uveal melanomas contain relatively few mitoses, that is, only 5 or 10 per
40 HPF. Not unexpectedly, patients whose tumors have more mitoses have
a poorer prognosis.
About 8% of 1,527 enucleated globes with uveal melanoma evaluated
in the COMS had some degree of extrascleral extension on histopathologic
examination (Figs. 11-11 and 11-18C). Although direct scleral infiltration
occurs in some cases, melanomas typically extend out of the eye through
the emissarial canals of vessels and nerves in the sclera or via the lumina
of the vortex veins (Fig.11-11A,B). Unlike retinoblastoma, uveal
melanoma rarely invades the optic nerve. Coupland and Damato found that
extraocular spread correlates with increased mortality because it is
associated with increased tumor malignancy and, in the case of posterior
tumors, more advanced disease.

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 The presence of tumor-infiltrating lymphocytes is associated with
decreased survival (Fig. 11-18G). De la Cruz et al. examined 1,078 cases
of uveal melanoma with known survival and found that 12.4% harbored
100 or more lymphocytes per 20 high-power (×400) microscopic fields.
The survival rate at 15 years was 36.7% for patients in the high
lymphocytic group and 69.6% for patients in the low lymphocytic group.
This seemingly counterintuitive observation is explained by the fact that
extraocular dissemination of tumor cells is a requisite for stimulation of a
T-lymphocyte–mediated immune response. The latter reflects the eye’s
status as an immunologically privileged site.
The number of tumor-infiltrating CD68–positive macrophages
infiltrating the tumor is another prognostic factor (Fig. 11-18H). Tumor
infiltration by M2-type macrophages, the main type found in uveal
melanoma, is associated with decreased survival. Tumors with monosomy
of chromosome 3 contain a greater number of M2 macrophages than
tumors with disomy of chromosome 3. M2-type macrophages are
alternatively activated macrophages that promote angiogenesis and have
anti-inflammatory properties.

The most powerful prognostic indicators of uveal melanoma require

special testing. These include the presence of certain nonrandom
chromosomal abnormalities in the tumor cells and the tumor’s gene
expression profile (Fig. 11-18I). Uveal melanomas harbor recurrent
nonrandom chromosomal abnormalities that include monosomy 3, trisomy
8, and structural or numerical abnormalities of chromosome 6. Loss of
chromosome 3 and gains in chromosome 8 are associated with metastatic
death. Monosomy 3 has been shown to be a significant predictor of poor
prognosis in uveal melanoma. In one study, 57% of patients with
monosomy 3 had developed metastases at 3 years, compared to none of the
patients with disomy 3. Chromosomal 3 abnormalities have been identified
using a variety of techniques including fluorescent in situ hybridization
(FISH), multiplex ligation–dependent probe amplification and DNA
amplification, and microsatellite assay.
Harbour and coworkers initially examined the expression of genes in
uveal melanomas using microarray technology and found that they fell into
two classes that differed markedly in survival (Fig. 11-18J). Their gene
expression profile of class I tumors resembles melanocytes. They are low
grade and have less than a 5% incidence of metastasis. In contrast, the risk
for metastasis in patients who have class II melanomas is >90%. The gene

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expression profile of class II melanomas resembles primitive neural or
ectodermal stem cells. These tumors typically contain epithelioid cells and
have monosomy of chromosome 3 and vascular mimicry patterns. They
are characterized by downregulation of neural crest and melanocyte-
specific genes and upregulation of epithelial genes. Recently, a subclass of
class I termed class IB has been recognized. Affected patients develop late
metastases. Tumors with gene expression profile 1B harbor mutations in
the preferentially expressed antigen in melanoma (PRAME) gene. Gene
expression profiling (GEP) of uveal melanomas currently is available as a
proprietary test that assesses tumor class by examining 13 genes. The test’s
proponents believe that it is the most accurate prognostic marker for
melanoma mortality and metastasis, but this remains controversial.
Many centers are now submitting specimens for GEP testing. Others
rely on monosomy 3, which can be assessed using several methods. The
use of these powerful ancillary tests is somewhat controversial because
there currently is no effective treatment for metastatic uveal melanoma.
Patients at risk for metastatic disease can be identified, but clinicians
currently have no effective treatment to offer them. Many patients want to
know their prognosis, however, and those in the low-risk categories can be
reassured and followed less rigorously. In addition, GEP can exclude
patients at low risk for metastasis from clinical trials investigating new
therapeutic agents. Inclusion of class I patients would bias the results of
such studies.

The Genetics of Uveal Melanoma

The mitogen-activated protein kinase pathway (MAP-K) is activated in
86% of uveal melanomas. In most melanocytic lesions, the oncogenic
mutations in the MAP-K signaling pathway are located in BRAF and
NRAS1. BRAF stands for (v-raf murine sarcoma viral oncogene homolog
B1). Sixty-four percent of cutaneous melanomas have activating mutations
in BRAF and 90% of these are the V600E mutation in which there is
replacement of the normal valine at position 600 in the molecule by
glutamic acid. The 600 E mutation is the target for the BRAF enzyme
inhibitor vemurafenib, which successfully controls melanoma that harbor
this mutation, albeit for a short period time. Unfortunately, BRAF
mutations are rare in uveal melanoma, but they do occur in conjunctival
melanoma.
Mutations in GNAQ/GNA11 are an alternate route to MAP kinase

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activation in uveal melanoma. GNAQ stands for guanine nucleotide–
binding protein G(q) subunit alpha. This gene encodes a guanine
nucleotide–binding protein that couples the seven transmembrane domain
receptor to activation of phospholipase C-beta. GNAQ/GNA11 mutations
have been found in 83% of blue nevi and 46% of uveal melanomas. They
appear to be an early event since they are also present in blue nevi and the
nevus of Ota. GNAQ/GNA11 mutations also activate YAP in the Hippo
pathway, which may be inhibited by verteporfin.
Inactivating mutations in the BAP1 gene play an important role in the
metastasis of uveal melanoma. BAP1 stands for breast cancer 1, early
onset (BRCA1)—associated protein-1 gene. BAP1 mutations are found in
84% of class II melanomas. The BAP1 gene is located on chromosome 3,
and the inactivating mutations are thought to be disclosed by loss of
chromosome 3 in tumors with monosomy 3. An autosomal dominantly
inherited familial cancer syndrome is caused by mutations in BAP1.
Patients with the BAP1 cancer syndrome develop uveal melanomas,
mesotheliomas, and benign atypical melanocytic skin tumors. These
BAP1-mutated atypical intradermal tumor (MBAITS) are biphasic nevus–
like lesions. They contain a conventional junctional, compound, or
intradermal component composed of small BAP1-positive melanocytes
and an adjacent dermal lesion composed of BAP1-negative epithelioid
melanocytes.

IRIS NEVUS AND MELANOMA

Most melanocytic lesions of the iris are benign nevi or low-grade spindle
cell tumors (Figs. 11-19 to 11-22). About half of the adult population has
small nonprogressive iris nevi called freckles (Fig. 11-19). Larger
pigmented iris lesions initially should be observed for growth. In one
series, only 6.5% enlarged during a 5-year observation period. Clinical
features that suggest that a pigmented iris tumor is a melanoma include
large size, documented growth, elevated intraocular pressure, hyphema,
and tumor vascularity. Other risk factors for malignant transformation
include a diffuse gross pattern and ectropion iridis. Subsequently, Shields
and coworkers analyzed 1,611 patients with iris nevus to determine factors
predictive of growth into melanoma. In that series, 8% had transformed
into melanoma in 15 years. That paper included an ABCDEF mnemonic
that listed risk factors for malignant transformation. They included: A =
age, young (<40 years), B = blood in the anterior chamber (hyphema), C =

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clock hour (mass located inferiorly), D = diffuse configuration and F =
feathery margins. Diffuse growth pattern and hyphema were the most
powerful risk factors.

FIG. 11-19. Iris freckle. A. Sharply delimited colony of nevus cells in SEM is
located anterior to the plane of the surrounding iris stroma. Round cellular
processes decorate surface of nevus. B. Iris freckles are small nonprogressive
nevi that occur in nearly half the adult population. Their constituent cells have
rounded cellular processes that are densely packed with large melanosomes. (A.
False-colorized SEM ×160 [modified from
Eagle RC Jr. Congenital, developmental and degenerative disorders of the iris and ciliary body. In: Albert DM,
Jakobiec FA, eds. Principles and Practice of Ophthalmology. Clinical Practice, vol. 1. Philadelphia, PA:
Saunders, 1993:367–389], B. Epon section, PD ×100.)

FIG. 11-20. Iris melanoma. A. Spindle cells with long tapering processes are

555
cover surface of iris melanoma. B. Low-grade spindle cell melanoma of the
iris. Moderately pigmented spindle cells infiltrate and thicken stroma and form
plaque on anterior iridic surface. The nuclei of the tumor cells are quite bland. C.
Mixed cell melanoma of the iris. SEM discloses bizarrely pleomorphic cells
presumed to be epithelioid cells on surface of tumor. D. Mixed cell melanoma of
the iris. The heavily pigmented tumor is composed of a mixture of spindle and
epithelioid melanoma cells. The epithelioid cells in the stroma are distinguished
by their round cytoplasmic profiles and round nuclei with prominent nucleoli.
The tumor cells form a plaque on the anterior surface of the iris. (A. SEM ×640,
B. H&E ×50, C. SEM ×320 [Modified from Eagle RC Jr. Iris pigmentation and
pigmented lesion: an ultrastructural study. Trans Am Ophthalmol Soc
1989;87:581–687], D. H&E ×50.)

FIG. 11-21. Iris melanoma, mixed cell type, arising from nevus. Goniophoto (A)
and photomicrograph (B) show tumor nodule that arose rapidly from long-
standing flat pigmented lesion. Bland spindle cells consistent with iris nevus form
plaque on anterior surface of the iris beneath the nodule (C,D). Melanoma cells in
nodule include small epithelioid cells with prominent nucleoli (E,F). Most
pigmented lesions of the iris are low-grade spindle cell lesions, but mixed cell
tumors do occur. (B. H&E ×25, C. H&E ×100, D. H&E ×400, E. H&E ×100, F.
H&E ×400.) (Figure A courtesy of the Wills Eye Ocular Oncology Service.)

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FIG. 11-22. Multicentric tapioca melanoma of the iris. A. Discrete tan nodules
are seen on the iris surface in an eye from a patient who developed unilateral
glaucoma and hyperchromic heterochromia iridis. Translucent nodules seen in
high magnification in macrophoto (B) were examined by SEM (C). False-
colorized SEM shows nodular aggregates and seeds of melanoma cells (brown)
on anterior iridic surface. Anterior surface of the iris between nodules is largely
tumor-free. D. Photomicrograph of sectioned specimen shows nodule of tumor
cells that includes epithelioid cells and mitotic figure. Multicentric tapioca
melanoma is a rare variant of diffuse iris melanoma. (C. SEM ×50, D. H&E
×250.) (Figure A courtesy of the Wills Eye Ocular Oncology Service.)

The mean age of patients with iris melanomas is about 10 years younger
(age 43 years) than the age of patients with posterior segment melanomas.
The prognosis of iris melanoma is also relatively favorable compared to
tumors of the posterior segment. Shields studied 169 patients with
histologically confirmed iris melanoma and found that distant metastases
developed in 5% at 10-year follow-up. In that series, metastases were more
likely to develop in older patients whose tumors involved the angle or iris
root and had elevated intraocular pressure and extraocular extension. The
relatively small size of most iris melanomas probably is a major factor in
their good prognosis. The majority are low-grade spindle cell melanomas

557
as well. Iris melanomas that contain epithelioid cells occasionally are
encountered however (Figs. 11-20B and 11-21).
Diffuse iris melanomas that cause hyperchromic heterochromia iridis
and secondary glaucoma are a rare but clinically important group of iris
tumors (Fig. 8-21). Many diffuse iris melanomas are higher-grade tumors
that contain epithelioid cells, which are poorly cohesive and prone to
aqueous dispersal. Patients are often misdiagnosed clinically and undergo
filtering surgery for glaucoma. The latter invariably fails and puts patients
at greater risk for extraocular extension and metastasis. Multicentric
tapioca melanoma is a variant of diffuse iris melanoma whose cells form
nodular aggregates on the anterior surface of the iris reminiscent of the
appearance of the pearl form of tapioca used to make tapioca pudding (Fig.
11-22). Pigmented tumors of the iris pigment epithelium are exceedingly
rare (Fig. 11-23).

FIG. 11-23. Adenoma of iris pigment epithelium. A. Cords and sheets of

intensely pigmented epithelial cells comprise rare iris tumor. B. Islands of heavily
pigmented iris pigment epithelial cells erode through the iris and invade anterior
chamber. (A. H&E ×50, B. H&E ×100.)

Treatment
Current therapy for uveal melanoma is unsatisfactory in many cases.
Although metastatic disease typically is not evident clinically when the
patient presents to the ophthalmologist, it currently is believed that many
uveal melanomas continuously shed tumor cells into the circulation and
that systemic micrometastases are present several years before the tumor is
treated. Therefore, the ophthalmologist merely achieves local control in
many instances, and what he or she does ultimately has little effect on
systemic spread or survival. To make matters worse, current
chemotherapeutic regimens have little effect on metastatic uveal

558
melanoma; more than 50% of patients die within 1 year.
Local tumor control is achieved in most patients by plaque
brachytherapy that employs plaques with seeds of radioisotopes such as
iodine-125 or ruthenium. The plaques are surgically affixed to the sclera
external to uveal tumors and left in place for period of time calculated to
deliver a lethal dose of radiation to the tumor. Radiation therapy with
beams of protons or helium ions is performed at a few centers. Larger
tumors or tumors that have caused secondary glaucoma generally are
enucleated. Medium-sized tumors can be treated with brachytherapy. The
COMS showed that the mortality rates after I125 plaque therapy and
enucleation are similar. Another arm of the COMS showed that pre-
enucleation external beam radiotherapy of large choroidal melanoma did
not improve survival. The COMS also shed doubt on Zimmerman’s
hypothesis that enucleation of an eye containing a malignant melanoma
might accelerate the dissemination of tumor cells (Fig. 11-17A).
Although plaque brachytherapy conserves the eyes, radiation
maculopathy or papillopathy occurs commonly leading to loss of useful
vision. Almost half of treated eyes have 20/200 vision 3 years after
therapy. Vascular endothelial growth factor inhibitors are now being used
prophylactically to decrease the incidence of this adverse effect of
radiation therapy. Some smaller tumors can be locally resected by partial
lamellar sclerouvectomy. Today, this technique generally is performed on
iridociliary tumors. Small relatively thin tumors of the posterior choroid
can be treated with transpupillary thermotherapy (TTT), an infrared diode
laser therapy that kills tumors cells by slowly heating them. A sandwich
technique combining TTT and plaque brachytherapy has been used to
prevent tumor recurrence from cells sheltered in scleral canals at the base
of a tumor. Endoresection of uveal melanoma has been investigated in
some centers and has been used to treat toxic tumor syndrome after
brachytherapy.
If a pigmented lesion of the iris is thought to be a melanoma based on
documented growth or other clinical factors, it can be locally excised by
iridectomy or by iridocyclectomy if there is focal angle and ciliary body
involvement. Enucleation is often necessary when an iris melanoma has
caused glaucoma or is unresectable. Enucleation also may be done after
histopathological examination has shown that a previously resected tumor
is a high-grade lesion. Unresectable iris melanomas can also be treated
successfully with plaque brachytherapy.

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THE DIFFERENTIAL DIAGNOSIS OF
UVEAL MELANOMA
The differential diagnosis of posterior uveal malignant melanoma includes
other benign and malignant neoplasms such as melanocytic nevi, choroidal
hemangioma, and metastases from distant nonocular primary neoplasms.
The list includes other rare primary intraocular neoplasms that arise in the
uveal stroma such as schwannoma, leiomyoma, hemangiopericytoma, and
adenomas and adenocarcinomas of the RPE and the pigmented and
nonpigmented ciliary epithelium that typically are situated on its inner
surface. Nonneoplastic conditions that can simulate posterior uveal
melanoma and other intraocular neoplasms include vascular and
hemorrhagic lesions, inflammatory and infectious conditions, and a variety
of miscellaneous disorders including the so-called vasoproliferative tumor
(VPT; see below). Age-related maculopathy and peripheral exudative
hemorrhagic chorioretinopathy (“peripheral disciform”) are important
vascular lesions. Inflammatory causes include nodular posterior scleritis,
uveal effusion syndrome, and granulomas. Many of these simulating
conditions are beautifully illustrated in Shields’ Atlas and Textbook of
Intraocular Tumors.

CHOROIDAL HEMANGIOMA
Choroidal hemangiomas are benign vascular hamartomas composed of
relatively large, thin-walled vascular channels lined by endothelial cells.
Choroidal hemangiomas occur sporadically or in association with the
Sturge-Weber syndrome (encephalotrigeminal angiomatosis). Sporadic
hemangiomas appear as discrete orange-red tumefactions (Fig. 11-18). In
contrast, the hemangiomas in patients with Sturge-Weber syndrome
typically are diffuse lesions that obscure normal choroidal landmarks and
impart a tomato ketchup appearance to the fundus on ophthalmoscopy
(Fig. 2-11). Both types of hemangiomas frequently have an associated
serous detachment of the neurosensory retina that involves the fovea.
Hemangiomas can produce visual loss if they are located beneath the fovea
and induce hyperopia, or if they produce a retinal detachment.
Based on the size of their vascular channels, choroidal hemangiomas
have been classified as cavernous, capillary, or mixed. In contrast to
cavernous hemangiomas in the orbit, choroidal hemangiomas have
relatively little stroma and lack the thick fibrous septa found in orbital

560
lesions (Fig. 11-24B). The individual vascular channels almost appear to
abut each other. Solitary tumors have clearly demarcated pushing margins
that compress adjacent melanocytes and choroidal lamellae. Patients with
Sturge-Weber syndrome have a diffuse angiomatosis that may involve
more than half of the choroid and shows intermixture of engorged
preexisting vessels with the vascular tumor.

FIG. 11-24. A. Sporadic choroidal hemangioma. Discrete orange-red tumor is

located beneath inferotemporal vascular arcade. The patient did not have Sturge-
Weber syndrome. B. Benign vascular tumor in choroid is composed of large thin-
walled vessels with little intervening stroma. (B. H&E ×50.)

In addition to causing exudative retinal detachment, choroidal

hemangiomas often produce secondary changes in adjacent ocular
structures such as photoreceptor degeneration and cystoid retinal edema
that can progress to retinoschisis. Varying degrees of RPE hyperplasia and
metaplasia may be present; in rare instance, circumscribed hemangiomas
may be capped by dense plaques of fibrous metaplasia or even bone.
Although choroidal hemangiomas are benign neoplasms, they can
prove “fatal” to the eye. Chronic retinal detachment and cystoid retinal
edema can cause loss of vision, and the eye, as well, can be lost to
secondary closed-angle glaucoma caused by iris neovascularization or
pupillary block induced by anterior displacement of the lens–iris
diaphragm by a high bullous exudative retinal detachment. About three
quarters of eyes with the diffuse hemangiomas of Sturge-Weber syndrome
have glaucoma. In addition to pupillary block, glaucoma mechanisms
include iris neovascularization, maldevelopment of the angle and elevation
of episcleral venous pressure related to associated epibulbar vascular
hamartomatous changes.
IVFA is often helpful in differentiating circumscribed choroidal
hemangiomas from melanomas or metastases. IVFA typically shows lacy

561
hyperfluorescence of vessels in the tumor in the prearterial phase and
diffuse late staining of the mass. Late cystoid edema within the overlying
retina may be prominent. Indocyanine green angiography shows early
filling and a characteristic “washout” of hyperfluorescence in the later
frames. EDI-OCT of choroidal hemangioma shows enhanced luminal size
of the choroidal vasculature.
A scan ultrasonography shows high internal reflectivity within the
tumor, and B scan shows a placoid or round choroidal mass that is
acoustically solid. Hemangiomas appear acoustically solid on B scan
ultrasonography because their constituent vascular channels form multiple
acoustic interfaces. Uveal melanomas usually show acoustic hollowness. A
highly reflective cap may be present on the surface of hemangiomas with
fibrous or osseous metaplasia. Magnetic resonance imaging shows a
choroidal hemangioma to be hyperintense to the vitreous on T1-weighted
images and isointense to vitreous on T2-weighted images.
Treatment of the benign vascular hamartoma is designed to preserve
the eye by controlling exudative retinal detachment. Treatment modalities
include delimiting laser photocoagulation, low-dose plaque radiotherapy,
lens-sparing external beam radiotherapy, TTT, and photodynamic therapy
using verteporfin. Visual prognosis is guarded, however. More than 60%
of patients have poor visual acuity 10 years after treatment despite
successful control of associated subretinal fluid.

VASOPROLIFERATIVE
TUMOR/REACTIVE RETINAL
ASTROCYTIC TUMOR
Initially thought to represent acquired retinal hemangiomas,
vasoproliferative tumors (VPTs) are elevated reddish-pink tumors that
occur in the pre-equatorial fundus, usually in the inferotemporal quadrant.
VPT are fed and drained by retinal vessels and typically are associated
with extensive retinal exudation and hemorrhage. Primary idiopathic and
secondary variants are recognized. Most VPT (80%) are idiopathic and
solitary, but secondary types, which occasionally are multiple, occur in
eyes with a variety of predisposing conditions including intermediate
uveitis (pars planitis), retinitis pigmentosa, retinopathy of prematurity,
ocular toxocariasis, and Coats disease.

562
 There currently is some controversy surrounding the nature of these
lesions and terminology applied to them. A number of histopathologic
studies have shown that VPT are composed primarily of glial fibrillary
acidic protein-positive spindle cells, while vessels, which typically are
thick walled and hyalinized, are a minor component (Fig. 11-25). VPT are
not neoplasms, rather they are thought to be reactive proliferations of
astrocytes, in response to a prior retinal insult. The terms reactive retinal
astrocytic tumor or focal nodular gliosis have been proposed to emphasize
the nonneoplastic reactive nature of these lesions that are composed
largely of glial cells.

FIG. 11-25. Retinal vasoproliferative tumor/reactive retinal astrocytic tumor.

Retinal lesions consistent with VPTs are masses composed primarily of glial
cells. (A) Vessels, which are typically thick walled and hyalinized (A), are a
minor component. VPTs are thought to be reactive proliferations of astrocytes
and are part of a spectrum that includes massive gliosis. (A. H&E ×25, B. H&E
×50.)

Uveal Metastases
Although ocular oncologists see many more patients with uveal melanoma,
metastatic cancer to the eye probably is the most common malignant
intraocular neoplasm. (Figs. 11-19 and 11-20) It has been estimated that
4% of patients dying from all types of cancer have ocular metastases. This
comprises 22,000 cases, more than 10 times the incidence of uveal
melanoma. Most of these secondary ocular tumors occur in terminally ill
patients, however, and few are detected clinically or are referred to
ophthalmologists.
Most of the solid tumors that metastasize to the uvea are carcinomas;
sarcomas rarely metastasize to the eye. Although any part of the eye may

563
be involved by metastatic tumor, the uveal tract, especially the posterior
part of the choroid, is affected most often (Fig. 11-26A). A retrospective
review of 520 eyes with uveal metastases in 420 patients evaluated by the
Oncology Service at the Wills Eye Hospital during a 20-year period
showed that 88% of 950 metastatic foci involved the choroid. Most of the
choroidal metastases involved the macula (12%) or the region between the
macula and the equator (80%). The posterior choroid is affected most often
because its blood supply is greater. Metastases to the retina, vitreous, and
optic disc are relatively uncommon.

FIG. 11-26. Carcinoma metastatic to choroid. A. The posterior pole contains

multiple nodules of amelanotic tumor. The patient was known to have metastatic
mammary carcinoma. B. Lung carcinoma metastatic to the choroid. Metastatic

564
 tumor diffusely thickens the choroid. The Bruch membrane is intact. The retina is
detached and the RPE is focally disrupted. The apparent pigmentation of the cut
surface of the extensively necrotic tumor was caused by dispersal of uveal
pigment. C. Choroidal metastasis, lung carcinoma. Nests and islands of
metastatic pulmonary adenocarcinoma infiltrate the choroidal stroma. The tumor
forms glands and is producing mucin. The detached retina is not seen. Uveal
metastasis may herald an occult lung cancer. D. Mucin-secreting adenocarcinoma
metastatic to choroid. Tumor forms gland-like structures and contains large
quantities of mucin. E. Alcian blue stain discloses presence of mucin in tumor.
F–H. Metastatic pulmonary carcinoma to choroid. Histology shows extensive
areas of tumor necrosis. (A. Photo courtesy of Dr. Carol L. Shields, Wills Eye
Hospital.) (C. H&E ×100, D. H&E ×100, E. Alcian blue ×250, G. H&E ×10, H.
H&E ×50.)

Choroidal metastases typically appear as yellow or creamy-yellow,

nummular, sessile dome, or plateau-shaped masses (Fig. 11-26A). Uveal
metastases may be solitary or multiple and occasionally involve both eyes.
Two or more separate foci of metastatic tumor are found in about 30% of
affected eyes. Visual loss usually is caused by an associated exudative
retinal detachment, which typically has shifting subretinal fluid.
Metastases often are creamy-yellow in color but may be hemorrhagic or
can appear partially pigmented if necrosis has dispersed uveal pigment or
the primary tumor is a cutaneous melanoma. Metastases from carcinoid
tumors, thyroid carcinoma, or renal cell carcinomas may be orange in
color. Cutaneous melanoma often seeds the vitreous with pigmented cells
(Fig. 10-9D,E). Retinal metastases are very rare and often are
misdiagnosed as inflammation.
Breast and lung carcinomas are responsible for more than two thirds of
uveal metastases. Nearly half (47%) of the 420 patients reported by
Shields and associates had breast carcinoma and about one fifth (21%) had
lung cancer. Other primary tumors included gastrointestinal (4%), kidney
(2%), skin (2%), prostate (2%), and other cancers (4%). Overall, about one
third of patients who present with uveal metastases have no prior history of
cancer. Systemic evaluation fails to disclose a primary tumor in half of
these patients. About 35% of occult primary tumors spawning uveal
metastases are lung carcinomas, and 7% are breast carcinomas. Women
with metastases from breast carcinoma usually have a prior history of
mastectomy. In contrast, metastasis is often the presenting manifestation of
an occult lung cancer; less than half of the patients with metastatic lung
cancer to the uvea were known to have cancer when the ocular diagnosis
was made. Metastatic lung cancer is more common in men.

565
 The prognosis of patients with uveal metastasis generally is quite poor;
the mean survival has been reported to be ~9 to 10 months. Today,
relatively few eyes with metastatic carcinoma are accessioned by
ophthalmic pathology laboratories because the diagnosis is made clinically
and most eyes are treated with radiotherapy and/or chemotherapy. Relief
of pain is a major indication for enucleation of eyes with advanced disease.
Plaque brachytherapy is advantageous compared to external beam
radiotherapy because it can be delivered over a relatively short period of
the patient’s limited remaining life span.
The diagnosis of intraocular metastasis usually is made by slit-lamp
biomicroscopy and ophthalmoscopy in a patient who has been carefully
questioned about a past medical history of cancer. Ancillary techniques
such as IVFA and ultrasonography often can assist in making the
diagnosis. Metastases generally begin to show hyperfluorescence in the
late venous phase fluorescein angiography, somewhat later than most
melanomas or hemangiomas. Metastases have many acoustical interfaces
because they are composed of nests, cords, and island of tumor cells
surrounded by stroma. Hence, they show high internal reflectivity on A
scan ultrasonography and appear acoustically solid in B scan,
characteristics they share with hemangiomas. EDI-OCT of choroidal
metastases often shows a “lumpy bumpy” surface and subretinal fluid.
When routine studies give equivocal results, cytopathological examination
of material obtained by FNAB may establish the diagnosis.
The macroscopic appearance of eyes with uveal metastases is
somewhat variable. In most instances, the uveal tract is diffusely thickened
by an infiltrate of white, pink, or yellow tissue (Fig. 11-26B,F). Metastases
occasionally have a multinodular growth pattern, and some larger lesions
may be oval in configuration. Some lesions may be hemorrhagic and
cavitary. Bruch membrane almost always remains intact. Although there
are exceedingly rare exceptions to the rule, one generally can conclude that
a mushroom-shaped tumor of the choroid is a malignant melanoma.
Microscopically, the uveal stroma is infiltrated by nests, cords, and
islands of tumor cells whose general appearance and arrangement is
dependent on the identity of the primary neoplasm (Fig. 11-26C,D). Most
of the breast and lung tumors that metastasize to the eye are mucus-
secreting adenocarcinomas. In such cases, special stains such as Alcian
blue, PAS, or mucicarmine can be used to demonstrate the presence of
intracytoplasmic mucin (Fig. 11-26E).
Immunohistochemical stains (IHCs) are used to confirm the diagnosis

566
and occasionally can suggest the site of the occult primary tumor that has
spawned the metastasis (Fig. 11-27). Carcinomas are distinguished by
positive immunoreactivity for epithelial markers such as cytokeratins and
epithelial membrane antigen. Most melanomas stain with S100 protein and
vimentin and a variety of other melanocytic markers including so-called
melanoma-specific antigen HMB-45, melan-A, and microphthalmia
associated transcription factor MITF2. The panel of IHCs used to evaluate
metastases often includes cytokeratins 7 and 20 (CK7 and CK20). Breast
and lung carcinomas typically are CK7 positive and CK20 negative,
compared to colorectal carcinoma, which is CK20 positive and CK7
negative. Specific markers such as gross cystic disease fluid protein 15
(GCDFP-15) or BRST-2, a monoclonal antibody against the same protein,
can confirm that a tumor is metastatic breast carcinoma (Fig. 16-7B).
Breast metastases also are evaluated for estrogen and progesterone
receptors and the HER2/neu gene product (Fig. 16-7C,D). The latter
markers provide information about prognosis and potential response to
therapy. Lung cancers are often immunoreactive for thyroid transcription
factor-1. Neuroendocrine carcinomas such as small cell lung carcinoma
and carcinoid tumors stain for some cytokeratins and for neuroendocrine
markers neuron-specific enolase (NSE), synaptophysin, and chromogranin
(Fig. 11-27F). Other primary tumors that often can be identified in a fairly
convincing manner using organ-specific markers include thyroid
carcinoma, renal cell carcinoma, and prostate carcinoma.

FIG. 11-27. Occult small cell pulmonary carcinoma metastatic to choroid. A.

Choroid metastasis shows extensive necrosis and perivascular growth pattern
reminiscent of retinoblastoma. B. Mitotically active, undifferentiated tumor cells
have scant cytoplasm. C. Negative immunoreactivity for melanocytic markers
excludes melanoma. D. Carcinoma cells express cytokeratin. E. Ki-67
proliferation index is >90%. F. Tumor cells are immunoreactive for
neuroendocrine marker synaptophysin. (A. H&E ×10, B. H&E ×250, C. IHC for
melan-A ×250, D. IHC for CAM 5.2, E. IHC for Ki-67 [MIB-1], F. IHC for
synaptophysin.)

IHC is particularly helpful in the assessment of the small amount of tissue

567
typically obtained by FNAB when the major clinical differential diagnosis
includes melanoma or a metastasis. Immunocytologic assessment
generally includes one or more melanoma markers such as S100 protein,
melan-A, MITF2 or HMB-45 and a carcinoma marker such as CAM 5.2,
which reacts with cytokeratin 8, or a cytokeratin “cocktail” such as
AE1/AE3 that reacts with a wide spectrum of high and low molecular
weight cytokeratins.

OTHER INTRAOCULAR TUMORS

Primary intraocular tumors occasionally arise from the neuroepithelial
layers of the eye. These include rare adenomas and adenocarcinomas of
the iris pigment epithelium (Fig. 11-23), the pigmented and nonpigmented
ciliary epithelia, and the RPE. Primary neoplasms of the RPE are
exceedingly rare. This is somewhat surprising since the RPE readily
undergoes reactive hyperplasia and metaplasia forming extensive amounts
of fibrous tissue and even bone. Although they occasionally are
amelanotic, RPE tumors classically are jet black in color and have abruptly
elevated margins (Fig. 11-28). They are located on the inner surface of the
choroid and frequently perforate the overlying retina, which shows
intraretinal lipid, exudation, and dilated vessels.

568
FIG. 11-28. RPE tumors. A. RPE adenoma. Heavily pigmented, highly vascular
tumor arises abruptly from the RPE. The tumor is located on the inner surface of
the Bruch membrane and does not involve the choroidal stroma. It contains many
small cystoid spaces. B. The adenoma contains bands and islands of cells and
small cystoid spaces that contain granular eosinophilic material. C. Low-grade
RPE carcinoma arising from CHRPE. Tumor rests on inner surface of the Bruch
membrane and perforates the retina. Varying degrees of pigmentation are present.
D. Arrow denotes thick layer of heavily pigments RPE consistent with residual
CHRPE at base of tumor. Extracellular matrix material separates bands and
islands of tumor cells, which vary in pigment content. Rare mitoses were present.
Tumor was observed to arise from preexisting CHRPE clinically. (A. H&E ×50,
B. H&E ×100, C. H&E ×10, D. H&E ×100.)

Histopathologically, tumors arising from the anterior part of the RPE often
have a vacuolated pattern similar to adenomas of the pigmented ciliary
epithelium (Fig. 11-28A,B). The cells comprising tumors of the posterior
RPE are often arranged in linear strands and may form tubules or
pseudoglands. The cells typically rest on prominent PAS-positive
connective tissue septa. Nuclear atypia, mitotic activity, and a locally
invasive growth pattern serve to distinguish RPE carcinomas from
adenomas. RPE carcinomas may show an infiltrative growth pattern, but
do not metastasize. Peripapillary RPE adenoma may simulate optic disc
melanocytoma. Care must be taken during FNAB of a pigmented lesion
where the differential diagnosis includes an RPE tumor. The cells of RPE
tumors often look quite atypical and are readily confused with epithelioid
melanoma cells in an FNAB. Furthermore, RPE tumors also are
immunoreactive for melan-A, a marker commonly used for melanoma. In
this situation, other melanoma markers such as HMB-45 or S100 protein
should be used.
Ciliary epithelial tumors (Figs. 11-29 to 11-31) can be predominantly
pigmented or nonpigmented. Small pseudoadenomatous proliferations of
the nonpigmented ciliary epithelium called Fuchs or coronal adenomas are
a common incidental finding in elderly eyes (Fig. 11-29). The cytoplasm
of many pigmented ciliary epithelial tumors contains multiple small
cystoid spaces. Nonpigmented tumors are white or yellowish-white in
color (Fig. 11-30A) and often produce focal cataract or lens dislocation.
Many contain pools of hyaluronic acid, which can be extensive in some
cases. In contrast to melanoma, which involves the uveal stroma, ciliary
epithelial tumors arise from the epithelial lining of the ciliary body and
typically rest on its inner surface and do not invade the stroma (Fig. 11-
30B,C). The cells rest on connective tissue septa and form nests, cords,

569
and islands (Fig. 11-30D). Local resection usually is curative. Although
most ciliary epithelial tumors are benign, malignant variants have been
reported. Invasion, mitotic activity, and nuclear pleomorphism are signs of
malignancy. Pleomorphic adenocarcinoma of the NPCE is a rare malignant
neoplasm that typically is found in phthisical eyes in adults that often have
been blind for decades (Fig. 11-31). In such cases, extraocular extension
appears to be a requisite for metastatic spread. Fatalities have been
associated with extraocular extension.

FIG. 11-29. Fuchs (coronal) adenoma. A. Miniature tumor appears grossly as an

enlarged, white ciliary process. B. Adenoma is composed of hyperplastic
nonpigmented ciliary epithelium surrounding acellular stroma of amorphous
eosinophilic extracellular matrix material. (B. H&E ×50.)

570
FIG. 11-30. Ciliary epithelial neoplasms. A. Adenoma of nonpigmented ciliary
epithelium arises from the inner surface of pars plicata. Tumor was locally
resected. B. Nonpigmented ciliary epithelial tumor rests on the inner surface of
the ciliary body and does not involve its stroma. Apical part of the tumor contains
clear vacuoles of hyaluronic acid. C. Benign adenoma arises from ciliary
epithelium on inner surface of pars plicata. It is composed of cords and bands of
nonpigmented ciliary epithelial cells. D. PAS-positive septa separate bands of
nonpigmented ciliary epithelial cells. (B. H&E ×10, C. H&E × 50, D. PAS
×100.)

FIG. 11-31. Pleomorphic carcinoma of the nonpigmented ciliary epithelium. A.

Tumor fills interior of a enucleated eye and extends extraocularly. The carcinoma
developed in an eye that had been blind for many decades after unsuccessful
retinal detachment surgery. B. Nests and cords of malignant epithelial cells rest
on the inner surface of pigmented ciliary epithelium. C. Prominent septa of PAS-
positive material envelop groups of tumor cells. (B and C. PAS ×400.)

Congenital hypertrophy of the RPE (CHRPE) appears

ophthalmoscopically as a flat, round, or oval pigmented spot (Fig. 11-
32A). The lesions are surrounded by a depigmented halo and usually
develop depigmented lacunae with time. CHRPE occasionally were
confused with melanomas before the advent of the modern binocular
indirect ophthalmoscope. Microscopy discloses patches of tall RPE cells
packed with large round melanosomes (Fig. 11-32B). Within lacunae, the
atrophic outer retina adheres to the denuded inner surface of the Bruch
membrane. Although CHRPE originally was considered to be stationary,
some lesions have been documented to grow by serial photography.
Recently, Shields has reported that CHRPE rarely may give rise to solid
tumors. Histopathology (Fig. 11-28C,D) showed that one of these lesions
was a low-grade adenocarcinoma of the RPE.

571
 FIG. 11-32. A. Congenital hypertrophy of the RPE (CHRPE). Oval CHRPE
lacks lacunae. B. Histopathology of similar lesion shows tall hypertrophic RPE
cells filled with pigment. Arrows denote large round macromelanosome. C.
Congenital grouped pigmentation of the RPE (“bear tracks”). Clinical photo
shows numerous flat, well-demarcated pigmented lesions that have been likened
to animal tracks. D. Corresponding photomicrograph shows increased numbers of
ellipsoidal melanin granules filling the cytoplasm of the RPE cells. In normal
RPE cells, melanosomes are confined to the apical cytoplasm. (B. H&E ×250, D.
Toluidine blue ×250.)

Congenital grouped pigmentation (“bear tracks”) is a variant of CHRPE

(Fig. 11-32C,D). Multiple bilateral pigmented RPE lesions that bear a
superficial resemblance to CHRPE recently have been reported to be an
ocular marker for the heritable cancer diathesis Gardner syndrome
(familial adenomatous polyposis with extracolonic manifestations). These
pigmented ocular fundus lesions (POFLs) do not resemble solitary
CHRPE. Rather, they typically are multiple, irregular, and partially
depigmented.
Leiomyomas are rare nonpigmented ciliary body tumors that usually
affect young women. Most are situated in the supraciliary space, and they
characteristically transmit light during transillumination rather than cast a
shadow. Compared to melanomas, leiomyomas are paucicellular and their
cells have fibrillar eosinophilic cytoplasm (Fig. 11-33). Positive
immunoreactivity for smooth muscle actin and other muscle markers
serves to differentiate leiomyoma from uveal melanoma and from rare
peripheral nerve sheath tumors (schwannoma) (Fig. 11-34), which also are
paucicellular. The latter distinction is important because some leiomyomas
have a distinctly neural appearance on routine light microscopy. The term
mesectodermal leiomyoma has been applied to such tumors, emphasizing
the derivation of intraocular smooth muscle from neural crest.

572
FIG. 11-33. Leiomyoma, ciliary body. A. This benign spindle cell tumor of
smooth muscle derivation is relatively paucicellular compared to an amelanotic
spindle cell melanoma. The spindle cells have bland nuclei and finely fibrillar
cytoplasm. B. IHC for smooth muscle actin is strongly positive. Ciliary muscle
(below) serves as normal internal control. Some uveal leiomyomas have a
distinctly neural appearance. (A. H&E ×250, B. IHC for SMA ×50.)

FIG. 11-34. Benign peripheral nerve sheath tumor, choroid. A. The cytology of
this bland, paucicellular choroidal tumor is consistent with a Schwannoma. B.
Another example is paucicellular. C. Tumor is immunoreactive for S100 protein
but did not stain with melanoma markers. Schwannomas are exceeding rare
intraocular tumors that are often impossible to distinguish from melanoma
clinically. IHC is necessary to confirm the diagnosis. (A. H&E ×50, B. H&E
×100, C. IHC for S100 protein ×25.)

Choroidal osteoma or osseous choristoma is another rare primary uveal

tumor that chiefly affects young women (Fig. 11-35). These interesting
lesions are often bilateral and peripapillary in their location. Choroidal
osteoma appears clinically as a yellow-orange placoid tumor with sharply
defined scalloped margins. The bone in osseous choristomas is located
within the choroid, not on its inner surface like the osseous metaplasia of
the RPE found in phthisical eyes. Osteomas may be confused
ophthalmoscopically with metastases, but are easily distinguished by

573
ultrasonography, which shows a highly reflective plaque that persists at
lower sensitivity, or by computed tomography that reveals a plaque with
bone density. Serum calcium, phosphorus, and alkaline phosphatase levels
usually are normal.

FIG. 11-35. Choroidal osteoma. A. Yellow-orange peripapillary tumor found in

young woman has characteristic scalloped margins. B. Choroidal osteomas are
composed of irregular spicules of bone that are surrounded by an areolar stroma
containing large vascular channels. The bone is found within the choroid, deep to
the Bruch membrane, choriocapillaris, and an intact layer of RPE. The
intrachoroidal location of the bone distinguishes choroidal osteoma from the bone
formed by osseous metaplasia of the RPE in blind phthisical eyes. Metaplastic
bone typically is located on the inner surface of the Bruch membrane. (B. H&E
×50.)

Iris pigment epithelial cysts are easily confused clinically with anterior
uveal malignant melanomas because they are heavily pigmented and may
cause focal shallowing of the anterior chamber. Histopathologically, these
cysts are composed of polarized iris pigment epithelium that is one or
more layers thick. The lumen contains clear fluid.
Primary lymphomas of the uvea were initially thought to be reactive
lymphoid hyperplasias. Immunophenotypic studies indicate that they
actually are low-grade MALT lymphomas (Fig. 11-36). The uveal stroma
may be affected in the late stages of a systemic lymphoma or by leukemia.
Primary CNS lymphoma involves the vitreous and retina but generally
spares the uveal tract. Visceral lymphoma rarely involves the vitreous
secondarily.

574
FIG. 11-36. Primary choroidal lymphoma. A. The choroid is massively thickened
by an infiltrate of lymphocytes. An additional focus of lymphoid cells is present
on the epibulbar surface of the eye. Previously called reactive lymphoid
hyperplasia of the uvea, such tumors are now thought to be low-grade MALT
lymphomas. B. Infiltrate is composed of well-differentiated lymphocytes. A few
germinal centers are present. They are often found in MALT lymphomas. (A.
H&E ×25, B. H&E ×50.)

BIBLIOGRAPHY
Nevi
Augsburger JJ, Schroeder RP, Territo C, et al. Clinical parameters predictive of
enlargement of melanocytic choroidal lesions. Br J Ophthalmol
1989;73:911–917.
Eagle RC Jr. Iris pigmentation and pigmented lesions: an ultrastructural study.
Trans Am Ophthalmol Soc 1988;86:581–687.
Gass JD. Problems in the differential diagnosis of choroidal nevi and malignant
melanomas. The XXXIII Edward Jackson Memorial Lecture. Am J
Ophthalmol 1977;83:299–323.
Li HK, Shields CL, Mashayekhi A, et al. Giant choroidal nevus clinical features
and natural course in 322 cases. Ophthalmology 2010;117(2):324–333.
Mashayekhi A, Siu S, Shields CL, et al. Slow enlargement of choroidal nevi: a
long-term follow-up study. Ophthalmology 2011;118(2):382–388.
Naumann G. Pigmented nevi of the choroid and ciliary bodies. A clinical and
histopathological study. Adv Ophthalmol 1970;23:187–272.
Naumann G, Yanoff M, Zimmerman LE. Histogenesis of malignant melanomas
of the uvea: I. Histopathologic characteristics of nevi of the choroid and
ciliary body. Arch Ophthalmol 1966;76:784–796.
Shields CL, Cater J, Shields JA, et al. Combination of clinical factors predictive
of growth of small choroidal melanocytic tumors. Arch Ophthalmol
2000;118:360–364.

575
Shields CL, Demirci H, Materin MA, et al. Clinical factors in the identification of
small choroidal melanoma. Can J Ophthalmol 2004;39:351–357.
Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into
melanoma: analysis of 2514 consecutive cases. Arch Ophthalmol
2009;127(8):981–987.
Shields CL, Furuta M, Mashayekhi A, et al. Clinical spectrum of choroidal nevi
based on age at presentation in 3422 consecutive eyes. Ophthalmology
2008;115(3):546–552.
Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population: the Blue
Mountains Eye Study. Arch Ophthalmol 1998;116:645–650.

Melanocytoma
Apple DJ, Craythorn JM, Reidy JJ, et al. Malignant transformation of an optic
nerve melanocytoma. Can J Ophthalmol 1984;19:320–325.
Bhorade AM, Edward DP, Goldstein DA. Ciliary body melanocytoma with
anterior segment pigment dispersion and elevated intraocular pressure. J
Glaucoma 1999;8:129–133.
Cogan DG. Discussion of melanocytoma. In: Boniuk M, ed. Ocular and Adnexal
Tumors: New and Controversial Aspects. St. Louis, MO: Mosby, 1964:385.
De Potter P, Shields CL, Eagle RC Jr, et al. Malignant melanoma of the optic
nerve. Arch Ophthalmol 1996;114:608–612.
Fineman MS, Eagle RC Jr, Shields JA, et al. Melanocytomalytic glaucoma in
eyes with necrotic iris melanocytoma. Ophthalmology 1998;105:492–496.
Frangieh GT, el Baba F, Traboulsi EI, et al. Melanocytoma of the ciliary body:
presentation of four cases and review of nineteen reports. Surv Ophthalmol
1985;29:328–324.
Joffe L, Shields JA, Osher RH, et al. Clinical and follow-up studies of
melanocytomas of the optic disc. Ophthalmology 1979;86:1067–1083.
Juarez CP, Tso MO. An ultrastructural study of melanocytomas (magnocellular
nevi) of the optic disk and uvea. Am J Ophthalmol 1980;90:48–62.
LoRusso FJ, Boniuk M, Font RL. Melanocytoma (magnocellular nevus) of the
ciliary body: report of 10 cases and review of the literature. Ophthalmology
2000;107:795–800.
Mansour AM, Zimmerman LE, La Piana FG, et al. Clinicopathologic findings in
a growing optic nerve melanocytoma. Br J Ophthalmol 1989;73:410–415.
Osher RH, Shields JA, Layman PR. Pupillary and visual field evaluation in
patients with melanocytoma of the optic disc. Arch Ophthalmol
1979;97:1096–1099.
Shields JA, Augsburger JJ, Bernardino V Jr, et al. Melanocytoma of the ciliary
body and iris. Am J Ophthalmol 1980;89:632–635.
Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of optic disc in 115
cases: the 2004 Samuel Johnson Memorial Lecture, part 1. Ophthalmology
2004;111:1739–1746.

576
Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of the optic disk: a
review. Surv Ophthalmol 2006;51:93–104.
Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented adenoma of the optic nerve
head simulating a melanocytoma. Ophthalmology 1992;99:1705–1708.
Shields JA, Shields CL, Eagle RC Jr, et al. Malignant melanoma associated with
melanocytoma of the optic disc. Ophthalmology 1990;97:225–230.
Shields JA, Shields CL, Eagle RC Jr, et al. Malignant melanoma arising from a
large uveal melanocytoma in a patient with oculodermal melanocytosis. Arch
Ophthalmol 2000;118:990–993.
Shields JA, Shields CL, Eagle RC Jr, et al. Central retinal vascular obstruction
secondary to melanocytoma of the optic disc. Arch Ophthalmol
2001;119:129–133.
Teichmann KD, Karcioglu ZA. Melanocytoma of the iris with rapidly developing
secondary glaucoma. Surv Ophthalmol 1995;40:136–144.
Zimmerman LE. Melanocytes, melanocytic nevi and melanocytomas. Invest
Ophthalmol Vis Sci 1965;4:11–41.
Zimmerman LE, Garron LK. Melanocytoma of the optic disk. Int Ophthalmol
Clin 1962;2:431–440.

Uveal Melanoma—Epidemiology and Predisposing

Features
Albert DM, Chang MA, Lamping K, et al. The dysplastic nevus syndrome. A
pedigree with primary malignant melanomas of the choroid and skin.
Ophthalmology 1985;92:1728–1734.
Albert DM, Lahav M, Packer S, et al. Histogenesis of malignant melanomas of
the uvea. Occurrence of nevus-like structures in experimental choroidal
tumors. Arch Ophthalmol 1974;92:318–323.
Albert DM, Robinson NL, Fulton AB, et al. Epidemiological investigation of
increased incidence of choroidal melanoma in a single population of chemical
workers. Int Ophthalmol Clin 1980;20:71–92.
Antle CM, Damji KF, White VA, et al. Uveal malignant melanoma and optic
nerve glioma in von Recklinghausen’s neurofibromatosis. Br J Ophthalmol
1990;74:502–504.
Bacin F, Kemeny JL, D’Hermies F, et al. Malignant melanoma of the choroid
associated with neurofibromatosis. J Fr Ophtalmol 1993;16:184–190.
Balmaceda CM, Fetell MR, O’Brien JL, et al. Nevus of Ota and leptomeningeal
melanocytic lesions. Neurology 1993;43:381–386.
Barr CC, Zimmerman LE, Curtin VT, et al. Bilateral diffuse melanocytic uveal
tumors associated with systemic malignant neoplasms. A recently recognized
syndrome. Arch Ophthalmol 1982;100:249–255.
Bordon AF, Wray ML, Belfort R, et al. Choroidal malignant melanoma in
association with oculodermal melanocytosis in a black patient. Br J
Ophthalmol 1995;79:191–192.

577
Broadway D, Lang S, Harper J, et al. Congenital malignant melanoma of the eye.
Cancer 1991;67:2642–2652.
Carbone M, Ferris LK, Baumann F, et al. BAP1 cancer syndrome: malignant
mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med
2012;10:179.
Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine
125 brachytherapy for choroidal melanoma: II. Characteristics of patients
enrolled and not enrolled: COMS report No. 17. Arch Ophthalmol
2001;119:951–965.
Dutton JJ, Anderson RL, Schelper RL, et al. Orbital malignant melanoma and
oculodermal melanocytosis: report of two cases and review of the literature.
Ophthalmology 1984;91:497–507.
Gass JD, Gieser RG, Wilkinson CP, et al. Bilateral diffuse uveal melanocytic
proliferation in patients with occult carcinoma. Arch Ophthalmol
1990;108:527–533.
Gass JD, Glatzer RJ. Acquired pigmentation simulating Peutz-Jeghers syndrome:
initial manifestation of diffuse uveal melanocytic proliferation. Br J
Ophthalmol 1991;75:693–695.
Gonder JR, Shields JA, Albert DM, et al. Uveal malignant melanoma associated
with ocular and oculodermal melanocytosis. Ophthalmology
1982;89:953–960.
Gunduz K, Shields JA, Shields CL, et al. Choroidal melanoma in a 14-year-old
patient with ocular melanocytosis. Arch Ophthalmol 1998;116:1112–1114.
Holly EA, Aston DA, Char DH, et al. Uveal melanoma in relation to ultraviolet
light exposure and host factors. Cancer Res 1990;50:5773–5777.
Honavar SG, Singh AD, Shields CL, et al. Iris melanoma in a patient with
neurofibromatosis. Surv Ophthalmol 2000;45:231–236.
Kivelä T. The epidemiological challenge of the most frequent eye cancer:
retinoblastoma, an issue of birth and death. Br J Ophthalmol
2009;93:1129–1131.
Lee SB, Au Eong KG, Saw SM, et al. Eye cancer incidence in Singapore. Br J
Ophthalmol 2000;84:767–770.
Leung AK, Kao CP, Cho HY, et al. Scleral melanocytosis and oculodermal
melanocytosis (nevus of Ota) in Chinese children. J Pediatr
2000;137:581–584.
Margo CE, McLean IW. Malignant melanoma of the choroid and ciliary body in
black patients. Arch Ophthalmol 1984;102:77–79.
Margo CE, Mulla Z, Billiris K. Incidence of surgically treated uveal melanoma by
race and ethnicity. Ophthalmology 1998;105:1087–1090.
Nik NA, Glew WB, Zimmerman LE. Malignant melanoma of the choroid in the
nevus of Ota of a black patient. Arch Ophthalmol 1982;100:1641–1643.
Rehany U, Rumelt S. Iridocorneal melanoma associated with type 1
neurofibromatosis: a clinicopathologic study. Ophthalmology
1999;106:614–618.

578
Rice CD, Brown HH. Primary orbital melanoma associated with orbital
melanocytosis. Arch Ophthalmol 1990;108:1130–1134.
Rodriguez-Sains RS. Ocular findings in patients with dysplastic nevus syndrome.
Ophthalmology 1986;93:661–665.
Sang DN, Albert DM, Sober AJ, et al. Nevus of Ota with contralateral cerebral
melanoma. Arch Ophthalmol 1977;95:1820–1824.
Schmidt-Pokrzywniak A, Jöckel KH, Bornfeld N, et al. Positive interaction
between light iris color and ultraviolet radiation in relation to the risk of uveal
melanoma: a case-control study. Ophthalmology 2009;116:340–348.
Shah CP, Weis E, Lajous M, et al. Intermittent and chronic ultraviolet light
exposure and uveal melanoma: a meta-analysis. Ophthalmology
2005;112:1599–1607.
Shields CL, Kaliki S, Livesey M, et al. Association of ocular and oculodermal
melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872
consecutive eyes. JAMA Ophthalmol 2013;131(8):993–1003.
Shields CL, Kligman BE, Suriano M, et al. Phacomatosis pigmentovascularis of
cesioflammea type in 7 patients: combination of ocular pigmentation
(melanocytosis or melanosis) and nevus flammeus with risk for melanoma.
Arch Ophthalmol 2011;129(6):746–750.
Shields CL, Shields JA, Milite J, et al. Uveal melanoma in teenagers and children.
A report of 40 cases. Ophthalmology 1991;98:1662–1666.
Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook.
Philadelphia, PA: Lippincott Williams & Wilkins, 2008.
Singh AD, De Potter P, Fijal BA, et al. Lifetime prevalence of uveal melanoma in
white patients with oculo(dermal) melanocytosis. Ophthalmology
1998;105:195–198.
Singh AD, Shields CL, Shields JA, et al. Uveal melanoma in young patients. Arch
Ophthalmol 2000;118:918–923.
Singh AD, Shields JA, Eagle RC, et al. Iris melanoma in a ten-year-old boy with
familial atypical mole-melanoma (FAM-M) syndrome. Ophthalmic Genet
1994;15:145–149.
Singh AD, Wang MX, Donoso LA, et al. Genetic aspects of uveal melanoma: a
brief review. Semin Oncol 1996;23:768–772.
Ticho BH, Tso MO, Kishi S. Diffuse iris nevus in oculodermal melanocytosis: a
light and electron microscopic study. J Pediatr Ophthalmol Strabismus
1989;26:244–250.
Vajdic CM, Kricker A, Giblin M, et al. Eye color and cutaneous nevi predict risk
of ocular melanoma in Australia. Int J Cancer 2001;92:906–912.
Wells CG, Bradford RH, Fish GE, et al. Choroidal melanomas in American
Indians COMS Group. Collaborative Ocular Melanoma Study. Arch
Ophthalmol 1996;114:1017–1018.
Wilkes TD, Uthman EO, Thornton CN, et al. Malignant melanoma of the orbit in
a black patient with ocular melanocytosis. Arch Ophthalmol
1984;102:904–906.

579
Uveal Melanoma—Clinical Features
Augsburger JJ, Shields JA, Folberg R, et al. Fine needle aspiration biopsy in the
diagnosis of intraocular cancer. Cytologic-histologic correlations.
Ophthalmology 1985;92:39–49.
Eagle RC Jr, Brucker AJ. Choroidal melanoma with retinal perforation and
vitreous hemorrhage: a scanning electron microscopic study. Jpn J
Ophthalmol 1983;27:512–521.
Eagle RC Jr, Grossniklaus HE, Syed N, et al. Inadvertent evisceration of eyes
containing uveal melanoma. Arch Ophthalmol 2009;127:141–145.
Eagle RC Jr, Shields JA. Pseudoretinitis pigmentosa secondary to preretinal
malignant melanoma cells. Retina 1982;2:51–55.
Eskelin S, Pyrhonen S, Summanen P, et al. Tumor doubling times in metastatic
malignant melanoma of the uvea: tumor progression before and after
treatment. Ophthalmology 2000;107:1443–1449.
Font RL, Zimmerman LE, Armaly MF. The nature of the orange pigment over a
choroidal melanoma. Histochemical and electron microscopical observations.
Arch Ophthalmol 1974;91:359–362.
Fuchs E. Sarcom des Uvealtractus. Wien: Wilhelm Braumüller, 1882.
Kaliki S, Eagle RC, Grossniklaus HE, et al. Inadvertent implantation of aqueous
tube shunts in glaucomatous eyes with unrecognized intraocular neoplasms:
report of 5 cases. JAMA Ophthalmol 2013;131(7):925–928.
Materin MA, Raducu R, Bianciotto C, et al. Fundus autofluorescence and optical
coherence tomography findings in choroidal melanocytic lesions. Middle East
Afr J Ophthalmol 2010;17(3):201–206.
Rashid AB, Grossniklaus HE. Clinical, pathologic, and imaging features and
biological markers of uveal melanoma. Methods Mol Biol 2014;1102:397–425
Say EA, Shah SU, Ferenczy S, et al. Optical coherence tomography of retinal and
choroidal tumors. J Ophthalmol 2012;2012:385058.
Shah SU, Kaliki S, Shields CL, et al. Enhanced depth imaging optical coherence
tomography of choroidal nevus in 104 cases. Ophthalmology
2012;119(5):1066–1072.
Shields CL, Bianciotto C, Pirondini C, et al. Autofluorescence of orange pigment
overlying small choroidal melanoma. Retina 2007;27:1107–1111.
Shields CL, Kaliki S, Rojanaporn D, et al. Enhanced depth imaging optical
coherence tomography of small choroidal melanoma: comparison with
choroidal nevus. Arch Ophthalmol 2012;130(7):850–856.
Shields CL, Manalac J, Das C, et al. Review of spectral domain enhanced depth
imaging optical coherence tomography of tumors of the choroid. Indian J
Ophthalmol 2015;63(2):117–121.
Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of choroidal nevus
in 64 cases. Retina 2008;28(8):1035–1043.
Shields CL, Santos MC, Shields JA, et al. Extraocular extension of unrecognized
choroidal melanoma simulating a primary optic nerve tumor: report of two

580
 cases. Ophthalmology 1999;106:1349–1352.
Shields CL, Shields JA, Shields MB, et al. Prevalence and mechanisms of
secondary intraocular pressure elevation in eyes with intraocular tumors.
Ophthalmology 1987;94:839–846.
Shields CL, Shields JA, Yarian DL, et al. Intracranial extension of choroidal
melanoma via the optic nerve. Br J Ophthalmol 1987;71:172–176.
Shields JA, Rodrigues MM, Sarin LK, et al. Lipofuscin pigment over benign and
malignant choroidal tumors. Trans Sect Ophthalmol Am Acad Ophthalmol
Otolaryngol 1976;81:871–881.
Shields JA, Shields CL. Massive orbital extension of posterior uveal melanomas.
Ophthal Plast Reconstr Surg 1991;7:238–251.
Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected
intraocular tumors. The 1992 Urwick Lecture. Ophthalmology
1993;100:1677–1684.
Yanoff M. Glaucoma mechanisms in ocular malignant melanomas. Am J
Ophthalmol 1970;70:898–904.
Zimmerman LE. Problems in the diagnosis of malignant melanoma of the choroid
and ciliary body. The 1972 Arthur J. Bedell Lecture. Am J Ophthalmol
1973;75:917–929.
Zimmerman LE, McLean IW. Metastatic disease from untreated uveal
melanomas. Am J Ophthalmol 1979;88:524–534.

Uveal Melanoma—Pathology
Callender G. Malignant melanotic tumors of the eye: a study of histologic types in
111 cases. Trans Am Acad Ophthalmol Otolarygol 1931;36:131–142.
Collaborative Ocular Melanoma Study Group. Histopathologic characteristics of
uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma
Study: COMS report no. 6. Am J Ophthalmol 1998;125:745–766.
Connolly BP, Regillo CD, Eagle RC Jr, et al. The histopathologic effects of
transpupillary thermotherapy in human eyes. Ophthalmology
2003;110:415–420.
Damato BE, Foulds WS. Tumour-associated retinal pigment epitheliopathy. Eye
1990;4:382–387.
Font RL, Spaulding AG, Zimmerman LE. Diffuse melanoma of the uveal tract. A
Clinicopathologic report of 54 cases. Trans Am Acad Ophthalmol Otolaryngol
1968;72:877–895.
Green WR. The uveal tract. In: Spencer W, ed. Ophthalmic Pathology: An Atlas
and Textbook, vol. 3. Philadelphia, PA: WB Saunders, 1996.
Lois N, Shields CL, Shields JA, et al. Cavitary melanoma of the ciliary body. A
study of eight cases. Ophthalmology 1998;105:1091–1098.
McLean IW, Foster WD, Zimmerman LE, et al. Modifications of Callender’s
classification of uveal melanoma at the Armed Forces Institute of Pathology.
Am J Ophthalmol 1983;96:502–509.

581
Shields CL, Shields JA, De Potter P, et al. Diffuse choroidal melanoma. Clinical
features predictive of metastasis. Arch Ophthalmol 1996;114:956–963.
Shields CL, Shields JA, Perez N, et al. Primary transpupillary thermotherapy for
small choroidal melanoma in 256 consecutive cases: outcomes and
limitations. Ophthalmology 2002;109:225–234.
Smith LT, Irvine AR. Diagnostic significance of orange pigment accumulation
over choroidal tumors. Mod Probl Ophthalmol 1974;12:536–543.

Iris Melanoma
Demirci H, Shields CL, Shields JA, et al. Diffuse iris melanoma: a report of 25
cases. Ophthalmology 2002;109:1553–1560.
Grossniklaus H, Brown RH, Stulting RD, et al. Iris melanoma seeding through a
trabeculectomy site. Arch Ophthalmol 1990;108:1287–1290.
Harbour JW, Augsburger JJ, Eagle RC Jr. Initial management and follow-up of
melanocytic iris tumors. Ophthalmology 1995;102:1987–1993.
Jakobiec FA, Silbert G. Are most iris “melanomas” really nevi? A
clinicopathologic study of 189 lesions. Arch Ophthalmol 1981;99:2117–2132.
Reese AB, Mund ML, Iwamoto T. Tapioca melanoma of the iris: 1. Clinical and
light microscopy studies. Am J Ophthalmol 1972;74:840–850.
Rones B, Zimmerman LE. The production of heterochromia and glaucoma by
diffuse malignant melanoma of the iris. Trans Am Acad Ophthalmol
Otolaryngol 1957;61:447–463.
Shields CL, Kaliki S, Hutchinson A, et al. Iris nevus growth into melanoma:
analysis of 1611 consecutive eyes: the ABCDEF guide. Ophthalmology
2013;120(4):766–772.
Shields CL, Kaliki S, Shah SU, et al. Iris melanoma: features and prognosis in
317 children and adults. J AAPOS 2012;16(1):10–16.
Shields CL, Shields JA, Materin M, et al. Iris melanoma. Risk factors for
metastasis in 169 consecutive patients. Ophthalmology 2001;108:172–178.
Territo C, Shields CL, Shields JA, et al. Natural course of melanocytic tumors of
the iris. Ophthalmology 1988;95:1251–1255.

Uveal Melanoma—Prognostic Features

Al-Jamal RT, Kivela T. KI-67 immunopositivity in choroidal and ciliary body
melanoma with respect to nucleolar diameter and other prognostic factors.
Curr Eye Res 2006;31:57–67.
Anastassiou G, Schilling H, Djakovic S, et al. Expression of VLA-2, VLA-3, and
alpha(v) integrin receptors in uveal melanoma: association with microvascular
architecture of the tumour and prognostic value. Br J Ophthalmol
2000;84:899–902.
Anastassiou G, Schilling H, Stang A, et al. Expression of the cell adhesion
molecules ICAM-1, VCAM-1 and NCAM in uveal melanoma: a

582
 clinicopathological study. Oncology 2000;58:83–88.
Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic
uveal melanoma. Am J Ophthalmol 2009;148:119–127.
Bechrakis NE, Sehu KW, Lee WR, et al. Transformation of cell type in uveal
melanomas: a quantitative histologic analysis. Arch Ophthalmol
2000;118:1406–1412.
Blom DJ, Luyten GP, Mooy C, et al. Human leukocyte antigen class I expression.
Marker of poor prognosis in uveal melanoma. Invest Ophthalmol Vis Sci
1997;38:1865–1872.
Bronkhorst IH, Jager MJ. Uveal melanoma: the inflammatory microenvironment.
J Innate Immun 2012;4(5–6):454–462.
Bronkhorst IH, Ly LV, Jordanova ES, et al. Detection of M2-macrophages in
uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci
2011;52(2):643–650.
Bronkhorst IH, Vu TH, Jordanova ES, et al. Different subsets of tumor-
infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in
uveal melanoma. Invest Ophthalmol Vis Sci 2012;53(9):5370–5378.
Carbone M, Ferris LK, Baumann F, et al. BAP1 cancer syndrome: malignant
mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med
2012;10:179. Available at: http://www.translational-
medicine.com/content/10/1/179
Chana JS, Wilson GD, Cree IA, et al. c-myc, p53, and Bcl-2 expression and
clinical outcome in uveal melanoma. Br J Ophthalmol 1999;83:110–114.
Chang SH, Worley LA, Onken MD, et al. Prognostic biomarkers in uveal
melanoma: evidence for a stem cell-like phenotype associated with metastasis.
Melanoma Res 2008;18:191–200.
Cheung M, Talarchek J, Schindeler K, et al. Further evidence for germline BAP1
mutations predisposing to melanoma and malignant mesothelioma. Cancer
Genet 2013;206(5):206–210.
Chowers I, Amer R, Pe’er J. The correlation among different immunostaining
evaluation methods for the assessment of proliferative activity in uveal
melanoma. Curr Eye Res 2002;25:369–372.
Coleman DJ, Rondeau MJ, Silverman RH, et al. Correlation of microcirculation
architecture with ultrasound backscatter parameters of uveal melanoma. Eur J
Ophthalmol 1995;5:96–106.
Coleman K, Baak JP, van Diest PJ, et al. DNA ploidy status in 84 ocular
melanomas: a study of DNA quantitation in ocular melanomas by flow
cytometry and automatic and interactive static image analysis. Hum Pathol
1995;26:99–105.
Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease
status at death in 435 patients with large choroidal melanoma in the
Collaborative Ocular Melanoma Study (COMS): COMS report no. 15. Arch
Ophthalmol 2001;119:670–676.
Coupland SE, Anastassiou G, Stang A, et al. The prognostic value of cyclin D1,

583
 p53, and MDM2 protein expression in uveal melanoma. J Pathol
2000;191:120–126.
Coupland SE, Bechrakis N, Schuler A, et al. Expression patterns of cyclin D1 and
related proteins regulating G1-S phase transition in uveal melanoma and
retinoblastoma. Br J Ophthalmol 1998;82:961–970.
Coupland SE, Campbell I, Damato B. Routes of extraocular extension of uveal
melanoma: risk factors and influence on survival probability. Ophthalmology
2008;115:1778–1785.
Cree IA. Cell cycle and melanoma—two different tumours from the same cell
type. J Pathol 2000;191:112–114.
Damato B, Coupland SE. Translating uveal melanoma cytogenetics into clinical
care. Arch Ophthalmol 2009;127:423–429.
Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal
melanomas with multiplex ligation-dependent probe amplification. Clin
Cancer Res 2010;16:6083–6092.
Damato B, Duke C, Coupland SE, et al. Cytogenetics of uveal melanoma: a 7-
year clinical experience. Ophthalmology 2007;114:1925–1931.
de la Cruz PO Jr, Specht CS, McLean IW. Lymphocytic infiltration in uveal
malignant melanoma. Cancer 1990;65:112–115.
De Vries TJ, Mooy CM, Van Balken MR, et al. Components of the plasminogen
activation system in uveal melanoma—a clinico-pathological study. J Pathol
1995;175:59–67.
Ehlers JP, Harbour JW. NBS1 expression as a prognostic marker in uveal
melanoma. Clin Cancer Res 2005;11:1849–1853.
Elavathil LJ, LeRiche J, Rootman J, et al. Prognostic value of DNA ploidy as
assessed with flow cytometry in uveal melanoma. Can J Ophthalmol
1995;30:360–365.
Field MG, Decatur CL, Kurtenbach S, et al. PRAME as an independent
biomarker for metastasis in uveal melanoma. Clin Cancer Res
2016;22(5):1234–1242.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in
metastatic melanoma. N Engl J Med 2010;363:809–819.
Folberg R, Pe’er J, Gruman LM, et al. The morphologic characteristics of tumor
blood vessels as a marker of tumor progression in primary human uveal
melanoma: a matched case-control study. Hum Pathol 1992;23:1298–1305.
Folberg R, Rummelt V, Parys-Van Ginderdeuren R, et al. The prognostic value of
tumor blood vessel morphology in primary uveal melanoma. Ophthalmology
1993;100:1389–1398.
Fuchs U, Kivela T, Summanen P, et al. An immunohistochemical and prognostic
analysis of cytokeratin expression in malignant uveal melanoma. Am J Pathol
1992;141:169–181.
Gamel JW, Greenberg RA, McLean IW, et al. A clinically useful method for
combining gross and microscopic measurements to select high-risk patients
after enucleation for ciliochoroidal melanoma. Cancer 1986;57:1341–1344.

584
Gamel JW, McCurdy JB, McLean IW. A comparison of prognostic covariates for
uveal melanoma. Invest Ophthalmol Vis Sci 1992;33:1919–1922.
Gamel JW, McLean IW. Quantitative analysis of the Callender classification of
uveal melanoma cells. Arch Ophthalmol 1977;95:686–691.
Gamel JW, McLean IW. Computerized histopathologic assessment of malignant
potential: III. Refinements of measurement and data analysis. Anal Quant
Cytol 1984;6:37–44.
Gamel JW, McLean IW, Foster WD, et al. Uveal melanomas: correlation of
cytologic features with prognosis. Cancer 1978;41:1897–1901.
Gamel JW, McLean IW, Greenberg RA, et al. Computerized histologic
assessment of malignant potential: a method for determining the prognosis of
uveal melanomas. Hum Pathol 1982;13:893–897.
Ghazvini S, Kroll S, Char DH, et al. Comparative analysis of proliferating cell
nuclear antigen, bromodeoxyuridine, and mitotic index in uveal melanoma.
Invest Ophthalmol Vis Sci 1995;36:2762–2767.
Grossniklaus HE. Tumor vascularity and hematogenous metastasis in
experimental murine intraocular melanoma. Trans Am Ophthalmol Soc
1998;96:721–752.
Grossniklaus HE. Progression of ocular melanoma metastasis to the liver: the
2012 Zimmerman lecture. JAMA Ophthalmol 2013;131(4):462–469.
Harbour JW. Eye cancer: unique insights into oncogenesis: the Cogan Lecture.
Invest Ophthalmol Vis Sci 2006;47:1736–1745.
Harbour JW. Molecular prognostic testing in uveal melanoma: has it finally come
of age? Arch Ophthalmol 2007;125:1122–1123.
Harbour JW. The genetics of uveal melanoma: an emerging framework for
targeted therapy. Pigment Cell Melanoma Res 2012;25:171–181.
Harbour JW, Chao DL. A molecular revolution in uveal melanoma: implications
for patient care and targeted therapy. Ophthalmology 2014;121(6):1281–1288.
doi: 10.1016/j.ophtha.2013.12.014.
Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in
metastasizing uveal melanomas. Science 2010;330:1410–1413.
Hendrix MJ, Seftor EA, Seftor RE, et al. Biologic determinants of uveal
melanoma metastatic phenotype: role of intermediate filaments as predictive
markers. Lab Invest 1998;78:153–163.
Hendrix MJ, Seftor EA, Seftor RE, et al. Regulation of uveal melanoma
interconverted phenotype by hepatocyte growth factor/scatter factor
(HGF/SF). Am J Pathol 1998;152:855–863.
Herwig MC, Bergstrom C, Wells JR, et al. M2/M1 ratio of tumor associated
macrophages and PPAR-gamma expression in uveal melanomas with class 1
and class 2 molecular profiles. Exp Eye Res 2013;107:52–58.
Herwig MC, Grossniklaus HE. Role of macrophages in uveal melanoma. Expert
Rev Ophthalmol 2011;6(4):405–407.
Hodge WG, Duclos AJ, Rocha G, et al. DNA index and S phase fraction in uveal
malignant melanomas. Br J Ophthalmol 1995;79:521–526.

585
Huntington A, Haugan P, Gamel J, et al. A simple cytologic method for
predicting the malignant potential of intraocular melanoma. Pathol Res Pract
1989;185:631–634.
Jager MJ, Volker-Dieben HJ, de Wolff-Rouendaal D, et al. Possible relation
between HLA and ABO type and prognosis of uveal melanoma. Doc
Ophthalmol 1992;82:43–47.
Jensen OA. Malignant melanomas of the human uvea: 25-year follow-up of cases
in Denmark, 1943–1952. Acta Ophthalmol (Copenh) 1982;60:161–182.
Kantelip B, Albuisson E, Bacin F, et al. Intratumoral blood pools and prognosis
of malignant uveal melanoma treated with enucleation. Ophtalmologie
1989;3:49–52.
Karlsson M, Boeryd B, Carstensen J, et al. Correlations of Ki-67 and PCNA to
DNA ploidy, S-phase fraction and survival in uveal melanoma. Eur J Cancer
1996;32A:357–362.
Kilic E, van Gils W, Lodder E, et al. Clinical and cytogenetic analyses in uveal
melanoma. Invest Ophthalmol Vis Sci 2006;47:3703–3707.
Kishore K, Ghazvini S, Char DH, et al. p53 gene and cell cycling in uveal
melanoma. Am J Ophthalmol 1996;121:561–567.
Lattman J, Kroll S, Char DH, et al. Cell cycling and prognosis in uveal
melanoma. Clin Cancer Res 1995;1:41–47.
Lawry J, Currie Z, Smith MO, et al. The correlation between cell surface markers
and clinical features in choroidal malignant melanomas. Eye
1999;13:301–308.
Maat W, Jordanova ES, van Zelderen-Bhola SL, et al. The heterogeneous
distribution of monosomy 3 in uveal melanomas: implications for
prognostication based on fine-needle aspiration biopsies. Arch Pathol Lab
Med 2007;131:91–96.
Makitie T, Summanen P, Tarkkanen A, et al. Microvascular loops and networks
as prognostic indicators in choroidal and ciliary body melanomas. J Natl
Cancer Inst 1999;91:359–367.
Mäkitie T, Summanen P, Tarkkanen A, et al. Tumor-infiltrating macrophages
(CD68(+) cells) and prognosis in malignant uveal melanoma. Invest
Ophthalmol Vis Sci 2001;42(7):1414–1421.
Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human
melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol
1999;155:739–752.
Marcus DM, Minkovitz JB, Wardwell SD, et al. The value of nucleolar organizer
regions in uveal melanoma. The Collaborative Ocular Melanoma Study
Group. Am J Ophthalmol 1990;110:527–534.
McCurdy J, Gamel J, McLean I. A simple, efficient, and reproducible method for
estimating the malignant potential of uveal melanoma from routine H & E
slides. Pathol Res Pract 1991;187:1025–1027.
McLean IW, Foster WD, Zimmerman LE. Uveal melanoma: location, size, cell
type, and enucleation as risk factors in metastasis. Hum Pathol

586
 1982;13:123–132.
McLean IW, Gamel JW. Prediction of metastasis of uveal melanoma: comparison
of morphometric determination of nucleolar size and spectrophotometric
determination of DNA. Invest Ophthalmol Vis Sci 1988;29:507–511.
McLean IW, Keefe KS, Burnier MN. Uveal melanoma. Comparison of the
prognostic value of fibrovascular loops, mean of the ten largest nucleoli, cell
type, and tumor size. Ophthalmology 1997;104:777–780.
McLean IW, Sibug ME, Becker RL, et al. Uveal melanoma: the importance of
large nucleoli in predicting patient outcome—an automated image analysis
study. Cancer 1997;79:982–988.
McLean IW, Zimmerman LE, Evans RM. Reappraisal of Callender’s spindle, a
type of malignant melanoma of choroid and ciliary body. Am J Ophthalmol
1978;86:557–564.
Meecham WJ, Char DH. DNA content abnormalities and prognosis in uveal
melanoma. Arch Ophthalmol 1986;104:1626–1629.
Mehaffey MG, Folberg R, Meyer M, et al. Relative importance of quantifying
area and vascular patterns in uveal melanomas. Am J Ophthalmol
1997;123:798–809.
Mehaffey MG, Gardner LM, Folberg R. Distribution of prognostically important
vascular patterns across multiple levels in ciliary body and choroidal
melanomas. Am J Ophthalmol 1998;126:373–378.
Mera M. AgNOR values in Callender histopathological types of malignant uveal
melanomas. Rom J Morphol Embryol 1995;41:125–128.
Merbs SL, Sidransky D. Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in
primary sporadic uveal melanoma. Invest Ophthalmol Vis Sci
1999;40:779–783.
Monique H, Hurks H, Metzelaar-Blok JA, et al. Expression of epidermal growth
factor receptor: risk factor in uveal melanoma. Invest Ophthalmol Vis Sci
2000;41:2023–2027.
Mooy C, Vissers K, Luyten G, et al. DNA flow cytometry in uveal melanoma: the
effect of pre-enucleation irradiation. Br J Ophthalmol 1995;79:174–177.
Mooy CM, De Jong PT. Prognostic parameters in uveal melanoma: a review.
Surv Ophthalmol 1996;41:215–228.
Mooy CM, Luyten GP, de Jong PT, et al. Immunohistochemical and prognostic
analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol
1995;147:1097–1104.
Mueller AJ, Folberg R, Freeman WR, et al. Evaluation of the human choroidal
melanoma rabbit model for studying microcirculation patterns with confocal
ICG and histology. Exp Eye Res 1999;68:671–678.
Mueller AJ, Freeman WR, Schaller UC, et al. Complex microcirculation patterns
detected by confocal indocyanine green angiography predict time to growth of
small choroidal melanocytic tumors: MuSIC Report II. Ophthalmology
2002;109:2207–2214.
Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations.

587
 Pathology 2013;45(2):116–126.
Onken MD, Ehlers JP, Worley LA, et al. Functional gene expression analysis
uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res
2006;66:4602–4609.
Onken MD, Worley LA, Ehlers JP, et al. Gene expression profiling in uveal
melanoma reveals two molecular classes and predicts metastatic death.
Cancer Res 2004;64:7205–7209.
Pe’er J, Gnessin H, Shargal Y, et al. PC-10 immunostaining of proliferating cell
nuclear antigen in posterior uveal melanoma. Enucleation versus enucleation
postirradiation groups. Ophthalmology 1994;101:56–62.
Pe’er J, Rummelt V, Mawn L, et al. Mean of the ten largest nucleoli,
microcirculation architecture, and prognosis of ciliochoroidal melanomas.
Ophthalmology 1994;101:1227–1235.
Petrausch U, Martus P, Tonnies H, et al. Significance of gene expression analysis
in uveal melanoma in comparison to standard risk factors for risk assessment
of subsequent metastases. Eye (Lond) 2007;22:997–1007.
Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3
in uveal melanoma. Lancet 1996;347:1222–1225.
Rai K, Pilarski R, Cebulla CM, et al. Comprehensive review of BAP1 tumor
predisposition syndrome with report of two new cases. Clin Genet
2015;89(3):285–294.
Rennie IG, Rees RC, Parsons MA, et al. Estimation of DNA content in uveal
melanomas by flow cytometry. Eye 1989;3:611–617.
Richardson RP, Lawry L, Rees RC, et al. DNA index and % S phase fraction in
posterior uveal melanoma: a 5 year prospective study of fresh tissue using
flow cytometry. Eye 1997;11:629–634.
Royds JA, Sharrard RM, Parsons MA, et al. C-myc oncogene expression in ocular
melanomas. Graefes Arch Clin Exp Ophthalmol 1992;230:366–371.
Rummelt V, Folberg R, Rummelt C, et al. Microcirculation architecture of
melanocytic nevi and malignant melanomas of the ciliary body and choroid. A
comparative histopathologic and ultrastructural study. Ophthalmology
1994;101:718–727.
Rummelt V, Folberg R, Woolson RF, et al. Relation between the microcirculation
architecture and the aggressive behavior of ciliary body melanomas.
Ophthalmology 1995;102:844–851.
Seddon JM, Polivogianis L, Hsieh CC, et al. Death from uveal melanoma.
Number of epithelioid cells and inverse SD of nucleolar area as prognostic
factors. Arch Ophthalmol 1987;105:801–806.
Seregard S, Spångberg B, Juul C, et al. Prognostic accuracy of the mean of the
largest nucleoli, vascular patterns, and PC-10 in posterior uveal melanoma.
Ophthalmology 1998;105:485–491.
Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma
millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol
2009;127:989–998.

588
Shields CL, Ganguly A, Materin MA, et al. Chromosome 3 analysis of uveal
melanoma using fine-needle aspiration biopsy at the time of plaque
radiotherapy in 140 consecutive cases: the Deborah Iverson, MD, Lectureship.
Arch Ophthalmol 2007;125:1017–1024.
Shields CL, Kaliki S, Livesey M, et al. Association of ocular and oculodermal
melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872
consecutive eyes. JAMA Ophthalmol 2013;131(8):993–1003.
Silverman RH, Folberg R, Boldt HC, et al. Correlation of ultrasound parameter
imaging with microcirculatory patterns in uveal melanomas. Ultrasound Med
Biol 1997;23:573–581.
Singh AD, Damato B, Howard P, et al. Uveal melanoma: genetic aspects.
Ophthalmol Clin North Am 2005;18:85–97.
Singh AD, Rennie IG, Kivela T, et al. The Zimmerman-McLean-Foster
hypothesis: 25 years later. Br J Ophthalmol 2004;88:962–967.
Singh AD, Topham A. Survival rates with uveal melanoma in the United States:
1973–1997. Ophthalmology 2003;110:962–965.
Sisley K, Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8
in posterior uveal melanoma correlate with prognosis. Genes Chromosomes
Cancer 1997;19:22–28.
Staibano S, Orabona P, Mezza E, et al. Morphometric analysis of AgNORs in
uveal malignant melanoma. Anal Quant Cytol Histol 1998;20:483–492.
Tschentscher F, Husing J, Holter T, et al. Tumor classification based on gene
expression profiling shows that uveal melanomas with and without
monosomy 3 represent two distinct entities. Cancer Res 2003;63:2578–2584.
Vaisanen A, Kallioinen M, von Dickhoff K, et al. Matrix metalloproteinase-2
(MMP-2) immunoreactive protein—a new prognostic marker in uveal
melanoma? J Pathol 1999;188:56–62.
Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations
of GNAQ in uveal melanoma and blue naevi. Nature 2009;457:599–602.
Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in
uveal melanoma. N Engl J Med 2010;363:2191–2199.
Weber A, Hengge UR, Urbanik D, et al. Absence of mutations of the BRAF gene
and constitutive activation of extracellular-regulated kinase in malignant
melanomas of the uvea. Lab Invest 2003;83:1771–1776.
Weichselbaum RR, Zakov ZN, Albert DM, et al. New findings in the
chromosome 13 long-arm deletion syndrome and retinoblastoma.
Ophthalmology 1979;86:1191–1201.
Whelchel JC, Farah SE, McLean IW, et al. Immunohistochemistry of infiltrating
lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci
1993;34:2603–2606.
White VA, Chambers JD, Courtright PD, et al. Correlation of cytogenetic
abnormalities with the outcome of patients with uveal melanoma. Cancer
1998;83:354–359.
Worley LA, Long MD, Onken MD, et al. Micro-RNAs associated with metastasis

589
 in uveal melanoma identified by multiplexed microarray profiling. Melanoma
Res 2008;18:184–190.
Worley LA, Onken MD, Person E, et al. Transcriptomic versus chromosomal
prognostic markers and clinical outcome in uveal melanoma. Clin Cancer Res
2007;13:1466–1471.
Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing
a malignant melanoma prevent or accelerate the dissemination of tumour
cells. Br J Ophthalmol 1978;62:420–425.
Zuidervaart W, van der Velden PA, Hurks MH, et al. Gene expression profiling
identifies tumour markers potentially playing a role in uveal melanoma
development. Br J Cancer 2003;89:1914–1919.
Zuidervaart W, van Nieuwpoort F, Stark M, et al. Activation of the MAPK
pathway is a common event in uveal melanomas although it rarely occurs
through mutation of BRAF or RAS. Br J Cancer 2005;92:2032–2038.

Uveal Melanoma—Treatment
Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal
melanoma. Am J Ophthalmol 1998;125:81–89.
Collaborative Ocular Melanoma Study Group. The Collaborative Ocular
Melanoma Study (COMS) randomized trial of pre-enucleation radiation of
large choroidal melanoma: II. Initial mortality findings: COMS report no. 10.
Am J Ophthalmol 1998;125:779–796.
Collaborative Ocular Melanoma Study Group. Incidence of cataract and outcomes
after cataract surgery in the first 5 years after iodine 125 brachytherapy in the
Collaborative Ocular Melanoma Study: COMS report no. 27. Ophthalmology
2007;114:1363–1371.
Damato B. Treatment of primary intraocular melanoma. Expert Rev Anticancer
Ther 2006;6:493–506.
Damato B, Kacperek A, Chopra M, et al. Proton beam radiotherapy of iris
melanoma. Int J Radiat Oncol Biol Phys 2005;63:109–115.
Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine
125 brachytherapy for choroidal melanoma: III. Initial mortality findings:
COMS Report No. 18. Arch Ophthalmol 2001;119:969–982.
Gragoudas ES. Long-term results after proton irradiation of uveal melanomas.
The 1996 Jules Gonin Lecture of the Retinal Research Foundation. Graefes
Arch Clin Exp Ophthalmol 1997;235:265–267.
Gunduz K, Shields CL, Shields JA, et al. Radiation retinopathy following plaque
radiotherapy for posterior uveal melanoma. Arch Ophthalmol
1999;117:609–614.
Melia BM, Abramson DH, Albert DM, et al. Collaborative Ocular Melanoma
Study (COMS) randomized trial of I-125 brachytherapy for medium choroidal
melanoma: I. Visual acuity after 3 years: COMS report no. 16.
Ophthalmology 2001;108:348–366.

590
Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and
transpupillary thermotherapy for choroidal melanoma: tumor control and
treatment complications in 270 consecutive patients. Arch Ophthalmol
2002;120:933–940.
Shields CL, Naseripour M, Shields JA, et al. Custom-designed plaque
radiotherapy for nonresectable iris melanoma in 38 patients: tumor control
and ocular complications. Am J Ophthalmol 2003;135:648–656.
Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy for the
management of uveal metastasis. Arch Ophthalmol 1997;115:203–209.
Shields CL, Shields JA, Gunduz K, et al. Radiation therapy for uveal malignant
melanoma. Ophthalmic Surg Lasers 1998;29:397–409.
Shields JA, Shields CL, De Potter P, et al. Diagnosis and treatment of uveal
melanoma. Semin Oncol 1996;23:763–767.

Choroidal Metastases
Augsburger JJ, Shields JA. Fine needle aspiration biopsy of solid intraocular
tumors: indications, instrumentation and techniques. Ophthalmic Surg
1984;15:34–40.
Dabbs DJ, Silverman JF. Immunohistochemical workup of metastatic carcinoma
of unknown primary. Pathol Case Rev 2001;6: 146–153.
Demirci H, Shields CL, Chao AN, et al. Uveal metastasis from breast cancer in
264 patients. Am J Ophthalmol 2003;136:264–271.
Eagle RC Jr. Immunohistochemistry in diagnostic ophthalmic pathology: a
review. Clin Experiment Ophthalmol 2008;36:675–688.
Eagle RC Jr, Ehya H, Shields JA, et al. Choroidal metastasis as the initial
manifestation of a pigmented neuroendocrine tumor. Arch Ophthalmol
2000;118:841–845.
ElSheikh TM, Silverman JF. Differential diagnosis of metastatic tumors. In:
Silverberg SG DR, Frable WJ, LiVolsi VA, et al., eds. Silverberg’s Principles
and Practice of Surgical Pathology and Cytopathology, vol. 1. Philadelphia,
PA: Churchill Livingston/Elsevier, 2006.
Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit: I. A
clinicopathologic study of 227 cases. Arch Ophthalmol 1974;92: 276–286.
Font RL, Naumann G, Zimmerman LE. Primary malignant melanoma of the skin
metastatic to the eye and orbit. Report of ten cases and a review of the
literature. Am J Ophthalmol 1967;63: 738–744.
Freedman MI, Folk JC. Metastatic tumors to the eye and orbit. Patient survival
and clinical characteristics. Arch Ophthalmol 1987;105:1215–1219.
Gunduz K, Shields JA, Shields CL, et al. Cutaneous melanoma metastatic to the
vitreous cavity. Ophthalmology 1998;105:600–605.
Gunduz K, Shields JA, Shields JA, et al. Lung carcinoma metastatic to the
vitreous cavity. Retina 1998;18:285–286.
Leys AM, Van Eyck LM, Nuttin BJ, et al. Metastatic carcinoma to the retina.

591
 Clinicopathologic findings in two cases. Arch Ophthalmol
1990;108:1448–1452.
Liu Q, Teh M, Ito K, et al. CDX2 expression is progressively decreased in human
gastric intestinal metaplasia, dysplasia and cancer. Mod Pathol
2007;20:1286–1297.
Nelson CC, Hertzberg BS, Klintworth GK. A histopathologic study of 716
unselected eyes in patients with cancer at the time of death. Am J Ophthalmol
1983;95:788–793.
Ormsby AH, Snow JL, Su WP, et al. Diagnostic histochemistry of cutaneous
breast carcinoma: a statistical analysis of the utility of gross cystic disease
fluid protein-15 and estrogen receptor protein. J Am Acad Dermatol
1995;32:711–716.
Robertson DM, Wilkinson CP, Murray JL, et al. Metastatic tumor to the retina
and vitreous cavity from primary melanoma of the skin: treatment with
systemic and subconjunctival chemotherapy. Ophthalmology
1981;88:1296–1301.
Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes with uveal
metastases. Ophthalmology 1997;104:1265–1276.
Shields JA, Shields CL, Brown GC, et al. Mushroom-shaped choroidal metastasis
simulating a choroidal melanoma. Retina 2002;22:810–813.
Shields JA, Shields CL, Kiratli H, et al. Metastatic tumors to the iris in 40
patients. Am J Ophthalmol 1995;119:422–430.
Shields JA, Shields CL, Singh AD. Metastatic neoplasms in the optic disc: the
1999 Bjerrum Lecture: part 2. Arch Ophthalmol 2000;118:217–224.
Spraul CW, Martin DF, Hagler WS, et al. Cytology of metastatic cutaneous
melanoma to the vitreous and retina. Retina 1996;16:328–332.
Traina A, Agostara B, Marasa L, et al. HER2/neu expression in relation to
clinicopathologic features of breast carcinoma patients. Ann N Y Acad Sci
2006;1089:159–167.
Young SE, Cruciger M, Lukeman J. Metastatic carcinoma to the retina: case
report. Ophthalmology 1979;86:1350–1354.

Leukemia
Brown GC, Shields JA, Augsburger JJ, et al. Leukemic optic neuropathy. Arch
Ophthalmol 1981;3:111–116.
Currie JN, Lessell S, Lessell IM, et al. Optic neuropathy in chronic lymphocytic
leukemia. Arch Ophthalmol 1988;106:654–660.
Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv
Ophthalmol 1983;27:211–232.
Leonardy NJ, Rupani M, Dent G, et al. Analysis of 135 autopsy eyes for ocular
involvement in leukemia. Am J Ophthalmol 1990;109:436–444.
Rosenthal AR. Ocular manifestations of leukemia. A review. Ophthalmology
1983;90:899–905.

592
Wallace RT, Shields JA, Shields CL, et al. Leukemic infiltration of the optic
nerve. Arch Ophthalmol 1991;109:1027.

Ocular Lymphoma
Brodsky MC, Casteel H, Barber LD, et al. Bilateral iris tumors in an
immunosuppressed child. Surv Ophthalmol 1991;36:217–222.
Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am
Ophthalmol Soc 2003;101:275–292.
Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin
Ophthalmol 2002;13:411–418.
Chan CC, Wallace DJ. Intraocular lymphoma: update on diagnosis and
management. Cancer Control 2004;11:285–295.
Chan CC, Whitcup SM, Solomon D, et al. Interleukin-10 in the vitreous of
patients with primary intraocular lymphoma. Am J Ophthalmol
1995;120:671–673.
Chatzistefanou K, Markomichelakis NN, Christen W, et al. Characteristics of
uveitis presenting for the first time in the elderly. Ophthalmology
1998;105:347–352.
Cho AS, Holland GN, Glasgow BJ, et al. Ocular involvement in patients with
posttransplant lymphoproliferative disorder. Arch Ophthalmol
2011;119:183–189.
Cockerham GC, Hidayat AA, Bijwaard KE, et al. Re-evaluation of “reactive
lymphoid hyperplasia of the uvea”: an immunohistochemical and molecular
analysis of 10 cases. Ophthalmology 2000;107:151–158.
Coupland SE, Damato B. Lymphomas involving the eye and the ocular adnexa.
Curr Opin Ophthalmol 2006;17:523–531.
Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment
Ophthalmol 2008;36:564–578.
Coupland SE, Heimann H, Bechrakis NE. Primary intraocular lymphoma: a
review of the clinical, histopathological and molecular biological features.
Graefes Arch Clin Exp Ophthalmol 2004;242:901–913.
Durant WJ, Flood T, Goldberg MF, et al. Vitrectomy and Whipple’s disease.
Arch Ophthalmol 1984;102:848–851.
Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory
investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology
1987;94:1631–1639.
Holz FG, Boehmer HV, Mechtersheimer G, et al. Uveal non-Hodgkin’s
lymphoma with epibulbar extension simulating choroidal effusion syndrome.
Retina 1999;19:343–346.
O’Hara M, Lloyd WC III, Scribbick FW, et al. Latent intracellular Epstein-Barr
virus DNA demonstrated in ocular posttransplant lymphoproliferative
disorder mimicking granulomatous uveitis with iris nodules in a child. J
AAPOS 2001;5:62–63.

593
Ryan SJ, Zimmerman LE, King FM. Reactive lymphoid hyperplasia. An unusual
form of intraocular pseudotumor. Trans Am Acad Ophthalmol Otolaryngol
1972;76:652–671.
Selsky EJ, Knox DL, Maumenee AE, et al. Ocular involvement in Whipple’s
disease. Retina 1984;4:103–106.
Whitcup SM, de Smet MD, Rubin BI, et al. Intraocular lymphoma. Clinical and
histopathologic diagnosis. Ophthalmology 1993;100:1399–1406.

Histiocytic Lesions
Angell LK, Burton TC. Posterior choroidal involvement in Letterer-Siwe disease.
J Pediatr Ophthalmol Strabismus 1978;15:79–81.
DeBarge LR, Chan CC, Greenberg SC, et al. Chorioretinal, iris, and ciliary body
infiltration by juvenile xanthogranuloma masquerading as uveitis. Surv
Ophthalmol 1994;39:65–71.
Mittelman D, Apple DJ, Goldberg MF. Ocular involvement in Letterer-Siwe
disease. Am J Ophthalmol 1973;75:261–265.
Shields JA, Eagle RC Jr, Shields CL, et al. Iris juvenile xanthogranuloma studied
by immunohistochemistry and flow cytometry. Ophthalmic Surg Lasers
1997;28:140–144.
Vermeulen TL, Isaacs TW, Spagnolo D, et al. Rosai-Dorfman disease presenting
as choroidal melanoma: a case report and review of the literature. Graefes
Arch Clin Exp Ophthalmol 2013;251(1): 295–299.

Leiomyoma and Hemangiopericytoma

Gengler C, Guillou L. Solitary fibrous tumour and haemangiopericytoma:
evolution of a concept. Histopathology 2006;48:63–74.
Jakobiec FA, Font RL, Tso MO, et al. Mesectodermal leiomyoma of the ciliary
body: a tumor of presumed neural crest origin. Cancer 1977;39:2102–2113.
Papale JJ, Frederick AR, Albert DM. Intraocular hemangiopericytoma. Arch
Ophthalmol 1983;101:1409–1411.
Shields JA, Shields CL, Eagle RC Jr. Mesectodermal leiomyoma of the ciliary
body managed by partial lamellar iridocyclochoroidectomy. Ophthalmology
1989;96:1369–1376.
Shields JA, Shields CL, Eagle RC Jr, et al. Observations on seven cases of
intraocular leiomyoma. The 1993 Byron Demorest Lecture. Arch Ophthalmol
1994;112:521–528.
Toth J, Kerenyi AA, Suveges II, et al. Leiomyoma of the ciliary body and
hemangiopericytoma of the choroid. Pathol Oncol Res 1996;2:89–93.

Hemangioma
Arevalo JF, Shields CL, Shields JA, et al. Circumscribed choroidal hemangioma:
characteristic features with indocyanine green videoangiography.

594
 Ophthalmology 2000;107:344–350.
Madreperla SA. Choroidal hemangioma treated with photodynamic therapy using
verteporfin. Arch Ophthalmol 2001;119:1606–1610.
Mashayekhi A, Shields CL. Circumscribed choroidal hemangioma. Curr Opin
Ophthalmol 2003;14:142–149.
Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome.
Ophthalmology 1978;85:276–286.
Shields CL, Honavar SG, Shields JA, et al. Circumscribed choroidal
hemangioma: clinical manifestations and factors predictive of visual outcome
in 200 consecutive cases. Ophthalmology 2001;108:2237–2248.
Shields JA, Shields CL, Eagle RC Jr. Cavernous hemangioma of the iris. Arch
Ophthalmol 2008;126:1602–1603.
Shields JA, Shields CL, Materin MA, et al. Changing concepts in management of
circumscribed choroidal hemangioma: the 2003 J. Howard Stokes Lecture,
Part 1. Ophthalmic Surg Lasers Imaging 2004;35:383–394.
Shields JA, Stephens RF, Eagle RC Jr, et al. Progressive enlargement of a
circumscribed choroidal hemangioma. A clinicopathologic correlation. Arch
Ophthalmol 1992;110:1276–1278.
Witschel H, Font RL. Hemangioma of the choroid. A clinicopathologic study of
71 cases and a review of the literature. Surv Ophthalmol 1976;20:415–431.

Vasoproliferative Tumor
Cohen VM, Shields CL, Demirci H, et al. Iodine I 125 plaque radiotherapy for
vasoproliferative tumors of the retina in 30 eyes. Arch Ophthalmol
2008;126:1245–1251.
Heimann H, Bornfeld N, Vij O, et al. Vasoproliferative tumours of the retina. Br J
Ophthalmol 2000;84:1162–1169.
Hiscott P, Mudhar H. Is vasoproliferative tumour (reactive retinal glioangiosis)
part of the spectrum of proliferative vitreoretinopathy? Eye
2009;23:1851–1858.
Irvine F, O’Donnell N, Kemp E, et al. Retinal vasoproliferative tumors: surgical
management and histological findings. Arch Ophthalmol 2000;118:563–569.
Li HK, Shields JA, Shields CL, et al. Retinal vasoproliferative tumour as the
initial manifestation of retinitis pigmentosa. Clin Experiment Ophthalmol
2008;36:895–897.
Murthy R, Honavar SG. Secondary vasoproliferative retinal tumor associated
with Usher syndrome type 1. J AAPOS 2009;13:97–98.
Poole Perry LJ, Jakobiec FA, Zakka FR, et al. Reactive retinal astrocytic tumors
(so-called vasoproliferative tumors): histopathologic, immunohistochemical,
and genetic studies of four cases. Am J Ophthalmol 2013;155(3):593–608.
Shields CL, Shields JA, Barrett J, et al. Vasoproliferative tumors of the ocular
fundus. Classification and clinical manifestations in 103 patients. Arch
Ophthalmol 1995;113:615–623.

595
Smeets MH, Mooy CM, Baarsma GS, et al. Histopathology of a vasoproliferative
tumor of the ocular fundus. Retina 1998;18: 470–472.

Peripheral Nerve Sheath Tumors

Fan JT, Campbell RJ, Robertson DM. A survey of intraocular schwannoma with a
case report. Can J Ophthalmol 1995;30:37–41.
Matsuo T, Notohara K. Choroidal schwannoma: immunohistochemical and
electron-microscopic study. Ophthalmologica 2000;214:156–160.
Shields JA, Font RL, Eagle RC Jr, et al. Melanotic schwannoma of the choroid.
Immunohistochemistry and electron microscopic observations.
Ophthalmology 1994;101:843–849.
Shields JA, Hamada A, Shields CL, et al. Ciliochoroidal nerve sheath tumor
simulating a malignant melanoma. Retina 1997;17: 459–460.
Shields JA, Sanborn GE, Kurz GH, et al. Benign peripheral nerve tumor of the
choroid: a clinicopathologic correlation and review of the literature.
Ophthalmology 1981;88:1322–1329.
Smith PA, Damato BE, Ko MK, et al. Anterior uveal neurilemmoma—a rare
neoplasm simulating malignant melanoma. Br J Ophthalmol 1987;71:34–40.
Woog JJ, Albert DM, Craft J, et al. Choroidal ganglioneuroma in
neurofibromatosis. Graefes Arch Clin Exp Ophthalmol 1983;220:25–31.

Medulloepithelioma in Adults
Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of
intraocular medulloepithelioma. Am J Ophthalmol 1978;85:407–418.
Carrillo R, Streeten BW. Malignant teratoid medulloepithelioma in an adult. Arch
Ophthalmol 1979;97:695–699.
Floyd BB, Minckler DS, Valentin L. Intraocular medulloepithelioma in a 79-year-
old man. Ophthalmology 1982;89:1088–1094.
Husain SE, Husain N, Boniuk M, et al. Malignant nonteratoid
medulloepithelioma of the ciliary body in an adult. Ophthalmology
1998;105:596–599.
Litricin O, Latkovic Z. Malignant teratoid medulloepithelioma in an adult.
Ophthalmologica 1985;191:17–21.
Shields JA, Eagle RC Jr, Shields CL, et al. Congenital neoplasms of the
nonpigmented ciliary epithelium (medulloepithelioma). Ophthalmology
1996;103:1998–2006.
Wilson ME, McClatchey SK, Zimmerman LE. Rhabdomyosarcoma of the ciliary
body. Ophthalmology 1990;97:1484–1488.

Astrocytic Tumors
Eagle RC Jr, Shields JA, Shields CL, et al. Hamartomas of the iris and ciliary
epithelium in tuberous sclerosis complex. Arch Ophthalmol

596
 2000;118:711–715.
Gunduz K, Eagle RC Jr, Shields CL et al. Invasive giant cell astrocytoma of the
retina in a patient with tuberous sclerosis. Ophthalmology 1999;106:639–642.
Jakobiec FA, Thanos A, Stagner AM, et al. So-called massive retinal gliosis: a
critical review and reappraisal. Surv Ophthalmol 2015;61(3):339–356.
Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in
tuberous sclerosis. Retina 1993;13:155–159.
Shields JA, Eagle RC Jr, Shields CL, et al. Aggressive retinal astrocytomas in
four patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc
2004;102:139–147.
Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina.
Differentiation of sporadic tumors from phakomatosis-associated tumors.
Arch Pathol Lab Med 1984;108:160–163.

Tumors of the Iris and Ciliary Epithelium

Bateman JB, Foos RY. Coronal adenomas. Arch Ophthalmol 1979;97:2379–2384.
Brown HH, Glasgow BJ, Foos RY. Ultrastructural and immunohistochemical
features of coronal adenomas. Am J Ophthalmol 1991;112:34–40.
Dryja TP, Albert DM, Horns D. Adenocarcinoma arising from the epithelium of
the ciliary body. Ophthalmology 1981;88:1290–1292.
Dryja TP, Zakov ZN, Albert DM. Adenocarcinoma arising from the epithelium of
the iris and ciliary body. Int Ophthalmol Clin 1980;20:177–190.
Grossniklaus HE, Lim JI. Adenoma of the nonpigmented ciliary epithelium.
Retina 1994;14:452–456.
Grossniklaus HE, Zimmerman LE, Kachmer ML. Pleomorphic adenocarcinoma
of the ciliary body. immunohistochemical and electron microscopic features.
Ophthalmology 1990;97:763–798.
Laver NM, Hidayat AA, Croxatto JO. Pleomorphic adenocarcinomas of the
ciliary epithelium. Immunohistochemical and ultrastructural features of 12
cases. Ophthalmology 1999;106:103–110.
Lieb WE, Shields JA, Eagle RC Jr, et al. Cystic adenoma of the pigmented ciliary
epithelium. Clinical, pathologic, and immunohistopathologic findings.
Ophthalmology 1990;97:1489–1493.
Rodrigues M, Hidayat A, Karesh J. Pleomorphic adenocarcinoma of ciliary
epithelium simulating an epibulbar tumor. Am J Ophthalmol
1988;106:595–600.
Shields JA, Eagle RC Jr, Shields CL. Adenoma of nonpigmented ciliary
epithelium with smooth muscle differentiation. Arch Ophthalmol
1999;117:117–119.
Shields JA, Eagle RC Jr, Shields CL, et al. Acquired neoplasms of the
nonpigmented ciliary epithelium (adenoma and adenocarcinoma).
Ophthalmology 1996;103:2007–2016.
Shields JA, Shields CL, Mercado G, et al. Adenoma of the iris pigment

597
 epithelium: a report of 20 cases: the 1998 Pan-American Lecture. Arch
Ophthalmol 1999;117:736–741.
Streeten BW, McGraw JL. Tumor of the ciliary pigment epithelium. Am J
Ophthalmol 1972;74:420–429.

Tumors of the Retinal Pigment Epithelial

Edelstein C, Shields CL, Shields JA, et al. Presumed adenocarcinoma of the
retinal pigment epithelium in a blind eye with a staphyloma. Arch Ophthalmol
1998;116:525–528.
Kasner L, Traboulsi EI, Delacruz Z, et al. A histopathologic study of the
pigmented fundus lesions in familial adenomatous polyposis. Retina
1992;12:35–42.
Lieb WE, Shields JA, Eagle RC Jr, et al. Cystic adenoma of the pigmented ciliary
epithelium. Clinical, pathologic, and immunohistopathologic findings.
Ophthalmology 1990;97:1489–1493.
Lloyd WC III, Eagle RC Jr, Shields JA, et al. Congenital hypertrophy of the
retinal pigment epithelium. Electron microscopic and morphometric
observations. Ophthalmology 1990;97:1052–1060.
Loeffler KU, Kivelä T, Borgman H, et al. Malignant tumor of the retinal pigment
epithelium with extraocular extension in a phthisical eye. Graefes Arch Clin
Exp Ophthalmol 1996;234:70–75.
Regillo CD, Eagle RC Jr, Shields JA, et al. Histopathologic findings in congenital
grouped pigmentation of the retina. Ophthalmology 1993;100:400–405.
Shields CL, Mashayekhi A, Ho T, et al. Solitary congenital hypertrophy of the
retinal pigment epithelium: clinical features and frequency of enlargement in
330 patients. Ophthalmology 2003;110: 1968–1976.
Shields JA, Shields CL, Eagle RC Jr, et al. Adenocarcinoma arising from
congenital hypertrophy of retinal pigment epithelium. Arch Ophthalmol
2001;119:597–602.
Shields JA, Shields CL, Gunduz K, et al. Neoplasms of the retinal pigment
epithelium: the 1998 Albert Ruedemann, Sr, memorial lecture, Part 2. Arch
Ophthalmol 1999;117:601–608.
Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital
hypertrophy of the retinal pigment epithelium. Arch Ophthalmol
2000;118:637–641.
Sommacal A, Campbell RJ, Helbig H. Adenocarcinoma of the retinal pigment
epithelium. Arch Ophthalmol 2003;121:1481–1483.
Traboulsi EI, Apostolides J, Giardiello FM, et al. Pigmented ocular fundus lesions
and APC mutations in familial adenomatous polyposis. Ophthalmic Genet
1996;17:167–174.
Traboulsi EI, Murphy SF, de la Cruz ZC, et al. A clinicopathologic study of the
eyes in familial adenomatous polyposis with extracolonic manifestations
(Gardner’s syndrome). Am J Ophthalmol 1990;110:550–561.

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Choroidal Osteoma and Sclerochoroidal
Calcification
Buettner H. Spontaneous involution of a choroidal osteoma. Arch Ophthalmol
1990;108:1517–1518.
Gupta R, Hu V, Reynolds T, et al. Sclerochoroidal calcification associated with
Gitelman syndrome and calcium pyrophosphate dihydrate deposition. J Clin
Pathol 2005;58:1334–1335.
Honavar SG, Shields CL, Demirci H, et al. Sclerochoroidal calcification: clinical
manifestations and systemic associations. Arch Ophthalmol
2001;119:833–840.
Noble KG. Bilateral choroidal osteoma in three siblings. Am J Ophthalmol
1990;109:656–660.
Schachat AP, Robertson DM, Mieler WF, et al. Sclerochoroidal calcification.
Arch Ophthalmol 1992;110:196–199.
Shields CL, Perez B, Materin MA, et al. Optical coherence tomography of
choroidal osteoma in 22 cases: evidence for photoreceptor atrophy over the
decalcified portion of the tumor. Ophthalmology 2007;114:e53–e58.
Shields CL, Shields JA, Augsburger JJ. Choroidal osteoma. Surv Ophthalmol
1988;33:17–27.
Shields CL, Sun H, Demirci H, et al. Factors predictive of tumor growth, tumor
decalcification, choroidal neovascularization, and visual outcome in 74 eyes
with choroidal osteoma. Arch Ophthalmol 2005;123:1658–1666.
Shields JA, Shields CL. CME review: sclerochoroidal calcification: the 2001
Harold Gifford Lecture. Retina 2002;22:251–261.
Shields JA, Shields CL, de Potter P, et al. Progressive enlargement of a choroidal
osteoma. Arch Ophthalmol 1995;113:819–820.
Shields JA, Shields CL, Ellis J, et al. Bilateral choroidal osteoma associated with
bilateral total blindness. Retina 1996;16:445–447.
Sivalingam A, Shields CL, Shields JA, et al. Idiopathic sclerochoroidal
calcification. Ophthalmology 1991;98:720–724.
Sun H, Demirci H, Shields CL, et al. Sclerochoroidal calcification in a patient
with classic Bartter’s syndrome. Am J Ophthalmol 2005;139:365–366.
Trimble SN, Schatz H. Decalcification of a choroidal osteoma. Br J Ophthalmol
1991;75:61–63.
Trimble SN, Schatz H, Schneider GB. Spontaneous decalcification of a choroidal
osteoma. Ophthalmology 1988;95:631–634.
Williams AT, Font RL, Van Dyk HJ, et al. Osseous choristoma of the choroid
simulating a choroidal melanoma. Association with a positive 32P test. Arch
Ophthalmol 1978;96:1874–1877.

599
 12 Retinoblastoma and
Simulating Lesions

Retinoblastoma is the most common intraocular tumor of childhood in

Europe and the United States. On a worldwide basis, it is the most
common primary intraocular tumor, reflecting the rarity of uveal
melanoma in Asia, Africa, and South America. Kivelä has estimated that
there are ~8,000 retinoblastomas yearly in the world and about 7,000 uveal
melanomas, which typically occur in older adults. Only 300 cases of this
rare tumor occur yearly in the United States. The incidence has been
estimated to be 1 in 15,000 to 1 in 34,000 births. All races and both sexes
are affected equally, and the tumor has no predilection for the right or left
eye. The mean age at diagnosis is 18 months, and about 90% of cases are
diagnosed before 3 years of age. Rare cases in older children and adults are
often misdiagnosed.

CLINICAL PRESENTATION
In the United States and Europe, about 90% of patients present with
leukocoria, an abnormal, typically white pupillary reflex that has been
fancifully likened to the tapetal light reflex of the cat (amaurotic cat’s-eye
reflex) (Fig. 12-1). The white pupillary reflex is caused by tumor in the
vitreous cavity (endophytic tumors) or the detached retina (exophytic
tumors). Strabismus occurs in about one third of cases. For this reason,
careful ophthalmoscopy should be performed on all children with
strabismus to exclude retinoblastoma or some other significant retinal
pathology. Rarer presentations include neovascular glaucoma (NVG),
which may cause secondary buphthalmos and iris heterochromia. Some
eyes with endophytic or diffuse infiltrative retinoblastomas develop
pseudohypopyons of tumor cells in the anterior chamber. Aseptic orbital
cellulitis caused by severe NVG that induces intraocular necrosis is

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another pseudoinflammatory presentation. Patients in underdeveloped
countries often present in the late stages of the disease with proptosis or an
orbital mass caused by extraocular extension of the tumor (Fig. 12-2).
Exceptional cases of clinically manifest congenital retinoblastoma have
been reported. These present with a massive hyphema and an enlarged
ectatic cornea that spontaneously perforates. It has been estimated that half
of retinoblastomas actually may be present at birth but are inapparent
clinically.

FIG. 12-1. A. Leukocoria. Unilateral sporadic retinoblastoma. About 90% of

patients with retinoblastoma in the United States present with a white pupillary
reflex. B. Bilateral leukocoria, familial retinoblastoma. Bilateral tumors occur
in about two thirds of patients with familial retinoblastoma. The presence of
bilateral tumors indicates that the affected patient is a carrier of familial
retinoblastoma who can transmit the tumor to progeny. (Photos courtesy of Dr.
Carol L. Shields, Wills Eye Hospital.)

FIG. 12-2. Late presentation. A. Tibetan child with massive orbital

involvement by retinoblastoma. Children in underdeveloped countries who
have little access to medical care often present in the late stages of the disease
with proptosis or an orbital mass. B. Neglected case of bilateral retinoblastoma
from the United States. Tumor fills left orbit. Leukocoria heralds a large tumor

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in the fellow eye. (From Zimmerman LE. Retinoblastoma, including a report of
illustrative cases. Med Ann Dist Columb 1969;38:366–374.)

GROSS PATHOLOGY AND GROWTH

PATTERNS
Macroscopically, retinoblastoma has a white encephaloid or brain-like
appearance, which is not surprising since the tumor arises from the retina,
a peripheral colony of brain cells (Fig. 12-3). Lighter flecks of
calcification or necrotic tumor usually are evident grossly in the tumor.
Necrotic retinoblastomas found in infants with aseptic orbital cellulitis
typically have a blood-tinged, orange, or soupy, grayish necrotic
appearance.

FIG. 12-3. Growth patterns. A. Endophytic retinoblastoma. Encephaloid tumor

arises from inner retina, which remains attached. Extensive vitreous seeding is
present. B. Leukocoria is caused by tumor in vitreous cavity. C. Exophytic
retinoblastoma. Exophytic retinoblastomas arise from the outer layers of the
retina and cause retinal detachment. Macrophoto of enucleated eye with
exophytic retinoblastoma shows encephaloid tumor in subretinal space and total
bullous retinal detachment, which adheres to the back of the lens. The lens–iris
diaphragm is displaced anteriorly causing secondary closure of the angle. D.

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 Retinal vessels are visible behind the lens in eyes with exophytic retinoblastoma.

Tumors with endophytic, exophytic, mixed, or indeterminate and diffuse

infiltrating growth patterns occur. Endophytic retinoblastomas arise from
the inner layers of the retina, which remains attached. The tumor invades
the vitreous cavity and can seed the anterior chamber (Figs. 12-3A,B and
12-5B). A pseudohypopyon of tumor cells can develop if there is extensive
seeding of the anterior chamber. Hence, endophytic tumors can be
confused with primary inflammatory disorders such as toxocariasis,
mycotic endophthalmitis, or granulomatous uveitis.
Exophytic retinoblastomas arise from the outer layers of the retina and
cause retinal detachment (Fig. 12-3B,C). The detached retina is often
highly elevated, and its vessels are visible behind the lens on clinical
examination. Exophytic retinoblastomas are usually confused clinically
with simulating lesions such as Coats disease that cause an exudative
retinal detachment. Strictly endo- or exophytic retinoblastomas are
actually relatively uncommon; most tumors have a mixed endophytic–
exophytic or indeterminate growth pattern. About 1.4% of retinoblastomas
diffusely thicken the retina without forming a distinct mass (Fig. 12-4).
This rare diffuse infiltrating growth pattern usually is found in older
children (mean age 6 years) who typically present with
pseudoinflammatory signs and invariably have unilateral sporadic tumors.
During gross or histopathologic examination, it is nearly impossible to
distinguish multifocal primary lesions spawned by germline mutations
from secondary tumors that result from tumor seeding.

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 FIG. 12-4. Diffuse infiltrating retinoblastoma. A. Pseudohypopyon. Layered
deposit of tumor cells in quiet eye was presenting manifestation of diffuse
infiltrating retinoblastoma in older child. B. Infiltration of zonule by tumor occurs
in many eyes with diffuse infiltrating tumors. C. The neoplasm diffusely
infiltrates, thickens, and opacifies part of the retina but does not form a distinct
mass. Tumor is present on the pars plana. The unilateral sporadic tumor was
found in a 7-year-old boy who presented with anterior chamber seeding. D. The
tumor diffusely infiltrates and thickens the retina but does not form a distinct
mass. Calcification is absent. (D. H&E ×10.)

HISTOPATHOLOGY
Under low magnification, retinoblastoma appears as a basophilic mass
with pink and purple foci that arises from and destroys the retina and fills
part or all of the vitreous cavity (Fig. 12-5). The basophilic areas are
composed of viable retinoblastoma cells. The poorly differentiated
neuroblastic cells appear blue because they have intensely basophilic
nuclei and scanty cytoplasm (Fig. 12-5A). Numerous mitoses and
fragments of apoptotic nuclear debris usually are present. Retinoblastoma
grows rapidly and has a marked propensity to outgrow its blood supply
and undergo spontaneous coagulative necrosis. This usually occurs when
the proliferating cells have extended about 90 to 110 μm away from a
blood vessel (Fig. 12-5D). The necrotic tumor cells lose their basophilic

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nuclear DNA and become pink or eosinophilic. The residual viable cells
typically form cuffs or sleeves around vessels, imparting a multilobulated
or papillary appearance to some tumors (Fig. 12-5C,D). These perivascular
cuffs were called pseudorosettes by some in the past. Foci of dystrophic
calcification develop in the necrotic parts of the tumor in many cases (Fig.
12-6). Histopathologically, the calcific foci appear reddish-purple in
hematoxylin and eosin sections, and the presence of calcium can be
confirmed by the von Kossa or alizarin red stains. Electron microscopy
suggests that calcification probably begins in the mitochondria of necrotic
cells. Clinically, the demonstration of calcification by ultrasonography or
computed tomography can help to differentiate retinoblastoma from other
simulating lesions.

FIG. 12-5. Histopathology. A. Viable parts of a retinoblastoma appear blue in

H&E-stained sections because the tumor is composed of poorly differentiated
neuroblastic cells that have scanty cytoplasm and prominent basophilic nuclei.
Mitoses and apoptotic cells are common. B. Endophytic retinoblastoma. This
poorly differentiated basophilic neoplasm arises from and destroys the retina. The
retina remains attached as the endophytic tumor invades the vitreous cavity.
Rosettes are not seen. C. Low-magnification photomicrograph of retinoblastoma
showing basophilic areas of viable tumor and eosinophilic zones of necrosis. The
viable cells form characteristic sleeves and cuffs around vessels. D. Perivascular
cuffs of tumor cells. Retinoblastoma typically outgrows its blood supply and

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undergoes necrosis. The necrotic cells become eosinophilic because they lose
their nuclear DNA. Necrosis generally occurs when its cells have grown ~90 to
100 μm away from a vessel. The persistent viable cells form basophilic sleeves
and cuffs around vessels. (A. H&E ×250, B. H&E ×50, C. H&E × 10, D. H&E
×50.)

FIG. 12-6. Calcification. A. CT scan shows foci of residual calcified tumor in

both eyes after chemoreduction therapy. B. Calcium and necrosis are evident
grossly as lighter flecks in tumor. C. Dystrophic calcification develops in necrotic
parts of tumor. The calcific foci appear purple in H&E-stained sections (arrow).
D. Calcified nuclei of tumor cells stain positively with von Kossa stain for
calcium. (A. Photo courtesy of Carol L. Shields, MD, Wills Eye Hospital, C.
H&E ×25, D. von Kossa ×100.)

Intensely basophilic deposits of DNA released from necrotic tumor cells

are another characteristic histopathologic feature of retinoblastoma (Fig.
12-7). DNA deposition generally is found in eyes with extensively necrotic
tumors. Typically, the DNA deposits surround retinal or iris vessels or are
found in the trabecular meshwork or in basement membranes such as the
lens capsule or the internal limiting membrane (ILM) of the retina.

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FIG. 12-7. DNA deposition. A. Basophilic material surrounding vessels is
nuclear DNA released by necrotic cells. The surrounding tumor cells are necrotic.
B. DNA deposition in iris stroma. DNA also may deposit in the ILM and the wall
of Schlemm canal. (A. H&E ×100, B. H&E ×100.)

Retinoblastoma cells often collect on the inner surface of Bruch membrane

causing focal retinal pigment epithelial (RPE) detachments. Such sub-RPE
deposits of tumor cells do not constitute choroidal invasion (Fig. 12-8F).
During histopathologic examination, care must be taken to distinguish
artifactual contamination of the choroid (and epibulbar tissues) from true
invasion (Fig. 12-8C,D). The presence of a mixture of viable and necrotic
cells is one feature that serves to identify artifactual seeding. Foci of
extramedullary hematopoiesis also can be confused with uveal invasion in
rare instances (Fig. 12-8E).

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FIG. 12-8. Histologic assessment of retinoblastoma. A. Good-quality section for
assessment of optic nerve includes center of nerve and lamina cribrosa. B.
Inadequate section lacks optic nerve head and lamina cribrosa precluding
assessment for tumor invasion. C. True choroidal invasion is characterized by
infiltrating sheets of viable retinoblastoma cells. D. Artifactitious contamination
of choroid is distinguished by presence of necrotic tumor cells and patchy
involvement. E. Extramedullary hematopoiesis can be confused with choroidal
invasion. It can be confirmed using immunohistochemistry. F. Focal detachment
of the RPE by tumor cells does not constitute choroidal invasion if the Bruch
membrane is intact. (A. H&E ×25, B. H&E ×25, C. H&E ×100, D. H&E ×100,
E. H&E ×250, F. H&E ×250.)

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More than 40% of eyes enucleated for retinoblastoma have iris
neovascularization, which may produce NVG, iris heterochromia, and
even secondary buphthalmos. NVG is almost three times more common in
eyes with high-risk features such as massive choroidal invasion or
retrolaminar optic nerve invasion.

TUMOR DIFFERENTIATION:
ROSETTES AND FLEURETTES
Varying degrees of retinal differentiation occur in retinoblastoma. This is
evident as Homer Wright and Flexner-Wintersteiner rosettes and
photoreceptor differentiation (fleurettes) as well (Figs. 12-9 and 12-10).
Flexner-Wintersteiner rosettes represent an early attempt at retinal
differentiation. Histologically, these rosettes are composed of a ring of
cuboidal cells surrounding a central lumen (Fig. 12-9B). The lumen, which
corresponds to the subretinal space, contains hyaluronidase-resistant acid
mucopolysaccharide (AMP) similar to photoreceptor matrix AMP. The
cells surrounding the lumen are joined near their apices by intercellular
connections (zonulae adherentes), analogous to the external limiting
membrane of the retina. Cilia, which exhibit the 9 + 0 pattern of
microtubular doublets found in the central nervous system, project into the
lumen. Cilia are hypothesized to be the precursor of photoreceptor outer
segments. Although highly characteristic of retinoblastoma, Flexner-
Wintersteiner rosettes are not pathognomonic because they do occur in
malignant medulloepitheliomas and some pineal tumors.

FIG. 12-9. Rosettes. A. Homer Wright rosettes. Each ring of cells surrounds a
central tangle of neural processes. A central lumen is not present. Homer Wright
rosettes are indicative of neuroblastic differentiation. They are the least
differentiated form of rosette found in retinoblastoma and also occur in other
tumors such as neuroblastoma. B. Flexner-Wintersteiner rosettes. Flexner-

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Wintersteiner rosettes represent differentiation toward primitive retina. The
central lumen corresponds to the subretinal space. The tumor cells surrounding
the lumen are joined near their apices by cellular connections that are analogous
to the external limiting membrane. (A. H&E ×250, B. H&E ×250.)

FIG. 12-10. Retinoblastoma, photoreceptor differentiation. A. Photoreceptor

differentiation typically is found in an area of viable tumor that appears relatively
eosinophilic compared to poorly differentiated retinoblastoma. B. Neoplastic
photoreceptors typically form bouquets of pink “flowers” called fleurettes. The
inner segments of the neoplastic photoreceptors appear as bulbous eosinophilic
processes aligned along a segment of neoplastic external limiting membrane. The
nuclei are bland, and mitoses and necrosis are not evident. Tumors composed
entirely of fleurettes are considered to be benign variants of retinoblastoma called
retinomas or retinocytomas. (A. H&E ×50, B. H&E ×250.)

Homer Wright rosettes (named after James Homer Wright) indicate

neuroblastic differentiation (Fig. 12-9A). They lack a central lumen, and
their constituent cells encompass a central tangle of neural filaments.
Wright rosettes are relatively nonspecific. They also occur in
neuroblastoma and are a characteristic feature of cerebellar
medulloblastoma.
Retinoblastoma tends to become less well differentiated with age.
Numerous Flexner-Wintersteiner rosettes typically are found in eyes
enucleated from younger infants, while tumors in older children tend to be
poorly differentiated. A recent study found that the mean age at
enucleation for tumors with many rosettes was 10.4 months; for moderate
rosettes, 18.3 months; for sparse rosettes, 20.4 months; and for poorly
differentiated tumors, 33.9 months. These differences were statistically
significant. The presence of many Flexner-Wintersteiner rosettes in a
tumor may have prognostic significance. In one series, patients who had
moderately well-differentiated tumors that contained abundant Flexner-
Wintersteiner rosettes had about a sixfold better prognosis than did those

610
whose tumors lacked rosettes.
About 15% to 20% of retinoblastomas harbor very well-differentiated
foci of actual photoreceptor differentiation (Figs. 12-10 and 12-13A). Such
areas contain aggregates of neoplastic photoreceptors called fleurettes by
Ts’o, Zimmerman, and Fine, who described them in 1970. Photoreceptor
differentiation typically is found in areas of viable tumor that appear
relatively eosinophilic and paucicellular compared to adjacent
undifferentiated retinoblastoma on low-magnification microscopy of
H&E-stained sections (Fig. 12-10A). The term “fleurette” denotes a
bouquet-like arrangement of cytologically benign cells joined by a series
of zonulae adherentes comprising a short segment of neoplastic external
limiting membrane. Neoplastic photoreceptor inner segments evident as
bulbous eosinophilic processes form the “flowers” of the bouquet (Figs.
12-10B and 12-13A). Electron microscopy has disclosed stacks of cellular
membranes representing early outer segment differentiation in some cases.
The demonstration and characterization of photoreceptor differentiation
firmly established that retinoblastoma was not a retinal glioma and
affirmed that the adoption of the name retinoblastoma by the American
Ophthalmological Society in 1926 at Frederick Verhoeff’s suggestion was
indeed appropriate.
A retinal tumor composed entirely of photoreceptor differentiation is
now thought to be a benign variant of retinoblastoma called a retinoma or
retinocytoma. The cells constituting retinoma/retinocytoma are quite bland
compared to those of retinoblastoma with a low nuclear to cytoplasmic
ratio, finely dispersed chromatin, and no apoptosis, mitoses, or necrosis.
Calcification is found, but occurs in viable parts of the tumor.
Retinomas or retinocytomas initially were thought to represent
spontaneously regressed retinoblastomas on clinical grounds because they
resemble retinoblastomas that have regressed after radiation therapy (Fig.
12-11A). They have a translucent “fish flesh” appearance, contain
abundant calcification that has been likened to cottage cheese, and are
surrounded by a ring of RPE depigmentation. Retinomas/retinocytomas
generally are small tumors that are found in eyes that retain useful vision.
They may be found incidentally or are discovered in a parent or sibling
when the detection of retinoblastoma in a child prompts examination of
other family members. Retinocytomas are relatively resistant to radiation,
as are other benign tumors. Therefore, it is not surprising that foci of
photoreceptor differentiation are found more often in eyes that are
enucleated after external beam radiotherapy or chemotherapy.

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FIG. 12-11. A. Retinocytoma. The tumor has a translucent “fish flesh”
appearance and contains large amounts of calcification that has been likened to
cottage cheese. An annulus of RPE depigmentation typically surrounds the tumor.
The tumor shown here was detected at a preschool vision screening and was
observed unchanged for several years before undergoing malignant
transformation. (From Eagle RC Jr, Shields JA, Donoso L, et al. Malignant
transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma
variant. Ophthalmology 1989;96:1389–1395, Courtesy of Ophthalmology). B.
Spontaneously regressed retinoblastoma, phthisical eye. Basophilic foci of
necrotic calcified tumor cells are the only remnants of retinoblastoma in this
phthisical eye. The calcified tumor is encased by scar tissue that contains strands
of hyperplastic RPE. The choroid is scarred and shows evidence of necrosis. (B.
H&E ×25.)

There is evidence that retinoma/retinocytoma is a precursor of

retinoblastoma. Rare cases of clinically documented malignant
transformation have been reported, and photoreceptor differentiation has
been observed repeatedly at the base of endophytic retinoblastomas in
enucleated eyes. Based on the results of molecular genetic studies,
Dimaras recently has redefined retinoma as a precancerous lesion
characterized by the loss of function of both copies of the RB1 gene, but
lacking the additional genomic changes characteristic of retinoblastoma.

NATURAL HISTORY AND

PROGNOSTIC FACTORS
Retinoblastoma is a highly malignant neoplasm that grows relentlessly and
is invariably fatal if untreated. The tumor arises from the retina and
invades the vitreous cavity and/or the subretinal space. Tumor cells
eventually breach the Bruch membrane and invade the choroidal stroma
(Figs. 12-8C and 12-12B,C). Choroidal vessels serve as a major route for

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distant hematogenous dissemination, and massive choroidal invasion is an
indication for adjuvant chemotherapy in many centers. Involvement of the
anterior chamber, iris stromal, and trabecular meshwork also is thought to
affect prognosis adversely, but the actual magnitude of this effect is
uncertain. Of 297 previously untreated eyes enucleated for retinoblastoma
at the Wills Eye Hospital, 16.5% were found to have uveal invasion, which
was classified as massive (>3 mm in diameter) in about half.
Histopathologic findings that are considered high-risk for metastasis are
summarized in (Fig. 12-12).

FIG. 12-12. Retinoblastoma high-risk features. High-risk histopathologic features

of retinoblastoma include A. retrolaminar optic nerve invasion, B. extraocular
extension, C. massive uveal invasion, and D. anterior segment involvement. A.
There is massive replacement of the retrolaminar parenchyma of the optic nerve
by basophilic tumor. Equivalent to extraocular extension, retrolaminar optic
nerve invasion is an indication for adjuvant chemotherapy in many centers. B.
Tumor is seen on the outer surface of the eye external to a significant focus of
uveal invasion. C. Basophilic retinoblastoma infiltrates and thickens the
juxtapapillary choroid. Massive uveal invasion has been defined as >3 mm in
diameter. D. Tumor infiltrates the stroma of the ciliary body, root of the iris, and
trabecular meshwork. Tumor is also present in the anterior chamber. The

613
 significance of anterior segment involvement is unclear because it typically is
found in eyes with other risk factors. (A. H&E ×10. B. H&E ×10. C. H&E ×15.
D. H&E ×25.)

Retinoblastoma has a marked proclivity to invade the optic nerve, and

optic nerve invasion is an extremely important prognostic factor (Fig. 12-
12A). The tumor can travel along the optic nerve to the brain, or malignant
cells may be dispersed along the neuraxis if they gain access to the
cerebrospinal fluid. Of the 297 untreated eyes in the Wills Eye Hospital
series, 38.7% had some degree of optic nerve invasion. Retrolaminar optic
nerve invasion, an important indication for adjuvant chemotherapy, was
present in about 10.4%. Mortality rates correlate directly with the depth of
optic nerve invasion. In one series, 10% died if there was superficial
invasion of the nerve head only (grade I) and 29% if the tumor reached and
invaded the lamina cribrosa (stage II). Mortality rose to 42% when there
was retrolaminar invasion (grade III) and 78% when the tumor extended to
the surgical margin (grade IV). Hence, surgeons should try to obtain as a
long a segment of optic nerve as possible when enucleating an eye that is
known or suspected to harbor retinoblastoma. In addition, enucleation
should not be performed by an inexperienced surgeon.
The Children’s Oncology Group recently conducted a large
prospective study that investigated the role of adjuvant chemotherapy in
patients with unilateral retinoblastoma. Histopathologic features in that
study that were considered high risk and served as an indication for
adjuvant chemotherapy included massive posterior uveal invasion,
retrolaminar optic nerve invasion, and any degree of concurrent choroidal
and optic nerve invasion. Massive choroidal invasion was defined as >3
mm in diameter. Only one of the 93 patients who had high-risk features
and received chemotherapy developed metastases. Central review of the
ocular histopathology disclosed that a significant number of cases (15.7%)
had been misclassified by pathologists at the contributing hospital (Fig.
12-8B).
Mendoza et al. have reported that severe anaplasia is an additional risk
for metastasis and death in patients with retinoblastoma who do not have
standard high-risk features. In their grading scheme, mild anaplasia was
characterized by moderate nuclear pleomorphism, occasional mitotic
figures, and early retinal differentiation evident as Flexner-Wintersteiner
and/or Homer Wright rosettes (Fig. 12-13). Tumors with moderate
anaplasia were poorly differentiated and had enlarged nuclei, definite
pleomorphism, and frequent mitotic figures. Severely anaplastic tumors

614
were poorly differentiated and had cells with large nuclei that were
extremely pleomorphic and angular, rhomboid, or fusiform in shape. Cell
wrapping and numerous mitotic figures were additional criteria.

FIG. 12-13. Grading of anaplasia in retinoblastoma. A. Nuclei of retinocytoma

cells appear bland with no evidence of anaplasia. Prominent photoreceptor
differentiation (fleurettes) is present. B. Mild anaplasia. The nuclei of cells
forming Flexner-Wintersteiner rosettes are not enlarged but show mild nuclear
pleomorphism. C. Moderate anaplasia is characterized by nuclear enlargement,
pleomorphism, and mitotic activity. D. Severely anaplastic tumor contains large
nuclei with extreme pleomorphism, cellular wrapping, numerous mitotic figures,
and poor differentiation. (A–D. H&E ×400.)

After retinoblastoma has filled the globe and destroyed its contents, it
extends extraocularly. Anteriorly, the tumor extends through the aqueous
outflow pathways, preexisting emissarial canals, or perforations in the
cornea. Posterior segment tumors that have invaded the choroid can extend
extraocularly through emissarial canals or can invade the orbit by directly
infiltrating and destroying the sclera. Secondary buphthalmos and
staphylomas caused by secondary glaucoma can facilitate extrascleral
extension. Secondary closed-angle glaucoma caused by pupillary block or

615
iris neovascularization is relatively common in eyes with retinoblastoma.
Forty-three percent of eyes enucleated for retinoblastoma have iris
neovascularization, and 26% have NVG. In addition, NVG is much more
common in eyes with high-risk histopathologic features.
Retinoblastoma typically metastasizes hematogenously to lungs,
bones, brain, and other organs. Cervical and preauricular adenopathy can
develop when tumors with extensive anterior segment involvement gain
access to lymphatics in the conjunctival stroma. Lymphatics are not
present in the orbit. Metastatic disease usually becomes evident within 1 or
2 years after therapy. Late metastasis is so rare in retinoblastoma that it
should raise the possibility of a second independent primary tumor such as
pineoblastoma.
Retinoblastoma occasionally undergoes spontaneous regression. A
typical bona fide example of spontaneous regression is a phthisical eye
that contains foci of calcified retinoblastoma cells (Fig. 12-11B). Both the
tumor regression and phthisis bulbi probably are caused by extensive
ischemic necrosis in an eye with severe NVG. Many lesions that
previously were thought to be spontaneously regressed tumors actually are
retinomas or retinocytomas.

MOLECULAR GENETICS AND THE

RETINOBLASTOMA ONCOGENE
Retinoblastoma is a hereditary cancer: 5% to 10% of the tumors are
inherited in what appears to be a classic mendelian autosomal dominant
trait; carriers transmit the tumor to one half of their offspring (Fig. 12-
14B). Bilaterality is a characteristic feature of heritable retinoblastoma.
Bilateral tumors occur in about 60% of patients who have germline
mutations in the RB1 gene. The average age of patients with familial
retinoblastoma is about 1 year. A germline mutation should be suspected
when retinoblastoma is found in a very young infant.

616
FIG. 12-14. A. Sporadic somatic retinoblastoma. Retinoblastomas caused by
sporadic somatic mutations are most common. They are always unilateral and
typically occur at about age 2 years. B. Familial retinoblastoma. Tumors in
patients with germline mutations typically are bilateral and multifocal. They
occur earlier than tumors caused by sporadic somatic mutations because only a
single “hit” or gene inactivation is required.

The great majority of retinoblastomas (85%) are sporadic tumors that arise
in patients with a negative family history (Fig. 12-14A). About 75% of
these sporadic tumors are caused by somatic mutations in retinal cells.
Sporadic retinoblastomas caused by somatic mutations are invariably
unilateral, unifocal tumors that cannot be passed on to progeny, and they
tend to occur in older infants (mean age 2 years). The remaining 25% of
sporadic cases are caused by germinal mutations and represent new
familial cases that are transmissible.
A small number (<5%) of retinoblastomas occur in infants who have a
variety of congenital anomalies and are found to have deletions in the long
arm of chromosome 13 that are evident in karyotypic analysis. In addition
to retinoblastoma, the 13Q deletion syndrome comprises severe mental
retardation and other anomalies including microcephaly, hypertelorism,
ptosis, micrognathia, deformed low-set ears, a wide nasal bridge, cardiac
anomalies, anal atresia, microphthalmia, colobomas, and cataracts. The
association of retinoblastoma with the 13Q deletion syndrome initially
suggested that the retinoblastoma gene was located on chromosome 13.
The paradigmatic human recessive oncogene or tumor suppressor
gene, the retinoblastoma or RB1 gene, is located in the 14 band of the Q or
long arm of chromosome 13 (13q14). The RB1 gene is 180,388 base pairs
in length, and its protein product pRB comprises 928 amino acids. pRB is
abundant in the nucleus, where it is involved in control of the cell cycle.
During the G1 or resting phase of the cell cycle, pRB is bound to
transcription factors such as E2F. Phosphorylation of pRB causes release

617
of E2F. Uncomplexed E2F, in turn, activates a variety of other genes and
transcription factors that are important in the initiation of DNA synthesis
(S phase). Absence of pRB causes continual cell division and lack of
terminal differentiation. The RB protein is phosphorylated by cyclin D2
and its cyclin-dependent kinase (cdk) partner. Certain oncoviruses cause
tumors by synthesizing proteins (e.g., adenoviral protein E1A and SV40
large T protein) that bind to pRB and inactivate it.
Classically, the RB1 gene is thought to cause cancer when its protein
product is absent or dysfunctional (Fig. 12-15). Healthy persons have two
normal or wild-type RB1 genes. Both alleles of the RB1 gene are absent or
inactivated in the retinoblastoma cells. Carriers of familial retinoblastoma
are heterozygous for the RB1 gene. Although the pRB produced by a
heterozygote’s single functional gene is sufficient to inhibit tumorigenesis,
heterozygotes are at substantial risk to develop retinoblastoma. Although
retinoblastoma appears to be inherited clinically as an autosomal dominant
trait, the gene is recessive at the molecular level (Fig. 12-16).

FIG. 12-15. The retinoblastoma gene. A. Normal individuals have two copies of
the retinoblastoma gene, which is located on the long arm of chromosome 13.
The gene encodes Rb protein that suppresses tumor formation. B. Patients with
familial retinoblastoma are heterozygous for the retinoblastoma gene. C.
Retinoblastoma develops when both copies of the retinoblastoma gene in a retinal
cell are lost or inactivated. D. The spontaneous mutation rate of the Rb gene is

618
 less than the number of mitoses required for the formation of each retina. This is
the basis for bilateral and multifocal tumors in heterozygous carriers.

FIG. 12-16. Familial retinoblastoma appears to be an autosomal dominant trait,

but the gene actually is recessive at the molecular level.

The genotype of a child with familial retinoblastoma includes one

functional copy of the RB1 gene (Fig. 12-15B). The second copy of the
gene is mutated and encodes dysfunctional RB protein or it may be absent.
Retinoblastoma develops when the solitary remaining wild-type gene is
lost or inactivated, by chance, in a cell within the developing retina (Fig.
12-15C). Cytogenetic mechanisms responsible for gene inactivation (and
resultant homozygosity for the recessive allele) include chromosomal loss
or deletion, somatic recombination, and point mutation. The spontaneous
mutation rate of the normal wild-type RB1 gene is 1 in 10 million or
greater. It is estimated that 100 million mitoses occur during the growth
and development of each retina. Hence, it is highly probable that the
second functional copy of the RB1 gene will be lost or inactivated in at
least one retinal cell in a carrier with a heterozygous genotype.
Furthermore, it is equally probable that gene inactivation and
tumorigenesis will occur in both eyes (Fig. 12-13D).
Immune surveillance appears to arrest some tumors, despite the

619
appropriate additional mutations. This probably is responsible, in part, for
the incomplete penetrance of the RB1 gene, which is estimated to be ~80%
(in other words, there is an 80% chance that one tumor will develop in one
eye). A few families with low-penetrance retinoblastoma have been
reported. They have reduced levels of wild-type RB protein or mutant RB
protein that retains partial activity.
About one third of patients with retinoblastoma have bilateral tumors
(Figs. 12-1B and 12-17). The sporadic occurrence of bilateral tumors
indicates that the affected patient has a germline mutation and is capable of
transmitting the disease to one half of his or her offspring. Unfortunately,
the opposite is not true. As a result of incomplete penetrance and
expressivity, 10% to 15% of unilateral, sporadic retinoblastomas are
caused by potentially transmissible, germline mutations. Statistics used for
genetic counseling (Table 12-1) reflect both the effect of gene penetrance
and the proportion of familial, chromosomal deletion and sporadic somatic
and germinal retinoblastomas in the population.

FIG. 12-17. Bilateral retinoblastoma. Both eyes had to be enucleated after

therapy failed to control the tumors. Bilateral involvement indicates that the
patient has a potentially transmissible germline mutation in the Rb gene.

Table 12-1 Genetic Counseling: Risk That Subsequent Child Will Have

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 Retinoblastoma

Molecular genetics readily explains several hitherto puzzling clinical

features of retinoblastoma. For example, retinoblastoma is predominantly a
tumor of early childhood. Although rare adult cases have been reported,
the mean age at diagnosis is 18 months and the tumor is extremely rare
after age 4 years. Cytogenetic misadventures that cause gene inactivation
generally occur during cellular division. Most mitotic activity in the retina
actually ceases before birth, making neoplastic transformation in older
persons highly unlikely. Retinoblastomas caused by germline mutations
typically develop at an earlier age than do retinoblastomas caused by
sporadic somatic mutations (mean age 12 months vs. 23 months),
presumably because only a single RB1 gene allele, rather than two, must
be inactivated. Knudson graphically compared the ages of patients who
had unilateral and bilateral tumors with the logarithm of the proportion in
each group as yet undiagnosed. His results led him to postulate that two
separate events or “hits” are necessary for the development of sporadic
retinoblastomas (“two-hit hypothesis”). The curve for bilateral, hereditary
tumors is a simple exponential relation, consistent with a single gene
inactivation or “hit” superimposed on the inherited genotypic defect.
Patients who are heterozygous carriers of familial retinoblastoma are
predisposed to develop other malignant tumors. A survivor of bilateral
retinoblastoma has a 20% to 50% chance of developing a second tumor
within 20 years (Armed Forces Institute of Pathology series: 26% within
30 years). These secondary nonocular tumors include osteogenic and other
soft tissue sarcomas, carcinomas of the upper respiratory passages,
malignant melanomas, and carcinomas of the skin. In the past, many
second tumors occurred within the field of irradiation many years after

621
external beam radiotherapy for intraocular retinoblastoma. However, a
500-fold increase in the incidence of osteogenic sarcoma in the
nonirradiated femur has been reported.
Some of the most interesting secondary nonocular neoplasms that
develop in patients with germline mutations are tumors of the pineal gland
or parasellar region that resemble ectopic retinoblastomas. This association
between pinealoma (also termed pineoblastoma) and bilateral hereditary
retinoblastoma has been termed “trilateral retinoblastoma.” The pineal
gland, which serves as a “third eye” in some primitive reptiles, shares
antigenic determinants with the retina and exhibits transient photoreceptor
differentiation in the neonatal rat. Photoreceptor differentiation has been
identified in human pineal tumors.
The RB1 gene has been implicated as a contributing factor in a variety
of other systemic malignancies, including breast, lung, and bladder cancer.
This is not surprising, considering the RB1 gene’s fundamental role in
control of the cell cycle.
Recent molecular genetic studies suggest that the initial concepts
outlined above concerning the RB1 tumor suppressor gene and its role in
the pathogenesis of retinoblastoma are an oversimplification. Dimaras
showed that both copies of the RB1 gene are inactivated and Rb protein is
absent in retinoma/retinocytoma, which is now considered to be a benign
precursor lesion of retinoblastoma. Additional mutations are necessary for
malignant transformation of retinoma into retinoblastoma. The
retinoblastoma gene plays an important role in the regulation of cellular
division in all cells in the body, yet only retinoblastoma, a relatively rare
neoplasm that affects a small population of highly differentiated cells,
results from the inactivation of both copies of the RB1 gene. The highly
retinal-specific predisposition imposed by mutations in the RB1 gene is
hypothesized to result from the specific pattern of expression of other
genes in the unidentified cell of origin in the developing human retina
rather than RB1.
Although it is generally accepted dogma that retinoblastoma is
initiated by mutations in both alleles of the RB1 gene, extensive genetic
testing fails to reveal mutations in the RB1 gene in ~2% of tumors from
probands who have unilateral tumors and a negative family history for
retinoblastoma. Rushlow and coworkers have proposed that RB1+/+
tumors could to be initiated by amplification of the NMYC oncogene.
They state that these tumors tend to be large and invasive, are diagnosed at
a very young age, and have characteristic histopathologic features. They

622
are composed of undifferentiated cells that have large, prominent nuclei,
multiple nucleoli, extensive apoptosis, and little calcification. Although
Homer Wright rosettes may be present, they lack Flexner-Wintersteiner
rosettes, which usually are abundant in retinoblastomas removed from
young children. The nuclei of these tumors are immunoreactive for RB1
protein. Affected children are not at risk for developing tumors in their
fellow eye, and siblings are not at risk for retinoblastoma as well. This
topic is somewhat controversial as significant amplification of the NMYC
gene is known to occur in other neoplasms and has been found in a number
of retinoblastomas with mutations in the RB1 gene (Fig. 12-18).

FIG. 12-18. RB1+/+ retinoblastoma. A. Aggressive retinoblastoma in young

child exhibits retrolaminar optic nerve invasion. B. Poorly differentiated tumor
cells have large nuclei with prominent nucleoli. C. Nuclei of retinoblastoma cells
stain positively for RB1 protein. Tumor cells also stained intensely for
phosphorylated Rb protein. D. Multiple copies of amplified NMYC oncogene are
evident as myriad yellow dots in nuclei of retinoblastoma cells. The child had no
detectable mutations in the RB1 gene, but the presence of phosphorylated RB1
protein rather than NMYC amplification may have spawned retinoblastoma. (A.
H&E ×50, B. H&E ×400, IHC for RB1 protein ×100, fluorescent in situ
hybridization (FISH) for NMYC ×1,000. Figure D courtesy of Dr. Fausto

623
 Rodriguez.)

THE CLASSIFICATION AND

TREATMENT OF
RETINOBLASTOMA
There are several staging systems for retinoblastoma. The older Reese-
Ellsworth classification has prognostic significance for retention of an eye,
maintenance of sight, and the control of local disease but is complicated
and recently has become less useful because it is based on the response to
external beam radiotherapy, a treatment modality that has fallen out of
favor and is now used infrequently. The newer International Classification
of Retinoblastoma (ICRB) is a relatively simple, practical classification
based on clinical findings that was designed primarily to evaluate the
potential response to modern therapy including chemoreduction. The
International Classification includes five stages A through E. Tumors with
localized subretinal seeds are placed in group C and more diffuse seeding
in group D. Group E tumors generally require enucleation. They fill more
than 50% of the globe or have opaque media, NVG, or high-risk features
such as postlaminar optic nerve invasion, significant choroidal invasion,
and invasion of the anterior chamber, sclera, or orbit.
A detailed discussion of the treatment of retinoblastoma is beyond the
scope of this chapter. A number of reports dealing with modern treatment
modalities are referenced below. In short, there have been major changes
in the treatment of retinoblastoma in developed countries in recent years.
A concerted effort has been made to avoid the use of external beam
radiotherapy, which leads to disfiguring facial deformities and predisposes
retinoblastoma gene carriers to secondary malignant neoplasms such as
soft tissue sarcomas in the field of radiation. In addition, fewer eyes with
retinoblastoma currently are being enucleated because there has been a
shift at major centers to eye and even sight-sparing therapy using
chemotherapy.
Chemotherapeutic treatment regimens include the intravenous
administration of chemotherapeutic agents, direct targeting of the tumor by
administration via the ophthalmic artery, and most recently intravitreal
injection of drugs such as melphalan to target vitreous seeds. In some
cases, intravenous chemotherapy is used to shrink tumors so they become
amenable to additional treatment or “consolidation” with local therapeutic

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agents such as cryotherapy, infrared laser transpupillary thermotherapy, or
plaque brachytherapy. This type of chemotherapy is called
chemoreduction and typically employs multiple cycles of vincristine,
etoposide, and carboplatin. It has been used frequently to treat patients
with bilateral retinoblastoma. Chemoreduction can help eradicate tumors
and save eyes that once required enucleation.
Intravenous chemotherapy is also used in an adjuvant fashion when
histopathologic examination of eyes treated by enucleation discloses
certain high-risk features that are believed to place a patient at high risk for
metastasis (see above). Intravenous chemotherapy kills retinoblastoma
cells that have metastasized from the primary intraocular tumor. In
addition, it may decrease the frequency of pineoblastoma, the potentially
fatal retinoblastoma-like tumor of the pineal gland that can develop in
patients with germline mutations in the RB1 gene. Adjuvant chemotherapy
is one of the factors that is responsible for improved survival in recent
years.
During the past several years, both of these forms of intravenous
chemotherapy have been supplanted, to some extent, by intra-arterial
chemotherapy (IAC), which is used extensively at some major centers.
Also termed ophthalmic artery chemosurgery, IAC of retinoblastoma
initially was developed by Kaneko et al. in Japan where enucleation is
abhorrent for cultural reasons. In this procedure, chemotherapeutic drugs,
typically melphalan, are directly administered to the tumor-containing eye
via a catheter inserted within or in close proximity to the ophthalmic
artery. The catheter is introduced into the femoral artery and advanced
under fluoroscopic guidance. Several treatment sessions usually are
required.
The topic of IAC remains controversial. IAC can totally eradicate
retinoblastomas in many instances, and spectacular treatment results have
been reported. Theoretically, the technique should decrease potential
complications of systemic chemotherapy since most of the drug is
administered solely to the eye. However, IAC has its limitations and does
not work in all cases. Furthermore, the technique theoretically carries a
higher risk for metastatic disease compared to intravenous chemotherapy
because the drug does not reach extraocular tissue where metastatic cells
can reside. About 20% of a series of eyes that were enucleated for
retinoblastoma at the Wills Eye Hospital were found to harbor high-risk
features such as massive choroidal or postlaminar optic nerve invasion that
are indications for adjuvant chemotherapy. These high-risk features will

625
not be detected if IAC is performed, and tumor cells that have
metastasized to extraocular sites will not be killed. Similarly, IAC should
not effectively control pineoblastoma.
Other complications of IAC such as ischemic chorioretinal and RPE
atrophy have been observed clinically and confirmed histopathologically.
Intravascular foreign bodies and thrombosed vessels have been found in
some cases, stressing the need for skilled operators and meticulous
technique. Pulsatile optic nerve and choroidal blanching, retinal artery
narrowing, and retinal artery precipitates have been observed during drug
infusion in infants and experimental animals, raising additional concerns
about IAC and the long-term vascular toxicity of melphalan.
The technique of intravitreal chemotherapy was reported after the last
edition of this text was published. This technique uses direct intravitreal
injections of chemotherapeutic drugs, usually the alkylating agent
melphalan, to treat vitreous seeds of retinoblastoma, which are one of the
most important causes of treatment failure and lost eyes. In the past,
clinicians were cautioned not to stick needles in eyes containing
retinoblastoma because the risk of extraocular extension and orbital
dissemination was considered high. Such complications have not been
encountered, however, because the new intravitreal injection technique
incorporates safeguards including multiple cycles of postinjection freeze–
thaw cryotherapy to the injection site.
In developed countries, retinoblastoma is one of the great success
stories of pediatric ocular oncology. Survival rates from the primary tumor
approach 100% at major centers, and secondary tumors are now the
primary cause of death. Unfortunately, this is not the case in developing
countries, where patients frequently present with advanced stages of the
disease and therapy generally is palliative (Fig. 12-2).

THE DIFFERENTIAL DIAGNOSIS OF

RETINOBLASTOMA
Retinoblastoma must be differentiated clinically from a variety of benign
childhood disorders that cause leukocoria. The three most common
conditions that are confused with retinoblastoma are ocular toxocariasis,
persistent fetal vasculature (PFV), and Coats disease (see Table 12-2).

Table 12-2 The Differential Diagnosis of Retinoblastoma

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TOXOCARIASIS
Ocular toxocariasis, particularly the nematode endophthalmitis form of the
disorder, is the most common inflammatory disease that simulates
retinoblastoma (Fig. 12-19A). Ocular toxocariasis is a localized ocular
manifestation of visceral larva migrans caused by second-stage larvae of
the canine ascarid Toxocara canis. Ocular toxocariasis usually is unilateral
and occurs in children toward the end of the first decade. Diffuse
nematode endophthalmitis, retinal detachment, or an eosinophilic abscess
located anteriorly in the vitreous can cause leukocoria. Subfoveal
granulomas occasionally present with visual loss in eyes with clear media.
Histopathology discloses necrotic larval fragments surrounded by
granulomatous inflammation containing many eosinophils (Fig. 12-16A).
Serial sections may be necessary to demonstrate the parasite in a
presumptive eosinophilic abscess. Clinically, an ELISA test for Toxocara
antigen excludes the diagnosis if it is negative. A positive ELISA test does
not exclude retinoblastoma, however, because antibodies to T. canis are
common in some populations.

627
 FIG. 12-19. A. Ocular toxocariasis. Arrow points to fragment of nematode in
eosinophilic abscess. B. Incontinentia pigmenti. Enucleated eye has total retinal
detachment caused by florid vitreoretinal neovascularization. Fellow eye had
nonperfusion of the peripheral retina. Patient had characteristic dermal
pigmentation. (A. H&E ×100.)

Other inflammatory diseases that occasionally are misdiagnosed as

retinoblastoma include endogenous endophthalmitis, congenital
toxoplasmosis, cytomegalovirus retinitis, herpes simplex virus retinitis,
and peripheral uveoretinitis.

PERSISTENT FETAL
VASCULATURE/PERSISTENT
HYPERPLASTIC PRIMARY
VITREOUS (PHPV)
Persistent fetal vasculature (PFV)/persistent hyperplastic primary vitreous
(PHPV) is an extremely common variety of pseudoretinoblastoma (Fig.
12-20). A congenital anomaly, PFV/PHPV is present at birth. Although
exceptions have been reported, PFV/PHPV classically occurs in a
microphthalmic eye that has a shallow anterior chamber and a clear lens.
The disorder usually is unilateral. Histopathologically, a plaque of
fibrovascular tissue that resembles primary vitreous adheres to the
posterior lens capsule, and the hyaloid artery is often patent. The tips of
the ciliary processes typically adhere to the margins of the retrolenticular
plaque. As the eye enlarges, the processes are drawn centrally and
elongated. Visible behind the clear lens through a dilated pupil, these
inwardly drawn ciliary processes are a helpful diagnostic sign (Fig. 12-
20A). Abnormal shunt vessels often traverse the iridic surface, and other

628
parts of the fetal vasculature may persist.

FIG. 12-20. Persistent fetal vasculature. A. Inwardly drawn ciliary processes

adhere to the margin of vascularized retrolental fibrous plaque. The lesion was
present at birth, and the affected eye was microphthalmic. B. Long attenuated
ciliary process (arrow) attaches to margin of fibrous plaque on posterior surface
of lens. An anterior subcapsular cataract also is present. (B. H&E ×5.)

PFV/PHPV may occur in isolation or in association with other ocular

abnormalities. It is a common finding in eyes with trisomy 13. Rare cases
have been reported in which both PFV/PHPV and retinoblastoma have
occurred together, either ipsilaterally or contralaterally. The posterior lens
capsule is interrupted in some cases. This occasionally leads to cataract
formation and may allow mesenchymal tissue to invade the interior of the
lens. Intraocular adipose tissue and even bone have been reported
histopathologically. Approximately one fifth (10/47) of eyes with
PFV/PHPV contain mature adipose tissue. Goldberg suggested that PFV is
a more appropriate for this disorder, which Reese initially called PHPV.
Other congenital or developmental disorders occasionally confused
with retinoblastoma include juvenile retinoschisis, dominant exudative
vitreoretinopathy, congenital retinal fold, the morning glory disk anomaly,
idiopathic retinal vascular hypoplasia, and coloboma.

COATS DISEASE
Simulating lesions that produce retinal detachment are often confused with
exophytic retinoblastoma. Coats disease is a classic example (Figs. 12-21
and 12-22). Coats disease is marked by an exudative retinal detachment
caused by leakage of fluid from abnormal telangiectatic retinal vessels.
Often called Leber miliary aneurysms, these fusiform or saccular “light
bulb” venous dilatations tend to involve the temporal parafoveal quadrant

629
of the retina and are especially common superotemporally. Intravenous
fluorescein angiography typically discloses an area of capillary
nonperfusion adjacent to the abnormal vessels (Fig. 12-21C). Some cases
may present with decreased vision due to macular exudation.

FIG. 12-21. Xanthocoria, Coats disease. A. Yellow pupillary reflex or

xanthocoria is caused by lipid-rich subretinal fluid. B. Clumps of exudate adhere
to posterior surface of totally detached retina. A focus of abnormal vessels is
evident centrally. C. Intravenous fluorescein angiography discloses abnormal
retinal vasculature including aneurysmal dilatations and areas of capillary
nonperfusion. D. Thick honey-colored subretinal fluid in sectioned eye contains
numerous sparkling crystals of cholesterol.

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 FIG. 12-22. Coats disease, histopathology. A. Abnormal telangiectatic vessels
are evident in the detached retina directly behind the lens. These leaky vessels
have caused an exudative retinal detachment. Yellowish lipid-rich subretinal fluid
produces xanthocoria instead of leukocoria. Coats disease may simulate an
exophytic retinoblastoma. B. The totally detached retina adheres to the back of
the lens and the pars plana. The lens–iris diaphragm is displaced forward
obliterating the anterior chamber and closing the angle. The yellow subretinal
exudate contains cholesterol crystals and aggregates of lipid-laden histiocytes.
The glaucomatous eye was enucleated because it was blind and painful and there
was concern about a possible retinoblastoma. C. Many large abnormal retinal
vessels are present. The outer two thirds of the retina is massively thickened by
eosinophilic exudates. D. The eosinophilic, densely proteinaceous subretinal fluid
contains slit-like cholesterol clefts and foamy histiocytes that have ingested lipid.
(C. H&E ×50, D. H&E ×100.)

Coats disease usually is unilateral, and two thirds of cases occur in boys.
Although most cases are diagnosed in the second half of the first decade
(age 4 to 10 years), the disease can affect children between 18 months and
18 years.
Macroscopically, enucleated eyes with Coats disease have a high
bullous retinal detachment that typically abuts the back surface of the lens
and ciliary body (Figs. 12-21A,B and 12-22A,B). The lens–iris diaphragm
is displaced anteriorly, causing secondary closed-angle glaucoma via a

631
pupillary block mechanism. The yellow, gelatinous subretinal fluid
contains glistening crystals of cholesterol. Affected patients may have
xanthocoria, a yellowish pupillary reflex (Figs. 12-21A and 12-22A). In
rare instances, the lipid-rich subretinal fluid has entered the anterior
chamber through defects in the retina and anterior vitreous.
Histopathologically, parts of the inner retina contain an increased
number of large telangiectatic vessels. The outer retinal layers are
massively thickened by exudates, which appear as pools of eosinophilic
material (Fig. 12-22C). The densely proteinaceous and lipid-rich subretinal
fluid contains aggregates of foamy histiocytes and empty clefts that
contained free, rhomboidal, crystals of cholesterol that were dissolved by
lipid solvents during processing (Figs. 12-21D and 12-22D).
A Coats disease–like picture may occur in patients who have
facioscapulohumeral muscular dystrophy caused by a partial deletion of
chromosome 4q35. This association should be considered if both eyes are
affected. Cases of Coats disease that have mutations in the NPD gene that
encodes norrin have been reported.

RETINOPATHY OF PREMATURITY
Organization or fibrosis of the vitreous (e.g., cyclitic membrane
formation), which may lead to tractional retinal detachment, occurs in
several conditions that simulate retinoblastoma, including retinopathy of
prematurity (ROP) (Fig. 12-23). The term retrolental fibroplasia, originally
applied to this largely iatrogenic disorder, emphasizes the causal role of
vitreous organization in the tractional retinal detachment that complicates
its final stages. ROP usually is bilateral and rarely is present at birth, two
features it shares with retinoblastoma. ROP usually develops in premature
infants who have received supplemental oxygen therapy. Infants born at a
gestational age of <32 weeks or weighing <1,500 g at birth are at risk for
developing ROP. However, occasional cases have been reported in full-
term infants and in premature infants who did not receive oxygen therapy.
Vascular proliferation and secondary vitreous fibrosis are thought to result
from the effect of increased oxygen levels on the immature, incompletely
vascularized retina. ROP typically arises in the temporal quadrant of the
retina, because the temporal retina usually is not completely vascularized
at term, especially in premature infants.

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FIG. 12-23. Retinopathy of prematurity. A. Macrophoto shows band of
vitreoretinal neovascularization bordering nonvascularized temporal periphery of
retina. B. Arrow points to new vessels in photomicrograph. The peripheral part of
the retina (at right) is avascular. C. Fibrovascular proliferation has led to the
formation of a mass of folded retina in the temporal periphery behind the lens.
The eye was obtained postmortem from a premature infant who had received
supplemental oxygen. D. Photomicrograph shows folded retina comprising mass
shown grossly in figure C. E. Retinal traction causes dragging of optic disk. F.
Disk is dragged temporally toward the mass of folded retina. (B. H&E ×25, D.
H&E ×10, F. H&E ×10.)

Experiments performed in newborn kittens suggest that excessive oxygen

induces transient vasoconstriction, subsequent dilatation, and ultimately
vaso-obliteration of immature retinal vessels. Retinal neovascularization
may be a response of the vanguard of primitive, vasoformative spindle

633
cells in the nonvascularized peripheral retina to elevated oxygen levels. In
the early active stages of ROP, a band of glomeruloid capillaries
proliferates at the junction between the peripheral nonperfused and the
posterior perfused retina (Fig. 12-23A,B). The proliferating vessels break
through the ILM and invade the vitreous, inciting fibrosis and contraction.
In the later cicatricial stages of ROP, the retina is folded on itself by the
organized vitreous, forming a fibroneural mass that drags the macula and
optic disc temporally (Fig. 12-23C–F). The end stage of the disease is
marked by total retinal detachment, leukocoria, blindness, and phthisis
bulbi.

Retinal Detachment
Retinal detachment in childhood can be confused with retinoblastoma, and
vice versa. The possibility of an underlying retinoblastoma should always
be considered when a child presents with retinal detachment and vitreous
hemorrhage, even when a history of trauma is obtained. Appropriate
preoperative studies (ultrasonography or computed tomography) are
indicated. If vitrectomy is performed, the specimen should be submitted
for cytologic examination. Clinicians must recall that retinoblastoma
occasionally presents in older children who may have the diffuse
infiltrative form of retinoblastoma. In addition, retinoblastoma or
medulloepithelioma must be ruled out in any infant or child with NVG.
NVG in a child is a neoplasm until proven otherwise. Finally, the
ophthalmologist always should recall the association between retinal
detachment and child abuse.

Incontinentia Pigmenti (Bloch-

Sulzberger)
Peripheral vascular abnormalities, which are believed to cause vitreoretinal
neovascularization and secondary retinal detachment and leukocoria, occur
in females who have incontinentia pigmenti or the Bloch-Sulzberger
syndrome. This rare multisystem disorder has an X-linked dominant
inheritance. Normal males die in utero, but the disorder has been reported
in males with Klinefelter syndrome (XXY) or XXY mosaicism. Affected
female infants develop vesiculobullous skin lesions on the trunk and
extremities at birth or shortly thereafter. The bullae contain many
eosinophils, and systemic eosinophilia is often present. The term

634
incontinentia pigmenti refers to the incontinence, or loss, of melanin from
epidermal basal cells. The pigment collects in the dermis as free granules
or as aggregates of melanophages. Clinically, the affected skin has a
characteristic marbleized or whorl-like pattern of pigmentation. Other
manifestations of the syndrome include alopecia, dental anomalies (late
dentition, absent or misshapen teeth), and central nervous system
abnormalities (seizures, mental retardation).
Ocular findings occur in approximately one third of patients and
include strabismus (18.2%) and pseudoglioma caused by a retrolental mass
of organized, chronically detached retina (15.4%). The latter probably is
caused by vitreoretinal neovascularization spawned by peripheral retinal
avascularity (Fig. 12-19B). Histopathologic examination, limited to “end-
stage” eyes enucleated as possible retinoblastomas, has revealed relatively
nonspecific findings.
Incontinentia pigmenti is caused by mutations in the NEMO/IKK
gamma gene (IKBKG) on Xq28, which interferes with NF-kappa B
activation. The NEMO gene activates the eosinophil chemokine eotaxin.
There is a single report of retinoblastoma arising in a patient with
incontinentia pigmenti.

Norrie Disease
Norrie disease, or the progressive oculoacousticocerebral degeneration of
Norrie, is a rare, X-linked recessive heritable disorder characterized by
bilateral leukocoria caused by retrolental masses of detached, malformed
retina. Affected boys classically have a triad of blindness, deafness, and
progressive mental retardation. Apparent at birth or in early infancy, the
ocular findings usually progress to phthisis bulbi. An identical disorder
found in a Cypriot kindred is called Episkopi blindness.
The Norrie disease gene NDP is located on the short arm of the X
chromosome (Xp11.4). The gene’s protein product norrin regulates
vascular development in the retina by binding to the Wnt receptor
Frizzled4. Mutations in the norrin gene have been found in patients with
other heritable retinal disorders including X-linked exudative
vitreoretinopathy, and abnormalities in the norrin/Frizzled4 signaling
pathway may predispose some premature infants to develop severe ROP.

Retinal Dysplasia and Trisomy 13

635
In the broadest sense, retinal dysplasia refers to an aberrant proliferation of
the developing retina as branching tubules that communicate with the
subretinal space. In routine histologic sections, such tubules appear as
dysplastic rosettes. Variable in appearance, dysplastic rosettes generally
are larger than the neoplastic Flexner-Wintersteiner rosettes of
retinoblastoma and usually are composed of multiple retinal layers (Fig. 2-
1C).
Retinal dysplasia and PFV/PHPV are characteristic ocular findings in
trisomy 13; in fact, trisomy 13 was called retinal dysplasia before the
chromosomal defect was identified. The multitude of systemic and ocular
findings found in patients with trisomy 13 may include bilateral
leukocoria. Rarely, retinal dysplasia occurs unilaterally in the congenitally
malformed eyes of otherwise healthy persons.

Medulloepithelioma and Other Pediatric

Intraocular Tumors
Embryonal medulloepithelioma is the second most common primary
intraocular tumor of childhood (Fig. 12-24). This rare intraocular
neoplasm is thought to arise from congenital rests or anlagen of the
embryonic medullary epithelium, which normally lines the forebrain and
optic vesicle. Embryonal medulloepithelioma is also called diktyoma.
Fuchs applied that term to an early case of the tumor that had an
interlacing, net-like pattern of neuroepithelial cells, but the diktyomatous
pattern is actually uncommon. Intraocular medulloepitheliomas bear a
resemblance to certain embryonal tumors of the central nervous system
that are composed of multilayered rosettes that are also called
medulloepitheliomas. Molecular genetic studies have confirmed that they
are distinct entities.

636
FIG. 12-24. Medulloepithelioma. A. Teratoid medulloepithelioma. Superonasal
ciliary body mass contains white foci of hyaline cartilage. A delicate cyclitic
membrane is present. (From Shields JA, Eagle, RC Jr, Shields CL, et al.
Fluorescein angiography and ultrasonography of malignant intraocular
medulloepithelioma. J Pediatr Ophthalmol Strabismus 1996;33:193–196.) B.
Macrophoto of ciliary body tumor shown in figure A. C. Centered on the inner
surface of the ciliary body, this medulloepithelioma is composed of cords of
neuroepithelial cells resembling the primitive medullary epithelium. The
epithelial elements are surrounded by loose stroma resembling embryonal
mesenchyme. Several tumor cysts are present. A sheet of tumor extends
anteriorly to envelop the lens at right. D. Nonteratoid medulloepithelioma
contains thick bands of polarized neuroepithelium that resemble embryonic
medullary epithelium. E. The tumor contains pools of vitreous-like material that
stain vividly (blue) for AMP. Pretreatment with hyaluronidase abolishes the
staining indicating that the mucin is hyaluronic acid, a major component of the

637
 vitreous humor. The medulloepithelioma rests on the inner surface of the ciliary
epithelium above. F. Teratoid medulloepitheliomas contains heteroplastic
elements including hyaline cartilage, striated muscle, rhabdomyoblasts, and brain.
This tumor contains prominent lobules of neoplastic cartilage. Cords and ribbons
of neuroepithelial cells are seen in the myxoid stroma at right. (C. H&E ×5, D.
H&E ×50, E. Colloidal iron ×50, F. H&E ×25.)

Embryonal medulloepithelioma presents most often with poor vision or

blindness (39%), pain (30%), an iris or ciliary body mass (18%), or
leukocoria (18%). In some cases, the tumor is an unexpected, incidental
finding in a blind, painful eye that has been enucleated or eviscerated.
Although the average age at presentation is about 4 years, treatment often
is delayed; thus, the median age at surgery and histopathologic diagnosis is
5 years. Unusual presentations include cataract and multiple translucent
neoplastic cysts in the posterior or anterior chamber. Intratumoral cysts,
which may be helpful diagnostic clues on ultrasonography, are present in
61% of patients and lens “colobomas” caused by segmental loss of zonular
fibers in 20%. In half, the tumor stroma forms a diaphanous neoplastic
cyclitic membrane behind the lens. Forty-four percent have secondary
glaucoma, and 50% have neovascularization of the iris. The author has
seen several cases of medulloepitheliomas in children who had NVG and
were treated with tube shunts. Tumor cells were present in the epibulbar
reservoir in one of these cases. NVG in a child is a tumor until proven
otherwise
Histopathologically, medulloepithelioma is composed of tubules,
cords, and bands of polarized neuroectodermal cells that resemble
neoplastic medullary epithelium (Fig. 12-24D). Although Homer Wright
and Flexner-Wintersteiner rosettes can be observed within retinoblastoma-
like foci in malignant medulloepitheliomas, most rosettes in
medulloepithelioma are larger and are composed of multiple layers of
elongated neuroepithelial cells, which closely resemble the embryonic
ciliary epithelium. The lumina of the rosettes and slit-like structures
formed by the polarized epithelium correspond to the subretinal space. The
outer side is lined by a basement membrane analogous to the retina’s ILM.
Tumors often contain pools of loose, mesenchymal stroma rich in
hyaluronic acid (Fig. 12-24E). This “neoplastic vitreous” typically adheres
to the side of the neuroepithelium that is lined by basement membrane.
Medulloepitheliomas are classified as benign or malignant and teratoid
or nonteratoid. Teratoid medulloepitheliomas contain heteroplastic
elements such as hyaline cartilage, rhabdomyoblasts, or brain-like tissue

638
(Fig. 12-24A,B,F). Slightly more than one third (37.5%) of tumors are
teratoid. Two thirds of the medulloepitheliomas in Broughton and
Zimmerman’s series of 56 cases from the Armed Forces Institute of
Pathology were malignant. Histologic criteria for malignancy include (1)
areas of poorly differentiated neuroblastic cells resembling those of
retinoblastoma, (2) pleomorphism and mitotic activity, (3) a sarcomatous
appearance of the stroma, and (4) aggressive behavior evidenced by
intraocular invasion of the uvea, cornea, sclera, or optic nerve, with or
without extrascleral extension. Malignant medulloepitheliomas are more
likely to be teratoid. Although typically a ciliary body tumor,
medulloepithelioma occasionally arises from the retina or optic nerve.
Direct intracranial invasion is responsible for most deaths and occurs in
cases with extraocular extension and orbital spread. Three of 41 cases
reported by Kaliki et al. developed metastases. All had extraocular
extension due to delayed diagnosis. Enucleation is the treatment of choice
because there is a high incidence of recurrence after local resection. Rare
cases in adults have been reported. Embryonal medulloepithelioma is a
rare manifestation of the pleuropulmonary blastoma syndrome caused by
germline mutations in the DICER1 gene on 14q31.

Astrocytic Lesions
Other rare intraocular neoplasms that present in childhood can be confused
with retinoblastoma clinically. These include astrocytomas and astrocytic
hamartomas of the retina and a reactive, nonneoplastic proliferation of
retinal glial cells. The latter, termed massive gliosis, has a variety of
causes, usually is unsuspected clinically, and is diagnosed
histopathologically. Massive gliosis usually is found incidentally during
the histopathologic examination of a blind and painful or phthisical eye.
Retinal astrocytic hamartomas or astrocytomas (Fig. 12-25) usually are
found in patients with tuberous sclerosis complex or von Recklinghausen
neurofibromatosis. Astrocytic lesions occur in more than 50% of cases of
tuberous sclerosis complex. Most are small, slow-growing astrocytic
hamartomas. These vary from small, semitranslucent plaques of the nerve
fiber layer to elevated, partially calcified nodules. The accumulation of
calcospherites often imparts a mulberry-like appearance to the nodules.
Larger, progressive retinal tumors that resemble subependymal giant cell
astrocytomas of the brain histopathologically occur rarely (Fig. 2-9). These
often affect the posterior retina and are readily confused with

639
retinoblastoma clinically. The term giant drusen of the optic nerve has
been applied to astrocytomas located in the prelaminar part of the disc.

FIG. 12-25. Acquired astrocytoma. A. White, smooth-surfaced retinal tumor

obscures underlying optic nerve. B. Epipapillary retinal tumor is composed of
bland glial cells with a spindled configuration seen at higher magnification in
inset. C. The cells were immunoreactive for GFAP. Patient had no history or
stigmata of tuberous sclerosis complex or neurofibromatosis. (B. H&E ×25, C.
H&E ×100.)

Glioneuroma is an extremely rare anterior segment tumor that arises from

the anterior lip of the optic cup; it actually may be a choristomatous
malformation. Histopathologically, glioneuroma contains both glial and
neuronal-like cells and has a brain-like appearance. In contrast to
retinoblastoma that has invaded the anterior chamber, glioneuroma is a
more distinct, cohesive mass.
A primitive neuroectodermal tumor of the retina with melanocytic
differentiation has been reported. This “retinal melanoma” was
misdiagnosed clinically as retinoblastoma. Frenkel has reported multiple
benign intraocular teratomas in an infant with a benign sacrococcygeal
teratoma.

Other Simulating Lesions

Cataract, congenital corneal opacities, colobomas, and myelinated nerve
fibers also are included in the differential diagnosis of retinoblastoma.
Although leukocoria caused by cataract should be obvious to the
ophthalmologist, infants with retinoblastoma have undergone cataract
surgery with fatal outcomes. Cataracts are rare in eyes with
retinoblastoma. Most develop in eyes with extensive intraocular necrosis.

640
Necrosis of the ciliary epithelium may also cause spontaneous dislocation
of the lens in such eyes.
Corneal opacities or white pupillary reflexes caused by choroidal
colobomas or myelinated nerve fibers understandably could confound the
pediatrician or a general physician unskilled at ophthalmoscopy. The
author recently processed an eye with a retinoblastoma that was initially
misdiagnosed as a coloboma. Such lesions should be easily diagnosed by
an ophthalmologist, however.

BIBLIOGRAPHY
Epidemiology
Abramson DH. Retinoblastoma incidence in the United States. Arch Ophthalmol
1990;108:1514.
al-Idrissi I, al-Kaff AS, Senft SH. Cumulative incidence of retinoblastoma in
Riyadh, Saudi Arabia. Ophthalmic Paediatr Genet 1992;13:9–12.
BenEzra D, Chirambo MC. Incidence of retinoblastoma in Malawi. J Pediatr
Ophthalmol 1976;13:340–343.
Berkow RL, Fleshman JK. Retinoblastoma in Navajo Indian children. Am J Dis
Child 1983;137:137–138.
Devesa SS. The incidence of retinoblastoma. Am J Ophthalmol 1975;80:263–265.
Freedman J, Goldberg L. Incidence of retinoblastoma in the Bantu of South
Africa. Br J Ophthalmol 1976;60:655–656.
Kivelä T. The epidemiological challenge of the most frequent eye cancer:
retinoblastoma, an issue of birth and death. Br J Ophthalmol
2009;93:1129–1131.
Kock E, Naeser P. Retinoblastoma in Sweden 1958–1971. A clinical and
histopathological study. Acta Ophthalmol (Copenh) 1979;57:344–350.
Mietz H, Hutton WL, Font RL. Unilateral retinoblastoma in an adult: report of a
case and review of the literature. Ophthalmology 1997;104:43–47.
Orjuela MA, Titievsky L, Liu X, et al. Fruit and vegetable intake during
pregnancy and risk for development of sporadic retinoblastoma. Cancer
Epidemiol Biomarkers Prev 2005;14:1433–1440.
Shields JA, Michelson JB, Leonard BC, et al. Retinoblastoma in an eighteen-
year-old male. J Pediatr Ophthalmol 1976;13:274–277.
Shields CL, Shields JA, Shah P. Retinoblastoma in older children. Ophthalmology
1991;98:395–399.
Tarkkanen A, Tuovinen E. Retinoblastoma in Finland 1912–1964. Acta
Ophthalmol (Copenh) 1971;49:293–300.
Verhoeff FH. A Retinoblastoma in a man aged forty-eight Years. Trans Am
Ophthalmol Soc 1929;27:176–188.

641
Clinical Features
Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J
Pediatr 1998;132:505–508.
Abramson DH, Gombos DS. The topography of bilateral retinoblastoma lesions.
Retina 1996;16:232–239.
Bhatnagar R, Vine AK. Diffuse infiltrating retinoblastoma. Ophthalmology
1991;98:1657–1661.
Byrnes GA, Shields CL, Shields JA, et al. Retinoblastoma presenting with
spontaneous hyphema and dislocated lens. J Pediatr Ophthalmol Strabismus
1993;30:334–336.
De Buen S. Retinoblastoma with spread by direct continuity to the contralateral
optic nerve: report of a case. Am J Ophthalmol 1960;49:815–819.
Fontanesi J, Pratt C, Meyer D, et al. Asynchronous bilateral retinoblastoma: the
St. Jude Children’s Research Hospital experience. Ophthalmic Genet
1995;16:109–112.
Gallenga PE, Mancini A, Di Bastiano W, et al. Congenital retinoblastoma:
appearance of calcifications during short-term follow-up. Ophthalmologica
1998;212(suppl 1):61–64.
Grossniklaus HE. Retinoblastoma. Fifty years of progress. The LXXI Edward
Jackson Memorial Lecture. Am J Ophthalmol 2014;158(5):875–891.
Morgan G. Diffuse infiltrating retinoblastoma. Br J Ophthalmol
1971;55:600–606.
Nicholson DH, Norton EW. Diffuse infiltrating retinoblastoma. Trans Am
Ophthalmol Soc 1980;78:265–289.
Plotsky D, Quinn G, Eagle R Jr, et al. Congenital retinoblastoma: a case report. J
Pediatr Ophthalmol Strabismus 1987;24:120–123.
Rubenfeld M, Abramson DH, Ellsworth RM, et al. Unilateral vs. bilateral
retinoblastoma. Correlations between age at diagnosis and stage of ocular
disease. Ophthalmology 1986;93:1016–1019.
Schofield PB. Diffuse infiltrating retinoblastoma. Br J Ophthalmol
1960;44:35–41.
Shields JA, Shields CL, Eagle RC, et al. Spontaneous pseudohypopyon secondary
to diffuse infiltrating retinoblastoma. Arch Ophthalmol 1988;106:1301–1302.
Shields JA, Shields CL, Eagle RC, et al. Calcified intraocular abscess simulating
retinoblastoma. Am J Ophthalmol 1992;114:227–229.
Shields JA, Shields CL, Eagle RC Jr, et al. Endogenous endophthalmitis
simulating retinoblastoma. The 1993 David and Mary Seslen Endowment
Lecture. Retina 1995;15:213–219.
Shields JA, Shields CL, Suvarnamani C, et al. Retinoblastoma manifesting as
orbital cellulitis. Am J Ophthalmol 1991;112:442–449.
Spaulding G. Rubeosis iridis in retinoblastoma and pseudoglioma. Trans Am
Ophthalmol Soc 1978;76:584–609.
Stafford WR, Yanoff M, Parnell BL. Retinoblastomas initially misdiagnosed as

642
 primary ocular inflammations. Arch Ophthalmol 1969;82:771–773.
Takahashi T, Tamura S, Inoue M, et al. Retinoblastoma in a 26-year-old adult.
Ophthalmology 1983;90:179–183.
Verhoeff FH, Jackson E. Minutes of proceedings, 62nd annual meeting. Trans Am
Ophthalmol Soc 1926;24:38.
Walton DS, Grant WM. Retinoblastoma and iris neovascularization. Am J
Ophthalmol 1968;65:598–599.
Yoshizumi MO, Thomas JV, Smith TR. Glaucoma-inducing mechanisms in eyes
with retinoblastoma. Arch Ophthalmol 1978;96:105–110.
Zimmerman LE. Retinoblastoma, including a report of illustrative cases. Med Ann
Dist Columbia 1969;38:366–374.

Histopathology and Ultrastructure

Albert DM, Craft J, Sang DN. Ultrastructure of retinoblastomas: transmission and
scanning electron microscopy. In: Jakobiec FA, ed. Ocular and Adnexal
Tumors. Birmingham, AL: Aesculapius, 1978:157–171.
Bunt AH, Tso MO. Feulgen-positive deposits in retinoblastoma. Incidence,
composition, and ultrastructure. Arch Ophthalmol 1981;99:144–150.
Burnier MN, McLean IW, Zimmerman LE, et al. Retinoblastoma. The
relationship of proliferating cells to blood vessels. Invest Ophthalmol Vis Sci
1990;31:2037–2040.
Datta BN. DNA coating of blood vessels in retinoblastomas. Am J Clin Pathol
1974;62:94–96.
Kyritsis AP, Tsokos M, Triche TJ, et al. Retinoblastoma: a primitive tumor with
multipotential characteristics. Invest Ophthalmol Vis Sci 1986;27:1760–1764.
Loeffler KU, McMenamin PG. An ultrastructural study of DNA precipitation in
the anterior segment of eyes with retinoblastoma. Ophthalmology
1987;94:1160–1168.
Madhavan J, Ganesh A, Roy J, et al. The relationship between tumor cell
differentiation and age at diagnosis in retinoblastoma. J Pediatr Ophthalmol
Strabismus 2008;45:22–25.
Mullaney J. Retinoblastomas with DNA precipitation. Arch Ophthalmol
1969;82:454–456.
Nork TM, Millecchia LL, de Venecia GB, et al. Immunocytochemical features of
retinoblastoma in an adult. Arch Ophthalmol 1996;114:1402–1406.
Nork TM, Schwartz TL, Doshi HM, et al. Retinoblastoma. Cell of origin Arch
Ophthalmol 1995;113:791–802.
Pe’er J, Neufeld M, Baras M, et al. Rubeosis iridis in retinoblastoma. Histologic
findings and the possible role of vascular endothelial growth factor in its
induction. Ophthalmology 1997;104:1251–1258.
Popoff NA, Ellsworth RM. The fine structure of retinoblastoma. In vivo and in
vitro observations. Lab Invest 1971;25:389–402.
Spaulding, G. Rubeosis iridis and retinoblastoma and pseudoglioma. Trans Am

643
 Ophthalmol Soc. 1978;76:584–609.
Stowe GCd, Zakov ZN, Albert DM, et al. Vascular basophilia in ocular and
orbital tumors. Invest Ophthalmol Vis Sci 1979;18:1068–1075.
Ts’o MO, Fine BS, Zimmerman LE. The Flexner-Wintersteiner rosettes in
retinoblastoma. Arch Pathol 1969;88:664–671.
Ts’o MO, Fine BS, Zimmerman LE. The nature of retinoblastoma. II.
Photoreceptor differentiation: an electron microscopic study. Am J
Ophthalmol 1970;69:350–359.
Ts’o MO, Zimmerman LE, Fine BS, et al. A cause of radioresistance in
retinoblastoma: photoreceptor differentiation. Trans Am Acad Ophthalmol
Otolaryngol 1970;74:959–969.
Ts’o MO, Zimmerman LE, Fine BS. The nature of retinoblastoma. I.
Photoreceptor differentiation: a clinical and histopathologic study. Am J
Ophthalmol 1970;69:339–349.
Tsokos M, Kyritsis AP, Chader GJ, et al. Differentiation of human retinoblastoma
in vitro into cell types with characteristics observed in embryonal or mature
retina. Am J Pathol 1986;123:542–552.
Vrabec T, Arbizo V, Adamus G, et al. Rod cell-specific antigens in
retinoblastoma. Arch Ophthalmol 1989;107:1061–1063.
Walton DS, Grant WM. Retinoblastoma and iris neovascularization. Am J
Ophthalmol 1968;65:598–599.
Yoshizumi MO, Thomas JV, Smith TR. Glaucoma-inducing mechanisms in eyes
with retinoblastoma. Arch Ophthalmol 1978;96:105–110.
Yuge K, Nakajima M, Uemura Y, et al. Immunohistochemical features of the
human retina and retinoblastoma. Virchows Arch 1995;426:571–575.

Risk Factors for Metastasis

Biswas J, Das D, Krishnakumar S, et al. Histopathologic analysis of 232 eyes
with retinoblastoma conducted in an Indian tertiary-care ophthalmic center. J
Pediatr Ophthalmol Strabismus 2003;40:265–267.
Brennan RC, Qaddoumi I, Billups CA, et al. Comparison of high-risk
histopathological features in eyes with primary or secondary enucleation for
retinoblastoma. Br J Ophthalmol 2015;99(10):1366–1371.
Carbajal UM. Metastasis in retinoblastoma. Am J Ophthalmol 1959;48:47–69.
Chantada GL, Dunkel IJ, de Dávila MT, et al. Retinoblastoma patients with high-
risk ocular pathological features: who needs adjuvant therapy? Br J
Ophthalmol 2004;88:1069–1073.
Chévez-Barrios P. Pathology of high-risk retinoblastoma. In: Ramasubrahmanian
A, Shields CL, eds. Retinoblastoma. New Delhi, India: Jaypee:223–230.
Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a
retrospective histopathologic study. Arch Pathol Lab Med
2009;133:1203–1209.
Kaliki S, Srinivasan V, Gupta A, et al. Clinical features predictive of high-risk

644
 retinoblastoma in 403 Asian Indian patients: a case-control study.
Ophthalmology 2015;122(6):1165–1172.
Kapatai G, Brundler MA, Jenkinson H, et al. Gene expression profiling identifies
different sub-types of retinoblastoma. Br J Cancer 2013;109(2):512–525.
Khelfaoui F, Validire P, Auperin A, et al. Histopathologic risk factors in
retinoblastoma: a retrospective study of 172 patients treated in a single
institution. Cancer 1996;77:1206–1213.
Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors
for metastasis in retinoblastoma treated by enucleation. Ophthalmology
1987;94:371–377.
Lennox EL, Draper GJ, Sanders BM. Retinoblastoma: a study of natural history
and prognosis of 268 cases. Br Med J 1975;3:731–734.
MacKay CJ, Abramson DH, Ellsworth RM. Metastatic patterns of retinoblastoma.
Arch Ophthalmol 1984;102:391–396.
Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in
retinoblastoma. Ophthalmology 1989;96:217–222.
McLean IW, Rosenberg SH, Messmer EP, et al. Prognostic factors in cases of
retinoblastoma: analysis of 974 patients from Germany and the United States
treated by enucleation. In: Bornfeld N, Gragoudas ES, Lommatzsch PK, eds.
Tumors of the Eye. Proceedings of the International Symposium on Tumors of
the Eye. Amsterdam, the Netherlands: Kugler Publications, 1991:69–72.
Mendoza PR, Specht CS, Hubbard GB, et al. Histopathologic grading of
anaplasia in retinoblastoma. Am J Ophthalmol 2015;159(4):764–776.
Messmer EP, Heinrich, T, Hopping W. Risk factors for metastases in patients
with retinoblastoma. Ophthalmology 1991;98:136–141.
Redler LD, Elllsworth RM. Prognostic importance of choroidal invasion in
retinoblastoma. Arch Ophthalmol 1973;90:294–296.
Rootman J, Ellsworth RM, Hofbauer J, et al. Orbital extension of retinoblastoma:
a clinicopathological study. Can J Ophthalmol 1978;13:72–80.
Rootman J, Hofbauer J, Ellsworth RM, et al. Invasion of the optic nerve by
retinoblastoma: a clinicopathological study. Can J Ophthalmol
1976;11:106–114.
Rubin CM, Robison LL, Cameron JD, et al. Intraocular retinoblastoma group V:
an analysis of prognostic factors. J Clin Oncol 1985;3:680–685.
Shields CL, Shields JA, Baez KA, et al. Choroidal invasion of retinoblastoma:
metastatic potential and clinical risk factors. Br J Ophthalmol
1993;77:544–548.
Sastre X, Chantada GL, Doz F, et al. Proceedings of the consensus meetings from
the International Retinoblastoma Staging Working Group on the pathology
guidelines for the examination of enucleated eyes and evaluation of
prognostic risk factors in retinoblastoma. Arch Pathol Lab Med
2009;133:1199–1202.
Shields CL, Shields JA, Baez K, et al. Optic nerve invasion of retinoblastoma.
Metastatic potential and clinical risk factors. Cancer 1994;73:692–698.

645
Taktikos A. Investigation of retinoblastoma with special reference to histology
and prognosis. Br J Ophthalmol 1966;50:225–234.
Uusitalo MS, Van Quill KR, Scott IU, et al. Evaluation of chemoprophylaxis in
patients with unilateral retinoblastoma with high-risk features on
histopathologic examination. Arch Ophthalmol 2001;119:41–48.
Wolter JR. Retinoblastoma extension into the choroid. Pathological study of the
neoplastic process and thoughts about its prognostic significance. Ophthalmic
Paediatr Genet 1987;8:151–157.

Retinoma/Retinocytoma and Spontaneous

Regression
Aaby AA, Price RL, Zakov ZN. Spontaneously regressing retinoblastomas,
retinoma, or retinoblastoma group 0. Am J Ophthalmol 1983;96:315–320.
Abramson DH. Retinoma, retinocytoma, and the retinoblastoma gene [editorial].
Arch Ophthalmol 1983;101:1517–1518.
Andersen SR, Jensen OA. Retinoblastoma with necrosis of central retinal artery
and vein and partial spontaneous regression. Acta Ophthalmol (Copenh)
1974;52:183–193.
Balmer A, Munier F, Gailloud C. Retinoma. Case studies. Ophthalmic Paediatr
Genet 1991;12:131–137.
Boniuk M, Girard LJ. Spontaneous regression of bilateral retinoblastoma. Trans
Am Acad Ophthalmol Otolaryngol 1969;73:194–198.
Demirci H, Eagle RC Jr, Shields CL, et al. Histopathologic findings in eyes with
retinoblastoma treated only with chemoreduction. Arch Ophthalmol
2003;121:1125–1131.
Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative
retinoma: increasing genomic instability correlates with progression to
retinoblastoma. Hum Mol Genet 2008;15(17):1363–1372.
Dimaras H, Khetan V, Halliday W, et al. Retinoma underlying retinoblastoma
revealed after tumor response to 1 cycle of chemotherapy. Arch Ophthalmol
2009;127:1066–1068.
Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a
retrospective histopathologic study. Arch Pathol Lab Med
2009;133:1203–1209.
Eagle RC Jr, Shields JA, Donoso L, et al. Malignant transformation of
spontaneously regressed retinoblastoma, retinoma/retinocytoma variant.
Ophthalmology 1989;96:1389–1395.
Gallie BL, Campbell C, Devlin H, et al. Developmental basis of retinal-specific
induction of cancer by RB mutation. Cancer Res 1999;59(7
suppl):1731s–1735s.
Gallie BL, Ellsworth RM, Abramson DH, et al. Retinoma: spontaneous regression
of retinoblastoma or benign manifestation of the mutation? Br J Cancer
1982;45:513–521.

646
 Gallie BL, Phillips RA, Ellsworth RM, et al. Significance of retinoma and
phthisis bulbi for retinoblastoma. Ophthalmology 1982;89:1393–1399.
Gangwar DN, Jain IS, Gupta A, et al. Bilateral spontaneous regression of
retinoblastoma with dominant transmission. Ann Ophthalmol
1982;14:479–480.
Lindley J, Smith S. Histology and spontaneous regression of retinoblastoma.
Trans Ophthalmol Soc U K 1974;94:953–967.
Margo C, Hidayat A, Kopelman J, et al. Retinocytoma. A benign variant of
retinoblastoma. Arch Ophthalmol 1983;101:1519–1531.
Singh AD, Santos CM, Shields CL, et al. Observations on 17 patients with
retinocytoma. Arch Ophthalmol 2000;118:199–205.
Ts’o MO, Fine BS, Zimmerman LE. The nature of retinoblastoma. II.
Photoreceptor differentiation: an electron microscopic study. Am J
Ophthalmol 1970;69:350–359.
Ts’o MO, Zimmerman LE, Fine BS, et al. A cause of radioresistance in
retinoblastoma: photoreceptor differentiation. Trans Am Acad Ophthalmol
Otolaryngol 1970;74:959–969.
Ts’o MO, Zimmerman LE, Fine BS. The nature of retinoblastoma. I.
Photoreceptor differentiation: a clinical and histopathologic study. Am J
Ophthalmol 1970;69:339–349.

The Retinoblastoma Gene and the Genetics of

Retinoblastoma
Albert DM, Dryja TP. Recent studies of the retinoblastoma gene. What it
means to the ophthalmologist. Arch Ophthalmol 1988;106:181–182.
Balaban G, Gilbert F, Nichols W, et al. Abnormalities of chromosome
#13 in retinoblastomas from individuals with normal constitutional
karyotypes. Cancer Genet Cytogenet 1982;6:213–221.
Balaban-Malenbaum G, Gilbert F, Nichols WW, et al. A deleted
chromosome no. 13 in human retinoblastoma cells: relevance to
tumorigenesis. Cancer Genet Cytogenet 1981;3:243–250.
Benedict WF, Murphree AL, Banerjee A, et al. Patient with 13
chromosome deletion: evidence that the retinoblastoma gene is a recessive
cancer gene. Science 1983;219:973–975.
Bookstein R, Lee WH. Molecular genetics of the retinoblastoma
suppressor gene. Crit Rev Oncog 1991;2:211–227.
Brantley MA Jr, Harbour JW. The molecular biology of
retinoblastoma. Ocul Immunol Inflamm 2001;9:1–8.
Cavenee WK, Dryja TP, Phillips RA, et al. Expression of recessive

647
alleles by chromosomal mechanisms in retinoblastoma. Nature
1983;305:779–784.
Cavenee WK, Hansen MF, Nordenskjold M, et al. Genetic origin of
mutations predisposing to retinoblastoma. Science 1985;228:501–503.
Cavenee WK, Murphree AL, Shull MM, et al. Prediction of familial
predisposition to retinoblastoma. N Engl J Med 1986;314:1201–1207.
Dryja TP, Bruns GA, Orkin SH, et al. Isolation of DNA fragments
from chromosome 13. Retina 1983;3:121–125.
Dryja TP, Cavenee W, White R, et al. Homozygosity of chromosome
13 in retinoblastoma. N Engl J Med 1984;310:550–553.
Dryja TP, Rapaport J, McGee TL, et al. Molecular etiology of low-
penetrance retinoblastoma in two pedigrees. Am J Hum Genet
1993;52:1122–1128.
Dryja TP, Rapaport JM, Weichselbaum R, et al. Chromosome 13
restriction fragment length polymorphisms. Hum Genet 1984;65:320–324.
Fitzgerald PH, Stewart J, Suckling RD. Retinoblastoma mutation rate
in New Zealand and support for the two-hit model. Hum Genet
1983;64:128–130.
Gaikwad N, Vanniarajan A, Husain A, et al. Knudson’s hypothesis
revisited in Indian retinoblastoma patients. Asia Pac J Clin Oncol
2015;11(4):299–307.
Gallie BL, Phillips RA. Retinoblastoma: a model of oncogenesis.
Ophthalmology 1984;91:666–672.
Gallie BL, Rushlow DE, Yee J, et al. A new disease: retinoblastoma
with no detectable RB1 mutations driven by MYCN. Abstract. XVth
Biannual Meeting, International Society of Ocular Oncology, Buenos
Aires, Nov 14, 2011.
Godbout R, Dryja TP, Squire J, et al. Somatic inactivation of genes on
chromosome 13 is a common event in retinoblastoma. Nature
1983;304:451–453.
Gordon H. Family studies in retinoblastoma. Birth Defects Orig Artic
Ser 1974;10:185–190.
Harbour JW. Overview of RB gene mutations in patients with
retinoblastoma. Implications for clinical genetic screening. Ophthalmology
1998;105:1442–1447.

648
 Knudson AG Jr. Mutation and cancer: statistical study of
retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820–823.
Knudson AG Jr. Retinoblastoma: a prototypic hereditary neoplasm.
Semin Oncol 1978;5:57–60.
Knudson AG Jr, Hethcote HW, Brown BW. Mutation and childhood
cancer: a probabilistic model for the incidence of retinoblastoma. Proc
Natl Acad Sci U S A 1975;72:5116–5120.
Kratzke RA, Otterson GA, Hogg A, et al. Partial inactivation of the
RB product in a family with incomplete penetrance of familial
retinoblastoma and benign retinal tumors. Oncogene 1994;9: 1321–1326.
McGee TL, Yandell DW, Dryja TP. Structure and partial genomic
sequence of the human retinoblastoma susceptibility gene. Gene
1989;80:119–128.
Mendoza PR, Grossniklaus HE. The biology of retinoblastoma. Prog
Mol Biol Transl Sci 2015;134:503–516.
Murphree AL. Molecular genetics of retinoblastoma. Ophthalmol Clin
North Am 1995;8:155–166.
Murphree AL, Benedict WF. Retinoblastoma: clues to human
oncogenesis. Science 1984;223:1028–1033.
Nielsen M, Goldschmidt E. Retinoblastoma among offspring of adult
survivors in Denmark. Acta Ophthalmol (Copenh) 1968;46: 736–741.
Otterson GA, Chen W, Coxon AB, et al. Incomplete penetrance of
familial retinoblastoma linked to germ-line mutations that result in partial
loss of RB function. Proc Natl Acad Sci U S A 1997;94:12036–12040.
Rushlow DE, Mol BM, Kennett JY, et al. Characterisation of
retinoblastomas without RB1 mutations: genomic, gene expression, and
clinical studies. Lancet Oncol 2013;14(4):327–334.
Shields CL, Shields JA, Donoso LA. Clinical genetics of
retinoblastoma. Int Ophthalmol Clin 1993;33:67–76.
Weichselbaum RR, Zakov ZN, Albert DM, et al. New findings in the
chromosome 13 long-arm deletion syndrome and retinoblastoma.
Ophthalmology 1979;86:1191–1201.
Weinberg RA. The retinoblastoma gene and gene product. Cancer
Surv 1992;12:43–57.
Wiggs J, Nordenskjold M, Yandell D, et al. Prediction of the risk of

649
hereditary retinoblastoma, using DNA polymorphisms within the
retinoblastoma gene. N Engl J Med 1988;318:151–157.

“Trilateral Retinoblastoma” and Other Second

Tumors
Abramson DH. Second nonocular cancers in retinoblastoma: a unified
hypothesis. The Franceschetti Lecture. Ophthalmic Genet
1999;20:193–204.
Abramson DH, Ellsworth RM, Zimmerman LE. Nonocular cancer in
retinoblastoma survivors. Trans Sect Ophthalmol Am Acad Ophthalmol
Otolaryngol 1976;81:454–457.
Bader JL, Meadows AT, Zimmerman LE, et al. Bilateral
retinoblastoma with ectopic intracranial retinoblastoma: trilateral
retinoblastoma. Cancer Genet Cytogenet 1982;5:203–213.
de Jong MC, Kors WA, de Graaf P, et al. The incidence of trilateral
retinoblastoma: a systematic review and meta-analysis. Am J Ophthalmol
2015;160(6):1116–1126.
de Jong MC, Kors WA, de Graaf P, et al. Trilateral retinoblastoma: a
systematic review and meta-analysis. Lancet Oncol
2014;15(10):1157–1167.
Dunkel IJ, Gerald WL, Rosenfield NS, et al. Outcome of patients with
a history of bilateral retinoblastoma treated for a second malignancy: the
Memorial Sloan-Kettering experience. Med Pediatr Oncol 1998;30:59–62.
Holladay DA, Holladay A, Montebello JF, et al. Clinical presentation,
treatment, and outcome of trilateral retinoblastoma. Cancer
1991;67:710–715.
Jakobiec FA, Tso MO, Zimmerman LE, et al. Retinoblastoma and
intracranial malignancy. Cancer 1977;39:2048–2058.
Li FP, Abramson DH, Tarone RE, et al. Hereditary retinoblastoma,
lipoma, and second primary cancers. J Natl Cancer Inst 1997;89:83–84.
Meadows AT, Leahey AM. More about second cancers after
retinoblastoma. J Natl Cancer Inst 2008;100:1743–1745.
Mohney BG, Robertson DM, Schomberg PJ, et al. Second nonocular
tumors in survivors of heritable retinoblastoma and prior radiation therapy.
Am J Ophthalmol 1998;126:269–277.

650
 Moll AC, Imhof SM, Bouter LM, et al. Second primary tumors in
patients with retinoblastoma. A review of the literature. Ophthalmic Genet
1997;18:27–34.
Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma. Am J
Ophthalmol 1989;107:121–126.
Roarty JD, McLean IW, Zimmerman LE. Incidence of second
neoplasms in patients with bilateral retinoblastoma. Ophthalmology
1988;95:1583–1587.
Shields JA, Pesin SR, Shields CL. Trilateral retinoblastoma. J Clin
Neuroophthalmol 1989;9:222–223.
Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after
retinoblastoma. Radiation dose and sarcoma risk. JAMA
1997;278:1262–1267.

Therapy
Abramson DH, Shields CL, Munier FL, et al. Treatment of retinoblastoma in
2015: agreement and disagreement. JAMA Ophthalmol
2015;133(11):1341–1347.
Baumal CR, Shields CL, Shields JA, et al. Surgical repair of rhegmatogenous
retinal detachment after treatment for retinoblastoma. Ophthalmology
1998;105:2134–2139.
Demirci H, Eagle RC Jr, Shields CL, et al. Histopathologic findings in eyes with
retinoblastoma treated only with chemoreduction. Arch Ophthalmol
2003;121:1125–1131.
Demirci H, Shields CL, Meadows AT, et al. Long-term visual outcome following
chemoreduction for retinoblastoma. Arch Ophthalmol 2005;123:1525–1530.
Doz F, Khelfaoui F, Mosseri V, et al. The role of chemotherapy in orbital
involvement of retinoblastoma. The experience of a single institution with 33
patients. Cancer 1994;74:722–732.
Doz F, Neuenschwander S, Plantaz D, et al. Etoposide and carboplatin in
extraocular retinoblastoma: a study by the Societe Francaise d’Oncologie
Pediatrique. J Clin Oncol 1995;13:902–909.
Francis JH, Abramson DH, Gaillard MC, et al. The classification of vitreous
seeds in retinoblastoma and response to intravitreal melphalan.
Ophthalmology 2015;122(6):1173–1179.
Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of
intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and
clinical study. Ophthalmology 2014;121(9):1810–1817.
Freire J, Miyamoto C, Brady LW, et al. Retinoblastoma after chemoreduction and
irradiation: preliminary results. Front Radiat Ther Oncol 1997;30:88–92.

651
Ghassemi F, Shields CL, Ghadimi H, et al. Combined intravitreal melphalan and
topotecan for refractory or recurrent vitreous seeding from retinoblastoma.
JAMA Ophthalmol 2014;132(8):936–941.
Gunduz K, Shields CL, Shields JA, et al. The outcome of chemoreduction
treatment in patients with Reese-Ellsworth group V retinoblastoma. Arch
Ophthalmol 1998;116:1613–1617.
Hernandez JC, Brady LW, Shields JA, et al. External beam radiation for
retinoblastoma: results, patterns of failure, and a proposal for treatment
guidelines. Int J Radiat Oncol Biol Phys 1996;35:125–132.
Howarth C, Meyer D, Hustu HO, et al. Stage-related combined modality
treatment of retinoblastoma. Results of a prospective study. Cancer
1980;45:851–858.
Manjandavida FP, Honavar SG, Reddy VA, et al. Management and outcome of
retinoblastoma with vitreous seeds. Ophthalmology 2014;121(2):517–524.
Munier FL. Classification and management of seeds in retinoblastoma. Ellsworth
Lecture Ghent August 24th 2013. Ophthalmic Genet 2014;35(4):193–207.
Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous
disease in retinoblastoma revisited: from prohibition to conditional
indications. Br J Ophthalmol 2012;96(8):1078–1083.
Chintagumpala MM, Langholz B, Eagle R, et al. A large prospective trial of
children with unilateral retinoblastoma with and without histopathologic high-
risk features and the role of adjuvant chemotherapy: a Children’s Oncology
Group (COG) study. J Clin Oncol 2012;30:609s (suppl; Abstract 9515).
Pratt CB, Fontanesi J, Chenaille P, et al. Chemotherapy for extraocular
retinoblastoma. Pediatr Hematol Oncol 1994;11:301–309.
Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial
management of intraocular retinoblastoma. Arch Ophthalmol
1996;114:1330–1338.
Shields CL, Lally SE, Leahey AM, et al. Targeted retinoblastoma management:
when to use intravenous, intra-arterial, periocular, and intravitreal
chemotherapy. Curr Opin Ophthalmol 2014;25(5):374–385.
Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for
persistent or recurrent retinoblastoma vitreous seeds preliminary results.
JAMA Ophthalmol 2014;132(3):319–325.
Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for
retinoblastoma in 70 eyes: outcomes based on the international classification
of retinoblastoma. Ophthalmology 2014;121(7):1453–1460.
Shields CL, Mashayekhi A, Au AK, et al. The International Classification of
Retinoblastoma predicts chemoreduction success. Ophthalmology
2006;113:2276–2280.
Shields CL, Mashayekhi A, Cater J, et al. Chemoreduction for retinoblastoma.
Analysis of tumor control and risks for recurrence in 457 tumors. Am J
Ophthalmol 2004;138:329–337.
Shields CL, Mashayekhi A, Sun H, et al. Iodine 125 plaque radiotherapy as

652
 salvage treatment for retinoblastoma recurrence after chemoreduction in 84
tumors. Ophthalmology 2006;113:2087–2092.
Shields CL, Meadows AT, Leahey AM, et al. Continuing challenges in the
management of retinoblastoma with chemotherapy. Retina 2004;24:849–862.
Shields CL, Palamar M, Sharma P, et al. Retinoblastoma regression patterns
following chemoreduction and adjuvant therapy in 557 tumors. Arch
Ophthalmol 2009;127:282–290.
Shields CL, Ramasubramanian A, Thangappan A, et al. Chemoreduction for
group E retinoblastoma: comparison of chemoreduction alone versus
chemoreduction plus low-dose external radiotherapy in 76 eyes.
Ophthalmology 2009;116:544–551 e541.
Shields CL, Shields JA. Basic understanding of current classification and
management of retinoblastoma. Curr Opin Ophthalmol 2006;17:228–234.
Shields CL, Shields JA. New strategies in the treatment of unilateral sporadic
retinoblastoma. J Pediatr Ophthalmol Strabismus 2015;52(3):134–137.
Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the
management of retinoblastoma. Use as a primary and secondary treatment
[see comments]. Ophthalmology 1993;100:216–224.
Shields CL, Shields JA, DePotter P, et al. The effect of chemoreduction on
retinoblastoma-induced retinal detachment. J Pediatr Ophthalmol Strabismus
1997;34:165–169.
Shields CL, Shields JA, Needle M, et al. Combined chemoreduction and adjuvant
treatment for intraocular retinoblastoma [see comments]. Ophthalmology
1997;104:2101–2111.
Shields JA, Shields CL. Current management of retinoblastoma. Mayo Clin Proc
1994;69:50–56.
Shields JA, Shields CL, De Potter P. Enucleation technique for children with
retinoblastoma. J Pediatr Ophthalmol Strabismus 1992;29:213–215.
Shields JA, Shields CL, De Potter P. Cryotherapy for retinoblastoma. Int
Ophthalmol Clin 1993;33:101–105.
Shields JA, Shields CL, De Potter P. Photocoagulation of retinoblastoma. Int
Ophthalmol Clin 1993;33:95–99.
Shields JA, Shields CL, De Potter P, et al. Bilateral macular retinoblastoma
managed by chemoreduction and chemothermotherapy. Arch Ophthalmol
1996;114:1426–1427.
Shields JA, Shields CL, Meadows AT. Chemoreduction in the management of
retinoblastoma. Am J Ophthalmol 2005;140:505–506.
Suzuki S, Aihara Y, Fujiwara M, et al. Intravitreal injection of melphalan for
intraocular retinoblastoma. Jpn J Ophthalmol 2015;59(3):164–172.
Tsokos M, Kyritsis AP, Chader GJ, et al. Differentiation of human retinoblastoma
in vitro into cell types with characteristics observed in embryonal or mature
retina. Am J Pathol 1986;123:542–552.
Vrabec T, Arbizo V, Adamus G, et al. Rod cell-specific antigens in
retinoblastoma. Arch Ophthalmol 1989;107:1061–1063.

653
Yannuzzi NA, Francis JH, Marr BP, et al. Enucleation vs ophthalmic artery
chemosurgery for advanced intraocular retinoblastoma: a retrospective
analysis. JAMA Ophthalmol 2015;133(9):1062–1066.

The Differential Diagnosis of Retinoblastoma

Howard GM, Ellsworth RM. Differential diagnosis of retinoblastoma. A
statistical survey of 500 children. I. Relative frequency of the lesions which
simulate retinoblastoma. Am J Ophthalmol 1965;60:610–618.
Robertson DM, Campbell RJ. Analysis of misdiagnosed retinoblastoma in a series
of 726 enucleated eyes. Mod Probl Ophthalmol 1977;18:156–159.
Francois J. Differential diagnosis of leukocoria in children. Ann Ophthalmol
1978;10:1375–1378, 1381–1372.
Margo CE, Zimmerman LE. Retinoblastoma: the accuracy of clinical diagnosis in
children treated by enucleation. J Pediatr Ophthalmol Strabismus
1983;20:227–229.
Shields JA, Parsons HM, Shields CL, et al. Lesions simulating retinoblastoma. J
Pediatr Ophthalmol Strabismus 1991;28:338–340.
Shields JA, Shields CL, Parsons HM. Differential diagnosis of retinoblastoma.
Retina 1991;11:232–243.
Smirniotopoulos JG, Bargallo N, Mafee MF. Differential diagnosis of leukokoria:
radiologic-pathologic correlation. Radiographics 1994;14:1059–1079; quiz
1081–1052.

Toxocariasis
Belmont JB, Irvine A, Benson W, et al. Vitrectomy in ocular toxocariasis. Arch
Ophthalmol 1982;100:1912–1915.
Benitez del Castillo JM, Herreros G, Guillen JL, et al. Bilateral ocular
toxocariasis demonstrated by aqueous humor enzyme- linked immunosorbent
assay. Am J Ophthalmol 1995;119:514–516.
Dernouchamps JP, Verougstraete C, Demolder E. Ocular toxocariasis: a
presumed case of peripheral granuloma. Int Ophthalmol 1990;14:383–388.
Ellis GS Jr, Pakalnis VA, Worley G, et al. Toxocara canis infestation. Clinical
and epidemiological associations with seropositivity in kindergarten children.
Ophthalmology 1986;93:1032–1037.
Kayes SG. Human toxocariasis and the visceral larva migrans syndrome:
correlative immunopathology. Chem Immunol 1997;66:99–124.
Luxenberg MN. An experimental approach to the study of intraocular Toxocara
canis. Trans Am Ophthalmol Soc 1979;77:542–602.
Maguire AM, Green WR, Michels RG, et al. Recovery of intraocular Toxocara
canis by pars plana vitrectomy. Ophthalmology 1990;97:675–680.
Rockey JH, Donnelly JJ, Stromberg BE, et al. Immunopathology of Toxocara
canis and Ascaris suum infections of the eye: the role of the eosinophil. Invest

654
 Ophthalmol Vis Sci 1979;18:1172–1184.
Schantz PM, Weis PE, Pollard ZF, et al. Risk factors for toxocaral ocular larva
migrans: a case-control study. Am J Public Health 1980;70:1269–1272.
Searl SS, Moazed K, Albert DM, et al. Ocular toxocariasis presenting as
leukocoria in a patient with low ELISA titer to Toxocara canis.
Ophthalmology 1981;88:1302–1306.
Shields JA. Ocular toxocariasis. A review. Surv Ophthalmol 1984;28:361–381.
Shields JA, Shields CL, Eagle RC Jr, et al. Endogenous endophthalmitis
simulating retinoblastoma. The 1993 David and Mary Seslen Endowment
Lecture. Retina 1995;15:213–219.
Watzke RC. Ocular Toxocara canis infection: clinical and experimental features.
Trans New Orleans Acad Ophthalmol 1983;31:263–271.
Wilder HC. Nematode endophthalmitis. Trans Am Acad Ophthalmol Otolaryngol
1950;55:99–109.
Zinkham WH. Visceral larva migrans. A review and reassessment indicating two
forms of clinical expression: visceral and ocular. Am J Dis Child
1978;132:627–633.

PHPV/PFV
Cockburn DM, Dwyer PS. Posterior persistent hyperplastic primary vitreous. Am
J Optom Physiol Opt 1988;65:316–317.
Dawson DG, Gleiser J, Movaghar M, et al. Persistent fetal vasculature. Arch
Ophthalmol 2003;121:1340–1341.
Dhingra S, Shears DJ, Blake V, et al. Advanced bilateral persistent fetal
vasculature associated with a novel mutation in the Norrie gene. Br J
Ophthalmol 2006;90:1324–1325.
Doro S, Werblin TP, Haas B, et al. Fetal adenoma of the pigmented ciliary
epithelium associated with persistent hyperplastic primary vitreous.
Ophthalmology 1986;93:1343–1350.
Federman JL, Shields JA, Altman B, et al. The surgical and nonsurgical
management of persistent hyperplastic primary vitreous. Ophthalmology
1982;89:20–24.
Font RL, Yanoff M, Zimmerman LE. Intraocular adipose tissue and persistent
hyperplastic primary vitreous. Arch Ophthalmol 1969;82:43–50.
Ganesh A, Mitra S, Koul RL, et al. The full spectrum of persistent fetal
vasculature in Aicardi syndrome: an integrated interpretation of ocular
malformation. Br J Ophthalmol 2000;84:227–228.
Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of
signs and symptoms associated with persistent hyperplastic primary vitreous
(PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol
1997;124:587–626.
Gulati N, Eagle RC, Jr, Tasman W. Unoperated eyes with persistent fetal
vasculature. Trans Am Ophthalmol Soc 2003;101:59–64; discussion 64–55.

655
Jampol LM. Persistent fetal vasculature. Arch Ophthalmol 2007;125:432.
Jensen OA. Persistent hyperplastic primary vitreous. Cases in Denmark 1942–
1966. A mainly histopathological study. Acta Ophthalmol (Copenh)
1968;46:418–429.
Meisels H, Goldberg M. Vascular anastomoses between the iris and persistent
primary vitreous. Am J Ophthalmol 1979;88:179–185.
Reese AB. Persistent hyperplastic primary vitreous. Am J Ophthalmol
1955;40:317–331.
Robitaille JM, Wallace K, Zheng B, et al. Phenotypic overlap of familial
exudative vitreoretinopathy (FEVR) with persistent fetal vasculature (PFV)
caused by FZD4 mutations in two distinct pedigrees. Ophthalmic Genet
2009;30:23–30.
Spaulding AG, Naumann G. Persistent hyperplastic primary vitreous in an adult.
A brief review of the literature and a histopathologic study. Arch Ophthalmol
1967;77:666–671.
Spitznas M, Koch F, Pohl S. Ultrastructural pathology of anterior persistent
hyperplastic primary vitreous. Graefes Arch Clin Exp Ophthalmol
1990;228:487–496.
Witschel H. Ultrastructure of persistent hyperplastic primary vitreous (PHPV).
Graefes Arch Clin Exp Ophthalmol 1991;229:297.

Coats Disease
Egbert PR, Chan CC, Winter FC. Flat preparations of the retinal vessels in Coats’
disease. J Pediatr Ophthalmol 1976;13:336–339.
Frayer WC. Coats’ disease; a clinical and pathologic study. AMA Arch
Ophthalmol 1955;54:240–244.
Goel SD, Augsburger JJ. Hemorrhagic retinal macrocysts in advanced Coats
disease. Retina 1991;11:437–440.
Green WR. Bilateral Coats’ disease. Massive gliosis of the retina. Arch
Ophthalmol 1967;77:378–383
Jaffe MS, Shields JA, Canny CL, et al. Retinoblastoma simulating Coats’ disease:
a clinicopathologic report. Ann Ophthalmol 1977;9:863–868.
Kremer I, Nissenkorn I, Ben-Sira I. Cytologic and biochemical examination of the
subretinal fluid in diagnosis of Coats’ disease. Acta Ophthalmol (Copenh)
1989;67:342–346.
Lai WW, Edward DP, Weiss RA, et al. Magnetic resonance imaging findings in a
case of advanced Coats’ disease. Ophthalmic Surg Lasers 1996;27:234–238.
Patel HK, Augsburger JJ, Eagle RC Jr. Unusual presentation of advanced Coats’
disease. J Pediatr Ophthalmol Strabismus 1995;32:120–122.
Pe’er J. Calcifications in Coats’ disease. Am J Ophthalmol 1988;106:742–743.
Reese AB. Telangiectasis of the retina and Coats’ disease. Am J Ophthalmol
1956;42:1–8.
Ridley ME, Shields JA, Brown GC, et al. Coats’ disease. Evaluation of

656
 management. Ophthalmology 1982;89:1381–1387.
Shields CL, Zahler J, Falk N, et al. Neovascular glaucoma from advanced Coats
disease as the initial manifestation of facioscapulohumeral dystrophy in a 2-
year-old child. Arch Ophthalmol 2007;125:840–842.
Shields JA, Eagle RC Jr, Fammartino J, et al. Coats’ disease as a cause of anterior
chamber cholesterolosis. Arch Ophthalmol 1995;113:975–977.
Shields JA, Shields CL. Differentiation of coats’ disease and retinoblastoma. J
Pediatr Ophthalmol Strabismus 2001;38:262–266.
Shields JA, Shields CL. Review: coats disease: the 2001 LuEsther T Mertz
lecture. Retina 2002;22:80–91.
Shields JA, Shields CL, Honavar SG, et al. Classification and management of
Coats disease: the 2000 Proctor Lecture. Am J Ophthalmol
2001;131:572–583.
Shields JA, Shields CL, Honavar SG, et al. Clinical variations and complications
of Coats disease in 150 cases: the 2000 Sanford Gifford Memorial Lecture.
Am J Ophthalmol 2001;131:561–571.
Silodor SW, Augsburger JJ, Shields JA, et al. Natural history and management of
advanced Coats’ disease. Ophthalmic Surg 1988;19:89–93.
Tasman W. Coats’ disease. Am Fam Physician 1977;15:107.

Retinopathy of Prematurity
Ashton N. Oxygen and the growth and development of retinal vessels. In vivo and
in vitro studies. The XX Francis I. Proctor Lecture. Am J Ophthalmol
1966;62:412–435.
Ashton N. Donders lecture, 1967. Some aspects of the comparative pathology of
oxygen toxicity in the retina. Br J Ophthalmol 1968;52:505–531.
Ashton N. The pathogenesis of retrolental fibroplasia. Ophthalmology
1979;86:1695–1699.
Ashton N. The story of blindness in premature babies. Trans Med Soc Lond
1987;104:114–125.
Ashton N, Cook C. Direct observation of the effect of oxygen on developing
vessels: preliminary report. Br J Ophthalmol 1954;38:433–440.
Ashton N, Ward B, Serpell G. Effect of oxygen on developing retinal vessels with
particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol
1954;38:397–432.
de Juan E Jr, Machemer R, Flynn JT, et al. Surgical pathoanatomy in stage 5
retinopathy of prematurity. Birth Defects Orig Artic Ser 1988;24:281–286.
Faris B, Tolentino FI, Freeman HM, et al. Retrolental fibroplasia in the cicatricial
stage. Fundus and vitreous findings. Arch Ophthalmol 1971;85:661–668.
Foos RY. Acute retrolental fibroplasia. Albrecht Von Graefes Arch Klin Exp
Ophthalmol 1975;195:87–100.
Foos RY. Chronic retinopathy of prematurity. Ophthalmology 1985;92:563–574.
Garner A, Ashton N. Vaso-obliteration and retrolental fibroplasia. Proc R Soc

657
 Med 1971;64:774–777.
Good WV, Hardy RJ, Dobson V, et al. The incidence and course of retinopathy of
prematurity: findings from the early treatment for retinopathy of prematurity
study. Pediatrics 2005;116:15–23.
Hittner HM, Kretzer FL. Vitamin E and retrolental fibroplasia: ultrastructural
mechanism of clinical efficacy. Ciba Found Symp 1983;101:165–185.
Hittner HM, Rhodes LM, McPherson AR. Anterior segment abnormalities in
cicatricial retinopathy of prematurity. Ophthalmology 1979;86:803–816.
International Committee for the Classification of Retinopathy of Prematurity. The
International Classification of Retinopathy of Prematurity revisited. Arch
Ophthalmol 2005;123:991–999.
Karlsberg RC, Green WR, Patz A. Congenital retrolental fibroplasia. Arch
Ophthalmol 1973;89:122–123.
Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental fibroplasia: a
report of the cooperative study. Pediatrics 1977;60:655–668.
Kretzer FL, McPherson AR, Hittner HM. An interpretation of retinopathy of
prematurity in terms of spindle cells: relationship to vitamin E prophylaxis
and cryotherapy. Graefes Arch Clin Exp Ophthalmol 1986;224:205–214.
Naiman J, Green WR, Patz A. Retrolental fibroplasia in hypoxic newborn. Am J
Ophthalmol 1979;88:55–58.
Palmer EA. Implications of the natural course of retinopathy of prematurity.
Pediatrics 2003;111:885–886.
Patz A. The role of oxygen in retrolental fibroplasia. Sinai Hosp J (Balt)
1954;3:6–20.
Patz A. Current status of role of oxygen in retrolental fibroplasia. Invest
Ophthalmol 1976;15:337–339.
Patz A, Eastham A, Higginbotham DH, et al. Oxygen studies in retrolental
fibroplasia. II. The production of the microscopic changes of retrolental
fibroplasia in experimental animals. Am J Ophthalmol 1953;36:1511–1522.
Reedy EA. The discovery of retrolental fibroplasia and the role of oxygen: a
historical review, 1942–1956. Neonatal Netw 2004;23:31–38.
Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of missense
mutations in the Norrie disease gene associated with advanced retinopathy of
prematurity. Arch Ophthalmol 1997;115:651–655.
Tasman W. Vitreoretinal changes in cicatricial retrolental fibroplasia. Trans Am
Ophthalmol Soc 1970;68:548–594.
Tasman W. The natural history of active retinopathy of prematurity.
Ophthalmology 1984;91:1499–1503.
Tasman W, Brown GC, Naidoff M, et al. Cryotherapy for active retinopathy of
prematurity. Graefes Arch Clin Exp Ophthalmol 1987;225:3–4.
Tasman W, Patz A, McNamara JA, et al. Retinopathy of prematurity: the life of a
lifetime disease. Am J Ophthalmol 2006;141:167–174.
The Committee for the Classification of Retinopathy of Prematurity. An
international classification of retinopathy of prematurity. Arch Ophthalmol

658
 1984;102:1130–1134.
The International Committee for the Classification of the Late Stages of
Retinopathy of Prematurity. An International Classification of Retinopathy of
Prematurity. II. The classification of retinal detachment. Arch Ophthalmol
1987;105:906–912.

Incontinentia Pigmenti
Bell WR, Green WR, Goldberg MF. Histopathologic and trypsin digestion studies
of the retina in incontinentia pigmenti. Ophthalmology 2008;115:893–897.
Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on
the molecular basis of pathophysiology. J Am Acad Dermatol
2002;47:169–187; quiz 188–190.
Brown CA. Incontinentia pigmenti: the development of pseudoglioma. Br J
Ophthalmol 1988;72:452–455.
Fowell SM, Greenwald MJ, Prendiville JS, et al. Ocular findings of incontinentia
pigmenti in a male infant with Klinefelter syndrome. J Pediatr Ophthalmol
Strabismus 1992;29:180–184.
Goldberg MF. The blinding mechanisms of incontinentia pigmenti. Trans Am
Ophthalmol Soc 1994;92:167–176; discussion 176–169.
Goldberg MF. Macular vasculopathy and its evolution in incontinentia pigmenti.
Trans Am Ophthalmol Soc 1998;96:55–65; discussion 65–72.
Goldberg MF. The skin is not the predominant problem in incontinentia pigmenti.
Arch Dermatol 2004;140:748–750.
Goldberg MF, Custis PH. Retinal and other manifestations of incontinentia
pigmenti (Bloch-Sulzberger syndrome). Ophthalmology
1993;100:1645–1654.
Heathcote JG, Schoales BA, Willis NR. Incontinentia pigmenti (Bloch-Sulzberger
syndrome): a case report and review of the ocular pathological features. Can J
Ophthalmol 1991;26:229–237.
Mensheha-Manhart O, Rodrigues MM, Shields JA, et al. Retinal pigment
epithelium in incontinentia pigmenti. Am J Ophthalmol 1975;79:571–577.
Nelson DL. NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin
Genet Dev 2006;16:282–288.
Pacheco TR, Levy M, Collyer JC, et al. Incontinentia pigmenti in male patients. J
Am Acad Dermatol 2006;55:251–255.
Shields CL, Eagle RC Jr, Shah RM, et al. Multifocal hypopigmented retinal
pigment epithelial lesions in incontinentia pigmenti. Retina 2006;26:328–333.

Norrie Disease
Apple DJ, Fishman GA, Goldberg MF. Ocular histopathology of Norrie’s disease.
Am J Ophthalmol 1974;78:196–203.
Caballero M, Veske A, Rodriguez JJ, et al. Two novel mutations in the Norrie

659
 disease gene associated with the classical ocular phenotype. Ophthalmic
Genet 1996;17:187–191.
Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene
(NDP) associated with X-linked familial exudative vitreoretinopathy. Nat
Genet 1993;5:180–183.
Chynn EW, Walton DS, Hahn LB, et al. Norrie disease. Diagnosis of a simplex
case by DNA analysis. Arch Ophthalmol 1996;114:1136–1138.
Dickinson JL, Sale MM, Passmore A, et al. Mutations in the NDP gene:
contribution to Norrie disease, familial exudative vitreoretinopathy and
retinopathy of prematurity. Clin Experiment Ophthalmol 2006;34:682–688.
Drenser KA, Fecko A, Dailey W, et al. A characteristic phenotypic retinal
appearance in Norrie disease. Retina 2007;27:243–246.
Enyedi LB, de Juan E Jr, Gaitan A. Ultrastructural study of Norrie’s disease. Am J
Ophthalmol 1991;111:439–445.
Holmes LB. Norrie’s disease: an X-linked syndrome of retinal malformation,
mental retardation, and deafness. J Pediatr 1971;79:89–92.
Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence
variants in an ethnically diverse population with retinopathy of prematurity.
Mol Vis 2005;11:501–508.
Johnson K, Mintz-Hittner HA, Conley YP, et al. X-linked exudative
vitreoretinopathy caused by an arginine to leucine substitution (R121L) in the
Norrie disease protein. Clin Genet 1996;50:113–115.
Kellner U, Fuchs S, Bornfeld N, et al. Ocular phenotypes associated with two
mutations (R121W, C126X) in the Norrie disease gene. Ophthalmic Genet
1996;17:67–74.
Luhmann UF, Lin J, Acar N, et al. Role of the Norrie disease pseudoglioma gene
in sprouting angiogenesis during development of the retinal vasculature.
Invest Ophthalmol Vis Sci 2005;46:3372–3382.
Mintz-Hittner HA, Ferrell RE, Sims KB, et al. Peripheral retinopathy in offspring
of carriers of Norrie disease gene mutations. Possible transplacental effect of
abnormal Norrin. Ophthalmology 1996;103:2128–2134.
Parsons MA, Curtis D, Blank CE, et al. The ocular pathology of Norrie disease in
a fetus of 11 weeks’ gestational age. Graefes Arch Clin Exp Ophthalmol
1992;230:248–251.
Perez-Vilar J, Hill RL. Norrie disease protein (norrin) forms disulfide-linked
oligomers associated with the extracellular matrix. J Biol Chem
1997;272:33410–33415.
Riveiro-Alvarez R, Cantalapiedra D, Vallespin E, et al. Gene symbol: NDP
disease: Norrie disease. Hum Genet 2008;124:308.
Schroeder B, Hesse L, Bruck W, et al. Histopathological and
immunohistochemical findings associated with a null mutation in the Norrie
disease gene. Ophthalmic Genet 1997;18:71–77.
Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of missense
mutations in the Norrie disease gene associated with advanced retinopathy of

660
 prematurity. Arch Ophthalmol 1997;115:651–655.
Smallwood PM, Williams J, Xu Q, et al. Mutational analysis of Norrin-Frizzled4
recognition. J Biol Chem 2007;282:4057–4068.
Townes PL, Roca PD. Norrie’s disease (hereditary oculo-acoustic-cerebral
degeneration). Report of a United States family. Am J Ophthalmol
1973;76:797–803.
Warburg M. Norrie’s disease. Trans Ophthalmol Soc U K 1965;85:391–408.
Warburg M. Norrie’s disease—differential diagnosis and treatment. Acta
Ophthalmol (Copenh) 1975;53:217–236.
Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial
exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol
2007;22:211–217.
Wolff G, Mayerova A, Wienker TF, et al. Clinical reinvestigation and linkage
analysis in the family with Episkopi blindness (Norrie disease). J Med Genet
1992;29:816–819.
Wu WC, Drenser K, Trese M, et al. Retinal phenotype-genotype correlation of
pediatric patients expressing mutations in the Norrie disease gene. Arch
Ophthalmol 2007;125:225–230.
Xu Q, Wang Y, Dabdoub A, et al. Vascular development in the retina and inner
ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell
2004;116:883–895.
Ye X, Wang Y, Cahill H, et al. Norrin, frizzled-4, and Lrp5 signaling in
endothelial cells controls a genetic program for retinal vascularization. Cell
2009;139:285–298.

Retinal Dysplasia
Chan A, Lakshminrusimha S, Heffner R, et al. Histogenesis of retinal dysplasia in
trisomy 13. Diagn Pathol 2007;2:48.
Godel V, Nemet P, Lazar M. Retinal dysplasia. Doc Ophthalmol
1981;51:277–288.
Green WR, Iliff WJ, Trotter RR. Malignant teratoid medulloepithelioma of the
optic nerve. Arch Ophthalmol 1974;91:451–454.
Hoepner J, Yanoff M. Ocular anomalies in trisomy 13–15: an analysis of 13 eyes
with two new findings. Am J Ophthalmol 1972;74:729–737.
Lahav M, Albert DM, Wyand S. Clinical and histopathologic classification of
retinal dysplasia. Am J Ophthalmol 1973;75:648–667.
Lloyd IC, Colley A, Tullo AB, et al. Dominantly inherited unilateral retinal
dysplasia. Br J Ophthalmol 1993;77:378–380.
Mullaney J. Primary malignant medulloepithelioma of the retinal stalk. Am J
Ophthalmol 1974;77:499–504.
Reese AB, Straatsma BR. Retinal dysplasia. Am J Ophthalmol 1958;45:199–211.
Silverstein AM, Osburn BI, Prendergast RA. The pathogenesis of retinal
dysplasia. Am J Ophthalmol 1971;72:13–21.

661
Medulloepithelioma
Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of
intraocular medulloepitheliomas. Am J Ophthalmol 1978;85:407–418.
Brownstein S, Barsoum-Homsy M, Conway VH, et al. Nonteratoid
medulloepithelioma of the ciliary body. Ophthalmology 1984;91:1118–1122.
Canning CR, McCartney AC, Hungerford J. Medulloepithelioma (diktyoma). Br J
Ophthalmol 1988;72:764–767.
Durieux E, Descotes F, Nguyen AM, et al. Somatic DICER1 gene mutation in
sporadic intraocular medulloepithelioma without pleuropulmonary blastoma
syndrome. Hum Pathol 2015;46(5):783–787.
Eagle RC Jr, Font RL, Swerczek TW. Malignant medulloepithelioma of the optic
nerve in a horse. Vet Pathol 1978;15:488–494.
Font RL, Rishi K. Diffuse retinal involvement in malignant nonteratoid
medulloepithelioma of ciliary body in an adult. Arch Ophthalmol
2005;123:1136–1138.
Husain SE, Husain N, Boniuk M, et al. Malignant nonteratoid
medulloepithelioma of the ciliary body in an adult. Ophthalmology
1998;105:596–599
Jakobiec FA, Howard GM, Ellsworth RM, et al. Electron microscopic diagnosis
of medulloepithelioma. Am J Ophthalmol 1975;79:321–329.
Jakobiec FA, Kool M, Stagner AM, et al. Intraocular medulloepitheliomas and
embryonal tumors with multilayered rosettes of the brain: comparative roles
of LIN28A and C19MC. Am J Ophthalmol 2015;159(6):1065–1074.
Kaliki S, Shields CL, Eagle RC Jr, et al. Ciliary body medulloepithelioma:
analysis of 41 cases. Ophthalmology 2013;120(12):2552–2559.
Kivela T, Kauniskangas L, Miettinen P, et al. Glioneuroma associated with
colobomatous dysplasia of the anterior uvea and retina. A case simulating
medulloepithelioma. Ophthalmology 1989;96:1799–1808.
Kivela T, Tarkkanen A. Recurrent medulloepithelioma of the ciliary body.
Immunohistochemical characteristics. Ophthalmology 1988;95:1565–1575.
Korshunov A, Jakobiec FA, Eberhart CG, et al. Comparative integrated molecular
analysis of intraocular medulloepitheliomas and central nervous system
embryonal tumors with multilayered rosettes confirms that they are distinct
nosologic entities. Neuropathology 2015;35(6):538–544.
Kramer GD, Arepalli S, Shields CL, et al. Ciliary body medulloepithelioma
association with pleuropulmonary blastoma in a familial tumor predisposition
syndrome. J Pediatr Ophthalmol Strabismus 2014;16:51
Laird PW, Grossniklaus HE, Hubbard GB. Ciliary body medulloepithelioma
associated with pleuropulmonary blastoma. Br J Ophthalmol
2013;97(8):1079, 1086–1087.
Lloyd WC III, O’Hara M. Malignant teratoid medulloepithelioma: clinical-
echographic-histopathologic correlation. J AAPOS 2001;5:395–397.
Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blastoma: a report

662
 on 350 central pathology-confirmed pleuropulmonary blastoma cases by the
International Pleuropulmonary Blastoma Registry. Cancer
2015;121(2):276–285.
O’Keefe M, Fulcher T, Kelly P, et al. Medulloepithelioma of the optic nerve
head. Arch Ophthalmol 1997;115:1325–1327.
Priest JR, Williams GM, Manera R, et al. Ciliary body medulloepithelioma: four
cases associated with pleuropulmonary blastoma—a report from the
International Pleuropulmonary Blastoma Registry. Br J Ophthalmol
2011;95(7):1001–1005.
Sahm F, Jakobiec FA, Meyer J, et al. Somatic mutations of DICER1 and KMT2D
are frequent in intraocular medulloepitheliomas. Genes Chromosomes Cancer
2016;55(5):418–427.
Schultz KA, Yang J, Doros L, et al. DICER1-pleuropulmonary blastoma familial
tumor predisposition syndrome: a unique constellation of neoplastic
conditions. Pathol Case Rev 2014;19(2):90–100.
Shields JA, Eagle RC Jr, Shields CL, et al. Congenital neoplasms of the
nonpigmented ciliary epithelium (medulloepithelioma). Ophthalmology
1996;103:1998–2006.
Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented medulloepithelioma of the
ciliary body. Arch Ophthalmol 2002;120:207–210.
Wilson ME, McClatchey SK, Zimmerman LE. Rhabdomyosarcoma of the ciliary
body. Ophthalmology 1990;97:1484–1488.

Astrocytic Hamartomas and Astrocytomas

Bornfeld N, Messmer EP, Theodossiadis G, et al. Giant cell astrocytoma of the
retina. Clinicopathologic report of a case not associated with Bourneville’s
disease. Retina 1987;7:183–189.
Cleasby GW, Fung WE, Shekter WB. Astrocytoma of the retina. Report of two
cases. Am J Ophthalmol 1967;64(suppl):633–637.
de Juan E Jr, Green WR, Gupta PK, et al. Vitreous seeding by retinal astrocytic
hamartoma in a patient with tuberous sclerosis. Retina 1984;4:100–102.
Eagle RC Jr, Shields JA, Shields CL, et al. Hamartomas of the iris and ciliary
epithelium in tuberous sclerosis complex. Arch Ophthalmol
2000;118:711–715.
Gunduz K, Eagle RC Jr, Shields CL, et al. Invasive giant cell astrocytoma of the
retina in a patient with tuberous sclerosis. Ophthalmology 1999;106:639–642.
Jakobiec FA, Brodie SE, Haik B, et al. Giant cell astrocytoma of the retina. A
tumor of possible Mueller cell origin. Ophthalmology 1983;90:1565–1576.
Jakobiec FA, Thanos A, Stagner AM, et al. So-called massive retinal gliosis: a
critical review and reappraisal. Surv Ophthalmol 2015;15.
Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis.
Arch Ophthalmol 1976;94:1277–1280.
Robertson DM. Ophthalmic manifestations of tuberous sclerosis. Ann N Y Acad

663
 Sci 1991;615:17–25.
Shields CL, Shields JA, Eagle RC Jr, et al. Progressive enlargement of acquired
retinal astrocytoma in 2 cases. Ophthalmology 2004;111:363–368.
Shields CL, Thangappan A, Hartzell K, et al. Combined hamartoma of the retina
and retinal pigment epithelium in 77 consecutive patients visual outcome
based on macular versus extramacular tumor location. Ophthalmology
2008;115:2246–2252 e2243.
Shields JA, Eagle RC Jr, Shields CL, et al. Aggressive retinal astrocytomas in
four patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc
2004;102:139–147; discussion 147–138.
Shields JA, Shields CL, Ehya H, et al. Atypical retinal astrocytic hamartoma
diagnosed by fine-needle biopsy. Ophthalmology 1996;103:949–952.
Tay A, Scheithauer BW, Cameron JD, et al. Retinal ependymoma: an
immunohistologic and ultrastructural study. Hum Pathol 2009;40:578–583.
Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina.
Differentiation of sporadic tumors from phakomatosis-associated tumors.
Arch Pathol Lab Med 1984;108:160–163.
Zimmer-Galler IE, Robertson DM. Long-term observation of retinal lesions in
tuberous sclerosis. Am J Ophthalmol 1995;119:318–324.

Hematopoietic Lesions
Chang MW, Frieden IJ, Good W. The risk intraocular juvenile xanthogranuloma:
survey of current practices and assessment of risk. J Am Acad Dermatol
1996;34:445–449.
Cho AS, Holland GN, Glasgow BJ, et al. Ocular involvement in patients with
posttransplant lymphoproliferative disorder. Arch Ophthalmol
2001;119:183–189.
Coupland SE, Foss HD, Bechrakis NE, et al. Secondary ocular involvement in
systemic “memory” B-cell lymphocytic leukemia. Ophthalmology
2001;108:1289–1295.
Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv
Ophthalmol 1983;27:211–232.
Leonardy NJ, Rupani M, Dent G, et al. Analysis of 135 autopsy eyes for ocular
involvement in leukemia. Am J Ophthalmol 1990;109:436–444.
O’Hara M, Lloyd WC III, Scribbick FW, et al. Latent intracellular Epstein-Barr
Virus DNA demonstrated in ocular posttransplant lymphoproliferative
disorder mimicking granulomatous uveitis with iris nodules in a child. J
AAPOS 2001;5:62–63.
Sanders TE. Intraocular juvenile xanthogranuloma (nevoxanthogranuloma): a
survey of 20 cases. Trans Am Ophthalmol Soc 1960;58:59–74.
Shields JA, Eagle RC Jr, Shields CL, et al. Iris juvenile xanthogranuloma studied
by immunohistochemistry and flow cytometry. Ophthalmic Surg Lasers
1997;28:140–144.

664
Zimmerman LE. Ocular lesions of juvenile xanthogranuloma.
Nevoxanthoedothelioma. Am J Ophthalmol 1965;60:1011–1035.

Lacrimal Gland Choristomas

Ghadially FN, Chisholm IA, Lalonde JM. Ultrastructure of an intraocular lacrimal
gland choristoma. J Submicrosc Cytol 1986;18:189–198.
Kobrin EG, Shields CL, Danzig CJ, et al. Intraocular lacrimal gland choristoma
diagnosed by fine-needle aspiration biopsy. Cornea 2007;26:753–755.
Shields JA, Eagle RC Jr, Shields CL, et al. Natural course and histopathologic
findings of lacrimal gland choristoma of the iris and ciliary body. Am J
Ophthalmol 1995;119:219–224.
Shields JA, Hogan RN, Shields CL, et al. Intraocular lacrimal gland choristoma
involving iris and ciliary body. Am J Ophthalmol 2000;129:673–675.

Other Rare Neoplasms

Freitag SK, Eagle RC Jr, Shields JA, et al. Melanogenic neuroectodermal tumor
of the retina (primary malignant melanoma of the retina). Arch Ophthalmol
1997;115:1581–1584.
Frenkel S, Trese MT, Walsh MK, et al. Intraocular teratoma in association with
sacrococcygeal teratoma: a clinicopathologic report. J Pediatr Ophthalmol
Strabismus 2010;21;47.
Kivela T, Kauniskangas L, Miettinen P, et al. Glioneuroma associated with
colobomatous dysplasia of the anterior uvea and retina. A case simulating
medulloepithelioma. Ophthalmology 1989;96:1799–1808.
Patel S, Dondey J, Chan HS, et al. Leukocoria caused by intraocular heterotopic
brain tissue. Arch Ophthalmol 2004;122:390–393.
Paysse EA, Coats D, Chevez-Barrios P. An unusual case of leukocoria:
heterotopic brain arising from the retina. Arch Ophthalmol
2003;121:119–122.
Spencer WH, Jesberg DO. Glioneuroma (choristomatous malformation of the
optic cup margin). Arch Ophthalmol 1973;89:387–391.
Tiberti A, Damato B, Hiscott P, et al. Iris ectopic thyroid tissue: report of a case.
Arch Ophthalmol 2006;124:1497–1500.

Miscellaneous Lesions
Black GC, Perveen R, Bonshek R, et al. Coats’ disease of the retina (unilateral
retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for
norrin in retinal angiogenesis. Hum Mol Genet 1999;8(11):2031–2035.
PubMed PMID: 10484772.
Brown GC, Shields JA, Oglesby RB. Anterior polar cataracts associated with
bilateral retinoblastoma. Am J Ophthalmol 1979;87:276.
Friendly DS, Parks MM. Concurrence of hereditary congenital cataracts and

665
 hereditary retinoblastoma. Arch Ophthalmol 1970;84:525–527.
Mouriaux F, Leroy-Rattier MP, Maurage CA, et al. Congenital duplication of the
anterior segment with central hamartomatous plaque. Arch Ophthalmol
2002;120:1377–1379.

666
INDEX

A
Acanthamoeba keratitis
Actinic keratosis
Acute allergic conjunctivitis
Acute angle recession, contusion injury
Acute dacryocystitis
Acute purulent conjunctivitis
Adnexal tumors
pilomatrixoma
syringocystadenoma papilliferum
syringomas
Age-related macular degeneration (ARMD)
atrophic form
basal laminar deposits
exudative form
genetic and environmental factors
hard drusen
macula
ocular histoplasmosis syndrome
serous and hemorrhagic detachments, RPE
soft drusen
subretinal neovascular membranes
Alkali injury
Allergic conjunctival granuloma
Allergic fungal sinusitis
Alveolar rhabdomyosarcoma
Angioid streaks
Angiomatosis retinae
Aniridia
Anterior pyramidal cataract
Anterior retinal avulsion, contusion injury
Anterior subcapsular cataract (ASC)

667
Apocrine hidrocystoma
Arcus senilis
Asteroid hyalosis (AH)
Astrocytic hamartomas
Ataxia-telangiectasia (A-T)
Atrophic macular degeneration
Axenfeld-Rieger syndrome

B
Bacterial endophthalmitis. see Endophthalmitis
Basal cell carcinoma
frozen section excision
morpheaform
nevus syndrome
nodulo-ulcerative
well-differentiated
Behçet disease
Benign cystic lesions
apocrine hidrocystoma
eccrine hidrocystoma
epidermal inclusion cysts
Benign epidermal lesions
Benson disease
Best disease
Bietti disease
Bilateral leukocoria
Bilateral retinoblastoma
Blot hemorrhages
Boat-shaped hemorrhages
Brushfield spots

C
Calcific band keratopathy
Caruncular lesions
Cat scratch fever
Cataract

668
 ASC
capsular fibrosis
complicated cataracts
cortical cataract
diabetes mellitus
galactosemia
morgagnian cataracts
nuclear sclerosis
posterior subcapsular cataract
pseudophakia
systemic disease
Fabry disease
myotonic dystrophy
Wilson disease
toxic
traumatic
Cavernous hemangioma
Chalazia
Chalcosis lentis
CHARGE syndrome
Choroidal hemangioma
magnetic resonance imaging
vs. melanomas, IVFA
scan ultrasonography
sporadic choroidal hemangioma
treatment
uveal metastases
breast and lung carcinomas
choroidal metastases
diagnosis
immunohistochemical stains
mucin-secreting adenocarcinoma
prognosis
vascular channels
Choroidal melanoma
Bruch membrane rupture
large tumors

669
 mushroom configuration
orange pigment
Choroidal osteoma
Chromosomal anomalies
Chronic follicular conjunctivitis
giant papillary conjunctivitis
papillary hypertrophy
phlyctenular keratoconjunctivitis
trachoma
conjunctival epithelial cells
inclusion conjunctivitis
vernal conjunctivitis
Chronic granulomatous inflammation
diffuse pattern
discrete pattern
granulation tissue
phacoanaphylactic endophthalmitis
zonal pattern
Chronic herpetic stromal keratitis
Chronic luetic interstitial keratitis
Chronic retinal venous occlusion (CRVO)
Ciliary body
ciliary epithelium
components
dentate process
hyalinization
melanoma
surface ectoderm
Ciliary epithelial tumors
Coats disease
Cobblestone degeneration
Coloboma
Complex choristoma, organoid nevus syndrome
Complicated cataracts
Congenital anomalies
embryogenesis, etiologic factors
heritable ocular diseases

670
 phakomatosis
Sturge-Weber syndrome
synophthalmia (see Synophthalmia)
tuberous sclerosis complex
Von Hippel-Lindau disease
Von Recklinghausen neurofibromatosis
Congenital grouped pigmentation
Congenital hereditary endothelial dystrophy (CHED)
Congenital hereditary stromal dystrophy
Congenital hypertrophy of the RPE (CHRPE)
Congenital ocular melanocytosis
Conjunctiva
amyloidosis
conjunctivitis (see Conjunctivitis)
cysts
degenerations
developmental lesions
tumors
pigmented lesions (see Pigmented lesions, conjunctiva)
primary acquired melanosis (see Primary acquired melanosis
(PAM))
squamous epithelial lesions (see Squamous epithelial lesions)
Conjunctival melanocytic intraepithelial neoplasia (C-MIN)
Conjunctivitis
acute anaphylactic conjunctivitis
acute conjunctivitis
chronic conjunctivitis (see Chronic follicular conjunctivitis)
histology
ligneous
Contusion injury
angle recession
anterior retinal avulsion
corneal blood staining
cyclodialysis
rosette cataract
Cornea
abrasion

671
calcific band keratopathy
chronic actinic keratopathy
congenital hereditary endothelial dystrophy
degenerative pannus
developmental anomalies
dystrophy
Fuchs dystrophy
stromal (see Stromal dystrophy, cornea)
superficial (see Superficial corneal dystrophy, cornea)
histology
inflammation
acute keratitis
corneal perforation
fungal keratitis
infectious crystalline keratopathy
interstitial keratitis
keloids
keratoconjunctivitis sicca
keratoconus
laceration
parasitic keratitis
peripheral corneal ulcers
posterior polymorphous dystrophy
pseudophakic bullous keratopathy
pterygium
Salzmann nodular degeneration
systemic disease
immunoglobulin deposition
paraprotein deposition
pars plana cysts
Wilson hepatolenticular degeneration
transplantation
viral keratitis
epidemic keratoconjunctivitis
herpes simplex keratitis
varicella zoster virus
vitamin A deficiency

672
Corneal blood staining
Corneal rings
Cortical cataract
Cotton-wool spots
Cyclodialysis, contusion injury
Cyclopia. see Synophthalmia
Cystoid macular edema (CME)
Cytomegalovirus retinitis
acquired immunodeficiency syndrome
cytopathic effect
owl’s eye inclusions

D
Dalen-Fuchs nodules
Deep lamellar anterior keratectomy (DALK)
Dermoid cyst
Dermolipoma (lipodermoid)
Descemet stripping endothelial keratoplasty (DSEK)
Developmental disease
conjunctiva
cornea
eyelid
lens
optic nerve
retina
albinism
congenital vascular abnormalities
dysplasia
Lange fold
myelinated nerve fibers
Developmental glaucoma
Diabetes mellitus
background retinopathy
basement membrane thickening
cataracts
diabetic retinopathy

673
 background retinopathy
neovascularization
prevalence
proliferative diabetic retinopathy
retinal capillary microaneurysms
trypsin retinal digestion technique
fungal infection
Lacy vacuolization
neovascularization of the iris
Diffuse iris melanomas
Dissection
Dot hemorrhages
Down syndrome
Dry macular degeneration

E
Eccrine hidrocystoma
Ectopia lentis
Electrical cataracts
Elephantiasis neuromatosa
Embryonal medulloepithelioma
Embryonal rhabdomyosarcoma
Encephalotrigeminal angiomatosis
Endophthalmitis
bacterial
exogenous endophthalmitis
localized endophthalmitis
retinal necrosis
fungal
endogenous
vitreous microabscesses
Endophytic retinoblastomas
Eosinophilic granuloma
Eosinophils
Epibulbar dermoid
Epidemic keratoconjunctivitis

674
Epidermal inclusion cysts
Epiretinal gliosis
Epithelial dystrophy
Epithelial facet, cornea
Epithelioid histiocytes
Essential iris atrophy
Exophytic retinoblastomas
Expulsive choroidal hemorrhage
Extranodal marginal zone lymphomas (EMZL)
Extraocular extension, uveal melanoma
Exudative retinal detachment
Eyelid
aging changes
congenital and developmental lesions
glands of moll
inflammatory lesions
lower eyelid
malignant tumors
actinic keratosis
adnexal tumors (see Adnexal tumors)
basal cell carcinoma (see Basal cell carcinoma)
melanocytic nevi (see Melanocytic nevi)
melanomas
sebaceous carcinoma (see Sebaceous carcinoma)
squamous cell carcinoma
markers, systemic malignancy
meibomian gland lobule
skin
upper eyelid
viral lesions
benign cystic lesions (see Benign cystic lesions)
benign epidermal lesions
keratoacanthoma
molluscum contagiosum
seborrheic keratoses (see Seborrheic keratoses)
verruca vulgaris
xanthelasmas

675
F
Familial retinoblastomas
Familial tumor syndromes
Fibrous histiocytoma
Flame-shaped hemorrhages
Fleck corneal dystrophy (FCD)
Flexner-Wintersteiner rosettes
Fuchs dystrophy (FECD)
Fundus flavimaculatus. see Stargardt disease
Fungal endophthalmitis. see Endophthalmitis
Fungal keratitis
Fusion anomaly. see Synophthalmia

G
Gelatinous drop-like dystrophy
Giant cell arteritis
Giant papillary conjunctivitis
Glaucoma
definition
developmental
iridocorneal endothelial syndrome
ocular tissue changes
optic atrophy
primary closed-angle
primary open-angle
schlemm canal and JXT
secondary closed-angle
secondary open-angle glaucoma (see Secondary open-angle
glaucoma)
trabecular meshwork
Granular corneal dystrophy
Granulomatous conjunctivitis
allergic conjunctival granuloma
Cat scratch fever
ocular cicatricial pemphigoid
parinaud oculoglandular syndrome

676
 pyogenic granuloma
synthetic fiber granuloma
Granulomatous inflammation
chronic granulomatous inflammation
diffuse pattern
discrete pattern
granulation tissue
phacoanaphylactic endophthalmitis
zonal pattern
sarcoidosis

H
Haab striae
Hemangiopericytomas
Hereditary benign intraepithelial dyskeratosis
Heritable ocular diseases
aniridia
autosomal recessively inherited disorders
Miller syndrome
X-linked recessive inheritance
Herpes simplex
viral retinitis
Herpes simplex (HSV) keratitis
Heterochromia iridum, hemosiderosis
Histochemical stains
Holoprosencephaly
Homer Wright rosettes
Homocystinuria
Hordeolums
Hyperkeratosis
Hypertensive retinopathy

I
Idiopathic orbital inflammation
biopsy
fibrosis, lacrimal gland

677
 orbital fat
sarcoidosis
Wegener granulomatosis
Immunohistochemistry (IHC)
breast carcinoma
flow cytometry
frozen section diagnosis
gene expression profiling
lymphoid tumors
markers
polymerase chain reaction
primary antibody binding
scanning electron microscopy
second antibody binding
in situ hybridization
solitary fibrous tumor
transmission electron microscopy
Incontinentia pigmenti
Inflammation
acute dacryocystitis
biochemical mediators
classification
endophthalmitis (see Endophthalmitis)
eosinophils
functio laesa
gaint cells
foreign body
langhans type
Touton giant cells
granulomatous inflammation (see Granulomatous inflammation)
lymphocytes
macrophages
mast cells
plasma cells
polymorphonuclear leukocyte
posterior synechiae
protein mediators

678
 Russell bodies
sequelae
cyclitic membrane
phthisis bulbi
toxoplasma retinochoroiditis
uveitis
vascular permeability
vasoactive inflammatory mediators
viral retinitis (see Viral retinitis)
International Classification of Retinoblastoma (ICRB)
Interstitial keratitis
Intraocular foreign body (BB)
Intraocular tumors
choroidal hemangiomas (see Choroidal hemangioma)
choroidal osteoma
ciliary epithelial tumors
congenital grouped pigmentation
congenital hypertrophy of the RPE
iris nevus and melanoma
freckles
treatment
iris pigment epithelial cysts
leiomyoma, ciliary body
melanocytic tumors, uveal tract
choroid tumor
malignant (see Uveal malignant melanoma)
melanocytoma
nevi
peripheral nerve sheath tumors
primary choroidal lymphoma
RPE tumors
Inverted follicular keratosis
Iridocorneal endothelial (IEC) syndrome
Iris bombé
Iris pigment epithelial cysts
Iris pigment epithelium
Iritis

679
J
Juvenile X-linked retinoschisis

K
Keratoacanthoma
Keratoconjunctivitis sicca
Keratoconus
Keratomalacia
Kruckmann-Wolfflin bodies

L
Lacrimal drainage system
Lacrimal gland lesions
acinic cell carcinoma
adenoid cystic carcinoma
ductal adenocarcinoma
epithelial tumors
malignant mixed tumor
mucoepidermoid carcinoma
pleomorphic adenoma
Lattice corneal dystrophy, Type I
Lattice dystrophy type II (LCDII)
Leber congenital amaurosis (LCA)
Leber hereditary optic neuropathy
Leiomyoma, ciliary body
Lens
capsular abnormalities
pseudoexfoliation
true exfoliation
cataract (see Cataract)
congenital anomalies
anterior pyramidal cataract
coloboma
developmental cataracts
lamellar cataract
Lowe syndrome

680
 persistent hyperplastic primary vitreous
posterior lenticonus
posterior umbilication
rubella embryopathy
zonular cataract
ectopia lentis
zonular fibers
Lens capsular abnormalities
pseudoexfoliation
true exfoliation
Leukocoria
Ligneous conjunctivitis
Lowe syndrome
Lymphangioma
Lymphocytes
Lymphoid tumors
B-cell lymphoma
follicular lymphoid hyperplasia
low-grade MALT lymphoma

M
Macrophages
Macular corneal dystrophy (MCD)
Malignant melanomas
Marfan syndrome
Mast cells
Medulloepithelioma
Meesmann epithelial dystrophy
Melanin pigment
Melanocytic nevi
compound nevi
intradermal nevus
junctional nevi
Melanocytic tumors, uveal tract
choroid tumor
malignant (see Uveal malignant melanoma)

681
 melanocytoma
nevi
Miller syndrome
Morgagnian cataracts
Mucocele
Mucoepidermoid carcinoma
Mucormycosis
Mucosa-associated lymphoid tissue (MALT)
Mueller cells

N
Necrotic uveal melanoma
Neovascular glaucoma
Neurofibromatosis type 2 (NF-2)
Norrie disease

O
Ocular anatomy and histology
anterior chamber
ciliary body
ciliary epithelium
components
dentate process
hyalinization
surface ectoderm
concentric coats
conjunctiva
cornea
eyelids
IPE termination
lens
epithelial monolayer
lens fibers
suspensory ligament
middle limiting membrane
optic nerve

682
 optic vesicle
orbit
outer plexiform layer
photoreceptor
retina
bipolar cells
internal limiting membrane
middle limiting membrane
Mueller cells
nuclear layer
plexiform layer
rods and cones
retinal pigment epithelium
Bruch membrane
flat preparations
melanin pigment
trabecular meshwork
Ocular cicatricial pemphigoid (OCP)
Ocular histoplasmosis syndrome (OHS)
Ocular toxocariasis
Ocular trauma
chemical injuries
contusion injury (see Contusion injury)
corneal laceration
epithelial facet, cornea
expulsive choroidal hemorrhage
intraocular foreign body
old ruptured globe
penetrating injury
ruptured globe
sympathetic uveitis
uveal and retinal incarceration, limbal wound
wound healing (see Wound healing)
Oculocutaneous albinism type 2 (OCA2)
Old ruptured globe
Onchocerciasis
Oncocytomas, caruncle

683
Ophthalmic pathology laboratory
inspection and description
specimen handling
fixation
laterality determination
ocular measurements
transillumination
Optic disc drusen
Optic nerve
colobomas
developmental anomalies
glioma
meningiomas
neoplasms
optic atrophy
Leber hereditary optic neuropathy
primary optic atrophy
retinal causes
Schnabel cavernous optic atrophy
optic disc drusen
optic neuritis
Optic neuritis
Orbit
clinical manifestation
inflammatory disease
idiopathic orbital inflammation (see Idiopathic orbital
inflammation)
mucormycosis
thyroid eye disease
orbital contents
tumors
lymphoid tumors
vascular lesions (see Vascular lesions, orbit)
Orbital cellulitis
Osseous choristoma, conjunctiva
Oxalate crystals, nuclear sclerosis

684
P
Panophthalmitis
Parasitic keratitis
Parinaud oculoglandular syndrome
Pars plana cysts
Patau syndrome
Pediatric intraocular tumors
Pediatric orbital lesions
Penetrating injury
Periodic acid-Schiff (PAS) stain
Peripheral anterior synechia
Peripheral corneal ulcers
Peripheral nerve sheath tumors
Peripheral retinal degenerations
cobblestone degeneration
juvenile X-linked retinoschisis
lattice degeneration
microcystoid degeneration
pars plana cysts
reticular cystoid degeneration
Persistent hyperplastic primary vitreous (PHPV)
Peters anomaly
Phacoanaphylactic endophthalmitis
Phakomatosis
Phakomatous choristoma
Phlyctenular keratoconjunctivitis
Phthisis bulbi
Pigmented lesions, conjunctiva
argyrosis
constitutional melanosis
nevi
Blue nevi
compound cystic nevus
hormonal changes
junctional nevi
ochronosis
Pilomatrixoma

685
Pineoblastoma
Pinguecula
Plasma cells
Polymorphonuclear leukocyte
Postcontusion angle recession, contusion injury
Posterior polymorphous dystrophy (PPMD)
Posterior subcapsular cataract
Posterior synechiae
Primary acquired melanosis (PAM)
conjunctival melanocytic intraepithelial neoplasia
melanomas
mild-moderate atypia
severe atypia
without atypia
Primary choroidal lymphoma
Primary closed-angle glaucoma
Primary congenital glaucoma
Primary open-angle glaucoma (POAG)
Primary vitreous lymphoma
Progressive outer retinal necrosis (PORN) syndrome
Proliferative vitreoretinopathy (PVR)
Propionibacterium acnes localized endophthalmitis
Psammomatoid ossifying fibroma
Pseudohypopyon
Pseudomonas sclerokeratitis
Pseudophakia
Pseudophakic bullous keratopathy (PBK)
Pterygium
Pyogenic granuloma

R
Reis-Bücklers dystrophy (RBCD)
Reticular cystoid degeneration
Retina
age-related macular degeneration (see Age-related macular
degeneration (ARMD))

686
angioid streaks
arteriosclerosis
bipolar cells
cystoid macular edema
developmental anomalies
albinism
congenital vascular abnormalities
dysplasia
Lange fold
myelinated nerve fibers
diabetes mellitus (see Diabetes mellitus)
exudates and edema
blood-retinal barrier
hard exudates
soft exudates
giant cell arteritis
hemorrhages
blot and dot hemorrhages
scaphoid or boat-shaped hemorrhages
splinter-or flame-shaped hemorrhages
vitreous hemorrhage
hypertensive retinopathy
internal limiting membrane
middle limiting membrane
Mueller cells
nuclear layer
peripheral retinal degenerations (see Peripheral retinal degenerations)
plexiform layer
retinal artery and arteriolar occlusions
central retinal artery occlusion
inner ischemic retinal atrophy
retinal emboli
retinal opacification
retinal detachment (see Retinal detachment)
retinal pigment epithelium
retinitis pigmentosa (see Retinitis pigmentosa)
rods and cones

687
 sickle hemoglobinopathy
Stargardt disease (see Stargardt disease)
Tay-Sachs disease
venous occlusions
Retinal arteriosclerosis
Retinal detachment
chronic retinal detachment
extracellular matrix material
morning glory configuration
exudative retinal detachment
rhegmatogenous retinal detachment
tractional retinal detachments
true and artifactitious
Retinal hemangioblastoma
Retinal pigment epithelium
Bruch membrane
flat preparations
melanin pigment
Retinal venous occlusions
Retinitis, cytomegalovirus. see-also Inflammation
acquired immunodeficiency syndrome
cytopathic effect
owl’s eye inclusions
Retinitis pigmentosa
autosomal dominant
intraretinal pigmentation
leber congenital amaurosis
RHO mutation
RP genes
Retinoblastoma
astrocytic hamartomas
classification
Coats disease
differential diagnosis
histopathology
basophilic nuclei and scanty cytoplasm
calcification

688
 coagulative necrosis
DNA deposition
iris neovascularization
necrotic tumor cells
perivascular cuffs
incontinentia pigmenti
leukocoria
medulloepithelioma
natural history
Norrie disease
ocular toxocariasis
oncogene and molecular genetics
bilateral tumors
familial retinoblastomas
genetic counseling
pineoblastoma
13Q-deletion syndrome
RB1 gene
second tumor
sporadic somatic retinoblastoma
orbital involvement
pathology and growth patterns
diffuse infiltrating growth pattern
endophytic retinoblastomas
exophytic retinoblastomas
persistent hyperplastic primary vitreous
prognostic factors
retinal detachment
retinal dysplasia and trisomy 13
retinopathy of prematurity
treatment
tumor differentiation
Flexner-Wintersteiner rosettes
Homer Wright rosettes
photoreceptor differentiation, fleurettes
retinocytoma
Retinocytoma

689
Retinopathy of prematurity (ROP)
Rhabdomyosarcoma
alveolar
cross striations and rhabdomyoblasts
embryonal
immunohistochemical diagnosis
Rhegmatogenous retinal detachment
Rheumatoid scleritis
Ring melanoma
Ruptured globe
Russell bodies

S
Salzmann nodular degeneration
Sarcoid optic neuropathy
Sarcoidosis
Scaphoid hemorrhages
Schnabel cavernous optic atrophy
Schnyder crystalline dystrophy (SCD)
Schwannoma
Sclera
Sebaceous carcinoma
chronic unilateral keratoconjunctivitis
comedocarcinoma pattern
foamy vacuolated cytoplasm
immunohistochemical techniques
intraepithelial spread
lipid in cytoplasmic vacuoles
meibomian carcinomas
pagetoid invasion
sebaceous adenoma
senile sebaceous gland hyperplasia
Seborrheic keratoses
adenoid type
benign sessile papilloma
dermatosis papulosa nigra

690
 inverted follicular keratosis
Secondary closed-angle glaucoma
Secondary open-angle glaucoma
choroidal melanomas and total retinal detachments
hemolytic glaucoma
iris melanoma
melanomalytic and melanocytomalytic glaucoma
ocular trauma
phacolytic glaucoma
pigmentary glaucoma
pseudoexfoliation
ring melanoma
Sectioning technique
Sickle hemoglobinopathy
Siderosis
Siderotic cataract
Small epithelioid cells
Soemmerring ring cataract
Splinter hemorrhages
Squamous cell carcinoma
Squamous epithelial lesions
actinic keratoses
CIN
conjunctival papillomas
hereditary benign intraepithelial dyskeratosis
invasive squamous cell carcinoma
mucoepidermoid carcinoma
Stargardt disease
autosomal recessively inherited
Best disease
RPE abnormalities
Stromal dystrophy, cornea
congenital hereditary stromal dystrophy
fleck corneal dystrophy
granular corneal dystrophy
lattice corneal dystrophy, type I
lattice dystrophy type II

691
 macular corneal dystrophy
Schnyder crystalline dystrophy
Sturge-Weber syndrome (SWS)
Subacute sclerosing panencephalitis (SSPE)
Subepithelial dystrophy
Subhyaloid hemorrhages
Sugar cataract
Superficial corneal dystrophy, cornea
gelatinous drop-like dystrophy
Meesman dystrophy
Reis-Bücklers dystrophy
Thiel-Behnke honey-comb dystrophy
Sympathetic uveitis
Synchysis scintillans
Synophthalmia
congenital cystic eye
uveal colobomas
bicentricity failure
CHARGE syndrome
cyst
definition
locations
macular colobomas
optic nerve aplasia
trisomy 13
Synthetic fiber granuloma
Syringocystadenoma papilliferum
Syringomas

T
Tay-Sachs disease
Teratoid medulloepithelioma
Thiel-Behnke corneal dystrophy (TBCD)
Thyroid ophthalmopathy
Tissue dehydration
Touton giant cells

692
Toxic cataract
Toxic retinopathies
Toxoplasma retinochoroiditis
Tractional retinal detachments
Transillumination
Traumatic cataracts
Tuberous sclerosis complex (TSC)
Tumor giant cells, uveal melanoma

U
Unilateral sporadic retinoblastoma
Uveal colobomas
bicentricity failure
CHARGE syndrome
cyst
definition
locations
macular colobomas
optic nerve aplasia
trisomy 13
Uveal malignant melanoma
clinical features
age-adjusted incidence
choroidal melanocyte, dendritic configuration
dendritic melanocytes
glaucoma
ocular/oculodermal melanocytosis
in older persons
race
tumor location
visual symptoms
diagnosis
differential diagnosis
gross pathology (see-also Choroidal melanoma)
choroidal melanomas
ciliary body melanomas

693
 extraocular extension
orange pigment
secondary glaucoma
histopathology
choroidal melanomas
epithelioid melanoma cells
fascicular melanoma
melanoma cells
mixed cell type
necrotic uveal melanoma
small epithelioid cells
spindle cell
prognostic factors
cell type
epithelioid cell absence
extracellular matrix patterns
extrascleral extension
gene expression profiling
infiltrating lymphocytes
liver metastases
mitotic activity
tumor size
vascular mimicry patterns
Uveitis

V
Varicella zoster virus (VZV)
Vascular lesions, orbit
cavernous hemangioma
hemangiopericytomas
neurogenic tumors
dermoid cyst
fibro-osseous lesions
fibrous histiocytoma
lacrimal gland (see-also Lacrimal gland)
mesenchymal tumors

694
 neurofibromas
rhabdomyosarcoma
schwannoma
pediatric orbital lesions
secondary orbital neoplasms
Vascular mimicry patterns
Vernal conjunctivitis
Viral keratitis
epidemic keratoconjunctivitis
herpes simplex keratitis
varicella zoster virus
Viral retinitis
cytomegalovirus
acquired immunodeficiency syndrome
cytopathic effect
owl’s eye inclusions
Herpes simplex
subacute sclerosing panencephalitis
Vitreous
amyloidosis
chronic vitreous hemorrhage
epiretinal gliosis
floaters
iridescent particles
asteroid hyalosis
synchysis scintillans
posterior vitreous detachment
proliferative vitreoretinopathy
tumors cells
cutaneous melanoma, metastasis
primary vitreous lymphoma
Whipple disease
vitreous abscess
Von Hippel-Lindau disease
Von Recklinghausen neurofibromatosis (NF-1)
choroidal infiltrate
elephantiasis neuromatosa

695
 lisch nodules
neurofibromin
Vossius ring

W
Weill-Marchesani syndrome
Whipple disease
Wound healing
central corneal wounds
limbal wounds
retinal scars
surgical complications
epithelial downgrowth
fibrous ingrowth
fibrous metaplasia, RPE
postoperative complications
unsutured wounds

X
Xanthelasmas
Xerophthalmia

Z
Zimmerman tumor
Zonular cataract

696
目录
Cover 2
Half Title 3
Title 4
Copyright 5
Dedication 7
Preface 8
Contents 11
Chapter 1. An Introduction to Ocular Anatomy and
13
Histology
Chapter 2. Congenital and Developmental Anomalies 36
Chapter 3. Inflammation 56
Chapter 4. Ocular Trauma 90
Chapter 5. Conjunctiva 113
Chapter 6. Cornea and Sclera 167
Chapter 7. The Lens 235
Chapter 8. Glaucoma 266
Chapter 9. Retina 298
Chapter 10. Vitreous 368
Chapter 11. Intraocular Tumors in Adults 527
Chapter 12. Retinoblastoma and Simulating Lesions 600
Chapter 13. Eyelid 383
Chapter 14. Orbit 434
Chapter 15. Optic Nerve 485
Chapter 16. Laboratory Techniques and Special Stains 502
Index 667

697