2

Intraocular Tumors
AN ATLAS AND TEXTBOOK

THIRD EDITION

Jerry A. Shields, MD
Director, Ocular Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University
Philadelphia, Pennsylvania, USA

Carol L. Shields, MD
Co-Director, Ocular Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University
Philadelphia, Pennsylvania, USA

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Third edition

Copyright © 2016 Wolters Kluwer.

Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins. Copyright © 1999 Lippincott
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Library of Congress Cataloging-in-Publication Data

Shields, Jerry A., author.

Intraocular tumors : an atlas and textbook / Jerry A. Shields, Carol L. Shields. – Third edition.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4963-2134-3 (alk. paper)
I. Shields, Carol L., author. II. Title.
[DNLM: 1. Uveal Neoplasms–Atlases. 2. Retinoblastoma–Atlases. WW 17]
RC280.E9
616.99’484–dc23
2015021546

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 This book is dedicated to our seven children,
Jerry, Patrick, Bill, Maggie Mae, John, Nellie, and Mary Rose.
They were toddlers and young children during the first two editions of this atlas
and now they are grown into young adults, developing their own careers.
We wish them satisfaction and success in their work
and unending happiness in life.

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 FOREWORD 1

For more than four decades, Jerry and Carol Shields have dedicated a significant
amount of their professional lives to the study of ocular oncology. Guided and
inspired by several mentors in this field, but particularly on the medical side by J.
Donald M. Gass and on the histopathological side by W. Richard Green, they have
worked diligently and productively on the Oncology Service at Wills Eye Hospital in
Philadelphia, indisputably the world’s leading institution in this field. Nowhere has
their primary work been assimilated and enhanced more than on this legendary
service which has emerged as a citadel for this division of ophthalmology. Their
original, innovative, and lasting work has not been limited to the malignant tumors
alone such as choroidal melanoma, retinoblastoma, and metastatic chorioretinal
disease, but it has also included important discoveries in degenerative,
inflammatory, infectious, and other rare chorioretinal diseases. The results have
been hundreds of clinical/scientific papers, virtually all in peer-review journals,
numerous books as authors and editors, and perhaps above all, the training of
countless residents and retina/ocular oncology fellows worldwide.
Several years ago, they realized the importance of intraocular pathology
throughout the world, specifically in terms of the prevalence and severe impact on
visual disabilities. This led to an attempt to meet the needs of the eye care
community with a comprehensive clinical atlas. That comprehensive atlas became
the standard reference in the field of intraocular tumors, read and referenced by the
medical community, residents and fellows in ophthalmology, and the rest of the
related eye care community. Prior to their original atlas, there was no standard for
the study of intraocular tumors. That stand-alone atlas is still the standard in our
field. So, why is there a need for a new edition? The answer is simple. Medical
knowledge is simply a moment in time. Advances in all phases of medical-scientific
disciplines have occurred since their first edition, particularly multimodal imaging.
This new edition has addressed intraocular tumor findings with optical coherence
tomography and its many sub-technological devices, the intravenous angiographies
and beyond. Through these advances in medical sciences, particularly technological
developments with advanced imaging, Jerry and Carol now have a new atlas which
describes new entities, new manifestations of old disorders, better explanations for
presumed mechanisms for the pathogenesis of these diseases, and a myriad of
suggested treatment modalities and approaches for their management. This new
atlas will clearly meet the expectations of its readers, students, distinguished
colleagues, and friends alike. It will provide a treasure of knowledge and experience
in the diagnosis and treatment of intraocular tumors. For sure, Jerry and Carol’s
combined efforts will be rewarded by the gratitude of clinicians, scientists,
ophthalmologists, retinal specialists, students, and patients, and by the incalculable
pleasure that will result on the part of the casual as well as the discerning reader of
this masterpiece in intraocular tumors.
Yours very truly,

Lawrence A. Yannuzzi, MD

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 Vitreous Retina Macula Consultants
of New York, New York, USA
LuEsther T. Mertz Retinal Research Center,
Manhattan Eye, Ear and Throat Hospital,
New York, USA

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 FOREWORD 2

In Greek mythology, Atlas (Ancient Greek: Aτλας) was the primordial Titan who
held up the celestial spheres.
In the sphere of ocular tumors, ophthalmologists, pathologists, and oncologists
have depended historically on our Shields Atlas for support. And this new edition
gives unprecedented service!
Intraocular Tumors: An Atlas and Textbook is a work of Olympian proportions:
this third edition includes an expanded and updated text; over 2,000 photographs
illustrate the spectrum of ocular neoplastic disease, including both common and rare
intraocular tumors; spectral domain enhanced depth imaging optical coherence
tomography examples abound, as well as a panoply of new ultrasound, fundus
autofluorescence, fluorescein angiographic, indocyanine green, magnetic resonance
imaging, and computed tomographic tumor images.
Also new to this edition of the atlas are a phalanx of tables marshalled to combat
ocular tumors, including those listing updated classifications, risk factors, clinical
features, differential diagnoses, and therapeutic options.
The atlas serves as well as a substantive reference work, with the bibliographic
material organized into major reviews, and small case series, and subdivided into
imaging, genetics/pathology, therapy, and case reports.
Chapters are color coded for fast reference, and there is an expanded and updated
emphasis on surgical illustrations and photographs. In short, this third atlas edition
features major upgrades and additions: the new ne plus ultra for state of the art,
comprehensive information on ocular tumors.
Jerry and Carol Shields, who rule the rarified heights of the 14th floor here at 840
Walnut Street in Philadelphia – and whose reach of course extends around the
world – are specially honored this year as we celebrate the 40th anniversary of the
Ocular Oncology Service at Wills Eye Hospital. A fitting time indeed to publish this
titanic magnum opus, crowning as it does four decades of globally and historically
unparalleled clinical experience with ocular oncology. This is a work of medicine
and of art, reflecting a heroic partnership with generations of patients and their
families, and with trainees from all over the world: a new standard for the field. The
broad shoulders of the Shields team support and epitomize in the finest way the
words of the Wills motto emblazoned on our seal: Skill with compassion. This Atlas
is both metaphorically and in actuality the fruition of that noble and herculean
labor.

Julia A. Haller, MD
Ophthalmologist-in-Chief, Wills Eye Hospital
William Tasman Endowed Chair
Professor and Chair of Ophthalmology
Thomas Jefferson University
Philadelphia, Pennsylvania, USA

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 PREFACE

Forty years in the management of intraocular tumors

Forty years is a long time. Forty years is half a lifetime and beyond the time of most
careers. Forty years represents the number of years that we have devoted our
medical and surgical practice to the study of intraocular tumors. U nlike nearly every
other ophthalmologist worldwide, we focus every minute of our career on the topic
of ocular tumors, benign or malignant, and the numerous simulating lesions. Every
working day, from early morning before the sunrise, we traveled to work, met and
examined patients, reviewed imaging and testing to establish the diagnosis,
provided treatment for a spectrum of intraocular tumors, finished a day’s work, and
traveled home in the early evening. Forty years represents the time that we used to
discover, think, design, critique, and perform hours-on-end research that culminated
in numerous ocular oncology projects with information pushing the field forward.
Slow and steady progress, but looking back, we participated in giant leaps of
knowledge.
And why choose such a rigorous vocation? For a singular goal—to improve
outcomes for patients with intraocular tumors.
Forty years ago, intraocular tumors were dismissed as rare, often requiring
enucleation. There was little clinical interest in this field. The subspecialty of ocular
oncology did not exist. But we saw the need for improvement in patient care and
our Ocular Oncology Service at Wills Eye Hospital was established. Over this 40-
year period, we participated in and witnessed the evolution of treatments such as
plaque radiotherapy for melanoma and retinoblastoma, targeted chemotherapy into
the ophthalmic artery for retinoblastoma, and photodynamic therapy for
hemangioma and other lesions.
Currently, ocular oncology has emerged as a vitally important subspecialty,
bursting with innovative treatments and remarkable success. We have achieved
ultimate goals of saving the patient’s life and the eye, and we are now focused on
visual outcomes with minimal local or systemic toxicities. Daily electronic
communication and online publication allow rapid spread of information to remote
regions of the world, at a button’s click. Organized local, national, and international
societies for ocular oncology educate physicians and patients. The playing field for
ocular cancer worldwide is gradually equalizing.
Retinoblastoma management has reached unsurpassed heights with novel methods
of intravenous, intra-arterial, and intravitreal chemotherapy with astounding high
rates of globe salvage, patient safety, and preservation of visual acuity. Remarkably,
some children are cured with two or three doses of single-agent chemotherapy
delivered into the ophthalmic artery. Vitreous retinoblastoma seeds, a previously
doomed finding, are now reversed with intravitreal chemotherapy, a technique that
was previously avoided for fear of tumor seeding outside the eye. Lack of
complications and reliable success has fueled this avenue of therapy.
U veal melanoma management has taken strong forward steps regarding early
tumor detection and unraveling genomic status to allow a more accurate estimation

10
of ultimate metastatic risk. A thin needle is slipped into the tumor to aspirate only
10 or 20 cells for DNA or RNA analysis, leading to a genetic profile of the tumor,
predicting high or low risk for metastasis. U veal melanoma can now be detected at
an incredibly small size, under 1 or 2 mm in thickness, using optical coherence
tomography (OCT) combined with established risk factors. Imagine, micro-
millimeter melanoma detection—a promise for better survival.
So looking back over these 40 years and particularly over the past 10 years since
the second edition of our atlases, we are proud of the enormous advancements in
the field of ocular oncology. A young girl with retinoblastoma that would have lost
her eye in the 1970s now will have the globe retained without cosmetic deformity
and likely with decent visual acuity. The uncle that might have lost his eye to a
large melanoma in the past will now possibly have detection of the tumor at a 2.0-
mm stage for early treatment and favorable prognosis. This remarkable progress in
ocular oncology has been achieved through collaboration worldwide.
This third edition of our book, Intraocular Tumors: An Atlas and Textbook, displays
the unparalleled headway in the field of ocular oncology. We have organized this
volume based on anatomic tumor origin with extensive documentation of clinical
and imaging features of nearly every intraocular tumor, benign or malignant. This
book is a treasure box for you to read and enjoy, and to use as a guide for patient
management.

Jerry A. Shields, MD
Carol L. Shields, MD

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 ACKNOWLEDGMENTS

This atlas is our masterpiece, our magnum opus, representing our careers in ocular
oncology. This atlas represents not only our work, but it embodies the work of our
team, a collaborative team working together each day in patient care and research
to achieve a magnificent, singular goal of excellence in ocular oncology. This team
includes physicians, nurses, technicians, photographers, administrators, secretaries,
and many others.
We are grateful to our professors for teaching us to the basic concepts of the
various benign and malignant tumors of the eye. This knowledge provided a solid
foundation for our understanding and further exploration of intraocular tumors. We
are thankful to our patients for granting us the honor to provide their medical care
and assist them in making medical decisions. Each patient story, with its ups and
downs, has added to our understanding of intraocular tumors.
From the Ocular Oncology Service at Wills Eye Hospital, we would like to thank
our outstanding team of ophthalmic photographers, Tika Siburt, Tessa Tintle,
Jacqueline Hanable, and Sandor Ferenczy for their masterful talents in capturing the
features of ophthalmic tumors. Each photograph is a resplendent display of tumor
characteristics. We thank Linda Warren for the illustrative surgical drawings.
Importantly, we would like to commend the entire staff on the Ocular Oncology
Service at Wills Eye Hospital under the direction of David Lashinsky for their
devotion and service to our patients. We particularly acknowledge the work of
Sandra Dailey in helping with day-to-day matters related to this book. Our staff is
the quintessential example of teamwork and dedication, with genuine care and
respect for each patient.
We are grateful to the medical staff at Wills Eye Hospital of Thomas Jefferson
U niversity, including Julia Haller MD, the Ophthalmologist-in-Chief, and the
members of the Pathology, Retina, U veitis, Cornea, Oculoplastics, Pediatric
Ophthalmology, Glaucoma, Neuro-Ophthalmology, and other services for assisting
with our patients and sharing ideas.
It has always been our practice to seek the best care for our patients from among
the several medical institutions in the Philadelphia region. Special thanks to the
entire staff at the Department of Medical Oncology at Thomas Jefferson U niversity,
particularly Takami Sato, MD, who has devoted his career to better understanding
and management of systemic uveal melanoma metastasis. In addition, we recognize
the world class, remarkably precise catheterization skills of Pascal Jabbour, MD, in
the Department of Neurosurgery, Endovascular Division. His provision of intra-
arterial chemotherapy to hundreds of babies worldwide has truly changed the lives
of those patients.
In addition, we would like to credit our pediatric oncology colleagues at The
Children’s Hospital of Philadelphia, especially the brilliantly accomplished Anne
Leahey, MD who designs and delivers systemic chemotherapy to children with
intraocular cancers. For her leadership regarding our patients and hundreds
worldwide, we are grateful. We credit the excellent work of Emi Caywood, MD at
Dupont Nemours Children’s Hospital of Thomas Jefferson U niversity, who monitors

12
all children receiving intra-arterial chemotherapy. We also recognize our team of
radiation oncologists at Drexel U niversity College of Medicine, Hahnemann
Hospital, under the direction of Lydia Komarnicky, MD. For the past 40 years, they
have provided cutting edge radiation therapy for our patients, including custom-
designed plaque radiotherapy and various methods of stereotactic teleradiotherapy.
We also recognize the leadership work of our genetics team at the U niversity of
Pennsylvania under the direction of Arupa Ganguly, PhD, who have skillfully and
authoritatively pioneered both retinoblastoma and melanoma genetic assessment.
Importantly, we would like to credit our ocular oncology associates who have
shared in the medical and surgical care of our patients. These include Arman
Mashayekhi, MD, an expert par excellence in intraocular tumors and laser
treatments, Sara Lally, MD, a maestro clinician with marvelous skills in patient
medical and surgical care, and Emil Say, MD, an outstanding specialist with
tremendous research abilities. In addition, there are hundreds of fellows and visitors
to the Oncology Service who should be recognized and commended for their
dedication to the field of ocular oncology.
There is one individual who deserves special recognition, our long-time friend
and ophthalmic pathologist, Ralph C. Eagle Jr, MD. Over the many years that we
have worked together, he has provided magnificent histopathology consultation on
ocular tumors, most of which were particularly challenging. We are indebted to him
for his dedication and consummate diagnostic acumen. Dr. Eagle has provided
numerous high-quality photographs of gross and microscopic specimens of many
conditions in this book, a testament to his bountiful pathology experience and
excellent photography skills. We would also like to thank Hormoz Eyha, MD, an
outstanding cytopathologist from Fox Chase Cancer Center, able to establish a tumor
diagnosis based on a few floating cells.
Finally, we would like to thank our seven children for allowing us the time and
support to complete this third edition of the atlases. When we wrote the first
edition, they were babies and toddlers, and with the second edition, they were
young children and teenagers. Now with this third edition, they are unfolding their
own careers as adults.
So, we have said enough. Now it is time for you to sit back and peruse the charm
of the 25 chapters in this textbook and atlas. You will note many new items in this
third edition including new illustrations, updated references and text, instructive
tables and classifications, and cutting edge imaging with current techniques
including autofluorescence and spectral domain optical coherence tomography. In
the end, our hope is that you will appreciate this work and find it useful for your
clinical practice.

Jerry A. Shields, MD
Carol L. Shields, MD

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 CONTENTS

PART 1 TUMORS OF THE UVEAL TRACT

Chapter 1 Congenital Uveal Lesions

Intraocular Lacrimal Gland Choristoma
Congenital Ocular Melanocytosis

Chapter 2 Melanocytic Tumors of Iris Stroma

Iris Nevus
Iris Melanoma

Chapter 3 Conditions That Simulate Iris Melanoma

Conditions That Simulate Iris Melanoma

Chapter 4 Iris Cysts

Iris Cysts
Iris Stromal Cysts

Chapter 5 Choroidal Nevus

Choroidal Nevus

Chapter 6 Melanocytoma of the Optic Disc and Posterior Uvea

Melanocytoma of the Optic Disc and Posterior Uvea

Chapter 7 Posterior Uveal Melanoma: Clinical Features

Clinical Features of Posterior Uveal Melanoma

Chapter 8 Posterior Uveal Melanoma: Pathology

Pathology of Posterior Uveal Melanoma

Chapter 9 Posterior Uveal Melanoma: Diagnostic Approaches

Posterior Uveal Melanoma: Diagnostic Approaches

Chapter 10 Posterior Uveal Melanoma: Management

Posterior Uveal Melanoma: Management

Chapter 11 Nonneoplastic Conditions That Can Simulate Posterior Uveal

Melanoma and Other Intraocular Neoplasms
Nonneoplastic Conditions That Can Simulate Posterior Uveal Melanoma
and Other Intraocular Neoplasms

Chapter 12 Metastatic Tumors to the Uvea, Retina, and Optic Disc

Metastatic Tumors to the Intraocular Structures

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Chapter 13 Vascular Tumors and Malformations of the Uvea
Circumscribed Choroidal Hemangioma
Diffuse Choroidal Hemangioma
Phakomatosis Pigmentovascularis
Uveal Hemangiopericytoma
Iris Vascular Tumors and Malformations

Chapter 14 Osseous, Myogenic, Neurogenic, Fibrous, and Histiocytic Tumors

of the Uvea
Choroidal Osteoma
Myogenic Tumors of the Uvea
Uveal Rhabdomyosarcoma
Uveal Schwannoma (Neurilemoma)
Uveal Neurofibroma
Uveal Juvenile Xanthogranuloma and Langerhans’ Cell Histiocytosis
Fibrous Histiocytoma, Primitive Neuroectodermal Tumor, and Other
Histiocytic Tumors of the Uvea

PART 2 TUMORS OF THE RETINA AND OPTIC DISC

Chapter 15 Retinoblastoma: Introduction, Genetics, Clinical Features,

Classification
Retinoblastoma: Introduction, Genetics, and Clinical Features

Chapter 16 Retinoblastoma: Diagnostic Approaches

Retinoblastoma: Diagnostic Approaches

Chapter 17 Retinoblastoma: Pathology

Retinoblastoma: Pathology

Chapter 18 Management of Retinoblastoma

Management of Retinoblastoma

Chapter 19 Lesions That Can Simulate Retinoblastoma

Lesions Simulating Retinoblastoma

Chapter 20 Vascular Tumors of the Retina and Optic Disc

Retinal Hemangioblastoma (Capillary Hemangioma)
Retinal Cavernous Hemangioma
Retinal Racemose Hemangioma
Vasoproliferative Tumor of the Ocular Fundus

Chapter 21 Glial Tumors of the Retina and Optic Disc

Solitary Circumscribed Retinal Astrocytic Proliferation
Retinal Astrocytic Hamartoma

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 Acquired Retinal Astrocytoma

PART 3 TUMORS OF THE PIGMENT EPITHELIUM, NONPIGMENTED

EPITHELIUM, AND LYMPHOMA/LEUKEMIA

Chapter 22 Tumors and Related Lesions of the Pigment Epithelium

Solitary Congenital Hypertrophy of the Retinal Pigment Epithelium
Multifocal Congenital Hypertrophy of the Retinal Pigment Epithelium
(Congenital Grouped Pigmentation; Bear Tracks)
Retinal Pigment Epithelial Hamartomas Associated with Familial
Adenomatous Polyposis and Gardner Syndrome
Pseudoneoplastic Reactive Hyperplasia of the Retinal Pigment Epithelium
Congenital Simple Hamartoma of the Retinal Pigment Epithelium
Torpedo Maculopathy
Combined Hamartoma of the Retina and Retinal Pigment Epithelium
Epithelioma (Adenoma) of the Iris Pigment Epithelium
Epithelioma (Adenoma) of the Ciliary Body Pigment Epithelium
Epithelioma (Adenoma) of the Retinal Pigment Epithelium

Chapter 23 Tumors of the Nonpigmented Ciliary Epithelium

Congenital Neoplasms (Medulloepithelioma)
Age-related Hyperplasia of the Nonpigmented Ciliary Epithelium (Coronal
Adenoma; Fuchs Adenoma)
Acquired Epithelioma of the Nonpigmented Ciliary Body Epithelium

Chapter 24 Intraocular Lymphoid Tumors and Leukemias

Intraocular Lymphoid Tumors
Benign Reactive Lymphoid Hyperplasia of the Uvea
Uveal Lymphoma
Uveal Plasmacytoma
Primary Vitreoretinal and Central Nervous System Lymphoma
Intraocular Leukemia

Chapter 25 Surgical Management of Intraocular Tumors

Surgical Management of Intraocular Tumors

Index

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 PART 1

TUMORS OF THE UVEAL TRACT

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 CHAPTER 1

CONGENITAL UVEAL LESIONS

INTRAOCULAR LACRIMAL GLAND CHORISTOMA

General Considerations
Several congenital abnormalities can affect the uvea, such as coloboma and aniridia,
but most of them are not directly related to the differential diagnosis of intraocular
tumors. The relationship between sporadic aniridia and nephroblastoma is well
known, but it is not usually associated with intraocular neoplasms. Other than the
systemic hamartomas and retinoblastoma, which are discussed in subsequent
chapters, there are only a few congenital abnormalities of the uvea that have
importance in the field of ocular oncology. Congenital iris cysts, that can simulate
iris tumors, are more appropriately discussed in Chapter 4, which covers both
congenital and acquired cysts. The two that are discussed here are intraocular
lacrimal gland choristoma and congenital ocular melanocytosis.
Ectopic lacrimal gland tissue can occur in the orbit, conjunctiva, or eye (1).
Intraocular lacrimal gland choristomas are rare and most have occurred in the iris
and with a few involving both the iris and ciliary body. Several theories on the
pathogenesis of intraocular lacrimal gland choristoma have been published (2).

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Clinical Features
Clinically, intraocular lacrimal gland choristoma usually is recognized in early
infancy as a fleshy reddish pink mass of the iris and/or ciliary body (1–11). It has a
slightly lobulated surface that appears almost identical to the normal lacrimal gland
as visualized at the time of orbital surgery. Clear cysts can sometimes appear within
the lesion early in the clinical course. These have been likened to lacrimal gland
cysts (dacryops). With regard to the natural course of intraocular lacrimal gland
choristoma, the main mass does not tend to grow substantially, but the cysts within
the lesion can progressively enlarge and cause iris atrophy, cataract, secondary
glaucoma, and hyphema. The differential diagnosis includes iris nevus, melanoma,
juvenile xanthogranuloma, and other iris granulomas in young patients. Although
our experience has been limited mostly to larger lesions, it is quite possible that
lacrimal gland choristoma can occur as a small, asymptomatic lesion that may
remain clinically insignificant. Fine needle aspiration biopsy (FNAB) has been used
to make the diagnosis in such cases (8).

Pathology
Histopathologically, intraocular lacrimal gland choristoma is a mass composed of
normal-appearing lacrimal gland tissue. On occasion, the ducts or acini within the
lesion become dilated due to accumulation of clear fluid, probably consistent with
tears, in the lumen. This explains the “cysts” that are sometimes seen clinically.

Management
Because iris lacrimal gland choristoma is usually diagnosed in young children and is
often stationary or slow growing, periodic observation is often an acceptable initial
management. As mentioned earlier, FNAB has been employed to make the
diagnosis based on recognition of typical benign epithelial cells consistent with
lacrimal gland. In such cases, observation may be initially employed because many
cases remain fairly stable. However, we believe that the appearance of a
progressively enlarging cyst within the lesion should prompt early surgical removal
of the mass to prevent glaucoma and visual impairment (9). If surgical excision of
the lesion is necessary, iridocyclectomy may be required to remove the entire lesion
(2,9). It is feasible that aspiration of the cyst could be a temporizing procedure,
although we have not yet performed cyst aspiration in this rare condition.

Selected References
1. Green WR, Zimmerman LE. Ectopic lacrimal gland tissue. Report of eight cases
with orbital involvement. Arch Ophthalmol 1967;78:318–327.
2. 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.
3. Conway VH, Brownstein S, Chisholm IA. Lacrimal gland choristoma of the
ciliary body. Ophthalmology 1985;92;449–453.
4. Morgan G, Mishin A. Ectopic intraocular lacrimal gland tissue. Br J Ophthalmol
1972;56:690–694.
5. O’Donnell BA, Martin FJ, Kan AE, et al. Intraocular lacrimal gland choristoma.

19
 Austral N Z J Ophthalmol 1990;18:211–213.
6. Kluppel M, Muller W, Sundmacher R. Lacrimal gland choristoma of the iris.
Arch Ophthalmol 1999;117:110–111.
7. Shields JA, Hogan RN, Shields CL, et al. Intraocular lacrimal gland choristoma
involving iris and ciliary body. Am J Ophthalmol 2000;129:673–675.
8. Kobrin EG, Shields CL, Danzig CJ, et al. Intraocular lacrimal gland choristoma
diagnosed by fine-needle aspiration biopsy. Cornea 2007;26(6):753–755.
9. Ramasubramanian A, Shields CL, Kytasty C, et al. Resection of intraocular
tumors (partial lamellar sclerouvectomy) in the pediatric age group.
Ophthalmology 2012;119(12):2507–2513.
10. Ranganathan D, Lenhart P, Hubbard GB, Grossniklaus H. Lacrimal gland
choristoma in a preterm infant, presenting with spontaneous hyphema and
increased intraocular pressure. J Perinatol 2010;30(11):757–759.
11. Kim BH, Henderson BA. Intraocular choristoma. Semin Ophthalmol
2005;20(4):223–229.

20
• INTRAOCULAR LACRIMAL GLAND CHORISTOMA
Intraocular lacrimal gland choristoma has characteristic clinical features and is generally
managed by local resection, which can be difficult in some cases due to the size and extent of
the lesion. Two clinicopathologic correlations are shown.

1. 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.
2. Shields JA, Hogan RN, Shields CL, et al. Intraocular lacrimal gland choristoma involving iris
and ciliary body. Am J Ophthalmol 2000;129:673–675.

Figure 1.1. Appearance of the lacrimal gland choristomas of the left iris in a 7-week-old baby girl. Note the pink
color of the lesion, with the clear cyst in the inferior part of the mass. The lesion was initially followed without
treatment.

21
Figure 1.2. Clinical appearance of the mass when the infant was 19 months old. A vascularized corneal
pannus is now present over the peripheral aspect of the mass. The inferior cyst is unchanged, but a new cyst
is emanating from the mass and filling almost half of the anterior chamber inferotemporally and obscuring part
of the pupil. The lesion was removed by a sector iridectomy. About 1 year later, retinal detachment ensued and
surgical repair was attempted elsewhere. According to unconfirmed history, enucleation was eventually
performed elsewhere.

Figure 1.3. Low-magnification photomicrograph showing glandular mass (above) and irregular, partially
collapsed cyst (below). (Hematoxylin–eosin ×10.)

22
Figure 1.4. Photomicrograph of the solid portion of the lesion, showing glandular tissue identical to normal
lacrimal gland. (Hematoxylin–eosin ×200.)

Figure 1.5. Clinical appearances of another lacrimal gland choristoma of the iris and ciliary body in a 12-
month-old boy. The lesion had been present since birth. Note the remarkable similarity to the prior case.

23
Figure 1.6. Histopathology of lesion seen in Figure 1.5, showing dense fibrous tissue (above) and normal
lacrimal gland tissue (below). (Hematoxylin–eosin ×40.)

24
 CONGENITAL OCULAR MELANOCYTOSIS

General Considerations
Congenital ocular melanocytosis is a well-known condition that has been the subject
of many reports, mainly because of its relationship to uveal melanoma (1–31). It
can be divided into ocular melanocytosis and oculodermal melanocytosis, or nevus
of Ota (1–5,10–12). They have identical episcleral and uveal pigmentation, but the
latter has periocular cutaneous pigmentation as well. Both predispose to uveal
melanoma, as well as melanoma of the ipsilateral skin, orbit, meninges, and central
nervous system, in areas where there are excess melanocytes as a part of this
condition. It has been estimated that about 1 in 400 Caucasian individuals with
ocular or oculodermal melanocytosis will develop uveal melanoma, sometimes in
childhood (6,9,11,12). Conversely, about 3% of patients with uveal melanoma will
have ocular melanocytosis (11). In extremely rare instances, the scleral pigmentation
can give rise to melanoma.
Several patients with bilateral ocular melanocytosis have developed bilateral
uveal melanoma (11). It has recently been found that uveal melanoma associated
with ocular melanocytosis has a more aggressive clinical course and an increased
chance of developing metastasis (11,12). About 10% of patients with ocular
melanocytosis have ipsilateral elevated intraocular pressure, seemingly related to
melanocytic hyperpigmentation of the anterior chamber angle (5).

Clinical Features
The most evident finding is unilateral (occasionally bilateral) hyperpigmentation of
the sclera and uveal tract. The scleral pigmentation is characterized by flat, gray-to-
brown patches of pigmentation that is quite different from the more localized
nodule of extraocular extension of uveal melanoma (11,12). Both the uveal and the
scleral pigment can have either a diffuse or sector distribution. Heterochromia is
often a predominant feature, with part or all of the affected iris being darker than
the iris of the fellow eye. The choroidal pigmentation is greater than in the opposite
eye. This condition most often involves the entire choroid but it can occur in a
partial or sector distribution in the choroid (10). With time, there develops
overlying degeneration of the retinal pigment epithelium and numerous drusen in
the area of choroidal involvement. A higher incidence of melanocytoma of the optic
nerve in affected eyes has been recognized (16). Multiple uveal melanoma can be
seen in patients with ocular melanocytosis (24,29). The presence of foci of orange
pigment over choroidal melanocytosis is a suggestion that the lesion is becoming
thicker and potentially evolving into choroidal melanoma.
Another interesting variation of ocular melanocytosis is iris mammillations
(22,25,28). These are numerous, villiform, closely compact dark-brown nodules that
occupy the anterior aspect of the iris. They can be appreciated to some degree in
most patients with ocular melanocytosis. In some instances the patient has only iris
mammillations, which is considered to be an incomplete expression (forme fruste)
of ocular melanocytosis (25). They are also seen in some patients with
neurofibromatosis and are different from the discrete iris Lisch nodules seen with
that condition. A relationship of ocular melanocytosis to phacomatosis

25
pigmentovascularis and nevus flammeus has recently been recognized and affected
patients also have an increased risk for uveal melanoma (14).

Diagnostic Approaches
The diagnosis of ocular and oculodermal melanocytosis is best made by recognition
of its typical clinical features described above. The recent use of optical coherence
tomography has confirmed increased choroidal thickness in the area of
pigmentation and such areas must be checked periodically to detect very early
melanoma (15).

Pathology
Histologically, ocular melanocytosis is characterized by dense, heavily pigmented
melanocytes in the affected uveal tract (16,17). The melanoma that can occur with
ocular melanocytosis usually arises in the choroid and/or ciliary body in patients of
any age (9–12). Iris melanoma in patients with ocular melanocytosis is rare.
However, we have observed a nodular iris melanoma arising from sector iris
melanosis in a child with ocular melanocytosis (30).

Management
Because of the increased incidence of melanoma, patients with ocular melanocytosis
should be carefully examined periodically for their entire life, looking for evidence
of uveal, orbital, or brain melanoma.

Selected References
Large Series
1. Gonder JR, Shields JA, Albert DM, et al. U veal malignant melanoma associated
with ocular and oculodermal melanocytosis. Ophthalmology 1982;89:953–960.
2. Gonder JR, Ezell PC, Shields JA, et al. Ocular melanocytosis. A study to
determine the prevalence rate of ocular melanocytosis. Ophthalmology
1982;89:950–952.
3. Gonder JR, Nichol J, Augsburger JJ, et al. Ocular and oculodermal
melanocytosis. Can J Ophthalmol 1985;20:176–178.
4. Teekhasaenee C, Ritch R, Rutnin U , et al. Ocular findings in oculodermal
melanocytosis. Arch Ophthalmol 1990;108:1114–1120.
5. Teekhasaenee C, Ritch R, Rutnin U , et al. Glaucoma in oculodermal
melanocytosis. Ophthalmology 1990;97:562–570.
6. Singh AD, De Potter P, Fijal BA, et al. Lifetime prevalence of uveal melanoma
in Caucasian patients with ocular (dermal) melanocytosis. Ophthalmology
1998;105:195–198.
7. Singh AD, Shields CL, Shields JA, et al. Bilateral primary uveal melanoma. Bad
luck or bad genes? Ophthalmology 1996;103:256–262.
8. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol
2004;49:3–24.
9. Shields CL, Kaliki S, Arepalli S, et al. U veal melanoma in children and
teenagers. Saudi J Ophthalmol 2013;27(3):197–201.
10. Shields CL, Qureshi A, Mashayekhi A, et al. Sector (partial) oculo(dermal)

26
 melanocytosis in 89 eyes. Ophthalmology 2011;118(12):2474–2479.
11. 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.
12. Mashayekhi A, Kaliki S, Walker B, et al. Metastasis from uveal melanoma
associated with congenital ocular melanocytosis: a matched study.
Ophthalmology 2013;120(7): 1465–1468.
Small Series
13. Donoso LA, Shields JA, Nagy RM. Epibulbar lesions simulating extraocular
extension of uveal melanomas. Ann Ophthalmol 1982;14:1120–1123.
14. 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.

Imaging
15. Pellegrini M, Shields CL, Arepalli S, Shields JA. Choroidal melanocytosis
evaluation with enhanced depth imaging optical coherence tomography.
Ophthalmology 2014:121:257–261.
Pathology
16. Zimmerman LE. Melanocytes, melanocytic nevi and melanocytomas. The Jonas
S. Friedenwald Memorial Lecture. Invest Ophthalmol 1965;4:11–41.
17. Ticho BH, Rosner M, Mets MB, et al. Bilateral diffuse iris nodular nevi. Clinical
and histopathologic characterization. Ophthalmology 1995;102:419–425.

Case Reports
18. Kiratli H, Bilgig S, Satilmis M. Ocular melanocytosis associated with intracranial
melanoma. Br J Ophthalmol 1996;80:1025.
19. Gonder JR, Shields JA, Shakin JL, et al. Bilateral ocular melanocytosis and
malignant melanoma of the choroid. Br J Ophthalmol 1981;65:843–845.
20. 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.
21. Cu-U njieng AB, Shields CL, Shields JA, et al. Iris melanoma in congenital
ocular melanocytosis. Cornea 1995;14:206–209.
22. Swann PG. Iris mammillations in ocular melanocytosis. Clin Exp Optom
2001;84:35–38.
23. Laquis SJ, Freeman JM, Fleming JC, et al. A rapidly growing choroidal
melanoma. Am J Ophthalmol 2002;133:580–581.
24. Honavar SG, Shields CL, Singh AD, et al. Two discrete choroidal melanomas in
an eye with ocular melanocytosis. Surv Ophthalmol 2002;47:36–41.
25. Gunduz K, Shields CL, Shields JA, et al. Iris mammillations as the only sign of
ocular melanocytosis in a child with choroidal melanoma. Arch Ophthalmol
2000;118:716–717.
26. Patel BC, Egan CA, Lucius RW, et al. Cutaneous malignant melanoma and
oculodermal melanocytosis (nevus of Ota): report of a case and review of the
literature. J Am Acad Dermatol 1998;38:862–865.
27. Kiratli H, Irkec M. Melanocytic glaucoma in a child associated with ocular

27
 melanocytosis. J Pediatr Ophthalmol Strabismus 1997;34:380–381.
28. Ragge NK, Acheson J, Murphree AL. Iris mammillations: significance and
associations. Eye 1996;10:86–91.
29. Shields CL, Eagle RC, Ip MS, et al. Two discrete uveal melanomas in a child
with ocular melanocytosis. Retina 2006;26:684–687.
30. Shields JA, Shields CL, Davidson R, et al. Iris melanoma arising from sector
congenital ocular melanocytosis in a child. Cornea 2009;28(10):1191–1193.
31. Louwagie CR, Baratz KH, Pulido JS, et al. Episcleral melanoma as a
complication of ocular melanocytosis. Graefes Arch Clin Exp Ophthalmol
2008;246(9):1351–1353.

28
• CONGENITAL OCULAR MELANOCYTOSIS: EXTERNAL FEATURES

Figure 1.7. Iris heterochromia secondary to ocular melanocytosis in the left eye of a 48-year-old woman. Note
that the left iris is darker. Note also the subtle skin hyperpigmentation on the sclera and left lower eyelid. These
findings are typical of oculodermal melanocytosis (nevus of Ota).

Figure 1.8. Closer view of affected iris in congenital ocular melanocytosis. Note that most of the iris is dark
brown and has numerous small nodules called mammillations, best seen inferiorly.

29
Figure 1.9. Marked scleral involvement with melanocytosis in a child. Note that this child also has very subtle
pigmentation of the left lower eyelid, meeting the criteria for oculodermal melanocytosis.

Figure 1.10. Inferior scleral melanocytosis in a 56-year-old woman.

30
Figure 1.11. Superior scleral melanocytosis in a 40-year-old man.

Figure 1.12. More severe melanocytosis in the left eye of a 30-year-old woman. Note that the scleral pigment
has a blue-gray color in this case.

31
• CONGENITAL OCULAR MELANOCYTOSIS: FUNDUS FEATURES

Figure 1.13. Fundus photograph of the unaffected right eye of the patient with contralateral ocular
melanocytosis. The background fundus color is normal.

Figure 1.14. Fundus photograph of the affected contralateral left eye of the patient shown in Figure 1.13. The
background fundus color is darker than the fellow right eye.

32
Figure 1.15. Montage fundus photograph of sector choroidal melanocytosis in a young man. In this case the
choroidal hyperpigmentation is nasal, inferior, and temporal, but it spares the superior quadrant.

Figure 1.16. Typical peripheral retinal pigment epithelial alterations and drusen in a 48-year-old person with
ocular melanocytosis. The extent and severity of these pigment epithelial changes increase with age.

33
Figure 1.17. Histopathology of the choroid in a patient with ocular melanocytosis. There is increased choroidal
thickness and hyperpigmentation secondary to increased number of choroidal melanocytes. (Hematoxylin–
eosin ×40.)

Figure 1.18. Melanocytoma of the optic disc in a patient with scleral melanocytosis in the opposite eye. There
appears to be a slight increased incidence of melanocytoma of the optic disc in patients with ocular
melanocytosis (personal observations). Note the juxtapapillary choroidal component of the lesion.

34
• CONGENITAL OCULODERMAL MELANOCYTOSIS (NEVUS OF OTA)
IN NON-CAUCASIANS

Figure 1.19. Oculodermal melanocytosis of right eye in an 8-year-old Indian boy.

Figure 1.20. Heavy scleral pigmentation is noted in patient in Figure 1.19.

35
Figure 1.21. Ipsilateral blue scalp melanocytosis is found in patient in Figure 1.19.

Figure 1.22. Ipsilateral subtle, pigmentation of the palate of patient in Figure 1.19. This subtle pigmentation
can be overlooked in patients with oculodermal melanocytosis.

36
Figure 1.23. Oculodermal melanocytosis on the right side in a 36-year-old African-American patient.
Oculodermal melanocytosis may be more difficult to diagnosis with dark-skinned individuals. However, as in
white patients, affected black patients also have a higher incidence of melanoma in the pigmented areas.

Figure 1.24. Fundus of the right eye in patient shown in Figure 1.23. Note the marked pigment epithelial
alterations secondary to the thickened, hyperpigmented choroid.

37
• UVEAL MELANOMA ASSOCIATED WITH OCULAR AND
OCULODERMAL MELANOCYTOSIS

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.

Figure 1.25. Right oculodermal melanocytosis in a 65-year-old woman.

She was referred because of recent diagnosis of choroidal melanoma in the right eye.

38
Figure 1.26. Gross appearance of melanoma-containing right eye after enucleation, showing the scleral and
episcleral pigmentation.

Figure 1.27. Sectioned eye with melanocytosis and melanoma, showing a large, dome-shaped mass,
characteristic of choroidal melanoma, and a total secondary retinal detachment.

39
Figure 1.28. Prominent scleral and episcleral melanocytosis in a 14-year-old boy with severely impaired vision
in the affected left eye. Ophthalmoscopy disclosed a macular choroidal melanoma, and enucleation was done.

Figure 1.29. Sectioned eye of patient shown in Figure 1.28, showing amelanotic choroidal melanoma arising
from diffuse choroidal melanocytosis. Note also the dense scleral and episcleral melanocytosis posterior to
the mass. Paradoxically, melanomas that arise from dense pigmentation of ocular melanocytosis and
melanocytoma are often amelanotic.

40
Figure 1.30. Histopathology of the lesion shown in Figure 1.29, revealing spindle malignant melanoma cells.
(Hematoxylin–eosin ×150.)

41
• MULTIFOCAL AND BILATERAL UVEAL MELANOMA ASSOCIATED
WITH CONGENITAL OCULAR MELANOCYTOSIS

Multifocal separate uveal melanomas can develop in an eye with diffuse ocular melanocytosis.
In addition, patients with bilateral ocular melanocytosis can develop bilateral uveal melanoma.
We have seen several instances of both. A case of each is depicted.

Figure 1.31. Wide-angle fundus photograph in a middle-aged woman who was followed for more than 20
years with oculodermal melanocytosis. At this examination she was found to have three new melanomas
located inferonasally, inferotemporally, and superotemporally (amelanotic).

42
Figure 1.32. Following enucleation of the eye of the patient in Figure 1.31, three separate melanomas were
documented. The two inferior melanomas are shown here.

Figure 1.33. Case of bilateral choroidal melanoma. Bilateral episcleral pigmentation characteristic of ocular
melanocytosis in a 54-year-old man. The lesions had been present since birth. A large melanoma in the left
eye prompted enucleation.

43
Figure 1.34. Gross section of enucleated left eye of patient shown in Figure 1.33 showing large, mostly
amelanotic choroidal melanoma.

Figure 1.35. Fundus of remaining right eye of patient shown in Figure 1.33, 9 years later, showing melanoma
superior to optic disc, with orange pigment on the surface. The patient declined treatment.

44
Figure 1.36. Fundus photograph of the right eye 2 years later, showing edge of large choroidal melanoma
superonasal to the optic disc. The patient was treated with radiotherapy, but ultimately lost all vision in the
remaining eye and eventually died from metastatic melanoma.

45
• DIFFUSE AND SECTOR OCULODERMAL MELANOCYTOSIS WITH
RELATED MELANOMA

Figure 1.37. Diffuse oculodermal melanocytosis causing dark heterochromia of the left eye.

Figure 1.38. Diffuse, scattered scleral melanocytosis of patient shown in Figure 1.37.

46
Figure 1.39. Small choroidal melanoma arising in the macular region with associated subretinal fluid and
orange pigment of patient shown in Figure 1.37.

47
Figure 1.40. Autofluorescence photography depicts the bright speckled hyperautofluorescence of the orange
pigment overlying the mass and within the subretinal fluid of tumor shown in Figure 1.39.

Figure 1.41. Sector ocular melanocytosis of the nasal aspect of the left eye.

48
Figure 1.42. Sector choroidal melanocytosis with inferonasal choroidal melanoma of patient shown in Figure
1.41.

49
• INTRACRANIAL MELANOMA ASSOCIATED WITH CONGENITAL
OCULAR MELANOCYTOSIS

As mentioned in the text, there is an increased incidence of uveal melanoma in patients with
ocular and oculodermal melanocytosis. Although less pronounced, there is also an increased
incidence of intracranial melanoma in affected patients. Two examples are shown.

Kiratli H, Bilgig S, Satilmis M. Ocular melanocytosis associated with intracranial melanoma. Br J

Ophthalmol 1996;80:1025.

Figure 1.43. Axial magnetic resonance imaging of the brain in a 46-year-old woman with severe headaches.
Note the large mass in the right temporal lobe. Histopathology of resected mass revealed malignant
melanoma. Metastatic melanoma to brain was suspected, but no primary melanoma was found. The patient
was referred for ocular examination to exclude a primary uveal melanoma.

50
Figure 1.44. Sagittal magnetic resonance imaging, showing the same lesion.

Figure 1.45. External appearance of both eyes in the patient shown in Figure 1.43. Note that the right eye has a
darker iris than the left eye, a finding present since birth. Note the episcleral pigmentation in the right eye.
There was diffuse choroidal melanocytosis but no uveal melanoma. It was concluded that the tumor was a
primary brain melanoma arising from intracranial melanocytosis in a patient with oculodermal melanocytosis,

51
but no intraocular melanoma.

Figure 1.46. Closer view of the right eye, showing scleral melanocytosis. There was also diffuse excess
pigmentation of the choroid of the right eye, but there was no uveal melanoma.

Figure 1.47. Prominent ocular melanocytosis found in the right eye of a 33-year-old woman who presented
with a right facial palsy. (Courtesy of Hayyam Kiratli, MD.)

52
Figure 1.48. Axial magnetic resonance imaging of the brain in the patient shown in Figure 1.47, note the large
intracranial mass. The brain lesion was excised and proved to be melanoma. The patient had no uveal
melanoma. (Courtesy of Hayyam Kiratli, MD.)

53
 CHAPTER 2

MELANOCYTIC TUMORS OF IRIS STROMA

IRIS NEVUS

General Considerations
The common iris nevus is well recognized in the literature (1–42). In contrast to iris
freckle, a nevus effaces the architecture of the iris stroma. Iris freckle occurs in about
60% of the population and probably has no malignant potential, whereas an iris
nevus occurs in approximately less than 5% of the population and can rarely give
rise to malignant melanoma. There are conflicting reports regarding the relationship
between iris nevus and choroidal melanoma (3,8,9,12). Iris nevus, like other
melanocytic uveal tumors, shows a predilection for Caucasians and becomes
clinically apparent during puberty or young adulthood. In a survey of 3,680 iris
tumors, iris melanocytic nevus was the most common solid tumor, accounting for
42% of such cases (1).

Clinical Features
The size, shape, and pigmentation of iris nevus can vary from case to case
(1,2,13,14). This tumor can be small and circumscribed, large and diffuse, or flat to
dome shaped, and can sometimes show surrounding dusting or satellite seeding into
the adjacent iris. It can be entirely amelanotic and transparent, or it can be deeply

54
pigmented. Greater than 80% are located in the inferior half of the iris (1,13). It was
once believed that an irregular pupil, angle involvement, secondary cataract,
secondary cyst, tapioca configuration, or adjacent trans-scleral extension were signs
of malignant transformation. However, we now know that many stable iris nevi can
produce such secondary changes (1). Overall, about 4% of borderline suspicious iris
pigmented lesions referred to an ocular oncology service showed growth within 10
years and evolved into low-grade melanoma (5,13). An ABCDEF guide has been
published to predict risk factors for an iris nevus transformation into melanoma (13)
(Table 2.1).
Secondary glaucoma associated with iris nevus is extremely rare, and any
pigmented lesion of the iris associated with elevated intraocular pressure should
raise suspicion of iris melanoma (1,14,16). It is of interest that iris nevus can be
associated with an iris pigment epithelial cyst immediately posterior to the lesion.
We have observed this on several occasions.
A variation of iris nevus is melanocytoma, a lesion that can simulate melanoma
and is best known to occur on the optic disc. In contrast to ordinary nevus and
melanoma, it is more deeply pigmented and can undergo spontaneous necrosis and
pigment dispersion, with induction of secondary glaucoma (16). The glaucoma seen
with melanocytoma is due to obstruction of trabecular meshwork by melanophages
that contain pigment liberated by necrotic melanocytoma cells. Hence, this
condition has been termed melanocytomalytic glaucoma (16). Histopathologically
confirmed iris melanocytoma has been documented to show clinical enlargement,
without malignant change, in adults and in young children (10). In some instances,
iris melanocytoma can represent anterior extension of a larger melanocytoma in the
ciliary body (11). Like other iris nevi, iris melanocytoma can rarely undergo
malignant transformation (1,10,11). Other variations of iris nevus include sector
nevus, tapioca nevus, and diffuse iris nevus. Sector iris nevus has received little
mention in the literature. This lesion appears as a well-defined sector of increased
pigment that extends from the pupil to the angle. It is usually 3 to 4 clock hours but
can range in size from 1 to 11 clock hours. This lesion is probably congenital, and
we consider it to be a localized form of ocular melanocytosis.

Table 2.1 The ABCDEF guide for factors predictive of iris nevus
transformation into iris melanoma

Tapioca iris nevus can have an amelanotic, multinodular surface that resembles
tapioca pudding. Such tapioca nevus tends to be nonpigmented with a nearly

55
transparent appearance and can be multifocal with seeding into the angle. Tapioca
nevus can be remarkably similar to tapioca melanoma, to be discussed later.
Although we are not aware of publications on tapioca nevi, we have diagnosed it on
many occasions.
The diffuse iris nevus syndrome is alternatively termed Cogan–Reese syndrome, a
condition that is included in the spectrum of the iridocorneal endothelial (ICE)
syndrome, discussed in Chapter 3.

Imaging
Imaging of iris nevus can be performed with fluorescein angiography, ultrasound
biomicroscopy (U BM), and anterior segment optical coherence tomography (OCT)
(18–24). Most nevi are minimally fluorescent on angiography. These lesions tend to
be acoustically dense and minimally thickened on U BM (21,23,24) and optically
dense with shadowing on anterior segment OCT (21,24).

Pathology
Histopathologically, iris nevus cells generally appear as slender spindle cells but can
occasionally show plump, rounded cells, as seen in melanocytoma (25–27). Rarely,
benign epithelioid cells can predominate, suggesting a diagnosis of melanoma. In
borderline cases, iris nevus can be difficult to differentiate microscopically from
low-grade melanoma. When there is malignant change in melanocytoma, the
melanoma component can be composed of a clone of amelanotic spindle-shaped
cells that are quite different from the round deeply pigmented cells that comprise
the melanocytoma.

Management
Concerning management, the patient with iris nevus should be informed that the
chances of malignant transformation into melanoma are relatively low. Ophthalmic
examination every 6 to 12 months is recommended to detect evidence of growth.
The patient should be informed of the chances of malignant transformation based
on the aforementioned ABCDEF guide (13). Baseline gonioscopy and photography
as well as anterior segment OCT or U BM can be helpful in detecting early
enlargement of the lesion. Fluorescein angiography has little value in differentiating
iris nevus from melanoma. Amelanotic tumors show hyperfluorescence and deeply
pigmented cells are hypofluorescent regardless of the diagnosis. U BM can help to
detect adjacent ciliary body involvement and to follow the lesion for growth. It can
help to differentiate nevus in the angle from cyst. If photographic evidence of
growth is documented, then interventional therapy should be considered. This is
covered in the next section on iris melanoma.

Selected References
Large Series
1. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119(2):407–414.
2. Shields JA, Sanborn GE, Augsburger JJ. The differential diagnosis of malignant
melanoma of the iris. A clinical study of 200 patients. Ophthalmology

56
 1983;90:716–720.
3. Michelson JB, Shields JA. The relationship of iris nevi to posterior uveal
melanoma. Am J Ophthalmol 1977;83:694–696.
4. 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.
5. Territo C, Shields CL, Shields JA, et al. Natural course of melanocytic tumors of
the iris. Ophthalmology 1988;95:1251–1255.
6. Workman DM, Weiner JW. Melanocytic lesions of the iris—a
clinicopathological study of 100 cases. Aust N Z J Ophthalmol 1990;18:381–384.
7. van Klink F, de Keizer RJ, Jager MJ, et al. Iris nevi and melanomas: a clinical
follow-up study. Doc Ophthalmol 1992;82:49–55.
8. Bataille V, Sasieni P, Cuzick J, et al. Risk of ocular melanoma in relation to
cutaneous and iris naevi. Int J Cancer 1995;60:622–626.
9. Harbour JW, Brantley MA Jr, Hollingsworth H, et al. Association between
posterior uveal melanoma and iris freckles, iris naevi, and choroidal naevi. Br J
Ophthalmol 2004;88:36–38.
10. Demirci H, Mashayekhi A, Shields CL, et al. Iris melanocytoma: clinical features
and natural course in 47 cases. Am J Ophthalmol 2005;139:468–475.
11. Shields JA, Shields CL, Eagle RC Jr. Melanocytoma (hyperpigmented
magnocellular nevus) of the uveal tract. The 34th G. Victor Simpson Lecture.
Retina 2007;27:730–739.
12. Weis E, Shah CP, Lajous M, et al. The association of cutaneous and iris nevi
with uveal melanoma: a meta-analysis. Ophthalmology 2009;116(3):536–543.
13. 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.
14. Shields CL, Shields PW, Manalac J, et al. Review of cystic and solid tumors of
the iris. Oman J Ophthalmol 2013;6(30):159–164.

Small Series
15. Jakobiec FA, Silbert G. Are most iris “melanomas” really nevi? Arch Ophthalmol
1981;99:2117–2132.
16. Fineman M, Eagle RC Jr, Shields JA, et al. Melanocytomalytic glaucoma in eyes
with necrotic iris melanocytoma. Ophthalmology 1998;105:492–496.
17. Kathil P, Milman T, Finger PT. Characteristics of anterior uveal melanocytomas
in 17 cases. Ophthalmology 2011;118(9):1874–1880.

Imaging/Pathology
18. Hodes BL, Gildenhar M, Choromokos E. Fluorescein angiography in pigmented
iris tumors. Arch Ophthalmol 1979;97:1086–1088.
19. Nordlund JR, Robertson DM, Herman DC. U ltrasound biomicroscopy in
management of malignant iris melanoma. Arch Ophthalmol 2003;121:725–727.
20. Malandrini A, Mittica V, Tosi GM, et al. Clinical and ultrasound biomicroscopic
features in iris melanocytoma. Ophthalmic Surg Lasers Imaging 2009;40(1):46–
49.
21. Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118(7):1297–1302.

57
22. Doro D, Parrozzani R, Midena E. U ltrasound biomicroscopy examination of
anterior uveal tumors: information on location and size only? Acta Clin Croat
2012;51(Suppl 1):37–44.
23. Giuliari GP, Krema H, McGowan HD, et al. Clinical and ultrasound
biomicroscopy features associated with growth in iris melanocytic lesions. Am J
Ophthalmol 2012;153(6):1043–1049.
24. Razzaq L, Emmanouilidis-van der Spek K, Luyten GP, et al. Anterior segment
imaging for iris melanocytic tumors. Eur J Ophthalmol 2011;21(5):608–614.
25. Grossniklaus HE, Oakman JH, Cohen C, et al. Histopathology, morphometry,
and nuclear DNA content of iris melanocytic lesions. Invest Ophthalmol Vis Sci
1995;36:745–750.
26. Ozdemir Y, Onder F, Cosar CB, et al. Clinical and histopathologic findings of
iris nevus (Cogan-Reese) syndrome. Acta Ophthalmol Scand 1999;77:234–237.
27. Schalenbourg A, U ffer S, Zografos L. U tility of a biopsy in suspicious
pigmented iris tumors. Ophthalmic Res 2008;40(5):267–272.

Case Reports
28. Shields JA, Annesley WH, Spaeth GL. Necrotic melanocytoma of iris with
secondary glaucoma. Am J Ophthalmol 1977;84:826–829.
29. Shields JA, Augsburger JJ, Bernardino V Jr, et al. Melanocytoma of the ciliary
body and iris. Am J Ophthalmol 1980;89:632–635.
30. Nakazawa M, Tamai M. Iris melanocytoma with secondary glaucoma. Am J
Ophthalmol 1984;97:797–799.
31. Shields JA, Karan DS, Perry HD, et al. Epithelioid cell nevus of the iris. Arch
Ophthalmol 1985;103:235–237.
32. Cialdini AP, Sahel JA, Jalkh AE, et al. Malignant transformation of an iris
melanocytoma. A case report. Graefes Arch Clin Exp Ophthalmol 1989;227:348–
354.
33. Paridaens D, Lyons CJ, McCartney A, et al. Familial aggressive nevi of the iris in
childhood. Arch Ophthalmol 1991;109:1552–1554.
34. Sneed SR, Vine AK. Spontaneous collapse of a primary iris cyst associated with
an iris nevus. Arch Ophthalmol 1991;109:21–22.
35. Teichmann KD, Karcioglu ZA. Melanocytoma of the iris with rapidly
developing secondary glaucoma. Surv Ophthalmol 1995;40:136–144.
36. Carlson DW, Alward WL, Folberg R. Aggressive nevus of the iris with secondary
glaucoma in a child. Am J Ophthalmol 1995;119:367–368.
37. Biswas J, D’Souza C, Shanmugam MP. Diffuse melanotic lesion of the iris as a
presenting feature of ciliary body melanocytoma: report of a case and review of
the literature. Surv Ophthalmol 1998;42:378–382.
38. Kiratli H, Bilgic S, Gedik S. Late normalization of melanocytomalytic
intraocular pressure elevation following excision of iris melanocytoma. Graefes
Arch Clin Exp Ophthalmol 2001;239:712–715.
39. Shields JA, Eagle RC Jr, Shields CL, et al. Progressive growth of an iris
melanocytoma in a child. Am J Ophthalmol 2002;133:287–289.
40. Sagoo MS, Shields CL, Eagle RC Jr, et al. Brown trabeculectomy bleb from
necrotic iris melanocytoma. Acta Ophthalmol Scand 2007;85(5):571-572.
41. Qian Y, Zakov ZN, Schoenfield L, et al. Iris melanoma arising in iris nevus in
oculo(dermal) melanocytosis. Surv Ophthalmol 2008;53(4):411–415.

58
42. Song WK, Yang WI, Lee SC. Iris naevus with recurrent spontaneous hyphema
simulating an iris melanoma. Eye (Lond) 2009;23(6):1486–1488.

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• IRIS FRECKLE AND IRIS NEVUS: PIGMENTED VARIATIONS

Figure 2.1. Multiple iris freckles. The freckle does not efface or alter the normal iris architecture.

Figure 2.2. Iris nevus adjacent to the pupil in a 69-year-old woman.

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Figure 2.3. Iris nevus in the mid-portion of the iris in a 40-year-old woman.

Figure 2.4. Slightly larger iris nevus in the inferonasal quadrant of the left iris in a middle-aged woman.

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Figure 2.5. Sector inferior iris nevus in a 39-year-old man. Most such sector nevi are noted at birth or shortly
thereafter and may represent a localized variation of ocular melanocytosis.

Figure 2.6. Two pigmented iris nevi in same eye. Note that there are also several iris freckles.

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• IRIS NEVUS: NONPIGMENTED AND MINIMALLY PIGMENTED
VARIATIONS

The nonpigmented or minimally pigmented iris nevus can resemble a leiomyoma, metastatic
carcinoma, lymphoma, and other nonpigmented iris lesions. The term nonpigmented is used
here for simplicity, even though some may contain slight pigmentation. Selected examples are
illustrated.

Figure 2.7. Circumscribed nonpigmented iris nevus in the inferior aspect of the iris stroma.

Figure 2.8. Very subtle nonpigmented iris nevus in peripheral iris inferotemporally. An unrelated pterygium is

63
present nasally.

Figure 2.9. Nonpigmented iris nevus inferior between the 6 o’clock and 7 o’clock positions. Note the peaking of
the pupil inferiorly and slight ectropion iridis.

Figure 2.10. Nonpigmented iris nevus adjacent to the pupil in the left iris.

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Figure 2.11. Nonpigmented peripheral nevus at the 5 o’clock position in the left iris.

Figure 2.12. Ultrasound biomicroscopy of the lesion shown in Figure 2.11. Note the thickening of the peripheral
iris and angle structures and relatively low internal reflectivity in the round mass.

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• IRIS NEVUS: EFFECTS ON ADJACENT STRUCTURES
Iris nevi can distort the adjacent pupil, involve the anterior chamber angle, produce a secondary
cataract or a secondary cyst, and even demonstrate trans-scleral involvement. Such findings can
occur with a nevus and do not necessarily indicate that the lesion is malignant.

Figure 2.13. Peaking of the pupil secondary to an iris nevus in a 32-year-old man.

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Figure 2.14. Ectropion of the pupillary margin secondary to a sector iris nevus in a 48-year-old man.

Figure 2.15. Gonioscopic view showing a peripheral iris nevus that affects the angle structures and stops
abruptly at Schwalbe’s line.

Figure 2.16. Sector cortical cataract secondary to a peripheral iris nevus. Such a cataract can occur with an iris
nevus, but transillumination, gonioscopy, and ultrasound biomicroscopy can be used to exclude involvement of
the ciliary body.

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Figure 2.17. Slit lamp view of an iris nevus with a secondary cyst of the iris pigment epithelium posterior to an
iris nevus. Such a cyst should not be misinterpreted as a malignant melanoma or a cystoid cavity within a
melanoma.

Figure 2.18. Iris nevus with trans-scleral involvement. Such a finding does not necessarily mean that the tumor
has invaded through the sclera. It may be a trans-scleral component of a congenital nevus and not an
extraocular extension of malignant melanoma.

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• IRIS MELANOCYTOMA
Melanocytoma is a deeply pigmented variant of melanocytic nevus. Although most are stable,
some can show very slow growth and tumor seeding, similar to melanoma.

Figure 2.19. Deeply pigmented presumed iris melanocytoma inferotemporally in the right eye in a young man
as seen in 1972.

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Figure 2.20. Same lesion in 2005, showing slight growth. The patient elected no treatment because growth
was minimal for 33 years at the time of this writing.

Figure 2.21. Friable iris melanocytoma with anterior chamber seeds. A fine needle aspiration was done, and
the cytopathologic diagnosis was melanocytoma. The patient is being followed closely because of possibility
of potential for secondary glaucoma, malignant transformation, and sampling error on needle biopsy.

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Figure 2.22. Melanocytoma near pupillary margin. The elevated lesion has a dark brown color and a rough,
mossy appearance. It was removed by sector iridectomy.

Figure 2.23. Histopathology of the lesion shown in Figure 2.22, demonstrating dense cytoplasmic melanin that
precludes a view of cell detail (Hematoxylin–eosin ×150).

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Figure 2.24. Bleached section of the lesion shown in Figure 2.23, allowing better visualization of cell detail and
features of melanocytoma (Hematoxylin–eosin ×75).

72
• IRIS MELANOCYTOMA WITH SECONDARY GLAUCOMA
(MELANOCYTOMALYTIC GLAUCOMA)

Iris melanocytoma is a deeply pigmented type of iris nevus. It has a tendency to undergo
spontaneous necrosis, pigment dispersion, and glaucoma (melanocytomalytic glaucoma). It can
rarely transform into malignant melanoma.

1. Shields JA, Annesley WH, Spaeth GL. Necrotic melanocytoma of iris with secondary
glaucoma. Am J Ophthalmol 1977;84:826–829.
2. Fineman M, Eagle RC Jr, Shields JA, et al. Melanocytomalytic glaucoma in eyes with necrotic
iris melanocytoma. Ophthalmology 1998;105:492–496.

Figure 2.25. Inferior iris melanocytoma in a 40-year-old woman. The lesion was producing seeding into the
angle and secondary glaucoma.

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Figure 2.26. Photomicrograph of the lesion shown in Figure 2.25 after removal by iridocyclectomy. Note the
dense pigmentation in the iris, trabecular meshwork, and base of the ciliary body (Hematoxylin–eosin ×10).

Figure 2.27. Photomicrograph of the lesion shown in Figure 2.25. This bleached section shows plump, round
cells with relative uniform nuclei (Hematoxylin–eosin ×250).

Figure 2.28. Iris melanocytoma in a 23-year-old man as seen in 1972.

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Figure 2.29. Gonioscopic view of the lesion shown in Figure 2.28, 3 years later. The lesion has produced
satellite seeds, pigment deposition into the anterior chamber angle, and secondary glaucoma. Although
enucleation was considered, it was elected to remove the lesion by iridectomy.

Figure 2.30. Appearance after removal of the main tumor. The satellites and angle pigmentation subsequently
resolved and the glaucoma disappeared. The patient has excellent vision and no tumor recurrence more than
30 years later.

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• IRIS MELANOCYTOMA WITH DOCUMENTED GROWTH
Even though iris melanocytoma is benign, it can show slow enlargement and simulate iris
melanoma. Such growth is more likely to occur in young children. A case is illustrated.

Figure 2.31. Appearance of the iris lesion in 1994 when the patient was 3 years old.

Figure 2.32. Same lesion in the year 2000, showing considerable enlargement.

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Figure 2.33. Appearance after tumor removal by sector iridectomy. The pupil is dilated pharmacologically.

Figure 2.34. Sectioned gross specimen, showing the black color of the circumscribed lesion. Note the lack of
cohesiveness in the lesion.

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Figure 2.35. Histopathology, showing dense cytoplasmic pigment that precludes a view of cell detail
(Hematoxylin–eosin ×250).

Figure 2.36. Bleached section, showing typical cytologic features of melanocytoma. There are a few prominent
nucleoli, but the tumor is otherwise cytologically benign (Hematoxylin–eosin ×200).

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IRIS MELANOMA

General Considerations
Iris melanoma is a malignant neoplasm that arises from melanocytes in the iris
stroma (1–59). This section only provides an overview and the reader is advised to
consult the many references for more details. Iris melanoma accounts for about 4%
of all uveal melanomas and has a strong predilection for Caucasians (98%) (5).
There are several clinical variations, including circumscribed, diffuse, tapioca, and
trabecular meshwork types.

Clinical Features
Circumscribed iris melanoma appears as a variably pigmented, reasonably well-
defined mass in the iris stroma and has a predilection to occur in the inferior
portion of the iris, with >80% located below the horizontal meridian (1,7).
Melanoma can be deeply pigmented, moderately pigmented, or clinically
amelanotic. The size and shape of circumscribed iris melanomas also vary
considerably from case to case. Some are relatively small and flat and others are
elevated and dome shaped. On average, iris melanoma shows mean basal diameter
of 6.2 mm and mean thickness of 2.3 mm (1). The margins can be distinct or ill
defined. Like iris nevus, it can cause an irregular pupil and ectropion of the
pupillary margin.
There are several other clinical variations of iris melanoma including diffuse,
trabecular meshwork and tapioca melanoma. Diffuse melanoma is a rare subtype
and has a tendency to produce a classic clinical picture of acquired hyperchromic
heterochromia from flat melanoma and secondary glaucoma from tumor infiltration
into the trabecular meshwork. Diffuse iris melanoma is commonly misdiagnosed
initially as pigmentary glaucoma or pigment dispersion syndrome and there is often
a delay in diagnosis (1,17). A variation of diffuse melanoma is the ring melanoma of
the trabecular meshwork, in which the tumor is predominately confined to the
trabecular meshwork with minimal iris involvement, and grows along the anterior
chamber angle, producing secondary glaucoma with little mass effect (16). This
form of melanoma is detected by gonioscopy. Tapioca melanoma is a name
introduced by Reese and associates to describe a variant of iris melanoma with
multiple amelanotic, nearly transparent, tiny nodules of tumor, giving a surface
appearance of tapioca pudding (29,30).
Iris melanoma is suspected based on typical clinical features found on slit lamp
biomicroscopy. In an analysis of 317 eyes with iris melanoma by Shields et al. (1),
related features include corectopia (45%), ectropion uveae (24%), glaucoma (35%),
angle seeding (28%), hyphema (3%), and extraocular extension (3%). Iris
melanoma can cause secondary glaucoma by a variety of mechanisms including
direct infiltration of the trabecular meshwork, iris neovascularization with angle
closure, or inflammatory posterior synechia with iris bombe (1,4). Often the
diagnosis is difficult. Iris melanoma can present as a spontaneous hyphema, in
which the blood obscures the underlying tumor. Others undergo necrosis and cause
inflammation, simulating iridocyclitis. Iris melanoma can rarely compress the
cornea, causing secondary calcific band keratopathy. Although iris melanoma can

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usually be diagnosed with slit lamp biomicroscopy alone, ultrasound biomicroscopy
can be used to detect ciliary body extension and to differentiate iris melanoma from
cystic lesions that can simulate melanoma (21–27).
There is an established American Joint Cancer Committee (AJCC, 7th edition)
classification of iris melanoma to assist in tumor classification for prognostication
(32). This is listed below.

Table 2.2 Iris Melanoma based on American Joint Cancer Committee (AJCC,
7th edition) classification

Pathology
A high-grade iris nevus and a low-grade melanoma can be similar
histopathologically, and in some instances, their differentiation can be challenging,
even for experienced ocular pathologists. In general, smaller iris melanomas are
composed of low-grade melanoma cells, usually of the spindle A or spindle B cell
types, but the larger, less cohesive ones often contain epithelioid melanoma cells,
imparting a worse prognosis (28,34).
Recent data on cytogenetic testing of iris melanoma have documented
chromosome 3 complete or partial monosomy (35). These mutations are believed
are found in patients with older age and tumors with high-grade cell type.

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Management
The management of iris melanoma can be controversial and the opinions expressed
here are based on the authors’ personal experience with hundreds of cases over 40
years (38–52). Based on original reports, only about 5% of untreated borderline
melanocytic iris lesions show growth over the first 5 years after detection (7).
Therefore, the majority of circumscribed melanocytic iris lesions are probably
benign nevi and do not require immediate treatment. In cases that are highly
suspicious for malignancy, fine needle aspiration biopsy (FNAB) can be of assistance
in the diagnosis of an iris melanoma although it has limitations because spindle cell
nevus and melanoma can be remarkably similar (33,34). We generally do not
recommend diagnostic FNAB in cases in which it appears certain that the lesion will
need resection by iridectomy or iridocyclectomy, since sufficient material will be
obtained to make a more definitive diagnosis histopathologically. However, FNAB
can be used to confirm the diagnosis if enucleation or plaque radiotherapy is the
anticipated treatment. In addition, FNAB for cytogenetic evaluation can be useful for
prognostication of survival (35–37). Melanocytic iris lesions that are large (>5 mm)
or show growth generally require treatment.
The best management of circumscribed iris melanomas that are less than 6 mm in
diameter is local excision with iridectomy (if angle involvement absent),
iridogoniectomy (if angle involvement present), or by iridogoniocyclectomy (if
ciliary body involvement present) (38–52). This can be supplemented by plaque
brachytherapy if there is residual or recurrent tumor (46). For tumors greater than 6
mm iris involvement or those with seeding on the iris or into the anterior chamber
angle structures, primary plaque radiotherapy is preferable (39,41,42,52).
Enucleation is sometimes necessary when more than half of the iris and trabecular
meshwork are involved by tumor and when there is advanced secondary glaucoma,
provided that the fellow eye has useful vision. It is important to emphasize that
there are indications and complications to consider when choosing local resection,
plaque radiotherapy, or enucleation. Although iris melanoma is usually well
controlled following plaque radiotherapy, we believe that the technique should be
reserved for selected growing iris melanomas that are unresectable or when the
tumor is located in the patient’s only useful eye. In our experience, surgical removal
of localized iris melanoma generally has very favorable results and fewer
complications than radiotherapy.

Table 2.3 Cumulative metastasis and death from iris melanoma: Comparison
between children, mid-adults, and older adults

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 The management of diffuse iris melanoma with secondary glaucoma has generally
been enucleation. However, observations on those treated with plaque radiotherapy
suggest that radiotherapy is an acceptable option for many tumors that would have
been managed by enucleation in the past (52). In an assessment of 144 eyes with
iris melanoma managed with plaque radiotherapy, Kaplan Meier estimates at 7
years for metastasis was 1% and enucleation was 12% (52). Eyes with melanoma-
related secondary glaucoma fared similar in these outcomes compared to those
without glaucoma.
Concerning prognosis, microscopically confirmed iris melanoma demonstrates
distant metastasis to liver or other organs in 9% of patients at 10 years of follow-up
(1). Metastases are more likely to develop in those patients who are older and
whose tumor involves the iris root and angle and when elevated intraocular
pressure or extraocular extension is present (1,3). More recently, fine needle
aspiration can be performed for cytogenetic studies that can help identify patients at
high risk for metastatic disease (35–37).

Selected References
Large Series
1. 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.
2. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119(2):407–414.
3. Shields CL, Shields JA, Materin M, et al. Iris melanoma: risk factors for
metastasis in 169 consecutive patients. Ophthalmology 2001;108:172–178.
4. Shields CL, Materin M, Shields JA, et al. Factors associated with elevated
intraocular pressure in eyes with iris melanoma. Br J Ophthalmol 2001;85:666–
669.
5. Shields CL, Kaliki S, Furuta M, et al. Clinical spectrum and prognosis of uveal
melanoma based on age at presentation in 8,033 cases. Retina
2012;32(7):1363–1372.
6. Rones B, Zimmerman LE. The production of heterochromia and glaucoma by
diffuse malignant melanomas of the iris. Trans Am Acad Ophthalmol Otolaryngol
1957;61:447–463.
7. Territo C, Shields CL, Shields JA, et al. Natural course of melanocytic tumors of
the iris. Ophthalmology 1988;95:1251–1255.
8. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected
intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.
9. 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.
10. Shields CL, Shields JA, DePotter P, et al. Treatment of nonresectable malignant
iris tumors with custom designed plaque radiotherapy. Br J Ophthalmol
1995;79:306–312.
11. Shields CL, Kaliki S, Arepalli S, et al. U veal melanoma in children and
teenagers. Saudi J Ophthalmol 2013;27(3):197–201.
12. Shields CL, Kaliki S, Hutchinson A, et al. Iris nevus growth into melanoma:

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 analysis of 1611 consecutive eyes: the ABCDEF guide. Ophthalmology
2013;120(4):766–772.
13. Kaliki S, Shields CL, Mashayekhi A, et al. Influence of age on prognosis of
young patients with uveal melanoma: a matched retrospective cohort study. Eur
J Ophthalmol 2013;23(2):208–216.
14. Weis E, Shah CP, Lajous M, et al. The association of cutaneous and iris nevi
with uveal melanoma: a meta-analysis. Ophthalmology 2009;116(3):536–543.
15. Shields CL, Qureshi A, Mashayekhi A, et al. Sector (partial) oculo(dermal)
melanocytosis in 89 eyes. Ophthalmology 2011;118(12):2474–2479.

Small Series
16. Demirci H, Shields CL, Shields JA, et al. Ring melanoma of the anterior
chamber angle. A report of 14 cases. Am J Ophthalmol 2001;132:33–42.
17. Demirci H, Shields CL, Shields JA, et al. Diffuse iris melanoma: a report of 25
cases. Ophthalmology 2002;109:1553–1560.
18. Demirci H, Shields CL, Shields JA, et al. Ring melanoma of the ciliary body:
report on twenty-three patients. Retina 2002;22:698–706.
19. Jakobiec FA, Silbert G. Are most iris “melanomas” really nevi? Arch Ophthalmol
1981;99:2117–2132.
20. 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.

Imaging
21. Nordlund JR, Robertson DM, Herman DC. U ltrasound biomicroscopy in
management of malignant iris melanoma. Arch Ophthalmol 2003;121:725–727.
22. Torres VL, Allemann N, Erwenne CM. U ltrasound biomicroscopy features of iris
and ciliary body melanomas before and after brachytherapy. Ophthalmic Surg
Lasers Imaging 2005;36:129–138.
23. Giuliari GP, McGowan HD, Pavlin CJ, et al. U ltrasound biomicroscopic imaging
of iris melanoma: a clinicopathologic study. Am J Ophthalmol 2011;151(4):579–
585.
24. Bianciotto CG, Shields CL, Romanelli M, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118:1297–1302.
25. Razzaq L, Emmanouilidis-van der Spek K, Luyten GP, et al. Anterior segment
imaging for iris melanocytic tumors. Eur J Ophthalmol 2011;21(5):608–614.
26. Doro D, Parrozzani R, Midena E. U ltrasound biomicroscopy examination of
anterior uveal tumors: information on location and size only? Acta Clin Croat
2012;51(Suppl 1):37–44.
27. Giuliari GP, Krema H, McGowan HD, et al. Clinical and ultrasound
biomicroscopy features associated with growth in iris melanocytic lesions. Am J
Ophthalmol 2012;153(6):1043–1049.
Pathology/Cytology/Genetics
28. Zimmerman LE. Clinical pathology of iris tumors: the Ward Burdick Award
Contribution. Am J Clin Pathol 1963;39:214–228.
29. Reese AB, Mund ML, Iwamoto T. Tapioca melanoma of the iris. I. Clinical and
light microscopy studies. Arch Ophthalmol 1972;74:840–850.

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30. Viestenz A, Conway RM, Kuchle M. Tapioca melanoma of the iris mimicking a
vascular tumour: a clinicopathological correlation. Clin Experiment Ophthalmol
2004;32:327–330.
31. Starr OD, Patel DV, Allen JP, et al. Iris melanoma: pathology, prognosis and
surgical intervention. Clin Experiment Ophthalmol 2004;32:294–296.
32. Khan S, Finger PT, Yu GP, et al. Clinical and pathologic characteristics of
biopsy-proven iris melanoma: a multicenter international study. Arch
Ophthalmol 2012;130(1):57–64.
33. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of
iris tumors in 100 consecutive cases. Technique and complications.
Ophthalmology 2006;113:2080–2086.
34. Schalenbourg A, U ffer S, Zografos L. U tility of a biopsy in suspicious
pigmented iris tumors. Ophthalmic Res 2008;40(5):267–272.
35. Shields CL, Ramasubramanian A, Ganguly A, et al. Cytogenetic testing of iris
melanoma using fine needle aspiration biopsy in 17 patients. Retina
2011;31(3):574–580.
36. Mensink HW, Vaarwater J, de Keizer RJ, et al. Chromosomal aberrations in iris
melanomas. Br J Ophthalmol 2011;95(3):424–428.
37. Harbour JW, Wilson D, Finger PT, et al. Gene expressing profiling of iris
melanomas. Ophthalmology 2013;120(1):213.

Management
38. Conway RM, Chua WC, Qureshi C, et al. Primary iris melanoma: diagnostic
features and outcome of conservative surgical treatment. Br J Ophthalmol
2001;85:848–854.
39. 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.
40. Bianciotto C, Shields CL, Kang B, Shields JA. Treatment of iris melanoma and
secondary neovascular glaucoma using bevacizumab and plaque radiotherapy.
Arch Ophthalmol 2008;126(4):578–579.
41. Razzaq L, de Keizer RJ. Ruthenium plaque radiation for iris and iridociliary
melanomas: development of dry eyes? Br J Ophthalmol 2010;94(11):1549–
1550.
42. Thomson RM, Furutani KM, Pulido JS, et al. Modified COMS plaques for 125I
and 103Pd iris melanoma brachytherapy. Int J Radiat Oncol Biol Phys
2010;78(4):1261–1269.
43. Petousis V, Finger PT, Milman T. Multifocal iris melanoma treated with total
anterior segment palladium-103 plaque radiation therapy. Graefes Arch Clin
Exp Ophthalmol 2011;249(6):937–940.
44. Scanderbeg DJ, Vasudev D, Rice RK, et al. A modified COMS plaque for iris
melanoma. J Contemp Brachytherapy 2011;3(3):131–133.
45. Tsimpida M, Hungerford J, Arora A, et al. Plaque radiotherapy treatment with
Ruthenium-106 for iris malignant melanoma. Eye (Lond) 2011;25(12):1607–
1611.
46. Shah SU , Shields CL, Bianciotto C, et al. Plaque radiotherapy for residual or
recurrent iris melanoma after surgical resection in 32 cases. Ophthalmology
2012;119(4):838–842.

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47. Razzaq L, Keunen JE, Schalij-Delfos NE, et al. Ruthenium plaque radiation
therapy for iris and iridociliary melanomas. Acta Ophthalmol 2012;90(3):291–
296.
48. Yousef YA, Finger PT. Lack of radiation maculopathy after palladium-103
plaque radiotherapy for iris melanoma. Int J Radiat Oncol Biol Phys
2012;83(4):1107–1112.
49. Klauber S, Jensen PK, Prause JU , et al. Surgical treatment of iris and ciliary
body melanoma: follow-up of a 25-year series of patients. Acta Ophthalmol
2012;90(2):122–126.
50. Razzaq L, Marinkovic M, Jager MJ, et al. Corneal endothelial cell density after
ruthenium plaque radiation therapy for iris melanoma patients. Acta
Ophthalmol 2012;90(7):e577–e579.
51. Konstantinidis L, Roberts D, Errington RD, et al. Whole anterior segment proton
beam radiotherapy for diffuse iris melanoma. Br J Ophthalmol 2013;97(4):471–
474.
52. Shields CL, Shah SU , Bianciotto CG, et al. Iris melanoma management with
iodine-125 plaque radiotherapy in 144 patients: impact of melanoma-related
glaucoma on outcomes. Ophthalmology 2013;120(1):55–61.

Case Reports
53. Browning DJ, Perkins SL, Lark KK. Iris cyst secondary to latanoprost mimicking
iris melanoma. Am J Ophthalmol. 2003;135:419–421.
54. Shields JA, Shields CL. Hepatic metastases of diffuse iris melanoma 17 years
after enucleation. Am J Ophthalmol 1988;106:749–750.
55. Honavar S, Singh AD, Shields CL, et al. Iris melanoma in a patient with
neurofibromatosis. Surv Ophthalmol 2000;45:231–236.
56. Singh AD, Shields JA, Eagle RC Jr, et al. Iris melanoma in a 10-year-old boy
with familial atypical mole-melanoma (FAM-M) syndrome. Ophthalmic Pediatr
Genet 1994;15:145–149.
57. Shah PG, Shields CL, Shields JA, et al. Band keratopathy secondary to an iris
melanoma. Cornea 1991;10:67–69.
58. Shields JA, Shields CL, Davidson R, et al. Iris melanoma arising from sector
congenital ocular melanocytosis in a child. Cornea 2009;28(10):1191–1193.
59. Skalicky SE, Giblin M, Conway RM. Diffuse iris melanoma: report of a case
with review of the literature. Clin Ophthalmol 2007;1(3):339–342.

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• IRIS MELANOMA: PIGMENTED VARIATIONS

Figure 2.37. Iris melanoma with documented growth in the midportion of the iris in a 40-year-old woman.

Figure 2.38. Abruptly elevated melanoma in the inferior portion of the iris in a 36-year-old woman. The
extension over the pupil would be unlike an iris nevus.

86
Figure 2.39. Melanoma occupying most of the inferior iris in a 53-year-old woman. This lesion is necrotic and
is producing deposits of pigmentation on the iris surface, findings suggesting that this is a melanocytoma
variant of nevus, to be discussed in more detail subsequently.

Figure 2.40. Large melanoma causing irregular pupil and touching corneal endothelium in a 60-year-old man.

87
Figure 2.41. Large, mildly pigmented melanoma in iris superonasally. The atypical superior location of the
lesion raised suspicion that the tumor has extended into the iris from the ciliary body. In this case, the lesion
proved to be primarily in the iris. Most true iris melanomas are located in the inferior aspect of the iris.

Figure 2.42. Histopathology of iris melanoma, showing low-grade spindle melanoma cells and occasional
balloon cells. A few macrophages are present inferiorly (Hematoxylin–eosin ×100).

88
• IRIS MELANOMA: NONPIGMENTED VARIATIONS

Figure 2.43. Amelanotic iris melanoma near the pupil in a 63-year-old man.

Figure 2.44. Amelanotic iris melanoma occupying a quadrant of the iris in a 35-year-old woman.

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Figure 2.45. Irregular lesion in the inferotemporal portion of the iris, producing an irregular pupil in a 35-year-
old woman in 1979. The lesion was followed without treatment.

Figure 2.46. Same lesion shown in Figure 2.45, 9 years later. Note that the tumor has grown slightly and the
pupil is more irregular.

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Figure 2.47. Amelanotic tapioca iris melanoma. Inferior lesion in a 20-year-old woman. There were numerous
tapioca-like nodules scattered in angle. Fine needle biopsy confirmed the diagnosis of melanoma, and it was
elected to perform enucleation because of the widespread involvement of the trabecular meshwork.

Figure 2.48. Gross photograph of the anterior segment of the sectioned eye shown in Figure 2.47 following
enucleation. Note the globular white nodules on the iris and in the angle.

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• IRIS MELANOMA: ATYPICAL CLINICAL VARIATIONS
In some instances, iris melanoma can have atypical clinical features, such as a multinodular
growth pattern, seeding into the trabecular meshwork, secondary spontaneous hyphema,
secondary cyst formation, and band keratopathy.

Figure 2.49. Bilobed ring melanoma of peripheral iris in an 81-year-old man. The more superior nodule is
nonpigmented and the inferior nodule is deeply pigmented.

Figure 2.50. Gonioscopic view of a friable, circumscribed iris melanoma with extensive seeding of tumor cells
and liberated pigment into the trabecular meshwork in a 66-year-old woman.

92
Figure 2.51. Spontaneous hyphema as the presenting feature of an iris melanoma in a 23-year-old man.

Figure 2.52. Iris pigment epithelial cyst adjacent to an iris melanoma in a 28-year-old woman. Note the small
second cyst near the papillary border.

93
Figure 2.53. Band keratopathy secondary to a large iris melanoma touching the cornea in a 27-year-old man.

Figure 2.54. Postoperative appearance after removal of tumor shown in Figure 2.53 by sector iridocyclectomy.
Note that the band keratopathy persists.

Atypical clinical features of iris melanoma are depicted. In addition, cases are shown in which
the tumor was diagnosed in children.

94
Figure 2.55. Diffuse, hemorrhagic melanoma of inferior iris simulating a hemangioma in a 53-year-old man.

Figure 2.56. Highly vascular amelanotic melanoma with dragging of the pupillary border in a 53-year-old
woman.

95
Figure 2.57. Bilobed, partially pigmented melanoma almost covering the entire pupil in a 59-year-old man.

Figure 2.58. Highly pedunculated melanoma in the iris superiorly in a 13-year-old boy. There was some ciliary
body involvement, and the eye was enucleated. It was not clearly determined whether the tumor originated in
the iris or the ciliary body.

96
Figure 2.59. Pedunculated, markedly pigmented melanoma arising near the pupillary border and covering the
entire pupil in a 12-year-old girl. The marked elevation of the tumor is not easily seen in this photograph.

Figure 2.60. Gonioscopic view of the lesion shown in Figure 2.58. Note the markedly pedunculated shape of
the tumor. It was removed by sector iridectomy and proved to be a mixed cell–type melanoma.

97
• IRIS MELANOMA: TAPIOCA TYPE
Tapioca melanoma has a very typical appearance of multiple nodules that may glisten on slit
lamp examination. Tapioca changes are very difficult to capture on routine photography, but
the nodules can be clearly visualized by slit lamp biomicroscopy. In many cases, only a portion
of the iris melanoma has the typical tapioca appearance.

Figure 2.61. Tapioca melanoma in the inferior aspect of the iris.

98
Figure 2.62. Tapioca melanoma with a diffuse multinodular configuration.

Figure 2.63. Tapioca melanoma producing irregular pupil and localized ectropion iridis. The lesion was
confirmed histopathologically to be a low-grade melanoma.

Figure 2.64. Gonioscopic view of the lesion shown in Figure 2.63, better depicting the tapioca nodules.

99
Figure 2.65. Large, moderately pigmented tapioca iris melanoma.

Figure 2.66. Histopathology of the lesion shown in Figure 2.65, demonstrating the irregular, nodular, anterior
surface of the mass. The tumor is composed predominantly of spindle melanoma cells (Hematoxylin–eosin
×50).

100
• IRIS MELANOMA: TAPIOCA TYPE SIMULATING COGAN–REESE
SYNDROME

The nodules of tapioca melanoma can simulate Lisch nodules of neurofibromatosis,

mammillations of ocular melanocytosis, and iris nodules of Cogan–Reese syndrome. In the
below case, this patient was treated with glaucoma therapy for unilateral glaucoma for a long
period of time until tapioca melanoma was suspected.

Figure 2.67. Multifocal pale brown nodules are noted on the iris surface, particularly superotemporally and
inferotemporally.

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Figure 2.68. On gonioscopy, the nodules are of different sizes and some involve the anterior chamber angle.

Figure 2.69. On ultrasound biomicroscopy, the surface nodularity of the iris is obvious.

Figure 2.70. Following enucleation, extensive tapioca nodules are found on the iris surface and into the
anterior chamber angle on gross pathology. Tumor dusting on the iris surface is noted.

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Figure 2.71. Histopathology discloses whorls of melanoma cells within the iris stroma.

Figure 2.72. Histopathology reveals the relatively low-grade melanoma on the iris surface.

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• DIFFUSE IRIS MELANOMA
Some diffuse melanomas grow in irregular patches, giving the impression that the tumor is
multifocal.

1. 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.
2. Demirci H, Shields CL, Shields JA, et al. Diffuse iris melanoma: a report of 25 cases.
Ophthalmology 2002;109:1553–1560.

Figure 2.73. Diffuse, pigmented lesion in the iris inferiorly in a 10-year-old girl. The lesion was followed
conservatively.

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Figure 2.74. Lesion shown in Figure 2.67, 3 years later. Note that the patchy pigmentation has become more
extensive. Secondary glaucoma supervened, and histopathology after enucleation revealed a diffuse iris
melanoma with involvement of the trabecular meshwork.

Figure 2.75. Patchy diffuse iris melanoma in an 18-year-old. Secondary glaucoma supervened, and
histopathology after enucleation revealed a diffuse iris melanoma with involvement of the trabecular
meshwork.

Figure 2.76. Melanoma confined to the region of the trabecular meshwork in a 59-year-old man. Such a
trabecular meshwork melanoma (ring melanoma of anterior chamber angle) is a rare variation of diffuse iris
melanoma.

105
Figure 2.77. Glaucomatous cupping of the optic disc in the patient shown in Figure 2.70.

Figure 2.78. Patient with diffuse iris melanoma who had undergone prior filtering surgery for unexplained
glaucoma. Note the diffuse iris melanoma and melanoma pigment within the filtering bleb superiorly. Patients
with diffuse iris melanoma are often treated for “idiopathic” glaucoma until the tumor is discovered at a later
date.

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• IRIS MELANOMA IMAGING WITH ULTRASOUND BIOMICROSCOPY
AND ANTERIOR SEGMENT OPTICAL COHERENCE TOMOGRAPHY

Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment tumors with
ultrasound biomicroscopy versus anterior segment OCT in 200 cases. Ophthalmology
2011;118(7):1297–1302.

Figure 2.79. Pigmented iris melanoma in the anterior chamber angle.

Figure 2.80. Ultrasound biomicroscopy of eye in Figure 2.79 reveals iridociliary solid mass.

107
Figure 2.81. Pigmented iris melanoma in the inferior iris.

Figure 2.82. Anterior segment optical coherence tomography of eye in Figure 2.81 reveals abruptly elevated iris
mass with posterior shadowing.

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Figure 2.83. Large pigmented iris melanoma abutting the endothelium.

Figure 2.84. Anterior segment optical coherence tomography of eye in Figure 2.83 reveals the mass
compressed against the endothelium and with posterior shadowing.

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• DIFFUSE IRIS MELANOMA MANAGED WITH ENUCLEATION
Shields JA, Shields CL. Hepatic metastases of diffuse iris melanoma 17 years after enucleation.
Am J Ophthalmol 1989;106:749–750.

Figure 2.85. Acquired hyperchromic heterochromia in a 52-year-old man. He had an intraocular pressure of 50
mm Hg in the affected eye.

Figure 2.86. Iris of the normal left eye. The color of the iris is blue.

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Figure 2.87. Iris of the affected right eye, showing diffuse pigmentation. The iris had changed from blue to
brown over 5 years.

Figure 2.88. Fundus photograph showing glaucomatous cupping of the optic disc in the right eye.

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Figure 2.89. Photomicrograph of anterior segment of the right eye following enucleation. Note the dense
pigmentation in the iris and trabecular meshwork. (Hematoxylin-eosin ×15.)

Figure 2.90. Histopathology of the iris tumor showing low-grade spindle cells that comprised the tumor. The
patient had no further problems until 17 years later, when he developed hepatic metastasis and died shortly
thereafter. There was no local recurrence of tumor in the orbit.

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• DIFFUSE IRIS MELANOMA MANAGEMENT

Figure 2.91. Chronic diffuse iris melanoma with extensive tumor seeding and iris neovascularization.

Figure 2.92. Treatment of diffuse iris melanoma in Figure 2.91 with plaque radiotherapy and intra-aqueous
bevacizumab.

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Figure 2.93. Chronic diffuse iris melanoma with extensive ectropion uveae and secondary glaucoma
previously treated with trabeculectomy.

Figure 2.94. Treatment of diffuse iris melanoma in Figure 2.93 with enucleation reveals extensive tumor growth
on the iris and endothelial surfaces as well as deep invasion.

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Figure 2.95. Patchy diffuse iris melanoma and secondary glaucoma and previously treated with
trabeculectomy.

Figure 2.96. Following treatment of iris melanoma in Figure 2.95 with enucleation, cyberknife radiotherapy was
delivered to the orbit.

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• DIFFUSE IRIS MELANOMA MANAGED WITH PLAQUE
BRACHYTHERAPY

In recent years, many patients with diffuse iris melanoma have been managed by special
techniques of plaque brachytherapy. A custom-designed plaque containing I-125 seeds is placed
directly over the cornea and sutured into the proper position. The cornea seems to tolerate the
radiation well, and this method has proved to be a good alternative to enucleation in selected
cases. It is used mostly in older patients with good vision in the affected eye and no severe
secondary glaucoma. A case is shown.

1. 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.
2. Shields CL, Shah SU, Bianciotto CG, et al. Iris melanoma management with iodine-125
plaque radiotherapy in 144 patients: impact of melanoma-related glaucoma on outcomes.
Ophthalmology 2013;120(1):55–61.

Figure 2.97. Elderly man with acquired hyperchromic heterochromia, showing darker-colored iris in the left eye
than in the right eye.

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Figure 2.98. Diffuse, irregular pigmented thickening of iris stroma, characteristic of diffuse iris melanoma.

Figure 2.99. Gonioscopy, depicting increased pigment in the trabecular meshwork.

117
Figure 2.100. Ultrasound biomicroscopy, showing diffuse thickening of the iris but no demonstrable
involvement of the ciliary body.

Figure 2.101. Design of the dummy plaque without seeds (left) and the active plaque (right) showing the
distribution of I-125 seeds. The dummy plaque is used for suture alignment before placement of the active
plaque.

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Figure 2.102. Plaque in position after placement. The next step (not shown here) is to mobilize the conjunctiva
to cover the plaque during the 3 to 4 days that the plaque is on the eye.

119
• IRIS MELANOMA IN A PATIENT WITH FAMILIAL ATYPICAL MOLE
SYNDROME (DYSPLASTIC NEVUS SYNDROME)

The dysplastic nevus syndrome is a familial condition consisting of multiple atypical cutaneous
nevi and a high incidence of cutaneous, uveal, and conjunctival melanomas.

Singh AD, Shields JA, Eagle RC Jr, et al. Iris melanoma in a 10 year old boy with familial
atypical mole-melanoma (FAM-M) syndrome. Ophthalmic Pediatr Genet 1994;15:145–149.

Figure 2.103. Amelanotic iris tumor in a 10-year-old boy who had secondary glaucoma.

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Figure 2.104. Gonioscopic view of angle, showing peculiar amelanotic tissue in the angle. The lesion was
removed by iridocyclectomy after subsequent growth was documented.

Figure 2.105. Gross appearance of a sectioned specimen, showing white vascular tumor.

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Figure 2.106. Appearance of anterior segment after successful iridocyclectomy. The glaucoma spontaneously
resolved after the tumor was removed, and the patient has 20/20 vision 10 years later.

Figure 2.107. Photomicrograph of the tumor, showing mixed cell–type melanoma, predominantly plump
spindle cells. Note the mitotic figure in the upper left.

122
Figure 2.108. Appearance of skin on the patient’s back, showing several dysplastic nevi. He has not yet
developed a cutaneous melanoma.

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• IRIS MELANOMA: MANAGEMENT BY SECTOR IRIDECTOMY AND
IRIDOGONIOCYCLECTOMY

Figure 2.109. Iris root extension of pigmented ciliary body melanoma.

Figure 2.110. Same eye shown in Figure 2.91, 2 weeks after surgery, depicting the peripheral iridectomy and
round pupil. In this case, a sector iridectomy was avoided and the lesion was removed with cyclectomy and
peripheral iridectomy. The pupil is partly dilated due to use of postoperative atropine drops.

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Figure 2.111. Inferior melanoma that had progressively enlarged for 1 year in a 51-year-old woman.

Figure 2.112. Appearance of the eye shown in Figure 2.91 after surgical removal by sector iridectomy.

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Figure 2.113. Temporal melanoma that had progressively enlarged for 1 year and had produced recurrent
hyphemas in a 25-year-old man.

Figure 2.114. Appearance of the eye shown in Figure 2.93 after surgical removal by sector iridectomy.

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• IRIS MELANOMA: MANAGEMENT BY SECTOR IRIDECTOMY AND
PUPILLOPLASTY

When the tumor is less than 2 clock hours in extent and the iridectomy is small enough, the
defect can be partly closed at the time of tumor excision, using a 10-nonabsorbable suture
(proline), giving the patient a fairly round rather than a keyhole pupil.

Figure 2.115. Inferior iris melanoma with documented growth in a 20-year-old woman.

Figure 2.116. Appearance of the eye shown in Figure 2.98 after surgical removal and pupilloplasty.

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Figure 2.117. Inferior documented growing melanoma in a 27-year-old man. The lesion proved to be a
malignant melanoma histopathologically after excision.

Figure 2.118. Appearance of the eye shown in Figure 2.99 after surgical removal and pupilloplasty.

128
Figure 2.119. Pedunculated amelanotic melanoma with documented growth and recurrent hyphema in a 73-
year-old woman.

Figure 2.120. Appearance of the eye shown in Figure 2.101 after surgical removal and pupilloplasty. The pupil
was dilated pharmacologically when this photograph was taken.

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• IRIS MELANOMA: MANAGEMENT OF UNRESECTABLE TUMOR BY
FINE NEEDLE ASPIRATION BIOPSY AND PLAQUE RADIOTHERAPY

In some cases of unresectable iris melanoma, enucleation can be avoided, confirming the
diagnosis with FNAB and treating the tumor with radioactive iris plaque. An example is shown.

1. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of iris tumors in
100 consecutive cases. Technique and complications. Ophthalmology 2006;113:2080–2086.
2. Shields CL, Shah SU, Bianciotto CG, et al. Iris melanoma management with iodine-125
plaque radiotherapy in 144 patients: impact of melanoma-related glaucoma on outcomes.
Ophthalmology 2013;120(1):55–61.

Figure 2.121. Highly suspicious atypical pigmented iris mass.

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Figure 2.122. Gonioscopy, showing a diffuse growth pattern with vascularized tumor nodules and involvement
of the trabecular meshwork.

Figure 2.123. The technique of iris fine needle aspiration biopsy.

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Figure 2.124. Cytopathology, showing pigmented spindle melanoma cells (Papanicolaou ×400).

Figure 2.125. Photograph of the iris plaque, showing the distribution of I-125 seeds.

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Figure 2.126. After the plaque is placed on cornea, the conjunctiva is mobilized and sutured over the plaque
until the plaque is removed after completion of irradiation, at which time the bulbar conjunctival is sutured into
its original location at the corneoscleral limbus.

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• IRIS MELANOMA: MANAGEMENT OF UNRESECTABLE TUMOR
WITH PLAQUE RADIOTHERAPY

Figure 2.127. Slit lamp view of lightly pigmented tapioca-type melanoma in a 37-year-old man. Angle
involvement for more than 180 degrees inferiorly made surgical resection inadvisable.

Figure 2.128. Appearance of the tumor shown in Figure 2.109, 3 years later, showing marked regression of the
tumor. Note that the cornea has maintained its clarity.

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Figure 2.129. Nodular melanoma with extension throughout the inferior half of the iris in a 60-year-old man.
His opposite eye was blind from childhood trauma.

Figure 2.130. Appearance of the eye shown in Figure 2.111, 2 years after radiotherapy. The tumor had not
recurred, and a radiation-induced cataract had been removed and intraocular lens inserted.

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Figure 2.131. Unusual appearance of two separate amelanotic lesions in a 20-year-old woman. There was no
evidence of continuity of the two lesions. Both lesions were confirmed by fine needle aspiration biopsy, and
they were treated simultaneously with a single radioactive plaque designed to cover 180 degrees of angle.

Figure 2.132. Appearance more than 2 years later, showing moderate regression of both tumors.

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 CHAPTER 3

CONDITIONS THAT SIMULATE IRIS MELANOMA

CONDITIONS THAT SIMULATE IRIS MELANOMA

A number of conditions can clinically simulate iris melanoma (1–34). Tumors and
cysts that can resemble iris melanoma are discussed in more detail elsewhere in this
atlas and are only alluded to here because they relate to the differential diagnosis of
iris melanoma. This section covers selected other nonneoplastic, noncystic
conditions that can sometimes simulate iris melanoma, including iridocorneal
endothelial (ICE) syndrome, foreign body, benign epithelioma (adenoma) of the iris
pigment epithelium, and selected others.
The most common pseudomelanoma is iris nevus (1–3). This tumor was discussed
earlier. Another tumor that commonly simulates iris melanoma is epithelioma
(adenoma) of the iris pigment epithelium. In contrast to melanoma, it is generally
dark black and tends to push through the iris stroma from posteriorly. It does not
appear to arise from the iris stroma as does a melanoma (10). Lymphoid tumors can
be confined to the iris and can be similar to melanoma (14).
Cysts of the iris pigment epithelium are often referred because of suspected iris or
ciliary body melanoma (11–13). They are discussed in detail in Chapter 4. The
pupillary margin cysts are rarely confused clinically with melanoma, but the
midzonal and peripheral cysts may closely resemble melanoma clinically.
The ICE syndrome is an idiopathic condition that usually occurs unilaterally
mainly in adult women and is characterized by corneal endothelial guttata, corneal
edema, peripheral anterior synechiae, iris stromal dehiscence, characteristic iris
nodules, and secondary glaucoma (4–9). The findings vary from patient to patient
and form a spectrum including those with predominant corneal changes (Chandler
syndrome), predominant iris changes (essential iris atrophy), and predominant iris
nodules (iris nevus syndrome or Cogan–Reese syndrome). It should be differentiated
from diffuse iris melanoma, which does not characteristically show the endothelial

137
changes and iris dehiscence. Shields et al. (9) described a large cohort of patients
with ICE syndrome mistaken for iris melanoma and compared the features of ICE
syndrome with iris melanoma.
Additional lesions that we have observed to simulate iris melanoma include iris
foreign body, granuloma, atypical hemorrhage, retained lens material, iris changes
from herpes infections, congenital ectropion iridis, and others (17–34) (Table 3.1).

Table 3.1 Nonneoplastic lesions simulating iris tumor or melanoma

Selected References
Large Series
1. Shields CL, Shields PW, Manalac J, et al. Review of cystic and solid tumors of
the iris. Oman J Ophthalmol 2013;6(30):159–164.
2. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119(2):407–414.
3. Shields JA, Sanborn GE, Augsburger JJ. The differential diagnosis of malignant
melanoma of the iris. A clinical study of 200 patients. Ophthalmology
1983;90:716–720.

Small Series
4. Campbell DG, Shields MB, Smith TR. The corneal endothelium and the
spectrum of essential iris atrophy. Am J Ophthalmol 1978;86:317–324.
5. Shields MB. Progressive essential iris atrophy, Chandler’s syndrome and the iris
nevus (Cogan-Reese) syndrome. A spectrum of disease. Surv Ophthalmol
1979;24:3–10.
6. Donders PC. Ring melanoma of the iris. Iridocorneal endothelial syndrome. Int
Ophthalmol 1985;7:161–167.
7. Eagle RC Jr, Font RL, Yanoff M, et al. Proliferative endotheliopathy with iris
abnormalities: the iridocorneal endothelial syndrome. Arch Ophthalmol

138
 1979;97:2104–2112.
8. Shields MB. Progressive essential iris atrophy, Chandler’s syndrome, and the iris
nevus (Cogan-Reese) syndrome: a spectrum of disease. Surv Ophthalmol
1979;24:3–20.
9. 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.
10. Shields JA, Shields CL, Mercado G, et al. Adenoma of the iris pigment
epithelium: a report of 20 cases: the 1998 Pan-American Lecture. Arch
Ophthalmol 1999;117:736–741.
11. Shields JA. Primary cysts of the iris. Trans Am Ophthalmol Soc 1981;79:771–
809.
12. Lois N, Shields CL, Shields JA, et al. Primary cysts of the iris pigment
epithelium. Clinical features and natural course in 234 patients. Ophthalmology
1998;105:1879–1885.
13. Shields JA, Shields CL, Lois N, et al. Iris cysts in children: classification,
incidence, and management. The 1998 Torrence A Makley Jr Lecture. Br J
Ophthalmol 1999;83:334–338.
14. Mashayekhi A, Shields CL, Shields JA. Iris involvement by lymphoma: a review
of 13 cases. Clin Experiment Ophthalmol 2013;41(1):19–26.

Pathology
15. Eagle RC Jr, Shields JA. Iridocorneal endothelial syndrome with contralateral
guttate endothelial dystrophy. A light and electron microscopic study.
Ophthalmology 1987;94:862–870.
16. Eagle RC Jr, Font RL, Yanoff M, et al. The iris naevus (Cogan-Reese) syndrome:
light and electron microscopic observations. Br J Ophthalmol 1980;64:446–452.

Case Reports
17. Eagle RC Jr, Shields JA, Canny CL, et al. Intraocular wooden foreign body
clinically resembling a pearl cyst. Arch Ophthalmol 1977;95:835–836.
18. Shields JA, Eagle RC Jr, Shields CL, et al. Progressive growth of benign
adenoma of the pigment epithelium of the ciliary body. Arch Ophthalmol
2001;119:1859–1861.
19. Shields CL, Shields JA, Cook GR, et al. Differentiation of adenoma of the iris
pigment epithelium from iris cyst and melanoma. Am J Ophthalmol
1985;100:678–681.
20. Shields JA, Augsburger JJ, Sanborn GE, et al. Adenoma of the iris pigment
epithelium. Ophthalmology 1983;90:735–739.
21. Shields JA, Shields CL, DePotter P, et al. Free-floating cyst in the anterior
chamber of the eye. J Pediatr Ophthalmol Strabismus 1996;33:330–331.
22. Alward WL, Ossoinig KC. Pigment dispersion secondary to cysts of the iris
pigment epithelium. Arch Ophthalmol 1995;113:1574–1575.
23. Olsen TW, Lim JI, Grossniklaus HE. Retained lens material masquerading as a
growing, pigmented iris tumor. Arch Ophthalmol 1996;114:1154–1155.
24. Ritch R, Forbes M, Hetherington J Jr, et al. Congenital ectropion uveae with
glaucoma. Ophthalmology 1984;91:326–331.
25. Gupta K, Hoepner JA, Streeten BW. Pseudomelanoma of the iris in herpes
simplex keratoiritis. Ophthalmology 1986;93:1524–1527.

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26. Klien BA, Farkas TG. Pseudomelanoma of the iris after herpes zoster
ophthalmicus. Am J Ophthalmol 1964;57:392–397.
27. Yanoff M, Zimmerman LE. Pseudomelanoma of anterior chamber caused by
implantation of iris pigment epithelium. Arch Ophthalmol 1965;74:302–305.
28. Sodhi PK. Iris cyst secondary to latanoprost mimicking iris melanoma. Am J
Ophthalmol 2003;136:780.
29. Sharma MC, Shields CL, Shields JA, et al. Benign lymphoid infiltrate of the iris
simulating a malignant melanoma. Cornea 2002;21:424–425.
30. Shields JA, Augsburger JJ, Gonder JR, et al. Localized benign lymphoid tumor
of the iris. Arch Ophthalmol 1981;99:2147–2148.
31. Shakin EP, Augsburger JJ, Eagle RC, et al. Multiple myeloma involving the iris.
Arch Ophthalmol 1988;106:524–526.
32. Hykin PG, Shields JA, Shields CL, et al. Recurrent systemic B-cell lymphoma of
the iris. Br J Ophthalmol 1996;80:929–930.
33. Manjandavida FP, Arepalli S, Tarlan B, Shields CL. Optical coherence
tomography characteristics of epi-iridic membrane in a child with recurrent
hyphema and presumed juvenile xanthogranuloma. J AAPOS 2014;18(1):93–
95. doi: 10.1016/j.jaapos.2013.10.022.
34. Shields JA, Shields CL, Pulido J, et al. Iris varix simulating an iris melanoma.
Arch Ophthalmol 2000;118:707–710.

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• IRIDOCORNEAL ENDOTHELIAL SYNDROME
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.

Figure 3.1. Iridocorneal endothelial syndrome in a 70-year-old woman, showing downward displacement of
the pupil toward a peripheral anterior synechia. Iris dehiscence had not developed.

Figure 3.2. Iridocorneal endothelial syndrome in a 45-year-old woman, showing upward displacement of the
pupil toward a synechia and a secondary dehiscence of the iris stroma inferiorly.

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Figure 3.3. Iridocorneal endothelial syndrome in a 40-year-old woman showing irregular pupil and two iris
dehiscences.

Figure 3.4. Gonioscopic view of peripheral anterior synechia in a 64-year-old woman with iridocorneal
endothelial syndrome.

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Figure 3.5. Superotemporal displacement of the pupil in a 49-year-old woman with iridocorneal endothelial
syndrome. Note that there are no iris dehiscences.

Figure 3.6. Same patient shown in Figure 3.5, as seen 5 years later. Note that a large iris dehiscence has
developed nasally.

143
• IRIS FOREIGN BODIES THAT SIMULATE IRIS MELANOMA
Occasionally a patient is diagnosed as having an iris melanoma or other iris tumor in which the
lesion proves on further evaluation to be a foreign body. In our experience, such patients often
do not recall any prior trauma, in spite of the fact that the foreign body has apparently
penetrated the globe anteriorly. A metallic foreign body can usually be recognized by its rusty,
metallic appearance. If melanoma is a serious diagnostic consideration, ultrasonography or
computed tomography might reveal the nature of the lesion. Some examples are shown in
which the patient was referred to rule out iris melanoma.

Olsen TW, Lim JI, Grossniklaus HE. Retained lens material masquerading as a growing,
pigmented iris tumor. Arch Ophthalmol 1996;114:1154–1155.

Figure 3.7. Metallic foreign body in the superior iris of a 73-year-old man.

144
Figure 3.8. Metallic foreign body in the superior iris of a 71-year-old man.

Figure 3.9. Metallic foreign body in the inferior iris in a 19-year-old man.

Figure 3.10. Metallic foreign body in the anterior chamber angle inferiorly causing downward displacement of
the pupil.

145
Figure 3.11. Gonioscopic view of the eye shown in Figure 3.10, showing the metallic foreign body in the iris
stoma inferiorly.

Figure 3.12. Wooden foreign body in the peripheral iris of a young boy, simulating a tumor.

146
• MISCELLANEOUS NONNEOPLASTIC CONDITIONS THAT SIMULATE
IRIS MELANOMA

Figure 3.13. Congenital ectropion iridis in a 29-year-old woman. It had apparently been present since birth.

Figure 3.14. Peripheral (iridociliary) cyst of iris pigment epithelium eroding through the iris and simulating an
iris melanoma.

147
Figure 3.15. Granuloma in superior iris secondary to sarcoidosis.

Figure 3.16. Atypical globular hemorrhage in the anterior chamber, presumably arising from a cataract wound.
This eventually resolved.

148
Figure 3.17. Iris prolapse within the cornea from presumed undisclosed trauma, simulating melanoma.

Figure 3.18. Ultrasound biomicroscopy of the lesion in Figure 3.17 discloses intracorneal cystic mass arising
from the iris.

149
• MISCELLANEOUS TUMORS THAT SIMULATE IRIS MELANOMA
Several additional lesions can simulate iris nevus and melanoma. Selected examples are shown.

Figure 3.19. Lisch nodules in a patient with neurofibromatosis type 1. These represent glial-melanocytic
hamartomas, which generally have their clinical onset by age 5 years. They should not be confused with
multiple nevi, primary melanoma, or metastatic melanomas to the iris. Sometimes typical Lisch nodules occur
in patients who have no clinical findings of neurofibromatosis.

Figure 3.20. Histopathology of Lisch nodule, showing an elevated lesion composed of spindle nevus cells on
the anterior surface of iris in a patient with neurofibromatosis type 1. The eye was enucleated because of
advanced choroidal melanoma. (Hematoxylin–eosin ×50.)

150
Figure 3.21. Iris melanocytoma simulating melanoma. This subject was discussed in detail in Chapter 2.

Figure 3.22. Gonioscopic view of benign epithelioma (adenoma) of the iris pigment epithelium. This subject is
discussed in Chapter 22.

151
Figure 3.23. Iris metastasis from renal cell carcinoma simulating nonpigmented melanoma.

Figure 3.24. Diffuse metastatic cutaneous melanoma to the iris simulating a primary diffuse iris melanoma. It
produced acquired hyperchromic heterochromia similar to a primary neoplasm, but it occurred as a
manifestation of systemic metastatic melanoma.

152
• IRIS PIGMENT EPITHELIAL MIDZONAL CYSTS THAT SIMULATE IRIS
MELANOMA

Figure 3.25. Midzonal cyst barely visible along the 4:00 meridian.

Figure 3.26. With full illumination of the lesion in Figure 3.25, the smooth surface of the retroiridic cyst is noted.

153
Figure 3.27. Midzonal cyst visible along the 4:00 meridian in an elderly patient following cataract surgery.

Figure 3.28. With retro-illumination of the cyst in Figure 3.25, the smooth silhouette is noted.

Figure 3.29. Large midzonal cyst simulating iris melanoma is noted behind the iris stroma.

154
Figure 3.30. Anterior segment optical coherence tomography depicts the thin wall and clear lumen of the
midzonal cyst.

155
 CHAPTER 4

IRIS CYSTS

IRIS CYSTS

Iris cysts can assume any of several clinical variations (1–22). Their classification,
clinical features, pathology, and management are summarized briefly here. Our
classification of iris cysts is as follows (1):

Table 4.1 Classification of iris cysts

156
Cysts of the Iris Pigment Epithelium

General Considerations
Iris pigment epithelium (IPE) cysts can be divided anatomically into central,
midzonal, peripheral, and dislodged types (1,2) (Tables 4.1, 4.2).

Central (Pupillary) Cysts. Pupillary cysts can be solitary or multiple. The solitary
type is nonfamilial and appears as a round, dark-brown lesion at the pupillary
border. The multiple variant is usually sporadic but can be autosomal dominant. It
is usually bilateral and is characterized by variable-sized, dark-brown lesions that
can encircle the pupil. They often spontaneously collapse and then re-form,
producing irregular, wrinkled lesions known as iris flocculi. Even when extensive,
they rarely cause visual impairment, and most remain relatively stable throughout
the patient’s life. Although there are usually no systemic associations, iris flocculi
can have a peculiar association with familial dissecting aortic aneurysm (15).

Midzonal (Retroiridic) Cysts. The midzonal cyst is usually discovered on routine

slit-lamp biomicroscopy as a round or fusiform, smooth, dark-brown lesion at the
pupillary margin. It can be unilateral or bilateral, solitary or multiple. With
pupillary dilation, it becomes more elongated, and its central border sometimes
rolls anteriorly over the papillary margin, findings that help to differentiate it from
a ciliary body melanoma. Like a melanoma, it blocks the transmission of light.

157
Iridociliary (Peripheral) Cysts. The more common peripheral cyst is usually
unilateral and more common in young women. It presents as an asymptomatic,
localized, anterior bulge of the iris stroma, usually on the temporal side, that is
noted coincidentally on slit-lamp biomicroscopy. With the pupil widely dilated, the
cyst can sometimes be visualized with slit-lamp biomicroscopy and gonioscopy, and
it tends to transmit light because it is partially covered by nonpigmented ciliary
epithelium. More often, however, ultrasound biomicroscopy (U BM) is necessary to
better demonstrate the lesion and confirm its cystic nature. On U BM, often the
patient is found to have more than one cyst. U sing U BM, a cyst has an extremely
thin wall with empty central portion whereas a tumor shows a solid pattern and a
cavitary melanoma would appear cystic but would have a thicker wall (9,10,12,13).

Dislodged Iris Pigment Epithelium Cysts. Any IPE cyst can become dislodged and
float freely in the vitreous or anterior chamber (17,22). Free-floating cysts can
eventually become fixed in the anterior chamber angle. U nlike melanoma in the
angle, a fixed cyst has sharp abrupt borders rather than gradual sessile borders. U BM
and anterior segment optical coherence tomography are excellent methods for the
recognition of all types of iris cysts.

Pathology
Each of the IPE cysts is lined by a monolayer of IPE cells and usually has clear fluid
in the lumen.

Management
IPE cysts rarely require treatment, except for the rare occasion in which the cyst
occludes the visual axis. At that time, pupillary dilation might allow vision and
avoid surgery. If not, then fine needle aspiration biopsy (FNAB) to deflate the cyst
or laser disruption of the lesion can be considered. We prefer FNAB as it is a
controlled method without dispersion of toxic contents into the eye.

Table 4.2 IPE cysts in 672 cases based on age at presentation

In a large analysis on 672 IPE cysts by Shields et al. (5), the types were as follows:

Selected References
Large Series
1. Shields JA. Primary cysts of the iris. Theses, American Ophthalmological
Society. Trans Am Ophthalmol Soc 1981;79:771–809.
2. Shields JA, Kline MW, Augsburger JJ. Primary iris cysts. Review of the

158
 literature and report of 62 cases. Br J Ophthalmol 1984;68:152–166.
3. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119:407–414.
4. Lois N, Shields CL, Shields JA, et al. Primary cysts of the iris pigment
epithelium: clinical features and natural course in 234 patients. Ophthalmology
1998;105:1879–1885.
5. Shields JA, Shields CL, Lois N, et al. Iris cysts in children: classification,
incidence, and management. The 1998 Torrence A Makley Jr Lecture. Br J
Ophthalmol 1999; 83:334–338.
6. Shields CL, Shields PW, Manalac J, et al. Review of cystic and solid tumors of
the iris. Oman J Ophthalmol 2013;6(30):159–164.

Small Series
7. Rao A, Gupta V, Bhadange Y, et al. Iris cysts: a review. Semin Ophthalmol 2011;
26(1):11–22.
8. Shields JA, Shields CL, Mercado G, et al. Adenoma of the iris pigment
epithelium: a report of 20 cases: the 1998 Pan-American Lecture. Arch
Ophthalmol 1999;117:736–741.
9. Lois N, Shields CL, Shields JA, et al. Cavitary melanoma of the ciliary body. A
study of eight cases. Ophthalmology 1998;105:1091–1098.
10. Zhang JJ, Demirci H, Shields CL, et al. Cavitary melanoma of ciliary body
simulating a cyst. Arch Ophthalmol 2005;123:569–571.
11. Kaliki S, Shields CL, Eagle RC Jr, et al. Ciliary body medulloepithelioma:
analysis of 41 cases. Ophthalmology 2013;120(12):2552–2559.

Imaging
12. Kozart DM. Echographic evaluation of primary cysts of the iris pigment
epithelium. Am J Ophthalmol 1996;121:100–101.
13. Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118(7):1297–1302.
Case Reports
14. Shields CL, Shields JA, Cook GR, et al. Differentiation of adenoma of the iris
pigment epithelium from iris cyst and melanoma. Am J Ophthalmol
1985;100:678–681.
15. Lewis RA, Merin LM. Iris flocculi and familial aortic dissection. Arch
Ophthalmol 1995;113:130–131.
16. Alward WL, Ossoinig KC. Pigment dispersion secondary to cysts of the iris
pigment epithelium. Arch Ophthalmol 1995;113:1574–1575.
17. Shields JA, Shields CL, De Potter P, et al. Free-floating cyst in the anterior
chamber of the eye. J Pediatr Ophthalmol Strabismus 1996;33:330–331.
18. Verma L, Venkatesh P, Sen S, et al. Surgical removal of a free floating cyst of
the iris pigment epithelium causing disturbing visual symptoms. Ophthalmic
Surg Lasers 1999;30:223–225.
19. Sallo FB, Hatvani I. Recurring transitory blindness caused by primary marginal
pigment epithelial iris cysts. Am J Ophthalmol 2002;133:407–409.
20. Obata R, Suzuki S, Numaga J, et al. Congenital iris bombe induced by large iris
cysts. Arch Ophthalmol 2003;121:906–907.

159
21. Lai IC, Kuo MT, Teng LM. Iris pigment epithelial cyst induced by topical
administration of latanoprost. Br J Ophthalmol 2003;87:366.
22. Lally DR, Shields JF, Shields CL, et al. Free floating vitreous cyst of pigment
epithelial origin. J Pediatr Ophthalmol Strabismus 2008;45(1):47–48.

160
• IRIS PIGMENT EPITHELIAL CYST: PUPILLARY (CENTRAL) TYPE
Kytasty C, Mahmood Z, Parvus BJ, et al. Spontaneous deflation of iris pigment epithelial cyst
documented with anterior segment optical coherence tomography. Ophthalmic Surg Lasers
Imaging 2010;28:41 Online:e1–e3.

Figure 4.1. Large solitary pupillary margin iris pigment epithelial cyst in a 38-year-old man. The lesion had
been present and relatively stable since early childhood.

Figure 4.2. Lesion shown in Figure 4.1 after pupillary dilation. Note that the lesion has now been pulled more
into the pupillary aperture, and its margin rolls anteriorly over the edge of the pupil.

161
Figure 4.3. Inflated pupillary margin iris pigment epithelial cyst in a 2-year-old child.

Figure 4.4. Anterior segment optical coherence tomography depicts the inflated cyst at the pupillary border.

162
Figure 4.5. Several months later the cyst spontaneously deflated.

Figure 4.6. Anterior segment optical coherence tomography depicts the deflated cyst.

163
• IRIS PIGMENT EPITHELIAL CYST: PUPILLARY (CENTRAL) TYPE
ASSOCIATED WITH AORTIC DISSECTION

In rare cases, iris pigment epithelial cysts can be associated with potentially fatal aortic
dissection. Below is a patient that we managed for several decades who eventually developed
aortic dissection but fortunately was detected when minimally symptomatic and repaired
serious complications.

Figure 4.7. An 18-year-old man with asymptomatic bilateral iris pigment epithelial cysts, showing multifocal
cysts in the right eye.

Figure 4.8. Multifocal and partially deflated cysts are noted in his left eye.

164
Figure 4.9. Thirty years later, when 48 years old, the cysts remain, slightly changed, in the right eye.

Figure 4.10. At the same time, the left eye shows slightly changed cysts.

165
Figure 4.11. Anterior segment optical coherence tomography demonstrates the cysts at the pupillary margin.

Figure 4.12. At this time, computed tomography of the chest depicted the aortic dissection that was urgently
repaired.

166
• IRIS PIGMENT EPITHELIAL CYST: MIDZONAL TYPE
A midzonal iris pigment epithelial cyst can resemble an iris or ciliary body melanoma. However,
a melanoma would not ordinarily arise from the back surface of the iris and overhang the
pupillary margin. In addition, the midzonal cyst becomes stretched with pupillary dilation,
which would not occur with a melanoma. In contrast to a peripheral IPE cyst (discussed
subsequently), a midzonal cyst tends to block transmission of light.

Figure 4.13. Slit-lamp appearance, using a slit beam, of a midzonal iris pigment epithelial cyst inferiorly in a
40-year-old man.

Figure 4.14. Midzonal iris pigment epithelial cyst inferiorly in a 65-year-old woman.

167
Figure 4.15. Midzonal iris pigment epithelial cyst inferiorly in a 42-year-old man.

Figure 4.16. Bilobed midzonal iris pigment epithelial cyst in a 43-year-old woman.

168
Figure 4.17. Midzonal iris pigment epithelial cyst located temporally in the right eye.

Figure 4.18. Ultrasound biomicroscopy of a midzonal retinal pigment epithelial cyst, showing an elongated,
thin-walled cyst immediately posterior to the iris.

169
• IRIS PIGMENT EPITHELIAL CYST: MIDZONAL TYPE WITH MASSIVE
ENLARGEMENT REQUIRING NEEDLE ASPIRATION FOR DEFLATION

Most cases of midzonal cyst of the IPE are managed with observation. In rare cases,
enlargement over the visual axis leads to vision loss and possible shallowing of the anterior
chamber with glaucoma so management with aspiration or resection is required.

Figure 4.19. A middle-age woman with midzonal cyst in her right eye.

Figure 4.20. Anterior segment optical coherence tomography depicts the cystic mass arising from the posterior
iris surface and entering the pupillary region.

170
Figure 4.21. Nearly 2 years later, the cyst has enlarged to fill the visual axis, resulting in reduced visual acuity.

Figure 4.22. Ultrasound biomicroscopy confirms cyst enlargement.

171
Figure 4.23. The cyst was managed with fine needle aspiration with cyst deflation.

Figure 4.24. Anterior segment optical coherence tomography confirms cyst deflation to a small residual cyst in
the sulcus.

172
• IRIS PIGMENT EPITHELIAL CYST: MIDZONAL (RETROIRIDIC) TYPE
This is the most common type of iris pigment epithelial cyst. It is often confused clinically with
an iris or ciliary body melanoma because it is readily seen on slit-lamp biomicroscopy as an
anterior bulging of the peripheral iris. However, an iris melanoma would be located in the iris
stroma and not posterior to the iris. In addition, the iridociliary cyst transmits light, whereas
most melanomas fail to transmit light with transillumination techniques. UBM is valuable in
confirming the diagnosis.

Figure 4.25. Slit-lamp view of an iridociliary iris pigment epithelial cyst in a 40-year-old woman. Note the
anterior displacement of the stroma seen with the slit beam.

Figure 4.26. Retroillumination view of an iridociliary iris pigment epithelial (IPE) cyst with the pupil widely
dilated, showing typical light transmission through the cyst. Before the advent of ultrasound biomicroscopy, this
was the only reliable way to confirm the suspected diagnosis of iridociliary IPE cyst.

173
Figure 4.27. Direct view of an iridociliary cyst nasally in a 12-year-old boy. The cyst is best seen by widely
dilating the pupil and adjusting the slit lamp to the side.

Figure 4.28. Gonioscopic view of an iridociliary cyst in a 25-year-old woman. Note that two ciliary processes
can be seen behind the transparent cyst, a finding that would be unlikely with a melanoma.

174
Figure 4.29. Ultrasound biomicroscopy of an iridociliary iris pigment epithelial (IPE) cyst. This technique can be
used to confirm the suspected cystic nature of the lesion. It has also led to discovery of unexpected iridociliary
IPE cysts, indicating that such cysts may be more common than previously believed.

Figure 4.30. Histopathology of an iridociliary cyst found on routine sectioning of an eye enucleated for an
unrelated choroidal melanoma. Note the round, thin-walled cyst in the iridociliary sulcus. Also note the
remarkable similarity to the ultrasound biomicroscopy appearance. (Hematoxylin–eosin ×10.)

175
• IRIS PIGMENT EPITHELIAL CYST: FREE-FLOATING TYPE
A free-floating iris cyst was probably originally attached in the iridociliary sulcus in most cases
and became dislodged into the adjacent ocular fluids. The cyst is heavier than aqueous humor,
so it sinks to the dependent part of the eye.

Shields JA, Shields CL, De Potter P, et al. Free-floating cyst in the anterior chamber of the eye. J
Pediatr Ophthalmol Strabismus 1996;33:330–331.

Figure 4.31. Free-floating iris pigment epithelial cyst in the anterior chamber of the right eye of a 12-year-old
girl.

Figure 4.32. Lesion shown in Figure 4.31, with the patient lying on her right side.

176
Figure 4.33. Same lesion, with the patient lying on the left side.

Figure 4.34. Same lesion, with patient tilting her head backward.

177
Figure 4.35. Free-floating iris pigment epithelial cyst in mid-vitreous cavity. The cyst is in focus, but the retina
posteriorly is out of focus.

178
Figure 4.36. Free-floating vitreous cyst near the retinal surface. The cyst and the retina are in good focus.

179
• IRIS PIGMENT EPITHELIAL CYST: FREE-FLOATING TYPE WITH
SUBSEQUENT FIXATION IN ANTERIOR CHAMBER ANGLE

Cysts can become dislodged from their pigmented epithelial location, migrate into the anterior
chamber, and subsequently become fixed in the anterior chamber angle.

Figure 4.37. Fixed iris pigment epithelial cyst in the anterior chamber angle at the 6 o’clock position. With this
view, the lesion can resemble a nevus or melanoma.

Figure 4.38. Gonioscopic view of the lesion shown in Figure 4.37. Note the abrupt rounded margins and the
location anterior to the iris stroma. A nevus or melanoma would have a more sessile shape and would be
located in the iris stroma.

180
Figure 4.39. Lesion located nasally (to the right in photograph) in the right eye of a 53-year-old woman.

Figure 4.40. Gonioscopic view of lesion shown in Figure 4.39.

181
Figure 4.41. Gonioscopic view of small, fixed iris pigment epithelial cyst found on routine gonioscopy.

Figure 4.42. Gonioscopic view of another small, fixed iris pigment epithelial cyst found on routine gonioscopy.

182
 IRIS STROMAL CYSTS

General Considerations
Cysts within the iris stroma are called stromal cysts because of their location within
the fibers of the iris stroma. They are generally clear in appearance and are lined by
surface epithelium rather than pigment epithelium and are better designated as
intrastromal surface epithelial cysts. They can be congenital or acquired (1–27).
Congenital iris stromal cysts are usually diagnosed in early childhood, with 81%
being recognized before age 10 years (1–5,9). Some are clearly evident at birth,
whereas others appear spontaneously later in life. The acquired type of iris stromal
cyst can be idiopathic or it can occur after penetrating ocular trauma or intraocular
surgery.

Clinical Features
Clinically, an iris stromal cyst has a thin wall, is located within the iris stroma and
dissects a plane within this tissue. The lumen usually contains clear or slightly turbid
fluid, sometimes with fluid/debris level. The IPE can often be seen along the
posterior wall of the clear cyst. The congenital type enlarges slowly and encroaches
on the pupil, leading to visual impairment. This lesion is more aggressive in
younger children than in teenagers and adults (9). The acquired stromal cyst of
adulthood has a similar appearance but tends to be stable or shows slow
enlargement. Either type can periodically deflate and inflate due to small ruptures
in the cyst wall, but these spontaneous ruptures often lead to anterior uveitis.
In a large study on 84 iris stromal cysts (Table 4.3), the types included:

Table 4.3 Iris stromal cysts in 84 cases based on age at presentation

Pathology
Histopathologically, an iris stromal cyst is lined by thin, nonkeratinizing stratified
epithelium that sometimes contains goblet cells. The pathogenesis is usually
undetermined, but the congenital cyst seems to be secondary to developmental
displacement of conjunctival epithelium into the iris during embryogenesis.
Displacement of surface cells into the anterior chamber at the time of prenatal
amniocentesis has been implicated. Immunohistochemically, the cyst epithelium is
positive for higher–molecular-weight keratins and negative for S-100 protein,
supporting the concept the cells originate from surface ectoderm and not
neuroectoderm.

Management

183
The management of iris stroma cyst can be difficult (12–20). When the lesion
extends toward the pupil, we generally employ aspiration with a 30-gauge needle
to collapse the cyst. Cryotherapy or cautery can then applied to the base of the
lesion near the limbus through the sclera. If the lesion shows recurrence, then
aspiration can be repeated or other treatments used. Laser treatment to the wall of
the cyst has also been used, but recurrence is frequent and there is fear of epithelial
downgrowth. In cases that do not respond to the foregoing measures, surgical
removal by iridectomy or iridocyclectomy may be required. The cyst can also recur
after surgical removal.
More recently, intracystic injection of sclerosing agents such as mitomycin C or
absolute alcohol has been employed (16,20). With microscopically controlled
injection of alcohol into the cyst and careful washout, cyst regression was noted in
more than 90% of cases (20). The affected child should have a refraction, and
appropriate amblyopic therapy with patching of the opposite eye if necessary.

Selected References
Large Series
1. Shields CL, Shields PW, Manalac J, et al. Review of cystic and solid tumors of
the iris. Oman J Ophthalmol 2013;6(30):159–164.
2. Shields JA. Primary cysts of the iris. Theses, American Ophthalmological
Society. Trans Am Ophthalmol Soc 1981;79:771–809.
3. Shields JA, Kline MW, Augsburger JJ. Primary iris cysts. Review of the
literature and report of 62 cases. Br J Ophthalmol 1984;68:152–166.
4. Shields JA, Shields CL, Lois N, et al. Iris cysts in children: classification,
incidence and management. The 1998 Torrence A Makley Jr. Lecture. Br J
Ophthalmol 1999;83:334–338.
5. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119:407–414.

Small Series
6. Waeltermann JM, Hettinger ME, Cibis GW. Congenital cysts of the iris stroma.
Am J Ophthalmol 1985;100:549–554.
7. Paridaens AD, Deuble K, McCartney AC. Spontaneous congenital non-pigmented
epithelial cysts of the iris stroma. Br J Ophthalmol 1992;76:39–42.
8. Capo H, Palmer E, Nicholson DH. Congenital cysts of the iris stroma. Am J
Ophthalmol 1993;116:228–232.
9. Lois N, Shields CL, Shields JA, et al. Primary iris stromal cysts: a report of 17
cases. Ophthalmology 1998;105:1317–1322.
10. Rosenthal G, Klemperer I, Zirkin H, et al. Congenital cysts of the iris stroma.
Arch Ophthalmol 1998;116:1696.

Imaging
11. Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118(7):1297–1302.

Management
12. Kawaguchi K, Yamamoto S, Nagae Y, et al. Treatment of recurrent giant iris cyst

184
 with intracyst administration of mitomycin C. Br J Ophthalmol 2000;84:800–
801.
13. Shin SY, Stark WJ, Haller J, et al. Surgical management of recurrent iris stromal
cyst. Am J Ophthalmol 2000;130(1):122–123.
14. Casey M, Cohen KL, Wallace DK. Recurrence of iris stromal cyst following
aspiration and resection. J AAPOS 2002;6(4):255–256.
15. Haller JA, Stark WJ, Azab A, et al. Surgical management of anterior chamber
epithelial cysts. Am J Ophthalmol 2003;135:309–313.
16. Behrouzi Z, Khodadoust A. Epithelial iris cyst treatment with intracystic ethanol
irrigation. Ophthalmology 2003;110:1601–1605.
17. Gupta A, Pandian DG, Babu KR, et al. Primary stromal iris cysts treated
successfully with ab externo laser Nd:YAG photocoagulation. J Pediatr
Ophthalmol Strabismus 2010;47:e1–e4.
18. Kemmanu V, Yadav NK, Rachna VK, et al. Iris stromal cyst with cataract
managed by cyst aspiration and diode laser photocoagulation in a child. Indian J
Ophthalmol 2011;59(4):333–334.
19. Wiwatwongwana A, Ittipunkul N, Wiwatwongwana D. Ab externo laser
photocoagulation for the treatment of spontaneous iris stromal cyst. Graefes
Arch Clin Exp Ophthalmol 2012;250(1):155–156.
20. Shields CL, Arepalli S, Lally SE, et al. Iris stromal cyst management with
absolute alcohol-induced sclerosis in 16 patients. JAMA Ophthamol
2014;132:703–708.

Case Reports
21. Sanborn GE, Shields JA. Epithelial cyst of the anterior segment following
cataract surgery. Ophthalmologica 1981;183:221–224.
22. Paul TO, Spencer WH, Webster R. Congenital intrastromal epithelial cyst of the
iris. Ann Ophthalmol 1994;26:94–96.
23. Finger PT, McCormick SA, Lombardo J, et al. Epithelial inclusion cyst of the
iris. Arch Ophthalmol 1995;113(6):777–780.
24. Brent GJ, Meisler DM, Krishna R, et al. Spontaneous collapse of primary
acquired iris stromal cysts. Am J Ophthalmol 1996;122(6):886–887.
25. Gupta M, Puri P, Rundle P, et al. Primary iris stromal cyst with
pseudohypopyon: an atypical presentation. Br J Ophthalmol 2001;85(7):887.
26. Casey M, Cohen KL, Wallace DK. Recurrence of iris stromal cyst following
aspiration and resection. J AAPOS 2002;6:255–256.
27. Kodjikian L, Gain P, Donate D, et al. Cataract formation with a primary iris
stromal cyst. J Pediatr Ophthalmol Strabismus 2004;41(4):232–235.

185
• IRIS STROMAL CYST: CONGENITAL TYPE
Typical cases are illustrated, with some older cases managed by surgical resection. Today, initial
management would involve aspiration, sometimes with injection of mitomycin C or absolute
alcohol.

Figure 4.43. Congenital iris stromal cyst located inferonasally in an 8-week-old girl.

Figure 4.44. Congenital iris stromal cyst located inferotemporally in a 7-week-old child.

186
Figure 4.45. Superior congenital iris stromal cyst in a 10-week-old child seen several years ago. The lesion
recurred after aspirations and required surgical removal.

Figure 4.46. Appearance of the eye shown in Figure 4.45 after surgical removal of the cyst. Note that a sector
iridectomy was necessary. Today, aspiration and irrigation with mitomycin C or absolute alcohol would possibly
be employed.

187
Figure 4.47. Bilobed superior congenital iris stromal cyst in an 8-week-old child seen several years ago.
Iridectomy was eventually required.

Figure 4.48. Histopathology of the lesion shown in Figure 4.47. Note that the cyst is lined by nonkeratinizing
stratified epithelium, surrounded by iris stromal tissue. (Hematoxylin–eosin ×15.)

188
• IRIS STROMAL CYST. CONGENITAL TYPE: MANAGEMENT WAS BY
ASPIRATION AND ALCOHOL IRRIGATION

In recent years, selected congenital stromal iris cysts have been managed by aspiration and
alcohol irrigation. Early follow-up information suggests that this technique appears to be safe
and reliable. A case example is shown.

Shields CL, Arepalli S, Lally SE, et al. Iris stromal cyst management with alcohol-induced
sclerosis in 16 patients. JAMA Ophthamol 2014;in press.

Figure 4.49. Congenital iris stromal cyst in an 8-month-old girl who had recurrence after prior simple
aspiration.

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Figure 4.50. Fluorescein angiograph, showing blood vessels that ramify over the surface of the cyst.

Figure 4.51. Transillumination shows the transmission of light, suggesting that the enlarging cyst has caused
marked atrophy of the iris pigment epithelium.

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Figure 4.52. Ultrasound biomicroscopy, showing a large, clear cyst that replaces the iris and part of the ciliary
body.

Figure 4.53. Aspiration and irrigation technique using a 30-gauge needle.

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Figure 4.54. Postoperative appearance after aspiration and alcohol irrigation. The lesion had not recurred after
18 months of follow-up.

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• IRIS STROMAL CYST: PRIMARY ACQUIRED TYPE
This type of cyst seems to occur spontaneously, usually in adults who have no history of trauma
or ocular surgery. In contrast to acquired pigment epithelial cyst, this lesion can sometimes
enlarge slowly and cause inflammation, elevated intraocular pressure, and visual loss. In some
instances, the cyst has a tendency to enlarge for a period of time and then spontaneously to
deflate and reinflate. It is clinically similar to the primary congenital iris stromal cyst.

Figure 4.55. Superior primary acquired iris stromal cyst in a 45-year-old man.

Figure 4.56. Superonasal primary acquired iris stromal cyst in a 40-year-old woman.

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Figure 4.57. Inferior primary acquired iris stromal cyst in a 34-year-old woman.

Figure 4.58. Iris stromal cyst in a 32-year-old man.

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Figure 4.59. Primary acquired iris stromal cyst located inferiorly in a 17-year-old male.

Figure 4.60. Ultrasound biomicroscopy of the lesion shown in Figure 4.59. Note the typical round cyst replacing
the iris stroma. The lesion was eventually managed by aspiration and alcohol irrigation because of
progression.

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• IRIS STROMAL CYST: IMAGING WITH ANTERIOR SEGMENT
OPTICAL COHERENCE TOMOGRAPHY AND ULTRASOUND
BIOMICROSCOPY

Iris stromal cysts can be imaged with either anterior segment optical coherence tomography, a
relatively noninvasive method, or with UBM, a method that requires a water bath over the eye.
UBM provides more information on anatomical disturbance behind the iris whereas anterior
segment optical coherence tomography provides high-resolution images of the iris, anterior
chamber, and cornea.

Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment tumors with
ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases.
Ophthalmology 2011;118(7):1297–1302.

Figure 4.61. Iris stromal cyst in a child.

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Figure 4.62. Imaging with anterior segment optical coherence tomography shows the cystic mass.

Figure 4.63. Iris stromal cyst in an adult.

Figure 4.64. Gonioscopy shows the cyst involving the angle structures.

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Figure 4.65. Imaging with ultrasound biomicroscopy shows the cyst and compression of the iris without ciliary
body involvement.

Figure 4.66. Imaging with anterior segment optical coherence tomography shows the cyst with compression of
the iris. Deeper details are not possible with current systems.

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• IRIS STROMAL CYST: PRIMARY ACQUIRED TYPE. NATURAL
COURSE AND TREATMENT

Figure 4.67. Inferonasal primary acquired iris stromal cyst in a 71-year-old man. Note the turbid appearance of
the lumen of the cyst and the subtle “pseudohypopyon” level inferiorly within the cyst.

Figure 4.68. Lesion shown in Figure 4.67, 1 year later, demonstrating slight enlargement and more irregularity
of the pupil.

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Figure 4.69. Inferonasal primary acquired iris stromal cyst in a 61-year-old man. The dark color is secondary to
complete disappearance of the stroma and exposure of the iris pigment epithelium posterior to the cyst.

Figure 4.70. Appearance of the lesion 6 months later, showing enlargement of the cyst.

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Figure 4.71. Primary acquired iris stromal cyst located temporally in a 36-year-old man.

Figure 4.72. Appearance of the lesion shown in Figure 4.71, 2 months later, showing the good result of the
aspiration of the cyst with cryotherapy to its base near the limbus. This was done prior to our use of aspiration
and alcohol irrigation.

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• IRIS STROMAL CYST: SECONDARY ACQUIRED TYPE FOLLOWING
NONSURGICAL AND SURGICAL TRAUMA

Epithelial downgrowth into the anterior chamber usually occurs as a flat sheet of epithelial cells
but can occasionally take the form of a cyst. Epithelial downgrowth cysts have become less
common as more refined techniques of cataract surgery and repair of traumatic wounds have
been developed.

Figure 4.73. Pedunculated epithelial downgrowth cyst at the site of prior perforating limbal trauma in a 52-year-
old man.

Figure 4.74. Epithelial downgrowth cyst arising at the temporal margin of incision for cataract surgery.

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Figure 4.75. Epithelial downgrowth cyst arising at the temporal margin of incision for cataract surgery. Note the
“pseudohypopyon” due to epithelial debris in the inferior aspect of the cyst.

Figure 4.76. Multiloculated epithelial downgrowth cyst arising from the incision for prior cataract surgery. Note
the “pseudohypopyon” levels in the individual cystic areas.

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Figure 4.77. Epithelial downgrowth cyst arising from a cataract wound in a 52-year-old man. Because of
recurrent bouts of intraocular inflammation, the lesion was excised.

Figure 4.78. Histopathology of the lesion shown in Figure 4.77, depicting the wall of the cyst lined by stratified
squamous epithelium. There is epithelial debris in the lumen. (Hematoxylin–eosin ×20.)

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 CHAPTER 5

CHOROIDAL NEVUS

CHOROIDAL NEVUS

General Considerations
Choroidal melanocytic nevus is the most common primary intraocular tumor and
several articles have been published on this subject (1–42). This lesion occurs in
about 7% of Caucasian adults (3). It is likely a precursor to most choroidal
melanomas (1,4–7). Therefore, clinicians should be aware of choroidal nevus and its
variations.

Clinical Features
Although it may be congenital, choroidal nevus is rarely observed in young children
(1). The precursor cells can be present at birth but do not become clinically
apparent until puberty, perhaps due in part to acquisition of pigment of a
previously nonpigmented lesion. Choroidal nevus usually is first detected in
adulthood and can be flat or minimally elevated and pigmented or amelanotic.
Based on the Blue Mountain population-based study, Sumich et al. (3) found
choroidal nevus detected in 7% of Caucasians over the age of 49 years and was, on
average, 1.5 mm in diameter. Based on a large clinic-based study by Shields et al.
(1) choroidal nevus was referred to an ocular oncology center at mean age of 60
years and was, on average, 5.5 mm diameter. Most choroidal nevi are <2 mm in
thickness. Overlying drusen develops with time. Retinal pigment epithelium (RPE)
detachment occurs in about 10% of cases (26,27) and choroidal neovascularization
(CNV) overlying nevus in <1% (1,36–39). Some choroidal nevi have a large size
(>10 mm diameter) but still lack risk factors and these are classified as giant
choroidal nevus (14). Another interesting finding with nevus is the nonpigmented

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halo that can be seen in 5% of choroidal nevi (13). Halo choroidal nevus is
associated with a previous diagnosis of cutaneous melanoma and might represent an
autoimmune reaction. Halo nevus is a favorable sign that implies less chance of
undergoing malignant transformation.
The frequency with which a choroidal nevus grows or evolves into melanoma has
been estimated in several reports (2–7). Mathematically, it has been estimate that 1
in 8,845 choroidal nevi grow into melanoma (7). Statistical risk factors for
identifying tumors at risk for growth into melanoma include initial features of
tumor thickness >2 mm, subretinal fluid, symptoms, overlying orange pigment, and
proximity to the optic disc of 3 mm or less (1,4–6,10) (Table 5.1). More recently,
additional factors of ultrasonographic hollowness, halo absent and drusen absent
were found to be factors for growth (6).
Enlargement of a choroidal nevus is believed to be highly suggestive of malignant
transformation into melanoma. However some nevi can show slow growth over
many years of approximately 1 mm or less and still remain benign (12).

Table 5.1 Choroidal nevus growth into melanoma based on risk factors in
2,514 consecutive cases. The mnemonic “To Find Small Ocular Melanoma
Using Helpful Hints Daily”

Diagnostic Approaches
There have been recent advances in diagnosis of choroidal nevus. Fluorescein
angiographic features vary from hypofluorescence of smaller, darker lesions to more
hyperfluorescence of larger, less-pigmented lesions. U ltrasonography has limited
diagnostic value but can be used for baseline thickness measurements for elevated
lesions that will be followed periodically. Enhanced depth imaging optical
coherence tomography (EDI-OCT) is used increasingly to detect subtle subretinal
fluid, cystoid retinal edema, and overlying orange pigment, thus identifying risk
factors at an earlier stage (24–28). Autofluorescence is used more often to detect
overlying orange pigment that is a relative risk factor for malignant change (29–32).

Pathology
Histopathologically, a choroidal nevus is composed of a low-grade, spindle-shaped,
ovoid, or round melanocyte with variable amounts of cytoplasmic pigmentation
(33). A specific variant of nevus, melanocytoma, is discussed later. Secondary
changes on the adjacent structures (34) are discussed subsequently under pathology

206
of posterior uveal melanoma.

Management
A typical choroidal nevus generally requires no active treatment. Baseline fundus
photography, autofluorescence photography, ultrasonography, and EDI-OCT should
be performed and the patient should be examined every 6 to 12 months to detect
growth of the lesion or other risk factors growth and metastasis. In cases with
symptomatic secondary subretinal fluid or CNV, specific methods of laser
photocoagulation, transpupillary thermotherapy, photodynamic therapy, or
injection of anti-vascular endothelial growth factor (anti-VEGF) have been employed
to bring about resolution of related subretinal fluid (1,36–39). Lesions that show
growth or have two or more risk factors for growth or metastasis should generally
be considered for treatment, with the assumption that it could be an early
melanoma (4–6), a subject covered subsequently.

Selected References
Large Series
1. 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.
2. Ganley JP, Comstock GW. Benign nevi and malignant melanomas of the
choroid. Am J Ophthalmol 1973;76:19–25.
3. Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population. Arch
Ophthalmol 1998;116:645–650.
4. Shields CL, Shields JA, Kiratli H, et al. Risk factors for metastasis of small
choroidal melanocytic lesions. Ophthalmology 1995;102:1351–1361.
5. Shields CL, Cater JC, Shields JA, et al. Combination of clinical factors predictive
of growth of small choroidal melanocytic tumors. Arch Ophthalmol
2000;118:360–364.
6. 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.
7. Singh AD, Kalyani P, Topham A. Estimating the risk of malignant
transformation of a choroidal nevus. Ophthalmology 2005;112:1784–1789.
8. Hale PN, Allen RA, Straatsma BR. Benign melanomas (nevi) of the choroid and
ciliary body. Arch Ophthalmol 1965;74:532–538.
9. Brown GC, Shields JA, Augsburger JJ. Amelanotic choroidal nevi.
Ophthalmology 1981;88:1116–1120.
10. Augsburger JJ, Schroeder RP, Territo C, et al. Clinical parameters predictive of
enlargement of melanocytic choroidal lesions. Br J Ophthalmol 1989;73: 911–
917.
11. Shields CL, Furuta M, Mashayekhi A, et al. Visual acuity in 3422 consecutive
eyes with choroidal nevus. Arch Ophthalmol 2007;125(11):1501–1507.
12. Mashayekhi A, Siu S, Shields CL, Shields JA. Slow enlargement of choroidal
nevi: a long-term follow-up study. Ophthalmology 2011;118(2):382–388.
13. Shields CL, Maktabi AM, Jahnle E, et al. Halo nevus of the choroid in 150
patients: the 2010 Henry van Dyke Lecture. Arch Ophthalmol 2010;128(7):859–

207
 864.
14. 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.
15. Shields CL, Shields JA. Clinical features of small choroidal melanoma. Curr
Opin Ophthalmol 2002;13:135–141.

Small Series
16. Mims J, Shields JA. Follow-up studies on suspicious choroidal nevi.
Ophthalmology 1978;85:929–943.
17. Pro M, Shields JA, Tomer TL. Serous detachment of the fovea associated with
presumed choroidal nevi. Arch Ophthalmol 1979;96:1374–1377.
18. Zografos L, Mantel I, Schalenbourg A. Subretinal choroidal neovascularization
associated with choroidal nevus. Eur J Ophthalmol 2004;14:123–131.
19. Gonder JR, McCarthy EF, Augsburger JJ, et al. Visual loss associated with
choroidal nevi. Ophthalmology 1982;89:961–965.
20. Shields CL, Ramasubramanian A, Kunz WB, et al. Choroidal vitiligo
masquerading as large choroidal nevus: a report of four cases. Ophthalmology
2010;117(1):109–113.
21. Shields CL, Nickerson S, Al-Daamash S, et al. Waardenburg syndrome: iris and
choroidal hypopigmentation: findings on anterior and posterior segment
imaging. JAMA Ophthalmol 2013;131:1167–1173.
22. You QS, Xu L, Jonas JB, et al. Change in choroidal nevi during a 5-year follow-
up study: the Beijing Eye Study. Br J Ophthalmol 2010;94(5):575–578.

Imaging
23. Johnson RN, McDonald HR, Ai E, et al. Camera artifacts producing the false
impression of growth of choroidal melanocytic lesions. Am J Ophthalmol
2003;135:711–713.
24. Muscat S, Parks S, Kemp E, et al. Secondary retinal changes associated with
choroidal naevi and melanomas documented by optical coherence tomography.
Br J Ophthalmol 2004;88:120–124.
25. Espinoza G, Rosenblatt B, Harbour JW. Optical coherence tomography in the
evaluation of retinal changes associated with suspicious choroidal melanocytic
tumors. Am J Ophthalmol 2004;137:90–95.
26. Shields CL, Mashayekhi A, Materin MA, et al. Optical coherence tomography of
choroidal nevus in 120 consecutive patients. Retina 2005;25:243–252.
27. 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.
28. 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.
29. Lavinsky D, Belfort RN, Navajas E, et al. Fundus autofluorescence of choroidal
nevus and melanoma. Br J Ophthalmol 2007;91(10):1299–1302.
30. Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of choroidal nevus
in 64 cases. Retina 2008;28(8):1035–1043.
31. Gündüz K, Pulido JS, Ezzat K, et al. Review of fundus autofluorescence in
choroidal melanocytic lesions. Eye (Lond) 2009;23(3):497–503.
32. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumors. Curr

208
 Opin Ophthalmol 2013;24:222–232.
Pathology
33. Naumann GO, Hellner K, Naumann LR. Pigmented nevi of the choroid. Clinical
study of secondary changes in the overlying tissue. Trans Am Acad Ophthalmol
Otolaryngol 1971;75:110–123.
34. Shields JA, Rodrigues MM, Sarin LK, et al. Lipofuscin pigment over benign and
malignant choroidal tumors. Trans Am Acad Ophthalmol Otolaryngol
1976;81:871–881.

Management
35. Shields, JA, Shields CL, Peairs R, et al. Laser photocoagulation of small
melanocytic choroidal lesion. Sixteen year follow up and rationale for
treatment. Ophthalmic Lasers Surg 2006;37:79–81.
36. Parodi MB. Transpupillary thermotherapy for subfoveal choroidal
neovascularization associated with choroidal nevus. Am J Ophthalmol
2004;138:1074–1075.
37. Stanescu D, Wattenberg S, Cohen SY. Photodynamic therapy for choroidal
neovascularization secondary to choroidal nevus. Am J Ophthalmol
2003;136:575–576.
38. García-Arumí J, Amselem L, Gunduz K, et al. Photodynamic therapy for
symptomatic subretinal fluid related to choroidal nevus. Retina 2012;32(5):936–
941.
39. Chiang A, Bianciotto C, Maguire JI, et al. Intravitreal bevacizumab for choroidal
neovascularization associated with choroidal nevus. Retina 2012;32(1):60–67.
Case Reports
40. Naseripour M, Shields CL, Shields JA, et al. Pseudohypopyon of orange
pigment overlying stable choroidal nevus. Am J Ophthalmol 2001;132: 416–417.
41. Sarici AM, Shah SU , Shields CL, et al. Cutaneous halo nevi following plaque
radiotherapy for uveal melanoma. Arch Ophthalmol 2011;129(11):1499–1501.
42. Hashmi F, Rojanaporn D, Kaliki S, et al. Orange pigment sediment overlying
small choroidal melanoma. Arch Ophthalmol 2012;130:937–938.

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• CHOROIDAL NEVUS PIGMENTED VARIATIONS
The majority of choroidal nevi have some degree of pigmentation and are located in the
posterior part of the choroid. More longstanding nevi or slightly elevated nevi can cause
overlying drusen.

Figure 5.1. Choroidal nevus on the temporal margin of the optic disc in a 39-year-old man.

210
Figure 5.2. Typical small choroidal nevus in the foveal region of a 20-year-old man.

Figure 5.3. Slightly larger choroidal nevus centered in the foveal region. Such lesions can eventually cause
visual loss due to photoreceptor degeneration and still be benign.

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Figure 5.4. Slightly larger, elevated choroidal nevus with surface drusen in a 46-year-old man.

Figure 5.5. Wide-angle fundus photograph of nevus near the superior equator.

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Figure 5.6. Histopathology of a choroidal nevus, showing closely compact benign spindle cells. (Hematoxylin–
eosin ×15.)

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• CHOROIDAL NEVUS: NONPIGMENTED VARIATIONS

Figure 5.7. Juxtapapillary amelanotic choroidal nevus in a 62-year-old woman.

Figure 5.8. Amelanotic choroidal nevus along the inferior vascular arcade in a 46-year-old man. The surface
drusen and slight visibility of choroidal vessels in the lesion suggest that the lesion is a melanocytic lesion
and not a choroidal metastasis or hemangioma.

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Figure 5.9. Amelanotic choroidal nevus in the superior fundus.

Figure 5.10. Amelanotic choroidal nevus inferotemporal to the optic disc. Note the subtle pigment in the
superior part of the lesion.

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Figure 5.11. Larger amelanotic choroidal nevus located temporally in the left eye. The prominent blood vessels
in the tumor are often seen with nevus or melanoma but are not usually visualized in choroidal metastasis,
choroidal hemangioma, or solitary granuloma.

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Figure 5.12. Large amelanotic choroidal nevus located near the equator superotemporally in the right eye.

217
• CHOROIDAL NEVUS: CLINICAL VARIATIONS
Shields CL, Maktabi AM, Jahnle E, et al. Halo nevus of the choroid in 150 patients: the 2010
Henry van Dyke Lecture. Arch Ophthalmol 2010;128(7):859–864.

Figure 5.13. Halo choroidal nevus, with the central portion pigmented and the peripheral ring amelanotic. Most
halo nevi have this configuration. The halo is sometimes due to balloon cell degeneration in the peripheral
portions of the tumor.

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Figure 5.14. Reverse halo nevus with the pigmented ring in the peripheral portion of the lesion in a 30-year-old
woman.

Figure 5.15. Choroidal nevus in which the upper half is pigmented and the lower half is nonpigmented in a 62-
year-old man.

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Figure 5.16. Multifocal choroidal nevus. Wide-angle image of the right fundus, showing two prominent small
choroidal nevi.

Figure 5.17. Wide-angle photograph of large presumed choroidal nevus in the nasal aspect of the fundus.

220
Even though the lesion is large in diameter, it is less than 2 mm thick and has numerous drusen and no
secondary subretinal fluid. It has remained clinically stable for several years. Such a lesion is called a “giant”
nevus.

Figure 5.18. “Giant” choroidal nevus in the nasal aspect of right eye, similar to the lesion shown in Figure 5.17.
It has been followed for 15 years without change.

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• CHOROIDAL NEVUS: EFFECTS ON ADJACENT STRUCTURES

Figure 5.19. Choroidal nevus with secondary serous retinal detachment affecting the foveal region in a 28-
year-old man.

222
Figure 5.20. Another choroidal nevus with localized secondary shallow retinal detachment extending into the
foveal region and producing visual loss. Delimiting argon laser photocoagulation has been just applied to
induce resolution of the subretinal fluid. A delimiting laser can be used without visual damage when the
margin of the nevus is >1.5 mm from the foveola.

Figure 5.21. Choroidal nevus with overlying detachment of the RPE. Note the subtle ring of orange pigment that
characteristically encircles the base of a pigment epithelial detachment over a choroidal nevus (or melanoma).

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Figure 5.22. Late fluorescein angiogram of the lesion shown in Figure 5.21, depicting characteristic
hyperfluorescence of the retinal pigment epithelium detachment.

Figure 5.23. Choroidal nevus with overlying choroidal neovascularization in a 68-year-old woman. Note the
characteristic crescent-shaped hemorrhage adjacent to the membrane. Prior to the development of the
choroidal neovascularization a typical nevus had been observed for several years. Occurrence of a
neovascular membrane does not usually imply malignant transformation.

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Figure 5.24. Fluorescein angiogram in the recirculation phase of the nevus shown in Figure 5.23. Note the
characteristic hyperfluorescence of the subretinal neovascular membrane of choroidal origin.

In addition to overlying drusen and orange pigment mentioned previously, an elevated choroidal
nevus can occasionally induce a secondary serous retinal detachment, detachment of the RPE,
or CNV.

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• CHOROIDAL NEVUS: FLUORESCEIN ANGIOGRAPHY

Figure 5.25. Typical choroidal nevus nasal to the optic disc in a 52-year-old woman.

Figure 5.26. Fluorescein angiogram in the recirculation phase, showing hypofluorescence of the lesion shown

226
in Figure 5.25.

Figure 5.27. Late angiogram, showing continued hypofluorescence of the nevus shown in Figure 5.25.

Figure 5.28. Choroidal nevus with overlying drusen in a 44-year-old man.

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Figure 5.29. Fluorescein angiogram in the recirculation phase of the lesion shown in Figure 5.28,
demonstrating hypofluorescence of the pigmented area and hyperfluorescence of the overlying drusen.

Figure 5.30. Late angiogram of the lesion shown in Figure 5.28, showing continued hypofluorescence of the
nevus and continued well-defined hyperfluorescence of the drusen.

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• CHOROIDAL NEVUS: OPTICAL COHERENCE TOMOGRAPHY
Spectral domain enhanced depth imaging optical coherence tomography has allowed
visualization of choroidal nevus and its effect on adjacent choroidal tissue as well the overlying
retina. These features provide information regarding tumor characteristics and visual acuity that
might not be detected on routine clinical examination. Some features such as fresh subretinal
fluid can be indirect evidence on tumor activity.

1. Shields CL, Mashayekhi A, Materin MA, et al. Optical coherence tomography of choroidal
nevus in 120 patients. Retina 2005;25:243–252.
2. 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.

Figure 5.31. Choroidal nevus in submacular location with localized retinal pigment epithelial loss, suggestive
of subretinal fluid.

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Figure 5.32. Optical coherence tomography demonstrates the choroidal mass, compressing the inner
choroidal tissue and with overlying irregularity of the ellipsoid layer and photoreceptors, with shallow subretinal
fluid.

Figure 5.33. Choroidal nevus in temporal macular region with overlying drusen and possible shallow
subretinal fluid.

Figure 5.34. Optical coherence tomography confirms the elevated choroidal mass with obliteration of choroidal
details. Note shallow subretinal fluid cleft with photoreceptor retraction, suggestive of chronic fluid.

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Figure 5.35. Choroidal nevus in temporal macular region with overlying drusen and central retinal pigment
epithelial atrophy.

Figure 5.36. Optical coherence tomography shows the choroidal mass with obvious overlying outer retinal
cystoid edema and irregularity to the overlying retinal pigment epithelium and outer retinal layers.

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• CHOROIDAL NEVUS: AUTOFLUORESCENCE
Autofluorescence fundus imaging depicts the status of the RPE. If irritated or with lipofuscin,
this tissue displays hyperautofluorescence and if atrophic or scarred, it appears
hypoautofluorescent. These features are important to judgment of chronicity of a choroidal
nevus.

Figure 5.37. Small juxtapapillary choroid nevus referred with possible overlying orange pigment.

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Figure 5.38. Autofluorescence reveals retinal pigment epithelial atrophy as hypoautofluorescence and lack of
orange pigment (lipofuscin) hyperautofluorescence.

Figure 5.39. Juxtapapillary choroid nevus with overlying drusen.

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Figure 5.40. Autofluorescence reveals retinal pigment epithelial atrophy near the disc as hypoautofluorescence
and then ring-shaped hyperautofluorescence of drusen.

Figure 5.41. Choroid nevus with overlying drusen and retinal pigment epithelial hyperplasia, fibrous
metaplasia, and atrophy.

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Figure 5.42. Autofluorescence reveals retinal pigment epithelial abnormalities as hypoautofluorescence.

235
• CHOROIDAL NEVUS: GROWTH INTO CHOROIDAL MELANOMA
Although most choroidal melanomas probably arise from a pre-existing nevus, most cases of
melanoma do not have photographic evidence of such transformation. Three such cases are
shown in which a small presumed choroidal nevus showed enlargement into a choroidal
melanoma.

Figure 5.43. Halo nevus inferonasal to the optic disc in a 60-year-old woman.

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Figure 5.44. Appearance of the lesion shown in Figure 5.37, 4 years later, demonstrating growth of the lesion
temporally and accumulation of overlying orange pigment. The tumor was clinically eradicated by laser
photocoagulation.

Figure 5.45. Small choroidal nevus immediately temporal to the foveola in a 65-year-old man.

237
Figure 5.46. Appearance of the lesion shown in Figure 5.39 when the patient returned 3 years later, showing
growth of the lesion and accumulation of orange pigment enucleation was performed but the patient eventually
developed metastasis.

Figure 5.47. Small choroidal nevus superonasal to the optic disc in a 60-year-old man. The lesion had been
followed for 10 years without change.

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Figure 5.48. Appearance of the lesion shown in Figure 5.41, 1 year after the 10-year visit at which time the
nevus was reportedly stable. The nevus had grown rapidly and evolved into a melanoma. Despite prompt
enucleation, the patient eventually developed metastatic melanoma to the liver.

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• CHOROIDAL NEVUS: GROWTH INTO CHOROIDAL MELANOMA

Figure 5.49. Small choroidal nevus, measuring 3 mm in basal dimension and without risk factors.

Figure 5.50. Twenty months later, the lesion shown in Figure 5.43 showed growth into a dome-shaped
melanoma, demonstrating orange pigment and shallow subretinal fluid.

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Figure 5.51. Elderly patient with geographic atrophy from macular degeneration showed a small juxtapapillary
choroidal nevus, measuring 3 mm in diameter.

Figure 5.52. Seven years later, the lesion shown in Figure 5.45 has grown into a mushroom-shaped choroidal
melanoma.

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Figure 5.53. Small choroidal nevus, measuring 4 mm in basal dimension, located in the macular region.

Figure 5.54. Eleven years later, the lesion shown in Figure 5.47 has grown into a circumpapillary diffuse
choroidal melanoma with orange pigment and shallow subretinal fluid.

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 CHAPTER 6

MELANOCYTOMA OF THE OPTIC DISC AND

POSTERIOR UVEA

MELANOCYTOMA OF THE OPTIC DISC AND POSTERIOR UVEA

General Considerations
Melanocytoma is a variant of melanocytic nevus that is classically located on the
optic disc. Since the nature of optic nerve melanocytoma was elucidated by
Zimmerman, many articles have been published on this ocular neoplasm (1–45). It
is presumed to be congenital and nonhereditary and is a deeply pigmented lesion
that usually is located on all or part of the optic disc. U nlike uveal melanoma, optic
disc melanocytoma does not appear to have a predilection for Caucasians, but seems
to occur in all races. Historically, optic disc melanocytoma was often believed to be
malignant melanoma both clinically and histopathologically. Today, however, it is
generally recognized by its typical clinical features, which differ from those of most
melanomas, and erroneous enucleation is rarely done for this benign lesion today.
Although it was originally believed to be unique to the optic disc, it is now
recognized to also occur in the iris, ciliary body, and choroid. Iris melanocytoma is
discussed in Chapter 2 because it is a variant of iris nevus. Because most choroidal
melanocytomas are impossible to differentiate clinically from other deeply
pigmented choroidal nevi, they do not come to histopathologic evaluation.

Clinical Features
The clinical features of posterior uveal melanocytoma vary depending on whether
the lesion is located on the optic nerve, choroid, or ciliary body.

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Optic Nerve Melanocytoma. A recent review of 115 patients with optic nerve
melanocytoma described the demographics of this tumor (4). The lesion was
unilateral in 99% and appeared dark brown in 100%. Visual symptoms related to
the melanocytoma were present in 24%, and an afferent pupillary defect was noted
in 9%. The mean tumor diameter was 2 mm, and the mean thickness was 1 mm.
Associated findings included a choroidal component (54%), retinal component
(30%), optic disc edema (25%), retinal edema (16%), localized subretinal fluid
(14%), retinal exudation (12%), retinal hemorrhage (5%), vitreous seeds (4%), and
retinal vein obstruction (3%) (4). It has recently been report to be associated with a
central retinal artery obstruction (21).
Optic nerve melanocytoma has a marked tendency to undergo spontaneous
necrosis, which can result in profound visual loss. About 10% to 15% show subtle
enlargement over several years, but that does not usually mean malignant
transformation. Malignant transformation into melanoma occurred in 1% to 2% (4)
(Table 6.1).

Table 6.1 Outcomes of optic nerve melanocytoma

Localized Choroidal Melanocytoma. U nlike its optic disc counterpart,

melanocytoma of the choroid does not possess highly specific clinical features.
Because it is a variant of choroidal nevus, it may be indistinguishable clinically from
other deeply pigmented choroidal nevi. The diagnosis can be suspected on the basis
of ophthalmoscopy that shows the lesion to be dark brown to black and it is, by
definition, never amelanotic. As mentioned earlier, most small ciliary body and
choroidal melanocytomas are not confirmed histopathologically, and no highly
reliable clinical diagnostic criteria have been established. Fluorescein angiography
and ultrasonography are probably of no benefit in making the diagnosis. Presumed
melanocytoma has rarely been recognized in the macular region, although
histopathologic confirmation is lacking.

Ciliary Body. Ciliary body melanocytoma, like choroidal melanocytoma, does not
have any specific diagnostic criteria. It appears to be similar to other deeply
pigmented ciliary body tumors such as melanoma and adenoma of the ciliary
pigment epithelium. However, we have made an accurate diagnosis of ciliary body
melanocytoma on several occasions based on its intense black color and vitreous
seeding from the tumor, presumably due to necrosis.

Diffuse Uveal Melanocytoma. In some patients with classic ocular melanocytosis,

the eye is enucleated for choroidal melanoma, and the entire uveal tract is found to
be thickened by deeply pigmented cells with cytologic features identical to those of
melanocytoma. This was pointed out by Zimmerman in his early publication on the
subject (13,14). It is believed that this diffuse melanocytoma and ocular

244
melanocytosis represent the same entity. Diffuse uveal melanocytoma, like ocular
melanocytosis, can be localized, multifocal, and diffuse and each type can give rise
to uveal melanoma (4,25,26,30).

Diagnostic Approaches
Fluorescein angiography of optic disc melanocytoma typically shows
hypofluorescence throughout the angiogram, sometimes with hyperfluorescence of
secondary disc edema or retinal pigment epithelium atrophy. It is probably of no
value in differentiating choroidal or ciliary body melanocytoma from melanoma,
nevus, or pigment epithelial tumors. Findings on EDI-OCT have been reported and
shows optically dense dome-shaped surface with abrupt shadowing and occasional
vitreous opacities (12). On several occasions, we have diagnosed melanocytoma of
the iris or ciliary body by cytopathologic study with fine-needle aspiration biopsy.

Pathology
Histopathologically, optic nerve melanocytoma is deeply pigmented due to
abundant large melanosomes in the cytoplasm (13–15). Bleached preparations
reveal the cells to be ovoid with abundant cytoplasm, relatively small nuclei, and
few prominent nucleoli. Zimmerman agreed that his term melanocytoma was
nonspecific, and credited Cogan with recommending the term magnocellular nevus
in its place. In cases that come to histopathologic confirmation, necrosis is a
common feature, sometimes with pseudocysts containing free-floating
melanophages. Melanocytoma of the iris, ciliary body, and choroid have identical
cytologic features.

Management
Rarely, a melanocytoma of the optic disc can evolve into malignant melanoma
(4,25,26,30). Therefore, fundus photography and clinical evaluation should be done
once or twice a year. Small degrees of growth may not signify malignant change.
However, more progressive growth and visual loss should suggest malignant
transformation. Enucleation may be the best treatment for an optic disc
melanocytoma with documentation of growth and severe visual loss. Fine-needle
aspiration biopsy may be done first to confirm transformation into melanoma.
Suspected melanocytoma of the choroid or ciliary body can be observed or managed
like a comparable-sized melanoma, as described subsequently in the chapter on the
management of posterior uveal melanoma. It has been our impression that
melanomas that evolve from melanocytoma are low grade and generally have an
excellent prognosis.

Selected References
Large Series
1. Shields JA. Melanocytoma of the optic nerve head. A review. Int Ophthalmol
1978;1:31–37.
2. Joffe L, Shields JA, Osher R, et al. Clinical and follow-up studies of
melanocytomas of the optic disc. Ophthalmology 1979;86:1067–1078.
3. Reidy JJ, Apple DJ, Steinmetz RL, et al. Melanocytoma: nomenclature,

245
 pathogenesis, natural history and treatment. Surv Ophthalmol 1985;29:319–327.
4. Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of the optic disc in
115 cases. The 2004 Samuel Johnson Memorial Lecture, part 1. Ophthalmology
2004;111:1739–1746.
5. Shields JA, Shields CL, Demirci H, et al. Melanocytoma of the optic nerve:
Review. Surv Ophthalmol 2006;51:93–104.
6. Shields JA, Shields CL, Eagle RC Jr. Melanocytoma (hyperpigmented
magnocellular nevus) of the uveal tract. The 34th G. Victor Simpson Lecture.
Retina 2007;27: 730–739.
7. Howard GM, Forrest AW. Incidence and location of melanocytomas. Arch
Ophthalmol 1967;77:61–67.

Small Series
8. Osher RH, Shields JA, Layman PR. Pupillary and visual field evaluation in
patients with melanocytoma of the optic disc. Ophthalmology 1979;97:1096–
1099.
9. Mazzuca DE Jr, Shields CL, Sinha N, et al. Progressive retinal invasion and
vitreous seeding from optic disc melanocytoma. Clin Experiment Ophthalmol
2012;40(1):e123–e125.
10. 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.

Imaging
11. Mohamed MD, Gupta M, Parsons A, et al. U ltrasound biomicroscopy in the
management of melanocytoma of the ciliary body with extrascleral extension.
Br J Ophthalmol 2005;89:14–16.
12. Shields CL, Perez B, Benavides R, et al. Optical coherence tomography of optic
disk melanocytoma in 15 cases. Retina 2008;28(3):441–446.
Pathology/Cytology
13. Zimmerman LE, Garron LK. Melanocytoma of the optic disc. Int Ophthalmol Clin
1962;2:431–440.
14. Zimmerman LE. Melanocytes, melanocytic nevi, and melanocytomas: The Jonas
S. Friedenwald Memorial Lecture. Invest Ophthalmol 1965;4:11–40.
15. Juarez CP, Tso MO. An ultrastructural study of melanocytomas (magnocellular
nevi) of the optic disk and uvea. Am J Ophthalmol 1980;90:48–62.
16. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
17. El-Harazi SM, Kellaway J, Font RL. Melanocytoma of the ciliary body diagnosed
by fine-needle aspiration biopsy. Diagn Cytopathol 2000;22:394–397.
Management
18. Raichand M, Peyman GA, Juarez CP, et al. Resection of uveal melanocytoma:
clinicopathological correlation. Br J Ophthalmol 1983;67:236–243.
19. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for
posterior uveal melanomas: the 1986 Schoenberg Lecture. Ophthalmic Surg

246
 1988;19:774–780.
20. Ramasubramanian A, Shields CL, Kytasty C, et al. Resection of intraocular
tumors (partial lamellar sclerouvectomy) in the pediatric age group.
Ophthalmology 2012; 119:2507–2513.
Case Reports
21. 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.
22. Croxatto JO, Ebner R, Crovetto L, et al. Angle closure glaucoma as initial
manifestation of melanocytoma of the optic disc. Ophthalmology 1983;90:830–
834.
23. Garcia-Arumi J, Salvador F, Corcostegui B, et al. Neuroretinitis associated with
melanocytoma of the optic disc. Retina 1994;14:173–176.
24. Wiznia RA, Price J. Recovery of vision in association with a melanocytoma of
the optic disc. Am J Ophthalmol 1974;78:236–238.
25. Apple DJ, Craythorn JM, Reidy JJ, et al. Malignant transformation of an optic
nerve melanocytoma. Can J Ophthalmol 1984;19:320–325.
26. Meyer D, Ge J, Blinder KJ, et al. Malignant transformation of an optic disc
melanocytoma. Am J Ophthalmol 1999;127:710–714.
27. Shields JA, Shields CL, Piccone M, et al. Spontaneous appearance of an optic
disc melanocytoma. Am J Ophthalmol 2002;134:614–615.
28. Shields JA, Shields CL, Lavrich J. Melanocytoma of optic disc in a patient with
type 2 neurofibromatosis. Retina 2002;22:222–223.
29. Shields JA, Shields CL, Ehya H, et al. Total blindness from presumed optic
nerve melanocytoma. Am J Ophthalmol 2005;139:1113–1114.
30. Roth AM. Malignant change in melanocytomas of the uveal tract. Surv
Ophthalmol 1978;22:404–412.
31. Reidy JJ, Apple DJ, Steinmetz RL, et al. Melanocytoma: nomenclature,
pathogenesis, natural history and treatment. Surv Ophthalmol 1985;29:319–327.
32. Shields JA, Font RL. Melanocytoma of the choroid clinically simulating a
malignant melanoma. Arch Ophthalmol 1972;87:396–400.
33. Shields JA, Augsburger JJ, Bernardino V, et al. Melanocytoma of the ciliary
body and iris. Am J Ophthalmol 1980;89:632–635.
34. Jurgens I, Roca G, Sedo S, et al. Presumed melanocytoma of the macula. Arch
Ophthalmol 1994;112:305–306.
35. Heitman KF, Kincaid MC, Steahly L. Diffuse malignant change in a
ciliochoroidal melanocytoma in a patient of mixed racial background. Retina
1988;8:67–72.
36. Shields JA, Shields CL, Eagle RC, et al. Malignant melanoma associated with
melanocytoma of the optic disc. Ophthalmology 1990;97:225–230.
37. Agarwal S, Shanmugam MP, Gopal L, et al. Necrotic melanocytoma of the optic
disk with central retinal vascular obstruction. Retina 2005;25:364–367.
38. Shanmugam MP, Khetan V, Sinha P. Optic disk melanocytoma with
neuroretinitis. Retina 2004;24:317–318.
39. Robertson DM, Campbell RJ, Salomao DR. Mushroom-shaped choroidal
melanocytoma mimicking malignant melanoma. Arch Ophthalmol 2002;120:82–
85.

247
40. 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.
41. Meyer D, Ge J, Blinder KJ, et al. Malignant transformation of an optic disk
melanocytoma. Am J Ophthalmol 1999;127:710–714.
42. Shukla SY, Shields JA, Eagle RC, et al. Transformation of optic disc
melanocytoma into melanoma over 33 years. Arch Ophthalmol
2012;130(10):1344–1347.
43. Rishi P, Venkatesh R. Central retinal artery occlusion secondary to optic disk
melanocytoma. Retinal Cases & Brief Reports 2012;6:212–215.
44. Reichstein DA, Shields JA, U yen T, et al. U nusual multifocal pigmented lesions
of the uvea in a patient with ocular melanocytosis. Retinal Cases & Brief Reports
2013;7:399–401.
45. Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented adenoma of the optic
nerve head simulating a melanocytoma. Ophthalmology 1992;99:1705–1708.

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• OPTIC DISC MELANOCYTOMA
Shown are examples of melanocytomas almost confined to the optic disc, with only minimal
extension outside the disc margins. Also shown is the pathology of optic nerve melanocytomas.

Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of the optic disc in 115 cases. The
2004 Samuel Johnson Memorial Lecture. Ophthalmology 2004;111:1739–1746.

Figure 6.1. Small melanocytoma of the optic disc in a 22-year-old man.

249
Figure 6.2. Melanocytoma of the optic disc in a 60-year-old woman.

Figure 6.3. Melanocytoma of the optic disc in a 34-year-old man.

Figure 6.4. Melanocytoma of the optic disc in a 47-year-old woman.

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Figure 6.5. Low-magnification photomicrograph of a melanocytoma of the optic disc, showing the deeply
pigmented lesion causing elevation of the optic nerve and extending into the retrolaminar portion of the optic
nerve. This is an older case, in which the eye was enucleated elsewhere for suspected optic disc melanoma.
(Hematoxylin–eosin × 20.) (Courtesy of Lorenz Zimmerman, MD, and the Armed Forces Institute of Pathology,
Washington, DC.)

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• OPTIC DISC MELANOCYTOMA: RETINAL NERVE FIBER LAYER
INVOLVEMENT

These lesions can have a feathery or fibrillated margin because of the anatomic arrangement of
the juxtapapillary nerve fibers.

Figure 6.6. Bleached preparation of a melanocytoma showing round cells with abundant cytoplasm and
uniform nuclei. (Hematoxylin–eosin ×200.)

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Figure 6.7. Melanocytoma over the superior portion of the optic disc in a 40-year-old woman as seen in 1977.
This lesion was followed from about 1960 through 1996 and it showed no appreciable change.

Figure 6.8. Melanocytoma over the nasal portion of the optic disc in a 40-year-old woman.

253
Figure 6.9. Melanocytoma over the inferior portion of the optic disc in a 51-year-old man.

Figure 6.10. Melanocytoma over the superotemporal portion of the optic disc in a 30-year-old man.

254
Figure 6.11. Melanocytoma over the inferior portion of the optic disc in a 16-year-old male as shown in 1977.

Figure 6.12. Appearance of lesion shown in Figure 6.11 as seen in 1993, showing no appreciable change in
the lesion over a 16-year period.

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• OPTIC DISC MELANOCYTOMA: JUXTAPAPILLARY CHOROIDAL
INVOLVEMENT

These lesions are juxtapapillary melanocytic nevi in which a portion of the lesion involves the
lamina choroidalis and appears clinically on the surface of the disc. In many cases, the
epipapillary component is more pigmented and the choroidal portion appears less pigmented
because the overlying retinal pigment epithelium does not allow its dark color to show.

Figure 6.13. Melanocytoma of juxtapapillary choroid with minimal optic disc involvement in a 12-year-old girl.

256
Figure 6.14. Melanocytoma on the temporal aspect of the optic disc in a 60-year-old man.

Figure 6.15. Melanocytoma on the nasal aspect of the optic disc in a 30-year-old man.

257
Figure 6.16. Melanocytoma over the temporal portion of the optic disc in a 60-year-old man.

Figure 6.17. Melanocytoma over the inferotemporal portion of the optic disc in a 19-year-old woman.

258
Figure 6.18. Appearance of the lesion shown in Figure 6.17 after 12 years. It has shown only questionable
enlargement. By 2007, after 30 years follow-up, the visual acuity has declined to finger counting, the lesion is
slightly larger, and enucleation is being considered.

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• OPTIC DISC MELANOCYTOMA: FLUORESCEIN ANGIOGRAPHY AND
OPTICAL COHERENCE TOMOGRAPHY

1. Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of the optic disc in 115 cases.
The 2004 Samuel Johnson Memorial Lecture. Ophthalmology 2004;111:1739–1746.
2. Shields JA, Shields CL, Demirci H, et al. Melanocytoma of the optic nerve. Surv Ophthalmol
2006;51:93–104.
3. Shields CL, Perez B, Benavides R, et al. Optical coherence tomography of optic disk
melanocytoma in 15 cases. Retina 2008;(3)28:441–446.

Figure 6.19. Melanocytoma over the temporal portion of the optic disc in a 28-year-old man.

260
Figure 6.20. Fluorescein angiogram in the early laminar venous phase, showing hypofluorescence of the
lesion.

Figure 6.21. Fluorescein angiogram in the full venous phase, showing continued hypofluorescence of the
lesion.

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Figure 6.22. Fluorescein angiogram in the late phase, showing continued hypofluorescence of the lesion with
only mild focal staining.

Figure 6.23. Melanocytoma of the optic disc with prepapillary component, mild disc edema, and subtle vitreous
seeding inferiorly.

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Figure 6.24. Optical coherence tomography of the lesion shown in Figure 6.23, revealing abruptly elevated
mass in the optic disc region, complete shadowing posteriorly, and clumps of vitreous seeds.

263
• OPTIC DISC MELANOCYTOMA: ASSOCIATIONS AND CLINICAL
VARIATIONS

Melanocytoma seems to occur more frequently in patients with ocular melanocytosis and
congenital hypertrophy of the retinal pigment epithelium. A rare case of probable
melanocytoma of the retina has also been recognized.

Jurgens I, Roca G, Sedo S, et al. Presumed melanocytoma of the macula. Arch Ophthalmol
1994;112:305–306.

Figure 6.25. Melanocytoma of the optic disc and juxtapapillary choroid in the left eye of a 43-year-old man.

264
Figure 6.26. Ocular melanocytosis of the opposite (right) eye in the patient shown in Figure 6.25. Although
there is a slight relationship between melanocytoma and ocular melanocytosis, this finding could be
coincidental in this case.

Figure 6.27. Melanocytoma of the optic disc in a 45-year-old African-American patient.

265
Figure 6.28. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the same eye shown in
Figure 6.27. We have noted a slight association of these two conditions.

Figure 6.29. Presumed melanocytoma of the sensory retina in the macular region. Note the seeding into the
nearby retina and vitreous, suggesting the lesion had undergone necrosis. There is a possibility that this
lesion could be hyperplasia or epithelioma of the pigment epithelium; it was diagnosed as a melanocytoma.
(Courtesy of Manuel Quintana, MD.)

266
Figure 6.30. Recirculation-phase fluorescein angiogram of the lesion seen in Figure 6.29, showing
hypofluorescence of the lesion. (Courtesy of Manuel Quintana, MD.)

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• OPTIC DISC MELANOCYTOMA: VISUAL LOSS FROM TUMOR
NECROSIS

Some patients with melanocytoma experience pain and visual loss in the affected eye. This can
occur with anyone, but appears to be more common in young African-American patients. The
melanocytoma in these cases appears discohesive and is associated with tumor cells in the
overlying vitreous, suggesting necrosis of the tumor. These tumors are hypofluorescent with
angiography suggesting tumor necrosis with deficient blood supply. Two examples are shown.

Shields JA, Shields CL, Ehya H, et al. Total blindness from presumed optic nerve melanocytoma.
Am J Ophthalmol 2005;139:1113–1114.

Figure 6.31. Face appearance of 30-year-old woman who has experienced persistent pain in the affected left
eye for several months. Externally her eye is normal, and intraocular pressures are normal, with no explanation
for the ocular pain.

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Figure 6.32. Left fundus in the patient shown in Figure 6.31. Note the elevated melanocytoma with clumps of
pigmented cells in the vitreous.

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Figure 6.33. Recirculation-phase fluorescein angiogram of the lesion shown in Figure 6.32, depicting
hypofluorescence of the mass.

Figure 6.34. Face appearance of 12-year-old girl with total visual loss to no light perception in her right eye.

Figure 6.35. Right fundus of the patient shown in Figure 6.34, showing melanocytoma with cells in the vitreous
inferior to the tumor.

270
Figure 6.36. Fluorescein angiography of the lesion shown in Figure 6.35, depicting hypofluorescence of the
mass.

271
• OPTIC DISC MELANOCYTOMA: VISUAL LOSS FROM CENTRAL
RETINAL VASCULAR OBSTRUCTION

Another cause of visual loss in a patient with melanocytoma of the optic disc is central retinal
vascular occlusion with hemorrhagic retinopathy. In such cases, the tumor has undergone
necrosis. A clinicopathologic correlation is shown.

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.

Figure 6.37. Fundus photograph showing the pigmented mass over the optic disc and hemorrhagic
retinopathy in a young adult African-American male.

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Figure 6.38. Fluorescein angiogram, showing patchy choroidal fluorescence and minimal flow in the retinal
blood vessels superiorly with less flow inferiorly.

Figure 6.39. After enucleation, the black intraneural mass was visible. (Hematoxylin–eosin ×2.)

273
Figure 6.40. Photomicrograph of unbleached section showing tumor replacing the optic disc. With bleached
sections, the nuclei were bland, and the nuclear cytoplasmic ratio was low. (Hematoxylin–eosin ×150.)

Figure 6.41. Optic disc melanocytoma (yellow arrow) with central retinal artery obstruction, with cilioretinal
involvement (white arrow) causing macular whitening (b lack arrow) and with superotemporal sparing (white
with b lack outline arrow).

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Figure 6.42. Fluorescein angiography of lesion in Figure 6.41 confirming artery obstruction from melanocytoma
with superotemporal sparing.

275
• OPTIC DISC MELANOCYTOMA: EVOLUTION INTO MALIGNANT
MELANOMA

Well-documented cases of malignant transformation of melanocytoma of the optic disc are rare.

Shields JA, Shields CL, Eagle RC, et al. Malignant melanoma associated with melanocytoma of
the optic disc. Ophthalmology 1990;97:225–230.

Figure 6.43. Melanocytoma of the optic disc with juxtapapillary, choroidal, and retinal nerve fiber layer
involvement in a 54-year-old man.

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Figure 6.44. The same lesion 6 years later, showing marked growth and vitreal seeding from the necrotic
tumor.

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Figure 6.45. Section of the enucleated eye, showing pigmented tumor in posterior pole of the eye. Note the
vitreal seeding of pigmented cells.

Figure 6.46. Histopathology, showing a deeply pigmented lesion of choroid, epipapillary region, and sensory

278
retina. Bleached sections were necessary to visualize cell detail. (Hematoxylin–eosin ×10.)

Figure 6.47. Bleached section of an area of tumor showing cells compatible with melanocytoma. The cells are
large and round with prominent nucleoli, but the nuclei are fairly uniform. (Hematoxylin–eosin ×250.)

Figure 6.48. Bleached section of another area of tumor, showing cells compatible with spindle cell melanoma.
(Hematoxylin–eosin ×250.)

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• CILIARY BODY MELANOCYTOMA
Melanocytoma in the ciliary body can attain a large size and still be cytologically benign. Two
cases are illustrated.

Figure 6.49. Melanocytoma of the ciliary body with iris extension in a 29-year-old woman as seen in 1979. At
that time, melanoma was suspected, and the patient elected to have enucleation. Today, we recommend local
resection for tumors like this in which melanocytoma is a likely diagnosis.

Figure 6.50. Low-magnification photomicrograph of the enucleated eye shown in Figure 6.49, showing the
well-defined ciliary mass with extension through the iris root. (Hematoxylin–eosin ×3.)

280
Figure 6.51. Photomicrograph of the lesion seen in Figure 6.49, showing deeply pigmented tumor cells with
pseudocysts with macrophages containing liberated pigment. (Hematoxylin–eosin ×50.)

Figure 6.52. Photomicrograph of a bleached section of the lesion shown in Figure 6.49. Note the typical
melanocytoma cells. (Hematoxylin–eosin ×200.)

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Figure 6.53. Melanocytoma of the ciliary body with secondary iris invasion in a 48-year-old man. The lesion
was removed successfully by iridocyclectomy, and the diagnosis was confirmed histopathologically.

Figure 6.54. Melanocytoma of the ciliary body in a 49-year-old man. The lesion was removed successfully by
iridocyclectomy, and the diagnosis was confirmed histopathologically.

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• CHOROIDAL MELANOCYTOMA
Localized choroidal melanocytoma can occur with diffuse melanocytoma of the uveal tract,
sclera, and episclera. The localized tumor is similar to other choroidal nevi but is dark brown to
black in color. The diffuse melanocytoma is similar but appears relatively flat.

Figure 6.55. Melanocytoma of choroid temporal to foveal area. In 1970, the eye was enucleated elsewhere
because choroidal melanoma was suspected. Today, a small lesion like this would be managed initially by
observation, plaque radiotherapy, or transpupillary thermotherapy rather than enucleation.

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Figure 6.56. Photomicrograph of the lesion shown in Figure 6.55. The retina was detached by artifact. Note the
deeply pigmented placoid lesion that involves the full thickness of the choroid. (Hematoxylin–eosin ×5.) The
inset below is a bleached section of melanocytoma showing plump benign cells. (Hematoxylin–eosin ×120.)

Figure 6.57. Montage photograph of the right eye of a 14-year-old girl showing a diffuse choroidal mass with
extensive surface orange pigment. There was an overlying secondary retinal detachment with shifting
subretinal fluid. This patient had sector iris, ciliary body, and scleral hyperpigmentation.

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Figure 6.58. B-scan ultrasonogram of the lesion shown in Figure 6.57, demonstrating diffuse thickening of the
choroid.

Figure 6.59. Following enucleation, the sectioned eye showed diffuse thickening of the posterior choroid with

285
thickening of the ciliary body and iris.

Figure 6.60. Bleached-section histopathology demonstrated small, round to ovoid cells with uniform nuclei,
findings typical of melanocytoma. Multiple sections showed this same pattern, with no convincing evidence of
malignant melanoma. (Bleached hematoxylin–eosin ×150.)

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• CHOROIDAL MELANOCYTOMA: GIANT DIFFUSE VARIANT GIVING
RISE TO MELANOMA IN A PATIENT WITH OCULODERMAL
MELANOCYTOSIS

There seems to be a close relationship between uveal melanocytoma and ocular melanocytosis,
and the two may represent clinical variations of the same histopathologic entity. When this
condition gives rise to malignancy, the melanoma is often nonpigmented and of spindle cell
type, quite different from the cells of the primary lesion. A case is illustrated.

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.

Figure 6.61. Episcleral pigmentation compatible with ocular melanocytosis in a 51-year-old man.

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Figure 6.62. Sector pigmented iris lesion in the same eye.

Figure 6.63. Wide-angle fundus photograph, showing a diffuse elevated mass involving the inferior half of the
fundus and surrounding the optic disc.

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Figure 6.64. Low-magnification photomicrograph, depicting diffuse pigmented lesion inferiorly. The deeply
pigmented lesion showed areas of transcleral involvement. Note the islands of amelanotic tumor within the
pigmented lesion.

Figure 6.65. Photomicrograph of a bleached section from the pigmented area, showing typical melanocytoma
cells. (Hematoxylin–eosin ×150.)

289
Figure 6.66. Photomicrograph of a section from the nonpigmented area, showing typical spindle melanoma
cells. (Hematoxylin–eosin ×150.)

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 CHAPTER 7

POSTERIOR UVEAL MELANOMA: CLINICAL

FEATURES

CLINICAL FEATURES OF POSTERIOR UVEAL MELANOMA

General Considerations
Melanoma of the posterior uvea (ciliary body and choroid) is the most common
primary malignancy of the eye encountered by ophthalmologists, and its
epidemiology and clinical features are well known (1–42). This malignancy arises
from melanocytes in the posterior uveal tract. The annual age-adjusted incidence in
the U nited States is approximately 6 cases per 1 million population (1,7). It is
decidedly more common in adult whites and is uncommon in children and in dark-
skinned individuals (1,2). Predisposing conditions for uveal melanoma include pre-
existing nevus, ocular melanocytosis, Caucasian race, and possibly dysplastic nevus
syndrome. It is important for ophthalmologists to be familiar with the clinical
features of ciliary body and choroidal melanoma, because this neoplasm can lead to
blindness, loss of the eye, and death.

Clinical Features of Ciliary Body Melanoma

In contrast to iris melanoma, ciliary body melanoma is often hidden by the iris and
can attain a large size before it is recognized clinically. However, it is frequently
associated with external ocular signs that suggest the underlying diagnosis. The most
important sign is one or more dilated episcleral blood vessels (sentinel vessels)
located over the tumor on the sclera. A second sign is an epibulbar pigmented

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lesion characteristic of transcleral extension of the tumor (2). When the pupil is
dilated widely, the ciliary body tumor can be visualized in the affected area as a
dome-shaped mass. Less frequently, it can assume a diffuse circumferential ring
growth pattern (ring melanoma) (1,2,5,11,13). Ciliary body melanoma can impinge
on the lens, causing subluxation and cataract. It can grow posteriorly into the
choroid (ciliochoroidal melanoma) and anteriorly into the anterior chamber angle
and iris (iridociliary melanoma). This malignancy can infiltrate the trabecular
meshwork, causing secondary glaucoma.

Clinical Features of Choroidal Melanoma

Choroidal melanoma usually presents as a sessile, dome-shaped, or mushroom-
shaped mass located deep to the sensory retina (Table 7.1). A smaller posterior
choroidal melanoma may have overlying orange pigment at the level of the retinal
pigment epithelium (RPE) (1–3,8–10). A secondary nonrhegmatogenous retinal
detachment frequently occurs. In contrast to a rhegmatogenous detachment, in which
the subretinal fluid does not shift, the fluid with melanoma and other tumors shifts
with positional changes of the patient’s head. Occasionally, a choroidal melanoma
can be partly or entirely nonpigmented. When the tumor is amelanotic, blood
vessels in the tumor are visible ophthalmoscopically. With continued growth, a
choroidal melanoma can rupture Bruch’s membrane and assume a mushroom shape.
When that occurs, the tumor has a tendency to bleed, and vitreal or subretinal blood
can sometimes obscure a view of the underlying tumor. Choroidal melanoma can
also assume a diffuse growth pattern with only minimal elevation of the tumor
(5,11,13). In some instances, ciliary body or choroidal melanoma can cause total
cataract, secondary glaucoma, and extraocular extension into the orbit. Such tumors
are generally larger and carry a worse prognosis (1,2).

Table 7.1 Clinical features of posterior uveal melanoma in 7,748 eyes

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Spontaneous Regression of Choroidal Melanoma
In unusual instances, choroidal melanoma has been documented to undergo
spontaneous regression (23,24). A spontaneously regressed melanoma generally is
mildly elevated or flat and has amelanotic areas that represent a region of necrosis
in the tumor. Areas of RPE alterations suggest that prior active retinal detachment
has resolved. Another typical feature is a well-defined overlying area of retinoschisis
(intraretinal cyst), at the base of which is a characteristic crater in the tumor.
Melanomas with such necrosis can rarely recur as an active tumor after months or
years.

Risk Factors for Growth and Metastasis of Small Melanocytic

Choroidal Lesions
Important risk factors for growth and metastasis of small melanocytic choroidal
lesions have been identified (8–10) (Table 7.2). Statistical risk factors for growth
include tumor thickness >2 mm at initial diagnosis, overlying subretinal fluid and
orange pigment <3 mm proximity to the optic disc, and presence of symptoms.
Clinical factors predictive of possible eventual metastasis of small melanoma
include tumor thickness >2 mm at initial diagnosis, tumor proximity to the optic
disc, the presence of symptoms, and documented enlargement. These should be
determined and used in counseling the patient and in determining whether a lesion
should be observed periodically or actively treated.

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 Table 7.2 Factors for detection of small choroidal melanoma at tumor
thickness ≤3 mm using the mnemonic “To Find Small Ocular Melanoma—Using
Helpful Hints Daily”

It has been identified that every millimeter increase in melanoma thickness

increases risk for metastasis by approximately 5% (3) (Table 7.3).

Table 7.3 Prognosis of posterior uveal melanoma based on tumor thickness in

7,354 cases

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Classification of Posterior Uveal Melanoma Using the American
Joint Commission on Cancer (AJCC) Classification
Classification of posterior uveal melanoma using the AJCC has shown correlation
with patient prognosis. First the physician should classify by tumor category (Table
7.4), then by subsets (Table 7.5), then by stage (Table 7.6) for patient prognosis.

Table 7.4 Classification of choroidal melanoma using the American Joint

Commission on Cancer Classification (AJCC), 7th edition. Tumor category

Table 7.5 Posterior uveal melanoma category based on American Joint Cancer
Committee (AJCC, 7th edition) classification subsets

Table 7.6 Staging of posterior uveal melanoma based on AJCC classification

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Selected References
Large Series
1. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features,
classification, and top ten pseudomelanomas. Current Opinion in Ophthal
2014;25(3):177–185.
2. Shields CL, Kaliki S, Furuta M, et al. Clinical spectrum and prognosis of uveal
melanoma based on age at presentation in 8033 cases. Retina 2012;32:1363–
1372.
3. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma
millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol
2009;127(8):989–998.
4. 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.
5. Shields CL, Shields JA, DePotter P, et al. Diffuse choroidal melanoma: clinical
features predictive of metastasis. Arch Ophthalmol 1996;114:956–963.
6. Biswas J, Kabra S, Krishnakumar S, et al. Clinical and histopathological
characteristics of uveal melanoma in Asian Indians. A study of 103 patients. Ind
J Ophthalmol 2004;52:41–44.
7. Scotti J, Fraumeni JF Jr, Lee JH. Melanomas of the eye and other noncutaneous
sites: epidemiologic aspects. J Natl Cancer Inst 1976;56:489–491.
8. Shields CL, Shields JA, Kiratli H, et al. Risk factors for growth and metastasis of
small choroidal melanocytic lesions. Ophthalmology 1995;102:1351–1361.
9. Shields CL, Cater JC, Shields JA, et al. Combination of clinical factors predictive
of growth of small choroidal melanocytic tumors. Arch Ophthalmol
2000;118:360–364.
10. 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.
11. Shields CL, Kaliki S, Furuta M, et al. Diffuse versus non-diffuse small (≤ 3
millimeters thickness) choroidal melanoma: Comparative analysis in 1,751
cases. The 2012 F. Phinizy Calhoun lecture. Retina 2013;33:1763–1776.

Small Series

296
12. Kivelä T. Diagnosis of uveal melanoma. Dev Ophthalmol 2012;49:1–15.
13. Font RL, Spaulding AG, Zimmerman LE. Diffuse malignant melanomas of the
uveal tract. Trans Am Acad Ophthalmol Otolaryngol 1968;72:877–895.
14. Shields JA, Shields CL. Massive orbital extension of posterior uveal melanoma.
J Ophthalmic Plast Reconstr Surg 1991;7:238–251.
15. Brown GC, Shields JA. Choroidal melanomas and paving-stone degeneration.
Ann Ophthalmol 1983;15:705–708.
16. Demirci H, Shields CL, Shields JA, et al. Ring melanoma of the ciliary body:
report on twenty-three patients. Retina 2002;22:698–706.
17. Lois N, Shields CL, Shields JA, et al. Cavitary melanoma of the ciliary body. A
study of eight cases. Ophthalmology 1998;105:1091–1098.
18. Shields CL, Shields JA, Milite J, et al. U veal melanoma in teenagers and
children. A report of 40 cases. Ophthalmology 1991;98:1662–1666.
19. Singh AD, Shields CL, Shields JA, et al. U veal melanoma in young patients.
Arch Ophthalmol 2000;118:918–923.
20. Shields CL, Kaliki S, Arepalli S, et al. U veal melanoma in children and
teenagers. Ophthalmol 2013;27:197–201.
21. Shields CL, Kaliki S, Arepalli S, et al. U veal melanoma in children and
teenagers. Saudi J Ophthalmol 2013;27:197–201.
22. Phillpotts BA, Sanders RJ, Shields JA, et al. U veal melanomas in black patients:
a case series and comparative review. J Nat Med Assoc 1995;87:709–714.
23. Shields CL, Shields JA, Santos CM, et al. Incomplete spontaneous regression of
choroidal melanoma associated with inflammation. Arch Ophthalmol
1999;117:1245–1247.
24. Rishi P, Shields CL, Khan MA, et al. Headache or eye pain as the presenting
feature of uveal melanoma. Ophthalmology 2013;120:1946–1947.

Imaging
25. Shields CL, Manalac J, Das C, et al. Review of spectral domain enhanced depth
imaging optical coherence tomography (EDI-OCT) of tumors of the choroid. Ind
J Ophthalmol 2015;63(2):117–121.
26. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014;34(8):1495–1512.
27. Say EA, Shah SU , Ferenczy S, et al. Optical coherence tomography of retinal
and choroidal tumors. J Ophthalmol 2012;2012:385058.
28. 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.
29. 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.
30. Sayanagi K, Pelayes DE, Kaiser PK, et al. 3D Spectral domain optical coherence
tomography findings in choroidal tumors. Eur J Ophthalmol 2011;21(3):271–
275.
31. Materin MA, Raducu R, Bianciotto C, et al. Fundus autofluorescence and optical
coherence tomography findings in choroidal melanocytic lesions. Middle East

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 Afr J Ophthalmol 2010;17(3):201–206.
32. Torres VL, Brugnoni N, Kaiser PK, et al. Optical coherence tomograph
enhanced depth imaging of choroidal tumors. Am J Ophthalmol
2011;151(4):586–593.
Pathology
33. Shields JA, Rodrigues MM, Sarin LK, et al. Lipofuscin pigment over benign and
malignant choroidal tumors. Trans Am Acad Ophthalmol Otolaryngol
1976;81:871–881.

Case Reports
34. Eagle RC, Shields JA. Pseudoretinitis pigmentosa secondary to preretinal
malignant melanoma cells. Retina 1982;2:51–55.
35. Lambert SR, Char DH, Howes E Jr, et al. Spontaneous regression of a choroidal
melanoma. Arch Ophthalmol 1986;104:732–734.
36. Shields JA, Shakin EP, Shields CL, et al. Diffuse amelanotic balloon cell
melanoma of the choroid. Ophthalmic Practice 1992;10:226–228.
37. Singh AD, Shields CL, Shields JA, et al. Occurrence of retinoblastoma and uveal
melanoma in the same patient. Retina 2000;20:305–306.
38. Spaide RF, Spirn MJ. Saccular aneurysms in a case of choroidal melanoma.
Retina 2003;23:726–728.
39. Shields JA, Shields CL, Kimmel A, et al. Contralateral blindness from chiasmal
extension of unsuspected choroidal melanoma. Ophthalmic Plast Reconstr Surg
2004; 20:384–387.
40. Shields JA, Naseripour M, Shields CL, et al. Choroidal melanoma in an
immunosuppressed child with minimal change nephrotic syndrome. Retina
2004;24:454–455.
41. Zhang JJ, Demirci H, Shields CL, et al. Cavitary melanoma of ciliary body
simulating a cyst. Arch Ophthalmol 2005;123:569–571.
42. Manquez ME, Shields CL, Demirci H, et al. Choroidal melanoma in a teenager
with Klippel Trenaunay syndrome. J Ped Ophthalmol Strabism 2006;43:197–
198.

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• CILIARY BODY MELANOMA: SENTINEL BLOOD VESSELS
Although dilated episcleral blood vessels usually signify an underlying ciliary body melanoma,
they can occasionally be seen with other, less common tumors like ciliary body metastasis,
leiomyoma, schwannoma, melanocytoma, and epitheliomas (adenomas) of the nonpigmented
or pigmented ciliary epithelium. On rare occasions, a dilated episcleral vessel is seen as a
normal variant with no evidence of a ciliary body mass.

Figure 7.1. Large typical sentinel blood vessels temporally in a 38-year-old man.

Figure 7.2. Photograph through the dilated pupil of the patient shown in Figure 7.1, clearly showing the
pigmented ciliary body mass.

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Figure 7.3. Large solitary sentinel vessel over a ciliary body melanoma in a 60-year-old man.

Figure 7.4. Multiple sentinel vessels over a ciliary body melanoma in a 77-year-old man.

300
Figure 7.5. Inferior and nasal sentinel vessels over a large ciliary body melanoma in an 84-year-old woman.

Figure 7.6. Pseudo-sentinel vessel in a 27-year-old person with an otherwise normal eye. Indirect
ophthalmoscopy, gonioscopy, ultrasound biomicroscopy, and transillumination were performed to rule out the
possibility of a small occult melanoma, and it was not present.

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• CILIARY BODY MELANOMA: TRANSCLERAL EXTENSION
Ciliary body melanoma can frequently extend through emissary channels to appear in the
episcleral tissues, sometimes forming an extraocular mass. It is more likely to occur with larger,
more aggressive tumors, particularly those that grow in a ring pattern. In rare instances, anterior
extraocular extension can invade the overlying conjunctiva. Transcleral extension usually
imparts a worse systemic prognosis.

Figure 7.7. Two small foci of transcleral extension inferiorly in a 65-year-old man.

Figure 7.8. More prominent nodules of transcleral extension superiorly in a 77-year-old woman.

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Figure 7.9. Slightly more posteriorly located nodule of transcleral extension in an 83-year-old man.

Figure 7.10. Multiple foci of a transcleral extension secondary to a ring melanoma of ciliary body in a 70-year-
old woman. Ring melanoma with a transcleral extension carries a worse prognosis.

303
Figure 7.11. Massive transcleral extension and invasion of the overlying conjunctiva in a 58-year-old man with a
ciliary body melanoma.

Figure 7.12. Massive extraocular extension of a neglected ciliary body melanoma in an 80-year-old man for
whom orbital exenteration was required. He had declined treatment for a relatively small ciliary body
melanoma detected 3 years earlier.

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• CILIARY BODY MELANOMA: IRIS EXTENSION
A ciliary body melanoma can grow through the iris root and appear as a mass in the peripheral
portion of the iris, simulating a primary iris tumor. Unlike a primary iris melanoma, anterior
extension of a ciliary body melanoma tends to pass through the iris root and produce a tumor-
induced iridodialysis.

Figure 7.13. Iris extension of a superotemporal ciliary body melanoma in a 70-year-old woman. Note the
sentinel vessels.

Figure 7.14. Iris extension of a superior ciliary body melanoma in a 52-year-old woman.

305
Figure 7.15. Iris extension of a superior ciliary body melanoma in a 37-year-old woman.

Figure 7.16. Iris extension of a temporal ciliary body melanoma in a 54-year-old man. Note the sentinel
vessels and the accordion-like folds in the iris. The ciliary body component of the tumor can be visualized
through the dilated pupil.

306
Figure 7.17. Iris extension of an inferior ciliary body melanoma in a 16-year-old girl.

Figure 7.18. Iris extension and secondary cataract in an 85-year-old man with a large temporal ciliary body
melanoma. Note the numerous sentinel vessels.

307
• CILIARY BODY MELANOMA: APPEARANCE THROUGH A DILATED
PUPIL

Ciliary body melanoma generally appears as a dome-shaped pigmented mass that can encroach
on the lens, producing subluxation and cataract. It can extend posteriorly into the choroid
(ciliochoroidal melanoma). Occasionally it grows in a ring rather than a nodular pattern.

Figure 7.19. Relatively small ciliary body melanoma located inferotemporally in the left eye. Note also the
subtle extension through the peripheral iris.

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Figure 7.20. Ciliary body melanoma in a 63-year-old man. The tumor has extended into the choroid and lifted
the ora serrata, so that it is visible on the dome of the tumor.

Figure 7.21. Ciliary body melanoma with an irregular surface in a 47-year-old man.

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Figure 7.22. Dome-shaped ciliary body melanoma in a 54-year-old man.

Figure 7.23. Ciliary body melanoma with overlying vitreal hemorrhage.

310
Figure 7.24. Ciliary body melanoma in a 63-year-old man. A unilateral cataract was removed when the
melanoma was not suspected. Any patient with an unexplained unilateral cataract should be evaluated for
underlying ciliary body melanoma.

311
• CILIARY BODY MELANOMA: WIDE-ANGLE IMAGING
Ciliary body melanomas lie in a fairly hidden location, and their full extent cannot be
appreciated with routine indirect ophthalmoscopy. Recent techniques of wide-angle imaging
and photography have provided a better overall view of such lesions.

Figure 7.25. Large nasal ciliary body melanoma. There is a hemiretinal detachment inferiorly that extends to
involve the macular region.

312
Figure 7.26. Inferior ciliary body melanoma. The surface of the lesion is out of focus because the camera is
focused on the posterior pole.

313
Figure 7.27. Superotemporal ciliary body melanoma. The lesion is bilobed due to an eccentric break through
Bruch’s membrane posterior to the ora serrata.

Figure 7.28. Large temporal ciliary body melanoma. The surface of the tumor is out of focus, and there is a
shallow retinal detachment inferiorly.

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Figure 7.29. Large, mildly pigmented ciliary body melanoma located superotemporally. Note the two lobes of
the secondary retinal detachment inferiorly. The photograph was taken with the patient in a sitting position
while the subretinal fluid had shifted inferiorly.

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Figure 7.30. Ciliary body melanoma located temporally in the left eye.

316
• CILIARY BODY MELANOMA: CAVITARY VARIANT
On occasion, a ciliary body melanoma can develop massive cavitary changes that can be seen
with B-scan ultrasonography and can be confused clinically with a ciliary body cyst. A
clinicopathologic correlation of such a case is shown.

Zhang JJ, Demirci H, Shields CL, et al. Cavitary melanoma of ciliary body simulating a cyst. Arch
Ophthalmol 2005;123:569–571.

Figure 7.31. Fundus appearance of a large ciliary body melanoma in a 38-year-old man.

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Figure 7.32. B-scan ultrasonogram, showing the cystic nature of the lesion. The B-scan appearance prompted
referral with a diagnosis of ciliary body cyst. We suspected a cavitary melanoma based on experience with
similar cases. The eye was enucleated.

Figure 7.33. Transillumination of the enucleated globe. Note that the light passes through the ciliary body
region corresponding to the lesion. This is paradoxical because pigmented melanoma would be expected to
cast a shadow.

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Figure 7.34. Sectioned eye after enucleation, showing a large ciliary body mass causing subluxation of the
lens. Inset shows a closer view of the cavitary lesion with a thick pigmented wall.

Figure 7.35. Photograph of a stained slide of the enucleated eye, showing what appears to be a clear ciliary
body cyst. However, the wall of the cystoid lesion is thicker than that seen with a cyst, particularly anteriorly.

319
Figure 7.36. Photomicrograph of cells that comprise the wall of the cysts, demonstrating spindle and
epithelioid melanoma cells.

320
• CILIARY BODY MELANOMA: RING VARIANT WITH EXTRAOCULAR
EXTENSION AND SECONDARY GLAUCOMA

In some instances, a ciliary body melanoma can cause cataract and secondary glaucoma, and
the patient may be subjected to glaucoma surgery while the melanoma remains unsuspected
clinically. A case is illustrated.

Figure 7.37. Filtering bleb superiorly following trabeculectomy for unexplained unilateral glaucoma in an elderly
woman.

Figure 7.38. Diffuse patches of iris pigmentation. Such pigment dispersion often accompanies ring melanoma

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of the ciliary body.

Figure 7.39. Inferonasal amelanotic nodule representing extraocular extension of the tumor.

Figure 7.40. Section of enucleated eye, showing a ciliary body nodule and an extraocular mass.

322
Figure 7.41. Microscopic appearance of the anterior segment, showing ciliary body mass. The tumor extends
diffusely around the ciliary body with the one prominent nodule shown in Figure 7.40. (Hematoxylin–eosin ×5.)

Figure 7.42. Photomicrograph showing loosely cohesive epithelioid melanoma cells. (Hematoxylin–eosin
×200.)

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• CHOROIDAL MELANOMA: DETECTION OF SMALL MELANOMA WITH
FUNDUS AUTOFLUORESCENCE AND OPTICAL COHERENCE
TOMOGRAPHY

Some lesions are borderline between a large choroidal nevus and small choroidal melanoma.
The risk factors for growth and metastasis of such lesions have been published and are
mentioned in the discussion at the opening of this chapter. Factors such as thickness is best
determined with ultrasonography, lipofuscin (orange pigment) is detected with
autofluorescence, and subtle subretinal fluid with OCT.

1. Shields CL, Cater JC, Shields JA, et al. Combination of clinical factors predictive of growth
of small choroidal melanocytic tumors. Arch Ophthalmol 2000;118:360–364.
2. 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;130:850–856.

Figure 7.43. Small melanocytic choroidal lesion with three subtle risk factors for growth including orange
pigment, subretinal fluid, and symptoms.

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Figure 7.44. Autofluorescence of lesion in Figure 7.43 demonstrates hyperautofluorescent lipofuscin (orange
pigment) and subtle subfoveal fluid with free fluorophores.

Figure 7.45. Optical coherence tomography of lesion in Figure 7.43 depicts an elevated choroidal mass with
overlying serous retinal detachment and debris on the posterior retinal surface (shaggy photoreceptors).

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Figure 7.46. Choroidal melanocytic lesion with ill-defined margins and dispersed orange pigment temporally
with subretinal fluid.

Figure 7.47. Autofluorescence of lesion in Figure 7.46 demonstrates hyperautofluorescent lipofuscin (orange

326
pigment) and subtle temporal subretinal fluid with free fluorophores.

Figure 7.48. Optical coherence tomography of lesion in Figure 7.46 depicts the elevated choroidal mass with
overlying serous retinal detachment and debris on the posterior retinal surface (shaggy photoreceptors).

327
• CHOROIDAL MELANOMA: PIGMENTED VARIATIONS
The most characteristic feature of choroidal melanoma is an elevated pigmented choroidal
mass. Smaller lesions are more likely to show typical orange pigment on the surface. Sizable
choroidal melanoma typically produces a secondary nonrhegmatogenous retinal detachment.

Figure 7.49. Choroidal melanoma superior to the optic disc in a 66-year-old woman. Note the orange pigment
over the central part of the tumor and forming a ring in the peripheral part of the mass.

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Figure 7.50. Choroidal melanoma in the inferior aspect of the macular region in a 73-year-old man.

Figure 7.51. Choroidal melanoma temporal to the foveal region in a 38-year-old man.

Figure 7.52. Dome-shaped choroidal melanoma overhanging the optic disc in a 40-year-old man.

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Figure 7.53. Wide-angle image of a small, deeply pigmented choroidal melanoma in the superonasal aspect
of the right eye.

Figure 7.54. Wide-angle image of a large, pigmented choroidal melanoma that extends from the foveal area to
the equator on the temporal side of the right eye. Note the secondary retinal detachment inferiorly.

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• CHOROIDAL MELANOMA: PARTLY PIGMENTED VARIATIONS
On occasion, a choroidal melanoma is partly pigmented and partly nonpigmented. Although the
nonpigmented component can suggest another diagnosis, such as choroidal metastasis, any
intrinsic pigment in the lesion is a strong suggestion that the lesion is a melanoma.

Figure 7.55. Choroidal melanoma in a 43-year-old man, showing pigmentation only in the inferior part of the
lesion.

Figure 7.56. Choroidal melanoma in macular region of a 61-year-old man, showing a small area of

331
pigmentation in the inferotemporal aspect of the lesion.

Figure 7.57. Choroidal melanoma adjacent to the optic disc in a 71-year-old woman. In this case, the flat tumor
base is pigmented, but a more elevated area of vertical growth is amelanotic.

Figure 7.58. Highly elevated choroidal melanoma with pigmented and nonpigmented components in a 72-
year-old man.

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Figure 7.59. Wide-angle image of melanoma with marked pigmentation of the superior portion and mild
pigmentation of the inferior portion.

333
Figure 7.60. Wide-angle image of a nonpigmented melanoma with a small focus of central pigmentation. Even
though the lesion is mostly nonpigmented, the focus of pigmentation suggests that the lesion is a melanoma
and not a choroidal metastasis or other nonpigmented neoplasm.

334
• CHOROIDAL MELANOMA: NONPIGMENTED VARIANT
When a melanoma is clinically nonpigmented, the differentiation from choroidal metastasis,
hemangioma, lymphoma, osteoma, and other choroidal tumors can be more difficult. However,
ophthalmoscopy generally shows well-defined blood vessels in the mass, which suggest
melanoma. In addition, melanoma is usually more highly elevated and drusen and pigment
epithelial proliferation are usually more evident over melanoma as compared to metastasis. In
the case of nonpigmented melanoma, ancillary studies like fluorescein angiography and
ultrasonography play a greater role in diagnosis.

Figure 7.61. Nonpigmented, yellow-colored melanoma in the macular region of a 62-year-old woman. Note the
rather prominent intrinsic vessels, which suggest the diagnosis of melanoma rather than choroidal
metastasis or hemangioma.

335
Figure 7.62. Nonpigmented yellow-colored melanoma superior to the optic disc in a 52-year-old woman.
Vessels in the tumor are evident.

336
Figure 7.63. Nonpigmented choroidal melanoma located at the equator temporally in the right eye.

Figure 7.64. Nonpigmented choroidal melanoma with a multinodular configuration located nasally in the left
eye. Note the secondary retinal detachment that overlies the tumor and extends to involve the inferior half of the
retina.

337
Figure 7.65. Choroidal melanoma (to the right) and secondary retinal detachment (to the left) in a 51-year-old
man.

338
Figure 7.66. Section of the enucleated eye shown in Figure 7.65. Note the large, lightly pigmented melanoma
with irregular surface due to two breaks in Bruch’s membrane and the overlying retinal detachment extending
posterior to the lens.

339
• CHOROIDAL MELANOMA: MUSHROOM-SHAPED TUMORS WITH
PIGMENTED DOME

When a choroidal melanoma ruptures Bruch’s membrane, it appears as a mushroom-shaped

mass. When the apical portion of the tumor is pigmented, prominent intrinsic vessels are
usually not evident. When the tumor is adjacent to the optic disc, it may grow around the
posterior aspect of Bruch’s membrane rather than rupturing the membrane, to assume the
mushroom shape. When a melanoma breaks through Bruch’s membrane, secondary choroidal,
subretinal, or vitreal hemorrhage often occurs.

Figure 7.67. Mushroom-shaped choroidal melanoma adjacent to the optic disc in a 56-year-old man. In this
case, the melanoma apparently grew around the posterior termination of Bruch’s membrane. This was
interpreted as a juxtapapillary melanoma and not a melanocytoma.

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Figure 7.68. Mushroom-shaped choroidal melanoma in a 43-year-old man.

Figure 7.69. Mushroom-shaped choroidal melanoma in a 61-year-old man.

341
Figure 7.70. Wide-angle image of choroidal melanoma inferior to the disc, with a distinct mushroom
configuration.

342
Figure 7.71. Wide-angle image of large, deeply pigmented, mushroom-shaped choroidal melanoma.

Figure 7.72. Wide-angle image of a large, deeply pigmented, mushroom-shaped choroidal melanoma. In this
instance, the tumor has assumed an eccentric shape.

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• CHOROIDAL MELANOMA: WIDE-ANGLE IMAGING OF MUSHROOM-
SHAPED TUMORS WITH PIGMENTED DOME

Figure 7.73. The dome of the melanoma has obscured a view of the optic disc.

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Figure 7.74. Melanoma with relatively flat base but with a large globular portion anterior to Bruch’s membrane,
also obscuring a view of the optic disc.

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Figure 7.75. Circumpapillary choroidal melanoma with a juxtapapillary break through Bruch’s membrane.

Figure 7.76. Melanoma with a small break through Bruch’s membrane and early retinal invasion.

346
Figure 7.77. Deeply pigmented melanoma with two breaks through Bruch’s membrane and retinal invasion at
both sites.

Figure 7.78. Massive melanoma with a large break through Bruch’s membrane, total retinal detachment, and
localized vitreal hemorrhage.

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• CHOROIDAL MELANOMA: MUSHROOM-SHAPED TUMORS WITH
NONPIGMENTED DOME

When the apical portion of the mushroom-shaped melanoma is nonpigmented, prominent

intrinsic vessels are usually very evident. Such a finding is highly suggestive, and perhaps
pathognomonic, of choroidal melanoma. Note the characteristic prominent vessels in each of
the illustrated cases.

Figure 7.79. Nonpigmented dome of mushroom-shaped melanoma inferotemporal to the left optic disc.

348
Figure 7.80. Nonpigmented dome of mushroom-shaped melanoma in a 63-year-old man. Note the subretinal
hemorrhage inferiorly.

Figure 7.81. Nonpigmented dome of mushroom-shaped melanoma. In this case, the dome is so large that the
base of the tumor cannot be seen with standard photography.

349
Figure 7.82. Small, nonpigmented dome of mushroom-shaped melanoma in a 49-year-old man. In this case,
the base of the tumor is pigmented and there is orange pigment on the superior margin of the base nearest
the fovea and drusen on the base inferiorly.

Figure 7.83. Nonpigmented dome of mushroom-shaped melanoma centered in the macular region in a 45-
year-old man.

350
Figure 7.84. Nonpigmented dome of mushroom-shaped melanoma with diffuse vitreal hemorrhage in a 68-
year-old man.

351
• CHOROIDAL MELANOMA: WIDE-ANGLE IMAGING OF MUSHROOM-
SHAPED TUMORS WITH NONPIGMENTED DOME. MORE
VARIATIONS IN SIZE AND SHAPE OF CHOROIDAL MELANOMAS ARE
SHOWN

Figure 7.85. Melanoma with deeply pigmented base and amelanotic dome.

352
Figure 7.86. Larger melanoma with relatively amelanotic base and dome.

Figure 7.87. Fluorescein angiogram of the lesion shown in Figure 7.86, demonstrating the prominent vessels
within the dome of the mass and the overlying retinal circulation (“double circulation”).

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Figure 7.88. Melanoma with deeply pigmented base and three confluent amelanotic breaks through Bruch’s
membrane.

Figure 7.89. Large melanoma with pigmented base and medium-sized amelanotic dome.

Figure 7.90. Gross appearance of the eye shown in Figure 7.89 following enucleation. Note the amelanotic

354
dome. The pigmented base of the melanoma is seen in the background, upward, and to the right.

355
• CHOROIDAL MELANOMA: EFFECTS ON ADJACENT STRUCTURES
Choroidal melanoma can induce changes in the adjacent ocular structures. It can affect the RPE
by causing atrophy and proliferation or it can produce orange pigment on its surface secondary
to aggregation of lipofuscin-laden macrophages derived from the RPE. Choroidal melanoma can
induce fibrous metaplasia of the RPE. Juxtapapillary melanoma can occasionally invade the
optic disc, causing disc hyperemia, and edema. In extremely rare instances, choroidal melanoma
can induce a yellow intraretinal or subretinal exudation around its margins. In some cases, it
can induce peripheral choroidal ischemia, which leads to a sectorial paving stone degeneration
in the quadrant of the tumor.

Shields CL, Kaliki S, Furuta M, et al. Clinical spectrum and prognosis of uveal melanoma based
on age at presentation in 8033 cases. Retina 2012;32:1363–1372.

Figure 7.91. Choroidal melanoma with overlying atrophy and proliferation of the retinal pigment epithelium in a
40-year-old woman.

356
Figure 7.92. Choroidal melanoma with abundant overlying orange pigment in a 54-year-old man.

Figure 7.93. Choroidal melanoma with overlying fibrous metaplasia of the retinal pigment epithelium in a 41-
year-old woman.

357
Figure 7.94. Juxtapapillary choroidal melanoma with secondary invasion of the optic disc, causing hyperemia
and disc edema.

Figure 7.95. Choroidal melanoma with circinate exudation in a 50-year-old man. This is a highly unusual
finding for choroidal melanoma but occurs frequently with epitheliomas of the retinal pigment epithelium. The

358
diagnosis was confirmed histopathologically after enucleation.

Figure 7.96. Wide-angle photograph of a choroidal melanoma with secondary choroidal atrophy (paving stone
degeneration) in the quadrant of the lesion inferiorly in a 40-year-old woman.

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• CHOROIDAL MELANOMA: RETINAL AND VITREAL INVASION
Choroidal melanoma can sometimes invade the overlying sensory retina and can break through
the retina into the vitreous cavity. Retinal and vitreal invasion is more likely to occur with
mushroom-shaped melanoma but can sometimes occur with dome-shaped and diffuse
melanomas. The dispersed pigment can sometimes produce a “pseudo–retinitis pigmentosa”
appearance ophthalmoscopically and angiographically.

Figure 7.97. Juxtapapillary choroidal melanoma with retinal invasion in a 54-year-old woman.

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Figure 7.98. Mushroom-shaped choroidal melanoma with retinal invasion in a 73-year-old woman.

Figure 7.99. Large mushroom-shaped choroidal melanoma with extensive retinal invasion.

Figure 7.100. Necrotic pedunculated choroidal melanoma with retinal and vitreal invasion in a 70-year-old

361
woman.

Figure 7.101. Retinal and vitreal invasion of a choroidal melanoma producing a “pseudo–retinitis pigmentosa”
picture in a 64-year-old woman.

Figure 7.102. Sectioned eye shown in Figure 7.101. Note the deeply pigmented equatorial mushroom–shaped
choroidal melanoma that invaded the retina and vitreous. A line of pigment deposition is evident at the vitreous
base.

362
• CHOROIDAL MELANOMA: RETINAL VEIN DILATION SECONDARY TO
RETINAL INVASION

In some cases of retinal invasion by choroidal melanoma, a retinal vein draining the retinal
portion of the tumor becomes dilated and tortuous. Unlike the retinal capillary hemangioma
that is associated with a dilated, tortuous artery and vein, only the vein is characteristically
abnormal in cases of melanoma, based on our experience with several such cases. The following
clinicopathologic correlation depicts this phenomenon.

Figure 7.103. Large dilated retinal vein superiorly to the optic disc in a 35-year-old man. Coincidental
myelinated retinal nerve fibers are present on the superior margin of the optic disc.

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Figure 7.104. Superior fundus showing a large amelanotic mass involving the sensory retina and choroid.

Figure 7.105. Fluorescein angiogram in venous phase, showing dilated tortuous retinal vein but no significant
dilation of the associated arteries.

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Figure 7.106. Enucleated eye, showing amelanotic choroidal mass.

Figure 7.107. Section through the tumor-infiltrated retina, showing a longitudinal section of a large blood
vessel. (Hematoxylin–eosin ×15.)

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Figure 7.108. Photomicrograph through the retinal portion of the tumor, showing a large dilated vessel in cross
section. (Hematoxylin–eosin ×100.)

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• CHOROIDAL MELANOMA: DIFFUSE GROWTH PATTERN
A choroidal melanoma can grow in a diffuse or flat pattern rather than the more characteristic
nodular or mushroom pattern. As compared to a typical choroidal melanoma, a diffuse
choroidal melanoma generally is more aggressive, has more a malignant cell type, tends to
extend extrasclerally, and carries a worse prognosis.

1. Shields CL, Shields JA, DePotter P, et al. Diffuse choroidal melanoma: clinical features
predictive of metastasis. Arch Ophthalmol 1996;114:956–963.
2. Shields CL, Kaliki S, Furuta M, et al. Diffuse versus non-diffuse small (≤3 millimeters
thickness) choroidal melanoma: Comparative analysis in 1751 cases. The 2012 F. Phinizy
Calhoun Lecture 2012; Retina 2013;33:1763–1776.

Figure 7.109. Diffuse choroidal melanoma in the posterior pole and superior fundus of a 58-year-old man.
Note the abundant orange pigment on the surface of the tumor.

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Figure 7.110. Photomicrograph of a section of the enucleated eye shown in Figure 7.109 through the thickest
part of the tumor. Note that the choroid is diffusely thickened to the left, which represents the superior fundus.

Figure 7.111. Photomicrograph of the eye shown in Figure 7.109, demonstrating pigmented thickening of the
choroid near the ora serrata.

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Figure 7.112. Wide-angle fundus photograph of diffuse amelanotic thickening of the choroid nasally in a 55-
year-old woman.

369
Figure 7.113. Photomicrograph of the section of enucleated eye shown in Figure 7.112 through the thickest part
of the tumor.

Figure 7.114. Photomicrograph of the tumor shown in Figure 7.112. Note the large, clear balloon melanoma
cells. It was probably these balloon cells that accounted for the yellow color of the lesion. (Hematoxylin–eosin
×200.)

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• CHOROIDAL MELANOMA: WIDE-ANGLE IMAGING OF DIFFUSE
TUMORS

Figure 7.115. Diffuse choroidal melanoma occupying the macular and juxtapapillary regions.

371
Figure 7.116. Diffuse choroidal melanoma centered in the macular region. There is a more elevated nodule in
the center of the lesion, probably representing a clone of more aggressive cells.

Figure 7.117. Diffuse choroidal melanoma with nonpigmented and pigmented components replacing the
entire choroid inferonasally. The relatively flat amelanotic area usually represents an area of tumor necrosis.

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The inferior secondary retinal detachment is best appreciated inferotemporally away from the main tumor.

Figure 7.118. Diffuse multinodular choroidal melanoma superotemporally with secondary total retinal
detachment.

Figure 7.119. Diffuse choroidal melanoma replacing the inferior two-thirds of the choroid and surrounding the
optic disc.

373
Figure 7.120. B-scan ultrasonogram of the lesion shown in Figure 7.119, depicting a relatively flat choroidal
melanoma pattern with a secondary retinal detachment.

374
• CHOROIDAL MELANOMA: DIFFUSE TUMOR WITH OPTIC NERVE
INVASION

Although most typical nodular melanomas have little tendency to invade the optic nerve,
diffuse melanoma is more aggressive and frequently does invade the optic nerve. The following
is a clinicopathologic correlation of a diffuse choroidal melanoma with optic nerve extension.

Figure 7.121. Thickening of the optic disc and diffuse choroidal thickening in a 66-year-old man. Diffuse
melanoma was suspected, and the eye was enucleated.

375
Figure 7.122. Section of the enucleated eye, showing a diffuse amelanotic tumor in the posterior choroid.

Figure 7.123. Photomicrograph of the optic disc region, showing a swollen disc with large blood vessels.

376
Figure 7.124. Photomicrograph showing melanoma cells in the subarachnoid space. (Hematoxylin–eosin
×40.)

Figure 7.125. Photomicrograph of a longitudinal section of the optic nerve, showing tumor cell infiltration.
(Hematoxylin–eosin ×40.)

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Figure 7.126. Photomicrograph showing mixed cell–type melanoma. (Hematoxylin–eosin ×100.)

378
• CHOROIDAL MELANOMA: DIFFUSE TUMOR PRESENTING AS
ATYPICAL EXTRAOCULAR EXTENSION

Figure 7.127. Multinodular extraocular extension of a diffuse uveal melanoma that appeared about 5 years after
cataract extraction for an unexplained unilateral cataract. Orbital exenteration was performed.

Figure 7.128. Eye of an elderly man who presented with a peculiar salmon-colored mass and an opaque cyst.
The inferior portion of the tumor shows a yellow, cyst-like structure that probably represents a focus of tumor
necrosis.

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Figure 7.129. B-scan ultrasonogram of the eye shown in Figure 7.128, revealing a diffuse thickening of the
choroid with medium internal reflectivity and shallow retinal detachment.

Figure 7.130. Gross appearance of the sectioned globe, showing a diffuse amelanotic tumor of the uveal tract.

380
Figure 7.131. The epibulbar mass comprises loosely cohesive, round malignant cells without cytoplasmic
pigment. (Hematoxylin–eosin ×200.)

Figure 7.132. The more posterior part of the tumor comprises mitotically active epithelioid cells with prominent
mitoses. (Hematoxylin–eosin ×150.) All tumor cells showed a strong immunohistochemical reaction to the
melanoma-specific antigen HMB-45.

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• CHOROIDAL MELANOMA: ADVANCED TUMOR PRESENTING WITH
ACUTE GLAUCOMA

Most posterior uveal melanomas are diagnosed at a relatively early stage when the tumor is still
in the eye and has not caused secondary glaucoma or severe inflammatory signs. In some
instances, however, a previously undiagnosed melanoma can cause severe congestive glaucoma
or conjunctival chemosis, simulating endophthalmitis.

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.

Figure 7.133. Cataract and acute congestive glaucoma secondary to choroidal melanoma in a 70-year-old
man. Ultrasonography revealed a dome-shaped choroidal melanoma.

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Figure 7.134. Section of an enucleated eye with choroidal melanoma, total retinal detachment, and anterior
displacement of the cataractous lens causing secondary glaucoma.

Figure 7.135. Another elderly patient with acute glaucoma, conjunctival hyperemia, and total cataract.
Ultrasonography also revealed a dome-shaped choroidal melanoma, and enucleation was done.

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Figure 7.136. Section of the enucleated eye shown in Figure 7.135. Note the melanoma (right), total funnel-
shaped retinal detachment (center), organizing subretinal blood (left), and anterior displacement of the
cataractous lens with loss of the anterior chamber.

Figure 7.137. Acute glaucoma and conjunctival chemosis simulating endophthalmitis in an 82-year-old
woman with choroidal melanoma.

384
Figure 7.138. Section of the enucleated eye, showing necrotic melanoma and subretinal hemorrhage. The
necrosis in the tumor probably induced the orbital inflammation simulating panophthalmitis.

385
• CHOROIDAL MELANOMA: ADVANCED TUMOR PRESENTING WITH
MASSIVE EXTRAOCULAR EXTENSION

Uveal melanoma can occur in the posterior orbit by primary transcleral extension or by
recurrence after enucleation. If the orbital involvement is small and circumscribed, modified
enucleation can be performed by a lateral orbitotomy approach without resorting to orbital
exenteration. Sometimes orbital recurrence can develop many years after enucleation. Orbital
melanoma is also discussed in the atlas of orbital tumors.

Shields JA, Shields CL. Massive orbital extension of posterior uveal melanoma. J Ophthalmic Plast
Reconstr Surg 1991;7:238–251.

Figure 7.139. Proptosis of the right eye in a 67-year-old woman. Fundus examination showed a relatively flat,
diffuse choroidal mass, and axial computed tomography showed an orbital mass immediately posterior to the
intraocular tumor. Modified enucleation (subtotal orbital exenteration) was done.

386
Figure 7.140. Section of a surgical specimen from the patient shown in Figure 7.139, demonstrating a small
choroidal melanoma and a larger orbital mass representing orbital extension of the choroidal melanoma.

Figure 7.141. Conjunctival chemosis and proptosis secondary to orbital extension of uveal melanoma in a 71-
year-old man. Sixteen years earlier, the patient had undergone retinal detachment surgery elsewhere, but no

387
retinal break was detected.

Figure 7.142. Orbital computed tomography, showing melanoma filling the globe and the orbit. Orbital
exenteration was performed.

Figure 7.143. Massive proptosis and upward displacement of right eye in an elderly woman.

388
Figure 7.144. Axial computed tomography of the patient shown in Figure 7.143, revealing that the globe and the
orbit are filled by a large mass. Advanced choroidal melanoma was confirmed after orbital exenteration.

389
• CHOROIDAL MELANOMA: INTRACRANIAL EXTENSION OF
UNSUSPECTED TUMOR CAUSING BILATERAL VISUAL LOSS

It is extremely rare for a uveal melanoma to cause contralateral blindness from a uveal
melanoma due to optic nerve extension to the optic chiasm. Such a case is depicted here.

Shields JA, Shields CL, Kimmel A, et al. Contralateral blindness from chiasmal extension of
unsuspected choroidal melanoma. Ophthalmic Plast Reconstr Surg 2004;20:384–387.

Figure 7.145. Fundus of the left eye in 1996, showing a disciform scar and fibrosis in the macular region. The
patient was diagnosed elsewhere as having macular degeneration, and the peripheral fundus was reported to
be normal.

390
Figure 7.146. Axial magnetic resonance imaging on a T1-weighted image with gadolinium enhancement 8
years later when the patient presented with no perception of light in the left eye and hand-motion vision in the
right eye. Note the enlarged left optic nerve and intracranial mass in the region of the cavernous sinus and
optic chiasm. A mass fills most of the globe.

Figure 7.147. Coronal magnetic resonance imaging on a T1-weighted image with gadolinium enhancement
and T1 coronal computed tomography showing enhancing intracranial mass.

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Figure 7.148. Coronal magnetic resonance imaging on a T2-weighted image showing a dome-shaped
choroidal mass in the left eye and nasal extraocular orbital extension of the mass.

Figure 7.149. Surgical photograph at the time of nasal orbitotomy, showing the back orbital mass. An incisional
biopsy was performed.

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Figure 7.150. Histopathology of the orbital tumor, showing anaplastic epithelioid melanoma cells.
(Hematoxylin–eosin ×200.) The patient declined further treatment and died shortly thereafter.

393
• CHOROIDAL MELANOMA IN YOUNG PATIENTS
Greater than 90% of uveal melanomas occur in middle-aged or older adults. However, uveal
melanoma is well known to occur in young individuals. Most affected patients have no
associated systemic findings. However, some have had additional systemic disease, such as
minimal change nephrotic syndrome and Klippel–Trenaunay–Weber syndrome. The significance
of these associations is unclear.

1. Shields CL, Shields JA, Milite J, et al. Uveal melanoma in teenagers and children. A report of
40 cases. Ophthalmology 1991;98:1662–1666.
2. Shields CL, Kaliki S, Arepalli S, et al. Uveal melanoma in children and teenagers. Saudi J
Ophthalmol 2013;27:197–201.
3. Kaliki S, Shields CL, Ganesh A, et al. Influence of age on young patients with uveal
melanoma: A matched retrospective cohort study. European J Ophthalmol 2013;43(3):208–
216.

Figure 7.151. Anterior segment view of a large fundus mass in an 8-year-old girl.

394
Figure 7.152. A more posterior fundus view of a large inferior amelanotic mass extending around the optic
disc. The eye was enucleated, and a mixed cell–type melanoma was confirmed. The child died about 5 years
later with metastatic melanoma.

Figure 7.153. Fundus photograph showing a dome-shaped choroidal mass superior to the optic disc in the left
eye of a 16-year-old boy with minimal change nephrotic syndrome.

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Figure 7.154. Choroidal melanoma in a 21-year-old man. The lesion was documented as enlarging and was
treated with plaque radiotherapy and transpupillary thermotherapy.

Figure 7.155. Choroidal melanoma in a 17-year-old boy. He was treated with plaque radiotherapy and
transpupillary thermotherapy.

396
Figure 7.156. Mushroom-shaped choroidal melanoma in a 15-year-old boy who also had clinical findings of
Klippel–Trenaunay–Weber syndrome. He was treated with plaque radiotherapy.

397
• CHOROIDAL MELANOMA IN NON-WHITES
Greater than 95% of uveal melanomas occur in whites. However, uveal melanoma is well
known to occur in non-whites. Although they are generally considered to be extremely rare, we
have seen many cases of uveal melanoma in blacks, Asians, and Hispanics.

1. Phillpotts BA, Sanders RJ, Shields JA, et al. Uveal melanomas in black patients: a case series
and comparative review. J Nat Med Assoc 1995;87:709–714.
2. Shields CL, Kaliki S, Cohen MN, et al. Prognosis of uveal melanoma based on race in 8100
patients. The 2015 Doyne Lecture. Eye 2015; in press.

Figure 7.157. Face of a 60-year-old African-American woman.

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Figure 7.158. Fundus of the patient shown in Figure 7.157, demonstrating a dome-shaped choroidal
melanoma measuring 4 mm in thickness. Subretinal fluid is visible around the tumor. It was managed with a
radioactive plaque and thermotherapy.

Figure 7.159. Face of a 67-year-old African-American man.

399
Figure 7.160. Fundus of the patient shown in Figure 7.159 demonstrating diffuse choroidal melanoma with
prominent orange pigment and subretinal fluid. It was managed with a radioactive plaque and thermotherapy.

Figure 7.161. Face of a 38-year-old Asian woman.

400
Figure 7.162. Fundus of the patient shown in Figure 7.161 demonstrating abruptly elevated choroidal
melanoma superotemporally, overhanging the macular region. The tumor was managed with a radioactive
plaque and thermotherapy.

401
• CHOROIDAL MELANOMA: SPONTANEOUS NECROSIS AND
REGRESSION

Uveal melanoma can occasionally undergo spontaneous necrosis and regression for uncertain
reasons. Such tumors develop depressed white areas with overlying localized retinoschisis and
pigment dispersion. They closely resemble melanomas that have been irradiated, except that
they lack radiation vasculopathy. Lesions with this appearance should be followed periodically
because they can occasionally show regrowth, even after several years of stability. The cases
shown here were all seen after the event, and no photographs were available of the original
lesions. They are presumed to be cases of spontaneous regression of choroidal melanoma.

Shields CL, Shields JA, Santos CM, et al. Incomplete spontaneous regression of choroidal
melanoma associated with inflammation. Arch Ophthalmol 1999;117:1245–1247.

Figure 7.163. Regressed choroidal melanoma with surrounding ring of atrophy of retinal pigment epithelium in
a 25-year-old woman.

402
Figure 7.164. The lesion shown in Figure 7.163, 13 years later, showing that the lesion is still regressed with
no regrowth.

Figure 7.165. Choroidal melanoma with spontaneous necrosis in a 49-year-old woman. The yellow-white
areas in the lesion represent fibrous tissue in areas of tumor necrosis.

403
Figure 7.166. Spontaneous regression of a choroidal melanoma in a 25-year-old woman.

Figure 7.167. Wide-angle image of choroidal melanoma superior to the optic disc in the left eye. The lesion
presumably had undergone spontaneous necrosis and was unchanged after 2 years.

404
Figure 7.168. Probably partial spontaneous regression of choroidal melanoma superonasal to the optic disc
in right eye. The lesion was unchanged after 3 years.

405
 CHAPTER 8

POSTERIOR UVEAL MELANOMA: PATHOLOGY

PATHOLOGY OF POSTERIOR UVEAL MELANOMA

The pathology of uveal melanoma is briefly discussed with regard to routine gross
and light microscopy and some more recent developments related to prognosis
(1–28). Posterior uveal melanoma can have characteristic features on both gross and
microscopic examination (8–14). Observations of growth patterns on grossly
sectioned eyes can be helpful to the clinician in understanding the clinical behavior
of the tumors and in predicting prognosis. Gross examination of an enucleated eye
can reveal signs of scleral melanocytosis, nodules of extrascleral extension, tumor
growth pattern, extent of secondary retinal detachment, and other important
features. Grossly, a choroidal or ciliary body melanoma can be dome-shaped,
mushroom-shaped, or diffuse. The mushroom shape occurs from rupture of Bruch’s
membrane secondary to tumor growth. Melanoma can be deeply pigmented, partly
pigmented, or nonpigmented. It can produce a secondary retinal detachment,
subluxation of the lens, or secondary cataract. It can invade the anterior chamber,
producing secondary glaucoma, or it can extend through the sclera. A diffuse
melanoma can assume a ring configuration in the ciliary body region or a flat,
slightly elevated appearance in the choroid.
Low-magnification study of uveal melanomas can provide similar information
regarding growth patterns, invasion of adjacent structures such as sclera, vortex
veins, optic nerve, retinal pigment epithelium (RPE), sensory retina, and vitreous
(Table 8.1). Occasionally, there are areas of tumor necrosis. The presence of
subretinal fluid and lipofuscin-laden macrophages at the level of the RPE that
correlate with the orange pigment can be seen on the tumor surface (14).

406
 In 1931, Callender proposed the widely used cytologic classification of uveal
melanoma, dividing melanoma cells into spindle A, spindle B, fascicular, mixed,
epithelioid, and necrotic cell types. Later, McLean and associates, from the Armed
Forces Institute of Pathology modified the Callender classification and dropped the
fascicular and necrotic cell types. Mixed cell type is a combination of spindle and
epithelioid cells. This McLean modification is used today by most eye pathologists
(8,9).
It has long been recognized that the cell type of uveal melanoma is related to
prognosis (5). Patients with tumors composed of pure spindle cells have a more
favorable prognosis, and those with a component of epithelioid cells (mixed or
epithelioid cell types) have a worse prognosis. Melanomas with a low mitotic
activity are associated with a better prognosis, whereas those with a greater mitotic
activity carry a worse prognosis. There is increased mortality in patients with
extrascleral extension of the tumor. More recently, it has been found that the
histopathologic presence of networks of closed vascular loops and other abnormal
vascular patterns are associated with a less favorable prognosis. Some uveal
melanomas have demonstrated evidence of tumor infiltration with lymphocytes, a
feature associated with decreased survival.

Table 8.1 Histopathologic features of uveal melanoma in 1,526 cases

The Collaborative Ocular Melanoma Study (COMS) reported histopathologic

findings in 1,526 eyes that came to enucleation (10). The following table provides
information on cell type, invasion of surrounding structures, and necrosis.
There are cytologic and genetic factors that relate to prognosis for uveal
melanoma (1–3,8–14,15–28). Basic genetic alterations are evident in melanoma at

407
the DNA and RNA level. Melanoma found with chromosome 3 monosomy plus 8q
amplification carry particularly poor prognosis (15–17,19–25,27,28).

Selected References
Large Series
1. Shields JA, Shields CL. Prognostic factors for uveal melanoma. In:
Gospodarowicz M, O’Sullivan B, Sobin LH, eds. Prognostic Factors in Cancer, 3rd
ed. Hoboken, NJ: Wiley-Liss, 2006:269–272.
2. Mooy CM, De Jong PT. Prognostic parameters in uveal melanoma: a review.
Surv Ophthalmol 1996;41:215–228.
3. Isager P, Ehlers N, Overgaard J. Prognostic factors for survival after enucleation
for choroidal and ciliary body melanomas. Acta Ophthalmol Scand 2004;82:517–
525.
4. Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with
malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44:4651–4659.
5. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma
millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol
2009;127(8):989–998.
6. Kujala E, Damato B, Coupland SE, et al. Staging of ciliary body and choroidal
melanomas based on anatomic extent. J Clin Oncol 2013;31(22):2825–2831.
7. Shields CL, Shields JA, De Potter P, et al. Diffuse choroidal melanoma. Clinical
features predictive of metastasis. Arch Ophthalmol 1996;114:956–963.

Pathology
8. 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.
9. 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.
10. 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.
11. Folberg R, Mehaffey M, Gardner LM, et al. The microcirculation of choroidal
and ciliary body melanomas. Eye 1997;11:227–238.
12. 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.
13. Durie FH, Campbell AM, Lee WR, et al. Analysis of lymphocytic infiltration in
uveal melanoma. Invest Ophthalmol Vis Sci 1990;31:2106–2110.
14. Shields JA, Rodrigues MM, Sarin LK, et al. Lipofuscin pigment over benign and
malignant choroidal tumors. Trans Am Acad Ophthalmol Otolaryngol
1976;81:871–881.

Cytogenetics
15. Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3
in uveal melanoma. Lancet 1996;347:1222–1225.
16. Sisley K, Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8

408
 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes
Cancer 1997; 19:22–28.
17. Scholes AG, Damato BE, Nunn J, et al. Monosomy 3 in uveal melanoma:
Correlation with clinical and histologic predictors of survival. Invest Ophthalmol
Vis Sci 2003;44:1008–1011.
18. 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.
19. Kilic E, van Gils W, Lodder E, et al. Clinical and cytogenetic analyses in uveal
melanoma. Invest Ophthalmol Vis Sci 2006;47:3703–3707.
20. Shields CL, Materin MA, Teixiera L, et al. Small choroidal melanoma with
chromosome 3 monosomy on fine needle aspiration biopsy. Ophthalmology
2007;114:1919–1924.
21. Damato B, Duke C, Coupland SE, et al. Cytogenetics of uveal melanoma: A 7-
year clinical experience. Ophthalmology 2007;114:1925–1931.
22. Shields CL, Ganguly A, Materin M, 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.
23. Shields JA, Shields CL, Materin MA, et al. Role of cytogenetics in the
management of uveal melanoma. Arch Ophthalmol 2008;126:416–419.
24. Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in
500 cases using genetic testing of needle aspiration biopsy specimens.
Ophthalmology 2011;118:396–401.
25. Shields CL, Ramasubramanian A, Ganguly A, et al. Cytogenetic testing of iris
melanoma using fine needle aspiration biopsy in 17 patients. Retina
2011;31:574–580.
26. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in
metastasizing uveal melanomas. Science 2010;330:1410–1413.
27. Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal
melanomas with multiplex ligation-dependent probe. Clin Cancer Res
2010;16:6083–6092.
28. Shields CL, Ganguly A, O’Brien J, et al. U veal melanoma trapped in the
Temple of Doom. Editorial. Am J Ophthalmol 2012;154:219–221.

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• CILIARY BODY MELANOMA: GROSS FEATURES
Shown are gross sections of eyes with ciliary body melanoma that were managed by
enucleation. Today some of the cases shown would likely be managed by radiotherapy.

Figure 8.1. Partly pigmented and partly nonpigmented ciliochoroidal melanoma.

Figure 8.2. Pigmented ciliary body melanoma causing subluxation of the lens.

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Figure 8.3. Mildly pigmented ciliary body melanoma, causing subluxation of the lens.

411
Figure 8.4. Nonpigmented ciliary body melanoma indenting the lens.

Figure 8.5. Partly pigmented and partly nonpigmented ciliochoroidal melanoma.

Figure 8.6. Deeply pigmented ciliary body melanoma causing marked subluxation of the lens.

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• CHOROIDAL MELANOMA: GROSS FEATURES

Figure 8.7. Deeply pigmented choroidal melanoma.

Figure 8.8. Large pigmented choroidal melanoma causing total retinal detachment.

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Figure 8.9. Another large pigmented choroidal melanoma causing total retinal detachment.

Figure 8.10. Pigmented melanoma filling the entire eye.

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Figure 8.11. Large, amelanotic, dome-shaped choroidal melanoma.

Figure 8.12. Diffuse choroidal melanoma with a nodule of extrascleral extension. This was detected with
ultrasonography prior to modified enucleation.

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• CHOROIDAL MELANOMA: MUSHROOM-SHAPED CONFIGURATION
Melanomas that have broken through Bruch’s membrane assume a mushroom (collar button)
configuration and can show any of several variations. Selected examples are shown.

Figure 8.13. Pigmented mushroom-shaped melanoma located near the equator of the globe.

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Figure 8.14. Pigmented mushroom-shaped melanoma located in the posterior choroid.

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Figure 8.15. Larger, equatorial mushroom-shaped melanoma with total retinal detachment.

Figure 8.16. Mushroom-shaped nonpigmented melanoma. In this case, the dome of the mushroom is larger
than its base.

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Figure 8.17. Large, mushroom-shaped nonpigmented melanoma with marked vascularity.

Figure 8.18. Nonpigmented melanoma with two breaks through Bruch’s membrane.

419
• POSTERIOR UVEAL MELANOMA: CELL TYPES
Uveal melanoma can often be diagnosed simply by looking at a microscopic slide. One can
determine the uveal location, growth pattern, pigmentation, and the presence of extraocular
extension, but the cell type must be identified with higher magnification.
The cell type of uveal melanoma was traditionally described in terms of the Callender
classification. It applies to iris, ciliary body, and choroidal melanoma. A modification of the
Callender classification is used in some pathology laboratories. It has dropped the fascicular
and necrotic categories and divides uveal melanocytic lesions into spindle cell nevus, spindle
cell melanoma, mixed cell–type melanoma, and epithelioid cell–type melanoma. The
photomicrographs are courtesy of Ralph C. Eagle, Jr, MD.

Figure 8.19. Photograph of a glass slide showing a dome-shaped postequatorial choroidal melanoma with a
small break through Bruch’s membrane.

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Figure 8.20. Photograph of a glass slide showing a mushroom-shaped choroidal melanoma.

Figure 8.21. Low-grade spindle cell melanoma. (Hematoxylin–eosin ×200.)

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Figure 8.22. Spindle A uveal melanoma showing the “nuclear stripe” in many nuclei, which ultrastructurally is
found to be an infolding of the nuclear membrane. (Hematoxylin–eosin ×200.)

Figure 8.23. Spindle B uveal melanoma. (Hematoxylin–eosin ×200.)

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Figure 8.24. Fascicular melanoma. This is a spindle cell melanoma that assumes a fascicular growth pattern,
similar to that seen with schwannoma. (Hematoxylin–eosin ×75.)

The photomicrographs are courtesy of Ralph C. Eagle, Jr, MD.

Figure 8.25. Mixed cell–type uveal melanoma. Note the spindle cells above and the larger epithelioid cells
below. (Hematoxylin–eosin ×200.)

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Figure 8.26. Mixed cell–type uveal melanoma. Note again the spindle cell component and the larger epithelioid
cell. (Hematoxylin–eosin ×200.)

Figure 8.27. Melanoma composed of small epithelioid cells. (Hematoxylin–eosin ×200.)

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Figure 8.28. Melanoma composed of large epithelioid cells. (Hematoxylin–eosin ×200.)

Figure 8.29. Melanoma composed of large epithelioid cells. (Hematoxylin–eosin ×200.)

425
Figure 8.30. Balloon cell choroidal melanoma. Note the large, round epithelioid cells with clear cytoplasm.
(Hematoxylin–eosin ×200.)

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• CHOROIDAL MELANOMA: CLINICOPATHOLOGIC CORRELATIONS
Correlation of clinical wide-angle fundus photographs and gross appearance of uveal melanoma
helps in understanding the growth patterns of this neoplasm.

Figure 8.31. Clinical appearance of inferior choroidal melanoma.

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Figure 8.32. Gross appearance of the lesion shown in Figure 8.31.

Figure 8.33. Clinical appearance of large amelanotic choroidal melanoma.

Figure 8.34. Gross appearance of the lesion shown in Figure 8.33. Note the large dilated cavernous blood

428
vessels in the mass.

Figure 8.35. B-scan ultrasonogram of a patient who presented with hyphema and severe glaucoma. There is a
suggestion of a dome-shaped mass, retinal detachment, and severe subretinal hemorrhage.

Figure 8.36. Gross appearance of the lesion shown in Figure 8.35. There is a total retinal detachment,
massive hyphema, extensive subretinal hemorrhage, and a necrotic, hemorrhagic, dome-shaped choroidal
melanoma to the right.

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 CHAPTER 9

POSTERIOR UVEAL MELANOMA: DIAGNOSTIC

APPROACHES

POSTERIOR UVEAL MELANOMA: DIAGNOSTIC APPROACHES

General Considerations
The diagnosis of ciliary body and choroidal melanoma can usually be made by
recognition of its classic features using slit-lamp biomicroscopy or indirect
ophthalmoscopy. However, the diagnosis and extent of the tumor can be supported
or confirmed by the judicious use of ancillary studies such as transillumination,
fluorescein angiography, indocyanine green angiography (ICGA), ultrasonography,
ultrasound biomicroscopy (U BM), optical coherence tomography (OCT), fundus
autofluorescence, computed tomography (CT), magnetic resonance imaging (MRI),
and fine-needle aspiration biopsy (FNAB) (1–34). Although the P32 test was used
extensively many years ago, it has been abandoned because of the development and
refinement of FNAB which provides a more definitive diagnosis. In cases that are
atypical ophthalmoscopically, these ancillary studies assume a more vital role in
diagnosis.
The most important ancillary studies include ultrasonography and fluorescein
angiography, CT, MRI, and the P32 test are rarely necessary to make the diagnosis of
uveal melanoma. FNAB has become the most reliable diagnostic method in cases in
which the lesion is atypical and a precise diagnosis is not clearly established.

Transillumination
Transillumination is an important technique in the diagnostic evaluation of ciliary

430
body and anterior choroidal melanoma in certain circumstances. There are several
techniques of transillumination including transscleral and transpupillary types.
Transillumination is performed by placing a bright focused light in the conjunctival
fornix, opposite the site of the intraocular tumor, with dim room illumination and
observing the sclera that normally transmits light. In the case of pigmented ciliary
body melanoma, a shadow will be cast that corresponds to the location of the
melanoma. In contrast, cystic lesions, leiomyomas, and several other conditions tend
to transmit light rather than cast a shadow. Often, this technique allows for
measuring the diameter of lesion tumor and in planning for radioactive plaque
application.

Fluorescein Angiography and Indocyanine Green Angiography

Fluorescein angiography displays choroidal melanoma with mottled
hyperfluorescence in the vascular filling phases and diffuse late staining of the mass
and its overlying subretinal fluid. A larger amelanotic melanoma, particularly one
that has broken through Bruch’s membrane, might show more clearly the
characteristic double circulation in which both the retinal vessels and the choroidal
vessels in the tumor are readily evident. Areas of tumor invasion of the overlying
sensory retina are relatively hypofluorescent throughout the angiogram sequence.
ICGA shows hypofluorescence of thin, minimally vascular melanoma and
hyperfluorescence of larger, thicker tumors (6). This technique is particularly
valuable when visualizing the pattern of choroidal blood vessels in the tumor,
especially when there is overlying blood. This is used more frequently in the
diagnosis of choroidal hemangioma to be discussed in Chapter 13.

Ultrasonography
With A-scan ultrasonography, choroidal melanoma typically shows medium to low
internal reflectivity, and with B-scan ultrasonography, it shows a choroidal mass
pattern with acoustic hollowness and choroidal excavation. The mass might show
flat (diffuse), dome shape, or mushroom shape to the melanoma. U ltrasonography
can delineate a small nodule of extraocular orbital extension of the tumor.
U ltrasonography is particularly helpful in eyes with opaque media from secondary
cataract or vitreous hemorrhage. This technique is useful for confirming the
diagnosis of uveal melanoma and also for measuring tumor size before and after the
tumor has been treated with irradiation. In some instances, ultrasonography of a
ciliary body melanoma reveals clear cavities in the lesion and a thick, solid lining of
the cavitary spaces, a finding termed cavitary melanoma (5). This should be
differentiated from a thin-walled ciliary body cyst.

Ultrasound Biomicroscopy
U BM is a variation of ultrasonography that is used daily in our practice to measure
the size and extent of tumors in the peripheral iris and ciliary body. It is particularly
useful for determining whether a peripheral iris tumor extends posteriorly into the
ciliary body and to plan surgical resection or plaque radiotherapy of such tumors. It
is helpful in differentiating a cyst from a melanoma or other solid tumors in the
ciliary body area (8–11).

431
Computed Tomography and Magnetic Resonance Imaging
CT and MRI can be used to visualize uveal melanoma and to completely delineate
larger areas of orbital extension. They are not usually employed to make the
diagnosis of uveal melanoma because the diagnosis can be readily made in the great
majority of cases by simpler and less expensive methods, particularly
ophthalmoscopy and ultrasonography. MRI is often used in cases where the
differential diagnosis includes subretinal hemorrhage versus melanoma as blood
would remain unenhanced whereas melanoma would enhance following
gadolinium contrast injection.

Fine-Needle Aspiration Biopsy

FNAB is an important method to establish the diagnosis of choroidal melanoma in
difficult cases that defy clinical diagnosis using less invasive measures (30). The most
commonly employed technique is a trans–pars plana, transvitreal approach using a
25- to 27-gauge needle with indirect ophthalmoscopy guidance. It is particularly
valuable in differentiating melanoma from metastasis, retinal pigment epithelial
tumors, lymphoma, and other lesions and requires collaboration with a
cytopathologist familiar with ocular pathology. The technique is described in detail
in the literature and in Chapter 22 (30). FNAB is also used to study cytogenetics of
uveal melanoma, a subject to be discussed subsequently (31–34).

Radioactive Phosphorus Uptake Test

The radioactive phosphorus uptake test (P32 test) is mentioned here for historical
reasons. This technique can be used to make the diagnosis in difficult cases (29).
Although it is a highly accurate and reliable test that was used extensively in the
past, it is rarely used today because of the advent and perfection of other diagnostic
techniques, particularly FNAB, which provides cytopathologic verification of the
diagnosis.

Optical Coherence Tomography

OCT is a more recently developed imaging technique that has assisted in the
diagnosis and management of many fundus disorders, particularly macular
degeneration. Concerning choroidal melanoma, it is used to detect subtle subretinal
fluid, orange pigment, or retinal abnormalities overlying a choroidal lesion (12–23).
Improvement with depth of imaging has allowed evaluation of the intrinsic features
of the mass itself. Hence, OCT is valuable in earlier detection of the established risk
factors for choroidal nevi transformation into melanoma. OCT is proving to be more
valuable that ultrasonography for measuring small tumor thickness. Based on
published reports, small choroidal melanoma shows a smooth dome-shaped
topography with overlying subretinal fluid showing fresh, “shaggy” photoreceptors
(19,22,23). Although this tool cannot specifically differentiate choroidal melanoma
from choroidal nevus and other tumors, the recent use of enhanced depth imaging
OCT (EDI-OCT) is showing promise in achieving more precise information in that
regard.

Autofluorescence

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Autofluorescence fundus photography is especially useful in the early detection of
small choroidal melanoma. This tumor tends to show bright, geographic
hyperautofluorescence of the overlying lipofuscin within the RPE that corresponds
to clinically visible orange pigment (24–28).

Selected References
Large Series
1. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features,
classification, and top ten pseudomelanomas. Curr Opin 2014;25:177–185.
2. Kivelä T. Diagnosis of uveal melanoma. Dev Ophthalmol 2012;49:1–15.
3. Shields JA, McDonald PR, Leonard BC, et al. The diagnosis of uveal melanomas
in eyes with opaque media. Am J Ophthalmol 1977;82:95–105.
4. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma
millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol
2009;127(8):989–998.

Small Series
5. Lois N, Shields CL, Shields JA, et al. Cavitary melanoma of the ciliary body. A
study of eight cases. Ophthalmology 1998;105:1091–1098.

Imaging
6. Shields CL, Shields JA, De Potter P. Patterns of indocyanine green angiography
of choroidal tumors. Br J Ophthalmol 1995;79:237–245.
7. Coleman DJ, Silverman RH, Chabi A, et al. High-resolution ultrasonic imaging
of the posterior segment. Ophthalmology 2004;111:1344–1351.
8. Maberly DA, Pavlin CJ, McGowan HD, et al. U ltrasound biomicroscopic
imaging of the anterior aspect of peripheral choroidal melanomas. Am J
Ophthalmol 1997; 123:506–514.
9. Marigo FA, Finger PT, McCormick SA, et al. Iris and ciliary body melanomas:
ultrasound biomicroscopy with histopathologic correlation. Arch Ophthalmol
2000;118:1515–1521.
10. Nordlund JR, Robertson DM, Herman DC. U ltrasound biomicroscopy in
management of malignant iris melanoma. Arch Ophthalmol 2003;121:725–727.
11. Bianciotto CG, Shields CL, Romanelli M, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118:1297–1302.
12. Muscat S, Parks S, Kemp E, et al. Secondary retinal changes associated with
choroidal naevi and melanomas documented by optical coherence tomography.
Br J Ophthalmol 2004;88:120–124.
13. Shields CL, Mashayekhi A, Materin MA, et al. Optical coherence tomography of
choroidal nevus in 120 consecutive patients. Retina 2005;25:243–252.
14. Shields CL, Materin MA, Shields JA. Review of optical coherence tomography
for intraocular tumors. Current Opinion Ophthalmol 2005;16:141–154.
15. Singh AD, Belfort RN, Sayanagi K, et al. Fourier domain optical coherence
tomographic and auto-fluorescence findings in indeterminate choroidal
melanocytic lesions. Br J Ophthalmol 2010;94(4):474–478.
16. Sayanagi K, Pelayes DE, Kaiser PK, et al. 3D Spectral domain optical coherence
tomography findings in choroidal tumors. Eur J Ophthalmol 2011;21(3):271–

433
 275.
17. Torres VL, Brugnoni N, Kaiser PK, et al. Optical coherence tomograph
enhanced depth imaging of choroidal tumors. Am J Ophthalmol
2011;151(4):586–593.
18. 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.
19. 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.
20. Say EA, Shah SU , Ferenczy S, et al. Optical coherence tomography of retinal
and choroidal tumors. J Ophthalmol 2012;2012:385058.
21. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid
and beyond. Surv Ophthalmol 2013;58(5):387–429.
22. Shields CL, Manalac J, Das C, et al. Review of spectral domain enhanced depth
imaging optical coherence tomography (EDI-OCT) of tumors of the choroid. Ind
J Ophthalmol 2015;63(2):117–121.
23. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014;34:1495–1512.
24. Shields CL, Bianciotto C, Pirondini C, et al. Autofluorescence of orange pigment
overlying small choroidal melanoma. Retina 2007;27:1107–1111.
25. Shields CL, Bianciotto C, Pirondini C, et al. Autofluorescence of choroidal
melanoma in 51 cases. Br J Ophthalmol 2008;92:617–622.
26. Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of choroidal nevus
in 64 cases. Retina 2008;8:1035–1043.
27. 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.
28. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr
Opin Ophthalmol 2013;24(3):222–232.
29. Shields JA. Accuracy and limitation of the P-32 test in the diagnosis of ocular
tumors. An analysis of 500 cases. Ophthalmology 1978;85:950–966.

Cytology
30. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
Cytogenetics
31. Shields CL, Materin MA, Teixiera L, et al. Small choroidal melanoma with
chromosome 3 monosomy on fine needle aspiration biopsy. Ophthalmology
2007;114:1919–1924.
32. Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in
500 cases using genetic testing of needle aspiration biopsy specimens.
Ophthalmology. 2011;118:396–401.
33. Shields JA, Shields CL, Materin MA, et al. Role of cytogenetics in the
management of uveal melanoma. Arch Ophthalmol 2008;126:416–419.

434
34. Shields CL, Ramasubramanian A, Ganguly A, et al. Cytogenetic testing of iris
melanoma using fine needle aspiration biopsy in 17 patients. Retina
2011;31:574–580.

435
• CHOROIDAL MELANOMA: FLUORESCEIN ANGIOGRAPHY OF A
DOME-SHAPED TUMOR

Figure 9.1. Wide-angle photograph of choroidal melanoma inferotemporally in the right eye of a 29-year-old
man.

Figure 9.2. Standard fundus photograph of the same lesion.

436
Figure 9.3. Angiogram in the late arterial phase, with focus on the optic disc, showing the filling of retinal
arteries over the tumor and minimal hyperfluorescence of the tumor.

Figure 9.4. Venous phase, showing further hyperfluorescence of the mass. The overlying retinal arteries and
veins are hyperfluorescent.

437
Figure 9.5. Early recirculation phase.

Figure 9.6. Late angiogram, showing continued hyperfluorescence of the mass.

438
• CHOROIDAL MELANOMA: FLUORESCEIN ANGIOGRAPHY OF A
MUSHROOM-SHAPED TUMOR

The prominent blood vessels seen in amelanotic, mushroom-shaped choroidal melanoma can
impart a “pseudoangiomatous” appearance to the lesion.

Figure 9.7. Clinical appearance of amelanotic melanoma temporal to the foveal region with the camera
focused on the background retina.

Figure 9.8. Clinical appearance with the camera focused on the dome of the mushroom-shaped mass shown
in Figure 9.7, showing prominent retinal and tumoral blood vessels.

439
Figure 9.9. Red-free photograph highlighting the prominent retinal and choroidal blood vessels.

Figure 9.10. Angiogram in the early laminar venous phase, showing retinal and tumoral blood vessels
(“double circulation”).

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Figure 9.11. Angiogram in the early recirculation phase, showing continued hyperfluorescence of the vessels
in the mass. Note that there is still some laminar flow in the overlying retinal vein.

Figure 9.12. Late angiogram, showing intense hyperfluorescence of the mass due to leakage from blood
vessels in the tumor.

441
• CHOROIDAL MELANOMA: FLUORESCEIN ANGIOGRAPHY OF A
TUMOR WITH OVERLYING CHOROIDAL NEOVASCULAR MEMBRANE

Choroidal neovascularization over a choroidal nevus or melanoma is rare. It has a clinical and
angiographic appearance similar to that seen in age-related macular degeneration.

Figure 9.13. Wide-angle fundus photograph of mushroom-shaped melanoma temporally in the left eye of a 40-
year-old man.

Figure 9.14. Standard fundus photograph, showing arborizing blood vessels on the surface of the tumor.

442
Figure 9.15. Arterial phase, showing well-defined hyperfluorescence of the overlying neovascular membrane.
Note that no retinal vessels feed the neovascular structure, suggesting that it is of choroidal origin from within
the tumor.

Figure 9.16. Late venous phase, showing early leakage from the neovascular membrane.

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Figure 9.17. Early recirculation phase, showing continued leakage.

Figure 9.18. Late recirculation phase, showing ill-defined hyperfluorescence secondary to leakage of the
neovascular membrane.

444
• CHOROIDAL MELANOMA: INDOCYANINE GREEN ANGIOGRAPHY
ICGA shows characteristic but not pathognomonic features in cases of choroidal melanoma.

Figure 9.19. Clinical photograph of choroidal melanoma inferotemporally in the right eye of a 29-year-old man.

Figure 9.20. Early indocyanine green angiography, showing prominent overlying retinal vessels and minimal
leakage from tumor vessels.

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Figure 9.21. Late indocyanine green angiography, showing moderate hyperfluorescence of the mass.

Figure 9.22. Clinical photograph of choroidal melanoma inferotemporal to the fovea in a 51-year-old man.

446
Figure 9.23. Early indocyanine green angiography showing prominent overlying retinal vessels and minimal
leakage from tumor vessels.

Figure 9.24. Late indocyanine green angiography showing moderate hyperfluorescence of the mass.

447
• CHOROIDAL AND CILIARY BODY MELANOMA: ULTRASONOGRAPHY
AND ULTRASOUND BIOMICROSCOPY

Ultrasonography using A-scan or B-scan is a commonly employed technique that is readily

available in many ophthalmologists’ offices. It shows characteristic features that can support
the diagnosis of choroidal or ciliary body melanoma. In cases with opaque ocular media, due to
corneal edema, cataract, or vitreal hemorrhage, ultrasound can localize and depict an underlying
melanoma. UBM is an important modification of ultrasonography that is used for smaller
tumors in the ciliary body area that are difficult to visualize with ophthalmoscopy or standard
ultrasonography.

Figure 9.25. A-scan ultrasonography of a choroidal melanoma, showing progressively decreasing amplitude
in the tumor (angle kappa).

Figure 9.26. B-scan ultrasonography of a medium-sized, dome-shaped choroidal melanoma, showing

448
characteristic acoustic hollowness and choroidal excavation.

Figure 9.27. Ultrasound biomicroscopy of a ciliary body melanoma measuring 3 mm in thickness.

Figure 9.28. B-scan ultrasonography of a medium-sized, mushroom-shaped choroidal melanoma, showing

typical acoustic solidity near the tumor apex and hollowness and choroidal excavation at the tumor base.

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Figure 9.29. B-scan ultrasonography of a larger, mushroom-shaped choroidal melanoma. This lesion shows
more acoustic solidity near the tumor apex, suggesting congested tumor vessels, mixed cell type, or tumor
necrosis.

Figure 9.30. B-scan ultrasonography of a choroidal melanoma with extrascleral extension. The echolucent
area in the orbital fat represents the nodule of the extrascleral tumor. Note also the curvilinear echo superior to
the solid tumor, representing a secondary retinal detachment.

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• CHOROIDAL AND CILIARY BODY MELANOMA: COMPUTED
TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING

Although CT and MRI can demonstrate a posterior uveal melanoma, they provide little clinical
information that cannot be obtained with ophthalmoscopy and ultrasonography. However, in
cases with massive orbital extension of the uveal melanoma, these techniques are better than
ultrasonography for demonstrating the full extent of the tumor.

Figure 9.31. Axial computed tomography of equatorial choroidal melanoma temporally in the left eye.

Figure 9.32. Axial computed tomography of choroidal melanoma with transcleral orbital extension of the tumor.

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Figure 9.33. Axial magnetic resonance imaging in a T1-weighted image with fat suppression and gadolinium
enhancement, showing a ciliary body mass in the right eye. The lesion is hyperintense to vitreous.

Figure 9.34. Axial magnetic resonance imaging in a T2-weighted image, showing the same mass seen in
Figure 9.33. Note that the melanoma is minimally hypointense to vitreous.

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Figure 9.35. Axial magnetic resonance imaging in a T1-weighted image with gadolinium enhancement,
showing a mushroom-shaped ciliary body melanoma that is hyperintense to vitreous.

Figure 9.36. Axial magnetic resonance imaging in a T1-weighted image with fat suppression and gadolinium
enhancement, showing in the left eye a dome-shaped choroidal melanoma (to the left) and a secondary retinal
detachment (to the right).

453
• CHOROIDAL MELANOMA: ENHANCED DEPTH IMAGING OPTICAL
COHERENCE TOMOGRAPHY

1. 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.
2. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical coherence
tomography (EDI-OCT) of intraocular tumors. From placid to seasick to rock and rolling
topography. The 2013 Francesco Orzalesi Lecture. Retina 2014;34:1495–512.

Figure 9.37. Small juxtapapillary choroidal melanoma with subtle overlying orange pigment and subretinal
fluid.

Figure 9.38. Optical coherence tomography of lesion in Figure 9.37 reveals shallow retinal detachment with

454
debris on the posterior surface (shaggy photoreceptors) in both the horizontal foveal image (top) and the
vertical tumor image (bottom).

Figure 9.39. Diffuse choroidal melanoma with overlying orange pigment and subretinal fluid.

Figure 9.40. Optical coherence tomography of lesion in Figure 9.39 reveals subfoveal retinal detachment with
fuzzy debris on the posterior surface (shaggy photoreceptors) in both the horizontal foveal image (top) and the
vertical tumor image (bottom).

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Figure 9.41. Macular choroidal melanoma with overlying orange pigment and subretinal fluid.

Figure 9.42. Optical coherence tomography of lesion in Figure 9.41 reveals serous retinal detachment with
prominent debris on the posterior surface (shaggy photoreceptors) in the horizontal foveal image (top) and
less subretinal fluid in the vertical tumor image (bottom).

456
• CHOROIDAL MELANOMA: FUNDUS AUTOFLUORESCENCE
IMAGING

1. Shields CL, Bianciotto C, Pirondini C, et al. Autofluorescence of choroidal melanoma in 51

cases. Br J Ophthalmol 2008;92:617–622.
2. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr Opin
Ophthalmol 2013;24(3):222–232.
3. Hashmi F, Rojanaporn D, Kaliki S, et al. Orange pigment sediment overlying small choroidal
melanoma. Arch Ophthalmol 2012;130:937–938.

Figure 9.43. Small juxtapapillary choroidal melanoma with overlying orange pigment and subfoveal fluid.

457
Figure 9.44. Fundus autofluorescence demonstrates lipofuscin (orange pigment) as hyperautofluorescent and
free fluorophores in the subretinal fluid.

Figure 9.45. Small macular choroidal melanoma with overlying and pocket of subretinal orange pigment.

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Figure 9.46. Fundus autofluorescence demonstrates lipofuscin (orange pigment) as hyperautofluorescent
overlying the tumor and into the pocket of subretinal fluid.

Figure 9.47. Diffuse choroidal melanoma with prominent overlying orange pigment layering into a sediment.

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Figure 9.48. Fundus autofluorescence demonstrates lipofuscin (orange pigment) as hyperautofluorescent
speckles and layering into a sediment overlying the tumor.

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• CHOROIDAL AND CILIARY BODY MELANOMA: RADIOACTIVE
PHOSPHORUS UPTAKE TEST AND FINE-NEEDLE ASPIRATION
BIOPSY

The radioactive phosphorus uptake test is a reliable technique for making the diagnosis in
difficult cases in which the differential diagnosis is between a melanoma and a benign
simulating lesion. Although it was once a standard procedure for diagnosing melanoma in
difficult cases, it is rarely used today because techniques of FNAB have been perfected and
provide a more definitive diagnosis.

Figure 9.49. The transconjunctival radioactive phosphorus uptake test for a ciliary body lesion. The Geiger
counter is placed directly over the base of the tumor as determined with transillumination.

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Figure 9.50. The transcleral radioactive phosphorus uptake test for a posterior choroidal lesion. For such
posterior lesions, a conjunctival incision is necessary to gain access to the sclera at the base of the tumor as
determined with transillumination.

Figure 9.51. Trans–pars plana, transvitreal technique of fine-needle aspiration biopsy. Indirect ophthalmoscopy
is used to guide the needle.

Figure 9.52. Atypical juxtapapillary lesion for which fine-needle aspiration biopsy was used to make a
diagnosis. Neither fluorescein angiography nor ultrasonography showed features typical of melanoma.

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Figure 9.53. Cytopathology of the lesion shown in Figure 9.40, showing spindle cells compatible with
melanoma. (Papanicolaou ×100.)

Figure 9.54. Immunohistochemical stain of the cells shown in Figure 9.41, showing positive immunoreactivity
for melanoma-specific antigen. (HMB-45 ×100.)

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• CHOROIDAL MELANOMA: FINE-NEEDLE ASPIRATION BIOPSY
In one patient, choroidal metastasis was a consideration, and another patient had
neurofibromatosis and schwannoma was a consideration.

Figure 9.55. Dark fundus lesion with choroidal folds. Choroidal melanoma was the clinical diagnosis, but the
patient requested histopathologic confirmation before plaque radiotherapy.

Figure 9.56. Transconjunctival–pars plana transvitreal approach to the mass for fine-needle aspiration biopsy
as shown in Figure 9.39.

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Figure 9.57. Cytopathology shows malignant spindle cells with pigment in the cytoplasm compatible with
melanoma. (Papanicolaou ×400.)

Figure 9.58. Pigmented choroidal mass in a patient with neurofibromatosis type 1. The differential diagnosis of
the fundus lesion was malignant choroidal melanoma and pigmented peripheral nerve sheath tumor
(schwannoma or neurofibroma).

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Figure 9.59. Cytopathology of the lesion shown in Figure 9.46, demonstrating epithelioid melanoma cells and
no cells compatible with peripheral nerve sheath tumor. (Papanicolaou ×400.)

Figure 9.60. Positive immunohistochemical reaction for melanoma-specific antigen (HMB-45) of the cells
shown in Figure 9.46.

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• CHOROIDAL MELANOMA: FINE-NEEDLE ASPIRATION BIOPSY IN AN
EYE PRESENTING WITH VITREOUS HEMORRHAGE

Choroidal melanoma can sometimes present as a vitreal hemorrhage. In such cases, carefully
guided FNAB can make a cytopathologic diagnosis. Microscopic study of the site of scleral
penetration shows no seeding of tumor cells into the needle tract.

Figure 9.61. Hazy fundus view of vitreous hemorrhage with a suggestion of an underlying mass in a middle-
aged man.

Figure 9.62. Axial magnetic resonance imaging, showing extensive vitreal hemorrhage.

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Figure 9.63. Cytopathology of fine-needle aspiration biopsy, showing epithelioid melanoma cells.
(Papanicolaou ×300.) Based on this finding, enucleation was done.

Figure 9.64. Section of enucleated eye, showing necrotic melanoma (to the right) and extensive subretinal and
vitreal hemorrhage.

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Figure 9.65. Histopathology, showing epithelioid melanoma cells. (Hematoxylin–eosin ×200.)

Figure 9.66. Histopathologic section through the needle tract in the pars plana, showing absence of tumor
cells in the needle tract. (Hematoxylin–eosin ×10.)

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• CHOROIDAL MELANOMA: GENETIC TESTING USING FINE-NEEDLE
ASPIRATION BIOPSY

Figure 9.67. Trans–pars plana approach with fine-needle aspiration biopsy using indirect ophthalmoscopic
viewing.

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Figure 9.68. Aspiration of Hanks preservative to fixate cells.

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Figure 9.69. Small choroidal melanoma with cytogenetic results of monosomy 3.

Figure 9.70. Variably pigmented macular choroidal melanoma with cytogenetic results of monosomy 3.

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Figure 9.71. Diffuse choroidal melanoma with cytogenetic results of monosomy 3.

Figure 9.72. Large choroidal melanoma with cytogenetic results of monosomy 3.

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 CHAPTER 10

POSTERIOR UVEAL MELANOMA: MANAGEMENT

POSTERIOR UVEAL MELANOMA: MANAGEMENT

In recent years, there have been advances in the management of posterior uveal
melanoma, and several options are now available (1–100). The selected
management of posterior uveal melanoma depends on factors such as the tumor
size, location, and activity as well as the status of the opposite eye and the age,
general health, and psychological status of the patient. Each patient should undergo
a detailed ophthalmic evaluation, and the size and extent of the tumor should be
carefully documented with accurate drawings. The known risk factors for growth
and metastasis should be considered (4–6), and the patient should then be counseled
about the therapeutic options (16–19).
Some informative results have come from the Collaborative Ocular Melanoma
Study (COMS). This study confirmed that plaque radiotherapy and enucleation offer
the same prognosis for medium-sized melanomas and large melanoma does not
require pre-enucleation radiotherapy for improved prognosis (92–95).

Observation
Most melanocytic choroidal nevi are managed with conservative observation. In
recent years, there has been a belief that borderline lesions, in which the diagnosis
of nevus versus melanoma is questionable, should be followed with fundus
photography and ultrasonography to document tumor growth before undertaking
definitive treatment. There is an emerging philosophy toward active treatment
rather than observation for selected small, high-risk choroidal melanocytic lesions

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(4–8). This has come about because recent studies have identified risk factors that
are statistically related to a greater chance of metastasis (4–6). Factors that
differentiate small choroidal melanoma from choroidal nevus can be remembered
by using the mnemonic TFSOM-U HHD, indicating To Find Small Ocular Melanoma,
U sing Helpful Hints Daily. The letters in this mnemonic represent T (thickness >2
mm), F (subretinal fluid), S (symptoms), O (orange pigment), M (margin touching
optic disc), U H (ultrasound hollow), H (halo absent), and D (drusen absent).
Choroidal melanocytic tumors that display no factors have 3% chance for growth at
5 years and most likely represent choroidal nevi. Tumors that display two or more
factors show growth in >50% of cases at 5 years (4–6).

Laser Photocoagulation
Some small- and some medium-sized melanomas can be managed with techniques
of laser photocoagulation (22). Standard photocoagulation is used less often today
because transpupillary thermotherapy (TTT) in the infrared range using a diode
laser delivery system has shown promising results in properly selected cases.

Transpupillary Thermotherapy
TTT involves heating the tumor by using light in the infrared range (810 nm) with a
diode laser delivery system. This treatment provides the best results in cases of small
melanomas ≤2.5 mm thick in which growth is documented. Although, it has been
used successfully for tumors up to 4 mm in thickness (23–35). Appropriate tumor
selection is critical to successful treatment. In our experience, tumors >3 mm in
thickness are best treated with plaque radiotherapy combined with TTT. Patients
with tumors abutting or overhanging the optic disc or those requiring more than
three sessions for tumor control are more likely to develop tumor recurrence if TTT
is used as the only treatment. Potential complications of TTT include retinal branch
vein obstruction, retinal traction, and induction of a retinal hole with secondary
retinal detachment, which is uncommon (34). However, many patients have had
complete tumor destruction and favorable visual outcomes. Longer follow-up with
carefully selected cases at 20 years find that tumors of 2.5 mm thickness, not
touching the optic disc and with minimal subretinal fluid respond well to TTT, with
<15% recurrence/complications.

Charged Particle Irradiation

Techniques of radiotherapy using charged particles have shown good results
(52–62). Published reports suggest that survival data and tumor control are similar
to results with plaque radiotherapy. Like plaque radiotherapy, charged particles
(proton beams or helium ions) can be used for many medium-sized or large
posteriorly located melanomas in which there is a reasonable chance of preserving
some vision. There is concern for anterior and posterior segment radiation toxicity.

Plaque Brachytherapy
Plaque radiotherapy is the most commonly used method of treating uveal
melanoma. Extensive experience with plaque brachytherapy has suggested that it
offers reliable tumor control, up to 98% in our hands. This therapy can often

475
preserve useful visual acuity and offers a prognosis comparable to that of
enucleation (36–51). Plaque radiotherapy requires close cooperation among ocular
oncologists, radiation oncologists, and radiation physicists. It is recognized that
plaque radiotherapy can be used to treat large melanomas (47), macular melanoma,
ciliary body melanoma (43), and extraocular extension of uveal melanoma,
although the majority of such patients experience considerably visual loss.
Enucleation might be necessary in some cases due to painful secondary glaucoma or
tumor recurrence (37). Similar results have been obtained with charged particle
irradiation. However, anterior segment complications appear to be greater after
charged particle irradiation than after plaque radiotherapy (53).
The COMS has also confirmed previous data comparing plaque radiotherapy and
enucleation with regard to metastasis and mortality. In COMS, mortality rates
following plaque brachytherapy with radioactive iodine-125 did not differ from
mortality rates following enucleation for up to 12 years after treatment of patients
with medium-sized choroidal melanoma (92–95).

Other Radiation Methods

Other methods of irradiation for uveal melanoma are under investigation, including
stereotactic radiosurgery, gamma-knife, and cyberknife methods.

Local Resection
Melanoma located in the ciliary body and peripheral choroid can be managed by
local resection of the tumor (63–74). Several years ago, a full-thickness eye wall
resection with a scleral graft was usually employed (63). More recently, techniques
of partial lamellar sclerouvectomy (PLSU ) have been used (64–70). The surgical
procedure can be difficult and requires considerable skill and experience, but the
results are often very gratifying. Supplemental plaque radiotherapy can be used
after local resection if the melanoma is high grade and near the margins of
resection.
There has been some recent interest in removing posterior uveal melanoma by
endoresection, using vitrectomy instrumentation (71–74). This is generally
performed following proton beam radiotherapy with the ultimate goal to prevent
the toxic tumor syndrome in which tumor necrosis from irradiation causes serve
intraocular inflammation and neovascular glaucoma (73).

Enucleation
Enucleation is appropriate for large melanomas in which there is little hope of
salvaging useful vision with more conservative treatments or for some tumors that
surround or invade the optic nerve head. Although there is some flexibility,
depending on the other clinical factors, we generally lean toward enucleation when
a melanoma is >18 mm in diameter and 10 mm in thickness because the morbidity
is greater following radiotherapy for tumors that large.
There are a number of techniques for replacing the orbital volume with an
implant. In recent years, we have used a 20-mm hydroxyapatite implant wrapped
with eye bank sclera. More recently, we have used a polymer-coated hydroxyapatite
implant (82). When there was a sizeable circumscribed nodule of orbital extension
of uveal melanoma, in several cases we used a method of enucleation via a lateral

476
orbitotomy approach as an alternative to orbital exenteration (84). Others prefer the
medpore implant, some prefer a simpler silastic ball implant.
The subject of pre-enucleation external irradiation for uveal melanoma has been a
topic of some debate. A COMS report (93) verified a prior report that there is no
difference in patient survival when comparing enucleation only with enucleation
preceded by external beam radiation for choroidal melanomas (78).

Orbital Exenteration
Occasionally, a uveal melanoma shows massive orbital extension at the time of
initial diagnosis, and in such cases, primary orbital exenteration is often warranted.
We have generally used an eyelid-sparing technique in such cases (56). The
technique is illustrated in Chapter 25.

Combination Methods
In recent years, there has been increasing use of combined methods to treat a
posterior uveal melanoma. Many patients have been treated by methods of plaque
radiotherapy combined with TTT and local resection followed by plaque
radiotherapy and other combined methods. At the time of this writing, most
choroidal melanomas on our service are treated with plaque radiotherapy combined
with TTT. With this approach, local tumor control has been achieved in
approximately 98% of cases (83). Ongoing protocols are currently employed in
which intravitreal injection anti-VEGF drugs are employed after plaque
radiotherapy to minimize radiation-induced retinopathy and cystoid foveal edema
and early results appear to be favorable (100).

Genetic Studies
Recent genetic studies of uveal melanoma have shown abnormalities on
chromosomes 1, 3, 6, 8, 11, and 13. The most significant predictor of poor life
prognosis at this time is chromosome 3 monosomy (96–100). Cytogenetic analysis
can also be performed on fine-needle aspiration biopsy specimens (98,99). Patients
with monosomy 3 abnormality are being offered more rigorous follow-up and
management with systemic chemotherapy or immunotherapy protocols. For patients
with multiple systemic cancers or family history of uveal melanoma, additional
blood testing for GNAQ, GNA11, and BAP-1 is performed.

Systemic Treatment
In the past, the treatment of posterior uveal melanoma was conducted mainly by the
ocular oncologists with techniques of enucleation, ocular irradiation, local resection,
laser photocoagulation, and other local treatments. U nfortunately, the survival rate
has not improved significantly. A push toward earlier diagnosis and treatment could
improve prognosis. In addition, there has been increasing emphasis on targeted
therapy toward overt or subclinical metastasis to liver and other sites (86,87,89,90).
Now that genetic studies can be used to determine which patients have a less
favorable prognosis; such patients are being offered these novel treatments.
Techniques of hepatic artery chemoembolization with a variety of agents and
local surgical removal of selected solitary distant metastasis have met with limited

477
success. In the future, it is expected that primary treatment of uveal melanoma will
be directed mostly toward eradicating subclinical distant metastasis (90). It is most
likely that the ideal management will be very early detection and prompt treatment
of small uveal melanoma combined with intensive systemic therapy in the form of
chemotherapy, immunotherapy, gene therapy, and/or other methods with
techniques yet to be elucidated.

Selected References
Large Series
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melanoma. Analysis of 2514 consecutive cases. Arch Ophthalmol 2009;127(8);
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7. Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma
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Opinions
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Radiotherapy: Brachytherapy
36. Shields JA, Augsburger JJ, Brady LW, et al. Cobalt plaque therapy of posterior
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39. Shields JA, Shields CL, DePotter P, et al. Plaque radiotherapy for uveal
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40. DePotter P, Shields CL, Shields JA, et al. The impact of enucleation versus
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41. Shields CL, Shields JA, Gunduz K, et al. Radiation therapy for uveal malignant
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44. Gunduz K, Shields CL, Shields JA, et al. Plaque radiotherapy for management of
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45. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for uveal melanoma.
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46. Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and
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75. Wilson RS, Fraunfelder FT. “No touch” cryosurgical enucleation: a minimal
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79. Dutton JJ. Coralline hydroxyapatite as an ocular implant. Ophthalmology 1991;
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1992;110:333–338.
81. Shields CL, Shields JA, DePotter P. Hydroxyapatite orbital implant after
enucleation for intraocular tumors. In: Shields JA, ed. Update on Malignant
Ocular Tumors. International Ophthalmology Clinics. Boston, MA: Little, Brown,
1993;33:83–93.
82. Shields CL, U ysal Y, Marr BP, et al. Experience with the polymer-coated
hydroxyapatite implant following enucleation in 126 patients. Ophthalmology
2007;114:367–373.
Exenteration
83. Shields JA, Shields CL, Suvarnamani C, et al. Orbital exenteration with eyelid
sparing: indications, technique and results. Ophthalmic Surg 1991;22:292–297.
84. DePotter P, Shields JA, Shields CL, et al. Modified enucleation via lateral
orbitotomy for choroidal melanomas with massive orbital extension. Ophthalmic
Plast Reconstr Surg 1992;8:109–113.
85. Shields JA, Shields CL, Demirci H, et al. Experience with eyelid-sparing orbital
exenteration. The 2000 Tullos O. Coston Lecture. Ophthalmic Plast Reconstr Surg
2001;17:355–361.

482
Systemic Therapies
86. Mavligit GM, Charnsangevej C, Carrasco H, et al. Regression of ocular
melanoma metastatic to the liver after hepatic arterial chemoembolization with
cisplatin and polyvinyl sponge. JAMA 1988;260:974–976.
87. Gunduz K, Shields JA, Shields CL, et al. Surgical removal of solitary hepatic
metastasis from choroidal melanoma. Am J Ophthalmol 1998;125:407–409.
88. Nathan FE, Berd D, Sato T, et al. BOLD +interferon in the treatment of
metastatic uveal melanoma: first report of active systemic therapy. J Exp Clin
Cancer Res 1997;16:201–208.
89. Aoyama T, Mastrangelo MJ, Berd D, et al. Protracted survival following
resection of metastatic uveal melanoma. Cancer 2000;89:1561–1568.
90. Patel K, Sullivan K, Berd D, et al. Chemoembolization of the hepatic artery with
1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU ) for metastatic uveal melanoma:
results of phase 2 study. Melanoma Res 2005;15:297–304.
91. Shields JA, Perez N, Shields CL, et al. Orbital melanoma metastatic from
contralateral choroid: management by complete surgical resection. Ophthalmic
Surg Lasers 2002;33:416–420.
Collaborative Ocular Melanoma Trials
92. The Collaborative Ocular Melanoma Study Group. 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.
93. The 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;126:779–796.
94. Gilson MM, Diener-West M, Hawkins BS. Comparison of survival among
eligible patients not enrolled versus enrolled in the Collaborative Ocular
Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large
choroidal melanoma. Ophthalmic Epidemiol 2007;14(4):251–257.
95. The Collaborative Ocular Melanoma Study Group. COMS randomized trial of
iodine 125 brachytherapy for choroidal melanoma. V. Twelve-year mortality
rate and prognostic factors: COMS report no. 28. Arch Ophthalmol
2006;124:1684–1693.
Cytogenetics
96. Sisley K, Rennie IG, Cottan DW, et al. Cytogenetic findings in 6 posterior uveal
melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosomes
Cancer 1990;2:205–209.
97. Prescher G, Bornfeld N, Hirshe H, et al. Prognostic implications of monosomy 3
in uveal melanoma. Lancet 1996;347:122–125.
98. Shields CL, Ganguly A, Materin M, et al. Chromosome 3 analysis of uveal
melanoma using fine needle aspiration biopsy at the time of plaque
radiotherapy in 140 consecutive cases. Ophthalmology 2011;118:1747–1753.
99. Shields CL, Ganguly A, Bianciotto CG, et al. Prognosis of uveal melanoma in
500 cases using genetic testing of needle aspiration biopsy specimens.
Ophthalmology 2011;118:396–401.
100. Böhm MR, Tsianakas A, Merté RL, et al. Mutational analysis of GNAQ and
GNA11 to aid therapy management of a choroidal melanoma metastatic to the

483
contralateral orbit. JAMA Ophthalmol 2013;131(6):812–814.

484
• CHOROIDAL MELANOMA: OBSERVATION
A tumor <2 mm in thickness with surface drusen and no surface orange pigment or subretinal
fluid can usually be followed until growth of the lesion in diameter or thickness is clearly
documented. Additional relative reasons for observation include a small lesion near the fovea in
an eye with good vision, the presence of the lesion in the patient’s only useful eye, or if the
patient is elderly or in poor general health. Recent recognition of risk factors for metastasis has
prompted earlier treatment of many lesions that would have been observed previously. Shown
are examples of lesions than would be initially followed without treatment according to current
philosophies, with the realization that such lesions may be treated more promptly in the future
as more information on this subject becomes available.

Figure 10.1. Suspicious subfoveal lesion in an asymptomatic 55-year-old woman.

Figure 10.2. Suspicious lesion >2 mm thick with numerous drusen in an asymptomatic 72-year-old woman.

485
Figure 10.3. Suspicious parafoveal lesion in an asymptomatic 67-year-old woman. The numerous large
drusen on the tumor surface suggest that the lesion is relatively dormant.

Figure 10.4. Suspicious lesion with overlying fibrous metaplasia of the retinal pigment epithelium in an
asymptomatic 75-year-old woman.

Figure 10.5. Suspicious lesion inferior to the optic disc in an asymptomatic 48-year-old woman. The shallow
retinal detachment inferior to the lesion is a bothersome finding but does not necessarily imply that this small
lesion is malignant.

486
Figure 10.6. Patient referred for choroidal melanoma but noted to have overlying drusen and retinal pigment
epithelial atrophy, suggestive of chronic nevus, so observation advised.

487
• CHOROIDAL MELANOMA: SMALL TUMORS THAT WERE INITIALLY
OBSERVED AND EVENTUALLY SHOWED GROWTH AND
DEVELOPED METASTASIS

Not all small presumed choroidal nevi remain stable. We have many documented cases of small
lesions that were initially followed and treated with enucleation or plaque radiotherapy after
growth was documented and the patients later developed metastatic disease. Recognition of
risk factors for future metastasis has prompted earlier treatment of many lesions that would
have been followed by observation in the past. Small lesions without risk factors should be
followed, but once growth is documented, then active treatment should generally be
considered.

Figure 10.7. Small presumed choroidal nevus superonasal to the optic disc in a 70-year-old man. The lesion
had been followed for 10 years, and it showed no change.

Figure 10.8. Same lesion shown in Figure 10.7 after 1 year. The lesion had shown pronounced growth.
Enucleation was performed, but liver metastasis became apparent 5 years later.

488
Figure 10.9. Small presumed choroidal nevus temporal to the fovea in a 75-year-old man.

Figure 10.10. Same lesion shown in Figure 10.9 after 3 years, showing growth and accumulation of orange
pigment. Liver metastasis was detected shortly thereafter.

Figure 10.11. Small choroidal melanocytic lesion inferior to the optic disc in a 38-year-old woman seen in
1986. This lesion has risk factors such as proximity to optic disc, elevation, and orange pigment, but she was
followed at that time without treatment.

489
Figure 10.12. Same lesion shown in Figure 10.11 after 1 year. Growth had occurred, and enucleation was
performed. The mixed cell–type melanoma demonstrated hepatic metastasis about 8 years later.

490
• CHOROIDAL MELANOMA: ARGON LASER PHOTOCOAGULATION
OR TRANSPUPILLARY THERMOTHERAPY FOR SMALL TUMORS

Argon laser photocoagulation is an effective method of treating selected small choroidal

melanomas located nasal to the optic disc. In recent years, transpupillary thermotherapy or
plaque radiotherapy combined with TTT has become the preferred treatment for these cases.

Figure 10.13. Small lesion nasal to the optic disc in a 37-year-old woman as seen in January 1992.

Figure 10.14. Same lesion in July 1993, showing definite growth.

491
Figure 10.15. B-scan ultrasonogram, showing the lesion 2 mm thick.

Figure 10.16. Appearance in July 1994, showing complete tumor destruction. The small amount of residual
pigment is flat.

Figure 10.17. Small melanoma in a diabetic patient with retinopathy.

Figure 10.18. Following transpupillary thermotherapy, the tumor showed complete regression to an atrophic
scar.

492
• CHOROIDAL MELANOMA: TRANSPUPILLARY THERMOTHERAPY
FOR SMALL TUMORS

Figure 10.19. Peripheral choroidal melanoma measuring 3.2 mm thickness.

Figure 10.20. Following transpupillary thermotherapy, the tumor completely regressed, leaving an atrophic scar
and bare sclera.

493
Figure 10.21. Peripheral choroidal melanoma measuring 3 mm thickness and with shallow subretinal fluid.

Figure 10.22. Following transpupillary thermotherapy, the tumor completely regressed, leaving a clean,
atrophic scar, and bare sclera.

Figure 10.23. Small juxtapapillary choroidal melanoma with orange pigment and subtle subretinal fluid.

494
Figure 10.24. Following transpupillary thermotherapy, the tumor regressed, leaving a fibrotic scar with retinal
traction.

495
• CHOROIDAL MELANOMA: TRANSPUPILLARY THERMOTHERAPY
FOR A SMALL TUMOR WITH DOCUMENTED GROWTH

The technique of TTT differs from that of argon laser photocoagulation in that a larger spot size
is used. An example is shown of a small choroidal melanoma treated with TTT.

Figure 10.25. Small choroidal melanoma temporal to the fovea in a 33-year-old man. The lesion was recently
found to have doubled in size.

Figure 10.26. B-scan ultrasonogram showing the 2-mm thick lesion with acoustic hollowness, compatible with
a small melanoma.

496
Figure 10.27. White color to the lesion immediately after the first session of transpupillary thermotherapy.

Figure 10.28. Appearance of the lesion after 3 months. At this time, a second session of transpupillary
thermotherapy was used.

Figure 10.29. Final appearance after 9 months. The lesion is completely eradicated clinically and has
remained stable for 10 years.

497
Figure 10.30. Ultrasonogram at the same time as Figure 10.29. Note that the lesion is flat.

498
• CHOROIDAL MELANOMA: TRANSPUPILLARY THERMOTHERAPY
In properly selected cases of small melanoma, the tumor can be eradicated with TTT with
anatomic and visual results as good as or better than with plaque brachytherapy or charged
particle irradiation.

Figure 10.31. Growing melanoma superior to the optic disc in left eye of a 50-year-old man. The tumor was 3
mm thick on ultrasonography.

Figure 10.32. Appearance of the macular area. The visual acuity was 20/40 due to shallow serous retinal
detachment beneath the fovea.

499
Figure 10.33. Appearance of prior tumor after three sessions of transpupillary thermotherapy. The tumor has
entirely resolved.

Figure 10.34. Appearance of the macular area at the same time as Figure 10.33. The vision returned to 20/20
and has remained so for more than 5 years.

Figure 10.35. Another patient with a small, growing melanoma inferior to the left optic disc.

500
Figure 10.36. The lesion shown in Figure 10.35 after completion of three sessions of transpupillary
thermotherapy. There is complete eradication of the tumor. The visual acuity is 20/20.

Depicted are three additional cases of small melanoma treated with TTT alone, showing
excellent tumor destruction with no complications.

Figure 10.37. Tumor after the first session of transpupillary thermotherapy.

Figure 10.38. Appearance after completion of three sessions of transpupillary thermotherapy.

501
Figure 10.39. Nonpigmented melanoma before transpupillary thermotherapy. The patient was treated with
indocyanine green–enhanced transpupillary thermotherapy.

Figure 10.40. Appearance of the lesion shown in Figure 10.39 after transpupillary thermotherapy.

Figure 10.41. Lesion immediately superior to the fovea prior to transpupillary thermotherapy.

502
Figure 10.42. Appearance of the lesion shown in Figure 10.41 after transpupillary thermotherapy. Because of
proximity to the foveola, this patient would be treated today with combined plaque brachytherapy followed by
extrafoveal transpupillary thermotherapy in the hope of controlling the tumor and preserving more central
vision.

503
• CHOROIDAL MELANOMA: SIDE EFFECTS OF TRANSPUPILLARY
THERMOTHERAPY

In some cases, local complications and recurrence can develop after TTT for choroidal
melanoma. Examples are shown of retinal vein obstruction, sectorial optic nerve atrophy, retinal
traction, and aggressive recurrence of melanoma.

Figure 10.43. Branch retinal vein obstruction with cystoid foveal edema secondary to the successful treatment
of choroidal melanoma with transpupillary thermotherapy.

Figure 10.44. Temporal optic nerve atrophy 5 years after completion of transpupillary thermotherapy for
choroidal melanoma.

504
Figure 10.45. Appearance of melanoma superotemporal to the fovea prior to transpupillary thermotherapy.

Figure 10.46. Area shown in Figure 10.45 after completion of transpupillary thermotherapy and excellent tumor
destruction. There is slight retinal traction with slight dragging of the fovea toward the treated area.

Figure 10.47. Choroidal melanoma touching the optic disc inferonasally. Transpupillary thermotherapy
appeared later to be successful in eradicating the tumor.

505
Figure 10.48. After 2 years, this aggressive tumor shown in Figure 10.47 developed multiple foci of recurrence
in the treated area and on the margins of treatment. There is an amelanotic nodule of tumor recurrence
superior to the disc in an area that was originally normal ophthalmoscopically. The patient was demonstrated
to have liver metastasis shortly thereafter.

506
• CHOROIDAL MELANOMA: PLAQUE RADIOTHERAPY FOR SMALL-
TO MEDIUM-SIZED TUMORS

Plaque radiotherapy is currently the most frequently employed method of treating patients with
posterior uveal melanoma. It can be used to treat small, medium-sized, and some large
melanomas. The method of plaque application is shown in Chapter 25. Examples of treatment
results are shown here with wide-angle imaging. All cases showed decrease in tumor thickness
as measured with ultrasonography. Today, these lesions might be treated with combined plaque
radiotherapy and TTT.

Figure 10.49. Melanoma at the equator superotemporally before plaque radiotherapy.

Figure 10.50. Same lesion 3 years after plaque treatment.

507
Figure 10.51. Melanoma inferior to the macular area before treatment.

Figure 10.52. Same lesion 3 months after treatment, showing excellent tumor regression.

Figure 10.53. Melanoma near the nasal equator of the right eye before treatment.

508
Figure 10.54. Same lesion 2 years after treatment, showing excellent tumor regression.

509
• CHOROIDAL MELANOMA: PLAQUE RADIOTHERAPY FOR MEDIUM-
SIZED TUMORS. WIDE-ANGLE IMAGING

Additional cases are shown, using wide-angle imaging. These are all older cases treated with
cobalt-60 plaques, which are rarely used today. The photographs were also done with an earlier
model wide-angle camera.

Figure 10.55. Pretreatment appearance of a melanoma at the equator temporally.

Figure 10.56. Posttreatment appearance of the melanoma shown in Figure 10.55 after 13 months.

510
Figure 10.57. Pretreatment appearance of a temporal melanoma in a 57-year-old woman.

Figure 10.58. Posttreatment appearance of the melanoma shown in Figure 10.57 after 3 years.

Figure 10.59. Pretreatment appearance of a melanoma in a 76-year-old woman. Note the subretinal
hemorrhage.

511
Figure 10.60. Posttreatment appearance of the melanoma shown in Figure 10.59 after 3 years.

512
• CHOROIDAL MELANOMA: PLAQUE RADIOTHERAPY FOR MEDIUM-
SIZED AND LARGE TUMORS. WIDE-ANGLE IMAGING

The photographs show an initial good response during 1 to 2 years after plaque radiotherapy.
With longer follow-up, most patients with melanomas of this size are expected to develop
cataract or severe radiation retinopathy.

Figure 10.61. Deeply pigmented, mushroom-shaped melanoma superiorly.

Figure 10.62. Appearance of the lesion shown in Figure 10.61, 2 years after plaque treatment.

513
Figure 10.63. Large amelanotic choroidal melanoma inferiorly in the left eye.

Figure 10.64. Appearance of the lesion shown in Figure 10.63, 1 year after plaque treatment.

Figure 10.65. Large choroidal melanoma inferotemporally with extensive retinal detachment.

514
Figure 10.66. Appearance of the lesion shown in Figure 10.65, 2 years after plaque treatment. The tumor has
regressed well, and the retinal detachment has resolved.

515
• CHOROIDAL MELANOMA: EARLY RESPONSE TO PLAQUE
RADIOTHERAPY

Shown are cases of early response to plaque radiotherapy using standard photography rather
than wide-angle imaging. The early response is often dramatic and satisfactory, but many
patients develop radiation complications on longer follow-up.

Figure 10.67. Pretreatment appearance of inferotemporal melanoma.

Figure 10.68. Appearance of the lesion shown in Figure 10.67, 4 months after treatment.

516
Figure 10.69. Pretreatment appearance of temporal melanoma in a 35-year-old man.

Figure 10.70. Appearance of the lesion shown in Figure 10.69, 7 months after treatment.

Figure 10.71. Pretreatment appearance of temporal melanoma.

Figure 10.72. Appearance of the lesion shown in Figure 10.71, 13 months after treatment.

517
• POSTERIOR UVEAL MELANOMA: PLAQUE RADIOTHERAPY FOR
LARGE TUMORS

As mentioned earlier, plaque radiotherapy can induce a dramatic initial response. Wide-angle
images are shown of short-term results of large melanomas treated with plaque radiotherapy.
However, there are considerable long-term problems, such as cataract, radiation retinopathy,
and/or secondary glaucoma, following radiotherapy. The expected complications of plaque
radiotherapy will be shown subsequently.

Figure 10.73. Large superonasal choroidal melanoma.

Figure 10.74. Tumor shown in Figure 10.73, 1 year after plaque radiotherapy.

518
Figure 10.75. Large ciliochoroidal melanoma located inferotemporally.

Figure 10.76. Tumor shown in Figure 10.75, 1 year after plaque radiotherapy.

Figure 10.77. Large nasal melanoma with vitreal and subretinal hemorrhage.

519
Figure 10.78. Tumor shown in Figure 10.77, 6 months after plaque radiotherapy.

520
• CHOROIDAL MELANOMA: PLAQUE RADIOTHERAPY FOR
MUSHROOM-SHAPED TUMORS

Choroidal melanoma with breaks through Bruch’s membrane can also be treated with plaque
radiotherapy. In such cases, the base of the tumor generally regresses, but a residual elevated
nodule still exists. Examples are shown.

Figure 10.79. Deeply pigmented, mushroom-shaped melanoma.

Figure 10.80. Appearance of the lesion shown in Figure 10.79, 1 year after plaque radiotherapy.

521
Figure 10.81. Deeply pigmented, mushroom-shaped melanoma, with amelanotic dome and mild subretinal
and vitreal hemorrhage.

Figure 10.82. Appearance of the lesion shown in Figure 10.81, 18 months after plaque radiotherapy.

Figure 10.83. Mushroom-shaped melanoma with secondary hemorrhagic retinal detachment.

522
Figure 10.84. Appearance of the lesion shown in Figure 10.83, 6 months after plaque radiotherapy. The tumor
has shown marked regression, and the hemorrhagic detachment has resolved. The optic disc and fovea still
appear normal at this time.

523
• CILIARY BODY MELANOMA: PLAQUE RADIOTHERAPY
Plaque radiotherapy can also be used to treat many ciliary body melanomas. Most patients
develop a cataract that can eventually be removed, and an intraocular lens can be used to
restore vision. Examples are shown, each of which showed a dramatic decrease in tumor
thickness with ultrasonography.

Gunduz K, Shields CL, Shields JA, et al. Plaque radiotherapy of uveal melanoma with
predominant ciliary body involvement. Arch Ophthalmol 1999;117:170–177.

Figure 10.85. Deeply pigmented melanoma inferiorly.

Figure 10.86. Lesion shown in Figure 10.85 after 1 year, showing a nice result.

524
Figure 10.87. Deeply pigmented ciliary body melanoma near the nasal equator.

Figure 10.88. Lesion shown in Figure 10.87 after 1 year, showing favorable initial result.

Figure 10.89. Mushroom-shaped ciliary body melanoma superotemporally.

525
Figure 10.90. Lesion shown in Figure 10.89 after 1 year, showing excellent initial result.

526
• CHOROIDAL MELANOMA: MANAGEMENT OF JUXTAPAPILLARY
MELANOMA WITH PLAQUE RADIOTHERAPY AND
THERMOTHERAPY

Melanoma that abuts the optic disc is termed juxtapapillary melanoma. Due to their posterior
location, treatment with radiotherapy is challenging and requires radiotherapy precision and
surgical skills. The plaque generally requires a posterior notch to fit the optic disc and
radiotherapy is delivered to the melanoma.

Sagoo MS, Shields CL, Mashayekhi A, et al. Plaque radiotherapy for juxtapapillary choroidal
melanoma. Tumor control in 650 consecutive cases. Ophthalmology 2011;118:402–407.

Figure 10.91. Documented enlarging small choroidal melanoma with subretinal fluid and overlying lipofuscin.

Figure 10.92. Following notched plaque radiotherapy and thermotherapy, the tumor showed regression to a flat
scar.

527
Figure 10.93. Juxtapapillary choroidal melanoma with subretinal fluid and ill-defined margins.

Figure 10.94. Following notched plaque radiotherapy and macula-sparing thermotherapy, the tumor showed
regression to a flat scar.

Figure 10.95. Circumpapillary choroidal melanoma with extensive subretinal fluid.

528
Figure 10.96. Following deeply notched plaque radiotherapy and thermotherapy, complete tumor regression
was achieved and remains stable at 11 years follow-up.

529
• CHOROIDAL MELANOMA: COMBINED PLAQUE RADIOTHERAPY
AND TRANSPUPILLARY THERMOTHERAPY

Juxtapapillary choroidal melanoma is known to carry a small risk for recurrence following
techniques of radiotherapy. To decrease the rate of recurrence, juxtapapillary melanomas can be
treated with notched plaque radiotherapy combined with either laser photocoagulation or TTT.
TTT is most often employed today. The first session of laser or TTT is given at the time of
plaque removal, and two or three additional treatments are given at 3- to 4-month intervals.

Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and transpupillary
thermotherapy for choroidal melanoma in 270 consecutive patients. Arch Ophthalmol
2002;120:933–940.

Figure 10.97. Choroidal melanoma nasal to the optic disc in a 52-year-old woman.

Figure 10.98. Appearance of the lesion almost 2 years after plaque and 1 year after completion of argon laser
photocoagulation.

530
Figure 10.99. Juxtapapillary melanoma inferior to the optic disc in a 32-year-old woman.

Figure 10.100. Appearance of the lesion shown in Figure 10.99 after completion of plaque radiotherapy and
transpupillary thermotherapy. Note the pallor of the optic disc inferiorly.

Figure 10.101. Large choroidal melanoma in the temporal fundus. Note the inferior bullous secondary retinal
detachment.

531
Figure 10.102. Same tumor shown in Figure 10.101, 2 years after plaque radiotherapy and transpupillary
thermotherapy, demonstrating excellent tumor regression and resolution of the retinal detachment.

532
• CILIARY BODY MELANOMA: PLAQUE RADIOTHERAPY FOR A
TUMOR WITH AN EXTRAOCULAR EXTENSION

An extraocular extension of uveal melanoma does not always require enucleation or orbital
exenteration. Today, most such cases are managed by plaque radiotherapy, regardless of
whether the extraocular extension is located in the ciliary body region or in the posterior
segment.

Gunduz K, Shields CL, Shields JA, et al. Plaque radiotherapy for management of ciliary body and
choroidal melanoma with extrascleral extension. Am J Ophthalmol 2000;130:97–102.

Figure 10.103. Ciliochoroidal melanoma with an extraocular extension. Note the subconjunctival pigmented
episcleral nodule.

Figure 10.104. Transillumination shows the shadow of the ciliary body mass.

533
Figure 10.105. Wide-angle image showing the mass itself. Note that the ciliary processes are visible in the
photograph, suggesting that the tumor involves and thickens the ciliary body.

Figure 10.106. Wide-angle image 1 year after plaque therapy, showing marked regression of the ciliochoroidal
mass. The nodule of the extraocular extension showed corresponding regression.

Figure 10.107. Extrascleral extension of large ciliary body melanoma. Note the iris extension. No biopsy was
done, and the patient was treated with an iodine-125 plaque.

534
Figure 10.108. Same lesion shown in Figure 10.107, 2 years after plaque radiotherapy, showing regression of
the extraocular and iris components of the neoplasm. The ciliary body component (not seen in photograph)
also showed a dramatic response.

535
• CHOROIDAL MELANOMA: ULTRASONOGRAPHY FOLLOWING
PLAQUE RADIOTHERAPY

Patients treated with plaque radiotherapy have baseline ultrasonography measurements, as well
as fundus photography, prior to treatment, and these studies are repeated on postoperative
visits to verify tumor regression. Examples of B-scan ultrasonography before and after treatment
are shown. In our experience, gradual tumor regression is generally considered to be a favorable
sign, whereas rapid and complete regression may be associated with a greater chance of
metastasis.

Figure 10.109. B-scan ultrasonography of a small choroidal melanoma prior to treatment.

Figure 10.110. Same area 15 months after plaque radiotherapy, showing complete tumor regression.

536
Figure 10.111. Medium-sized choroidal melanoma prior to treatment.

Figure 10.112. Same area 18 months after treatment, showing favorable regression.

Figure 10.113. Large choroidal melanoma prior to treatment.

537
Figure 10.114. Same area 2 years after treatment, showing favorable regression.

538
• CHOROIDAL MELANOMA: SIDE EFFECTS OF PLAQUE
RADIOTHERAPY

Most adverse secondary effects of radiotherapy occur between 1 and 5 years after radiotherapy.
Radiation treatment of melanoma in the posterior aspect of the choroid is likely to induce
clinically significant radiation maculopathy and papillopathy. Treatment of anterior choroidal
and ciliary body lesions is likely to induce cataract and, rarely, melting of the overlying sclera,
particularly if a rectus muscle was removed during plaque application. Although many cases of
scleral melting require no treatment, more severe ones can be repaired with a scleral patch
graft.

Figure 10.115. Radiation retinopathy, showing nerve fiber layer infarctions and hemorrhages in the posterior
pole adjacent to the treated melanoma.

Figure 10.116. Radiation retinopathy with accumulation of yellow subretinal and intraretinal exudation
surrounding the residual melanoma in the posterior pole.

539
Figure 10.117. Severe radiation papillopathy following treatment of a melanoma superotemporal to the foveal
area.

Figure 10.118. Radiation cataract and posterior synechiae secondary to anterior segment ischemic
inflammation after radiotherapy.

Figure 10.119. Scleral melting secondary to plaque radiotherapy of a ciliochoroidal melanoma. At that time, a
scleral patch graft was performed.

540
Figure 10.120. Appearance of the area shown in Figure 10.119, 8 years after a successful scleral patch graft.

541
• CILIOCHOROIDAL MELANOMA: LOCAL RESECTION BY PARTIAL
LAMELLAR CYCLOCHOROIDECTOMY

Melanoma and other tumors that involve the peripheral choroid and ciliary body can be
removed by PLSU. The surgery is difficult and requires experience, but the results can be
gratifying. The technique of PLSU is discussed in Chapter 25. The goal of surgery is to remove
the tumor intact while preserving the outer sclera, retina, and vitreous. PLSU is particularly
applicable for a tumor >6 mm in thickness, in which case radiotherapy would necessitate a
higher dose of irradiation to normal ocular structures.

Figure 10.121. Fundus drawing of a mushroom-shaped melanoma at the equator superiorly in a 69-year-old
man.

Figure 10.122. B-scan ultrasonogram of lesion shown in Figure 10.121, showing a mushroom-shaped lesion.

542
Figure 10.123. A-scan ultrasonogram, showing a characteristic melanoma pattern.

Figure 10.124. Sectioned mushroom-shaped melanoma after removal by partial lamellar sclerouvectomy.

Figure 10.125. Postoperative fundus drawing, showing a flat retina posteriorly with a normal optic disc and
macular region. The flat yellow area is the sclera, as seen after tumor and pigment epithelium, leaving intact
the sensory retina.

543
Figure 10.126. Postoperative wide-angle fundus photograph, showing the resected area above and the normal
posterior segment. The inferior bright area is due to the transillumination used to take the photograph.

544
• CILIOCHOROIDAL MELANOMA: LOCAL RESECTION BY PARTIAL
LAMELLAR CYCLOCHOROIDECTOMY IN AN EYE WITH EXTENSIVE
RETINAL DETACHMENT

Extensive retinal detachment should not be considered a contraindication to PLSU. In fact, the
presence of a retinal detachment may facilitate removing the tumor without damage to the
sensory retina.

Figure 10.127. Fundus drawing of peripheral choroidal and ciliary body melanoma and retinal detachment
(drawn in b lue) in a 68-year-old woman.

Figure 10.128. Wide-angle photograph of the lesion shown in Figure 10.127.

545
Figure 10.129. B-scan ultrasonogram, showing melanoma with extensive retinal detachment.

Figure 10.130. A-scan ultrasonogram, showing a typical melanoma pattern.

Figure 10.131. Wide-angle photograph after resection of the tumor, showing the resected area (superonasally)
and normal disc and macular area. The retinal detachment is gone.

546
Figure 10.132. Fundus drawing after resection of the tumor.

547
• CILIOCHOROIDAL MELANOMA: RESULTS OF PARTIAL LAMELLAR
SCLEROUVECTOMY. LONG-TERM RESULTS

Although PLSU has potential complications such as vitreous hemorrhage, retinal detachment,
and cataract, it usually provides gratifying results and avoids enucleation and radiotherapy.
Results of iridocyclectomy for iris and ciliary body melanoma are shown in Chapter 2.

Figure 10.133. Wide-angle photograph of inferotemporal ciliochoroidal melanoma in a 59-year-old woman.

Figure 10.134. Appearance of the same eye shown in Figure 10.133, after partial lamellar sclerouvectomy,
showing the resection site and flat retina.

548
Figure 10.135. Wide-angle photograph of superotemporal choroidal melanoma in a 26-year-old woman who
declined enucleation.

Figure 10.136. Appearance of the eye shown in Figure 10.135 after partial lamellar sclerouvectomy, showing
the resection site and flat retina.

Figure 10.137. Standard 45-degree photograph of the same lesion shown in Figure 10.135, showing proximity
of the tumor to the fovea.

549
Figure 10.138. Postoperative photograph of the same area shown in Figure 10.137. Note the clear margins of
the resected area.

550
• CHOROIDAL MELANOMA: LOCAL RESECTION BY PARTIAL
LAMELLAR SCLEROCHOROIDECTOMY WITH 20-YEAR FOLLOW-UP

A selected case is shown of an excellent response to PLSU for choroidal melanoma with a 20-
year follow-up. Although this was highly successful, such a lesion today would probably be
managed with a radioactive plaque.

Figure 10.139. Wide-angle photograph of melanoma at the inferior equator in a 41-year-old woman in 1985.

Figure 10.140. Closer view of the lesion shown in Figure 10.139. The lesion has a break through Bruch’s
membrane.

551
Figure 10.141. Fundus drawing of the tumor, showing extent of surrounding secondary retinal detachment
(shown in b lue)

Figure 10.142. Montage photograph taken nearly 30 years later, showing chorioretinal scar with visible sclera
and thin overlying retina.

Figure 10.143. Closer view of the resection area shown in Figure 10.142. Note that the retinal vessels are still
visible over the resected area, indicating that the choroidal tumor was removed, leaving the overlying sensory
retina intact.

552
Figure 10.144. View of the posterior fundus as it appeared after 30 years, showing normal foveal region. The
patient still maintains 20/20 vision in the affected eye.

553
• CHOROIDAL MELANOMA: ENUCLEATION FOR A LARGE TUMOR.
WIDE-ANGLE IMAGING BY EQUATOR-PLUS CAMERA

There are no firm rules regarding when enucleation should be used for choroidal melanoma, and
the entire clinical situation must be taken into account. In general, tumors >18 mm in diameter
and 10 mm in thickness are best managed by enucleation because of the morbidity of treating
such larger tumors with radiotherapy or local resection. However, in older patients whose
melanoma is located in their better eye, enucleation may be deferred and irradiation employed.
The following wide-angle photographs depict examples in which enucleation is probably
justified because the morbidity with any form of radiotherapy is greater and patient quality of
life is more likely to be compromised after radiotherapy for such large lesions.

Figure 10.145. Large temporal choroidal melanoma, measuring about 18 × 17 × 10 mm, in a 40-year-old
woman.

Figure 10.146. Large mushroom-shaped choroidal melanoma, measuring about 20 × 19 × 12 mm, in a 35-
year-old man.

554
Figure 10.147. Large nasal melanoma, measuring about 19 × 19 × 12 mm, with a secondary total retinal
detachment in a 58-year-old woman.

Figure 10.148. Large superior melanoma, measuring about 19 × 17 × 11 mm, with a secondary total retinal
detachment in a 72-year-old man.

Figure 10.149. Large superior melanoma, measuring about 20 × 19 × 13 mm, with a secondary total retinal
detachment in a 45-year-old man.

555
Figure 10.150. Large bilobed ciliochoroidal melanoma, measuring about 22 × 18 × 12 mm, in a 23-year-old
woman.

556
• CHOROIDAL MELANOMA: ENUCLEATION FOR LARGE TUMORS.
WIDE-ANGLE IMAGING

Although the majority of patients with uveal melanoma are managed by eye-saving procedures
today, some still present with advanced tumors that are too large or inappropriately located for
conservative treatment. In such instances, primary enucleation is the best therapeutic option.
The relative indications for enucleation were discussed previously. Currently, about 15% of
patients with uveal melanoma require primary enucleation.

Figure 10.151. Mushroom-shaped melanoma arising inferior to the optic disc, measuring about 15 × 15 × 15
mm, and obscuring a view of the optic disc and macular region.

Figure 10.152. Dome-shaped melanoma, measuring about 18 × 18 × 16 mm.

557
Figure 10.153. Melanoma, measuring about 20 × 15 × 12 mm, extending from the ciliary body to the macular
region.

Figure 10.154. Mushroom-shaped superior melanoma, measuring about 20 × 15 × 15 mm.

Figure 10.155. Temporal ciliochoroidal melanoma, measuring about 15 × 15 × 15 mm.

558
Figure 10.156. Melanoma, measuring about 20 × 20 × 15 mm, with total secondary retinal detachment.

559
• CHOROIDAL MELANOMA: ENUCLEATION FOR SMALL- AND
MEDIUM-SIZED MELANOMAS

Some small- and medium-sized melanomas are often best managed by enucleation. This is true
when they occur in young people with a poor visual prognosis, when they surround or invade
the optic nerve, or when they assume a diffuse growth pattern. There is a gradual trend,
however, toward treating more juxtapapillary and epipapillary melanomas with plaque
radiotherapy.

Figure 10.157. Choroidal melanoma in the macular area and overhanging optic disc in a 34-year-old woman.
The patient could be treated with plaque radiotherapy, but the tumor location and her young age favor
enucleation.

Figure 10.158. Choroidal melanoma in the macular area in a 14-year-old girl. Once again, the tumor location
and the young age of the patient are factors that favor enucleation.

560
Figure 10.159. Small choroidal melanoma with optic nerve invasion.

Figure 10.160. Medium-sized melanoma surrounding and invading the optic nerve.

Figure 10.161. Small circumpapillary diffuse choroidal melanoma.

561
Figure 10.162. Larger circumpapillary, subfoveal diffuse melanoma. The tumor occupied the entire superior
fundus.

562
• CHOROIDAL MELANOMA: ENUCLEATION FOR SMALL- AND
MEDIUM-SIZED TUMORS

Some examples are shown of small choroidal melanomas for which enucleation was appropriate
management.

Figure 10.163. Circumpapillary choroidal melanoma.

Figure 10.164. Circumpapillary choroidal melanoma with hyperemia of the optic disc.

563
Figure 10.165. Small melanoma with invasion and replacement of the optic disc.

Figure 10.166. Diffuse circumpapillary melanoma with extension beneath the fovea.

Figure 10.167. Large circumpapillary melanoma with a break through Bruch’s membrane.

564
Figure 10.168. Gross section of the lesion shown in Figure 10.167, following enucleation.

565
• CHOROIDAL MELANOMA: MODIFIED ENUCLEATION USING A
LATERAL ORBITOTOMY APPROACH FOR A TUMOR WITH SIZEABLE
ORBITAL EXTENSION

Occasionally, a uveal melanoma exhibits a circumscribed orbital extension. Orbital exenteration

in such cases is controversial, and the entire tumor can sometimes be removed intact by using a
lateral orbitotomy approach. An enucleation orbital implant and prosthesis can then be
employed. A clinicopathologic correlation of such a case is shown.

DePotter P, Shields JA, Shields CL, et al. Modified enucleation via lateral orbitotomy for
choroidal melanomas with massive orbital extension. Ophthalmic Plast Reconstr Surg 1992;8:109–
113.

Figure 10.169. Small macular melanoma with orange pigment on the surface.

Figure 10.170. Magnetic resonance imaging of orbits in a T1-weighted image, showing a circumscribed orbital
tumor behind the globe.

566
Figure 10.171. Gross appearance of the specimen following removal via lateral orbitotomy. Note the intact
black tumor in the orbit and the long section of optic nerve.

Figure 10.172. Gross appearance of the sectioned specimen, demonstrating intraocular and orbital
components of the tumor.

Figure 10.173. Microscopic section, showing intraocular and orbital components of the tumor. It proved to be a
mixed cell–type melanoma.

567
Figure 10.174. Appearance of the patient 6 years after enucleation, hydroxyapatite implant, and peg placement.
She was healthy and without evidence of metastasis.

568
• POSTERIOR UVEAL MELANOMA: ORBITAL EXENTERATION AND
MODIFIED ENUCLEATION FOR RECURRENT ORBITAL TUMOR
FOLLOWING TREATMENT OF UVEAL MELANOMA

Figure 10.175. Protrusion of the prosthesis on the left side of a patient who had enucleation for choroidal
melanoma 20 years earlier. In retrospect, a small focus of transcleral extension by spindle melanoma cells
was evident histopathologically on the enucleated eye.

Figure 10.176. Axial computed tomography of the patient shown in Figure 10.175, depicting a large ovoid mass
posterior to the orbital implant. The patient was managed by eyelid-sparing orbital exenteration.

569
Figure 10.177. Aggressive orbital recurrence of ciliochoroidal melanoma 5 years after enucleation. Note the
characteristic black nodules appearing on the conjunctival surface. Orbital exenteration was performed.

Figure 10.178. Fundus appearance of a middle-aged woman who had plaque and laser for choroidal
melanoma nasal to the optic disc in the left eye several years earlier, with good anatomic result.

Figure 10.179. Axial magnetic resonance imaging in a T1-weighted image of the patient shown in Figure
10.178, revealing a round retrobulbar mass nasal to the optic disc.

Figure 10.180. Gross appearance of the globe and the black circumscribed melanoma adjacent to the optic
nerve in orbit, following modified enucleation.

570
• POSTERIOR UVEAL MELANOMA: ORBITAL EXENTERATION FOR A
TUMOR WITH A MASSIVE ORBITAL EXTENSION

Orbital exenteration is generally considered to be the treatment of choice for a melanoma with
a massive transcleral extension into the orbital soft tissues. The technique is illustrated in
Chapter 25.

Shields CL, Shields JA, Yarian DL, et al. Intracranial extension of choroidal melanoma via the
optic nerve. Br J Ophthalmol 1987;71:172–176.

Figure 10.181. Appearance of the left ocular region in a 62-year-old woman, showing proptosis and eyelid
swelling.

Figure 10.182. Closer view of the left eye, showing epibulbar injection, flat anterior chamber, iris atrophy, and
cataract.

571
Figure 10.183. Axial computed tomogram of the orbit, showing the globe and orbit filled by a mass.

Figure 10.184. Cytology of fine-needle aspiration biopsy performed through the inferior conjunctival fornix,
showing epithelioid melanoma cells. (Papanicolaou ×300.)

Figure 10.185. Sectioned exenteration specimen, showing melanoma filling the globe, orbit, and infiltrating
optic nerve. The optic nerve was subsequently resected to the chiasm, and there was no residual tumor.

572
Figure 10.186. Histopathology, showing epithelioid cell–type melanoma. (Hematoxylin–eosin ×250.) The
patient did not develop metastatic disease, but died 5 years later of an unrelated cause.

573
• POSTERIOR UVEAL MELANOMA: ORBITAL EXENTERATION
FOLLOWING EVISCERATION ELSEWHERE FOR UNSUSPECTED
UVEAL MELANOMA THAT SIMULATED ENDOPHTHALMITIS

Severe endophthalmitis and panophthalmitis can be managed by evisceration of the globe

contents. However, uveal melanoma can induce an inflammatory response that simulates
endophthalmitis, so the clinician should exclude the possibility of underlying melanoma before
performing evisceration. Two cases are shown in which evisceration was performed elsewhere
on such eyes while the underlying melanoma was unsuspected. We subsequently were referred
these patients for management with orbital exenteration.

Figure 10.187. Elderly man with persistent conjunctival chemosis and proptosis following evisceration
elsewhere for presumed endophthalmitis. Histopathology revealed melanoma cells.

Figure 10.188. Axial computed tomography of the patient shown in Figure 10.187. Note the disorganized
intraocular contents and large mass in the right orbit that proved on exenteration to be orbital melanoma.

574
Figure 10.189. Middle-aged man with persistent conjunctival chemosis and proptosis following evisceration
for presumed endophthalmitis. Histopathology revealed melanoma cells.

Figure 10.190. Appearance of the anterior segment after evisceration. Computed tomography demonstrated
orbital mass.

Figure 10.191. Gross view of the sectioned exenteration specimen of the patient shown in Figure 10.190. Note
the amelanotic mass adjacent to the sclera. Most of the intraocular contents (to the right), which included
necrotic uveal melanoma, were removed at the time of evisceration.

575
Figure 10.192. Appearance of the patient after eyelid-sparing orbital exenteration. He was subsequently fitted
with an orbital prosthesis.

576
 CHAPTER 11

NONNEOPLASTIC CONDITIONS THAT CAN

SIMULATE POSTERIOR UVEAL MELANOMA AND
OTHER INTRAOCULAR NEOPLASMS

NONNEOPLASTIC CONDITIONS THAT CAN SIMULATE POSTERIOR

UVEAL MELANOMA AND OTHER INTRAOCULAR NEOPLASMS

Several conditions can clinically simulate posterior uveal melanoma (1–40). A list of
the various pseudomelanomas and their frequency is provided in a recent survey
from the Oncology Service at Wills Eye Hospital (1,5) (Table 11.1). Other tumors
that can resemble melanoma are discussed in their respective chapters in this book.
Almost every fundus tumor described in this book can, at one time or another, have
features similar to those of choroidal or ciliary body melanoma. This section covers
selected nonneoplastic-simulating conditions that are not discussed elsewhere in this
book. The following is a brief outline of some of these pseudomelanomas that are
seen in a practice of ocular oncology and are discussed and illustrated.
A. Vascular and hemorrhagic lesions
1. Age-related macular degeneration (ARMD; CEHCR)
2. Peripheral exudative hemorrhagic chorioretinopathy (PEHCR)
3. Hemorrhagic retinal macroaneurysm
4. Miscellaneous subretinal and intraretinal hemorrhage
5. Idiopathic choroidal neovascular membrane
6. Localized choroidal hemorrhage
7. Vortex vein varix
B. Inflammatory and infectious conditions
1. Nodular posterior scleritis
2. U veal effusion
3. Granulomas (sarcoidosis, tuberculosis, solitary idiopathic choroiditis)
4. Solitary infectious lesions
C. Miscellaneous conditions
1. Bilateral diffuse uveal melanocytic proliferation (BDU MP)
2. Sclerochoroidal calcification

577
 3. Rhegmatogenous retinal detachment
4. Scleral buckle after retinal detachment surgery
5. Bullous degenerative retinoschisis
6. Ciliochoroidal detachment
7. Subluxed lens
8. Globe compression by orbital tumor
9. Staphyloma
10. Postsurgical uveal prolapse Postsurgical uveal prolapse Postsurgical uveal
prolapse

Table 11.1 Choroidal pseudomelanomas in 1,739 cases. Top 30 diagnoses

578
Selected References
Large Series
1. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features,
classification, and top ten pseudomelanomas. Curr Opin 2014;25:177–185.
2. Ferry AP. Lesions mistaken for malignant melanoma of the posterior uvea. Arch
Ophthalmol 1964;72:463–469.
3. Shields JA, Zimmerman LE. Lesions simulating malignant melanomas of the

579
 posterior uvea. Arch Ophthalmol 1973;89:466–471.
4. Shields JA, Augsburger JJ, Brown GC, et al. The differential diagnosis of
posterior uveal melanoma. Ophthalmology 1980;87:543–548.
5. Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal
tract. The 2006 Taylor Smith Lecture. Retina 2005;25:767–771.

Choroidal Simulators
6. Gass JD, Gieser RG, Wilkinson CP, et al. Bilateral diffuse uveal melanocytic
proliferation in patients with occult carcinoma. Arch Ophthalmol 1990;108:527–
533.
7. Rohrbach JM, Roggendorf W, Thanos S, et al. Simultaneous bilateral diffuse
melanocytic uveal hyperplasia. Am J Ophthalmol 1990;110:49–56.
8. Ritland JS, Eide N, Tausjø J. Bilateral diffuse uveal melanocytic proliferation
and uterine cancer. A case report. Acta Ophthalmol Scand 2000;78:366–368.
9. Duong HV, McLean IW, Beahm DE. Bilateral diffuse melanocytic proliferation
associated with ovarian carcinoma and metastatic malignant amelanotic
melanoma. Am J Ophthalmol 2006;142:693–695.
10. Sen J, Clewes AR, Quah SA, et al. Presymptomatic diagnosis of bronchogenic
carcinoma associated with bilateral diffuse uveal melanocytic proliferation. Clin
Experiment Ophthalmol 2006;34:156–158.
11. Pulido JS, Flotte TJ, Raja H, et al. Dermal and conjunctival melanocytic
proliferations in diffuse uveal melanocytic proliferation. Eye (Lond)
2013;27:1058–1062.
12. Rahimy E, Coffee RE, McCannel TA. Bilateral diffuse uveal melanocytic
proliferation as a precursor to multiple systemic malignancies. Semin
Ophthalmol 2013; [Epub ahead of print].
13. Hong PH, Jampol LM, Dodwell DG, et al. U nifocal helioid choroiditis. Arch
Ophthalmol 1997;115:1007–1013.
14. Gunduz K, Shields CL, Shields JA, et al. Presumed choroidal granuloma with
vitreous hemorrhage resembling choroidal melanoma. Ophthalmic Surg Lasers
1998;29:422–425.
15. Shields JA, Shields CL, Demirci H, et al. Solitary idiopathic choroiditis. Richard
B. Weaver Lecture. Arch Ophthalmol 2002;120:311–319.
16. Fung AT, Kaliki S, Shields CL, et al. Solitary idiopathic choroiditis. Enhanced
depth imaging optical coherence tomography in 10 cases. Ophthalmology
2013;120:852–858.
17. Schepens CL, Brockhurst RJ. U veal effusion. 1. Clinical picture. Arch
Ophthalmol 1963;70:189–201.
18. Gass JD, Jallow S. Idiopathic serous detachment of the choroid, ciliary body,
and retina (uveal effusion syndrome). Ophthalmology 1982;89:1018–1032.
19. Regillo C, Shields CL, Shields JA, et al. Ocular tuberculosis. JAMA
1991;266:1490.
20. Demirci H, Shields CL, Shields JA, et al. Ocular tuberculosis masquerading as
ocular tumors. Surv Ophthalmol 2004;49:78–89.
21. Phillips W, Shields CL, Shields JA, et al. Nocardia choroidal abscess. Br J
Ophthalmol 1992;76:694–696.
22. You JY, Finger PT, Iacob C, et al. Intraocular schwannoma. Surv Ophthalmol
2013;58(1):77–85.

580
23. Frota AC, Bakalian S, Grégoire FJ, et al. Pseudomelanoma in a patient with
prostate adenocarcinoma. Can J Ophthalmol. 2007;42:305–306.
24. Fung AT, Fulco EM, Shields CL, et al. Choroidal hemorrhage simulating
choroidal melanoma. Retina 2013;33:1726–1728.
25. Morgan CM, Gragoudas ES. Limited choroidal hemorrhage mistaken for a
choroidal melanoma. Ophthalmology 1987;94:41–46.
26. Gunduz K, Shields CL, Shields JA. Varix of vortex vein simulating choroidal
melanoma. Report of four cases. Retina 1998;18:343–347.

Retinal Simulators
27. Silva VB, Brockhurst RJ. Hemorrhagic detachment of the peripheral retinal
pigment epithelium. Arch Ophthalmol 1976;94:1295–1313.
28. Hiss PW, Shields JA, Augsburger JJ. Solitary retinovitreal abscess as the initial
manifestation of cryptococcosis. Ophthalmology 1988;96:162–165.
29. Shields CL, Salazar P, Mashayekhi A, et al. Peripheral exudative hemorrhagic
chorioretinopathy (PEHCR) simulating choroidal melanoma in 173 eyes.
Ophthalmology 2009;116:529–535.
30. Grunwald L, Kligman B, Shields CL. Acute exudative polymorphous
paraneoplastic vitelliform maculopathy in a patient with carcinoma, not
melanoma. Arch Ophthalmol 2011;129:1104–1105.
31. Al-Daamash S, Shields CL, Bianciotto C, et al. Acute exudative paraneoplastic
polymorphous vitelliform maculopathy in five cases. Ophthalmic Surg Lasers
Imaging 2012;43:366–373.

Scleral Simulators
32. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;60:163–
191.
33. Benson WE, Shields JA, Tasman WS, et al. Posterior scleritis. Arch Ophthalmol
1979;97:1482–1486.
34. Demirci H, Shields CL, Honavar SG, et al. Long-term follow-up of giant nodular
posterior scleritis simulating choroidal melanoma. Arch Ophthalmol
2000;118:1290–1292.
35. Arevalo JF, Shields CL, Shields JA. Giant nodular posterior scleritis simulating
choroidal melanoma and birdshot retinochoroidopathy. Ophthalmic Surg Lasers
Imaging 2003;34:403–405.
36. Shields JA, Shields CL. Sclerochoroidal calcification. Review. The 2001 Harold
Gifford lecture. Retina 2002;22:251–261.
37. Honavar SG, Shields CL, Demirci H, et al. Sclerochoroidal calcification: Clinical
manifestations and systemic associations. Arch Ophthalmol 2001;119:833–840.
38. Fung AT, Arias JD, Shields CL, et al. Sclerochoroidal calcification is primarily a
scleral condition based on enhanced depth imaging optical coherence
tomography. JAMA Ophthalmol 2013;131:960–963.
39. Shields CL, Hasanreisoglu M, Saktanasate J, et al. Sclerochoroidal calcification:
Clinical features, outcomes and relationship with hypercalcemia and
parathyroid adenoma in 179 eyes. Retina 2015;35(3):547–554.
Other Simulators
40. Shields CL, Pellegrini M, Kligman BE, et al. Ciliary body and choroidal
pseudomelanoma from ultrasonographic imaging of hypermature cataract in 20

581
cases. Ophthalmology 2013;120:2546–2551.

582
• AGE-RELATED MACULAR DEGENERATION SIMULATING
CHOROIDAL MELANOMA

ARMD is a common cause of visual loss in older patients. It often produces hemorrhage that
can clinically simulate a pigmented choroidal melanoma. The patients shown were all referred
for suspicion of choroidal melanoma. However, a comparable-sized melanoma would be
unlikely to cause extensive hemorrhage. ARMD often shows exudation and fibrous tissue
representing resolving blood and proliferation of the retinal pigment epithelium (RPE), findings
that would also be unlikely for melanoma.

1. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features, classification,
and top ten pseudomelanomas. Curr Opin 2014;25:177–185.
2. Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal tract. The
2006 Taylor Smith Lecture. Retina 2005;25:767–771.

Figure 11.1. Resolving hemorrhagic disciform lesion simulating melanoma as part of age-related macular
degeneration in an 80-year-old man. Note the yellow fibrous tissue resulting from prior hemorrhage.

Figure 11.2. Age-related macular degeneration with exudation and hemorrhage in the foveal region and along
the inferior arcade.

583
Figure 11.3. Resolving hemorrhagic age-related macular degeneration with secondary hyperplasia of the
retinal pigment epithelium, centered in the macular region. Note the yellow intraretinal exudation at the
superior margin of the lesion.

Figure 11.4. Fluorescein angiogram of the lesion in Figure 11.3 in the late recirculation phase, showing
hypofluorescence of the lesion. The focus of hyperfluorescence in the papillomacular bundle region
represents choroidal neovascularization that led to the hemorrhage. Indocyanine green angiography would
demonstrate the choroidal neovascularization more clearly.

Figure 11.5. Age-related macular degeneration in which the blood had resolved, leaving the yellow-gray fibrous
tissue that is typical of prior bleeding. This should not be mistaken for amelanotic melanoma.

584
Figure 11.6. Wide-angle image of age-related macular degeneration showing fresh blood, resolved blood, and
pigment epithelial detachment and hyperplasia, findings that would be unexpected with melanoma.

585
• PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY
SIMULATING CHOROIDAL MELANOMA

PEHCR is a term we use to define a peripheral condition that is similar clinically to ARMD in the
central retina. It is also called peripheral disciform degeneration, eccentric disciform
degeneration, or peripheral hemorrhagic detachment of the RPE. Like its macular counterpart, it
is common in older patients and can simulate a choroidal melanoma. In our most recent series
of pseudomelanomas, PEHCR was second in frequency to choroidal nevus among simulating
lesions. Wide-angle photographs of this lesion are shown.

1. Shields CL, Salazar P, Mashayekhi A, et al. Peripheral exudative hemorrhagic

chorioretinopathy (PEHCR) simulating choroidal melanoma in 173 eyes. Ophthalmology
2009;116:529–535.
2. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features, classification,
and top ten pseudomelanomas. Curr Opin 2014;25:177–185.

Figure 11.7. Peripheral exudative hemorrhagic chorioretinopathy characterized by a hemorrhagic detachment

of the retinal pigment epithelium near the temporal equator in the left eye.

Figure 11.8. Peripheral exudative hemorrhagic chorioretinopathy near the temporal equator, showing
superficial and deep retinal hemorrhage and yellow circinate exudation.

586
Figure 11.9. Peripheral exudative hemorrhagic chorioretinopathy located inferotemporally in the left eye,
showing a localized area of large subretinal hemorrhage that has undergone resolution.

Figure 11.10. Peripheral exudative hemorrhagic chorioretinopathy located inferiorly and temporally in the left
eye with more extensive hemorrhage, pigment proliferation, and widespread exudation and an elevated
detachment of the retinal pigment epithelium temporal to the macular region.

Figure 11.11. Peripheral exudative hemorrhagic chorioretinopathy in the inferotemporal quadrant of the right
eye. In this case, the blood has entirely resolved, leaving an irregular white fibrous tissue scar. This
appearance is unlike that of a nonpigmented choroidal melanoma.

587
Figure 11.12. Widespread temporal fibrous tissue in the temporal portion of the left fundus, with secondary
proliferation of the retinal pigment epithelium.

588
• PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY
SIMULATING CHOROIDAL MELANOMA

Additional examples are shown of this important pseudomelanoma.

Figure 11.13. Large combined serous and hemorrhagic detachment of the retinal pigment epithelium in the
temporal quadrant of the left fundus. Note that the serosanguineous fluid is more superior and the fresh blood
is more inferior within the pigment epithelial detachment.

Figure 11.14. Closer view of lesion shown in Figure 11.13 with red-free photography. Note the similarity to a
lightly pigmented melanoma.

589
Figure 11.15. Fluorescein angiogram in the recirculation phase, showing hypofluorescence of the lesion. In
contrast, a lightly pigmented melanoma would be hyperfluorescent.

Figure 11.16. Massive peripheral exudative hemorrhagic chorioretinopathy located near the temporal equator
of the right eye.

Figure 11.17. Closer view of the lesion shown in Figure 11.16. Note the remarkable similarity to a dome-
shaped ciliochoroidal melanoma.

Figure 11.18. Fluorescein angiogram in the late venous phase of the lesion shown in Figure 11.17,
demonstrating hypofluorescence of the lesion. The hyperfluorescent focus probably represents a partial view
of the neovascular membrane that led to the hemorrhage. In contrast, a melanoma would show more
extensive hyperfluorescence.

590
• RETINAL ARTERIAL MACROANEURYSM WITH HEMORRHAGE
SIMULATING CHOROIDAL MELANOMA

Retinal arterial macroaneurysm is a well-known vascular abnormality that occurs more often in
patients with systemic hypertension. It can be present as a solitary lesion without complications
or it can be complicated by exudation or hemorrhage. When it bleeds, it produces a dark retinal
lesion that can be confused with choroidal melanoma.

Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal tract. The 2006
Taylor Smith Lecture. Retina 2005;25:767–771.

Figure 11.19. Subretinal and preretinal hemorrhage probably secondary to an intraretinal arterial
macroaneurysm in a 60-year-old woman. The patient was referred with the diagnosis of mushroom-shaped
melanoma.

Figure 11.20. Lesion shown in Figure 11.20 after 3 months, showing resolution of the hemorrhage. The
macroaneurysm had also resolved.

591
Figure 11.21. Hemorrhage retinal arterial macroaneurysm on the inferotemporal retinal artery that has bled
and produced a dark mass. The light lesion seen within the blood is the macroaneurysm and should not be
confused with a break through Bruch’s membrane of a melanoma.

Figure 11.22. Atypical retinal macroaneurysm that has caused a hemorrhage that has extended superiorly into
the foveal region. Apparently the hemorrhage is resolving, with serosanguineous material superiorly and more
dense blood inferiorly. Note the prominent macroaneurysm and the inferotemporal yellow exudation.

Figure 11.23. Retinal arterial macroaneurysm in the papillomacular bundle, producing hemorrhage into the
subretinal space, sensory retina, and vitreous.

592
Figure 11.24. Homogeneous retinal hemorrhage along the inferotemporal vascular arcade. This is presumed
to be arising from a macroaneurysm that is obscured by the extensive hemorrhage.

593
• MISCELLANEOUS SUBRETINAL AND INTRARETINAL
HEMORRHAGES SIMULATING CHOROIDAL MELANOMA

In some instances, subretinal or intraretinal hemorrhage can develop spontaneously without an

apparent cause and suggest a pigmented choroidal melanoma. Possible etiologies include occult
trauma, occult choroidal neovascularization, straining, coughing, systemic hypertension, and
use of anticoagulants, such as aspirin or dicoumarol, and Valsalva maneuver. Such hemorrhage
generally resolves with time, leaving typical fibrous scar tissue.

1. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features, classification,
and top ten pseudomelanomas. Curr Opin 2014;25:177–185.
2. Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal tract. The
2006 Taylor Smith Lecture. Retina 2005;25:767–771.

Figure 11.25. Preretinal and subretinal hemorrhage in the macular area.

Figure 11.26. Fluorescein angiogram in the recirculation phase, showing hypofluorescence of the lesion in
Figure 11.25.

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Figure 11.27. Dense retinal hemorrhage in the macular region.

Figure 11.28. Hemorrhage and exudation in the macular region of uncertain cause. Neither choroidal
neovascularization nor macroaneurysm could be demonstrated.

Figure 11.29. Resolving hemorrhage nasal to the optic disc. Although the etiology was uncertain, this could
have been related to deep buried drusen of the optic disc.

595
Figure 11.30. Large idiopathic retinal hemorrhage located superotemporal to the macular region in the right
eye.

596
• CHOROIDAL NEOVASCULAR MEMBRANE IN YOUNG PATIENTS
SIMULATING CHOROIDAL MELANOMA AND NEVUS

In some instances, an idiopathic choroidal neovascular membrane in a young person with no

reason for ARMD can develop a gray color, prompting referral to rule out a small choroidal
melanoma or nevus. Examples are shown that were referred to rule out early melanoma.

Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal tract. The 2006
Taylor Smith Lecture. Retina 2005;25:767–771.

Figure 11.31. Gray lesion in the foveal region. The patient was referred because of suspected small choroidal
melanoma.

Figure 11.32. Venous-phase fluorescein angiogram of the lesion shown in Figure 11.31, showing reticular
hyperfluorescence within the lesion.

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Figure 11.33. Late fluorescein angiogram of the same lesion, showing intense hyperfluorescence of the
lesion, characteristic of choroidal neovascularization.

Figure 11.34. Another patient with a gray fundus lesion located immediately superotemporal to the foveola in
the left eye.

Figure 11.35. Late fluorescein angiogram of the lesion in Figure 11.34, depicting hyperfluorescence
compatible with choroidal neovascular membrane.

598
Figure 11.36. Optical coherence tomography of the lesion shown in Figure 11.35. Note the optically dense
juxtafoveal deep retinal material with early cystic retinal changes, compatible with choroidal neovascularization
and early cystoid retinal edema.

599
• CHOROIDAL HEMORRHAGE SIMULATING CHOROIDAL MELANOMA
A circumscribed choroidal hemorrhage can develop occasionally after cataract surgery and
possibly after other surgical procedures in which the intraocular pressure is lowered
temporarily. Such a hemorrhage can be remarkably similar ophthalmoscopically to a choroidal
melanoma. Unlike melanoma, however, the lesion is relatively hypofluorescent with
angiography and resolves over a few weeks.

1. Fung AT, Fulco EM, Shields CL, et al. Choroidal hemorrhage simulating choroidal melanoma.
Retina 2013;33:1726–1728.
2. Morgan CM, Gragoudas ES. Limited choroidal hemorrhage mistaken for a choroidal
melanoma. Ophthalmology 1987;94:41–46.

Figure 11.37. Wide-angle fundus photograph of a limited choroidal hemorrhage superior to the optic disc in the
right eye. Note the remarkable similarity to choroidal melanoma.

Figure 11.38. Closer view of the posterior margin of the lesion shown in Figure 11.37. The patient has
unrelated atrophic age-related macular degeneration.

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Figure 11.39. Fluorescein angiogram of the same lesion in the recirculation phase, showing hyperfluorescent
concentric choroidal folds that are often seen with this condition.

Figure 11.40. B-scan ultrasonogram of the same lesion, showing a dome-shaped choroidal lesion with
medium internal reflectivity, a pattern remarkably similar to that of melanoma.

Figure 11.41. Wide-angle photograph of the same lesion shown in Figure 11.37 after 2 months. Note that the
lesion has shown marked regression when compared to Figure 11.37.

601
Figure 11.42. Wide-angle fundus photograph of another patient with a limited choroidal hemorrhage after
cataract surgery. It showed resolution similar to that of the prior case. Follow-up ultrasonography on both
patients showed complete flattening of the lesion, compatible with the resolution of blood.

602
• VORTEX VEIN VARIX SIMULATING CHOROIDAL MELANOMA
Vortex vein varix is an intriguing condition in which there is an apparent dilation of a vortex
vein in certain fields of gaze. When the patient looks in another direction, the lesion seems to
disappear as the aneurysm deflates. The swelling is believed to be due to partial obstruction of
the vein by the superior or inferior oblique muscle. The nodular swelling has been known to
simulate choroidal melanoma (16). Small lesions of this type are very commonly seen on
routine eye examination, but they are subtle and do not usually prompt referral because of
suspected melanoma.

Gunduz K, Shields CL, Shields JA. Varix of vortex vein simulating choroidal melanoma. Report
of four cases. Retina 1998;18:343–347.

Figure 11.43. Normal-appearing fundus in primary gaze. Note the venous bifurcation.

Figure 11.44. On downgaze, the vortex ampulla is filled with blood, directly under the bifurcation.

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Figure 11.45. Fluorescein angiography (left) shows no disturbance, but indocyanine green angiography (right)
demonstrates the filled vortex ampulla.

Figure 11.46. B-scan of the elevated mass that was referred for possible melanoma, but proved to be a varix.

Figure 11.47. Another vortex vein varix seen on up gaze, showing the dark, elevated lesion with irregular
borders corresponding to pattern or vortex vein ampulla.

604
Figure 11.48. Disappearance of the lesion shown in Figure 11.47 when the patient looks straight. The vortex
vein is still visible, but the elevated varix has deflated.

605
• NODULAR POSTERIOR SCLERITIS SIMULATING CHOROIDAL
MELANOMA

Nodular posterior scleritis can manifest as a mass that appears to be within the choroid. Hence,
it can closely simulate an intraocular tumor, particularly an amelanotic choroidal melanoma.
Unlike melanoma, it is generally nonpigmented and is often associated with choroidal folds. The
example shown is an extremely large lesion that did not resolve with corticosteroids. The lesion
has been followed for almost 20 years and has enlarged very slowly. In many cases, however,
nodular posterior scleritis is small and shows some response to corticosteroids.

1. Arevalo JF, Shields CL, Shields JA. Giant nodular posterior scleritis simulating choroidal
melanoma and birdshot retinochoroidopathy. Ophthalmic Surg Lasers Imaging 2003;34:403–
405.
2. Demirci H, Shields CL, Honavar SG, et al. Long-term follow-up of giant nodular posterior
scleritis simulating choroidal melanoma. Arch Ophthalmol 2000;118:1290–1292.

Figure 11.49. Epibulbar injection inferonasally in a 30-year-old woman.

Figure 11.50. Standard fundus photograph showing an inferonasal amelanotic mass.

606
Figure 11.51. Wide-angle photograph showing the full extent of the inferonasal lesion.

Figure 11.52. Fluorescein angiography in the venous filling phase, showing hypofluorescence of the mass.
There was mild late hyperfluorescence.

Figure 11.53. B-scan ultrasonogram, showing the mass with high internal reflectivity secondary to scleral
thickening.

607
Figure 11.54. Histopathology of a scleral biopsy in the same patient, showing chronic inflammatory cells within
the scleral collagen. (Hematoxylin–eosin ×100.)

608
• UVEAL EFFUSION SIMULATING CILIOCHOROIDAL MELANOMA
Uveal effusion syndrome is a peculiar entity characterized by a serous elevation of the ciliary
body and peripheral choroid, often associated with low-grade inflammation. It is sometimes
confused clinically with a ring melanoma of the ciliary body and peripheral choroid. Unlike
most melanomas, it has several lobes and it transmits light on transillumination. The
pathogenesis is uncertain in most cases. Some patients have hyperopia or nanophthalmos.

Figure 11.55. Peripheral choroidal detachment as part of the idiopathic uveal effusion syndrome in a 69-year-
old man. The patient also had a nonrhegmatogenous retinal detachment extending posteriorly.

Figure 11.56. B-scan ultrasonography of idiopathic uveal effusion syndrome, showing typical choroidal
detachment.

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Figure 11.57. Wide-angle fundus photograph of uveal effusion syndrome, showing bilobed ciliochoroidal
detachment nasally and a serous retinal detachment inferiorly. The scalloped area is the ora serrata seen
without scleral depression.

Figure 11.58. Superior view of the fundus in the patient shown in Figure 11.57. Note that there is also a
superior component of the ciliochoroidal effusion and extension of the serous retinal detachment superior to
the vascular arcade. The ora serrata can be seen superiorly.

Figure 11.59. Wide-angle fundus photograph of another patient with uveal effusion syndrome in the left eye.
Note the multilobed elevation of the choroidal and ciliary body nasally and superiorly with a dark appearance
simulating a ring melanoma.

610
Figure 11.60. B-scan ultrasonogram of the patient in Figure 11.59. Note the elevation of the choroid by diffuse,
lowly reflective material.

611
• CHOROIDAL GRANULOMAS (SARCOIDOSIS AND TUBERCULOSIS)
SIMULATING CHOROIDAL MELANOMA

Granulomatous inflammation of the choroid can manifest as a localized mass that can
sometimes closely resemble a nonpigmented choroidal melanoma. Many cases prove to be
“idiopathic,” but sometimes a specific etiology like sarcoidosis or tuberculosis can be proven.

Shields JA, Shields CL, Demirci H, et al. Solitary idiopathic choroiditis. Richard B. Weaver
Lecture. Arch Ophthalmol 2002;120:311–319.

Figure 11.61. Large presumed granuloma in a 30-year-old man believed to represent a sarcoid granuloma.

Figure 11.62. Posterior choroidal granuloma secondary to sarcoidosis.

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Figure 11.63. Yellow chorioretinal mass in a 25-year-old African man. Within 2 weeks after this photograph was
taken, the eye became blind and painful and was enucleated.

Figure 11.64. Pathology of the lesion shown in Figure 11.63 after enucleation. A gross photograph of the
section globe shows a dome-shaped white mass. Inset shows Langhan’s giant cell. Acid-fast stains
confirmed the diagnosis of tuberculosis.

Figure 11.65. Amelanotic choroidal mass involving the temporal fundus of the right eye. Although a neoplasm
was considered, systemic evaluation disclosed tuberculosis. (Courtesy of A. Verbeek, MD.)

Figure 11.66. Appearance of the lesion shown in Figure 11.65 after tuberculosis therapy, showing excellent
resolution of the lesion. (Courtesy of A. Verbeek, MD.)

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• SOLITARY IDIOPATHIC CHOROIDITIS SIMULATING AMELANOTIC
CHOROIDAL MELANOMA

We chose the term solitary idiopathic choroiditis to describe a yellow-white choroidal lesion
that is presumed to be a granuloma but for which standard systemic evaluation and laboratory
studies fail to disclose a specific etiology. This has also been called helioid choroiditis because
of its similarity to appearance of the sun. We have reported 60 cases that prompted referral to
exclude amelanotic choroidal melanoma, metastasis, or other neoplasm. In the past, the lesion
was presumably an active granuloma that became quiescent.

1. Hong PH, Jampol LM, Dodwell DG, et al. Unifocal helioid choroiditis. Arch Ophthalmol
1997;115:1007–1013.
2. Shields JA, Shields CL, Demirci H, et al. Solitary idiopathic choroiditis. Richard B. Weaver
Lecture. Arch Ophthalmol 2002;120:311–319.

Figure 11.67. Solitary idiopathic choroiditis superior to the optic disc.

Figure 11.68. Solitary idiopathic choroiditis inferior to the optic disc.

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Figure 11.69. Solitary idiopathic choroiditis located superiorly in the right fundus. Note the reddish halo that
surrounds the lesion, a common finding with this condition.

Figure 11.70. Late-phase fluorescein angiogram of the lesion shown in Figure 11.69, revealing late
hyperfluorescence of the lesion.

Figure 11.71. Solitary idiopathic choroiditis superonasal to the optic disc. The light area below the main lesion
probably represents retinal pigment epithelium atrophy from subretinal fluid that was present during the active
phase of the inflammation.

615
Figure 11.72. Bright-yellow solitary idiopathic choroiditis superior to the optic disc in the left eye.

616
• SOLITARY INFECTIOUS FUNDUS LESIONS SIMULATING
CHOROIDAL MELANOMA

On occasion, a bacterial or mycotic organism can cause a localized infection in the fundus that
simulates a neoplasm. The diagnosis can sometimes be established by fine-needle aspiration
biopsy.

Figure 11.73. Yellow peripheral fundus mass in an elderly man who was immunosuppressed from chronic
use of corticosteroids for arthritis.

Figure 11.74. B-scan ultrasonogram of the lesion shown in Figure 11.73. The lesion is acoustically hollow,
similar to some choroidal melanomas.

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Figure 11.75. Cytopathology following fine-needle aspiration biopsy of the lesion seen in Figure 11.73,
showing budding yeast compatible with Cryptococcus neoformans.

Figure 11.76. Yellow hemorrhagic mass in the right macular area of an adult man.

Figure 11.77. Early fluorescein angiogram of the lesion shown in Figure 11.76.

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Figure 11.78. Late fluorescein angiogram of the same lesion. Fine-needle biopsy confirmed the diagnosis of
nocardiosis.

619
• BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION:
CLINICAL VARIATIONS

BDUMP is a peculiar paraneoplastic syndrome that occurs in patients with systemic malignancy,
particularly ovarian cancer, small cell carcinoma of the lung, and several other neoplasms. The
mean age at diagnosis is 63 years. Unlike true choroidal melanoma, it is usually bilateral and
appears as a diffuse, irregular thickening of the uveal tract with multiple pigmented lesions of
variable size throughout the choroid and sometimes the ciliary body and iris. There is disruption
of the RPE and a typical mottling seen clinically and with fluorescein angiography and
autofluorescence, sometimes called a “giraffe-like” fundus. The affected eye usually has signs of
low-grade inflammation and rapid onset and progression of cataract. The pathogenesis is
unknown, and treatment with corticosteroids and irradiation does not appear to be helpful. It
has recently been shown that plasmapheresis can be of benefit for affected patients. Depicted is
a case of BDUMP in a 66-year-old woman with ovarian cancer.

Rahimy E, Coffee RE, McCannel TA. Bilateral diffuse uveal melanocytic proliferation as a
precursor to multiple systemic malignancies. Semin Ophthalmol 2013; [Epub ahead of print].

Figure 11.79. Fundus drawing of the right eye, showing numerous pigmented nodules and an inferior retinal
detachment.

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Figure 11.80. Fundus drawing of the left eye, showing numerous pigmented nodules and no retinal
detachment.

Figure 11.81. Macular area of the right eye, showing retinal detachment and minimal retinal pigment epithelial
alterations.

Figure 11.82. Fundus photograph of the area superior to the optic disc in the left eye, showing typical diffuse
uveal pigmentation.

Figure 11.83. Cataract and pigmented iris tumor in the right eye of the same patient.

621
Figure 11.84. Late fluorescein angiogram of the right eye, showing typical mottled hyperfluorescence that
characterizes bilateral diffuse uveal melanocytic proliferation.

622
• BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION
SIMULATING UVEAL MELANOMA

In addition to the ocular pigmentation, affected patients can develop cutaneous and mucous
membrane pigmentation in nonocular areas.

Figure 11.85. Bilateral diffuse uveal melanocytic proliferation with prominent lipofuscin pigment (orange
pigment) in macular area of the right eye.

Figure 11.86. Similar findings in the left eye.

623
Figure 11.87. Fundus autofluorescence of bilateral diffuse uveal melanocytic proliferation, highlighting the
hyperautofluorescence of lipofuscin pigment in the right eye.

Figure 11.88. Similar autofluorescence in the left eye.

Figure 11.89. Acquired pigmentation of the lip in a patient with bilateral diffuse uveal melanocytic proliferation.
(Courtesy of J. Donald M. Gass, MD.)

Figure 11.90. Acquired pigmentation of the penis in the patient shown in Figure 11.89. (Courtesy of J. Donald
M. Gass, MD.)

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• MISCELLANEOUS CONDITIONS SIMULATING POSTERIOR UVEAL
MELANOMA

The conditions depicted here were referred because the lesion was suspected to be a choroidal
melanoma. These include idiopathic sclerochoroidal calcification (36–39), rhegmatogenous
retinal detachment, scleral buckle after retinal detachment surgery, bullous degenerative
retinoschisis, and ciliochoroidal detachment after intraocular surgery.

1. Shields CL, Hasanreisoglu M, Saktanasate J, et al. Sclerochoroidal calcification: Clinical

features, outcomes and relationship with hypercalcemia and parathyroid adenoma in 179
eyes. Retina 2015;35(3):547–554.
2. Shields JA, Shields CL. Sclerochoroidal calcification. Review. The 2001 Harold Gifford
Lecture. Retina 2002;22:251–261.

Figure 11.91. Sclerochoroidal calcification with three yellow-white lesions along the superotemporal arcade in
the right eye.

Figure 11.92. Larger solitary focus of sclerochoroidal calcification along the superotemporal arcade of the right
eye of another patient.

625
Figure 11.93. Rhegmatogenous retinal detachment referred because of suspected choroidal melanoma
because retinal breaks were difficult to identify. The ripples in the lesion and the presence of a retinal hole
should differentiate this condition from melanoma.

Figure 11.94. Highly elevated scleral buckle following retinal detachment repair that was mistaken for
melanoma.

Figure 11.95. Bullous retinoschisis simulating choroidal melanoma. In contrast to melanoma, the flat
choroidal vascular pattern can be seen through the lesion. Pigment clumping around the outer layer holes can
occasionally simulate melanoma.

626
Figure 11.96. Ciliochoroidal detachment seen shortly after cataract surgery, simulating a ciliochoroidal
melanoma. Note that the ora serrata is visible through the dilated pupil, further supporting the diagnosis. In
contrast to melanoma, ciliochoroidal detachment readily transmits light with transillumination techniques. The
cataract surgery was done many years ago by intracapsular extraction and sector iridectomy.

627
• MISCELLANEOUS OTHER CONDITIONS THAT SIMULATE
POSTERIOR UVEAL MELANOMA

Other nonneoplastic conditions that can simulate melanoma include subluxed cataractous lens,
post–cataract extraction ciliary body cyst, compression of the eye by an orbital tumor, scleral
staphyloma, and postsurgical uveal prolapse.

Shields CL, Pellegrini M, Kligman BE, et al. Ciliary body and choroidal pseudomelanoma from
ultrasonographic imaging of hypermature cataract in 20 cases. Ophthalmology
2013;120(12):2546–2551.

Figure 11.97. Subluxed mature cataract resembling ciliary body melanoma.

Figure 11.98. Post–cataract extraction ciliary body cyst simulating melanoma.

628
Figure 11.99. Compression of the globe by an orbital tumor, causing the appearance of an intraocular tumor.
Note the apparent elevation of the inferior fundus from the fovea to the inferior equator.

Figure 11.100. Axial computed tomography of patient shown in Figure 11.99, showing the orbital cavernous
hemangioma that was compressing the globe and causing the indentation.

Figure 11.101. Scleral staphyloma simulating a ciliary body melanoma with extraocular extension.

629
Figure 11.102. Uveal prolapse after cataract surgery, simulating an extraocular extension of uveal melanoma.

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 CHAPTER 12

METASTATIC TUMORS TO THE UVEA, RETINA,

AND OPTIC DISC

METASTATIC TUMORS TO THE INTRAOCULAR STRUCTURES

General Considerations
Metastatic cancer probably represents the most common form of intraocular
malignancy. There are many large series, reviews, and case reports on metastatic
neoplasms to the intraocular structures, and only selected reports are cited here
(1–53). Even though uveal metastasis is the most common intraocular malignancy,
in a practice of ocular oncology it is not encountered as frequently as uveal
melanoma, possibly because many affected patients have advanced systemic cancer
and do not come to the attention of an ophthalmologist. Metastatic cancer reaches
the intraocular structures through hematogenous routes and most commonly
develops in the uveal tract, with >90% involving the posterior aspect of the
choroid and <10% arising in the iris and/or ciliary body. Metastasis to the retina,
optic disc, and vitreous are very uncommon (7).
Most intraocular metastases are carcinomas, with sarcomas and melanomas being
less common. The majority of uveal metastases originate from breast cancer in
women and lung cancer in men. Less often, the primary malignancy arises from
carcinoma of the alimentary tract, kidney, thyroid gland, pancreas, prostate, and
other organs. Cutaneous melanoma and bronchial carcinoid tumors occasionally
metastasize to the uveal tract and have distinctive features. Of patients who present
to the ophthalmologist with uveal metastasis, about 25% to 30% have no known
history of systemic cancer (1). After subsequent systemic evaluation, about 17% have
no detectable primary cancer, the primary being occult (1). Hence, the clinician
should be familiar with the clinical manifestations of intraocular metastatic disease.

Clinical Features
The clinical features of an intraocular metastasis vary with the location of the tumor
(1–53). Iris metastasis can show diverse features (4,5). It can appear as single or

631
multiple yellow, white, or pink nodules in the iris stroma. It can appear as one or
more circumscribed tumors, or it can be friable and seed cells into the aqueous,
producing a clinical picture of intraocular inflammation and a tumor-induced
pseudohypopyon. A ciliary body metastasis is often more difficult to detect
clinically. It can appear as a solitary mass, or it can produce inflammatory signs,
simulating iridocyclitis.
Choroidal metastasis usually appears as one or more yellow lesions in one or
both eyes. It has a tendency to affect the posterior choroid, frequently in the macular
area. In contrast to iris and ciliary body metastasis, choroidal metastasis tends not to
produce many inflammatory signs, but it usually causes a quiet secondary serous
retinal detachment. Although choroidal metastasis usually has a yellow color,
metastasis from melanoma often has a gray or brown color and metastasis from
carcinoid tumor, thyroid cancer, and renal cell carcinoma often has an orange color.
Retinal metastasis, which is extremely rare, can simulate an occlusive vasculitis and
can seed into the vitreous. Vitreous metastasis is also rare and probable derives from
the retina. It generally presents with tumor cells in the vitreous, resembling a
primary inflammatory process of primary lymphoma. Optic disc metastasis can
develop by contiguous spread from juxtapapillary choroidal metastasis, or it can
involve only the optic nerve, where it produces a unilateral elevation of the optic
disc (6). Secondary glaucoma frequently occurs, particularly with iris and ciliary
body tumors.

Diagnostic Approaches
The diagnosis of intraocular metastasis is generally made by taking a history for
prior cancers and by careful slit-lamp biomicroscopy and ophthalmoscopy. Ancillary
studies such as fluorescein angiography and ultrasonography can be of assistance in
diagnosis. Fluorescein angiography of a choroidal metastasis generally shows
beginning hyperfluorescence of the mass in the late venous phase, usually later than
with choroidal hemangioma or melanoma. With ultrasonography it usually shows
high internal reflectivity with A-scan and acoustic solidity with B-scan, a pattern
similar to that seen with choroidal hemangioma. In rare instances, a choroidal
metastasis can assume a mushroom configuration similar to that of a choroidal
melanoma (19).
Enhanced depth imaging optical coherence tomography (EDI-OCT) is a new
method for detection of subclinical metastasis within the eye and for confirmation of
surface topography and invasive features. By EDI-OCT, small choroidal metastasis
displayed choriocapillaris compression and a “lumpy bumpy” contour in most cases.
Photoreceptor loss and subretinal fluid were also noted (21). In difficult cases that
cannot be diagnosed with the aforementioned methods, fine-needle aspiration with
cytologic evaluation of aspirate can be used to establish the diagnosis (17).

Pathology
Most intraocular metastases are diagnosed clinically and no histopathologic material
is available. However, uveal metastasis can assume classic gross and microscopic
patterns. Grossly, this malignancy is usually white or yellow and sessile, nodular, or
diffuse. Histopathology of uveal metastasis varies considerably, depending on the
type, primary site, and degree of differentiation (1–3). Some tumors are so poorly

632
differentiated that the primary site is difficult to determine based on examination of
the ocular tissue. In such instances, immunohistochemistry may be of some value in
classifying the neoplasm and in determining the primary site.

Management
Management options for uveal metastasis vary with the clinical situation
(1–8,22–25). Small, asymptomatic tumors or those that have responded to prior or
present chemotherapy may require no immediate treatment and can be followed
periodically. Larger, symptomatic tumors may require external beam irradiation or
plaque radiotherapy. It has recently been reported that photodynamic therapy
(PDT) has been highly effective in treating small metastases in the posterior choroid.
PDT takes only a few minutes compared to much longer time with any method of
irradiation (22,24).
The systemic prognosis varies with the type of tumor. Patients with choroidal
metastasis from breast cancer often have a more favorable prognosis, whereas
patients with metastasis from lung cancer or melanoma have a worse prognosis.
Patients with metastasis from carcinoid tumor often have a much better prognosis,
and metastatic foci from this tumor can remain relatively dormant for months or
years (1).

Selected References
Major Series
1. Shields CL, Shields JA, Gross N, et al. Survey of 520 uveal metastases.
Ophthalmology 1997;104:1265–1276.
2. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I.
Clinicopathologic study of 227 cases. Arch Ophthalmol 1975;92:276–286.
3. Stephens RF, Shields JA. Diagnosis and management of cancer metastatic to the
uvea. A study of 70 cases. Ophthalmology 1979;86:1336–1349.
4. Shields JA, Shields CL, Kiratli H, et al. Metastatic tumors to the iris in 40
patients. Am J Ophthalmol 1995;119:422–430.
5. Shields CL, Kaliki S, Crabtree GS, et al. Iris metastasis from systemic cancer in
104 patients. The 2014 Jerry A. Shields Lecture. Cornea 2015;34(1):42–48.
6. Shields JA, Shields CL, Singh AD. Metastatic neoplasms in the optic disc: the
1999 Bjerrum Lecture: part 2. Arch Ophthalmol 2000;118:217–224.
7. Shields CL, McMahon JF, Atalay HT, et al. Retinal metastasis from systemic
cancer in 8 cases. JAMA Ophthalmol 2014;132(11):1303–1308.
8. Shields JA. Metastatic tumors to the uvea. In: Shields JA, ed. Update on
Malignant Ocular Tumors. International Ophthalmology Clinics. Boston, MA: Little,
Brown; 1993;33:155–161.

Small Series Based on Select Primary Cancer Sites

9. Kindermann WR, Shields JA, Eiferman RA, et al. Metastatic renal cell carcinoma
to the eye and adnexae. A report of 3 cases and review of the literature.
Ophthalmology 1981;88:1347–1350.
10. DePotter P, Shields CL, Shields JA, et al. U veal metastasis from prostate
carcinoma. Cancer 1993;71:2791–2796.
11. Shah S, Bianciotto C, Shields CL, et al. Pancreatic cancer metastasis to choroid.

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 Ophthalmology 2011;118:1483–1484.
12. Shah SU , Mashayekhi A, Shields CL, et al. U veal metastasis from lung cancer:
Clinical features, treatment, and outcome in 194 patients. Ophthalmology
2014;121:352–357.
13. Demirci H, Shields CL, Chao AN, et al. U veal metastasis from breast cancer in
264 patients. Am J Ophthalmol 2003;136:264–271.
14. Amichetti M, Caffo O, Minatel E, et al. Ocular metastases from breast
carcinoma: A multicentric retrospective study. Oncol Rep 2000;7:761–765.
15. Lam A, Shields CL, Shields JA. U veal metastases from breast cancer in three
male patients. Ophthalmic Surg Lasers Imaging 2006;37:320–323.
16. Feinstein E, Kaliki S, Shields CL, et al. Choroidal metastasis from
leiomyosarcoma: A report of 2 cases. Oman J Ophthalmol 2014;7(1):19–21.

Imaging
17. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
18. DePotter P, Shields JA, Shields CL, et al. U nusual MRI findings in metastatic
carcinoma to choroid and optic nerve. Int Ophthalmol 1992;16:39–44.
19. Shields JA, Shields CL, Brown GC, et al. Mushroom-shaped choroidal metastasis
simulating a choroidal melanoma. Retina 2002;22:810–812.
20. Shields CL, Say EA, Stanciu NA, et al. Cavitary choroidal metastasis from lung
neuroendocrine tumor. Report of 3 cases. Arch Ophthalmol 2011;129(1):102–
104.
21. Al-Damash S, Shields CL, Kaliki S, et al. Enhanced depth imaging optical
coherence tomography of choroidal metastasis in 14 eyes. Retina
2014;34(8):1588–1593.

Management
22. Rudoler SB, Shields CL Corn BW, et al. Functional vision is improved in the
majority of patients treated with external beam radiotherapy for choroidal
metastasis: a multivariate analysis of 188 cases. J Clin Oncol 1997;15:1244–
1251.
23. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the
management of uveal metastasis. Arch Ophthalmol 1997;115:203–209.
24. Kaliki S, Shields CL, Al-Dahmash SA, et al. Photodynamic therapy for choroidal
metastasis in 8 cases. Ophthalmology 2011;119:1218–1222.
25. Nakashima C, Keino H, Watanabe T, et al. Intravitreal bevacizumab for iris
metastasis of small-cell lung carcinoma with neovascular glaucoma. Jpn J
Ophthalmol 2011; 55(1):80–81.
Case Reports
26. Shields JA, Shields CL, Shakin EP, et al. Metastasis of choroidal melanoma to
the contralateral choroid, orbit, and eyelid. Br J Ophthalmol 1988;72:456–460.
27. Lieb WE, Shields JA, Shields CL, et al. Mucinous adenocarcinoma metastatic to
the iris, ciliary body and choroid. Br J Ophthalmol 1990;74:373–376.
28. Hykin PG, Shields JA, Shields CL, et al. Carcinoid tumor metastatic to the
choroid. Br J Ophthalmol 1996;80:8452–8453.
29. Gunduz K, Shields JA, Shields CL, et al. Ewing’s sarcoma metastatic to the iris.

634
 Am J Ophthalmol 1997;124:550–552.
30. Shields JA, Perez N, Shields CL, et al. Simultaneous choroidal and brain
metastasis as initial manifestations of lung cancer. Ophthalmic Surg Lasers
2002;33:323–325.
31. Shields JA, Shields CL, Perez N. Choroidal metastasis from medullary thyroid
carcinoma in multiple endocrine neoplasia. Am J Ophthalmol 2002;134:607–
609.
32. Shields JA, Shields CL, Eagle RC Jr, et al. Lung cancer presenting as vitreous
hemorrhage from choroidal metastasis. Retina 2004;24:168–170.
33. Shields JA, Shields CL, Eagle RC Jr. Choroidal metastasis from lung cancer
masquerading as sarcoidosis. Retina 2005;25:367–370.
34. Schwab L, Doshi H, Shields JA, et al. Hepatocellular carcinoma metastatic to
the orbit in an African patient. Ophthalmic Surg 199;25:105–106.
35. Imamura Y, Suzuki M, Nakajima KI, et al. Gastric signet ring cell
adenocarcinoma metastatic to the iris. Am J Ophthalmol 2001;131:379–381.
36. Shields JA, Carvalho C, Shields CL, et al. Bilateral choroidal metastasis from
adenoid cystic carcinoma of the submandibular gland. Retina 2000;20:406–407.
37. Ramaesh K, Marshall JW, Wharton SB, et al. Intraocular metastases of cutaneous
malignant melanoma: a case report and review of the literature. Eye
1999;13:247–250.
38. Paoli D. Regression of choroidal metastasis from a carcinoma of the male
breast: Case report. Ophthalmologica 1998;212(Suppl 1):74–76.
39. 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.
40. Saornil MA, Blanco G, Sarasa JL, et al. Isolated metastasis of gastric
adenocarcinoma to the retina: first presentation of systemic disease. Acta
Ophthalmol Scand 2004; 82:86–88.
41. Adachi N, Tsuyama Y, Mizota A, et al. Optic disc metastasis presenting as an
initial sign of recurrence of adenoid cystic carcinoma of the larynx. Eye
2003;17:270–272.
42. 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.
43. Gunduz K, Shields JA, Shields CL, et al. Cutaneous melanoma metastatic to the
vitreous cavity. Ophthalmology 1998;105:600–605.
44. Gunduz K, Shields JA, Shields CL, et al. Lung carcinoma metastatic to the
vitreous cavity. Retina 1998;18:285–286.
45. Shields JA, Tovilla-Canales J, Shields CL, et al. Metastatic breast carcinoma to
the iris. JAMA 2000;283:178.
46. Singh AD, Shields JA, Shields CL, et al. Choroidal melanoma metastatic to the
contralateral choroid. Am J Ophthalmol 2001;132:941–943.
47. Shields CL, Piccone MR, Fung KL, et al. Spontaneous regression of metastatic
cutaneous melanoma to the choroid. Retina 2002;22:806–807.
48. Montero J, Shields CL, Bianciotto C, et al. Iris metastasis from adenoid cystic
carcinoma of parotid gland. Cornea 2011;30(3):351–353.
49. Kirwan C, Carney D, O’Keefe M. Merkel cell carcinoma metastasis to the iris in

635
 a 23 year old female. Ir Med J 2009;102(2):53–54.
50. Lee WB, Sy HM, Filip DJ, et al. Metastatic esophageal adenocarcinoma
presenting in the iris. Am J Ophthalmol 2007;144(3):477–479.
51. Kaliki S, Eagle RC Jr, Shields CL, et al. Ciliochoroidal metastasis as the initial
manifestation of an occult soft tissue extraosseous sarcoma in a 10-year-old girl.
J AAPOS 2013;17:217–220.
52. Shah CP, Shienbaum G, Shields CL, et al. Neovascular glaucoma as the
presenting sign of metastatic small cell lung carcinoma. Retinal Cases & Brief
Reports 2011;5:26–29.
53. Solomon JD, Shields CL, Shields JA, et al. Posterior capsule opacity as initial
manifestation of metastatic cutaneous melanoma. Graefe’s Arch Clin Exp
Ophthalmol 2011:249:127–131.

636
• IRIS METASTASIS FROM BREAST CANCER
Among tumors that metastasize to the iris, breast cancer represents the most frequent primary
neoplasm. In most instances, iris metastasis from breast cancer has no specific features that
differentiate it from other iris metastases. The color and configuration can vary considerably
from case to case. The clinical characteristics were described previously. Some examples of iris
metastasis from breast cancer are illustrated.

1. Shields CL, Kaliki S, Crabtree GS, et al. Iris metastasis from systemic cancer in 104 patients.
The 2014 Jerry A. Shields Lecture Note. 2014;34(1):42–48.
2. Shields JA, Shields CL, Kiratli H, et al. Metastatic tumors to the iris in 40 patients. The 1994
J. D. Allen Lecture. Am J Ophthalmol 1995;119:422–430.
3. Shields JA, Tovilla-Canales J, Shields CL, et al. Metastatic breast carcinoma to the iris. JAMA
2000;283:178.

Figure 12.1. Small irregular iris metastasis from breast carcinoma.

Figure 12.2. Diffuse multinodular iris metastasis from breast carcinoma.

637
Figure 12.3. Superior diffuse iris metastasis from breast carcinoma.

Figure 12.4. Large inferior iris metastasis from breast carcinoma.

Figure 12.5. Peripheral iris metastasis from breast cancer. This lesion is poorly circumscribed and has a tan
color.

638
Figure 12.6. Cytopathology of fine-needle aspiration biopsy of iris metastasis from breast cancer, showing
linear arrangement of malignant cells. (Papanicolaou ×200.)

639
• IRIS METASTASIS FROM CUTANEOUS MELANOMA
Iris metastasis can take several clinical variations, and some forms of iris metastasis have a
rather typical color. Metastatic melanoma to the iris may be brown to black, and occasionally it
is clinically nonpigmented. The skin is by far the most common primary site for melanoma
metastatic to the iris. Iris metastasis from melanoma tends to be more aggressive than breast
carcinoma metastasis.

1. Shields CL, Kaliki S, Crabtree GS, et al. Iris metastasis from systemic cancer in 104 patients.
The 2014 Jerry A. Shields Lecture Note. 2014;34(1):42–48.
2. Shields JA, Shields CL, Kiratli H, et al. Metastatic tumors to the iris in 40 patients. Am J
Ophthalmol 1995;119:422–430.

Figure 12.7. Metastatic cutaneous melanoma to iris. Note that there is a pigmented lesion in the iris both
nasally and temporally. Note also the secondary hyphema, admixed with loosely cohesive melanoma cells.

Figure 12.8. Acquired hyperchromic heterochromia secondary to metastatic cutaneous melanoma to right iris.
Note also the pigmented metastasis to the left lower eyelid. The patient had widespread melanomatosis.

640
Figure 12.9. Closer view of the right iris in the patient in Figure 12.8, showing diffuse thickening of the iris but
no distinct nodule. This eye also had elevated intraocular pressure secondary to infiltration of tumor through
the trabecular meshwork.

Figure 12.10. Closer view of the normal left iris in the patient in Figure 12.8, showing normal iris architecture
for comparison.

Figure 12.11. Right iris of a patient with bilateral anterior chamber metastasis from cutaneous melanoma.
Note the ill-defined iris metastasis inferiorly and the pigmented neoplastic keratic precipitates on the corneal
endothelium and lens.

641
Figure 12.12. Left iris of the patient shown in Figure 12.11. There is a pigmented tumor-induced
“pseudohypopyon” inferiorly and a confluent sheet of tumor cells on the corneal endothelium.

642
• IRIS METASTASIS FROM MISCELLANEOUS SITES
Shields CL, Kaliki S, Crabtree GS, et al. Iris metastasis from systemic cancer in 104 patients. The
2014 Jerry A. Shields Lecture Note. 2014;34(1):42–48.

Figure 12.13. Iris metastasis from lung cancer with bleeding and secondary hyphema.

Figure 12.14. Metastatic bronchial carcinoid tumor to the iris, showing the characteristic fleshy, pink-orange
color.

Figure 12.15. Multiple iris metastases from small cell carcinoma of lung in a 78-year-old woman.

643
Figure 12.16. Same eye depicted in Figure 12.15 after external beam radiotherapy, showing resolution of the
tumors.

Figure 12.17. Nodular metastasis from stomach cancer with a pseudohypopyon secondary to seeding from
the main tumor.

Figure 12.18. Iris metastasis from Ewing’s sarcoma of the femur in a 19-year-old woman. Note that there are
multiple tumor nodules on the iris surface and the friable tumor has assumed a “pseudohypopyon”
appearance inferiorly.

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• IRIDOCILIARY AND CILIARY BODY METASTASIS
Metastatic tumors to the ciliary body and peripheral iris are more difficult to visualize and may
masquerade as an iridocyclitis and secondary glaucoma, often resulting in a delay in diagnosis.

Figure 12.19. Severe intraocular inflammation and hyphema secondary to a diffuse metastatic mucin-secreting
intestinal carcinoma to the ciliary body and iris in a 67-year-old woman. The patient was treated for “uveitic
glaucoma” for several months. The blind painful eye was enucleated, and the diagnosis was established
histopathologically.

Figure 12.20. Gross appearance of the enucleated eye, showing tumor cells in the ciliary body region,
surrounding the lens, and occupying the anterior chamber.

645
Figure 12.21. Photomicrograph of iris and ciliary body region, showing a monolayer of mucin-secreting tumor
cells growing across the iris and ciliary body. (Alcian blue ×20.)

Figure 12.22. Sentinel blood vessels on sclera in the ciliary body region of a 62-year-old woman. A ciliary body
mass was visualized. Systemic evaluation failed to reveal a primary tumor, and the painful eye was enucleated.

Figure 12.23. Section of the enucleated eye, showing diffuse, hemorrhagic tumor of the ciliary body and
peripheral choroid.

Figure 12.24. Histopathologic section of mucin-secreting adenocarcinoma in the ciliary body of the patient
shown in Figures 12.22 and 12.23. (Hematoxylin–eosin ×200.) Several months later, the patient developed
evident systemic metastasis, and it was believed that the primary cancer was in the common bile duct.

646
• CHOROIDAL METASTASIS FROM BREAST CANCER
Choroidal metastasis can assume a variety of clinical variations. However, the typical lesion
appears as a creamy-yellow sessile or dome-shaped mass in the posterior choroid. Depicted here
are examples of typical choroidal metastases.

1. Shields CL, Shields JA, Gross N, et al. Survey of 520 uveal metastases. Ophthalmology
1997;104:1265–1276.
2. Demirci H, Shields CL, Chao AN, et al. Uveal metastasis from breast cancer in 264 patients.
Am J Ophthalmol 2003;136:264–271.

Figure 12.25. Small choroidal metastasis inferior to the optic disc in a 35-year-old woman with metastatic
breast cancer.

Figure 12.26. Choroidal metastasis in a typical location inferotemporal to the fovea in a 67-year-old woman
with metastatic breast cancer.

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Figure 12.27. Choroidal metastasis inferior to the optic disc in a 55-year-old woman with breast cancer.

Figure 12.28. Choroidal metastasis superior to the fovea in a 45-year-old woman with breast cancer. Note the
subtle serous detachment of the adjacent fovea. Patients with this finding may be initially misdiagnosed as
having central serous chorioretinopathy.

Figure 12.29. Typical choroidal metastasis extending temporally from the foveal area in a 58-year-old woman.
She was referred with the diagnosis of central serous chorioretinopathy, had no prior diagnosis of cancer, and
denied any knowledge of breast problems. Because the lesion was very suggestive of metastasis, a breast
examination was performed.

648
Figure 12.30. Appearance of the breast of the patient shown in Figure 12.29, revealing advanced, ulcerating
breast cancer. Although the patient was aware of this lesion, she chose to deny its existence.

649
• CHOROIDAL METASTASIS FROM BREAST CANCER: MULTIFOCAL
AND BILATERAL TUMORS

Choroidal metastasis can have several clinical variations. Although it is often a solitary lesion, it
can be multifocal and bilateral. Very early in its clinical course, choroidal metastasis can
produce an extensive secondary nonrhegmatogenous retinal detachment.

Figure 12.31. Multiple choroidal metastases to the posterior pole of the right eye in a 43-year-old woman with
metastatic breast cancer.

Figure 12.32. Multiple choroidal metastases superior and nasal to the optic disc in a 38-year-old woman with
metastatic breast cancer.

650
Figure 12.33. Wide-angle photograph, showing multiple choroidal metastases in the right eye of a 36-year-old
woman with metastatic breast cancer.

Figure 12.34. Wide-angle photograph of the left eye of the same patient in Figure 12.33, showing similar
multiple metastasis.

Figure 12.35. Total retinal detachment secondary to multifocal large choroidal metastases.

651
Figure 12.36. Total retinal detachment secondary to multiple large confluent metastases.

652
• CHOROIDAL METASTASIS FROM LUNG CANCER
Choroidal metastasis from lung cancer can have a similar appearance to choroidal metastasis
from breast cancer.

Figure 12.37. Large nasal choroidal metastasis from lung cancer.

Figure 12.38. Macular choroidal metastasis from lung cancer.

653
Figure 12.39. Numerous small miliary choroidal metastases from lung cancer.

Figure 12.40. Left eye of the patient shown in Figure 12.39, demonstrating similar findings.

Figure 12.41. Multiple, variable-sized choroidal metastases from lung cancer.

654
Figure 12.42. Multiple superior and temporal choroidal metastases from lung cancer causing a total
secondary retinal detachment.

655
• CHOROIDAL METASTASIS FROM CUTANEOUS MELANOMA
Choroidal metastasis from cutaneous or uveal melanoma is often pigmented but can
occasionally be amelanotic.

Figure 12.43. Multiple pigmented choroidal metastases from known cutaneous melanoma. The larger
macular lesion produced painless visual loss, and the small, more peripheral ones were found on
examination for blurred vision.

Figure 12.44. Left eye of the patient shown in Figure 12.43, revealing multiple pigmented metastases.

656
Figure 12.45. Closer view of the macular lesion shown in Figure 12.43.

Figure 12.46. Closer view of the more peripheral lesions shown in Figure 12.43.

Figure 12.47. Solitary macular choroidal metastasis from cutaneous melanoma.

657
Figure 12.48. Left fundus of the patient shown in Figure 12.47, revealing a small, subtle metastasis in
peripheral fundus inferonasally. This lesion cannot be differentiated from a benign choroidal nevus. The
superficial retinal hemorrhage adjacent to the optic disc may be coincidental.

658
• CHOROIDAL METASTASIS FROM CHOROIDAL MELANOMA
Although it is rare, we have seen patients with uveal metastasis from uveal melanoma. Two
examples are shown, one with contralateral choroidal metastasis and the other with ipsilateral
choroidal metastasis.

Shields JA, Shields CL, Shakin EP, et al. Metastasis of choroidal melanoma to the contralateral
choroid, orbit, and eyelid. Br J Ophthalmol 1988;72:456–460.

Figure 12.49. Primary juxtapapillary choroidal melanoma in a 52-year-old woman. The affected eye was
enucleated, and the patient was free of demonstrable metastasis for 4 years.

Figure 12.50. Four years after enucleation, the previously normal right eye now has solitary metastasis
superior to the optic disc.

659
Figure 12.51. A second choroidal metastasis is present inferotemporally in the right eye. The patient was
subsequently found to have metastatic melanoma to skin and liver.

Figure 12.52. Primary choroidal melanoma located inferotemporally in the right eye. The tumor was treated
with plaque radiotherapy.

Figure 12.53. Normal macular area at same time as the photograph in Figure 12.52.

Figure 12.54. The patient shown in Figure 12.52 developed systemic metastasis after 3 years, and a
metastatic focus is seen in ipsilateral eye just above the fovea. The pigment below represents the area of the
treated primary tumor.

660
• CHOROIDAL METASTASIS FROM CARCINOID TUMORS
Carcinoid tumors have a greater tendency to metastasize to the uveal tract and tend to remain
dormant or grow very slowly in that location. Many uveal metastases from carcinoid tumors
have a peculiar orange color that may be very similar to that of a choroidal hemangioma. It is of
interest that bronchial carcinoid tumors have a tendency to metastasize to the uveal tract and
small bowel and appendiceal carcinoid tumors have a tendency to metastasize to the orbital
soft tissue. An exception to that rule is illustrated. All of the cases shown had a proven primary
carcinoid tumor with systemic metastasis.

Figure 12.55. A 55-year-old woman with bilateral choroidal metastatic carcinoid tumors from lung. Note the
three orange lesions.

Figure 12.56. Left eye of the patient shown in Figure 12.55, revealing a solitary lesion temporal to the macular
area. Some surface retinal pigment epithelium alterations are present over the tumor.

661
Figure 12.57. Presumed metastatic bronchial carcinoid tumor to the peripheral choroid. The lesion was found
on routine eye examination, metastasis was suspected, and chest x-ray detected a primary bronchial carcinoid
tumor.

Figure 12.58. Large choroidal metastasis from bronchial carcinoma. A small, flat lesion was seen at the same
location 3 years earlier and diagnosed as a choroidal nevus. The patient was later found to have a primary
bronchial carcinoid, and blurred vision prompted an eye examination; the lesion was much larger. There is a
second, small, orange-colored metastasis near the equator at the 5 o’clock location.

Figure 12.59. Metastatic bronchial carcinoid tumor to the choroid with secondary retinal pigment epithelium
alterations.

662
Figure 12.60. The lesion shown in Figure 12.59 after external beam irradiation. The lesion has shown
satisfactory, but not dramatic, regression.

663
• CHOROIDAL METASTASIS FROM KIDNEY, BILE DUCT, AND
ESOPHAGEAL CARCINOMAS

Figure 12.61. Presumed choroidal metastasis to the choroid of the right eye in a man with proven renal cell
carcinoma with metastatic disease.

Figure 12.62. The left fundus of the patient shown in Figure 12.61, revealing a larger choroidal metastasis from
renal cell carcinoma.

664
Figure 12.63. Presumed choroidal metastasis in a patient with known primary carcinoma of the common bile
duct.

Figure 12.64. Choroidal metastasis from esophageal carcinoma with secondary retinal detachment.

Figure 12.65. Another patient with choroidal metastasis from esophageal carcinoma. Note the extensive
secondary retinal detachment that overlies the yellow tumor.

665
Figure 12.66. The patient shown in Figure 12.65 after external beam irradiation, demonstrating marked
regression of the neoplasm and resolution of the retinal detachment.

666
• CHOROIDAL METASTASIS FROM UNDETERMINED PRIMARY SITES,
DIAGNOSED BY FINE-NEEDLE ASPIRATION BIOPSY

On occasion, a patient is found to have a uveal lesion compatible with a metastasis but has no
history of cancer, and systemic evaluation fails to reveal a primary neoplasm. In such instances,
fine-needle aspiration biopsy (FNAB) can be employed to confirm the diagnosis of metastasis. In
some cases, typical cytopathologic features or immunohistochemistry can suggest the primary
site. In other instances, however, cytopathology discloses metastatic carcinoma, but the
primary site is never clearly determined. Such cases are shown, all of which had cytopathologic
studies of FNAB specimens to document the diagnosis, but the primary neoplasm was never
determined.

Shields CL, Shields JA, Gross N, et al. Survey of 520 uveal metastases. Ophthalmology
1997;104:1265–1276.

Figure 12.67. Choroidal metastasis superior to the optic disc.

Figure 12.68. Choroidal metastasis in the macular area.

667
Figure 12.69. Choroidal metastasis superior to the optic disc.

Figure 12.70. Choroidal metastasis in the macular area.

Figure 12.71. Choroidal metastasis inferior to the optic disc with fibrous metaplasia of retinal pigment
epithelium.

668
Figure 12.72. Choroidal metastasis surrounding and invading the optic disc.

669
• UVEAL METASTASIS FROM SARCOMAS
Most uveal metastases are carcinomas, few are melanomas, and uveal metastasis from sarcoma
is very rare. We have seen several such cases, two of which are shown.

Kaliki S, Eagle RC Jr, Shields CL, et al. Ciliochoroidal metastasis as the initial manifestation of
an occult soft tissue extraosseous sarcoma in a 10-year-old girl. J AAPOS 2013;17:217–220.

Figure 12.73. Face photograph of a 10-year-old girl with total loss of vision in the left eye. Note the loss of red
reflex in the left eye.

Figure 12.74. Axial magnetic resonance imaging in a T1-weighted image, showing a dome-shaped choroidal
mass filling half of the globe. The nature of the neoplasm was unknown, but melanoma was considered, and
the blind painful eye was enucleated.

670
Figure 12.75. Gross appearance of the sectioned globe, showing a large, dome-shaped mass.
Histopathology revealed findings compatible with poorly differentiated sarcoma. The patient died within a few
months of disseminated cancer.

Figure 12.76. Histopathology of the enucleated eye. The choroidal lesion has a myxoid pattern (to the left)
(hematoxylin–eosin ×50) and scattered spindle-shaped malignant cells (hematoxylin–eosin ×200).
Subsequent evaluation detected a previously occult primary myxoid sarcoma of the fibula. The patient died
from widespread metastases several months after enucleation, despite intensive chemotherapy.

Figure 12.77. Superonasal ciliochoroidal mass in an elderly man, seen by ophthalmoscopy and
transillumination technique. Note that the lesion transmits light. The patient had a history of retroperitoneal
liposarcoma, and ocular fine-needle aspiration biopsy showed blood cells and a few sarcoma cells that
supported the diagnosis of metastasis from that neoplasm, although there was still controversy as to the
precise nature of the neoplasm.

Figure 12.78. Axial magnetic resonance imaging in T1-weighted image of the lesion shown in Figure 12.77,
demonstrating enhancing ciliochoroidal mass.

671
• CHOROIDAL METASTASIS: EFFECTS ON ADJACENT STRUCTURES
Choroidal metastases cause changes in adjacent structures. They can induce pigment epithelial
alterations, secondary retinal detachment, and choroidal detachment, or, rarely, can assume a
nodular configuration, simulating the mushroom shape seen with some primary melanomas.

Figure 12.79. Typical pigment clumping over a choroidal metastasis, producing the “leopard skin” appearance.

Figure 12.80. Pigment epithelial proliferation over a choroidal metastasis.

Figure 12.81. Large inferior bullous retinal detachment secondary to a diffuse metastasis in the macular
region.

672
Figure 12.82. Total retinal detachment with the retina against the posterior surface of the lens, secondary to a
choroidal metastasis. Such a patient sometimes requires enucleation because of severe, uncontrollable
ocular pain.

Figure 12.83. Ciliochoroidal detachment secondary to choroidal metastasis. Wide-angle fundus photograph of
a metastasis in the superior fundus from lung cancer. Note the prominent secondary ciliochoroidal
detachment for 360 degrees, most pronounced inferotemporally and inferonasally. The mechanism of
choroidal detachment in such cases is uncertain.

Figure 12.84. Retinal invasion of choroidal metastasis. Wide-angle fundus photograph of a choroidal
metastasis inferiorly from lung cancer with nodular surface, simulating a mushroom-shaped melanoma. Like
some melanomas, the lesion had produced a rupture in Bruch’s membrane.

673
• ORANGE-COLORED CHOROIDAL METASTASIS
Some forms of choroidal metastasis have an orange color, simulating a choroidal hemangioma.
This orange color is seen most often with some choroidal metastases from bronchial carcinoid
tumor, thyroid cancer, and renal cell carcinoma. Carcinoid tumor metastasis can be stable or
slowly progressive.

Figure 12.85. Macular region of the right eye of a 23-year-old woman with a history of systemic metastasis from
a bronchial carcinoid, showing two small, orange choroidal tumors. There was a similar lesion nasal to the
optic disc of the left eye.

Figure 12.86. Choroidal metastasis from a bronchial carcinoid tumor in a 58-year-old woman. Note the
similarity of the lesion to a circumscribed choroidal hemangioma. There were three other choroidal
metastases in the same eye.

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Figure 12.87. Metastatic bronchial carcinoid tumor to the choroid inferotemporally in right eye. The diagnosis
was confirmed with fine-needle aspiration biopsy.

Figure 12.88. Metastatic thyroid cancer to the choroid in the superior fundus, showing orange color.

Figure 12.89. Metastatic renal cell carcinoma to the macular area in a man who had nephrectomy 10 years
earlier for renal cell carcinoma. The eye was enucleated for suspected choroidal melanoma because the
patient and his family failed to reveal the history of renal cell carcinoma. The dark areas in the clinical
photograph were due to hemorrhage, a common finding in metastatic renal cell carcinoma.

675
Figure 12.90. Histopathology of the lesion shown in Figure 12.89, showing clear cells characteristic of renal
cell carcinoma. (Hematoxylin–eosin ×200.)

676
• CHOROIDAL METASTASIS: PATHOLOGY
The gross appearance of a choroidal metastasis can vary considerably from case to case. It is
usually a nonpigmented, yellow, or pink lesion with a diffuse or multinodular growth pattern. A
detailed discussion of the histopathology of all types of choroidal metastases is beyond the
scope of this text. The microscopic pathology of choroidal metastasis often, but not always,
reflects the histopathology of the primary tumor.

Figure 12.91. Metastatic breast cancer to the choroid with a diffuse, multinodular growth pattern.

Figure 12.92. Metastatic breast cancer to the choroid with a diffuse, flat growth pattern. Note that the entire
posterior uveal tract is only minimally thickened, and there is a total bullous retinal detachment.

677
Figure 12.93. Metastatic gastric carcinoma to the choroid.

Figure 12.94. Metastatic cutaneous melanoma to the choroid. The lesion was seen clinically and confirmed on
histopathologic examination of this eye postmortem.

Figure 12.95. Choroidal metastasis, presumably from bronchogenic carcinoma. The tumor has many blood
vessels and foci of hemorrhage.

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Figure 12.96. Histopathology of tumor shown in Figure 12.95. (Hematoxylin–eosin ×150.)

679
• CHOROIDAL METASTASIS: METASTASIS FROM LUNG CARCINOMA
SIMULATING SARCOIDOSIS

Choroidal metastasis and choroidal granuloma can sometimes be clinically similar. A

clinicopathologic correlation of such a case is described and illustrated.

Shields JA, Shields CL, Eagle RC Jr. Choroidal metastasis from lung cancer masquerading as
sarcoidosis. Retina 2005;25:367–370.

Figure 12.97. Yellow choroidal lesion inferonasal to the optic disc in right eye of a 57-year-old African-American
woman with systemic sarcoidosis. Chest x-ray findings were interpreted as compatible with sarcoidosis.

Figure 12.98. The same lesion 6 weeks later, showing that the lesion has enlarged and produced focal
hemorrhage. The patient was treated with systemic corticosteroids with presumptive diagnosis of sarcoidosis.

680
Figure 12.99. A few weeks later, the patient presented with tumor nodules in the anterior chamber and painful
glaucoma, and the eye was enucleated. The sectioned eye shows a white mass with extensive hemorrhagic
retinal detachment.

Figure 12.100. Closer view of the irregular yellow-white choroidal mass in the posterior segment of the
enucleated eye.

Figure 12.101. Low-magnification photomicrograph of the choroidal mass, showing the ovoid choroidal mass
with an overlying hemorrhagic retinal detachment. One can appreciate the papillary configuration of the tumor
cells. (Hematoxylin–eosin ×20.)

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Figure 12.102. Higher-magnification photomicrograph demonstrating the papillary configuration. The
diagnosis was metastatic papillary carcinoma to the choroid. The primary cancer was subsequently
documented in the lung. The patient died a few months later with disseminated carcinoma. (Hematoxylin–
eosin ×300.)

682
• MUSHROOM-SHAPED CHOROIDAL METASTASIS
It is generally true that a mushroom-shaped configuration of an intraocular tumor is highly
suggestive that the tumor is a primary melanoma. There are, however, exceptions. We are aware
of a mushroom-shaped configuration of choroidal metastasis, age-related macular degeneration,
choroidal hemangioma, and mycotic infection. Depicted is a case of a rapidly growing
mushroom-shaped choroidal metastasis that simulated a choroidal melanoma. The rapid growth
of the tumor is more characteristic of a metastasis than of a melanoma.

Figure 12.103. Fundus appearance of an amelanotic choroidal lesion superior to the foveal area in the left eye
of an elderly man. Visual acuity was 20/50 due to shallow retinal detachment involving the fovea. The
differential diagnosis included amelanotic choroidal nevus, melanoma, and metastasis. Systemic evaluation
was recommended, but the patient declined to have it done.

Figure 12.104. Three weeks later, the lesion was much larger, and visual acuity was finger counting. The
patient declined treatment.

683
Figure 12.105. Six weeks after initial evaluation, the patient returned with ocular pain, large hyphema,
secondary glaucoma, and scattered yellow nodules on iris. There was no fundus view, but B-scan
ultrasonography showed this mushroom-shaped mass. The blind, painful eye was managed by enucleation.

Figure 12.106. Gross photograph of the enucleated eye, depicting an amelanotic mass near the disc with an
extension anterior to Bruch’s membrane.

Figure 12.107. Low-magnification photomicrograph of lobules of the malignant tumor. An interruption in

Bruch’s membrane is seen to the left side, accounting for the mushroom configuration. (Hematoxylin–eosin
×30.)

684
Figure 12.108. Histopathology showing acini and cords of malignant tumor cells. (Mucicarmine ×100.) Chest
magnetic resonance imaging, previously reported as normal, now revealed a primary lung cancer. The patient
developed widespread metastasis and died 6 months later, despite aggressive treatment.

685
• CHOROIDAL METASTASIS: CLINICOPATHOLOGIC CORRELATION OF
METASTASIS FROM AN UNDETERMINED PRIMARY NEOPLASM

Choroidal metastasis can sometimes occur in an otherwise healthy person with no history of
cancer. In some cases, the primary site of the tumor is never determined. Described here is a
clinicopathologic correlation of such a case in a 51-year-old man who developed rapid pain and
blindness in his left eye secondary to a mucous-secreting adenocarcinoma of uncertain origin.
The patient died a few weeks later with widespread metastasis, and no autopsy was permitted.

DePotter P, Shields JA, Shields CL, et al. Unusual MRI findings in metastatic carcinoma to
choroid and optic nerve. Int Ophthalmol 1992;16:39–44.

Figure 12.109. External appearance of the left eye, showing epibulbar injection. The patient had severe ocular
pain.

Figure 12.110. Fundus photograph, showing diffuse choroidal thickening, edema, and hemorrhage on the
optic disc, and inferior retinal detachment.

686
Figure 12.111. B-scan ultrasonogram, showing diffuse choroidal thickening and overlying retinal detachment.

Figure 12.112. Sectioned eye after enucleation, showing diffuse choroidal tumor.

Figure 12.113. Photomicrograph of the optic nerve, showing poorly differentiated tumor cells. (Hematoxylin–
eosin ×150.)

687
Figure 12.114. Mucin stain, showing a positive reaction in the cytoplasm of the tumor cells. (Alcian blue ×150.)

688
• CHOROIDAL METASTASIS: FLUORESCEIN ANGIOGRAPHY
The diagnosis of uveal metastasis can usually be made by taking a history and by recognizing
the characteristic clinical features mentioned previously. However, ancillary studies like
fluorescein angiography and ultrasonography may assist in the diagnosis, particularly in atypical
cases. In the vascular filling phases of angiography, choroidal metastasis begins to show
hyperfluorescence somewhat later than choroidal hemangioma or melanoma as mentioned in
the chapters on those tumors.

Figure 12.115. Choroidal metastasis superotemporal to the foveola in the left eye.

Figure 12.116. Fluorescein angiogram in the laminar venous phase of the lesion shown in Figure 12.115,
revealing the lesion to be slightly hypofluorescent with minimal focal hyperfluorescence of blood vessels in the
tumor. At this stage, the fluorescein angiogram alone cannot differentiate the lesion from a choroidal nevus or
melanoma.

689
Figure 12.117. The same lesion in the recirculation phase, showing mild hyperfluorescence with discrete
pinpoint foci of more intense hyperfluorescence. In the very late angiograms, the lesion is slightly more
hyperfluorescent.

Figure 12.118. The clinical appearance of large choroidal metastasis in the macular area of the right eye of a
68-year-old woman.

Figure 12.119. Fluorescein angiogram in the laminar venous phase, showing hypofluorescence of the lesion.

690
Figure 12.120. Late angiogram, showing mild hyperfluorescence of the lesion.

691
• CHOROIDAL METASTASIS: ULTRASONOGRAPHY
Ultrasonography can be of additional help in differentiating choroidal metastases in many cases.
It generally shows higher reflectivity and melanoma with A-scan and more acoustic solidity with
B-scan.

Figure 12.121. Wide-angle photograph of choroidal metastasis in the macular area of a 43-year-old woman.

Figure 12.122. A-scan ultrasonogram of the lesion in Figure 12.121, showing medium internal reflectivity of the
tumor.

Figure 12.123. B-scan ultrasonogram, showing a choroidal mass with acoustic solidity and no choroidal
excavation. Note the linear echo inferiorly, typical of secondary retinal detachment.

692
Figure 12.124. Wide-angle image of atypical choroidal metastasis and secondary retinal detachment.

Figure 12.125. B-scan ultrasonogram of the eye shown in Figure 12.124 showing acoustic solidity of the tumor
and secondary bullous retinal detachment.

Figure 12.126. B-scan ultrasonogram of another quadrant of the eye shown in Figure 12.124, demonstrating
diffuse choroidal mass and secondary retinal detachment.

693
• CHOROIDAL METASTASIS: MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging can show typical but not pathognomonic features in cases of
choroidal metastasis. We rarely use it to diagnose choroidal metastasis because the diagnosis is
generally established by other methods, such as clinical history, ophthalmoscopic features, and
ultrasonography.

Figure 12.127. Axial magnetic resonance imaging in T1-weighted image, fat suppression, and gadolinium
enhancement of diffuse choroidal melanoma in the left eye, showing an enhancing lesion that is hyperintense
to vitreous.

Figure 12.128. Axial magnetic resonance imaging in T1-weighted image, showing the lesion to be
hypointense to vitreous.

694
Figure 12.129. Wide-angle image of a choroidal metastasis with secondary inferior retinal detachment.

Figure 12.130. Axial magnetic resonance imaging in T1-weighted image of the lesion in Figure 12.129,
showing the lesion to be hyperintense to vitreous.

Figure 12.131. Further growth of the lesion shown in Figure 12.130 despite the patient’s receiving
chemotherapy.

695
Figure 12.132. Magnetic resonance imaging in T1-weighted image of the same patient, showing total
serosanguineous retinal detachment in the left eye.

696
• CHOROIDAL METASTASIS: FUNDUS AUTOFLUORESCENCE AND
OPTICAL COHERENCE TOMOGRAPHY

1. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumors. Curr Opin

Ophthalmol 2013 May;24(3):222–32.
2. Shields CL, Pellegrini M, Ferenczy SR, Shields JA. Enhanced depth imaging optical coherence
tomography (EDI-OCT) of intraocular tumors. From placid to seasick to rock and rolling
topography. The 2013 Francesco Orzalesi Lecture. Retina 2014;34(8):1495–512.

Figure 12.133. Macular choroidal metastasis from breast cancer.

Figure 12.134. Fundus autofluorescence of lesion in Figure 12.133 demonstrates overlying

hyperautofluorescent lipofuscin.

697
Figure 12.135. Optical coherence tomography depicts the “lumpy bumpy” tumor surface and overlying
subretinal fluid.

Figure 12.136. Multifocal choroidal metastases from breast cancer.

Figure 12.137. Fundus autofluorescence of lesion in Figure 12.136 demonstrates overlying

hyperautofluorescent lipofuscin and pooled fluorophores in the subretinal fluid.

Figure 12.138. Optical coherence tomography depicts the “lumpy bumpy” tumor surface and overlying

698
subretinal fluid.

699
• CHOROIDAL METASTASIS: FINE-NEEDLE ASPIRATION BIOPSY
In some instances where the diagnosis is uncertain, FNAB with appropriate cytopathologic
studies can establish the diagnosis of uveal metastasis and can determine the site of the primary
neoplasm.

Figure 12.139. Clinical appearance of an atypical yellow-orange choroidal thickening in the posterior pole of an
otherwise healthy 61-year-old woman. Systemic evaluation revealed no abnormalities.

Figure 12.140. Cytology of fine-needle aspiration biopsy, showing cells compatible with metastatic breast
cancer. Subsequent systemic evaluation of the patient shown in Figure 12.140 revealed a subtle breast cancer.
(Papanicolaou ×200.)

700
Figure 12.141. Wide-angle image of atypical choroidal mass and secondary retinal detachment in a middle-
aged woman. The choroidal mass superiorly appears to be pigmented. Because the patient had a history of
breast cancer and the diagnosis was uncertain, fine-needle aspiration biopsy was done.

Figure 12.142. Cytopathology of the lesion shown in Figure 12.142, showing the positive
immunohistochemical reaction of malignant cells to epithelial membrane antigen. Melanoma markers were
negative, and the final diagnosis was choroidal metastasis from breast cancer.

Figure 12.143. Clinical appearance of a large amelanotic ciliochoroidal mass in a 52-year-old woman. The
diagnosis was uncertain, but primary melanoma was suspected.

701
Figure 12.144. Cytology of fine-needle aspiration biopsy, showing cells with cytoplasmic granules compatible
with metastatic carcinoid tumor. Subsequent systemic evaluation revealed a subtle bronchial carcinoid tumor.
(Papanicolaou ×200.)

702
• CHOROIDAL METASTASIS: RESPONSE TO EXTERNAL BEAM
RADIOTHERAPY

Choroidal metastasis may require no treatment if it appears clinically to have regressed

spontaneously or from prior treatment. Active choroidal metastasis can be treated with
chemotherapy, hormonal therapy, external beam radiotherapy (EBRT), or plaque brachytherapy.
The response of the tumor is similar regardless of the treatment employed.

Figure 12.145. Wide-angle image of choroidal metastasis from breast cancer inferotemporal to the optic disc
in the right eye.

Figure 12.146. Following external beam radiotherapy, the tumor showed regression and typical brown pigment
clumps on the surface, representing macrophages containing melanin and lipofuscin.

703
Figure 12.147. Wide-angle image of the left eye of the patient shown in Figure 12.145, revealing choroidal
metastasis superior to the optic disc.

Figure 12.148. Following external beam radiotherapy, similar tumor regression was found.

Figure 12.149. Choroidal metastasis from thyroid cancer in a 42-year-old man.

704
Figure 12.150. The same lesion shown in Figure 12.149 after external beam radiotherapy, showing excellent
tumor regression.

705
• CHOROIDAL METASTASIS: RESPONSE TO PLAQUE
RADIOTHERAPY

Plaque radiotherapy is an excellent method for treating selected solitary choroidal metastases.
Although it requires a surgical procedure under local anesthesia, it takes only 2 to 3 days, as
opposed to EBRT, which takes 4 to 5 weeks to complete treatment.

Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the management of uveal
metastasis. Arch Ophthalmol 1997;115:203–209.

Figure 12.151. Choroidal metastasis from breast cancer located inferior to the disc and fovea.

Figure 12.152. Appearance of the lesion shown in Figure 12.151, 2 years after plaque radiotherapy, showing
excellent response to treatment.

706
Figure 12.153. Choroidal metastasis from breast cancer temporal to the foveal region in a 64-year-old woman.

Figure 12.154. The same lesion shown in Figure 12.153, 12 months after plaque radiotherapy, showing
excellent tumor regression.

Figure 12.155. Choroidal metastasis from lung cancer superior to the optic disc in a 74-year-old man.

707
Figure 12.156. The same lesion shown in Figure 12.155, 3 months after plaque radiotherapy, showing
excellent tumor regression.

708
• CHOROIDAL METASTASIS: RESPONSE TO PHOTODYNAMIC
THERAPY

PDT can be delivered in a transpupillary technique to treat relatively small choroidal metastasis.
In general, one session with standard fluence is sufficient.

Kaliki S, Shields CL, Al-Dahmash SA, et al. Photodynamic therapy for choroidal metastasis in 8
cases. Ophthalmology 2011;119:1218–1222.

Figure 12.157. Choroidal metastasis from breast cancer.

Figure 12.158. Following photodynamic therapy, the tumor showed regression.

709
Figure 12.159. Choroidal metastasis from lung cancer.

Figure 12.160. Following photodynamic therapy, the tumor showed regression.

Figure 12.161. Subtle choroidal metastasis from lung cancer along the superior vascular arcade.

710
Figure 12.162. Following photodynamic therapy, the tumor showed regression and overlying retinal pigment
epithelial hyperplasia.

711
• OPTIC DISC METASTASIS
Metastatic cancer can affect the optic disc secondary to invasion from juxtapapillary choroidal
metastasis or it can occur on the optic disc as a solitary ocular finding without clinically evident
choroidal involvement. It is generally associated with profound visual loss and should be
treated promptly with radiotherapy.

Shields JA, Shields CL, Singh AD. Metastatic neoplasms in the optic disc. The 1999 Bjerrum
Lecture: part 2. Arch Ophthalmol 2000;118:217–224.

Figure 12.163. Diffuse optic disc involvement secondary to choroidal metastasis in a 51-year-old woman with
metastatic breast cancer.

Figure 12.164. Optic disc metastasis from lung cancer in a 50-year-old man. Note the typical solid yellow
appearance of the swollen disc.

712
Figure 12.165. Optic disc metastasis from lung cancer in a 78-year-old man. No primary tumor was found, and
the diagnosis was made by fine-needle aspiration biopsy, which led to further evaluation and detection of a
small lung cancer.

Figure 12.166. Fluorescein angiogram of the lesion shown in Figure 12.165 in the venous phase, showing
hypofluorescent foci in the lesion.

Figure 12.167. Angiogram in the recirculation phase, showing diffuse hyperfluorescence of the mass and
surrounding subretinal fluid.

713
Figure 12.168. Immunohistochemistry of a fine-needle aspiration biopsy specimen of lesion shown in Figure
12.153, showing positive reaction to epithelial membrane antigen.

714
• RETINAL AND VITREAL METASTASIS
Metastases to the retina and/or vitreous are rare. They can both masquerade as an inflammatory
process, and there is often a delay in diagnosis.

1. Gunduz K, Shields JA, Shields CL, et al. Cutaneous melanoma metastatic to the vitreous
cavity. Ophthalmology 1998;105:600–605.
2. Shields CL, McMahon JF, Atalay HT, Hasanreisoglu M, Shields JA. Retinal metastasis from
systemic cancer in 8 cases. JAMA Ophthalmol 2014;132(11):1303–1308.

Figure 12.169. Amelanotic retinal metastasis from cutaneous melanoma, producing total retinal detachment.

Figure 12.170. Perivascular retinal metastasis from cutaneous melanoma. (Courtesy of Murat Hasanreisoglu,
MD.)

715
Figure 12.171. Retinal metastasis from undiscovered lung carcinoma.

Figure 12.172. Following plaque radiotherapy and sector laser photocoagulation for patient in Figure 12.171,
the tumor shows complete regression.

Figure 12.173. Vitreal metastasis from primary cutaneous melanoma. Note the golden brown cells attached to
the vitreous framework.

716
Figure 12.174. Cytology of fine-needle aspiration biopsy of the vitreous of eye shown in Figure 12.161, showing
malignant melanoma cells. (Papanicolaou ×400.)

717
• RETINAL METASTASIS FROM ESOPHAGEAL CARCINOMA

Figure 12.175. Retinal metastasis from esophageal carcinoma. The diagnosis was uncertain, and the lesion
was followed without treatment.

Figure 12.176. The lesion shown in Figure 12.175, 3 months later. There was definite growth and tumor
extension into the macular region.

718
Figure 12.177. Fluorescein angiogram in the venous phase showed leakage from the retinal blood vessels.

Figure 12.178. Fluorescein angiogram in the recirculation phase, showing persistent leakage.

Figure 12.179. Fluorescein angiogram in the late phase, showing further intraretinal leakage.

Figure 12.180. Ultrasonography, showing the retinal echo, but no specific diagnosis can be made on
ultrasonography alone. (Case courtesy of Kimberly A. Neely, MD, and David A. Quillen, MD.)

719
 CHAPTER 13

VASCULAR TUMORS AND MALFORMATIONS OF

THE UVEA

CIRCUMSCRIBED CHOROIDAL HEMANGIOMA

General Considerations
There are several vascular tumors and malformations that can affect the uveal tract.
The most important is choroidal hemangioma, which can occur as a circumscribed
tumor or as a diffuse tumor in patients with variations of the Sturge–Weber
syndrome. This section covers the topic of circumscribed choroidal hemangioma, a
benign vascular tumor that has been the subject of considerable attention in the
literature (1–64). The etiology of circumscribed choroidal hemangioma is unknown,
but it is usually diagnosed in adulthood when it becomes symptomatic. It is
speculated that some cases may be congenital or develop in early childhood.
Circumscribed choroidal hemangioma usually has typical clinical features.

Clinical Features
Circumscribed choroidal hemangioma is almost always unilateral. It appears as a
subtle, red-orange mass in the posterior choroid. It can produce visual loss because
of a subfoveal location or a secondary retinal detachment that involves the fovea
(1–6). This tumor can induce overlying hyperplasia and fibrous metaplasia of the
overlying retinal pigment epithelium. In addition to retinal detachment, secondary
retinoschisis commonly occurs over or adjacent to the tumor. Occasionally,
neovascular glaucoma can develop, particularly if there is a complete retinal
detachment, and the subsequent pain may necessitate enucleation (1,3,23,54).

Diagnostic Approaches
Fluorescein angiography typically shows hyperfluorescence of the tumor blood

720
vessels in the pre-arterial phase and diffuse late staining of the mass (8–10).
Indocyanine green angiography reveals early filling of the lesion and a characteristic
“wash out” of the hyperfluorescence in the later frames (11,12). A-scan
ultrasonography shows high internal reflectivity within the tumor, and B-scan
ultrasonography shows a placoid or ovoid choroidal mass pattern with acoustic
solidity. U ltrasonography occasionally demonstrates a highly reflective plaque over
the tumor surface, which corresponds to fibrous or osseous metaplasia of the
overlying RPE.
Recent studies with EDIOCT have shown that the tumor usually has a dome-
shaped contour with no compression of the choriocapillaris (16,17). Computed
tomography and magnetic resonance can also demonstrate choroidal hemangioma,
but the results are not necessarily diagnostic. With MRI, choroidal hemangioma
generally differs from other intraocular tumors in that it is hyperintense to vitreous
on T1-weighted images and isointense on T2-weighted images. Most other
intraocular tumors are hypointense on T2 images.

Pathology
Grossly, a circumscribed choroidal hemangioma is a red-orange placoid or ovoid
choroidal tumor. Microscopically, it is usually composed of large congested blood
vessels separated by thin intervascular septae. Overlying cystoid retinal edema and
retinoschisis are consistent features over choroidal hemangiomas that come to
histopathologic examination (1).

Management
There have been a numerous reports publications on the management of
circumscribed choroidal hemangioma. If the affected patient is asymptomatic, no
treatment is necessary. When there is visual loss because of a serous detachment of
the fovea, the traditional treatment was laser photocoagulation to the tumor surface
to induce resolution of the subretinal fluid (18–20). Plaque or external beam
radiotherapy can be employed in cases with more advanced detachment (21–30).
Plaque radiotherapy has been effective in treating choroidal hemangioma with total
retinal detachment resulting in reattachment of the retina (24). External beam
irradiation, delivering about 2000 cGy to the whole eye, has been effective in
bringing about a decrease in tumor thickness and resolution of the retinal
detachment for both circumscribed and diffuse choroidal hemangioma.
There has been recent enthusiasm for other methods of treatment. Transpupillary
thermotherapy has met with some success (31–38). In recent years, a number of
authors have reported good results with photodynamic therapy (PDT), using a
method similar to that used for age-related macular degeneration (39–52). We have
been impressed with PDT and its ability to induce decrease in tumor thickness,
resolution of subretinal fluid and improvement of vision. Optical coherence
tomography can be used to document the presence of cystoid retinal edema and
subretinal fluid before and after treatment with PDT. We have seen a dramatic
resolution of these findings and a significant return of vision in a number of patients
treated with PDT. In rare instances, painful neovascular glaucoma may necessitate
enucleation (58).

721
Selected References
Large Series
1. 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.
2. Anand R, Augsburger JJ, Shields JA. Circumscribed choroidal hemangiomas.
Arch Ophthalmol 1989;107:1338–1342.
3. 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.
4. Mashayekhi A, Shields CL. Circumscribed choroidal hemangioma. Curr Opin
Ophthalmol 2003;14:142–149.
5. Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal
tract. The 2006 Taylor Smith Lecture. Retina 2005;25:767–771.
6. Heimann H, Damato B. Congenital vascular malformations of the retina and
choroid. Eye (Lond) 2010;24(3):459–467.
7. 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 2004;35:383–393.

Imaging
8. Norton EWD, Gutman F. Fluorescein angiography of hemangiomas of the
choroid. Arch Ophthalmol 1967;78:121–125.
9. Lanning R, Shields JA. Comparison of radioactive phosphorus (32P) uptake test
in comparable sized choroidal melanomas and hemangiomas. Am J Ophthalmol
1979;87:769–772.
10. Jarrett WH 2nd, Hagler WS, Larose JH, et al. Clinical experience with
presumed hemangioma of the choroid: radioactive phosphorus uptake studies
as an aid in differential diagnosis. Trans Sect Ophthalmol Am Acad Ophthalmol
Otolaryngol 1976;81:862–870.
11. Shields CL, Shields JA, De Potter P. Patterns of indocyanine green angiography
of choroidal tumors. Br J Ophthalmol 1995;79:237–245.
12. Arevalo JF, Shields CL, Shields JA, et al. Circumscribed choroidal hemangioma:
characteristic features with indocyanine green videoangiography. Ophthalmology
2000;107:344–350.
13. Ramasubramanian A, Shields CL, Harmon SA, Shields JA. Autofluorescence of
choroidal hemangioma in 34 consecutive eyes. Retina 2010;30(1):16–22.
14. Torres VL, Brugnoni N, Kaiser PK, Singh AD. Optical coherence tomography
enhanced depth imaging of choroidal tumors. Am J Ophthalmol
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15. Liu W, Zhang Y, Xu G, et al. Optical coherence tomography for evaluation of
photodynamic therapy in symptomatic circumscribed choroidal hemangioma.
Retina 2011;31(2):336–343.
16. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014;34(8):1495–1512.
17. Rojanaporn D, Kaliki S, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography of circumscribed choroidal hemangioma in 10

722
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Management in General
18. Augsburger JJ, Shields JA, Moffat KP. Circumscribed choroidal hemangiomas:
long-term visual prognosis. Retina 1981;1:56–61.
19. Sanborn GE, Augsburger JJ, Shields JA. Treatment of circumscribed choroidal
hemangiomas. Ophthalmology 1982;89:1374–1380.
20. Shields JA. The expanding role of laser photocoagulation for intraocular
tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 1994;14:310–
322.

Plaque Radiotherapy
21. Zografos L, Bercher L, Chamot L, et al. Cobalt-60 treatment of choroidal
hemangiomas. Am J Ophthalmol 1996;121:190–199.
22. Shields JA. Radiotherapy of circumscribed choroidal hemangiomas.
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23. Hannouche D, Frau E, Desjardins L, et al. Efficacy of proton therapy in
circumscribed choroidal hemangiomas associated with serous retinal
detachment. Ophthalmology 1997;104:100–103.
24. Chao AN, Shields CL, Shields JA, et al. Plaque radiotherapy for choroidal
hemangioma with total retinal detachment and iris neovascularization. Retina
2001;21:682–684.
25. Kivela T, Tenhunen M, Joensuu T, et al. Stereotactic radiotherapy of
symptomatic circumscribed choroidal hemangiomas. Ophthalmology
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26. Aizman A, Finger PT, Shabto U , et al. Palladium 103 (103 Pd) plaque radiation
therapy for circumscribed choroidal hemangioma with retinal detachment. Arch
Ophthalmol 2004;122:1652–1656.
27. Frau E, Rumen F, Noel G, et al. Low-dose proton beam therapy for
circumscribed choroidal hemangiomas. Arch Ophthalmol 2004;122:1471–1475.
28. Levy-Gabriel C, Rouic LL, Plancher C, et al. Long-term results of low-dose
proton beam therapy for circumscribed choroidal hemangiomas. Retina
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29. López-Caballero C, Saornil MA, De Frutos J, et al. High-dose iodine-125
episcleral brachytherapy for circumscribed choroidal haemangioma. Br J
Ophthalmol 2010; 94(4):470–473.
30. Arepalli S, Shields CL, Kaliki S, Komarnicky L, Shields JA. Diffuse choroidal
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Transpupillary Thermotherapy
31. Othmane IS, Shields CL, Shields JA, et al. Circumscribed choroidal hemangioma
managed by transpupillary thermotherapy. Arch Ophthalmol 1999;117:136–137.
32. Kamal A, Watts, AR, Rennie IG. Indocyanine green enhanced transpupillary of
circumscribed choroidal haemangioma. Eye 2000;14:701–705.
33. Garcia-Arumi J, Ramsay LS, Guraya BC. Transpupillary thermotherapy for
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723
35. Vianna RN, Fernandes L, Muralha A, et al. Transpupillary thermotherapy in the
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36. Gunduz K. Transpupillary thermotherapy in the management of circumscribed
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Photodynamic Therapy
39. Madreperla SA. Choroidal hemangioma treated with photodynamic therapy
using verteporfin. Arch Ophthalmol 2001;119:1606–1610.
40. Schmidt-Erfurth U M, Michels S, Kusserow C, et al. Photodynamic therapy for
symptomatic choroidal hemangioma: visual and anatomic results.
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41. Verbraak FD, Schlingemann RO, Keunen JE, et al. Longstanding symptomatic
choroidal hemangioma managed with limited PDT as initial or salvage therapy.
Graefes Arch Clin Exp Ophthalmol 2003;241:891–898.
42. Porrini G, Giovannini A, Amato G, et al. Photodynamic therapy of
circumscribed choroidal hemangioma. Ophthalmology 2003;110:674–680.
43. Scott IU , Gorscak J, Gass JD, et al. Anatomic and visual acuity outcomes
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retinal detachment. Ophthalmic Surg Lasers Imaging 2004;35:281–291.
44. Bains H, Gunduz K. Transpupillary thermotherapy in the management of
circumscribed choroidal hemangioma. Surv Ophthalmol 2004;49:316–327.
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edema following photodynamic therapy of choroidal hemangioma. Ophthalmic
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47. Chan RV, Yonekawa Y, Lane AM, et al. Proton beam irradiation using a light-
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circumscribed macular choroidal hemangioma in Chinese patients. Am J
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49. Blasi MA, Tiberti AC, Scupola A, et al. Photodynamic therapy with verteporfin
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724
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intravitreal dexamethasone implant (Ozurdex®) for circumscribed choroidal
hemangioma]. J Fr Ophtalmol 2012;35(10):798–802.
Anti-Vascular Endothelial Growth Factor
53. Querques G, Forte R, Querques L, Souied EH. Intravitreal ranibizumab for
choroidal neovascularization associated with circumscribed choroidal
haemangioma. Clin Experiment Ophthalmol 2011;39(9):916–918.
54. Mandal S, Naithani P, Venkatesh P, Garg S. Intravitreal bevacizumab (avastin)
for circumscribed choroidal hemangioma. Indian J Ophthalmol 2011;59(3):248–
251.
Propranolol
55. Arevalo JF, Arias JD, Serrano MA. Oral propranolol for exudative retinal
detachment in diffuse choroidal hemangioma. Arch Ophthalmol 2011;129:1373–
1375.
56. Sanz-Marco E, Gallego R, Siaz-Liopis M. Oral propranolol for circumscribed
choroidal hemangioma. Case Rep Ophthalmol 2011;2:84–90.
57. Tanabe H, Sahashi K, Kitano T, et al. Effects of oral propranolol on
circumscribed choroidal hemangioma: a pilot study. JAMA Ophthalmol
2013;131:1617–1622.
Case Reports
58. 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.
59. Cohen VM, Rundle PA, Rennie IG. Choroidal hemangiomas with exudative
retinal detachments during pregnancy. Arch Ophthalmol 2002;120:862–864.
60. Amirikia A, Scott IU , Capo H, et al. Increasing hyperopia and esotropia as the
presenting signs of bilateral diffuse choroidal hemangiomas in a patient with
Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 2002;39:121–122.
61. Li H, Wen F, Wu D. Polypoidal choroidal vasculopathy in a patient with
circumscribed choroidal hemangioma. Retina 2004;24:629–631.
62. Shields CL, Materin MA, Marr BP, et al. Resolution of advanced cystoid macular
edema following photodynamic therapy of choroidal hemangioma. Ophthalmic
Surg Lasers Imaging 2005;36:237–239.
63. Shields JA, Eagle RC Jr, Shields CL, et al. Total blindness from circumscribed
choroidal hemangioma in a child. Am J Ophthalmol 2005;139:1113–1114.
64. Tuncer S, Demirci H, Shields CL, Shields JA. Polypoidal choroidal vasculopathy
following photodynamic therapy for choroidal hemangioma. Eur J Ophthalmol
2009; 19(1):159–162.

725
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: CLINICAL FEATURES
In most instances, the characteristic orange color of a circumscribed choroidal hemangioma
strongly suggests the diagnosis.

Figure 13.1. Subtle, asymptomatic choroidal hemangioma located nasal to the optic disc in a 69-year-old
woman. Because it is the same color as the background fundus, it is often difficult to visualize in photographs,
but it would appear elevated with binocular indirect ophthalmoscopy.

Figure 13.2. Choroidal hemangioma inferior to the fovea in a 47-year-old woman.

726
Figure 13.3. Choroidal hemangioma superior to the fovea in a 46-year-old man.

Figure 13.4. Choroidal hemangioma nasal to the optic disc and slightly overhanging the disc in a 39-year-old
woman.

Figure 13.5. Choroidal hemangioma superior to the optic disc causing visual loss due to a secondary serous
detachment of the retina extending into the foveal area.

727
Figure 13.6. Choroidal hemangioma inferior to the fovea causing visual loss due to foveal elevation by the
tumor.

728
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: WIDE-ANGLE
IMAGING

Figure 13.7. Choroidal hemangioma with shallow subretinal fluid superior to the optic disc in a 54-year-old
woman.

Figure 13.8. Choroidal hemangioma with shallow subretinal fluid inferotemporal to the fovea in a 71-year-old
man.

729
Figure 13.9. Choroidal hemangioma superior to the optic disc in a 54-year-old woman.

Figure 13.10. Choroidal hemangioma inferior to the disc and fovea in a 63-year-old woman.

Figure 13.11. Choroidal hemangioma in the superior half of the macular area with evident secondary retinal
detachment.

730
Figure 13.12. Slightly larger choroidal hemangioma superotemporal to the macular region in a 61-year-old
man.

731
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: EFFECTS ON
ADJACENT STRUCTURES

In some instances, circumscribed choroidal hemangioma can cause secondary hyperplasia,

fibrous metaplasia, or osseous metaplasia of the retinal pigment epithelium, as well as
secondary retinal detachment and secondary retinoschisis.

Figure 13.13. Focus of proliferation of the retinal pigment epithelium on the surface of a choroidal
hemangioma superior to the optic disc in a 30-year-old woman.

Figure 13.14. Subtle retinal pigment epithelium hyperplasia and fibrous metaplasia over a choroidal
hemangioma in a 30-year-old woman.

732
Figure 13.15. Very subtle subfoveal choroidal hemangioma causing loss of foveal reflex.

Figure 13.16. Optical coherence tomography of the lesion in Figure 13.15, showing marked elevation of
subfoveal choroid and shallow subretinal fluid with photoreceptor attenuation.

Figure 13.17. Moderate-sized choroidal hemangioma in inferior macular region.

Figure 13.18. Optical coherence tomography of the lesion shown in Figure 13.17, demonstrating the elevated
choroidal mass with subfoveal fluid.

733
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: FLUORESCEIN AND
INDOCYANINE GREEN ANGIOGRAPHY

Although the findings are not pathognomonic, fluorescein angiography and indocyanine green
angiography can often be helpful in differentiating a choroidal hemangioma from amelanotic
melanoma, choroidal metastasis, and other nonpigmented fundus tumors.

Figure 13.19. Choroidal hemangioma located in the central macular area.

Figure 13.20. Standard fluorescein angiogram of lesion depicted in Figure 13.19 in the early arterial phase,
showing reticular hyperfluorescence corresponding to the filling of choroidal vessels in the tumor.

734
Figure 13.21. Recirculation phase of lesion shown in Figure 13.19 demonstrating marked hyperfluorescence
of the lesion.

Figure 13.22. Choroidal hemangioma temporal to the foveal region in the left eye of a 39-year-old man.

Figure 13.23. Early indocyanine green angiography of lesion shown in Figure 13.22 revealing reticular
hyperfluorescence of the lesion.

735
Figure 13.24. Late indocyanine green angiography of lesion shown in Figure 13.22 demonstrating the halo of
hyperfluorescence and the central “wash out” phenomenon.

736
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA:
ULTRASONOGRAPHY

Ultrasonography of choroidal hemangioma generally shows high internal reflectivity with A-scan
and acoustic solidity with B-scan. Fibrous or osseous metaplasia of the overlying pigment
epithelium can produce a highly reflective echo that can sometimes confuse the diagnosis.

Figure 13.25. Clinical appearance of a tumor in the macular area in a 70-year-old woman.

Figure 13.26. A-scan ultrasonogram, showing high initial spike and high internal reflectivity in the tumor.

737
Figure 13.27. B-scan ultrasonogram, showing acoustic solidity and lack of choroidal excavation.

Figure 13.28. Large circumscribed choroidal hemangioma with severe overlying fibrous and/or osseous
metaplasia of retinal pigment epithelium in a 9-year-old boy.

Figure 13.29. B-scan ultrasonogram of the lesion in Figure 13.28, showing highly reflective plaque on the
tumor surface.

Figure 13.30. B-scan ultrasonogram at lowered sensitivity, showing the persistence of the echo from the
surface plaque after soft tissue echoes have disappeared, suggesting calcification of the overlying plaque.

738
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA:
ULTRASONOGRAPHY, COMPUTED TOMOGRAPHY, AND MAGNETIC
RESONANCE IMAGING

Computed tomography and magnetic resonance imaging can demonstrate characteristic but not
pathognomonic features of circumscribed choroidal hemangioma. In most instances, the
diagnosis can be established without these modalities, but they can be helpful in difficult cases.
Shown is the case of a 16-year-old girl with a circumscribed choroidal hemangioma that was
studied with CT and MRI.

Figure 13.31. Large red choroidal hemangioma temporal to the macular area.

Figure 13.32. B-scan ultrasonogram, showing characteristic acoustic solidity.

739
Figure 13.33. Axial computed tomography, showing a large intraocular mass.

Figure 13.34. Axial magnetic resonance imaging (T1-weighted image), showing a mass hyperintense to the
vitreous.

Figure 13.35. Axial magnetic resonance imaging (T1-weighted image with gadolinium enhancement),
showing marked enhancement of the mass.

Figure 13.36. Axial magnetic resonance imaging (T2-weighted image), showing poor visibility of the mass
because it is isointense to the vitreous.

740
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: FUNDUS
AUTOFLUORESCENCE

Choroidal hemangioma shows various patterns on fundus autofluorescence, depending on the

chronicity of the subretinal fluid. Some show lipofuscin-related hyperautofluorescence of the
overlying retinal pigment epithelium whereas chronically degenerated retinal pigment
epithelium is hypoautofluorescent.

Figure 13.37. Choroidal hemangioma located in inferotemporal macular region.

Figure 13.38. Fundus autofluorescence showing rim of hyperautofluorescence but mainly central chronic
hypoautofluorescence from retinal pigment epithelium loss.

741
Figure 13.39. Choroidal hemangioma in the superior juxtapapillary region.

Figure 13.40. Fundus autofluorescence depicts fresh overlying lipofuscin hyperautofluorescence and free
fluorphores in subfoveal fluid.

Figure 13.41. Choroidal hemangioma in the inferior perimacular region.

Figure 13.42. Fundus autofluorescence shows chronic retinal pigment epithelial atrophy as

742
hypoautofluorescent and surrounding subretinal fluid as hyperautofluorescent.

743
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA:
CLINICOPATHOLOGIC CORRELATION OF A PROGRESSIVELY
ENLARGING TUMOR

The majority of circumscribed choroidal hemangiomas are stable lesions that show no
significant growth. Occasionally, this tumor can show progressive enlargement, possibly due to
vascular engorgement. This is particularly likely to occur during pregnancy. Illustrated is a case
of progressive growth of circumscribed choroidal hemangioma that ultimately necessitated
enucleation.

Figure 13.43. Choroidal hemangioma superonasal to the optic disc in a 30-year-old man as seen in 1981. It
was treated elsewhere with a laser because of a shallow serous detachment of the fovea.

Figure 13.44. The lesion 3 years later in 1984, showing apparent increase in the size and fibrous metaplasia
of the retinal pigment epithelium.

744
Figure 13.45. Appearance of the lesion in 1989, showing further enlargement. A retinal detachment
progressed in spite of further laser treatment.

Figure 13.46. The appearance of the lesion in 1990, showing further enlargement and large bullous retinal
detachment. Pain secondary to glaucoma and low suspicion of atypical choroidal melanoma prompted
enucleation of the blind eye.

Figure 13.47. Gross photograph of the sectioned eye, showing a red tumor in the posterior pole and overlying
total retinal detachment.

745
Figure 13.48. Photomicrograph showing large dilated, thin-walled vascular channels. (Hematoxylin–eosin
×100.)

746
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA:
CLINICOPATHOLOGIC CORRELATION OF A LARGE TUMOR
SIMULATING CHOROIDAL MELANOMA

A clinicopathologic correlation is shown of a circumscribed choroidal hemangioma that had

produced a loss of vision by the age of 7 years and possibly even earlier.

Shields JA, Eagle RC Jr, Shields CL, et al. Total blindness from circumscribed choroidal
hemangioma in a child. Am J Ophthalmol 2005;139:1113–1114.

Figure 13.49. Retinal detachment immediately behind the lens in a 38-year-old woman with a blind eye for
many years. She had no evidence of Sturge–Weber syndrome.

Figure 13.50. Wide-angle image, showing large bullous retinal detachment. A red-orange mass is barely seen
through the hazy subretinal fluid.

747
Figure 13.51. B-scan ultrasonogram, showing a large, dome-shaped mass with acoustic solidity and overlying
bullous retinal detachment. The differential diagnosis included choroidal melanoma and choroidal
hemangioma. The blind eye was enucleated.

Figure 13.52. Sectioned eye, showing a large, red choroidal mass with secondary retinal detachment. The
retina is still attached to the central aspect of the tumor.

Figure 13.53. Microscopic section through a superficial aspect of the mass, showing dilated veins compatible
with choroidal hemangioma and overlying fibrous metaplasia of the retinal pigment epithelium and cystoid
retinopathy. (Hematoxylin–eosin ×40.)

748
Figure 13.54. Section through the main aspect of the tumor, showing large, thin-walled vascular channels filled
with blood, compatible with choroidal hemangioma. (Hematoxylin–eosin ×100.)

749
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: LASER
PHOTOCOAGULATION AND PHOTODYNAMIC THERAPY

Laser photocoagulation can be employed when a circumscribed choroidal hemangioma causes

visual loss due to a serous detachment of the sensory retina. Currently, PDT is more often used
as it directly causes involution of the tumor with subsequent resolution of subretinal fluid.

Figure 13.55. Circumscribed choroidal hemangioma superior to the foveal area in a 48-year-old man. There
was visual loss due to a serous detachment of the fovea.

Figure 13.56. Appearance of the lesion shown in Figure 13.55 immediately after properly placed laser
photocoagulation.

750
Figure 13.57. Circumscribed choroidal hemangioma superior to the macula.

Figure 13.58. Optical coherence tomography depicts the elevated choroidal mass with subfoveal fluid.

Figure 13.59. Following photodynamic therapy for lesion in Figure 13.57, the mass showed regression.

Figure 13.60. Following photodynamic therapy for lesion in Figure 13.57, the subretinal fluid showed

751
resolution.

752
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: PHOTODYNAMIC
THERAPY

PDT has become widely used to manage choroidal hemangiomas with secondary retinal
detachment and cystoid retinal edema. In many instances, it has been shown to decrease or
eliminate subretinal fluid, decrease cystoid retinal edema, improve vision, and induce shrinkage
of the choroidal hemangioma. Optical coherence tomography can be used to document these
changes.

1. Schmidt-Erfurth UM, Michels S, Kusserow C, et al. Photodynamic therapy for symptomatic

choroidal hemangioma: visual and anatomic results. Ophthalmology 2002;109:2284–2294.
2. Shields CL, Materin MA, Marr BP, et al. Resolution of advanced cystoid macular edema
following photodynamic therapy of choroidal hemangioma. Ophthalmic Surg Lasers Imaging
2005;36:237–239.

Figure 13.61. Circumscribed choroidal hemangioma in the superior juxtapapillary region with subtle subretinal
fluid resulting in 20/40 visual acuity.

Figure 13.62. Indocyanine green angiography confirms the vascular mass.

753
Figure 13.63. Optical coherence tomography through the foveola reveals temporal subretinal fluid with
photoreceptor loss.

Figure 13.64. Optical coherence tomography through the tumor shows the marked elevation and shallow
subretinal fluid.

Figure 13.65. Following photodynamic therapy, the tumor appears stable.

Figure 13.66. Following photodynamic therapy, optical coherence tomography shows near complete resolution
of subretinal fluid. Visual acuity returned to 20/25.

754
• CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: PHOTODYNAMIC
THERAPY

In this case, PDT was successful in restoring foveal anatomy and in bringing about visual
improvement. Before treatment is on the left and after treatment on the right.

Figure 13.67. Choroidal hemangioma in the inferotemporal macular region.

Figure 13.68. Following photodynamic therapy, the tumor scar is visible.

755
Figure 13.69. B-scan ultrasonography, showing the elevated tumor with acoustic solidity.

Figure 13.70. Following photodynamic therapy, ultrasonography depicts tumor flattening.

Figure 13.71. Optical coherence tomography demonstrating intraretinal and subretinal fluid.

Figure 13.72. Following photodynamic therapy, the subretinal fluid completely resolved.

756
• CHOROIDAL HEMANGIOMA: PLAQUE RADIOTHERAPY
Plaque brachytherapy or proton beam irradiation can be employed for circumscribed choroidal
hemangiomas that produce a serous retinal detachment that cannot be controlled with standard
laser treatment. Illustrated is a case that showed excellent response to plaque radiotherapy after
laser treatment failed to control the subretinal fluid.

Chao AN, Shields CL, Shields JA, et al. Plaque radiotherapy for choroidal hemangioma with total
retinal detachment and iris neovascularization. Retina 2001;21:682–684.

Figure 13.73. Fundus drawing of circumscribed choroidal hemangioma temporal to the foveal region in a 39-
year-old man. Note the retinal detachment inferiorly, shown in blue. The detachment could not be controlled
with laser treatment.

Figure 13.74. Wide-angle fundus photograph of the tumor shown in Figure 13.73.

757
Figure 13.75. Standard fundus photograph, showing the typical clinical appearance of circumscribed choroidal
hemangioma.

Figure 13.76. B-scan ultrasonogram of the lesion, showing an acoustically solid mass typical of choroidal
hemangioma. Note the linear echo representing a retinal detachment inferior to the lesion.

Figure 13.77. B-scan ultrasonogram about 1 year after plaque radiotherapy, showing complete resolution of
the elevated mass and associated retinal detachment.

758
Figure 13.78. Clinical appearance of the lesion 1 year after plaque radiotherapy, showing complete resolution
of the mass.

759
DIFFUSE CHOROIDAL HEMANGIOMA

General Considerations
Diffuse choroidal hemangioma frequently is located ipsilateral to a facial
hemangioma (“nevus flammeus”), usually as a component of a variant of Sturge–
Weber syndrome that can also include leptomeningeal hemangiomatosis, seizures,
congenital and juvenile and other manifestations (1–8). It is generally diagnosed
when the affected patient is young (median age 8 years), either because the facial
hemangioma prompts a fundus examination or because of visual loss from
hyperopic amblyopia or secondary retinal detachment. The ipsilateral pupil
characteristically shows a bright red reflex (“tomato catsup fundus”) in contrast to
the normal opposite pupil (3). The facial nevus flammeus and the choroidal
hemangioma can sometimes occur bilaterally (4).

Clinical Features
Ophthalmoscopy reveals a diffuse red-orange thickening of the posterior choroid.
The tumor is often thickest in the macular area, and it sometimes blends
imperceptibly into the normal choroid anteriorly near the equator. Cystoid
degeneration of the overlying retina and disruption of the retinal pigment
epithelium commonly occur. Mildly dilated and tortuous retinal blood vessels are
frequently present in eyes with diffuse choroidal hemangioma. Diffuse choroidal
hemangioma can also produce a total retinal detachment and secondary neovascular
glaucoma.

Diagnostic Approaches
U ltrasonography of a diffuse choroidal hemangioma demonstrates a markedly
thickened choroid, often with overlying retinal detachment. The mass shows high
internal reflectivity with A-scan and acoustic solidity with B-scan. Fluorescein
angiography shows diffuse leakage similar to the circumscribed choroidal
hemangioma but with more widespread involvement (9). Autofluorescence shows
bright hyperautofluorescence if the subretinal fluid is fresh and loss of
autofluorescence in those with chronic retinal detachment or subretinal fibrosis (10).
Optical coherence tomography discloses thickening of the choroid with expanded
choroidal vessels and smooth surface.

Pathology
Pathologically, diffuse choroidal hemangioma is very similar to the circumscribed
type except that it is larger in diameter and less well defined (1).

Management
The management of diffuse choroidal hemangioma can be difficult, and several
therapeutic options are available, mostly including external radiotherapy (11–15),
plaque radiotherapy (16,17), transpupillary thermotherapy (18), PDT (19–24), and
oral propranolol (25–27). In some cases, especially those without retinal

760
detachment, this tumor is managed by observation, refraction for induced
hyperopia, and possibly amblyopic therapy. Plaque radiotherapy or external beam
radiotherapy, delivering approximately 2,000 to 3,500 cGy to the tumor, has been
effective in reducing tumor thickness and resolution of the retinal detachment. PDT
can be effective if the subretinal fluid is shallow and the tumor smaller in basal
diameter. Oral propranolol has been reported in single cases to be effective for
resolution of subretinal fluid but results remain controversial (25–27).

Selected References
Large Series
1. 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.
2. Sullivan TJ, Clarke MP, Morin JD. The ocular manifestations of the Sturge-
Weber syndrome. J Pediatr Ophthalmol Strabismus 1992;29:349–356.
3. Susac JO, Smith JL, Scelfo RJ. The “tomato-catsup” fundus in Sturge-Weber
syndrome. Arch Ophthalmol 1974;92:69–70.
4. Lindsey PS, Shields JA, Goldberg RE, et al. Bilateral choroidal hemangiomas
and facial nevus flammeus. Retina 1981;1:88–95.
5. Scott IU , Alexandrakis G, Cordahi GJ, Murray TG. Diffuse and circumscribed
choroidal hemangiomas in a patient with Sturge-Weber syndrome. Arch
Ophthalmol 1999; 117(3):406–407.
6. Amirikia A, Scott IU , Murray TG. Bilateral diffuse choroidal hemangiomas with
unilateral facial nevus flammeus in Sturge-Weber syndrome. Am J Ophthalmol
2000;130(3):362–364.
7. Wen F, Wu D. Indocyanine green angiographic findings in diffuse choroidal
hemangioma associated with Sturge-Weber syndrome. Graefes Arch Clin Exp
Ophthalmol 2000;238(7):625–627.
8. 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.

Imaging
9. Horgan N, O’Keefe M, McLoone E, Lanigan B. Fundus fluorescein angiographic
characterization of diffuse choroidal hemangiomas. J Pediatr Ophthalmol
Strabismus 2008; 45(1):26–30.
10. Ramasubramanian A, Shields CL, Harmon SA, et al. Autofluorescence of
choroidal hemangioma in 34 consecutive eyes. Retina 2010;30(1):16–22.

External Beam Radiotherapy

11. Gottlieb JL, Murray TG, Gass JD. Low-dose external beam irradiation for
bilateral diffuse choroidal hemangioma. Arch Ophthalmol 1998;116(6):815–817.
12. Zografos L, Egger E, Bercher L, et al. Proton beam irradiation of choroidal
hemangiomas. Am J Ophthalmol 1998;126(2):261–268.
13. Packwood EA, Havertape SA, Cruz OA, et al. Visual rehabilitation in a child
with diffuse choroidal hemangioma by using aggressive amblyopia therapy with
low-dose external beam irradiation. J AAPOS 2000;4:321–322.
14. Grant LW, Anderson C, Macklis RM, Singh AD. Low dose irradiation for diffuse

761
 choroidal hemangioma. Ophthalmic Genet 2008;29(4):186–188.
15. Yonekawa Y, MacDonald SM, Shildkrot Y, Mukai S. Standard fractionation low-
dose proton radiotherapy for diffuse choroidal hemangiomas in pediatric
Sturge-Weber syndrome. J AAPOS 2013;17(3):318–322.
Plaque Radiotherapy
16. Murthy R, Hanovaz SG, Naik M, et al. Ruthenium-106 plaque brachytherapy for
the treatment of diffuse choroidal haemangioma in Sturge-Weber syndrome.
Indian J Ophthalmol 2005;53(4):274–275.
17. Arepalli S, Shields CL, Kaliki S, et al. Diffuse choroidal hemangioma
management with plaque radiotherapy in 5 cases. Ophthalmology
2013;120(11):2358–2359.
Transpupillary Thermotherapy
18. Gambrelle J, Kivelä T, Grange JD. Sturge-Weber syndrome: decrease in
intraocular pressure after transpupillary thermotherapy for diffuse choroidal
haemangioma. Acta Ophthalmol 2011;89(2):190–193.
Photodynamic Therapy
19. Bains HS, Cirino AC, Ticho BH, et al. Photodynamic therapy using verteporfin
for a diffuse choroidal hemangioma in Sturge-Weber syndrome. Retina
2004;24:152–155.
20. Anand R. Photodynamic therapy for diffuse choroidal hemangioma associated
with Sturge Weber syndrome. Am J Ophthalmol 2003;136:758–760.
21. Bains HS, Cirino AC, Ticho BH, et al. Photodynamic therapy using verteporfin
for a diffuse choroidal hemangioma in Sturge-Weber syndrome. Retina
2004;24(1):152–155.
22. Huiskamp EA, Müskens RP, Ballast A, et al. Diffuse choroidal haemangioma in
Sturge-Weber syndrome treated with photodynamic therapy under general
anaesthesia. Graefes Arch Clin Exp Ophthalmol 2005;243(7):727–730.
23. Tsipursky MS, Golchet PR, Jampol LM. Photodynamic therapy of choroidal
hemangioma in Sturge-Weber syndrome, with a review of treatments for diffuse
and circumscribed choroidal hemangiomas. Surv Ophthalmol 2011;56(1):68–85.
24. Ang M, Lee SY. Multifocal photodynamic therapy for diffuse choroidal
hemangioma. Clin Ophthalmol 2012;6:1467–1469.

Propranolol
25. Arevalo JF, Arias JD, Serrano MA. Oral propranolol for exudative retinal
detachment in diffuse choroidal hemangioma. Arch Ophthalmol 2011;129:1373–
1375.
26. Thapa R, Shields CL. Oral propranolol therapy for management of exudative
retinal detachment from diffuse choroidal hemangioma in Sturge Weber
syndrome. Eur J Ophthalmol 2013;23(6):922–924.
27. Krema H, Yousef YA, Durairaj P, et al. Failure of systemic propranolol therapy
for choroidal hemangioma of Sturge-Weber syndrome: a report of 2 cases.
JAMA Ophthalmol 2013;131:681–683.

762
• DIFFUSE CHOROIDAL HEMANGIOMA: STURGE–WEBER
SYNDROME

Figure 13.79. Right facial hemangioma in a teen-aged boy. Note the prominent episcleral vessels on the
ipsilateral side. The acne is unrelated.

Figure 13.80. Photograph of the right fundus, showing the bright red color typical of diffuse choroidal
hemangioma (“tomato catsup fundus”) and no visibility of the normal choroidal pattern. Note also the
characteristic retinal venous tortuosity (arteries and veins) that is commonly seen in the affected fundus.

763
Figure 13.81. Photograph of the left fundus, showing a normal brunette background choroidal pattern and no
retinal vascular abnormalities.

Figure 13.82. Facial hemangioma of a 2-year-old boy with a variant of Sturge–Weber syndrome. In this case,
the right side of the face is extensively involved, including both eyelids, and the inferior portion of the left side is
also involved.

Figure 13.83. Right fundus of the patient shown in Figure 13.82. There is a total retinal detachment overlying a
diffuse choroidal hemangioma. Note again the characteristic retinal vascular tortuosity.

764
Figure 13.84. Color fluorescein angiogram of the fundus shown in Figure 13.83, clearly showing the retinal
detachment and the marked retinal venous tortuosity.

765
• DIFFUSE CHOROIDAL HEMANGIOMA: STURGE–WEBER
SYNDROME

Diffuse choroidal hemangioma usually occurs ipsilateral to a facial nevus flammeus, often as a
part of the Sturge–Weber syndrome. Other ocular components of the syndrome include
ipsilateral tortuous dilated epibulbar, and retinal vessels, retinal detachment, secondary
retinoschisis, and congenital or juvenile glaucoma.

Figure 13.85. Facial hemangioma (nevus flammeus). This shows the left side of the face, but the cutaneous
vascular lesion was bilateral. This lesion generally is distributed along the course of the ramifications of the
trigeminal nerve.

Figure 13.86. Epibulbar vascular changes in the patient shown in Figure 13.85. This excess vascular tissue is
usually located in the episclera but can involve the conjunctiva as well.

766
Figure 13.87. Appearance of the “tomato catsup” fundus secondary to a diffuse choroidal hemangioma. The
right eye is normal, and the left eye shows a more red background color. Note again the typical retinal vascular
tortuosity and the cupping of the optic disc. A few years later, a secondary retinal detachment developed and
required treatment.

Figure 13.88. Facial photograph of a 3-year-old child with bilateral facial nevus flammeus. He had bilateral
diffuse choroidal hemangiomas. He had extensive laser treatment for shallow retinal detachment.

Figure 13.89. The same patient shown in Figure 13.88 after 30 years. There has been no appreciable change
in the distribution of the facial lesion.

767
Figure 13.90. Fundus appearance at the same time as Figure 13.89. Note that the retina is attached and there
is pigment proliferation and gliosis. The retinal vein tortuosity in evident.

768
• DIFFUSE CHOROIDAL HEMANGIOMA: ULTRASONOGRAPHY AND
MAGNETIC RESONANCE IMAGING IN STURGE–WEBER
SYNDROME

Figure 13.91. Irregular left facial nevus flammeus in a 31-year-old woman. There is subtle involvement of the
temple and both upper and lower eyelids.

Figure 13.92. Wide-angle fundus image of the left eye of the patient shown in Figure 13.91, revealing a large,
diffuse, elevated choroidal hemangioma inferotemporal to the foveal region.

Figure 13.93. Axial magnetic resonance imaging in T1-weighted image, showing diffuse choroidal
hemangioma in the temporal aspect of the choroid in the left eye. Like the circumscribed choroidal

769
hemangioma, the lesion is hyperintense to the vitreous on T1-weighted image.

Figure 13.94. Axial magnetic resonance imaging in T2-weighted image. Note that the lesion is not visible
because it is isointense to the vitreous on T2-weighted image.

Figure 13.95. Another patient with irregular nevus flammeus, most pronounced on the right side and involving
both eyelids on the right side. Note also the right esotropia, secondary to diffuse choroidal hemangioma, that
extended beneath the fovea and caused amblyopia in early life.

770
Figure 13.96. B-scan ultrasonogram of the right eye of the patient shown in Figure 13.95, revealing a diffuse
choroidal hemangioma with acoustic solidity.

771
• DIFFUSE CHOROIDAL HEMANGIOMA: EXTERNAL BEAM
RADIOTHERAPY AND PLAQUE RADIOTHERAPY

In the past, surgical drainage of subretinal fluid and laser or cryotherapy was employed to treat
diffuse choroidal hemangiomas with limited success. Now, external beam irradiation (2,000–
3,500 cGy) or plaque radiotherapy (3,500 cGY) is successful in achieving retinal reattachment
in such cases.

Figure 13.97. Total retinal detachment over a diffuse choroidal hemangioma.

Figure 13.98. After 2,000 cGy of external beam irradiation to right eye the retina is totally reattached.

772
Figure 13.99. Extensive diffuse choroidal hemangioma with chronic subretinal fibrosis and total retinal
detachment.

Figure 13.100. Ultrasonography confirms the echogenic mass and inferior detachment.

Figure 13.101. Following plaque radiotherapy, the tumor shows involution and the retina is reattached.

773
Figure 13.102. Following plaque radiotherapy, ultrasonography confirms reduction in tumor thickness and
resolution of subretinal fluid.

774
 PHAKOMATOSIS PIGMENTOVASCULARIS

General Considerations
Phacomatosis pigmentovascularis represents the coexistence of a cutaneous vascular
malformation, most often nevus flammeus (port-wine stain), with melanocytic
nevus, most often ocular and/or dermal melanocytosis. There have been relatively
few clinical series published on this rare condition (1–4). In the dermatology
literature, small case series on this topic have been written. In the ophthalmology
literature, the relationship of this syndrome with glaucoma and melanoma has been
recognized.

Clinical Features
Phacomatosis pigmentovascularis is the combination of features of Sturge–Weber
syndrome with oculodermal melanocytosis (Nevus of Ota).

Diagnostic Approaches
This rare condition is best detected by external examination of the skin and
funduscopic examination. The patients can manifest nevus flammeus, choroidal
hemangioma, and/or choroidal melanoma. Testing with fluorescein angiography,
indocyanine green angiography, ultrasonography, and magnetic resonance imaging
can be helpful. High-resolution optical coherence tomography can assist in early
detection of tumors and subretinal fluid.

Pathology
There is little information available about the pathology of this rare condition.

Management
These patients should be followed up annually for the development of both
choroidal hemangioma and choroidal melanoma. U ltrasonography and optical
coherence tomography are useful diagnostic tests.

Selected References
1. Shields CL, Kligman BE, Suriano M, et al. Phacomatosis pigmentovascularis of
cesioflammea type in 7 cases. Combination of ocular pigmentation
(melanocytosis, melanosis) and nevus flammeus with risk for melanoma.
Ophthalmology 2011;129:746–750.
2. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch
Dermatol 2005;141:385–388.
3. Teekhasaenee C, Ritch R. Glaucoma in phacomatosis pigmentovascularis.
Ophthalmology 1997;104:150–157.
4. Tran HV, Zografos L. Primary choroidal melanoma in phacomatosis
pigmentovascularis IIa. Ophthalmology 2005;112:1232–1235.

775
• PHAKOMATOSIS PIGMENTOVASCULARIS
Phakomatosis pigmentovascularis generally manifests at birth with nevus flammeus and/or
oculodermal melanocytosis. Patients should be monitored life-long for the development of
choroidal hemangioma and melanoma.

Figure 13.103. Young baby shortly after birth with bilateral nevus flammeus.

Figure 13.104. Same child at older age with resolution of nevus flammeus following cutaneous laser therapy.

Figure 13.105. Right fundus of child in Figure 13.104 demonstrating ocular melanocytosis.

776
Figure 13.106. Left fundus of child in Figure 13.104 demonstrating no melanocytosis or hemangioma.

Figure 13.107. Elderly man with life-long bilateral nevus flammeus and subtle ocular melanocytosis.

Figure 13.108. Left fundus of man in Figure 13.107 showing melanoma and vitreous hemorrhage.

777
UVEAL HEMANGIOPERICYTOMA

General Considerations
Hemangiopericytoma, a tumor presumably composed of a proliferation of vascular
pericytes, is extremely rare in the uveal tract, with only a few reported cases (1–5).
In recent years, the existence of a true hemangiopericytoma in other parts of the
body has been challenged, and some of these tumors have been reclassified as
fibrous histiocytoma or solitary fibrous tumor. This tumor can occur in the
supraciliary region (3).

Clinical Features
U veal hemangiopericytoma is described as an amelanotic mass that can be clinically
similar to an amelanotic melanoma, leiomyoma, choroidal hemangioma, or
metastatic carcinoma.

Diagnostic Approaches
Fluorescein angiography shows early hyperfluorescence and marked late
hyperfluorescence. A-scan ultrasonography demonstrates low-to-medium internal
reflectivity, and B-scan ultrasonography shows acoustic hollowness and choroidal
excavation. None of these studies has specific findings for this tumor.

Pathology
Histopathologically, uveal hemangiopericytoma is composed of sinusoidal vascular
channels separated by spindle-shaped cells that have immunohistochemical and
electron microscopic features compatible with pericytes. Based on more recent
study, it is possible that some tumors classified as hemangiopericytoma could be
solitary fibrous tumors.

Management
Because uveal hemangiopericytoma is rare, there is no specific information on
treatment. Cases are usually diagnosed as choroidal melanoma or hemangioma, and
the tumor mostly treated by standard methods like enucleation or plaque
radiotherapy, under the assumption that the lesion is a melanoma.

Selected References
1. Papale JJ, Frederick AR, Albert DM. Intraocular hemangiopericytoma. Arch
Ophthalmol 1983;101:1409–1415.
2. Gieser SC, Hufnagel TJ, Jaros PA, et al. Hemangiopericytoma of the ciliary
body. Arch Ophthalmol 1988;106:1269–1272.
3. Brown HH, Brodsky MC, Hembree K, et al. Supraciliary hemangiopericytoma.
Ophthalmology 1991;98:378–382.
4. Toth J, Kerenyi AA, Suveges I, et al. Leiomyoma of the ciliary body and
hemangiopericytoma of the choroid. Pathol Oncol Res 1996;2:89–93.
5. Shimura M, Suzuki K, Fuse N, et al. Intraocular hemangiopericytoma. A case

778
report. Ophthalmologica 2001;215:378–382.

779
• CHOROIDAL HEMANGIOPERICYTOMA
Uveal hemangiopericytoma is rare, with only a few well-documented cases in the literature.
Depicted is the clinicopathologic correlation of such a case. (Case courtesy of Oscar Croxatto,
MD.)

Figure 13.109. Fundus photograph of an amelanotic fundus tumor.

Figure 13.110. Late fluorescein angiogram, showing intense hyperfluorescence of the lesion.

780
Figure 13.111. B-scan ultrasonogram, showing a choroidal mass with moderate acoustic hollowness and
choroidal excavation. The lesion was removed by local resection.

Figure 13.112. Photomicrograph showing closely compact cells with branching “staghorn” vessels.
(Hematoxylin–eosin ×100.)

Figure 13.113. Higher-magnification photomicrograph, showing spindle-shaped cells with small- and
medium-caliber vascular channels. (Hematoxylin–eosin ×250.)

Figure 13.114. Photomicrograph of reticulin-stained section, showing that the tumor cells are outside of the
basement membrane of blood vessels, characteristic of hemangiopericytoma. (Reticulin ×250.)

781
IRIS VASCULAR TUMORS AND MALFORMATIONS

General Considerations
Vascular tumors and pseudotumors can occur in the iris (1,2). Ferry reviewed
reported cases of iris hemangioma and concluded that almost all of them had been
misdiagnosed histopathologically and that they actually were vascular melanomas,
juvenile xanthogranuloma, or other granulomas (3). He raised some doubts about
the existence of iris hemangioma. However, there have been a number of cases of
iris hemangioma that are acceptable (4–29). Like hemangioma of the retina, iris
hemangioma can be classified into capillary, cavernous, and racemose types. Iris
varix has also been recognized (22). Iris hemangiomas are usually sporadic, but they
are rarely associated with the vascular neuro-oculocutaneous syndromes (27).

Clinical Features
Iris capillary hemangioma is seen rarely in children with congenital periocular
cutaneous capillary hemangioma. This tumor is a circumscribed or diffuse red iris
mass that tends to regress spontaneously, simultaneously with its cutaneous
counterpart.
There appear to be two variations of iris cavernous hemangioma. One can occur
in the iris stroma as a solitary cavernous vascular mass that can produce recurrent
hyphemas (18,23). The second type is more common and is typically very small,
multiple, and located near the pupillary border (12). It has been called iris
microhaemangioma or vascular tuft. It is generally subtle and best detected with slit-
lamp biomicroscopy but can be difficult to photograph. On occasion, it is located in
the iris stroma away from the pupillary border and is more clearly visible. This tiny
microhemangioma can occasionally bleed and cause a hyphema, which can resolve
and recur periodically (12). There is a rare association with a syndrome with similar
lesions in brain, kidney, and skin (27).
Arteriovenous communication (racemose hemangioma) of the iris is not a true
neoplasm but rather an anomalous arteriovenous malformation with a tangle of
vascular channels at the site of the communication (5). In a recent report of 14
cases, these unusual vascular malformations were divided into simple and complex
types (5). U nlike the retinal racemose hemangioma, it apparently has no systemic
associations.
Iris varix occurs as a smooth blue mass in the iris stroma. U nlike true vascular
tumors, it lacks a distinct blood supply and is generally hypofluorescent with
fluorescein angiography because the lesion has undergone thrombosis (22).

Pathology
There is limited histopathologic information available on iris hemangiomas. The
solitary cavernous hemangioma that we studied had features identical to better-
known cavernous hemangioma in the orbit. To our knowledge, there are no good
reports on the histopathology of iris pupillary microhemangiomas or arteriovenous
malformations. We suspect that it would show a uniformly enlarged but otherwise
normal blood vessel. Iris varix appears as a large, otherwise normal vein. It may

782
have histopathologic evidence of thrombosis, with blood in the lumen being clotted.

Management
Most iris hemangiomas are benign and nonprogressive and do not require treatment
if they are asymptomatic. Capillary hemangioma in young children can be observed
for regression which usually occurs gradually over a few months. Cavernous
hemangioma that causes recurrent hyphemas can be removed surgically by
iridectomy. Microhemangiomas at the pupillary can be managed by laser
photocoagulation if they cause recurrent hyphemas. Such patients should be
evaluated for systemic hemangiomatosis. Racemose hemangioma does not appear to
cause complications and can be simply observed periodically. Iris varix can be
removed surgically because of recurrent bleeding or because it can resemble a
hemorrhagic melanoma.

Selected References
Large Series
1. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119:407–414.
2. Shields CL, Shields PW, Manalac J, et al. Review of cystic and solid tumors of
the iris. Oman J Ophthalmol 2013;6(30):159–164.
3. Ferry AP. Hemangiomas of the iris and ciliary body. Do they exist? A search for
a histologically proved case. Int Ophthalmol Clin 1972;12(1):177–194.
4. Shields JA, Bianciotto C, Kligman BE, et al. Vascular tumors of the iris in 45
patients: The 2009 Helen Keller Lecture. Arch Ophthalmol 2010;128(9):1107–
1113.
5. Shields JA, Streicher TFE, Spirkova JHJ, et al. Arteriovenous malformation of
the iris in 14 cases. The 2004 Alvaro Rodriquez MD Gold Medal Award Lecture.
Arch Ophthalmol 2006;124:370–375.

Imaging
6. Meades KV, Francis IC, Kappagoda MB, et al. Light microscopic and electron
microscopic histopathology of an iris microhaemangioma. Br J Ophthalmol
1986;70(4):290–294.
7. Lee BJ, Jeng BH, Singh AD. OCT and ultrasound biomicroscopic findings in iris
arteriovenous malformation. Ophthalmic Surg Lasers Imaging 2008;39(5):426–
468.

Management
8. Bandello F, Brancato R, Lattanzio R, et al. Laser treatment of iris vascular tufts.
Ophthalmologica 1993;206:187–191.
9. Strauss EC, Aldave AJ, Spencer WH, et al. Management of prominent iris
vascular tufts causing recurrent spontaneous hyphema. Cornea 2005;24:224–
226.
10. Wyse JP, McWhae J, Simms C. Diagnosis and management of a spontaneous
hyphema from a microhemangioma suspended in the anterior chamber: a case
report. Can J Ophthalmol 2010;45(6):645–646.
11. Matlach J, Kasper K, Kasper B, et al. Successful argon and diode laser
photocoagulation treatment of an iris varix with recurrent hemorrhage. Eur J

783
 Ophthalmol 2013;23(3):431–435.
12. Ni N, Johnson T, Koval M, et al. Iris microhemangiomatosis with
videographically-documented active bleeding and visual loss. JAMA Ophthalmol
2013;131(12):1649–1651.
Case Reports
13. Naidoff MA, Kenyon KR, Green WR. Iris hemangioma and abnormal retinal
vasculature in a case of diffuse congenital hemangiomatosis. Am J Ophthalmol
1971;72:633–644.
14. Andersen SR, Other A. Varix of the iris. Arch Ophthalmol 1975;93(1):32–33.
15. Prost M. Cavernous hemangioma of the iris. Ophthalmologica 1987;195:183–
187.
16. Thomas R, Aylward GM, Billson FA. Spontaneous hyphaema from an iris
microhaemangioma. Aust N Z J Ophthalmol 1988;16:367–368.
17. Lam S. Iris cavernous hemangioma in a patient with recurrent hyphema. Can J
Ophthalmol 1993;28:36–39.
18. Ruttum MS, Mittelman D, Singh P. Iris hemangiomas in infants with periorbital
capillary hemangiomas. J Pediatr Strabismus 1993;30:331–333.
19. Shields JA, Shields CL, O’Rourk T. Racemose hemangioma of the iris. Br J
Ophthalmol 1996;80:770–771.
20. Ebenezer GJ, Daniel E, Job CK. Cavernous haemangioma of the iris in a leprosy
patient. Br J Ophthalmol 1997;81:610–612.
21. Bryce IG, Pai V, Bradbury JA. Spontaneous resolution of iris and cutaneous
haemangiomata in diffuse neonatal haemangiomatosis. Eye 1999;13:388–390.
22. Shields JA, Shields CL, Pulido J, et al. Iris varix simulating an iris melanoma.
Arch Ophthalmol 2000;118:707–710.
23. Larson SA, Oetting TA. Presumed iris hemangioma associated with multiple
central nervous system cavernous hemangiomas. Arch Ophthalmol
2002;120:984–985
24. Akram I, Reck AC, Sheldrick J. Iris microhaemangioma presenting with total
hyphaema and elevated intraocular pressure. Eye 2003;17:784–785.
25. Woo SJ, Kim CJ, Yu YS. Cavernous hemangioma of the iris in an infant. J
AAPOS 2004;8(5):499–501.
26. Bakke EF, Drolsum L. Iris microhaemangiomas and idiopathic juxtafoveolar
retinal telangiectasis. Acta Ophthalmol Scand 2006;84(6):818–822.
27. Thangappan A, Shields CL, Gerontis CC, et al. Iris cavernous hemangioma
associated with multiple cavernous hemangiomas in the brain, kidney, and skin.
Cornea. 2007;26:481–483.
28. Shields JA, Shields CL, Eagle RC Jr. Cavernous hemangioma of the iris. Arch
Ophthalmol 2008;126(11):1602–1603.
29. Broaddus E, Lystad LD, Schonfield L, et al. Iris varix: report of a case and
review of iris vascular anomalies. Surv Ophthalmol 2009;54(1):118–127.

784
• IRIS CAPILLARY AND CAVERNOUS HEMANGIOMA
Iris capillary hemangioma can occur in conjunction with the cutaneous capillary hemangioma
of infancy. Iris cavernous hemangioma can be an isolated lesion, or it can be associated with
similar systemic vascular lesions.

Ruttum MS, Mittelman D, Singh P. Iris hemangiomas in infants with periorbital capillary
hemangiomas. J Pediatr Strabismus 1993;30:331–333.

Figure 13.115. Facial capillary hemangioma involving the left eyelid in an infant. (Courtesy of Mark Ruttum, MD.)

Figure 13.116. Capillary hemangioma involving the superotemporal quadrant of the ipsilateral iris in the child
shown in Figure 13.115. (Courtesy of Mark Ruttum, MD.)

785
Figure 13.117. Appearance of the iris after spontaneous regression of the cutaneous and iris lesion.

Figure 13.118. Capillary hemangioma of the iris superiorly in an infant, associated with periocular cutaneous
hemangioma.

Figure 13.119. Presumed cavernous hemangioma in iris stroma inferiorly in an adult. Although difficult to
demonstrate photographically, the lesion appeared as a “bunch of grapes” similar to the cavernous
hemangioma seen in the retina. Slit-lamp examination also showed several globular vascular lesions at the
pupillary margin that are not visualized in the photograph.

786
Figure 13.120. Fluorescein angiography of the lesion shown in Figure 13.119, showing hypofluorescence of
the lesion. There are several vascular lesions at the pupillary margin that are hyperfluorescent.

787
• IRIS CAVERNOUS HEMANGIOMA: ISOLATED CASE, AND CASE WITH
CUTANEOUS AND CENTRAL NERVOUS SYSTEM CAVERNOUS
HEMANGIOMA

Iris cavernous hemangioma can occur as a solitary lesion or as part of a multiple cavernous
hemangioma syndrome. The syndrome of retinal cavernous hemangioma associated with similar
lesions of skin and central nervous system (CNS) is well known and is discussed later in the
section on retinal tumors. It is not so well known that iris cavernous hemangioma can also have
associated skin and CNS lesions, presumably part of the same syndrome. A case of solitary iris
cavernous hemangioma is illustrated. A case is also shown of an iris cavernous hemangioma in a
child who had hydrocephalus diagnosed at the age of 3 months secondary to multiple brain
hemangiomas. The child also had kidney and cutaneous hemangiomas. The iris lesion was
eventually found after it had caused a spontaneous hyphema.

Figure 13.121. Dark globular mass in the temporal aspect of the right iris in a 55-year-old man who had
experienced multiple spontaneous hyphemas.

Figure 13.122. Closer view of the lesion shown in Figure 13.121, more clearly depicting the large, blood-filled
spaces. The lesion was removed successfully by sector iridectomy.

788
Figure 13.123. Histopathology of the same lesion, showing large, cavernous channels characteristic of
cavernous hemangioma. Note the overlying blood in the anterior chamber (above) and the disruption of the iris
pigment epithelium (below).

Figure 13.124. Small blue-black mass at the superior edge of the pupil in the right eye of a 7-year-old girl with
a prior hyphema and negative family history.

Figure 13.125. Slit-lamp view of lesion shown in Figure 13.124. A blood-plasma level can be seen on the part
of the lesion to the left.

789
Figure 13.126. Magnetic resonance imaging of brain in T1-weighted image in child whose eye is shown in
Figure 13.124, demonstrating a paraventricular hyperintense mass, presumably a cavernous hemangioma.

790
• IRIS ARTERIOVENOUS COMMUNICATION (RACEMOSE
HEMANGIOMA)

Iris arteriovenous (AV) communication (racemose hemangioma) has typical but variable clinical
features. We have classified these lesions into simple and complex types. The first is a direct
arteriovenous communication, and the second has a more complex arrangement of blood
vessels at the site of the communication, similar to retinal arteriovenous communication. The
lesions are generally stationary and are not known to have systemic associations.

Shields JA, Streicher TFE, Spirkova JHJ, et al. Arteriovenous malformation of the iris in 14
cases. The 2004 Alvaro Rodriguez MD Gold Medal Award Lecture. Arch Ophthalmol
2006;124:370–375.

Figure 13.127. Dilated radial blood vessels in the iris inferiorly in an adult.

Figure 13.128. Fluorescein angiogram of the lesion shown in Figure 13.127, clearly demonstrating the lesion.
This was classified as a simple arteriovenous communication.

791
Figure 13.129. Similar vascular lesion in an adult woman at 1:30 to 2:30 meridians of the iris.

Figure 13.130. Fluorescein angiogram of the lesion shown in Figure 13.127, clearly demonstrating the lesion.
This was classified as a complex arteriovenous communication because the lesion had more intertwining
convolutions.

Figure 13.131. Racemose hemangioma of the iris in a 40-year-old man. The peculiar vascular complex
appears to be near the pupillary border.

792
Figure 13.132. Fluorescein angiogram of the lesion shown in Figure 13.131, clearly demonstrating the feeding
vessels to the vascular complex. This was classified as a complex arteriovenous communication.

793
• IRIS VARIX
Iris varix is rarely recognized clinically unless it undergoes thrombosis, at which time it becomes
visible as a blue-black mass that can simulate an iris melanoma. Such a case is illustrated.

Shields JA, Shields CL, Pulido J, et al. Iris varix simulating an iris melanoma. Arch Ophthalmol
2000;118:707–710.

Figure 13.133. Clinical appearance of a dark iris mass located nasally in the left eye in an adult male.

Figure 13.134. Ultrasound biomicroscopy, showing acoustic solidity of the mass. It was removed by sector
iridectomy.

794
Figure 13.135. Gross appearance of the excised specimen, showing a normal iris surrounding a dark mass.

Figure 13.136. Postsurgical appearance. A sector iridectomy was performed to remove the lesion, and a
pupilloplasty was done to make the pupil fairly round.

Figure 13.137. A large, blood-filled channel and an associated hemorrhage thicken and totally replace the iris
stroma (to the right). The pupillary part of the iris is seen at left. (Hematoxylin–eosin ×25.)

795
Figure 13.138. Another view, showing thrombosed varix (above) and compressed iris tissue (below).

796
 CHAPTER 14

OSSEOUS, MYOGENIC, NEUROGENIC,

FIBROUS, AND HISTIOCYTIC TUMORS OF THE
UVEA

CHOROIDAL OSTEOMA

General Considerations
Choroidal osteoma is an unusual benign bony tumor that has received much
attention in the literature (1–76). Its etiology and pathogenesis are unknown, but it
has typical clinical and histopathologic features. It is unilateral in 79% of cases, is
bilateral in 21% of cases, and is most often diagnosed in young adult women (67%)
(1–3). More than one family member has been affected in 5% of cases (1–3,5). The
mean age at diagnosis is 26 years, the median age is 25 years, and it has been
diagnosed in young children (1–4). Most cases are not strictly congenital. We have
noted the development of choroidal osteoma in previously normal choroid. Bilateral
total blindness from bilateral atypical choroidal osteoma has been recognized (52).

Clinical Features
Choroidal osteoma typically appears as a yellow-orange placoid, juxtapapillary, or
macular lesion with well-defined margins that may show pseudopodia-like
projections. One study of 74 eyes with choroidal osteoma disclosed that at 10 years,
tumor growth was documented in about 50%, tumor decalcification in about 50%,
visual loss greater than three lines in 50%, vision of 20/200 or worse in 50%, and
the development of choroidal neovascular membrane in 30% (figures rounded to
nearest 5%) (3). Lesions presumed to be choroidal osteoma have been associated
with other ocular abnormalities, including Rieger anomaly, histiocytosis X, and
others, but these associations are possibly coincidental (55,59).
The differential diagnosis includes several conditions, including sclerochoroidal
calcification (9), intrascleral cartilage associated with organoid nevus syndrome (8),

797
choroidal metastasis, amelanotic choroidal nevus and melanoma, choroidal
granuloma, posterior scleritis, subretinal fibrosis, and other nonpigmented fundus
lesions. The first two can be highly echogenic with ultrasonography and be
indistinguishable from choroidal osteoma using that technique. However, the
ophthalmoscopic features are quite different (1–4).

Diagnostic Approaches
Fluorescein angiography of choroidal osteoma shows patchy early hyperfluorescence
and intense late staining of the lesion (1–4,10). Vascular tufts are sometimes seen
emerging through the bone. Indocyanine green angiography can depict the intrinsic
large tumor vessels and overlying choroidal neovascularization (11–13).
A-scan and B-scan ultrasonography show a highly reflective echo that persists at
lower sensitivity. CT reveals a choroidal plaque with bone density. MRI shows the
tumor to be hyperintense to vitreous on the T1-weighted image and hypointense to
vitreous on the T2-weighted image, similar to most other choroidal tumors (24).
The OCT and autofluorescence features of choroidal osteoma have recently been
reported. Time domain OCT shows outer retinal atrophy overlying an irregular
choroidal mass with undulating surface topography (16). Spectral domain enhanced
depth imaging OCT shows preservation of retinal photoreceptors in the calcified
region of the tumor and loss of photoreceptors in the decalcified region (21). The
tumor shows spongy appearance (18,19,76) and with careful imaging one can see
the intralesional vascular channels, bone lamella, and Haversian and Volkman
canals (21). The pathogenesis of choroidal osteoma is unknown. Serum calcium,
phosphorus, and alkaline phosphatase levels are generally normal.
Fundus autofluorescence tends to show bright autofluorescence in areas of fresh
subretinal fluid and loss of autofluorescence in areas of decalcification (22–23).

Pathology
Histopathologically, choroidal osteoma is composed of mature bone at the level of
the choroid. The overlying retinal pigment epithelium is usually intact, a finding
quite different from that in osseous metaplasia or the retinal pigment epithelium in
which case there is no normal RPE in the affected area (1,25).

Management
Choroidal osteoma was originally managed by observation because no specific
treatment was believed to be effective. More recently, choroidal neovascularization
that threatens vision has been managed by laser photocoagulation, transpupillary
thermotherapy, photodynamic therapy, and anti-vascular endothelial growth (anti-
VEGF) factors to obliterate the neovascularization and prevent extensive hemorrhage
(27–45). Currently, photodynamic therapy is employed to treat extramacular
neovascularization and to induce decalcification of the mass if it is outside the foveal
region.
Treatment with anti-VEGF has been shown effective for resolving choroidal
neovascularization. In a series from Wills Eye Hospital, Khan et al. (45) found
neovascularization control with multiple injections anti-VEGF in 87% of cases.
Surgical removal of subretinal neovascular membrane has rarely been performed.
The visual prognosis is often unpredictable. However, we have observed that if

798
the osteoma is pure orange-yellow in color, the overlying sensory retina is more
normal with optical coherence tomography (OCT), and if it is subfoveal in location,
the vision remains fairly good (16). In contrast, if the lesion has overlying black
patches of RPE proliferation, suggesting spontaneous decalcification, the retina is
more damaged and the vision is likely to be worse.
These observations may have therapeutic implications. If it were possible to
maintain intact bone beneath the fovea or to prevent decalcification from
progressing to the fovea, then better vision might be maintained. Methods for
achieving this may not yet be available, but it is possible that the use of a barrier
laser with photodynamic therapy to prevent progressive decalcification may prove
to be of some benefit in preserving better vision. Photodynamic therapy has been
recently shown to induce dramatic resolution of a choroidal osteoma as well as the
associated choroidal neovascular membrane (38). This method deserves further
investigation.

Selected References
Large Series
1. Shields CL, Shields JA, Augsburger JJ. Choroidal osteoma. Surv Ophthalmol
1988;33:17–27.
2. Aylward GW, Chang TS, Pautler SE, et al. A long-term follow-up of choroidal
osteoma. Arch Ophthalmol 1998;116:1337–1341.
3. 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;123:658–666.
Small Series
4. Gass JD. New observations concerning choroidal osteomas. Int Ophthalmol
1979;1:71–84.
5. Noble KG. Bilateral choroidal osteoma in three siblings. Am J Ophthalmol
1990;109:656–660.
6. Warrasak S, Suvaranamani C, Euswas A, et al. Choroidal osteoma in Oriental
patients. J Med Assoc Thai 2003;86:562–572.
7. Yiu G, Young LH. Choroidal osteomas. JAMA Ophthalmol 2013;131(1):124.
8. Shields JA, Shields CL, Eagle RC Jr, et al. Ocular manifestations of the organoid
nevus syndrome. Ophthalmology 1997;104:549–557.
9. Shields JA, Shields CL. Sclerochoroidal calcification: the 2001 Harold Gifford
Lecture. Retina 2002;22:251–261.

Imaging
10. Bloom PA, Ferris JD, Laidlaw A, et al. Appearances of choroidal osteomas with
diagnostic imaging. Br J Radiol 1992;65:845–848.
11. Yuzawa M, Kawamura A, Haruyama M, et al. Indocyanine green video-
angiographic findings in choroidal osteoma. Eur J Ophthalmol 1994;4:191–198.
12. Shields CL, Shields JA, De Potter P. Patterns of indocyanine green
videoangiography of choroidal tumours. Br J Ophthalmol 1995;79:237–245.
13. Lafaut BA, Mestdagh C, Kohno T, et al. Indocyanine green angiography in
choroidal osteoma. Graefes Arch Clin Exp Ophthalmol 1997;235:330–337.
14. Ide T, Ohguro N, Hayashi A, et al. Optical coherence tomography patterns of

799
 choroidal osteoma. Am J Ophthalmol 2000;130:131–134.
15. Fukasawa A, Iijima H. Optical coherence tomography of choroidal osteoma.
Am J Ophthalmol 2002;133:419–421.
16. 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(12):e53–e58.
17. Haruta M, Hangai M, Taguchi C, et al. Spectral-domain optical coherence
tomography of the choroid in choroidal osteoma. Ophthalmic Surg Lasers
Imaging 2011;42:e118–e121.
18. Freton A, Finger PT. Spectral domain-optical coherence tomography analysis of
choroidal osteoma. Br J Ophthalmol 2012;96(2):224–228.
19. Pellegrini M, Invernizzi A, Giani A, et al. Enhanced depth imaging optical
coherence tomography features of choroidal osteoma. Retina 2014;34(5):958–
963.
20. Dinah C, Sandinha T. Enhanced depth imaging as an adjunctive tool in the
diagnosis of decalcified choroidal osteoma. Eye (Lond) 2014;28(3):356–358.
21. Shields CL, Arepalli S, Atalay HT, et al. Choroidal osteoma shows bone lamella
and vascular channels on enhanced depth imaging optical coherence
tomography in 15 eyes. 2015;35(4):750–757.
22. Ascaso FJ, Villén L. Fundus autofluorescence imaging findings in choroidal
osteoma. Retina 2011;31(5):1004–1005.
23. Sisk RA, Riemann CD, Petersen MR, et al. Fundus autofluorescence findings of
choroidal osteoma. Retina 2013;33(1):97–104.
24. DePotter P, Shields JA, Shields CL, et al. Magnetic resonance imaging of
choroidal osteoma. Retina 1991;11:221–223.

Pathology
25. Williams AT, Font RL, Van Dyk H, et al. Osseous choristoma of the choroid
simulating a choroidal melanoma. Arch Ophthalmol 1978;96:1874–1877.
26. Foster BS, Fernandez-Suntay JP, Dryja TP, et al. Surgical removal and
histopathologic findings of a subfoveal neovascular membrane associated with
choroidal osteoma. Arch Ophthalmol 2003;121:273–276.

Management
Laser Photocoagulation
27. Burke JF Jr, Brockhurst RJ. Argon laser photocoagulation of subretinal
neovascular membrane associated with osteoma of the choroid. Retina
1983;3:304–307.
28. Grand MG, Burgess DB, Singerman LJ, et al. Choroidal osteoma. Treatment of
associated subretinal neovascular membranes. Retina 1984;4:84–90.
29. Hoffman ME, Sorr EM. Photocoagulation of subretinal neovascularization
associated with choroidal osteoma. Arch Ophthalmol 1987;105:998–999.
30. Morrison DL, Magargal LE, Ehrlich DR, et al. Review of choroidal osteoma:
successful krypton red laser photocoagulation of an associated subretinal
neovascular membrane involving the fovea. Ophthalmic Surg 1987;18:299–303.
31. Rose SJ, Burke JF, Brockhurst RJ. Argon laser photoablation of a choroidal
osteoma. Retina 1991;11:224–228.
32. Gurelik G, Lonneville Y, Safak N, et al. A case of choroidal osteoma with

800
 subsequent laser induced decalcification. Int Ophthalmol 2001;24:41–43.
Transpupillary Thermotherapy
33. Sharma S, Sribhargava N, Shanmugam MP. Choroidal neovascular membrane
associated with choroidal osteoma (CO) treated with trans-pupillary thermo
therapy. Ind J Ophthalmol 2004;52:329–330.
34. Shukla D, Tanawade RG, Ramasamy K. Transpupillary thermotherapy for
subfoveal choroidal neovascular membrane in choroidal osteoma. Eye (Lond)
2006;20(7):845–847.
Photodynamic Therapy
35. Battaglia Parodi M, Da Pozzo S, et al. Photodynamic therapy for choroidal
neovascularization associated with choroidal osteoma. Retina 2001;21:660–661.
36. Blaise P, Duchateau E, Comhaire Y, et al. Improvement of visual acuity after
photodynamic therapy for choroidal neovascularization in choroidal osteoma.
Acta Ophthalmol Scand 2005;83:515–516.
37. Singh AD, Talbot JF, Rundle PA, et al. Choroidal neovascularization secondary
to choroidal osteoma: successful treatment with photodynamic therapy. Eye
(Lond) 2005;19:482–484.
38. Shields CL, Materin MA, Mehta S, et al. Regression of extrafoveal choroidal
osteoma following photodynamic therapy. Arch Ophthalmol 2008;126(1):135–
137.
39. Morris RJ, Prabhu VV, Shah PK, et al. Combination therapy of low-fluence
photodynamic therapy and intravitreal ranibizumab for choroidal neovascular
membrane in choroidal osteoma. Indian J Ophthalmol 2011;59(5):394–396.
Anti-VEGF
40. Ahmadieh H, Vafi N. Dramatic response of choroidal neovascularization
associated with choroidal osteoma to the intravitreal injection of bevacizumab
(Avastin). Graefes Arch Clin Exp Ophthalmol 2007;245(11):1731–1733.
41. Shields CL, Salazar P, Demirci H, et al. Intravitreal bevacizumab (Avastin) and
ranibizumab (Lucentis) for choroidal neovascularization overlying choroidal
osteoma. Retinal Cases and Brief Reports 2008;2(1):18–20.
42. Narayanan R, Shah VA. Intravitreal bevacizumab in the management of
choroidal neovascular membrane secondary to choroidal osteoma. Eur J
Ophthalmol 2008;18(3):466–468.
43. Song JH, Bae JH, Rho MI, et al. Intravitreal bevacizumab in the management of
subretinal fluid associated with choroidal osteoma. Retina 2010;30(6):945–951.
44. Jang JH, Kim KH, Lee SJ, et al. Photodynamic therapy combined with
intravitreal bevacizumab in a patient with choroidal neovascularization
secondary to choroidal osteoma. Korean J Ophthalmol 2012;26(6):478–480.
45. Khan MA, DeCroos FC, Storey PP, et al. Outcomes of anti-vascular endothelial
growth factor (VEGF) therapy in the management of choroidal
neovascularization associated with choroidal osteoma. Retina 2014;34(9):1750–
1756.

Case Reports
46. Gass JD, Guerry RK, Jack RL, et al. Choroidal osteoma. Arch Ophthalmol
1978;96:428–435.
47. Joffe L, Shields JA, Fitzgerald JR. Osseous choristoma of the choroid. Arch

801
 Ophthalmol 1978;96:1809–1812.
48. Teich SA, Walsh JB. Choroidal osteoma. Ophthalmology 1981;88:696–698.
49. Cunha SL. Osseous choristoma of the choroid. A familial disease. Arch
Ophthalmol 1984;102:1052–1054.
50. Alexander TA, Hunyor AB. Choroidal osteomas. Aust J Ophthalmol
1984;12(4):373–378.
51. Trimble SB, Schatz H, Schneider GB. Spontaneous decalcification of a choroidal
osteoma. Ophthalmology 1988;95:631–644.
52. Shields JA, Shields CL, Ellis J, et al. Bilateral choroidal osteoma associated with
bilateral total blindness. Retina 1996;16:445–447.
53. Fava GE, Brown GC, Shields JA, et al. Choroidal osteoma in a 6-year-old child.
J Pediatr Ophthalmol Strabismus 1980;17:203–205.
54. Erkilic K, Ozkiris A, Evereklioglu C, et al. Rieger anomaly with bilateral
choroidal osteoma: coincidence or association? Eur J Ophthalmol 2003;13:496–
499.
55. Wilson MW, Moshfeghi DM, Haik BG, et al. Choroidal osteoma in a patient
with contralateral persistent hyperplastic primary vitreous. Retina 2002;22:358–
360.
56. Pamer Z, Kovacs B. A case of a fast-growing bilateral choroidal osteoma. Retina
2001;21:657–659.
57. Augsburger JJ, Shields JA, Rife CJ. Bilateral choroidal osteoma after nine years.
Can J Ophthalmol 1979;14:281–284.
58. Kadrmas EF, Weiter JJ. Choroidal osteoma. Int Ophthalmol Clin 1997;37:171–
182.
59. Okada K, Minamoto A, Sakata H, et al. Bilateral choroidal osteomas associated
with histiocytosis X. Jpn J Ophthalmol 1996;40:111–115.
60. Tsuchihashi T, Murayama K, Saito T, et al. Midperipheral mottling
pigmentation with familial choroidal osteoma. Retina 2005;25:63–68.
61. Coston TO, Wilkinson CP. Choroidal osteoma. Am J Ophthalmol 1978;86:368–
372.
62. Verma L, Venkatesh P, Lakshmaiah NC, et al. Osseous choristoma of the
choroid. Ind J Ophthalmol 2000;48:135–137.
63. Mizota A, Tanabe R, Adachi-U sami E. Rapid enlargement of choroidal osteoma
in a 3-year-old girl. Arch Ophthalmol 1998;116:1128–1129.
64. Giuffre G. Vascular modifications within a choroidal osteoma. Doc Ophthalmol
1993;83:349–356.
65. Trimble SN, Schatz H. Decalcification of a choroidal osteoma. Br J Ophthalmol
1991;75:61–63.
66. Buettner H. Spontaneous involution of a choroidal osteoma. Arch Ophthalmol
1990; 108:1517–1518.
67. McLeod BK. Choroidal osteoma presenting in pregnancy. Br J Ophthalmol 1988;
72:612–614.
68. Kline LB, Skalka HW, Davidson JD, et al. Bilateral choroidal osteomas
associated with fatal systemic illness. Am J Ophthalmol 1982;93:192–197.
69. Kelinske M, Weinstein GW. Bilateral choroidal osteomas. Am J Ophthalmol
1981; 92:676–680.
70. Murthy R, Das T, Gupta A. Bilateral choroidal osteoma with optic atrophy. J
AAPOS 2010;14(5):438–440.

802
71. Karanjia R, Gale JG, ten Hove MW. Macular choroidal osteoma with
progressive widespread outer-retinal dysfunction. Can J Ophthalmol
2010;45(2):179–180.
72. Ascaso FJ, Lasierra R. Idiopathic dural optic nerve sheath calcification
associated with choroidal osteoma. Ophthalmic Surg Lasers Imaging
2011;9:42.e53–e55.
73. Voluck M, Say EAT, Shields CL. Progressive growth of bilateral choroidal
osteomas in a child. J Ped Ophthalmol Strabism 2012;48:e66–e68.
74. Yoshikawa T, Takahashi K. Decalcified choroidal osteoma found in the retina.
Clin Ophthalmol 2012;6:1823–1825.
75. Adhi M, Bryant JS, Alwassia AA, et al. De novo appearance of a choroidal
osteoma in an eye with previous branch retinal vein occlusion. Ophthalmic Surg
Lasers Imaging. Retina 2013;44(1):77–80.
76. Navajas EV, Costa RA, Calucci D, et al. Multimodal fundus imaging in choroidal
osteoma. Am J Ophthalmol 2012;153(5):890–895.

803
• CHOROIDAL OSTEOMA: CLINICAL FEATURES
Some clinical variations of choroidal osteoma are shown. All patients had ultrasonographic
support of the diagnosis, and many also had computed tomography performed, which also
supported the diagnosis.

1. Joffe L, Shields JA, Fitzgerald J. Osseous choristoma of the choroid. Arch Ophthalmol
1978;96:1809–1812.
2. Shields JA, Shields CL, DePotter P, et al. Progressive enlargement of a choroidal osteoma.
Arch Ophthalmol 1995;113:819–820.
3. 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;123:658–666.

Figure 14.1. Choroidal osteoma inferior to the optic disc in a 30-year-old woman. Prior to referral, the patient
was suspected to have a choroidal metastasis elsewhere, and breast biopsy was done in the hope of locating
the primary neoplasm. Eventually, ultrasonography showed a bony plaque, supporting the diagnosis of
choroidal osteoma.

Figure 14.2. Choroidal osteoma in the macular region of the right eye in a 28-year-old man. The patient had a
similar macular lesion in the left eye.

804
Figure 14.3. Irregular choroidal osteoma inferior to the optic disc and extending into the foveal region in a 16-
year-old girl.

Figure 14.4. Opposite eye of the patient shown in Figure 14.3, showing small, early choroidal osteoma
superior to the optic disc. The same area had been photographed 2 years earlier, and no lesion was present.

Figure 14.5. Small choroidal osteoma in the foveal region in a 20-year-old woman. The lesion was originally
diagnosed as an amelanotic choroidal nevus. The lesion subsequently showed progressive growth and
developed ultrasonographic evidence of calcium.

805
Figure 14.6. Appearance of the lesion shown in Figure 14.5 after 6 years. Note the significant enlargement. It
continues to enlarge after 12 years and the vision has slowly deteriorated.

806
• CHOROIDAL OSTEOMA: WIDE-ANGLE IMAGING

Figure 14.7. Wide-angle fundus image of circumpapillary choroidal osteoma in the left eye of a woman. Note
the visibility of the choroidal vessels nasally (to the left), which represents areas of spontaneous
decalcification of the tumor.

Figure 14.8. Yellow-orange choroidal osteoma extending superiorly from the optic disc in an 11-year-old girl.

Figure 14.9. Choroidal osteoma in right eye with extensive decalcification. There is marked tumor

807
decalcification in foveal region. This 36-year-old woman has been followed photographically for >30 years.
There has been progressive decalcification in the foveal region, and the vision has remained stable at finger
counting in this eye.

Figure 14.10. Left eye of the patient shown in Figure 14.9. Note that the nasal decalcification has not reached
the fovea and the vision has remained at 20/30 for 30 years, whereas the tumor has shown slow
decalcification that still spares the fovea.

Figure 14.11. Subfoveal choroidal osteoma in a 12-year-old African-American boy.

Figure 14.12. Choroidal osteoma that extends inferior to the optic disc and foveal area. Note the orange color
superiorly, which represents viable osteoma, and an area of decalcification in the macular area, accounting for

808
visual loss.

809
• CHOROIDAL OSTEOMA: CHOROIDAL NEOVASCULARIZATION,
DECALCIFICATION, AND FAMILIAL OCCURRENCE

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;123:658–666.

Figure 14.13. Choroidal osteoma superior to the optic disc, with the choroidal neovascular membrane
extending into the foveal region. Note the gray lesion in the foveal area, characteristic of a choroidal
neovascular membrane.

Figure 14.14. Same lesion shown in Figure 14.13 after laser photocoagulation to the juxtafoveal neovascular
membrane. Note the proliferation of the retinal pigment epithelium at the site of the photocoagulation adjacent
to the foveola.

810
Figure 14.15. Large circumpapillary choroidal osteoma in a 30-year-old woman with extensive decalcification
nasally and in the papillomacular bundle. Note the more orange color in the peripheral portion of the lesion,
which represents intact bone without decalcification.

Figure 14.16. Opposite eye of the patient in Figure 14.15, showing a large choroidal osteoma with
decalcification nasally. Again the calcified intact bone is more orange in color.

Figure 14.17. Circumpapillary choroidal osteoma in the right eye of a 20-year-old woman who has no light
perception with both eyes. Note the pallor of the optic disc, indicating marked optic atrophy.

811
Figure 14.18. Left eye of the patient shown in Figure 14.17, demonstrating similar findings as seen in the right
eye. Drusen of the optic discs were also visualized and documented with ultrasonography. This patient
subsequently had a child with similar bilateral fundus lesions and blindness in both eyes.

812
• CHOROIDAL OSTEOMA: FLUORESCEIN ANGIOGRAPHY AND
OPTICAL COHERENCE TOMOGRAPHY FINDINGS

Ancillary studies like fluorescein angiography and OCT can show some features of choroidal
osteoma, but they are particularly helpful in detecting choroidal neovascularization and its
effects.

1. Shields CL, Arepalli S, Atalay HT, et al. Choroidal osteoma shows bone lamella and vascular
channels on enhanced depth imaging optical coherence tomography in 15 cases. Retina
2015;35(4):750–757.
2. Shields CL, Materin MA, Mehta S, et al. Regression of extrafoveal choroidal osteoma
following photodynamic therapy. Arch Ophthalmol 2008;126(1):135–137.

Figure 14.19. Choroidal osteoma in the macular region of the right eye. Note the central pigment disruption,
which probably represents early decalcification.

Figure 14.20. Fluorescein angiogram of the lesion shown in Figure 14.19 in the full venous phase. Note the
hyperfluorescence of the lesion and hypofluorescence of the central pigment proliferation.

813
Figure 14.21. Calcified choroidal osteoma in the macular region.

Figure 14.22. Optical coherence tomography (OCT) shows replacement of the choroid with full thickness bone
and vertical Haversian canals.

Figure 14.23. Small choroidal osteoma superior to the optic disc. It was elected to treat the patient because of
choroidal neovascular membrane and persistent hemorrhage. She was treated with photodynamic therapy.

Figure 14.24. Appearance of the lesion in Figure 14.23, 5 years later with complete regression and retinal

814
pigment epithelial alterations.

815
• CHOROIDAL OSTEOMA: ULTRASONOGRAPHY, COMPUTED
TOMOGRAPHY, MAGNETIC RESONANCE IMAGING, AND
CLINICOPATHOLOGIC CORRELATION

1. Gass JDM, Guerry RK, Jack RL, et al. Choroidal osteoma. Arch Ophthalmol 1978;96:428–435.
2. Williams AT, Font RL, Van Dyk HJ, et al. Osseous choristoma of the choroid simulating a
choroidal melanoma. Arch Ophthalmol 1978;96:1874–1877.

Figure 14.25. B-scan ultrasonogram of the patient in Figure 14.10, showing a placoid lesion in the posterior
pole with an acoustic shadow in the orbital fat posterior to the lesion.

Figure 14.26. B-scan ultrasonogram at lower sensitivity, showing persistence of the placoid calcific lesion after
soft tissue echoes resolved.

816
Figure 14.27. Axial computed tomogram of the same patient, showing bilateral placoid lesions of bone density
in the posterior choroid.

Figure 14.28. Axial magnetic resonance imaging of the same patient, showing a lesion in the left eye that is
hyperintense to vitreous. The osteoma in the right eye is not clearly shown in this cut.

Figure 14.29. Choroidal osteoma located nasal to the optic disc in right eye of a middle-aged woman. The
patient was seen and underwent enucleation elsewhere because the lesion was suspected to be a choroidal
melanoma.

817
Figure 14.30. Histopathology of the lesion shown in Figure 14.29. Note the plaque of mature bone at the level
of the choroid. (Hematoxylin–eosin ×25.) This was the first patient in recent history to have histopathologic
confirmation, which subsequently allowed recognition clinically of all additional cases.

818
 MYOGENIC TUMORS OF THE UVEA

Uveal Leiomyoma

General Considerations
Myogenic tumors of the uvea include leiomyoma and rhabdomyosarcoma, both of
which are rare. Leiomyoma is a benign, smooth muscle tumor that generally occurs
in the uterus but also can arise in the uveal tract, most often in the iris and ciliary
body (1–32). About 80% to 90% occur in females, with a tendency to involve young
adult females.

Clinical Features
U veal leiomyoma is clinically similar to an amelanotic melanoma in producing
sentinel blood vessels and extending through the sclera (26). In contrast to
melanoma, however, it more often occurs in young adult females and may
sometimes arise in the suprauveal space rather than in the uveal stroma (1–3).

Diagnostic Approaches
Clinically, uveal leiomyoma may be difficult to easily differentiate from amelanotic
melanoma. However, on transillumination, light tends to pass through the lesion,
and it often appears even brighter than that seen with amelanotic melanoma.
Carefully performed ultrasonography can sometimes suggest that the lesion is
mainly in the suprauveal space, outside the uveal stroma. In recent years, we have
become more accurate in predicting the diagnosis of leiomyoma based on clinical
findings combined with transillumination and ultrasonography. However, if there is
great uncertainty, fine-needle aspiration biopsy (FNAB) may be helpful. Although
the cytologic differential may be very difficult, immunohistochemistry of the
aspirate could be of help. The cytopathologist should be informed of the differential
diagnosis so that the melanoma-specific antigen and smooth muscle antigen stains
can be performed to help make this differentiation.

Pathology
Histopathologically, leiomyoma shows bland, nonpigmented spindle cells with
abundant intervening connective tissue. The cells generally show a positive reaction
to muscle-specific actin and smooth muscle antigen but a negative reaction to
melanoma-specific antigens (6–13).

Management
Historically, uveal leiomyoma was almost impossible to differentiate clinically from
amelanotic melanoma. However, the diagnosis has become more accurate due to the
aforementioned clinical features. If the diagnosis can be made clinically, small iris
leiomyoma can usually be observed without treatment. Larger growing iris or ciliary
body tumors may be managed by local resection of the tumor by partial iridectomy
or a partial lamellar sclerouvectomy (14–18). When the tumor is located in the
suprauveal space, it may be removed by that technique, sometimes leaving the uveal

819
tract intact (14,18). Malignant transformation does not tend to occur, and the
prognosis is excellent. However, some uveal leiomyomas have attained a large size
by the time of diagnosis and enucleation has often been performed because of the
suspected melanoma.

Selected References
Small Series
1. Shields JA, Shields CL. Observations on intraocular leiomyomas. Trans Pa Acad
Ophthalmol Otolaryngol 1990;42:945–950.
2. 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.
3. Heegaard S, Jensen PK, Scherfig E, et al. Leiomyoma of the ciliary body. Report
of 2 cases. Acta Ophthalmol Scand 1999;77:709–712.
4. Odashiro AN, Fernandes BF, Al-Kandari A, et al. Report of two cases of ciliary
body mesectodermal leiomyoma: unique expression of neural markers.
Ophthalmology 2007;114(1):157–161.

Imaging
5. Oh KJ, Kwon BJ, Han MH, et al. MR imaging findings of uveal leiomyoma:
three cases. AJNR 2005;26(1):100–103.
Pathology
6. Meyer SL, Fine BS, Font RL, et al. Leiomyoma of the ciliary body. Electron
microscopic verification. Am J Ophthalmol 1968;66(6):1061–1068.
7. Lowe RF, Greer CH. Leiomyoma of the ciliary body. A clinico-pathological case
report. Br J Ophthalmol 1970;54(6):383–387.
8. Jakobiec FA, Witschel H, Zimmerman LE. Choroidal leiomyoma of vascular
origin. Am J Ophthalmol 1976;82:205–212.
9. Takagi T, U eno Y, Matsuya N. Mesectodermal leiomyoma of the ciliary body.
An ultrastructural study. Arch Ophthalmol 1985;103:1711–1714.
10. Ishigooka H, Yamabe H, Kobashi Y, et al. Clinical and pathological status of
mesectodermal leiomyoma of the ciliary body. A case report and review of the
literature. Graefes Arch Clin Exp Ophthalmol 1989;227(2):101–105.
11. Foss AJ, Pecorella I, Alexander RA, et al. Are most intraocular “leiomyomas”
really melanocytic lesions? Ophthalmology 1994;101(5):919–924.
12. Biswas J, Kumar SK, Gopal L, et al. Leiomyoma of the ciliary body extending to
the anterior chamber: clinicopathologic and ultrasound biomicroscopic
correlation. Surv Ophthalmol 2000;44:336–342.
13. Schlotzer-Schrehardt U , Junemann A, Naumann GO. Mitochondria-rich
epithelioid leiomyoma of the ciliary body. Arch Ophthalmol 2002;120:77–82.

Management
14. Shields JA, Shields CL, Eagle RC. Mesectodermal leiomyoma of the ciliary body
managed by partial lamellar iridocyclochoroidectomy. Ophthalmology
1989;96:1369–1376.
15. Peyman GA, Martinez CE, Hew A, et al. Endoresection of a ciliary body
leiomyoma. Can J Ophthalmol 1998;33(1):32–34.

820
16. Richter MN, Bechrakis NE, Stoltenburg-Didinger G, et al. Transscleral resection
of a ciliary body leiomyoma in a child: case report and review of the literature.
Graefes Arch Clin Exp Ophthalmol 2003;241:953–957.
17. Tuncer S, Peksayar G, Demiryont M, et al. Longterm follow-up of a patient with
iris leiomyoma treated with partial lamellar iridocyclectomy. Acta Ophthalmol
Scand 2004;82(1):112–114.
18. Razzaq L, Semenova EA, Marinkovic M, et al. Mesectodermal suprauveal
iridociliary leiomyoma: transscleral excision without postoperative iris defect.
Arch Ophthalmol 2011;129(12):1635–1637.

Case Reports
19. Blodi FC. Leiomyoma of the ciliary body. Am J Ophthalmol 1950;33(6):939–
942.
20. De Buen S, Olivares ML, Charlín C. Leiomyoma of the iris. Report of a case. Br
J Ophthalmol 1971;55(5):353–356.
21. 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.
22. Croxatto JO, Malbran ES. U nusual ciliary body tumor. Mesectodermal
leiomyoma. Ophthalmology 1982;89:1208–1212.
23. Orsoni JG, Daicker B, Cardillo Piccolino F. Mesectodermal leiomyoma of the
ciliary body extending into the anterior chamber. Ophthalmologica
1985;191(2):127–129.
24. White V, Stevenson K, Garner A, et al. Mesectodermal leiomyoma of the ciliary
body: case report. Br J Ophthalmol 1989;73:12–18.
25. Yu DY, Cohen SB, Peyman G, et al. Mesectodermal leiomyoma of the ciliary
body: new evidence for neural crest origin. J Pediatr Ophthalmol Strabismus
1990;27(6):317–321.
26. Shields CL, Shields JA, Varenhorst M. Transcleral leiomyoma. Ophthalmology
1991;98:84–87.
27. Shields JA, Eagle RC Jr, Shields CL. Adenoma of nonpigmented ciliary
epithelium with smooth muscle differentiation. Arch Ophthalmol 1999;117:117–
119.
28. Ceballos EM, Aaberg TM Jr, Halpern RL, et al. Choroidal leiomyoma: report of
a case. Retina 1999;19:349–351.
29. Chotiner E, Shields CL, Shields JA, et al. Ciliary body leiomyoma with anterior
chamber invasion. Arch Ophthalmol 2001;119:1218–1220.
30. Perri P, Paduano B, Incorvaia C, et al. Mesectodermal leiomyoma exclusively
involving the posterior choroid. Am J Ophthalmol 2002;134:451–454.
31. Lai CT, Tai MC, Liang CM, et al. U nusual uveal tract tumor: mesectodermal
leiomyoma of the ciliary body. Pathol Int 2004;54(5):337–342.
32. Kanavi MR, Soheilian M, Peyman GA. Ciliary body leiomyoma with atypical
features. Can J Ophthalmol 2007;42(2):336–337.

821
• UVEAL LEIOMYOMA: CLINICAL VARIATIONS
Uveal leiomyoma can assume different clinical appearances, but it is usually a nonpigmented
tumor of the ciliary body region. Even though it is amelanotic, it can appear pigmented on
clinical examination. However, it usually transmits light readily with transillumination. It can
occasionally erode through the sclera and appear in the epibulbar tissues. The clinical features
that serve to differentiate leiomyoma from ciliary body melanoma have been described. The
cases depicted here were all confirmed histopathologically to be leiomyoma.

1. Shields CL, Shields JA, Varenhorst M. Transcleral leiomyoma. Ophthalmology 1991;98:84–87.

2. Chotiner E, Shields CL, Shields JA, et al. Ciliary body leiomyoma with anterior chamber
invasion. Arch Ophthalmol 2001;119:1218–1220.

Figure 14.31. Leiomyoma involving the iris in an elderly woman. The lesion also extended to involve the ciliary
body, and it is uncertain whether it originated in the iris or the ciliary body.

Figure 14.32. Leiomyoma of the ciliary body with iris extension inferiorly in a young man. The lesion was
removed successfully by iridocyclectomy and histopathology, and immunohistochemistry confirmed the
diagnosis of leiomyoma.

822
Figure 14.33. Leiomyoma arising from the ciliary body and peripheral choroid in a 24-year-old man. Note the
red-orange color to the lesion as it transmits light.

Figure 14.34. Grossly sectioned eye enucleated for ciliochoroidal mass clinically believed to be a melanoma.
Note that the tumor is amelanotic. The lesion proved by histopathology and immunohistochemistry to be a
leiomyoma.

Figure 14.35. Transcleral extension of a ciliary body leiomyoma in a 31-year-old woman. The red-orange tumor
was removed by local excision. The uveal tract over the lesion was intact and not disrupted at surgery,
suggesting that the tumor arose in the suprauveal space.

823
Figure 14.36. Scleral graft sutured into position after removal of the lesion shown in Figure 14.35. The patient
had an excellent recovery. Histopathologically the lesion proved to be a vascular leiomyoma.

824
• UVEAL LEIOMYOMA: CLINICOPATHOLOGIC CORRELATION
Shields JA, Shields CL, Eagle RC. Mesectodermal leiomyoma of the ciliary body managed by
partial lamellar iridocyclochoroidectomy. Ophthalmology 1989;96:1369–1376.

Figure 14.37. Ciliochoroidal mass nasally in the right eye of an 11-year-old girl. Although the lesion appears to
be pigmented in the photograph, it transmitted light readily.

Figure 14.38. Fluorescein angiogram in the recirculation phase, showing mild, patchy hyperfluorescence of the
mass.

825
Figure 14.39. B-scan ultrasonogram, showing a dome-shaped mass with acoustic hollowness.

Figure 14.40. Appearance of the tumor after removal by partial lamellar iridocyclochoroidectomy, showing that
the lesion is nonpigmented.

Figure 14.41. Histopathology, showing low-grade spindle cells with abundant intercellular collagen.
Immunohistochemistry confirmed the diagnosis of a smooth muscle tumor.

Figure 14.42. Appearance of the posterior pole after 9 years. The patient maintained excellent vision, and there
was no tumor recurrence.

826
 UVEAL RHABDOMYOSARCOMA

Uveal Rhabdomyosarcoma

General Considerations
Rhabdomyosarcoma is an important malignant mesenchymal tumor of childhood.
Although it is uncommon among all orbital tumors, it is still the most common
primary malignant orbital tumor of childhood (1,2). It has rarely been reported in
the iris and ciliary body (3–6).

Clinical Features
Rhabdomyosarcoma tends to arise in the anterior uveal tract and, to our knowledge,
it has not been reported in the choroid. It appears as a pink-yellow, fleshy mass that
arises from the stroma of the iris or ciliary body (3–6).

Pathology
U veal rhabdomyosarcoma is similar histopathologically to its counterpart in the
orbit. Because it is rare, it is uncertain whether it can take the forms seen in the
orbit. In the uvea, it consists of rhabdomyoblasts that are fairly well differentiated.
The pathogenesis has been the subject of interesting speculation. Because some
ciliary body teratoid medulloepitheliomas contain heterotopic skeletal muscle
(rhabdomyoblasts), one might argue that this tumor could be a medulloepithelioma
with complete rhabdomyoblastic differentiation.

Management
Although the diagnosis is rarely made clinically, the recommended treatment is local
resection of the tumor. In some instances, needle biopsy could possibly establish the
diagnosis. Rarely, the tumor may be so large that enucleation is necessary. To our
knowledge, uveal rhabdomyosarcoma has not been known to metastasize.

Selected References
Small Series
1. Shields CL, Shields JA, Honavar SG, et al. The clinical spectrum of primary
ophthalmic rhabdomyosarcoma. Ophthalmology 2001;108:2284–2292.
2. Shields JA, Shields CL. Rhabdomyosarcoma: review for the ophthalmologist.
The 2001 Henry Dubins Lecture. Surv Ophthalmol 2003;48:39–57.

Pathology
3. Font RL, Zimmerman LE. Electron microscopic verification of primary
rhabdomyosarcoma of the iris. Am J Ophthalmol 1972;74:110–117.

Case Reports
4. Woyke S, Chwirot R. Rhabdomyosarcoma of the iris. Report of the first
recorded case. Br J Ophthalmol 1972;56:60–64.
5. Wilson ME, McClatchey SK, Zimmerman LE. Rhabdomyosarcoma of the ciliary

827
 body. Ophthalmology 1990;97:1484–1488.
6. Elsas FJ, Mroczek EC, Kelly DR, et al. Primary rhabdomyosarcoma of the iris.
Arch Ophthalmol 1991;109:982–984.

828
• IRIS AND CILIARY BODY RHABDOMYOSARCOMAS
Iris and ciliary body rhabdomyosarcomas are rare, but well-documented cases have been
reported.

1. Elsas FJ, Mroczek EC, Kelly DR, et al. Primary rhabdomyosarcoma of the iris. Arch
Ophthalmol 1991;109:982–984.
2. Wilson ME, McClatchey SK, Zimmerman LE. Rhabdomyosarcoma of the ciliary body.
Ophthalmology 1990;97:1484–1488.

Figure 14.43. Facial photograph of a 2-year-old girl who developed fleshy iris mass inferotemporally in the right
eye.

Figure 14.44. Closer view of the same iris lesion.

829
Figure 14.45. Fine-needle aspiration biopsy of the iris lesion, showing a clump of malignant cells. The
cytopathologist did not make a specific diagnosis, but rhabdomyosarcoma was not suspected and
immunohistochemistry was not performed. (Papanicolaou ×250.) The eye was subsequently enucleated.

Figure 14.46. Photomicrograph of the iris area in the enucleated eye, showing malignant strap cells with
abundant eosinophilic cytoplasm. (Hematoxylin–eosin ×200.)

Figure 14.47. Photomicrograph of the tumor, showing cross striations in some of the tumor cells. (Muscle-
specific actin ×200.)

830
Figure 14.48. Rhabdomyosarcoma of the ciliary body in a 12-year-old boy. Note the beefy-red color of the
lesion. The diagnosis was confirmed following enucleation, but there is speculation that the lesion could
represent extensive rhabdomyoblastic differentiation in a teratoid medulloepithelioma.

831
 UVEAL SCHWANNOMA (NEURILEMOMA)

General Considerations
Neural tumors that can rarely arise in the uveal tract include schwannoma
(neurilemoma), neurofibroma, and primitive neuroectodermal tumor. Because
schwannoma and neurofibroma are similar histopathologically, some authorities
prefer to group them together under the rubric “benign peripheral nerve sheath
tumors.”
Schwannoma is a benign peripheral nerve sheath tumor that can develop in
various parts of the body including the uvea (1–23). Although rare in the ocular
region, it can sometimes occur in the orbit, eyelid, and conjunctiva. It can also arise
from the Schwann cells of the ciliary nerves in the uveal tract and has been reported
in the iris, ciliary body, or choroid (1–24).

Clinical Features
In any part of the uvea, schwannoma classically appears as a nonpigmented mass
that may be impossible to differentiate from amelanotic melanoma. In rare
instances, it can be pigmented and appear identical to a pigmented melanoma (3).
Although most peripheral nerve sheath tumors occur in patients with
neurofibromatosis, most cases of uveal schwannoma have been solitary lesions in
patients who do not have neurofibromatosis.

Diagnostic Approaches
The diagnosis of uveal schwannoma is difficult because the tumor probably cannot
be differentiated clinically from melanotic uveal melanoma. Fluorescein
angiography and ultrasonography show similar, if not identical, findings to those of
amelanotic uveal melanoma. However, schwannoma generally transmits light
similar to leiomyoma. FNAB could probably be helpful in the diagnosis, but we
have not had the opportunity to use it on such a case. The abundant collagen in
schwannoma, like leiomyoma, could limit the cellular yield with FNAB.

Pathology
Histopathologically, uveal schwannoma is composed of a pure proliferation of
Schwann cells that may be similar to low-grade spindle melanoma cells. However,
the neuroid appearance, sometimes with Antoni A and Antoni B patterns, is quite
typical and unlike that of a melanoma (2–4). In some cases, choroidal schwannoma
is pigmented, making it virtually impossible to differentiate from a pigmented uveal
melanoma (3). Immunohistochemistry, however, would show a positive reaction to
neural cell markers and a negative reaction for melanoma-specific antigens. Electron
microscopy reveals long spacing collagen (Luse bodies) in the extracellular
connective tissue (4).

Management
Most uveal schwannomas have been managed with enucleation or radiotherapy

832
with the presumptive diagnosis of melanoma. We have managed two patients who
had plaque radiotherapy for presumed choroidal melanoma and later were found
after enucleation to have a schwannoma. If the diagnosis is suspected clinically, then
partial lamellar sclerouvectomy can be performed, sparing the globe (7).

Selected References
Imaging
1. Xian J, Xu X, Wang Z, et al. MR imaging findings of the uveal schwannoma.
AJNR Am J Neuroradiol 2009;30(4):769–773.

Pathology
2. Freedman SF, Elner VM, Donev I, et al. Intraocular neurilemmoma arising from
the posterior ciliary nerve in neurofibromatosis. Pathologic findings.
Ophthalmology 1988;95:1559–1564.
3. Shields JA, Font RL, Eagle RC Jr, et al. Melanotic schwannoma of the choroid:
immunohistochemistry and electron microscopic observations. Ophthalmology
1994;101:843–849.
4. Matsuo T, Notohara K. Choroidal schwannoma: immunohistochemical and
electron-microscopic study. Ophthalmologica 2000;214:156–160.

Management
5. Kuchle M, Holbach L, Schlotzer-Schrehardt U , et al. Schwannoma of the ciliary
body treated by block excision. Br J Ophthalmol 1994;78:397–400.
6. Goto H, Mori H, Shirato S, U sui M. Ciliary body schwannoma successfully
treated by local resection. Jpn J Ophthalmol 2006;50(6):543–546.
7. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for
posterior uveal melanomas: the 1986 Schoenberg Lecture. Ophthalmic Surg
1988;19:774–780.

Case Reports
8. Donovan BF. Neurilemoma of the ciliary body. AMA Arch Ophthalmol
1956;55(5):672–675.
9. Vannas S, Raitta C, Tarkkanen A. Neurilemmoma of the choroid in
Recklinghausen’s disease. Acta Ophthalmol Suppl 1974;123:126–133.
10. Vogel M, Spitznas M, Waubke TN. Leiomyoma of the ciliary body. Albrecht Von
Graefes Arch Klin Exp Ophthalmol 1978;209(2):89–98.
11. Shields JA, Sanborn GE, Kurz GH, et al. Benign peripheral nerve tumor of the
choroid. Ophthalmology 1981;88:1322–1329.
12. Packard RB, Harry J. Choroidal neurilemmoma—an unusual clinical
misdiagnosis. Br J Ophthalmol 1981;65:189–191.
13. Rosso R, Colombo R, Ricevuti G. Neurilemmoma of the ciliary body: report of a
case. Br J Ophthalmol 1983;67:585–587.
14. Midena E. Neurilemmoma of the ciliary body. Br J Ophthalmol 1984;68(4):289.
15. Smith PA, Damato BE, Ko MK, et al. Anterior uveal neurilemmoma—a rare
neoplasm simulating malignant melanoma. Br J Ophthalmol 1987;71:34–40.
16. Hufnagel TJ, Sears ML, Shapiro M, et al. Ciliary body neurilemoma recurring
after 15 years. Graefes Arch Clin Exp Ophthalmol 1988;226:443–446.
17. Fan JT, Campbell RJ, Robertson DM. A survey of intraocular schwannoma with

833
 a case report. Can J Ophthalmol 1995;30:37–41.
18. Pineda R 2nd, U rban RC Jr, Bellows AR, Jakobiec FA. Ciliary body
neurilemoma. U nusual clinical findings intimating the diagnosis. Ophthalmology
1995;102(6):918–923.
19. Shields JA, Hamada A, Shields CL, et al. Ciliochoroidal nerve sheath tumor
simulating a malignant melanoma. Retina 1997;17:459–460.
20. Thaller VT, Perinti A, Perinti A. Benign schwannoma simulating a ciliary body
melanoma. Eye (Lond) 1998;12(Pt 1):158–159.
21. Kim IT, Chang SD. Ciliary body schwannoma. Acta Ophthalmol Scand
1999;77:462–466.
22. Saavedra E, Singh AD, Sears JE, et al. Plexiform pigmented schwannoma of the
uvea. Surv Ophthalmol 2006;51:162–168.
23. Kiratli H, U stünel S, Balci S, et al. Ipsilateral ciliary body schwannoma and
ciliary body melanoma in a child. J AAPOS 2010;14(2):175–177.
24. Huang Y, Wei W. Choroidal schwannoma presenting as nonpigmented
intraocular mass. J Clin Oncol 2012;30(31):e315–e317.

834
• UVEAL SCHWANNOMA (NEURILEMOMA)
Uveal schwannoma may be difficult to differentiate clinically from a nonpigmented choroidal
melanoma. Although it is rarer than melanoma, the diagnosis of leiomyoma should be
entertained in all purely amelanotic uveal tumors. A clinicopathologic correlation is shown of a
choroidal schwannoma that was believed clinically to be a melanoma.

Shields JA, Sanborn GE, Kurz GH, et al. Benign peripheral nerve tumor of the choroid.
Ophthalmology 1981;88:1322–1329.

Figure 14.49. Fundus appearance of a nonpigmented choroidal mass temporal to the foveal area in a 30-year-
old man.

Figure 14.50. Late fluorescein angiogram, showing moderately intense hyperfluorescence of the tumor.

835
Figure 14.51. Appearance of the lesion 1 year later, after it had demonstrated growth in spite of treatment with a
radioactive plaque.

Figure 14.52. B-scan ultrasonogram, showing the mass with acoustic hollowness and choroidal excavation.

Figure 14.53. Low-power photomicrograph of the sectioned eye, showing elevated choroidal mass.

836
Figure 14.54. Photomicrograph, showing abundant uniform spindle cells with abundant extracellular collagen.
Electron microscopy confirmed that the tumor was composed of Schwann cells. (Hematoxylin–eosin ×150.)

837
• CHOROIDAL MELANOTIC SCHWANNOMA
In some instances, a schwannoma can be pigmented, and, in such cases, its differentiation from
melanoma may be impossible. On the case illustrated, special studies supported the diagnosis of
melanotic schwannoma.

Shields JA, Font RL, Eagle RC Jr, et al. Melanotic schwannoma of the choroid:
immunohistochemistry and electron microscopic observations. Ophthalmology 1994;101:843–
849.

Figure 14.55. Fundus drawing of a diffuse pigmented choroidal mass in a 21-year-old woman.

Figure 14.56. B-scan ultrasonogram of the mass, showing acoustic hollowness and slight choroidal
excavation.

838
Figure 14.57. A-scan ultrasonogram, showing decreasing amplitude reflectivity in the mass.

Figure 14.58. Sectioned eye after enucleation, showing a diffuse pigmented choroidal mass.

Figure 14.59. Histopathology, showing whorls of benign spindle cells. (Hematoxylin–eosin ×100.)

839
Figure 14.60. Higher-magnification histopathology, showing whorls of benign spindle cells, some of which
contain dense cytoplasmic pigment. (Hematoxylin–eosin ×300.)

840
UVEAL NEUROFIBROMA

General Considerations
Neurofibroma can occur rarely in the uveal tract, usually in association with von
Recklinghausen neurofibromatosis (1–11).

Clinical Features
U veal neurofibroma can appear as a nonpigmented mass that, like schwannoma,
may be impossible to differentiate from amelanotic melanoma. In contrast to
schwannoma, most neurofibromas occur in patients with neurofibromatosis type 1
(NF1). It should be stressed that there is also an increased incidence of uveal
melanoma in patients with neurofibromatosis (11). We have seen patients with
neurofibromatosis and a choroidal mass in which we could not differentiate
clinically melanoma from a peripheral nerve sheath tumor. In two such cases, we
performed FNAB and made the diagnosis of melanoma. True nodular neurofibroma
of the uvea is very rare.
In patients with NF1, uveal neurofibroma can also manifest as a diffuse
infiltration of the uveal tract by neural and melanocytic cells. This tumor can be
similar to a diffuse uveal melanoma. However, it is usually associated with other
cutaneous signs of NF1. It is probably more common than the nodular form of
neurofibroma.

Other Uveal Manifestations of Neurofibromatosis Type 1

There are other fundus findings in NF1 that should also be mentioned for
completeness (3). Lisch nodules, which occur on the iris, represent one of the most
common ocular manifestations of this syndrome (2). Although these were suspected
by some to be neurofibromas, they have been shown by electron microscopy to be
melanocytic hamartomas, quite similar to a typical iris nevus (6). However, they
occur as bilateral pigmented elevations from the anterior border layer of the iris
rather than deeper in the stroma. The choroid in patients with NF1 can also show
multiple bilateral pigmented lesions, each of which appears to be identical to a
standard choroidal nevus (5). These are probably identical to the solitary choroidal
nevus discussed previously, and they may be a posterior expression of the iris Lisch
nodules. In addition, we have seen several patients with NF1 who developed a
retinal vascular mass, similar to the retinal vasoproliferative tumor.

Diagnostic Approaches
The diagnosis of uveal neurofibroma is the same as for schwannoma and melanoma.
Clinical findings of neurofibromatosis should suggest the possible diagnosis.
However, we believe that uveal melanoma is more common than uveal
neurofibroma in patients with neurofibromatosis.

Pathology
Ophthalmic pathologists may have difficulty in differentiating uveal neurofibroma

841
from amelanotic melanoma. Histopathologically, uveal neurofibroma is composed
of a combined proliferation of Schwann cells and fibroblasts. It may also be
remarkably similar to low-grade spindle melanoma cells. As mentioned earlier,
Lisch nodules appear to be composed of spindle-shaped melanocytes and represent
a melanocytic hamartoma similar to a uveal melanocytic nevus.

Management
Most cases of uveal neurofibroma have been managed with enucleation or
radiotherapy with the presumptive diagnosis of melanoma. Lisch nodules can be
observed only, because they have no proven malignant predisposition.

Selected References
Series
1. Brownstein S, Little JM. Ocular neurofibromatosis. Ophthalmology
1983;90:1595–1599.
2. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis. Incidence of
iris hamartomas. Ophthalmology 1981;88:348–354.
3. Huson S, Jones D, Beck L. Ophthalmic manifestations of neurofibromatosis. Br J
Ophthalmol 1987;71:235–238.
4. Yasunari T, Shiraki K, Hattori H, et al. Frequency of choroidal abnormalities in
neurofibromatosis type 1. Lancet 2000;16:988–992.

Imaging
5. Viola F, Villani E, Nattacci F, et al. Choroidal abnormalities detected by near-
infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis
1. Ophthalmology 2012;119:369–375.

Pathology
6. Perry HD, Font RL. Iris nodules in von Recklinghausen’s neurofibromatosis.
Electron microscopic confirmation of their melanocytic origin. Arch Ophthalmol
1982;100:1635–1640.

Case Reports
7. Wei WB, Jie Y, Mo J, et al. Clinical characteristics and treatment of
neurofibroma of the choroid. Chin Med J (Engl) 2012;125(10):1832–1835.
8. Burke JP, Leitch RJ, Talbot JF, et al. Choroidal neurofibromatosis with
congenital iris ectropion and buphthalmos: relationship and significance. J
Pediatr Ophthalmol Strabismus 1991;28:265–267.
9. Klein RM, Glassman L. Neurofibromatosis of the choroid. Am J Ophthalmol
1985;99:367–368.
10. Warwar RE, Bullock JD, Shields JA, et al. Coexistence of 3 tumors of neural
crest origin: neurofibroma, meningioma, and uveal malignant melanoma. Arch
Ophthalmol 1998;116:1241–1243.
11. Friedman SM, Margo CE. Choroidal melanoma and neurofibromatosis type 1.
Arch Ophthalmol 1998;116:694–695.

842
• UVEAL INVOLVEMENT IN NEUROFIBROMATOSIS: LISCH NODULES
AND UVEAL NEUROFIBROMA

Lisch nodules are very common in patients with NF1, and have their clinical onset in the first
decade of life. The Lisch nodule is not a neurofibroma, but is actually a melanocytic nevus.
Similarly pigmented lesions (nevi) are often present in the choroid in patients with NF1.

Figure 14.61. Typical Lisch nodules in a patient with neurofibromatosis type 1.

Figure 14.62. Histopathology of Lisch nodules, showing an elevated mass of spindle cells on the anterior
surface of the iris. (Hematoxylin–eosin ×20.) They represent melanocytic hamartomas.

843
Figure 14.63. Choroidal neurofibromatosis. Diffuse amelanotic choroidal thickening in a patient with
neurofibromatosis. Note also the pigmented choroidal nevi within the yellow-colored choroidal thickening.
These may be similar histopathologically to the Lisch nodules seen in the iris.

Figure 14.64. Face of the patient whose fundus is shown in Figure 14.63, demonstrating facial neurofibromas.

Figure 14.65. Photomicrograph of diffuse neurofibroma from a patient with intraocular and orbital plexiform
neurofibroma, showing diffuse thickening of the choroid. (Hematoxylin–eosin ×20.)

Figure 14.66. Higher-magnification view of diffuse choroidal neurofibroma from the same patient. The cells
that thicken the uveal tract are believed to represent a combination of neurons and melanocytes.
(Hematoxylin–eosin ×150.)

844
 UVEAL JUVENILE XANTHOGRANULOMA AND LANGERHANS’ CELL
HISTIOCYTOSIS

Histiocytic disorders that can sometimes involve the uveal tract include juvenile
xanthogranuloma (JXG) and Langerhans’ cell histiocytosis (LCH). Earlier reports
described cases of uveal involvement by histiocytosis X and Letterer–Siwe disease. It
is possible that some of those reports may have been describing LCH, which is the
most acceptable term today for the three classic histiocytosis X entities. JXG, LCH,
and other histiocytic lesions have been known to affect the ocular tissues (1–36).
Most of this discussion focuses on JXG, but intraocular LCH and other
granulomatous histiocytic diseases can rarely affect the eyes in similar fashion.

General Considerations
JXG is an idiopathic benign inflammatory disorder of young children and
occasionally adults. In young children, it is characterized by multiple cutaneous
yellow-pink papules that develop rapidly and resolve spontaneously without
treatment. Most cases are confined to the skin, but involvement of ocular tissue can
occur in the iris, posterior uvea, eyelid, conjunctiva, and optic nerve and orbit
(1–35). Many patients with intraocular JXG have no history of the cutaneous lesions.

Clinical Features
The clinical manifestations of intraocular JXG vary with the tissue affected. Iris
involvement, which is the most common intraocular variant, can range from a
distinct nodule to a diffuse thickening of the entire iris. The color can vary from
fleshy pink to a light brown. Prominent blood vessels are often apparent in the
mass. The diffuse variant can cause a darker-colored iris either due to the infiltration
itself or to iris neovascularization. Hence, JXG should be considered in the
differential diagnosis of acquired heterochromia in a child. Spontaneous hyphema,
which can sometimes induce secondary glaucoma, is the best-known ocular
complication of JXG. A child with spontaneous hyphema should be evaluated for
JXG, retinoblastoma, leukemia, and other conditions. Iris JXG is sometimes seen in
patients with NF1, but the nature of that relationship is unclear (4,5,12,15).

Pathology and Pathogenesis

Histopathologically, iris JXG appears as a variably sized mass that usually has
numerous small blood vessels. The infiltration is composed of normal-appearing
histiocytes with inflammatory cells, including lymphocytes, eosinophils, and
multinucleated giant cells, usually of the Touton type. The pathogenesis is not well
understood, and no causative organism has been demonstrated. The stain for S-100
protein is negative, excluding other histiocytoses, such as LCH and Rosai–Dorfman
sinus histiocytosis. In contrast to LCH, electron microscopy does not show
cytoplasmic Birbeck granules.

Diagnostic Approaches
The diagnosis of intraocular JXG should be considered in any child who has a uveal

845
lesion and typical cutaneous lesions. When the diagnosis of an iris lesion is
uncertain, fine-needle aspiration can be employed to establish the diagnosis
cytopathologically, which demonstrates histiocytes, other inflammatory cells, and
sometimes typical Touton giant cells (12). Caution should be taken, however, since
we have diagnosed iris JXG clinically in a 6-year-old and cytopathology of a needle
biopsy demonstrated malignant melanoma. In advanced cases of iris JXG with
buphthalmos, the diagnosis has been recognized histopathologically after
enucleation.

Management
Some cases of iris JXG are small and asymptomatic and tend to resolve without
treatment or with topical corticosteroids. However, larger, more aggressive lesions
are also generally responsive to corticosteroids. We have employed mainly systemic
and topical corticosteroids in standard doses, but in more aggressive cases,
periocular injection of corticosteroids has been necessary. Other methods include
local excision by iridectomy or iridocyclectomy and irradiation, which are rarely
advocated today.

Selected References
Small Series
1. Zimmerman LE. Ocular lesions of juvenile xanthogranuloma.
Nevoxanthoedothelioma. Am J Ophthalmol 1965;60:1011–1035.
2. Harley RD, Romayananda N, Chan GH. Juvenile xanthogranuloma. J Pediatr
Ophthalmol Strabismus 1982;19:33–39.
3. Karcioglu ZA, Mullaney PB. Diagnosis and management of iris juvenile
xanthogranuloma. J Pediatr Ophthalmol Strabismus 1997;34:44–51.
4. Ackerman CD, Cohen BA. Juvenile xanthogranuloma and neurofibromatosis.
Pediatr Dermatol 1991;4:339–340.
5. Cambiaghi S, Restano L, Caputo R. Juvenile xanthogranuloma associated with
neurofibromatosis 1: 14 patients without evidence of hematologic malignancies.
Pediatr Dermatol 2004;21:97–101.

Imaging
6. Lichter H, Yassur Y, Barash D, et al. U ltrasound biomicroscopy in juvenile
xanthogranuloma of the iris. Br J Ophthalmol 1999;83(3):375–376.
7. Danzig C, Shields CL, Mashayekhi A, et al. Fluorescein angiography of iris
juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 2008;45(2):110–
112.
8. Manjandavida FP, Arepalli S, Tarlan B, et al. Optical coherence tomography
characteristics of epi-iridic membrane in a child with recurrent hyphema and
presumed juvenile xanthogranuloma. J AAPOS 2014;18(1):93–95.

Pathology/Cytology
9. Schwartz LW, Rodrigues MM, Hallett JW. Juvenile xanthogranuloma diagnosed
by paracentesis. Am J Ophthalmol 1974;77:243–246.
10. Shields JA, Eagle RC, Shields CL, et al. Iris juvenile xanthogranuloma studied
by immunohistochemistry and flow cytometry. Ophthalmic Surg Lasers
1997;98:40–44.

846
11. Zamir E, Wang RC, Krishnakumar S, et al. Juvenile xanthogranuloma
masquerading as pediatric chronic uveitis: a clinicopathologic study. Surv
Ophthalmol 2001;46:164–171.
12. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of
iris tumors in 100 consecutive cases. Technique and complications.
Ophthalmology 2006;113:2080–2086.

Management
13. Casteels I, Olver J, Malone M, et al. Early treatment of juvenile
xanthogranuloma of the iris with subconjunctival steroids. Br J Ophthalmol
1993;77:57–60.

Case Reports
14. 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.
15. Algros MP, Laithier V, Montard M, et al. Juvenile xanthogranuloma of the iris
as the first manifestation of a neurofibromatosis. J Pediatr Ophthalmol
Strabismus 2003; 40:166–167.
16. Bruner WE, Stark WJ, Green WR. Presumed juvenile xanthogranuloma of the
iris and ciliary body in an adult. Arch Ophthalmol 1982;100:457–459.
17. Smith ME, Sanders TE, Bresnick GH. Juvenile xanthogranuloma of the ciliary
body in an adult. Arch Ophthalmol 1969;81:813–814.
18. Parmley VC, George DP, Fannin LA. Juvenile xanthogranuloma of the iris in an
adult. Arch Ophthalmol 1998;116:377–379.
19. Vijayalakshmi P, Shetty S, Jethani J, et al. Bilateral spontaneous hyphema in
juvenile xanthogranuloma. Ind J Ophthalmol 2006;54:45–46.
20. Hildebrand GD, Timms C, Thompson DA, et al. Juvenile xanthogranuloma with
presumed involvement of the optic disc and retina. Arch Ophthalmol
2004;122:1551–1555.
21. Rad AS, Kheradvar A. Juvenile xanthogranuloma: concurrent involvement of
skin and eye. Cornea 2001;20:760–762.
22. Raz J, Sinnreich Z, Freund M, et al. Congenital uveal xanthogranuloma. J
Pediatr Ophthalmol Strabismus 1999;36:344–346.
23. Parmley VC, George DP, Fannin LA. Juvenile xanthogranuloma of the iris in an
adult. Arch Ophthalmol 1998;116:377–379.
24. Wertz FD, Zimmerman LE, McKeown CA, et al. Juvenile xanthogranuloma of
the optic nerve, disc, retina, and choroid. Ophthalmology 1982;89:1331–1335.
25. Hadden OB. Bilateral juvenile xanthogranuloma of the iris. Br J Ophthalmol
1975;59:699–702.
26. 21. Kim IT, Lee SM. Choroidal Langerhans’ cell histiocytosis. Acta Ophthalmol
Scand 2000;78:97–100.
27. Walton DS. Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus
2005;42(3):192.
28. Lahav M, Albert DM. U nusual ocular involvement in acute disseminated
histiocytosis X. Arch Ophthalmol 1974;91:455–458.
29. Rupp RH, Holloman KR. Histiocytosis X affecting the uveal tract. Arch
Ophthalmol 1970;84:468–470.
30. Angell LK, Burton TC. Posterior choroidal involvement in Letterer-Siwe disease.

847
 J Pediatr Ophthalmol Strabismus 1978;15:79–81.
31. Mittelman D, Apple DJ, Goldberg MF. Ocular involvement in Letterer-Siwe
disease. Am J Ophthalmol 1973;75:261–265.
32. Bjornsson S, Sperry H, Barcos MP, et al. Blindness in a patient with malignant
histiocytosis. Cancer 1977;39:1752–1757.
33. Borne MJ, Gedde SJ, Augsburger JJ, et al. Juvenile xanthogranuloma of the iris
with bilateral spontaneous hyphema. J Pediatr Ophthalmol Strabismus
1996;33(3):196–197.
34. Sukavatcharin S, Cursino S, Li G, et al. Xanthogranuloma of the iris simulating
melanoma in an adult. Am J Ophthalmol 2007;143(3):529–531.
35. Longmuir S, Dumitrescu A, Kwon Y, et al. Juvenile xanthogranulomatosis with
bilateral and multifocal ocular lesions of the iris, corneal scleral limbus, and
choroid. J AAPOS 2011;15(6):598–600.
36. Shields CL, Hogarty MD, Kligman B, et al. Langerhans cell histiocytosis of the
uvea with with neovascular glaucoma. Diagnosis by needle biopsy and
management with intraocular bevacizumab and brachytherapy. J Am Assoc Ped
Ophthalm Strab 2010;14(6):534–537.

848
• IRIS JUVENILE XANTHOGRANULOMA: CLINICAL FEATURES AND
RESPONSE TO TREATMENT

Danzig C, Shields CL, Mashayekhi A, et al. Fluorescein angiography of iris juvenile

xanthogranuloma. J Pediatr Ophthalmol Strabismus 2008;45(2):110–112.

Figure 14.67. Iris juvenile xanthogranuloma presenting as a tan mass in a 6-year-old girl.

Figure 14.68. The same lesion 1 week after starting oral corticosteroids, showing regression of the mass. It
eventually resolved completely.

849
Figure 14.69. Superior iris juvenile xanthogranuloma in a 4-year-old boy.

Figure 14.70. Color fluorescein angiography of the lesion shown in Figure 14.69. Note that the superior mass
and the entire iris show hyperfluorescence, a finding in juvenile xanthogranuloma in contrast to solitary
melanocytic lesions.

Figure 14.71. Cytopathology of a fine-needle biopsy specimen of the lesion shown in Figure 14.69, revealing
histiocytes compatible with juvenile xanthogranuloma.

850
Figure 14.72. Appearance of the lesion shown in Figure 14.69 after beginning oral corticosteroids. It eventually
resolved completely.

851
• UVEAL JUVENILE XANTHOGRANULOMA AND LANGERHANS’ CELL
HISTIOCYTOSIS

In addition to the more common JXG, LCH can also involve the uveal tract, particularly the
posterior uveal tract.

Shields CL, Hogarty MD, Kligman B, et al. Langerhans cell histiocytosis of the uvea with
neovascular glaucoma. Diagnosis by needle biopsy and management with intraocular
bevacizumab and brachytherapy. J Am Assoc Ped Ophthalm Strab 2010;14(6):534–537.

Figure 14.73. Juvenile xanthogranuloma of the iris in a 19-month-old child. The lesion failed to respond to
corticosteroids, and fine-needle aspiration biopsy was not diagnostic, so the lesion was resected by
iridectomy because of possible malignancy.

Figure 14.74. Histopathology of the lesion shown in Figure 14.73, demonstrating granulomatous inflammation
with one typical Touton giant cell. (Hematoxylin–eosin ×200.)

852
Figure 14.75. Iris mass with photophobia in a 6-year-old boy with Langerhans’ histiocytosis.

Figure 14.76. Funduscopically, a yellow choroidal mass was found.

Figure 14.77. Ultrasonography confirmed the solid mass.

853
Figure 14.78. Following plaque radiotherapy, the mass resolved and the photophobia disappeared.

854
FIBROUS HISTIOCYTOMA, PRIMITIVE NEUROECTODERMAL
TUMOR, AND OTHER HISTIOCYTIC TUMORS OF THE UVEA

Some miscellaneous rare uveal tumors that are not mentioned elsewhere are
mentioned here for completeness (1–7). The two that are illustrated are fibrous
histiocytoma and primitive neuroectodermal tumor (PNET). We are aware of cases
of uveal fibrous histiocytoma solitary fibrous tumor, and Rosai–Dorfman disease
lesions that occur more often in the orbit. These rare lesions are known to produce
a large, nonpigmented choroidal mass that simulates an amelanotic melanoma,
schwannoma, or leiomyoma. PNET is also rare and could also fit in the chapter on
neural tumors. We have seen one case that seems to be compatible with uveal
PNET.

Selected References
Case Reports
1. Mittelman D, Apple DJ, Goldberg MF. Ocular involvement in Letterer-Siwe
disease. Am J Ophthalmol. 1973;75:261–265.
2. Bjornsson S, Sperry H, Barcos MP, et al. Blindness in a patient with malignant
histiocytosis. Cancer 1977;39:1752–1757.
3. Angell LK, Burton TC. Posterior choroidal involvement in Letterer-Siwe disease.
J Pediatr Ophthalmol Strabismus 1978;15:79–81.
4. Croxatto JO, D’Alessandro C, Lombardi A. Benign fibrous tumor of the choroid.
Arch Ophthalmol 1989;107(12):1793–1796.
5. Lam DS, Chow LT, Gandhi SR, et al. Benign fibrous histiocytoma of the choroid.
Eye (Lond) 1998;12(Pt 2):208–211.
6. Park JK, Palexas GN, Streeten BW, et al. Ocular involvement in familial
erythrophagocytic lymphohistiocytosis. Graefes Arch Clin Exp Ophthalmol
1997;235:647–652.
7. Grossniklaus HE, Shehata B, Sorensen P, et al. Primitive neuroectodermal
tumor/Ewing sarcoma of the retina. Arch Pathol Lab Med 2012;136(7):829–831.

855
• MISCELLANEOUS UVEAL TUMORS: FIBROUS HISTIOCYTOMA AND
PRIMITIVE NEUROECTODERMAL TUMOR

Figure 14.79. Choroidal fibrous histiocytoma. Fundus appearance of a nonpigmented choroidal mass. The
eye was enucleated because of suspicion of amelanotic choroidal melanoma.

Figure 14.80. Histopathology of the lesion shown in Figure 14.79, demonstrating the storiform pattern of the
benign spindle cells. Special studies supported the diagnosis of fibrous histiocytoma.

Figure 14.81. Unusual intraocular tumor, possibly a primitive neuroectodermal tumor of the ciliary body and
peripheral choroid, in a 16-month-old girl. Clinically, it presented as a fleshy-pink peripheral fundus mass. A

856
similar tumor was removed from the child’s neck at birth. (Courtesy of Oscar Croxatto, MD.)

Figure 14.82. Photograph of a sectioned globe following enucleation of the eye shown in Figure 14.81. Note
the dome-shaped mass of the ciliary body and peripheral choroid with exudative retinal detachment and
subluxation of the lens. (Courtesy of Oscar Croxatto, MD.)

Figure 14.83. Photomicrograph of the same tumor, showing a mass arising from the ciliary body region.
(Hematoxylin–eosin ×25.)

Figure 14.84. Photomicrograph, showing sheets of poorly differentiated cells. Although there was not uniform
agreement among the ophthalmic pathologists who reviewed the case, most favored the diagnosis of primitive
neuroectodermal tumor, based on histopathologic and immunohistochemical findings. (Hematoxylin–eosin
×200.)

857
 PART 2

TUMORS OF THE RETINA AND OPTIC DISC

858
 CHAPTER 15

RETINOBLASTOMA: INTRODUCTION, GENETICS,

CLINICAL FEATURES, CLASSIFICATION

RETINOBLASTOMA: INTRODUCTION, GENETICS, AND CLINICAL

FEATURES

Introduction
Retinoblastoma is the most common intraocular malignancy of childhood (1–45),
occurring in about 1 in 15,000 live births. This malignancy can manifest covertly
with painless leukocoria and threatens survival of the patient (1,2). If untreated,
retinoblastoma can lead to death within 1 to 2 years. Advanced disease with massive
tumor, invasive into surrounding structures, is at greatest risk for metastasis.
Worldwide, survival parallels economic development as retinoblastoma survival is
approximately 30% in Africa, 60% in Asia, 80% in Latin American, and 95% to
97% in Europe and North America (1).

Genetics
Retinoblastoma results from a somatic or germline mutation of chromosome 13
(3–8). All bilateral and familial forms of retinoblastoma have germline mutation.
U nilateral retinoblastoma shows germline mutation in 15% and somatic mutation
in 85%. Germline mutation patients can manifest overt clinical signs of the 13q
syndrome as well as risk for pinealoblastoma and second cancers.
The pinealoblastoma and other parasellar tumors are neoplasms that are similar
to retinoblastoma from embryologic, anatomic, and immunologic standpoint (9–16).
This malignancy tends to manifest in germline mutation patients, usually within 1
year of detection of retinoblastoma and nearly always by the age of 5 years (14).
The association of bilateral retinoblastoma with pinealoblastoma has been termed
trilateral retinoblastoma. This term can be inaccurate, in that some patients with
pinealoblastoma have unilateral retinoblastoma or no retinoblastoma at all.
Second cancers, on the other hand, can occur life-long (17–21). The most common

859
second cancers include osteosarcoma of long bones, soft tissue sarcoma, and
cutaneous melanoma. Germline mutation patients are additionally at risk for third,
fourth, and fifth cancers if they survive the second cancer. Children that receive
systemic chemotherapy for retinoblastoma are at reduced risk for long-term second
cancers (21).

Clinical Features
The clinical features of retinoblastoma vary depending on the extent of tumor
(22–45). Most cases are detected in children under the age of 3 years. However, this
tumor can be detected late in the teenage years or adulthood (29,30). In the U nited
States, the most common presenting signs include leukocoria (56%), strabismus
(24%), and poor vision (8%) (22). Further study on another U S cohort of nearly
1,200 eyes found median patient age at presentation of 15 months with 51% male,
49% female and 53% unilateral, 47% bilateral (23). On the other extreme, in parts
of Africa, this malignancy most often presents with buphthalmos (56%) and
leukocoria (32%), with high risk for bilateral enucleation and ultimate death (24).
Clinically, retinoblastoma begins as a small, transparent lesion in the sensory
retina that may be easily overlooked with ophthalmoscopy. As the tumor enlarges,
it becomes opaque white and develops a dilated retinal feeding artery and draining
vein, and a secondary retinal detachment can occur. The best-known initial clinical
sign is a white pupillary reflex, called leukocoria. As the tumor enlarges, it can
leave its intraretinal location and assume an exophytic growth pattern, endophytic
growth pattern, or a combination of the two. The exophytic pattern is characterized
by growth of the tumor outward toward the subretinal space, producing an
overlying retinal detachment. The endophytic pattern is characterized by seeding of
tumor cells into the overlying vitreous, sometimes obscuring a clear view of the
retina. Rarely, retinoblastoma can manifest an internal cavity, suggestive of low-
grade tumor (36).
The less common diffuse infiltrating growth pattern is characterized by flat or
minimally elevated growth of the tumor (31); although diffuse retinoblastoma is
usually in the posterior retina, it has rarely appeared near the ora serrata and over
the ciliary body without posterior involvement (32). Retinoblastoma can produce
secondary glaucoma in about 17% of cases, usually due to iris neovascularization
and secondary angle closure (33). The iris neovascularization can lead to a
spontaneous hyphema, a rare presenting sign. Inflammation from necrotic
intraocular retinoblastoma can simulate or cause orbital cellulitis (34). Although the
lens is usually clear and in the correct position, there is a rare association with
cataract and subluxed lens. It advanced cases, can extend extrasclerally and present
as an advanced, erosive mass.

Table 15.1 The international classification of retinoblastoma

860
Spontaneous Regression
Retinoblastoma has a tendency to undergo spontaneous regression in about 3% of
cases (37–40). Spontaneously regressed retinoblastoma was initially recognized early
to have rather typical clinical features. Subsequently, a benign variant of
retinoblastoma, called retinocytoma or retinoma, was described. We prefer to use
the term spontaneously regressed retinoblastoma for a tumor that actually grows to
a certain size and then regresses. We use the term spontaneously arrested
retinoblastoma for the benign variant that grows to a certain size and then stabilizes
(1).

International Classification of Retinoblastoma

The International Classification of Retinoblastoma is currently used at major centers
where retinoblastoma patients are managed (41–43) (Table 15.1). The details of this
classification and its implications for predicting prognosis for ocular salvage using
chemoreduction and intra-arterial chemotherapy have been reported (44,45). The
classification is summarized in the following table.
The following sections describe and illustrate clinical variations, diagnostic
approaches, management, and differential diagnosis of retinoblastoma.

Selected References
Epidemiology
1. Kivela T. The epidemiological challenge of the most frequent eye cancer:
retinoblastoma, an issue of birth and death. Br J Ophthalmol 2009;93:1129–
1131.
2. Wong JR, Tucker MA, Kleinerman RA, et al. Retinoblastoma incidence patterns
in the U S Surveillance, Epidemiology, and End Results program. JAMA
Ophthalmol 2014;132:478–483.

Genetics

861
 3. Sparkes RS, Murphree AL, Lingua RW, et al. Gene for hereditary retinoblastoma
assigned to human chromosome 13 by linkage to esterase D. Science
1983;219:971–973.
4. Shields CL, Shields JA, Donoso LA. Clinical genetics of retinoblastoma. In:
Shields JA, ed. Update on Malignant Ocular Tumors. Boston: Little, International
Ophthalmology Clinics, Brown; 1993;33:67–76.
5. Ganguly A, Nichols K, Grant G, et al. Molecular karyotype of sporadic unilateral
retinoblastoma tumors. Retina. 2009;29:1002–1012.
6. Ganguly A, Shields CL. Differential gene expression profile of retinoblastoma
compared to normal retina. Mol Vis 2010;16:1292–1303.
7. Nichols KE, Walther S, Chao E, et al. Recent advances in retinoblastoma genetic
research. Curr Opin Ophthalmol 2010;20:351–355.
8. Chen A, Moran K, Richard-Yutz J, et al. Enhanced sensitivity for detection of
low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases
using deep semiconductor sequencing. Hum Mutat 2013;35(3):384–391.

Pinealoblastoma
9. Donoso LA, Shields JA, Felberg NT, et al. Intracranial malignancy in patients
with bilateral retinoblastoma. Retina 1981;1:67–74.
10. Bader JL, Meadows AT, Zimmerman LE, et al. Bilateral retinoblastoma with
ectopic intracranial retinoblastoma: trilateral retinoblastoma. Cancer Genet
Cytogenet 1982;5:203–213.
11. Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma. Am J Ophthalmol
1989;107:121–126.
12. De Potter P, Shields CL, Shields JA. Clinical variations of trilateral
retinoblastoma. A report of 13 cases. J Pediatr Ophthalmol Strabismus
1994;31:26–31.
13. Marcus DM, Brooks SE, Leff G, et al. Trilateral retinoblastoma: insights into
histogenesis and management. Surv Ophthalmol 1998;43:59–70.
14. Kivela T. Trilateral retinoblastoma: a meta-analysis of hereditary
retinoblastoma associated with primary ectopic intracranial retinoblastoma. J
Clin Oncol 1999;17:1829–1837.
15. Singh AD, Shields CL, Shields JA. New insights into trilateral retinoblastoma.
Cancer 1999;86:3–5.
16. Ramasubramanian A, Kytasty C, Meadows AT, et al. Incidence of pineal gland
cyst and pineoblastoma in children with retinoblastoma during the
chemoreduction era. Am J Ophthalmol 2013;156(4):825–829.

Second Cancers
17. Abramson DH, Ellsworth RM, Zimmerman LE. Nonocular cancer in
retinoblastoma survivors. Trans Am Acad Ophthalmol 1976;81:454–456.
18. Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in
patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583–1587.
19. Moll AC, Imhof SM, Bouter LM, et al. Second primary tumors in patients with
hereditary retinoblastoma: a register-based follow-up study, 1945–1994. Int J
Cancer 1996;67:515–519.
20. Abramson DH, Melson MR, Dunkel IJ, et al. Third (fourth and fifth) nonocular
tumors in survivors of retinoblastoma. Ophthalmology 2001;108:1868–1876.
21. Turaka K, Shields CL, Leahey A, et al. Second malignant neoplasms following

862
 chemoreduction with carboplatin, etoposide, and vincristine in 245 patients
with intraocular retinoblastoma. Pediatr Blood Cancer 2012;59:121–125.
Clinical
22. Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J
Pediatr 1998;132:505–508.
23. Epstein J, Shields CL, Shields JA. Trends in the management of retinoblastoma;
Evaluation of 1,196 consecutive eyes during 1974–2001. J Ped Ophthalmol
Strabismus 2003;40:196–203.
24. Boubacar T, Fatou S, Fousseyni T, et al. A 30-month prospective study on the
treatment of retinoblastoma in the Gabriel Toure Teaching Hospital, Bamako,
Mali. Br J Ophthalmol 2010;94:467–469.
25. Shields CL, Shields JA. Basic understanding of current classification and
management of retinoblastoma. Curr Opin Ophthalmol 2006;17:228–234.
26. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with
intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye
(Lond) 2013;27(2):253–264.
27. Shields CL, Shields JA. Pearls in the management of children with
retinoblastoma. Saudi J Ophthalmol 2009;23:43–50.
28. Shields CL, Schwendeman R, Lally SE, et al. Targeted retinoblastoma
management. When to use intravenous, intra-arterial, subTenon’s, and
intravitreal chemotherapy. Curr Opin 2014;25(5):374–385.
29. Shields CL, Shields JA, Shah P. Retinoblastoma in older children.
Ophthalmology 1991;98:395–399.
30. Kaliki S, Shields CL, Gupta A, et al. Newly-diagnosed active retinoblastoma in
adults. A study of 8 cases. Retina 2015; in press.
31. Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating
retinoblastoma in 34 consecutive eyes. Ophthalmology 2008;115:2253–2258.
32. Grossniklaus HE, Dhaliwal RS, Martin DF. Diffuse anterior retinoblastoma.
Retina 1998;18:238–241.
33. 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.
34. Shields JA, Shields CL, Suvarnamani C, et al. Retinoblastoma manifesting as
orbital cellulitis. Tenth Annual David and Mary Seslen Endowment Lecture. Am
J Ophthalmol 1991;112:442–449.
35. Shields CL, Piccone MR, Shields JA, et al. Mushroom-shaped choroidal
recurrence of retinoblastoma 25 years after therapy. Arch Ophthalmol
2002;120:844–846.
36. Palamar M, Pirondini C, Shields CL, et al. Cavitary retinoblastoma.
U ltrasonography and fluorescein angiographic findings in 3 cases. Arch
Ophthalmol 2008;126(11):1598–1600.
37. 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.
38. Margo C, Hidayat A, Kopelman J, et al. Retinocytoma. A benign variant of
retinoblastoma. Arch Ophthalmol 1983;101;1519–1531.
39. Eagle RC, Shields JA, Donoso LA, et al. Malignant transformation of

863
 spontaneously regressed retinoblastoma, retinoma/retinocytoma variant.
Ophthalmology 1989;96:1389–1395.
40. Singh AD, Santos MC, Shields CL, et al. Observations on 17 patients with
retinocytoma. Arch Ophthalmol 2000;118:199–205.
41. Shields CL, Shields JA. Basic understanding of current classification and
management of retinoblastoma. Curr Opin Ophthalmol 2006;113:2080–2086.
42. Shields CL. The International Classification of Retinoblastoma is practical and
predictable. In: Rapuano C, ed, Yearbook of Ophthalmology. St Louis, MO:
Mosby; 2008; 227–230.
43. Chantada GL, Sampor C, Bosaleh A, et al. Comparison of staging systems for
extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol
2013;131(9):1127–1134.
44. Shields CL, Au A, Czyz C, et al. The International Classification of
Retinoblastoma (ICRB) predicts chemoreduction success. Ophthalmology
2006;113:2276–2280.
45. Shields CL, Manjandavida FP, Pieretti G, et al. Intra-arterial chemotherapy for
retinoblastoma in 70 eyes: Outcomes based on the International Classification of
Retinoblastoma. Ophthalmology 2014;121(7):1453–1460.

864
• RETINOBLASTOMA: LEUKOCORIA
Leukocoria (white pupillary reflex) is the most common presenting feature of retinoblastoma.

Figure 15.1. Leukocoria in the left eye in a 4-month-old child.

Figure 15.2. Mild leukocoria in the right eye in a 13-month-old child.

865
Figure 15.3. Leukocoria in the left eye in a 3-year-old child.

Figure 15.4. Leukocoria in the left eye due to endophytic retinoblastoma in a 4-year-old child.

Figure 15.5. Bilateral leukocoria in a 3-month-old child. Note the retinal blood vessels immediately posterior to
the clear lens.

866
Figure 15.6. Bilateral leukocoria in a 4-month-old child with left esotropia.

867
• RETINOBLASTOMA: CLINICAL FEATURES
In the early stages, retinoblastoma is a small, transparent lesion in the retina. When it becomes
slightly larger, it becomes opaque and more visible and eventually displays a dilated feeding
retinal artery and draining vein. Chalk-white foci of calcification can sometimes be seen
ophthalmoscopically in the tumor. Tumors in the foveal region can cause loss of visual fixation
and strabismus, either esotropia or exotropia. With time, the tumor produces a characteristic
white pupillary reflex (leukocoria). Most tumors are diagnosed following the development of
leukocoria.

Figure 15.7. Small retinoblastoma inferior to the fovea in the right eye.

Figure 15.8. Slightly larger retinoblastoma superior to the optic disc. Note the dilated feeding artery and
draining vein.

868
Figure 15.9. Larger retinoblastoma in the superior macular area. Note that the superior vessels coming from
the disc are dilated and the inferior vessels are not dilated.

Figure 15.10. Two retinoblastomas adjacent to the optic disc. The superior tumor is seeding the overlying
vitreous (endophytic), and the inferior tumor is still within the retina.

Figure 15.11. Massive retinoblastoma of endophytic type.

869
Figure 15.12. Massive retinoblastoma of exophytic type.

870
• RETINOBLASTOMA: WIDE-ANGLE IMAGING OF SMALL TUMORS
In children with a family history of retinoblastoma, the tumors are often discovered at an earlier
stage due to screening of such patients. Shown are five eyes with small retinoblastomas that
were discovered through such screening. The following are wide-angle fundus photographs of
selected cases of small retinoblastoma.

Figure 15.13. Extremely small and subtle retinoblastoma inferotemporal to the fovea of the right eye.

Figure 15.14. Three small but distinct tumors in the left eye of the patient shown in Figure 15.13.

871
Figure 15.15. Solitary retinoblastoma superior to the fovea in the right eye.

Figure 15.16. Two small confluent retinoblastomas in the left eye of the patient shown in Figure 15.15.

Figure 15.17. Retinoblastoma centered in the macular region of the right eye.

872
Figure 15.18. Left eye of the patient shown in Figure 15.17, revealing a small retinoblastoma immediately
superotemporal to the fovea.

873
• RETINOBLASTOMA: WIDE-ANGLE IMAGING OF MEDIUM-SIZED
TUMORS

Figure 15.19. Retinoblastoma in the macular region of right eye. Note the second small tumor located more
peripherally.

Figure 15.20. Retinoblastoma in the macular region of the left eye.

874
Figure 15.21. Retinoblastoma in the macular region of the right eye.

Figure 15.22. Retinoblastoma in the macular region of the left eye.

Figure 15.23. Retinoblastoma overhanging and obscuring the optic disc.

Figure 15.24. Retinoblastoma overhanging and obscuring the optic disc.

875
• RETINOBLASTOMA: WIDE-ANGLE IMAGING OF LARGE TUMORS
Retinoblastoma can show a diversity of clinical appearances. Most are solid, but some show
large, cystlike cavities within the solid component. Such pseudocysts are generally seen in
better differentiated tumors.

Figure 15.25. Two large retinoblastomas nasal and temporal to the optic disc.

Figure 15.26. Large retinoblastoma in the posterior fundus with subretinal seeds of tumor cells.

876
Figure 15.27. Large retinoblastoma in the posterior fundus, showing typical fine blood vessels that ramify near
the tumor surface.

Figure 15.28. Large superior endophytic retinoblastoma with inferior retinal detachment and subretinal tumor
seeds.

Figure 15.29. Large bilobed retinoblastoma obscuring the optic disc.

Figure 15.30. Large retinoblastoma with a cavitary nodule on the tumor surface.

877
• RETINOBLASTOMA: EXOPHYTIC GROWTH PATTERN
Retinoblastoma begins in the sensory retina. With time, it can grow either into the subretinal
area (exophytic growth pattern) or into the vitreous cavity (endophytic growth pattern).
Advanced tumors may show both endophytic and exophytic components. Endophytic tumors
can sometimes seed into the anterior chamber, simulating intraocular inflammation or
infection. They often occur in somewhat older children.

Figure 15.31. The solid tumor is to the right and a secondary retinal detachment (with subretinal tumor seeds)
is to the left. The retinal blood vessels are seen posterior to the clear lens.

Figure 15.32. In this instance, the tumor involves all lobes of the retinal detachment.

878
Figure 15.33. Multilobed exophytic retinoblastoma.

Figure 15.34. Fluorescein angiogram of the lesion shown in Figure 15.33 with leakage of dye in the subretinal
space over the tumor (to the left).

Figure 15.35. Exophytic retinoblastoma (to the left) with tumor seeds on the posterior surface of the detached
retina (to the right).

879
Figure 15.36. Multilobular exophytic retinoblastoma replacing most of the posterior portion of the retina.

880
• RETINOBLASTOMA: ENDOPHYTIC GROWTH PATTERN

Figure 15.37. Endophytic growth pattern. Note the white tumor inferiorly with no overlying retinal vessels.

Figure 15.38. More extensive endophytic tumor, filling most of the retrolental area.

Figure 15.39. Anterior chamber seeding of endophytic retinoblastoma forming semisolid tumor nodules on the
iris surface in a 6-year-old child.

881
Figure 15.40. Anterior chamber seeding of endophytic retinoblastoma forming a “pseudohypopyon” in the
inferior aspect of the anterior chamber. This is a “diffuse” infiltrating retinoblastoma, a subject discussed in the
next section.

Figure 15.41. Endophytic retinoblastoma with overlying vitreal seeds.

Figure 15.42. View of midportion of the vitreous in the patient in Figure 15.41, showing typical “snowballs”
attached to the vitreous framework.

882
• RETINOBLASTOMA PRESENTING WITH NEOVASCULAR
GLAUCOMA

In some instances, retinoblastoma can induce secondary glaucoma by any of several

mechanisms. About 17% of eyes with newly diagnosed retinoblastoma have glaucoma, and
about 50% that come to enucleation have elevated intraocular pressure, usually secondary to
iris neovascularization (neovascular glaucoma).

Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating retinoblastoma
in 34 consecutive eyes. Ophthalmology 2008;115:2253–2258.

Figure 15.43. Small inferior “pseudohypopyon” in a 7-year-old child.

Figure 15.44. Posterior fundus, showing diffuse gray-white thickening of the retina but no distinct mass.

883
Figure 15.45. Section of the enucleated eye, showing diffuse white thickening of the retina.

Figure 15.46. Gross appearance of the retrolental area, showing characteristic seeding of white tumor cells in
the ciliary body and zonule.

Figure 15.47. Cross section of the retina, showing islands of retinoblastoma cells in the inner layers.
(Hematoxylin–eosin ×20.)

884
Figure 15.48. Cross section of the optic nerve, showing invasion by retinoblastoma cells mostly in the pial
septa. (Hematoxylin–eosin ×20.)

885
• RETINOBLASTOMA: DIFFUSE GROWTH PATTERN
Diffuse infiltrating retinoblastoma is an unusual variant in which the tumor grows in a flat,
infiltrating pattern and does not appear as an elevated mass. It is usually unilateral, endophytic,
and nonfamilial and is diagnosed in older children. Intraocular calcium is usually not
demonstrable with ultrasonography or computed tomography. There is often a delay in
diagnosis and misdirected therapy in such cases because the lesion can simulate an
inflammatory process. Optic nerve invasion is frequently present, and enucleation is generally
the treatment of choice. Illustrated is a clinicopathologic correlation of a diffuse infiltrating
retinoblastoma.

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.

Figure 15.49. Total retinal detachment with iris neovascularization secondary to exophytic retinoblastoma.

Figure 15.50. Fluorescein angiogram of the eye shown in Figure 15.49, better depicting the dilated retinal
blood vessels over the tumor and leakage of dye from the abnormal iris vasculature.

886
Figure 15.51. Acquired heterochromia iridis secondary to iris neovascularization. Note that the affected right iris
is darker.

Figure 15.52. Iris neovascularization causing secondary glaucoma in an eye with a large retinoblastoma.

Figure 15.53. Spontaneous hyphema secondary to iris neovascularization in a child with retinoblastoma.

887
Figure 15.54. Section of the enucleated eye shown in Figure 15.53. Note the hyphema and the diffuse irregular
white mass involving the entire sensory retina.

888
• RETINOBLASTOMA PRESENTING AS ORBITAL CELLULITIS
Occasionally, a large retinoblastoma can become necrotic and produce inflammatory signs
resembling bacterial orbital cellulitis.

Shields JA, Shields CL, Suvarnamani C, et al. Retinoblastoma manifesting as orbital cellulitis.
Tenth Annual David and Mary Seslen Endowment Lecture. Am J Ophthalmol 1991;112:442–449.

Figure 15.55. Preseptal cellulitis of the left eye secondary to necrotic retinoblastoma.

Figure 15.56. Pseudohypopyon in the anterior chamber of the patient shown in Figure 15.55, suggesting that
the cellulitis is secondary to retinoblastoma.

889
Figure 15.57. Section of the enucleated eye of the patient shown in Figure 15.55, revealing the nodule of tumor
cells with characteristic diffuse seeding in the pars plana and zonule of the lenses.

Figure 15.58. Signs of acute orbital cellulitis in the left eye of a child with necrotic retinoblastoma.

Figure 15.59. Axial computed tomography of the patient shown in Figure 15.58, revealing retinoblastoma in
both eyes. Even though there was periocular soft tissue swelling around the left eye, there was no pathologic
evidence of extraocular extension of the tumor.

Figure 15.60. Gross section of the enucleated eye in the patient in Figure 15.58, showing hemorrhagic,
necrotic retinoblastoma.

890
• RETINOBLASTOMA: MASSIVE EXTRAOCULAR EXTENSION
In some advanced instances, retinoblastoma can extend from the eye into the orbital soft
tissues and cause massive extraocular involvement by the neoplasm. This is seen most often in
underdeveloped countries, where medical care is not readily available.

Figure 15.61. Massive proptosis and periocular edema secondary to retinoblastoma. (Courtesy of Amelia
Pifano, MD.)

Figure 15.62. Axial computed tomogram of the child shown in Figure 15.61, showing the globe and orbit filled
by the neoplasm. (Courtesy of Amelia Pifano, MD.)

891
Figure 15.63. Massive extraocular extension of retinoblastoma. The opposite eye had developed phthisis
secondary to spontaneous necrosis and regression of the retinoblastoma.

Figure 15.64. Massive extraocular extension of retinoblastoma due to unavailable medical care. (Courtesy of
Jimmy Rodgers, MD.)

Figure 15.65. Massive extraocular extension of retinoblastoma. Treatment was refused by the parents when
the tumor was recognized about a year earlier. (Photograph courtesy of Albert Biglan, MD.)

892
Figure 15.66. Side view of the patient in Figure 15.65, showing metastasis to preauricular lymph nodes.
(Photograph courtesy of Albert Biglan, MD.)

893
• RETINOBLASTOMA: CONGENITAL AGGRESSIVE TYPE
Retinoblastoma is generally diagnosed between age 3 months and 3 years. However, it can be
clinically evident at birth. Some congenital retinoblastomas are highly aggressive. Described
here is a sporadic congenital retinoblastoma that eventually led to brain metastasis and death.

Figure 15.67. Extensive conjunctival and precorneal hemorrhage noted at birth.

Figure 15.68. Axial computed tomogram showing marked enlargement of the right eye (buphthalmos). In spite
of the buphthalmos, the calcified mass appeared to be confined to the eye. Enucleation was performed
elsewhere, and the globe ruptured at the tumor on surgery.

894
Figure 15.69. Histopathology, showing anaplastic retinoblastoma cells. (Hematoxylin–eosin ×200.)

Figure 15.70. Clinical appearance a few months later when the child presented with orbital recurrence in spite
of maximal chemotherapy and irradiation.

Figure 15.71. Axial computed tomogram, showing massive tumor recurrence anterior to the spherical orbital
implant. Systemic evaluation revealed no metastasis, and orbital exenteration was performed.

Figure 15.72. Histopathology of orbital recurrence, showing highly atypical anaplastic cells. Brain metastasis
became apparent a few months later. (Hematoxylin–eosin ×300.)

895
• RETINOBLASTOMA IN OLDER CHILDREN
Although retinoblastoma is generally diagnosed between age 3 months and 3 years, it is not so
widely recognized that retinoblastoma may not become clinically clear until later. The majority
of such tumors have an endophytic (often diffuse) growth pattern and are sporadic. Examples of
retinoblastoma occurring at an older age are depicted.

1. Shields CL, Shields JA, Shah P. Retinoblastoma in older children. Ophthalmology.

1991;98:395–399.
2. Kaliki S, Shields CL, Gupta A, et al. Newly-diagnosed active retinoblastoma in adults. A study
of 8 cases. Retina 2015; in press.

Figure 15.73. Diffuse anterior retinoblastoma presenting as clumps of tumor cells in the anterior chamber in a
17-year-old boy.

Figure 15.74. Wide-angle fundus photograph of the patient shown in Figure 15.73, demonstrating normal optic
disc and macular region and relatively flat white retinal lesion posterior to the ora serrata inferotemporally. Note
the dilated, tortuous retinal feeding artery and draining vein.

896
Figure 15.75. Retinoblastoma in a 13-year-old girl.

Figure 15.76. Retinoblastoma presenting as a pseudohypopyon in a 16-year-old girl.

Figure 15.77. Retinoblastoma in a 17-year-old boy.

Figure 15.78. Retinoblastoma in an 18-year-old girl.

897
• RETINOBLASTOMA: INTERNATIONAL CLASSIFICATION OF
RETINOBLASTOMA

The new International Classification of Retinoblastoma has been adopted at most centers and is
used in selecting treatment and in predicting prognosis of salvaging the affected eye. Careful
drawings by experienced clinicians are important in classification because fundus photography
and ultrasonography are not as sensitive as ophthalmoscopy in detecting small areas of
subretinal fluid and tumor seeding that assist in classification and in selecting management.

1. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol
Clin North Am 2005;18:41–53.
2. Shields CL, Shields JA. Basic understanding of current classification and management of
retinoblastoma. Curr Opin Ophthalmol 2006;113:2080–2086.
3. Shields CL, Au A, Czyz C, et al. The International Classification of Retinoblastoma (ICRB)
predicts chemoreduction success. Ophthalmology 2006;113:2276–2280.

Figure 15.79. Group A, small lesion confined to the sensory retina <3 mm in size and located near the equator
superotemporally.

Figure 15.80. Group B, showing macular retinoblastoma confined to the sensory retina.

898
Figure 15.81. Group C, characterized by retinoblastoma with focal vitreous and subretinal seeds. Note the
subtle vitreal seed inferior to the optic disc.

Figure 15.82. Diagram of the lesion shown in Figure 15.81, depicting the retinal detachment (in blue) and the
subretinal seeds, neither of which is clearly seen in the fundus photograph.

Figure 15.83. Group C, showing multiple tumors superiorly in the left eye. The overlying vitreous seeds are not
clearly seen.

899
Figure 15.84. Diagram of the group C retinoblastoma shown in Figure 15.83. The areas shown in green depict
the vitreous seeds.

Figure 15.85. Group D retinoblastoma, showing a large tumor with secondary retinal detachment and diffuse
subretinal seeds.

Figure 15.86. Diagram of group D retinoblastoma, showing the retinal detachment (blue) around the tumor
and the subretinal tumor seeds (orange), findings not clearly seen in the photograph in Figure 15.85.

900
Figure 15.87. Group D retinoblastoma, showing extensive vitreous seeding of the tumor.

Figure 15.88. Diagram of group D retinoblastoma, showing vitreous seeds (green dots) over the tumor shown
in Figure 15.87.

Figure 15.89. Group E retinoblastoma, showing extensive intraocular tumor with vitreous seeds.

901
Figure 15.90. Diagram of group E retinoblastoma, depicting a large tumor and extensive, diffuse vitreal seeds.

902
• RETINOBLASTOMA: SPONTANEOUSLY ARRESTED AND
SPONTANEOUSLY REGRESSED TUMORS (RETINOCYTOMA)

Some retinoblastomas appear to be stationary and nonprogressive and may represent a “benign”
variant of this disease. Terms like retinoma and retinocytoma have been applied to such lesions.
We have employed the clinically descriptive term spontaneously arrested retinoblastoma for
tumors that appear clinically to have reached their final size and ceased to grow. We prefer the
term spontaneously regressed retinoblastoma for those that appear to have reached a certain
size and then regressed. The latter appears to have surrounding alterations in the retinal pigment
epithelium, similar to a tumor that has been successfully treated. Large spontaneously regressed
retinoblastoma can cause phthisis bulbi.

Figure 15.91. Spontaneously arrested retinoblastoma in a 30-year-old man, showing a calcified central area
and a surrounding semiopaque “fish flesh” appearance.

Figure 15.92. Spontaneously arrested retinoblastoma in a 12-year-old girl, showing similar features to the
case shown in Figure 15.91.

903
Figure 15.93. Spontaneously arrested retinoblastoma in a 25-year-old woman.

Figure 15.94. Spontaneously regressed retinoblastoma as originally seen in a 6-year-old girl. The lesion has
remained stable for 15 years.

Figure 15.95. Spontaneously regressed retinoblastoma as originally seen in a 6-year-old boy. It has remained
stable for 8 years.

904
Figure 15.96. Spontaneously arrested retinoblastoma in opposite eye of the child shown in Figure 15.95.
There was no family history of retinoblastoma.

905
• RETINOBLASTOMA: SPONTANEOUSLY ARRESTED AND
SPONTANEOUSLY REGRESSED TUMORS (RETINOCYTOMA).
WIDE-ANGLE IMAGING

Figure 15.97. Regressed retinoblastoma superonasally in the right eye in a 36-year-old man. Note that the
superior portion of the lesion is translucent and the inferior part shows chalk-white calcification and retinal
pigment epithelium loss, revealing a view of the underlying choroidal blood vessels. This is a type 3
regression pattern.

Figure 15.98. Regressed retinoblastoma in the peripheral fundus in a 25-year-old woman.

906
Figure 15.99. Montage photograph of a spontaneously regressed retinoblastoma in a 45-year-old woman.
Note the dilated, feeding retinal artery (to the right) and the more dilated, tortuous retinal draining vein (to the
left).

Figure 15.100. Standard photograph of the lesion shown in Figure 15.99. The white area represents dense
calcification. The adjacent alterations in the retinal pigment epithelium suggest that the lesion was once larger
and then regressed.

Figure 15.101. Spontaneously arrested retinoblastoma in a 12-year-old boy who had enucleation of the
opposite eye for advanced retinoblastoma. Note the two foci of calcification within the tumor. This lesion was
recognized on initial examination and has remained stable for 6 years.

907
Figure 15.102. Spontaneously arrested retinoblastoma in a 31-year-old man. The lesion has only minimal
calcification and has remained stable for many years.

908
• SPONTANEOUSLY REGRESSED RETINOBLASTOMA
(RETINOCYTOMA): MALIGNANT TRANSFORMATION

On rare occasions, a retinoblastoma that appears to have been arrested or regressed may show
growth and malignant transformation. Such a case is depicted.

Eagle RC, Shields JA, Donoso LA, et al. Malignant transformation of spontaneously regressed
retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989;96:1389–1395.

Figure 15.103. Spontaneously regressed retinoblastoma as seen initially in a 3-year-old child. The patient was
followed for 3 years, and the lesion remained stable.

Figure 15.104. Same lesion shown at the age of 7 years, when there was florid regrowth of the tumor.

909
Figure 15.105. Enucleated eye, showing a fluffy white mass arising from retina.

Figure 15.106. Photomicrograph, showing well-differentiated tumor cells with fleurette formation.
(Hematoxylin–eosin ×100.)

Figure 15.107. Photomicrograph, showing characteristic fleurettes. (Hematoxylin–eosin ×200.)

910
Figure 15.108. Photomicrograph in another area of the tumor, showing foci of calcification in an area of viable,
well-differentiated tumor cells. This is a characteristic histopathologic feature seen with retinocytoma.
(Hematoxylin–eosin ×100.)

911
• RETINOBLASTOMA: ASSOCIATED WITH PINEALOBLASTOMA
(“TRILATERAL RETINOBLASTOMA”) AND PINEAL CYST SIMULATING
PINEALOBLASTOMA

A number of second tumors are known to occur in patients with the familial form of
retinoblastoma. This subject is mentioned in the atlas of orbital tumors. Mentioned here is one
form of second tumor, termed trilateral retinoblastoma. Trilateral retinoblastoma is a term
applied to the occurrence in the same patient of bilateral retinoblastoma and pinealoblastoma
or other parasellar intracranial tumors. Depicted in Figures 15.109 to 15.112 is a case of
familial retinoblastoma in which multiple small tumors in each eye were controlled with
radiotherapy but later a pinealoblastoma developed and proved to be fatal.

1. Karatza E, Shields CL, Flanders AE, et al. Pineal cyst simulating pinealoblastoma in 11
children with retinoblastoma. Arch Ophthalmol 2006;124:595–597.
2. Ramasubramanian A, Kytasty C, Meadows AT, et al. Incidence of pineal gland cyst and
pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J
Ophthalmol 2013;156(4):825–829.

Figure 15.109. Papilledema of the right optic disc at age 36 months in a child with headaches. He was cured
shortly after birth with external beam irradiation for bilateral familial retinoblastoma with small tumors in both
eyes.

Figure 15.110. Papilledema of the left eye at the same time.

912
Figure 15.111. Cranial computed tomography, showing a large pineal tumor.

Figure 15.112. Another section of cranial computed tomography, showing dilated ventricles characteristic of
hydrocephalus.

Figure 15.113. Sagittal magnetic resonance imaging (MRI) in a child with familial retinoblastoma. Note the
mass at the posterior edge of the corpus callosum, measuring 1.7 × 1.3 cm. Inset shows sagittal MRI of the
spine, revealing a metastatic focus of pinealoblastoma in the same patient.

913
Figure 15.114. Sagittal magnetic resonance image in T1-weighted image of a child with bilateral
retinoblastoma, demonstrating a cystic lesion at the posterior margin of the corpus callosum. With gadolinium
contrast, the wall of the lesion showed enhancement and the lumen did not enhance, characteristic of a cyst.
Despite initial concern for a pinealoblastoma, it was diagnosed as a pineal cyst and has remained stable for 8
years.

914
• RETINOBLASTOMA: ASSOCIATION WITH 13Q DELETION
SYNDROME

A gene deletion on the long arm of chromosome 13 is responsible for the development of
retinoblastoma. In some instances, detection of physical findings of 13q syndrome, like low-set
ears and typical facies, has led to the early diagnosis of retinoblastoma.

Figure 15.115. Face appearance of a 3-month-old girl with 13q syndrome, showing low-set ears, wide nasal
bridge, and bulbous tip of the nose.

Figure 15.116. Retinoblastoma in the left eye of the child shown in Figure 15.115.

915
Figure 15.117. Typical facies of 13q syndrome in a 3-month-old child. She had right buphthalmos at birth and
underwent enucleation for advanced retinoblastoma. She has a prosthesis over the right socket.

Figure 15.118. Face of a child with 13q syndrome. She had slow development and underwent genetic studies
that revealed 13q syndrome. Subsequent examination revealed retinoblastoma in the left eye.

Figure 15.119. Facial appearance of a child with 13q syndrome. This appearance prompted ocular
examination and detection of unilateral multifocal retinoblastoma.

Figure 15.120. Facial appearance of another child with 13q syndrome. This child had bilateral retinoblastoma.

916
• RETINOBLASTOMA: ASSOCIATION WITH OTHER CHROMOSOMAL
ABNORMALITIES

Desai VN, Shields CL, Shields JA, et al. Retinoblastoma associated with holoprosencephaly. Am
J Ophthalmol 1990;109:355–356.

Figure 15.121. Appearance of a 2-month-old girl with ring chromosome 13. She had two separate
retinoblastomas in the left eye.

Figure 15.122. Appearance of a 6-month-old with ring chromosome 13. She had advanced multifocal bilateral
retinoblastoma.

917
Figure 15.123. Facial appearance of a child with atypical cleft lip and holoprosencephaly.

Figure 15.124. Axial cranial computed tomography, showing holoprosencephaly of the child in Figure 15.123.

Figure 15.125. Retinoblastoma in the left eye of the child shown in Figure 15.123.

918
Figure 15.126. Section of the enucleated eye shown in Figure 15.125, demonstrating large exophytic
retinoblastoma.

919
 CHAPTER 16

RETINOBLASTOMA: DIAGNOSTIC APPROACHES

RETINOBLASTOMA: DIAGNOSTIC APPROACHES

The diagnosis of retinoblastoma is best made by the recognition of its typical

clinical features using indirect ophthalmoscopy and slit-lamp biomicroscopy (1–3).
In many cases, however, ancillary studies like fluorescein angiography,
ultrasonography, computed tomography (CT), and magnetic resonance imaging
(MRI) can provide valuable diagnostic information, especially in cases that are
atypical (1–38).

Fluorescein Angiography
Fluorescein angiography shows a vascular tumor that fills rapidly with fluorescein
and shows later hyperfluorescence. During the vascular filing phase, the feeding
arteries fill rapidly, and fine reticular blood vessels are typically seen in the
superficial portions of the tumor (3,6,7). Leakage into the vitreous and subretinal
space is seen in more advanced tumors. After successful treatment of the tumor, the
blood supply is diminished or absent and the lesion is more hypofluorescent.
Spontaneously arrested or regressed retinoblastomas also show variable degrees of
hyperfluorescence even though they are clinically inactive.

Ultrasonography
U ltrasonography is used routinely to assist in the diagnosis and to measure tumor
size before and after treatment (3,8,9). With B-scan ultrasonography, retinoblastoma
usually appears as an acoustically solid mass with highly reflective foci representing
calcification. A-scan ultrasonography shows uniform high internal reflectivity.
U ltrasound is especially useful for exophytic tumors with overlying retinal
detachment when the tumor cannot be seen ophthalmoscopically. In such cases,
Coats disease is often a diagnostic consideration, but ultrasonography shows a mass
in retinoblastoma but usually no mass with Coats disease or other nontumor causes
of retinal detachment (3,4). Diffuse infiltrating retinoblastoma is often an exception

920
because it frequently shows no distinct mass and no calcification (5).

Optical Coherence Tomography

Optical coherence tomography plays an important role in retinoblastoma
management as it is used to image the foveola and estimate visual potential. This
technology can provide cross-sectional imaging of the retinal anatomy and assist in
monitoring small tumor response, subretinal fluid, and foveolar anatomy (10,11).

Autofluorescence
Autofluorescence is helpful in the differential diagnosis of retinoblastoma at the
calcification within this tumor is hyperautofluorescent and most simulating retinal
lesions show lack of autofluorescence (12,13). Following therapy, with tumor
regression and calcification, the autofluorescence generally increases (13).

Computed Tomography/Magnetic Resonance Imaging

CT and MRI also has a role in the diagnosis of retinoblastoma (14–29). CT
demonstrates an intraocular mass, often with foci of calcification. Its main advantage
over MRI is that it is more sensitive for detecting calcification, which generally
supports the diagnosis of retinoblastoma. It usually has no advantage over
ultrasonography when the tumor is clearly within the eye. However, it may be
better for demonstrating the unusual presence of a nodule of extrascleral or optic
nerve extension. In such cases, the orbital component of the tumor does not usually
show calcification (9). As with ultrasonography, diffuse infiltrating retinoblastoma
often fails to show calcium with CT. One distinct advantage over ultrasonography is
that it images the pineal gland region and can detect pinealoblastoma in cases of
“trilateral retinoblastoma.” Spiral CT has been found to be useful for children with
retinoblastoma because it can be done without general anesthesia and is associated
with less radiation exposure (20). In most cases, CT is not necessary to establish the
diagnosis of retinoblastoma. Due to the minor radiation exposure to the child, this
technique is avoided in general and MRI is used for imaging the orbits and brain.
MRI has advantages over CT in that it can provide superior soft tissue contrast
resolution, especially when surface coil, gadolinium enhancement, and fat
suppression techniques are used (14–29). It can demonstrate enhancement of
retinoblastoma with resolution to 2 mm in thickness. Like most other intraocular
tumors, retinoblastoma is hyperintense to vitreous on T1-weighted images and
hypointense to vitreous on T2-weighted images. MRI can detect calcification in
many retinoblastomas, although not as well as CT. MRI can better detect small
degrees of optic nerve and orbital invasion and can also provide better definition of
the pineal gland. Recent studies have stressed the importance of differentiating
pinealoblastoma from a simple pineal cyst, which can be mistaken for pineal
malignancy in children with retinoblastoma (28,29). New high-resolution techniques
with a new surface coil have recently been advanced and have superior contrast and
spatial resolution compared to other techniques.

Fine-Needle Aspiration Biopsy

Although fine-needle aspiration biopsy has a role in the diagnosis of a number of

921
atypical intraocular lesions, it is generally considered to be contraindicated in cases
of suspected retinoblastoma. Retinoblastoma is a loosely cohesive tumor, and there
is a risk of seeding tumor cells through the needle tract. Only in extremely rare
instances is needle biopsy justified in childhood cases when retinoblastoma is a
diagnostic consideration (31–38). If it is done in such cases, it should be performed
by a modified technique in which the needle is passed through the peripheral
cornea, anterior chamber, iris, and zonule and into the suspected lesion. In addition,
FNAB may occasionally be justified in children who have white cells in the anterior
chamber in which atypical retinoblastoma is a diagnostic consideration. In such
instances, it should generally be done with a 30- or 32-gauge needle through clear
cornea, peripheral iris, and zonule, into the posterior tumor. This provides a buffer
zone to decrease the chance of extraocular seeding of tumor cells. If the patient has
typical retinoblastoma, however, FNAB should generally not be done just to confirm
the diagnosis.

Selected References
Series/Reviews
1. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with
intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye
(Lond) 2013;27(2):253–264.
2. Shields CL, Lally SE, Leahey AM, et al. Targeted retinoblastoma management.
When to use intravenous, intra-arterial, periocular, and intravitreal
chemotherapy. Curr Opin in Ophthalmol 2014;25(5):374–385.
3. Shields CL, Schoenberg E, Kocher K, et al. Lesions simulating retinoblastoma
(pseudoretinoblastoma) in 604 cases: results based on age at presentation.
Ophthalmology 2013;120(2):311–316.
4. 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.
5. Shields CL, Ghassemi F, Tuncer S, et al. Clinical spectrum of diffuse infiltrating
retinoblastoma in 34 consecutive eyes. Ophthalmology 2008;115:2253–2258.

Imaging
Fluorescein Angiography
6. Shields JA, Sanborn GE, Augsburger JJ, et al. Fluorescein angiography of
retinoblastoma. Retina 1982;2:206–214.
7. Palamar M, Pirondini C, Shields CL, et al. Cavitary retinoblastoma.
U ltrasonography and fluorescein angiographic findings in 3 cases. Arch
Ophthalmol 2008;126(11):1598–1600.
Ultrasonography
8. Sterns GK, Coleman DJ, Ellsworth RM. The ultrasonographic characteristics of
retinoblastoma. Am J Ophthalmol 1974;78:606–611.
9. Shields JA, Michelson JB, Leonard BC, et al. B-scan ultrasonography in the
diagnosis of atypical retinoblastomas. Can J Ophthalmol 1976;11:42–51.
Optical Coherence Tomography
10. Rootman DB, Gonzalez E, Mallipatna A, et al. Hand-held high-resolution

922
 spectral domain optical coherence tomography in retinoblastoma: Clinical and
morphologic considerations. Br J Ophthalmol 2013;97(1):59–65.
11. Cao C, Markovitz M, Ferenczy SR, et al. Hand-held spectral domain optical
coherence tomography of small macular retinoblastoma in infants before and
after chemotherapy. J Pediatr Ophthalmol Strabism 2014;51(4):230.
Autofluorescence
12. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr
Opin Ophthalmol 2013;24(3):222–232.
13. Ramasubramanian A, Shields CL, Mellen PL, et al. Autofluorescence of treated
retinoblastoma. J AAPOS 2011;15:167–172.
Computed Tomography/Magnetic Resonance Imaging
14. Arrigg PG, Hedges TR 3rd, Char DH. Computed tomography in the diagnosis of
retinoblastoma. Br J Ophthalmol 1983;67:588–591.
15. Katz NN, Margo CE, Dorwart RH. Computed tomography with histopathologic
correlation in children with leukocoria. J Pediatr Ophthalmol Strabismus
1984;21:50–56.
16. Mafee MF, Goldberg MF, Greenwald MJ, et al. Retinoblastoma and simulating
lesions: Role of CT and MR imaging. Radiol Clin North Am 1987;25:667–682.
17. Peyster RG, Augsburger JJ, Shields JA, et al. Intraocular tumors: evaluation
with MR imaging. Radiology 1988;168:773–779.
18. Mafee MF, Goldberg MF, Cohen SB, et al. Magnetic resonance imaging versus
computed tomography of leukocoric eyes and use of in vitro proton magnetic
resonance spectroscopy of retinoblastoma. Ophthalmology 1989;96(7):965–975.
19. Karr DJ, Kalina RE. Computerized tomography fails to show calcification in
diffuse retinoblastoma. J Pediatr Ophthalmol Strabismus 1991;28:14–16.
20. O’Brien JM, Char DH, Tucker N, et al. Efficacy of anaesthetized spiral
computed tomography scanning in initial evaluation of childhood leukocoria.
Ophthalmology 1995;102:1345–1350.
21. De Potter P, Flanders AE, Shields JA, et al. Magnetic resonance imaging of
intraocular tumors. Int Ophthalmol Clin 1993;33:37–45.
22. Beets-Tan RG, Hendriks MJ, Ramos LM, et al. Retinoblastoma: CT and MRI.
Neuroradiology 1994;36:59–62.
23. DePotter P, Flanders AE, Shields JA, et al. The role of fat-suppression technique
and gadopentetate dimeglumine in magnetic resonance imaging evaluation of
intraocular tumors and simulating lesions. Arch Ophthalmol 1994;112:340–348.
24. Ainbinder DJ, Haik BG, Frei DF, et al. Gadolinium enhancement: improved
MRI detection of retinoblastoma extension into the optic nerve. Neuroradiology
1996;38:778–781.
25. DePotter P, Shields CL, Shields JA, et al. The role of magnetic resonance
imaging in children with intraocular tumors and simulating lesions.
Ophthalmology 1996;103:1774–1783.
26. Schueler AO, Hosten N, Bechrakis NE, et al. High resolution magnetic
resonance imaging of retinoblastoma. Br J Ophthalmol 2003;87:330–335.
27. Bagley LJ, Hurst RW, Zimmerman RA, et al. Imaging in the trilateral
retinoblastoma syndrome. Neuroradiology 1996;38:166–170.
28. Karatza E, Shields CL, Flanders AE, et al. Pineal cyst simulating
pinealoblastoma in 11 children with retinoblastoma. Arch Ophthalmol

923
 2006;124:595–597.
29. Ramausbramanina A, Kytasty C, Meadows AT, et al. Incidence of pineal gland
cyst and pineoblastoma in children with retinoblastoma during the
chemoreduction era. Am J Ophthalmol 2013;156(4):825–829.
Technitium Scan
30. Kiratli PO, Kiratli H, Ercan MT. Visualization of orbital retinoblastoma with
technetium-99 m (V) dimercaptosuccinic acid. Ann Nucl Med 1998;12:157–159.
Pathology
31. Karcioglu ZA. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina
2002;22:707–710.
32. Shanmugam MP, Biswas J. Fine needle aspiration biopsy in the diagnosis of
intraocular mass lesions. Ind J Ophthalmol 1997;45:105–108.
33. Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
34. O’Hara BJ, Ehya H, Shields JA, et al. Fine needle aspiration biopsy in pediatric
ophthalmic tumors and pseudotumors. Acta Cytol 1993;37:125–130.
35. Das DK, Das J, Chachra KL, et al. Diagnosis of retinoblastoma by fine-needle
aspiration and aqueous cytology. Diagn Cytopathol 1989;5:203–206.
36. Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle
aspiration biopsy. Ophthalmology 1985;92:1763–1767.
37. Char DH, Miller TR. Fine needle biopsy in retinoblastoma. Am J Ophthalmol
1984;97:686–690.
38. Shields CL, Honavar S, Shields JA, et al. Vitrectomy in eyes with unsuspected
retinoblastoma. Ophthalmology 2000;107:2250–2255.

924
• RETINOBLASTOMA: FLUORESCEIN ANGIOGRAPHY
The fluorescein angiogram has characteristic features with retinoblastoma, which can vary with
the growth pattern of the tumor. Intraretinal tumors show marked vascularity, which is less
evident in endophytic tumors.

Figure 16.1. Small intraretinal retinoblastoma.

Figure 16.2. Venous phase of the patient shown in Figure 16.1, showing large feeding and draining vessels
and fine intrinsic vascular channels in the tumor.

925
Figure 16.3. Epipapillary retinoblastoma in the right eye of a baby.

Figure 16.4. Venous phase of the patient shown in Figure 16.3, showing rapid filling of the mass.

Figure 16.5. Multifocal retinoblastoma in the left eye of the baby in Figure 16.3.

926
Figure 16.6. Venous phase of the patient, showing rapid filling of all of the tumors.

927
• RETINOBLASTOMA: WIDE-ANGLE FLUORESCEIN ANGIOGRAPHY
Wide-angle fundus photography has provided a method of documenting in one photograph the
full extent of retinoblastoma. Wide-angle color fluorescein angiography has been used to further
document retinoblastoma and to assess its blood supply after treatment. Examples of wide-
angle fluorescein angiography are shown.

Figure 16.7. Inferonasal equatorial retinoblastoma in the left eye.

Figure 16.8. Color fluorescein angiography in the venous phase of the lesion shown in Figure 16.7. Note that
the blood vessels that ramify through the tumor are showing early leakage.

928
Figure 16.9. Macular retinoblastoma in the right eye.

Figure 16.10. Fluorescein angiography in the venous phase of the lesion shown in Figure 16.9. Note the retinal
feeding artery and draining vein and the blood vessels that ramify through the tumor, with early leakage of dye.

Figure 16.11. Large retinoblastoma in the macular area of the left eye, overhanging and obscuring a view of the
optic disc.

Figure 16.12. Fluorescein angiography in the venous phase of the lesion shown in Figure 16.11. Note the
retinal feeding artery and draining vein and the blood vessels that ramify through the peripheral aspect of the
tumor. The central hypofluorescence may represent areas of ischemic necrosis or cavitary change in the
tumor.

929
• RETINOBLASTOMA: ULTRASONOGRAPHY, COMPUTED
TOMOGRAPHY, AND MAGNETIC RESONANCE IMAGING

Ultrasonography and CT show rather characteristic features with retinoblastoma. With these
techniques, the size and extent of the tumor(s) can be assessed and calcium within the lesion
can be detected. Orbital and optic nerve extension of the tumor can generally be well
appreciated with CT. MRI with contrast enhancement may provide even better definition of the
soft tissues and may provide early detection of orbital extension and associated
pinealoblastoma.

Figure 16.13. B-scan ultrasonogram of medium-sized retinoblastoma, showing mass with dense echoes
compatible with calcium. There is a characteristic shadow in the orbital soft tissues posterior to the tumor.

Figure 16.14. B-scan ultrasonogram of a slightly larger endophytic retinoblastoma, showing a mass with small
foci of calcification near the tumor base. These prominent echoes persist on lower sensitivities, supporting the
presence of calcium in the mass.

930
Figure 16.15. Axial computed tomography of bilateral retinoblastoma in a bone window setting. Note the small
calcified tumor in the right and the extensive calcified tumor in the buphthalmos left eye.

Figure 16.16. Axial computed tomography, showing large calcified retinoblastoma in the left eye with orbital
and optic nerve extension.

Figure 16.17. Magnetic resonance imaging of retinoblastoma in T1-weighted image with gadolinium
enhancement showing the extent of the mass and associated retinal detachment.

931
Figure 16.18. Magnetic resonance imaging of the same tumor in T2-weighted image, showing that the tumor
is slightly hypointense to vitreous.

932
• RETINOBLASTOMA: HANDHELD OPTICAL COHERENCE
TOMOGRAPHY FOR RETINOBLASTOMA

Handheld optical coherence tomography can be used in the operating room to image the
macula, obtain information on the foveola, and to image small retinoblastomas. We have found
this technique useful in judging the status of the foveola and estimating potential visual acuity.
In many instances, larger tumors show draping of normal retina over the tiny retinoblastoma
remnant following chemotherapy.

Cao C, Markovitz M, Ferenczy SR, et al. Hand-held spectral domain optical coherence
tomography of small macular retinoblastoma in infants before and after chemotherapy. J Pediatr
Ophthalmol Strabism 2014;51(4):230.

Figure 16.19. Small retinoblastomas surrounding the foveola.

Figure 16.20. Handheld optical coherence tomography of the lesion inferonasal to the foveola demonstrates
the full thickness retinal mass with normal retinal draped over tumor margins.

933
Figure 16.21. Following first session of chemoreduction with thermotherapy, all three tumors appear
regressed.

Figure 16.22. Following first session of chemoreduction with thermotherapy, handheld optical coherence
tomography demonstrates tumor regression.

Figure 16.23. Following completion of chemoreduction with thermotherapy, the tumors are completely
regressed.

Figure 16.24. Following completion of chemoreduction with thermotherapy, handheld optical coherence
tomography demonstrates complete flattening of the mass.

934
 CHAPTER 17

RETINOBLASTOMA: PATHOLOGY

RETINOBLASTOMA: PATHOLOGY

Pathologically, retinoblastoma has characteristic gross and microscopic features

(1–10). Grossly, it is a white tumor that arises from the sensory retina. The
endophytic, exophytic, or diffuse growth pattern or combinations of them can
usually be recognized easily on gross examination. The tumor often has chalky foci
of calcification. Choroidal and optic nerve extension of the tumor can often be
recognized on gross examination of the sectioned eye. Areas of tumor necrosis,
hemorrhage, and choroidal and optic nerve extension can often be seen on gross
examination.
Microscopically, retinoblastoma is a neuroblastic tumor with small, round cells.
On low magnification, the tumor appears basophilic because of numerous closely
arranged nuclei and scant cytoplasm. Areas of necrosis appear pink with scattered
nuclei of tumor cells. Dystrophic calcification, seen in necrotic portions of the
tumor, is basophilic and acellular.
The better-differentiated tumors contain Flexner–Wintersteiner rosettes and
fleurettes. The more poorly differentiated tumors comprise mostly anaplastic cells
without rosette or fleurette formation and have more nuclear pleomorphism and
mitotic figures. Special stains and electron microscopy have confirmed that the
rosettes represent an abortive attempt of the tumor cells to undergo photoreceptor
differentiation (3). In some instances, the tumor cells are recognized in the anterior
chamber, choroid, or optic nerve (1,4,5). The blood vessels in retinoblastoma are
sometimes encircled by basophilic deposits. This is believed to represent deposited
DNA liberated from necrotic tumor cells. Such deposition is sometimes seen in areas
of the iris and choroid where there is no direct tumor involvement.
Histopathologic studies can be helpful in prognosis for the patient with
retinoblastoma. Risk factors for tumor recurrence of metastasis include the presence
and degree of orbital extension, optic nerve extension, and choroidal extension
(1,4,5,8–10). Cystlike cavities have been identified in some cases in retinoblastoma,
and their presence is believed to be associated with better-differentiated tumors that

935
would be more resistant to chemotherapy and radiotherapy (6).

Selected References
Series/Reviews
1. Kaliki S, Shields CL, Rojanaporn D, et al. High-risk retinoblastoma based on
International Classification of Retinoblastoma. Analysis of 519 enucleated eyes.
Ophthalmology 2013;120:997–1003.
2. Eagle RC. High-risk features and tumor differentiation in retinoblastoma: A
retrospective histopathologic study. Arch Pathol Lab Med 2009;133:1203–1209.
3. Tso MOM, Zimmerman LE, Fine BS. The nature of retinoblastoma:
Photoreceptor differentiation: a clinical and histopathological study. Am J
Ophthalmol 1970;69:3390–3399.
4. Shields CL, Shields JA, Baez K, et al. Choroidal invasion of retinoblastoma.
Metastatic potential and clinical risk factors. Br J Ophthalmol 1993;77:544–548.
5. Shields CL, Shields JA, Baez K, et al. Optic nerve invasion of retinoblastoma.
Metastatic potential and clinical risk factors. Cancer 1994;73:692–698.
6. Mashayekhi A, Shields CL, Eagle RC Jr, et al. Cavitary changes in
retinoblastoma. Relationship to chemoresistance. Ophthalmology
2005;112:1145–1150.
7. Grossniklaus HE. Retinoblastoma. Fifty years of progress. The LXXI Edward
Jackson Memorial Lecture. Am J Ophthalmol 2014;158(5):875–891.

Management
8. Shields JA, Shields CL, Lally SE, et al. Harvesting fresh tumor from enucleated
eyes: The 2008 Jack S. Guyton Lecture. Arch Ophthalmol 2010;128(2):241–243.
9. Honavar SG, Singh AD, Shields CL, et al. Post-enucleation adjuvant therapy in
high-risk retinoblastoma. Arch Ophthalmol 2002;120:923–931.
10. Kaliki S, Shields CL, Shah SU , et al. Postenucleation adjuvant chemotherapy
with vincristine, etoposide and carboplatin for the treatment of high-risk
retinoblastoma. Arch Ophthalmol 2011;129:1422–1427.

936
• RETINOBLASTOMA: PATHOLOGY, GROSS FEATURES
Grossly, retinoblastoma appears as a chalky-white tumor, frequently with areas of calcification.
Microscopically, it is a neuroblastic tumor that can show viable tumor cells with areas of
necrosis and calcification. The better-differentiated tumors often show typical Flexner–
Wintersteiner rosettes and fleurettes, structures that represent attempts of the tumor toward
photoreceptor differentiation. (Most pathology photographs are courtesy of Ralph C. Eagle, Jr,
MD.)

Figure 17.1. Exophytic retinoblastoma with endophytic component and vitreal seeds.

Figure 17.2. Slightly larger exophytic retinoblastoma. Note the chalklike calcification in the posterior aspect of
the tumor.

937
Figure 17.3. Large retinoblastoma with diffuse hemorrhage.

Figure 17.4. Large exophytic retinoblastoma filling most of the globe. Note the anterior displacement of the
lens-iris diaphragm. The patient had secondary glaucoma.

Figure 17.5. Large exophytic retinoblastoma filling most of the globe. Note the extensive foci of calcification in
the mass.

938
Figure 17.6. Gross appearance of exophytic retinoblastoma with choroidal invasion (seen toward bottom and
left). Calcification is seen within the retinal portion of the tumor but not in the choroidal portion in the lower part
of the photograph.

939
• RETINOBLASTOMA: PATHOLOGY AND MICROSCOPIC FEATURES

Figure 17.7. Low-magnification photomicrograph of necrosis in retinoblastoma. The pink area to the right of
center represents the necrotic tumor. The blue areas (down and to the left) represent islands of viable tumor
cells around blood vessels forming pseudorosettes. (Hematoxylin–eosin ×25.)

Figure 17.8. Dystrophic calcification in retinoblastoma. The blue-red area is the calcification, and the
surrounding pink areas represent necrotic tumor cells without calcification. (Hematoxylin–eosin ×25.)

Figure 17.9. Necrotic retinoblastoma cells with dense basophilic calcification. To the right of the calcification

940
are blood vessels encircled by basophilic deposits. This is believed to represent DNA deposition from necrotic
tumor cells.

Figure 17.10. Poorly differentiated viable retinoblastoma. (Hematoxylin–eosin ×200.)

Figure 17.11. Typical Flexner–Wintersteiner rosettes characteristic of well-differentiated retinoblastoma.

(Hematoxylin–eosin ×200.)

Figure 17.12. Typical eosinophilic fleurette in an area of well-differentiated retinoblastoma. The fleurette, like
the Flexner–Wintersteiner rosette, represents a better-differentiated attempt at photoreceptor formation.
(Hematoxylin–eosin ×200.)

941
• RETINOBLASTOMA: CAVITARY VARIANT AND CLINICOPATHOLOGIC
CORRELATIONS

Cavitation is often seen clinically and histopathologically in patients with retinoblastoma. It has
been observed that retinoblastomas containing ophthalmoscopically visible cavitary spaces do
not show a substantial decrease in size after chemotherapy. Cavitary changes in retinoblastoma
may be a sign that the tumor is well differentiated and may impart a better prognosis.

Mashayekhi A, Shields CL, Eagle RC Jr, et al. Cavitary changes in retinoblastoma. Relationship to
chemoresistance. Ophthalmology 2005;112:1145–1150.

Figure 17.13. Cavitary retinoblastoma in the macular region of the left eye. The arrow depicts the area of
cavitation where no retinal blood vessels are evident.

Figure 17.14. Same lesion shown in Figure 17.13 after chemoreduction. Note that the cavity has become more
distinct.

942
Figure 17.15. Another cavitary retinoblastoma in the macular region of the left eye (shown to the right in the
photograph).

Figure 17.16. Histopathology of the cavitary area seen in Figure 17.15. The inset shows a fleurette, near the
wall of the cavity, suggesting that the cavity is located in an area of well-differentiated tumor. (Hematoxylin–
eosin ×30.)

Figure 17.17. Large cavity in the superficial aspect of retinoblastoma.

943
Figure 17.18. Histopathology of the cavity shown in Figure 17.15. The inset to the right shows Flexner–
Wintersteiner rosettes near the cavity wall, suggesting that the cavity is in an area of well-differentiated
retinoblastoma.

944
• RETINOBLASTOMA: HIGH-RISK PATHOLOGY FEATURES
Retinoblastoma at high risk for metastasis typically shows features on pathology of optic nerve
invasion deep to the lamina cribrosa, choroidal invasion of more than 3 mm dimension, anterior
chamber invasion, or any combination of optic nerve or choroidal invasion.

Kaliki S, Shields CL, Rojanaporn D, et al. High-risk retinoblastoma based on International

Classification of Retinoblastoma. Analysis of 519 enucleated eyes. Ophthalmology
2013;120:997–1003.

Figure 17.19. Extensive retinoblastoma filling an eye.

Figure 17.20. The optic nerve appears thickened.

945
Figure 17.21. On sectioning the globe, massive postlaminar invasion of the optic nerve is found and the child
was treated with systemic chemotherapy to prevent metastasis.

Figure 17.22. Large retinoblastoma with vitreous seeding is seen. Note the white infiltration deep to the main
mass.

Figure 17.23. In this view, the main white retinoblastoma is flanked by infiltration of tumor into the choroid,
giving a gray appearance.

Figure 17.24. Histopathology confirms choroidal invasion as dark blue cells. This child was treated with
systemic chemotherapy.

946
 CHAPTER 18

MANAGEMENT OF RETINOBLASTOMA

MANAGEMENT OF RETINOBLASTOMA

General Considerations
The management of retinoblastoma has gone through a remarkable evolution in the
last century, and the treatment has become increasingly complex (1–51). Today, the
selected treatment of this important childhood tumor depends on many factors and
requires considerable knowledge and experience (1–4). Affected children are
examined under general anesthesia, at which time various treatments are employed,
depending on the clinical findings. The relative indications, methods, and results of
the various treatment methods are detailed in the references and they are briefly
summarized and illustrated here.
The proper management of retinoblastoma requires periodic examination under
anesthesia with ophthalmoscopy using scleral depression, and large fundus drawings
to document size and location of all tumors, extent of retinal detachment, and tumor
seeding into the subretinal space and vitreous and anterior chamber. This is
supplemented by further documentation with fundus photography, ultrasonography,
fluorescein angiography, and optical coherence tomography.
Based on the findings the most appropriate treatment for each case is selected.
When all tumors are controlled, examinations are done less frequently.

Enucleation
For many years, enucleation was the only legitimate treatment, and it remains the
primary management for advanced unilateral cases and often for the worst eye in
many bilateral cases (5,6). There has been a decrease in the frequency of
enucleation in recent years, although it is still used primarily for advanced group E
retinoblastoma in eyes with no hope for useful vision. It is important for the
surgeon to cut the optic nerve as far posteriorly in the orbit as possible because the
main route of tumor spread is via the optic nerve to the brain. Considerable
experience has been obtained using integrated implants and prostheses that improve

947
cosmetic appearance and ocular motility after enucleation (6).

External Beam Radiotherapy

In the mid-1900s, external beam radiotherapy (EBRT) became the main alternative
to enucleation for salvaging eyes with retinoblastoma. It achieved good local control
in most cases, and was the best alternative to enucleation for many years. However,
EBRT is associated with an increased incidence of second cancers, mainly in the field
of irradiation (7–9) and with facial cosmetic problems. Therefore, in recent years,
there has been a trend toward avoiding both enucleation and EBRT when possible.
There are five tumor regression patterns following treatment for retinoblastoma.
These patterns were originally applied to EBRT. However, they are also now
applied to other more recent methods, including plaque radiotherapy,
chemoreduction (CRD), laser photocoagulation, and cryotherapy, and they can even
be applied to spontaneously regressed or spontaneously arrested tumors. These
regression patterns are classified into type 0 (tumor regression with complete tumor
disappearance leaving no observable scar); type 1 (tumor regression with complete
calcification); type 2 (tumor regression with no calcification [“fish-flesh”
appearance]); type 3 (tumor regression with partial calcification); and type 4
(tumor regression with flat atrophic scar). Selected examples are illustrated in
subsequent sections.

Plaque Radiotherapy
Because of the potential complications of EBRT, plaque brachytherapy gradually
becomes more popular, mainly for medium size, localized retinoblastoma (10–12).
It was initially used as a primary treatment, and later was used most often for
tumors that failed EBRT, cryotherapy, or laser photocoagulation (10–12). Plaque
radiotherapy continues to be a valuable adjunct as primary or secondary treatment
for selected cases of retinoblastoma. A custom-designed radioactive plaque, usually
with iodine-125 seeds, is sutured to the sclera directly over the base of the tumor.
This can be a very difficult technique that requires considerable experience and
meticulous alignment using binocular indirect ophthalmoscopy and scleral
indentation to achieve precise localization for plaque placement.

Cryotherapy
Several alternative or supplemental methods of management have been popularized
in recent years. Cryotherapy became popular for localized, more peripheral lesions
between the equator and the ora serrata. It is generally applied by a triple freeze–
thaw technique with indirect ophthalmoscopy, allowing the ice ball to form and
recede, between each application using a standard cryoprobe used in retinal
detachment treatment (13). Cryotherapy is an important supplemental method that
is used routinely on many cases today.

Laser Photocoagulation
Argon laser photocoagulation is very important for the management of small,
posteriorly located tumors, and the results were encouraging. The technique is to
apply moderately heavy laser treatment around the tumor to destroy its blood

948
supply and induce its regression (14,15). In recent years, argon laser has been
replaced in many centers by transpupillary thermotherapy (TTT).

Transpupillary Thermotherapy
TTT is very important method for treatment for many small retinoblastomas that are
located in the posterior fundus. It delivers thermal heat to the tumor and results in a
smaller residual scar than laser or cryotherapy treatment. TTT can be used as a
primary treatment for small retinoblastomas, but it is used more often as
consolidation after tumor treatment with CRD, plaque radiotherapy, or other
methods. We use it extensively in managing retinoblastoma (16).

Chemotherapy
Systemic chemotherapy can be used as a primary or secondary therapy for control of
intraocular retinoblastoma or it can be used to prevent metastasis, prevent
pinealoblastoma, and minimize long-term second cancers. The agents and the
techniques are discussed in the literature (1–4,17–51).

Intravenous Chemotherapy (Chemoreduction)

In the early 1990s, intravenous chemotherapy was first used by four centers to treat
active intraocular retinoblastoma (17–20). This method, termed CRD, quickly
became popular around the world for retinoblastoma management. The principle of
CRD is to administer chemotherapy as an initial treatment for pure intraocular
disease, with the goal of decreasing tumor size which will allow more definitive
conservative methods of treatment rather than enucleation (17–31). Hence, many
eyes that would have been enucleated previously have been salvaged with CRD.
Consolidation after tumor reduction is performed using thermotherapy, cryotherapy,
or plaque radiotherapy. The main agents used for CRD are vincristine, etoposide,
and carboplatin in appropriate doses (1–4).
Based on the International Classification of Retinoblastoma, CRD is successful with
globe salvage in 100% of group A, 94% of group B, 90% of group C, 47% of group
D, and 25% of group E eyes (29,30). For eyes classified as group D or E, additional
intra-arterial chemotherapy is often required, achieving approximately 60% globe
salvage (30).

Intra-arterial Chemotherapy
Intra-arterial chemotherapy is a powerful option for the management of eyes with
retinoblastoma, particularly unilateral cases (32–38). This technique requires
catheterization of the femoral artery up to the ophthalmic artery with direct
injection of chemotherapy agent under fluoroscopy.
In one series, globe salvage at 2 years was 82% if IAC was primary treatment and
58% if secondary treatment (32). In our series, we found IAC particularly effective
as primary therapy with globe salvage 72% of primary IAC in 62% of secondary
IAC (37). Specifically, globe salvage was achieved in 100% of group B, 100% of
group C, 94% of group D, and 36% of group E eyes (37).

Periocular Chemotherapy

949
Periocular injection of chemotherapy has been used for retinoblastoma control,
often as an adjunct to systemic chemotherapy. Periocular chemotherapy achieves
rapid levels within the vitreous in 30 minutes, achieves doses that are 6 to 10 times
that achieved by intravenous route, and can last for hours. The method of injection
as a plain liquid injection or injection with a vehicle such as a Lincoff balloon,
iontophoresis, long-acting fibrin sealant, or nanoparticles has been explored.

Intravitreal Chemotherapy
Intravitreal chemotherapy for retinoblastoma has become an acceptable method for
control of vitreous seeding (39–43). The technique involves direct injection into the
eye through the pars plana of a minute amount of chemotherapy. Most clinicians
use melphalan or topotecan, but others prefer methotrexate. The injection should be
cautiously performed to avoid tumor seeding outside the eye into the orbit.
We reviewed a small series of eyes with recurrent retinoblastoma vitreous seeding
and found intravitreal injection of melphalan with 100% tumor control with
minimal toxicity (41). Others have explored combination of melphalan and
topotecan with high control rate (43).

Prognosis
With the modern methods of treatment now available, the prognosis for patients
with retinoblastoma has improved greatly. In medically developed countries, the
cure rate for retinoblastoma is >95%, mainly due to earlier diagnoses and prompt
treatment. In areas that are lacking in good medical care, mortality is still greater
than 50%. Overall, more eyes are being salvaged today and the visual prognosis
continues to improve.
Patients at high risk for metastasis include those with evidence of orbital, optic
nerve, or choroidal extension. These patients require additional systemic
chemotherapy to prevent metastasis (44–46). Patients with germline mutation
retinoblastoma are at risk for pinealoblastoma and long-term second cancers. New
observations have documented that systemic chemotherapy can minimize or prevent
these risks (47–51).

Summary
In summary, the treatment of retinoblastoma has changed greatly in the last century.
There are many therapeutic options, and it takes considerable knowledge and
experience to manage these complicated cases. Treatment decisions should be made
by experienced ocular oncologists, pediatric oncologists, radiation oncologists, and
others who have had specific training in this field. The management of
retinoblastoma involves life concerns as well as salvage of the eye and vision (1–4).

Selected References
Series/Reviews
1. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with
intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye
(Lond) 2013;27(2):253–264.
2. Shields CL, Kaliki S, Rojanaporn D, et al. Intravenous and intra-arterial

950
 chemotherapy for retinoblastoma: what have we learned? Curr Opin Ophthalmol
2012;23(3):202–209.
3. Shields CL, Shields JA. Retinoblastoma management: Advances in enucleation,
intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin
Ophthalmol 2010;21:203–212.
4. Shields CL, Lally SE, Leahey A, et al. Targeted retinoblastoma management.
When to use intravenous, intra-arterial, subtenon’s, and intravitreal
chemotherapy. Curr Opin Ophthalmol 2014;25(5):374–385.

Management
Enucleation
5. Shields JA, Shields CL, DePotter P. Enucleation technique for children with
retinoblastoma. J Pediatr Ophthalmol Strabismus 1992;29:213–215.
6. Shah SU , Shields CL, Lally SE, et al. Hydroxyapatite orbital implant in children
following enucleation: Analysis of 531 sockets. Ophthalm Plast Reconstr Surg
2015; 31(2):108–114.
External Beam Radiotherapy
7. Hungerford JL, Toma NM, Plowman PN, et al. External beam radiotherapy for
retinoblastoma: I. Whole eye technique. Br J Ophthalmol 1995;79:109–111.
8. Toma NM, Hungerford JL, Plowman PN, et al. External beam radiotherapy for
retinoblastoma: II. Lens sparing technique. Br J Ophthalmol 1995;79:112–117.
9. Krengli M, Hug EB, Adams JA, et al. Proton radiation therapy for
retinoblastoma: comparison of various intraocular tumor locations and beam
arrangements. Int J Radiat Oncol Biol Phys 2005;61:583–593.
Plaque Radiotherapy
10. Shields CL, Minelli S, Shields JA, et al. Plaque radiotherapy for retinoblastoma.
U se as a primary and secondary treatment. Ophthalmology 1993;100:216–224.
11. Shields CL, Shields JA, Minelli S, et al. Regression of retinoblastoma after
plaque radiotherapy. Am J Ophthalmol 1993;115:181–187.
12. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma:
Long term tumor control and treatment complications in 208 tumors.
Ophthalmology 2001;108:2116–2121.
Cryotherapy/Laser Photocoagulation/Thermotherapy
13. Shields JA, Parsons H, Shields CL, et al. The role of cryotherapy in the
management of retinoblastoma. Am J Ophthalmol 1989;108:260–264.
14. Shields JA, Shields CL, Parsons H, et al. The role of photocoagulation in the
management of retinoblastoma. Arch Ophthalmol 1990;108:205–208.
15. Shields CL, Shields JA, Kiratli H, et al. Treatment of retinoblastoma with
indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol
Strabismus 1995;32:317–322.
16. Shields CL, Santos C, Diniz W, et al. Thermotherapy for retinoblastoma. Arch
Ophthalmol 1999;117:885–893.
Intravenous Chemotherapy
17. Kingston JE, Hungerford JL, Madreperla SA, et al. Results of combined
chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch
Ophthalmol 1996;114:1339–1343.

951
18. Murphree AL, Villablanca JG, Deegan WF, et al. Chemotherapy plus focal
treatment in the management of intraocular retinoblastoma. Arch Ophthalmol
1996;114:1348–1356.
19. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can
cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol
1996;114:1321–1328.
20. Shields CL, De Potter P, Himmelstein B, et al. Chemoreduction in the initial
management of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1330–
1338.
21. Shields CL, Shields JA, Needle M, et al. Combined chemoreduction and
adjuvant treatment for intraocular retinoblastoma. Ophthalmology
1997;104:2101–2111.
22. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction plus focal therapy
for retinoblastoma: factors predictive of need for treatment with external beam
radiotherapy or enucleation. Am J Ophthalmol 2002;133:657–664.
23. Shields CL, Honavar SG, Shields JA, et al. Factors predictive of recurrence of
retinal tumor, vitreous seeds and subretinal seeds following chemoreduction for
retinoblastoma. Arch Ophthalmol 2002;120:460–464.
24. Demirci H, Eagle RC, Shields CL, et al. Histopathologic findings in eyes with
retinoblastoma treated only with chemoreduction. Arch Ophthalmol
2003;121:1125–1131.
25. Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al. Chemoreduction for
retinoblastoma. Arch Ophthalmol 2003;121:1513.
26. Shields CL, Mashayekhi A, Cater J, et al. Macular retinoblastoma managed with
chemoreduction: analysis of tumor control with or without adjuvant
thermotherapy in 68 tumors. Arch Ophthalmol 2005;123:765–773.
27. Shields CL, Palamar M, Sharma P, et al. Retinoblastoma regression patterns
following chemoreduction and adjuvant therapy in 557 tumors. Arch
Ophthalmol 2009;127(3):282–290.
28. Narang S, Mashayekhi A, Rudich D, et al. Predictors of long-term visual
outcome after chemoreduction for management of intraocular retinoblastoma.
Clin Experiment Ophthalmol 2012;40(7):736–742.
29. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of
Retinoblastoma predicts chemoreduction success. Ophthalmology
2006;113:2276–2280.
30. Shields CL, Kaliki S, Al-Dahmash S, et al. Management of advanced
retinoblastoma with intravenous chemotherapy then intra-arterial
chemotherapy as alternative to enucleation. Retina 2013;33(10):2103–2109.
31. Chantada GL, Fandiño AC, Schvartzman E, et al. Impact of chemoreduction for
conservative therapy for retinoblastoma in Argentina. Pediatr Blood Cancer
2014; 61(5):821–826.
Intra-arterial Chemotherapy
32. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the
management of retinoblastoma. Four year experience. Arch Ophthalmol
2011;129:732–737.
33. Shields CL, Bianciotto CG, Ramasubramanian A, et al. Intra-arterial
chemotherapy for retinoblastoma. Report #1: Control of tumor, subretinal
seeds, and vitreous seeds. Arch Ophthalmol 2011;129:1399–1406.

952
34. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for
retinoblastoma. Report #2: Treatment complications. Arch Ophthalmol
2011;129:1407–1415.
35. Abramson DH, Gobin YP, Marr BP, et al. Intra-arterial chemotherapy for
retinoblastoma. Ophthalmology 2012;119(8):1720–1721.
36. Shields CL, Kaliki S, Shah SU , et al. Minimal exposure (one or two cycles) of
intra-arterial chemotherapy in the management of retinoblastoma.
Ophthalmology 2012;119(1):188–192.
37. Shields CL, Manjandavida FP, Pieretti G, et al. Intra-arterial chemotherapy for
retinoblastoma in 70 eyes: Outcomes based on the International Classification of
Retinoblastoma. Ophthalmology 2014;121:1453–1460.
38. Superstein R, Lederer D, Dubois J, et al. Retinal vascular precipitates during
administration of melphalan into the ophthalmic artery. JAMA Ophthalmol
2013; 131(7):963–965.
Intravitreal Chemotherapy
39. 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;96:1078–1083.
40. Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent
vitreous seeding from retinoblastoma. Arch Ophthalmol 2012;130(10):1268–
1271.
41. 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.
42. Smith SJ, Smith BD, Mohney BG. Ocular side effects following intravitreal
injection therapy for retinoblastoma: A systematic review. Br J Ophthalmol
2014;98(3):292–297.
43. 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.
Chemotherapy to Prevent Metastasis, Pinealoblastoma, or Second Cancers
44. Kiratli H, Bilgic S, Ozerdem U . Management of massive orbital involvement of
intraocular retinoblastoma. Ophthalmology 1998;105:322–326.
45. Honavar SG, Singh AD, Shields CL, et al. Post-enucleation adjuvant therapy in
high-risk retinoblastoma. Arch Ophthalmol 2002;120:923–931.
46. Kaliki S, Shields CL, Shah SU , et al. Postenucleation adjuvant chemotherapy
with vincristine, etoposide, and carboplatin for the treatment of high-risk
retinoblastoma. Arch Ophthalmol 2011;129:1422–1427.
47. Shields CL, Meadows AT, Shields JA, et al. Chemoreduction for retinoblastoma
may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma).
Arch Ophthalmol 2001;119:1269–1272.
48. Ramasubramanian A, Kytasty C, Meadows AT, et al. Incidence of pineal gland
cyst and pineoblastoma in children with retinoblastoma during the
chemoreduction era. Am J Ophthalmol 2013;156(4):825–829.
49. Turaka K, Shields CL, Leahey A, et al. Second malignant neoplasms following
chemoreduction with carboplatin, etoposide, and vincristine in 245 patients
with intraocular retinoblastoma. Pediatr Blood Cancer 2012;59:121–125.

953
50. Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after
retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997;278:1262–1267.
51. Kleinerman RA, Tucker MA, Abramson DH, et al. Risk of soft tissue sarcomas by
individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst
2007;99:24–31.

954
• RETINOBLASTOMA: LASER PHOTOCOAGULATION AND
CRYOTHERAPY

Laser photocoagulation and cryotherapy can be employed to treat selected small

retinoblastomas. They can be used as primary management or as supplemental treatment
following CRD or irradiation. The former is used for more posteriorly located tumors and the
latter for more peripheral tumors. More recently, TTT has been used more often instead than
laser photocoagulation.

1. Shields CL, Shields JA, Kiratli H, et al. Treatment of retinoblastoma with indirect
ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus 1995;32:317–322.
2. Shields JA, Parsons H, Shields CL, et al. The role of cryotherapy in the management of
retinoblastoma. Am J Ophthalmol 1989;108:260–264.

Figure 18.1. Photocoagulation of a retinoblastoma, showing laser marks around the margin of the tumor.

Figure 18.2. Appearance of the lesion 3 weeks later. The tumor is still viable. A second surrounding treatment
was performed, and tumor control was achieved.

955
Figure 18.3. Appearance of the same lesion 6 months later. There is no viable tumor, and the scar contains
proliferated pigment epithelium.

Figure 18.4. A peripheral retinoblastoma that is ideal for treatment with cryotherapy.

Figure 18.5. Appearance of the retinoblastoma during cryotherapy. An ice ball has incorporated the tumor and
extends slightly into the overlying vitreous.

956
Figure 18.6. Appearance of the scar following successful cryotherapy for retinoblastoma.

957
• RETINOBLASTOMA: EXTERNAL BEAM RADIOTHERAPY
EBRT is an effective method of treating selected retinoblastomas. It can sometimes contribute
to the development of second cancers, particularly in children with familial retinoblastoma, and
it can cause dry eye symptoms, cataract, radiation retinopathy, and cosmetic problems in the
field of radiation. It is used mostly for large tumors or tumors with extensive vitreous or
subretinal tumor seeds.

Figure 18.7. Retinoblastoma superotemporal to the optic disc prior to external beam radiotherapy.

Figure 18.8. Appearance of the same lesion 1 year later, showing regression and almost total calcification of
the tumor. This is called a type 1 regression pattern. If the lesion shows a “fish-flesh” appearance without
calcification, it is called type 2. A tumor that is partly calcified and partly displays a “fish-flesh” pattern is called
type 3.

958
Figure 18.9. Endophytic retinoblastoma inferior to the optic disc.

Figure 18.10. Appearance of the same lesion 1 year after external beam radiotherapy, showing excellent tumor
regression. This is a type 3 regression pattern with partial calcification of the tumor.

Figure 18.11. Radiation blepharopathy during external beam radiotherapy for retinoblastoma. Note the
erythema to the periocular skin. The purple line outlines part of the irradiation field.

959
Figure 18.12. Radiation-induced enophthalmos, secondary to orbital and periorbital soft tissue atrophy,
following bilateral external beam radiotherapy for retinoblastoma.

960
• RETINOBLASTOMA: PLAQUE RADIOTHERAPY
Brachytherapy, using a radioactive plaque, is an effective way of treating selected
retinoblastomas, particularly circumscribed tumors without extensive vitreous seeding. It has
the advantage over EBRT in that it takes only 3 to 4 days to complete the irradiation, appears to
have fewer ocular complications, and appears to be less likely to cause radiation-induced
second cancers. It has the minor disadvantage of requiring surgery for accurate plaque
placement. Plaque radiotherapy is particularly useful for residual or recurrent tumor after failure
of other treatment methods. We speculate that the lower incidence of second cancers after
plaque radiotherapy is due to the fact that the plaque can be shielded to prevent excess
radiation to surrounding tissues.

Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: long term tumor
control and treatment complications in 208 tumors. Ophthalmology 2001;108:2116–2121.

Figure 18.13. Superonasal circumscribed retinoblastoma in a 12-month-old child. The opposite eye had been
enucleated for advanced disease.

Figure 18.14. Lesion shown in Figure 18.13, 2 years after plaque radiotherapy. Note the focus of white
calcification with surrounding atrophy of the retinal pigment epithelium.

961
Figure 18.15. Retinoblastoma in the central macular area.

Figure 18.16. Appearance of lesion shown in Figure 18.15, 1 month after plaque radiotherapy, showing
excellent tumor regression. Over the next few years, there was progressive atrophy of the surrounding retinal
pigment epithelium.

Figure 18.17. Larger macular tumor with dilated retinal blood vessels.

962
Figure 18.18. Appearance of the lesion shown in Figure 18.17, 2 years after plaque radiotherapy, showing
excellent tumor regression. The treated lesion has remained stable for 9 years.

963
• RETINOBLASTOMA: PLAQUE RADIOTHERAPY
Plaque radiotherapy can bring about good regression of retinoblastoma and still preserve a good
cosmetic appearance. A case example is shown.

Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma: Long term tumor
control and treatment complications in 208 tumors. Ophthalmology 2001;108:2116–2121.

Figure 18.19. Large retinoblastoma inferotemporal to the foveal region with endophytic and exophytic
components.

Figure 18.20. B-scan ultrasonogram, showing the lesion.

964
Figure 18.21. Appearance of the lesion 6 months after plaque radiotherapy, showing excellent resolution.

Figure 18.22. Appearance 11 years after plaque radiotherapy, showing complete disappearance of tumor with
no signs of recurrence.

Figure 18.23. Appearance of foveal region 11 years after treatment, showing only mild alterations in the retinal
pigment epithelium. Visual acuity was 6/9 (20/30).

965
Figure 18.24. Facial appearance of the patient 6 years after treatment, showing good cosmetic appearance.
Compare this with the appearance of the child shown in Figure 18.12, who had external beam irradiation.

966
• RETINOBLASTOMA: PLAQUE RADIOTHERAPY, WIDE-ANGLE
IMAGING AND TUMOR REGRESSION PATTERNS

There are five tumor regression patterns following treatment for retinoblastoma. These patterns
can be applied to EBRT, plaque radiotherapy, CRD, laser photocoagulation, and cryotherapy.
These are type 0, tumor regression with complete tumor disappearance, leaving no scar; type 1,
tumor regression with complete calcification; type 2, tumor regression with no calcification
(“fish-flesh” appearance); type 3, tumor regression with partial calcification; and type 4, tumor
regression with flat atrophic scar. Selected examples are illustrated.

Figure 18.25. Macular retinoblastoma in the right eye.

Figure 18.26. Type 1 regression pattern. Appearance of the lesion shown in Figure 18.25, 18 months after
plaque radiotherapy, showing marked tumor regression with complete calcification consistent with a type 1
regression pattern.

967
Figure 18.27. Retinoblastoma superior to the foveal area in the left eye.

Figure 18.28. Type 2 regression pattern. Appearance of the lesion shown in Figure 18.27, 12 months after
plaque radiotherapy, showing a translucent tumor with central atrophy of fibrosis but no calcification.

Figure 18.29. Retinoblastoma in the superior half of the papillomacular bundle in the left eye.

968
Figure 18.30. Type 3 regression pattern. Appearance of the lesion shown in Figure 18.29, 4 months after
plaque radiotherapy, showing slight tumor regression. There is partial calcification, making it a type 3
regression pattern.

969
• RETINOBLASTOMA: WIDE-ANGLE IMAGING OF PLAQUE
RADIOTHERAPY FOR MACULAR RECURRENCE OF
RETINOBLASTOMA AFTER CHEMOREDUCTION

Plaque radiotherapy is an effective method for supplementing or consolidating treatment by

CRD and for treating recurrent tumor after failed CRD, thermotherapy, or cryotherapy. Results
are shown of such treatment for retinoblastoma in the macular area.

Shields CL, Mashayekhi A, Sun H, et al. Iodine 125 plaque radiotherapy as salvage treatment for
retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 2006;113:2087–
2092.

Figure 18.31. Retinoblastoma previously treated with chemoreduction has viable recurrence on posterior
aspect of the lesion.

Figure 18.32. The tumor shown in Figure 18.31 after use of a small radioactive I-125 plaque. Note that there is
excellent regression of the tumor. It shows mainly a type 4 regression pattern with only a questionable focus of
calcification.

970
Figure 18.33. Retinoblastoma previously treated with chemoreduction, showing viable recurrence of the lesion
temporal to the foveal area.

Figure 18.34. The tumor shown in Figure 18.33 after use of a small radioactive I-125 plaque. Note that there is
excellent regression of the active tumor (type 0 regression).

Figure 18.35. Retinoblastoma previously treated with chemoreduction, showing viable recurrence occupying
the central macular region.

971
Figure 18.36. The tumor shown in Figure 18.35 after use of a small radioactive I-125 plaque. Note that there is
excellent type 1 regression of the tumor.

972
• RETINOBLASTOMA: PLAQUE RADIOTHERAPY FOR TUMOR
RECURRENCE AFTER CHEMOREDUCTION

Plaque radiotherapy is an effective method for supplementing or consolidating treatment by

CRD and for treating recurrent tumor after failed CRD, thermotherapy, or cryotherapy.
Additional cases are shown.

Shields CL, Mashayekhi A, Sun H, et al. Iodine 125 plaque radiotherapy as salvage treatment for
retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 2006;113:2087–
2092.

Figure 18.37. Macular retinoblastoma previously treated with chemoreduction, showing viable recurrence
around the tumor margin, characterized by new onset of “fish-flesh” translucent tissue.

Figure 18.38. The tumor shown in Figure 18.37, 1 month after plaque radiotherapy. The tumor is completely
controlled, and the viable tumor on the margin is regressing. The lesion remained stable after 2 more years of
follow-up.

973
Figure 18.39. Nodule of viable retinoblastoma arising from previously regressed retinoblastoma after
chemoreduction. The yellow-gray material elsewhere represents resolved subretinal blood that was present
before treatment.

Figure 18.40. The lesion shown in Figure 18.39, 18 months after plaque radiotherapy, showing complete
resolution of the recurrence with a type 3 regression pattern.

Figure 18.41. Nodule of active vitreous recurrence of retinoblastoma following chemoreduction.

974
Figure 18.42. Appearance of the lesion shown in Figure 18.39, 6 months after plaque radiotherapy, showing
the disappearance of vitreal retinoblastoma and type 4 regression of the main tumor.

975
• RETINOBLASTOMA: CHEMOTHERMOTHERAPY
Chemothermotherapy involves giving intravenous carboplatin followed by treatment of the
tumor with TTT using a specific protocol. The combined effect of the chemotherapy and TTT
brings about tumor destruction.

Shields CL, Santos C, Diniz W, et al. Thermotherapy for retinoblastoma. Arch Ophthalmol
1999;117:885–893.

Figure 18.43. Small retinoblastoma located temporal to the optic disc in the papillomacular bundle in a child
with familial retinoblastoma.

Figure 18.44. Fluorescein angiogram showing tumor vascularity.

976
Figure 18.45. Appearance after chemothermotherapy, showing complete tumor destruction and preservation of
the fovea. Note that there are retinal blood vessels that still supply the foveal region.

Figure 18.46. Fluorescein angiogram after treatment, showing hypofluorescence of the lesion, suggesting that
the tumor is no longer vascularized.

Figure 18.47. Small retinoblastoma superior to the optic disc in the opposite eye of the same patient
immediately after chemothermotherapy.

977
Figure 18.48. Appearance of the lesion shown in Figure 18.47 several months after chemothermotherapy.

978
• RETINOBLASTOMA: CHEMOREDUCTION IN BILATERAL AND
UNILATERAL CASES

Chemotherapy has been traditionally used to treat retinoblastoma with optic nerve extension,
orbital invasion, and distant metastasis. CRD, using a combination of carboplatin, vincristine,
and etoposide, is a more recently employed method in which chemotherapy is given in hopes of
either controlling the tumor(s) or reducing tumor size so that a more conservative method of
treatment can be employed. Such consolidation treatment usually involves thermotherapy,
cryotherapy, or plaque brachytherapy. In addition, secondary retinal detachment shows
dramatic resolution after CRD. In some instances, very large tumors with extensive secondary
retinal detachment often show a dramatic initial response to CRD. However, recurrence or
persistence of vitreal or subretinal seeds is a frequent problem that necessitates further
treatment and sometimes enucleation. Very advanced unilateral tumors are generally best
managed by enucleation rather than attempts at CRD.

Figure 18.49. Two retinoblastomas in the right eye.

Figure 18.50. The same lesions 4 years later, showing good response to chemoreduction and consolidation
treatment.

979
Figure 18.51. Large retinoblastoma occupying the entire macular region of the left eye.

Figure 18.52. The same area 4 years after chemoreduction and consolidation.

Figure 18.53. Superior retinoblastoma obscuring a view of the optic disc.

980
Figure 18.54. The same lesion 3 months after chemoreduction, showing tumor regression and a view of the
optic disc and the foveal region.

981
• RETINOBLASTOMA: COMBINED CHEMOREDUCTION AND FOCAL
THERMOTHERAPY FOR MACULAR TUMORS

In some cases, a combination of CRD and chemothermotherapy can be used to achieve tumor
control. An example is shown of bilateral macular retinoblastoma treated by such an approach.

Shields JA, Shields CL, De Potter P, et al. Bilateral macular retinoblastoma managed by
chemoreduction and chemothermotherapy. Arch Ophthalmol 1996;114:1426–1427.

Figure 18.55. Macular tumor in the right eye.

Figure 18.56. Macular tumor in the left eye.

982
Figure 18.57. Appearance of the right eye after chemoreduction.

Figure 18.58. Appearance of the left eye after chemoreduction. Because such tumors frequently recur after
chemoreduction alone, additional chemothermotherapy was deemed necessary.

Figure 18.59. Appearance of the right eye after chemoreduction and chemothermotherapy.

983
Figure 18.60. Appearance of the left eye after chemoreduction and chemothermotherapy.

984
• RETINOBLASTOMA: CHEMOREDUCTION AND FOVEAL-SPARING
TRANSPUPILLARY THERMOTHERAPY FOR MACULAR TUMORS

If a retinoblastoma is located immediately adjacent to the fovea, CRD alone may sometimes
allow complete cure and avoid visually destructive TTT. However, when there is a question of
residual viable tumor after CRD, then TTT should generally be employed. Examples are shown.

Shields CL, Mashayekhi A, Cater J, et al. Macular retinoblastoma managed with

chemoreduction. Analysis of tumor control with or without adjuvant thermotherapy in 68
tumors. Arch Ophthalmol 2005;123:765–773.

Figure 18.61. Retinoblastoma in the macular area.

Figure 18.62. The same tumor after chemoreduction and foveal-sparing transpupillary thermotherapy.

985
Figure 18.63. Retinoblastoma in the macular area. Note the two small, separate tumors inferior to the larger
mass.

Figure 18.64. The same tumors after chemoreduction and foveal-sparing transpupillary thermotherapy. Note
the regression of the main tumor to a nearly completely calcified mass and regression of the two smaller
tumors to atrophic, flat chorioretinal scars.

Figure 18.65. Appearance of successfully treated retinoblastoma inferotemporal to the optic disc. A scar is
seen superotemporally where chemoreduction and cryotherapy were used for a more peripheral tumor.

986
Figure 18.66. Subsequent recurrence of retinoblastoma inferior to the optic disc shown in Figure 18.65 after
prior treatment with chemoreduction. External beam irradiation was subsequently employed, and the tumor
was again controlled.

987
• RETINOBLASTOMA: INTRA-ARTERIAL CHEMOTHERAPY FOR
PRIMARY TREATMENT

Intra-arterial chemotherapy is a method of chemotherapy delivery directly to the ophthalmic

artery behind the eye via a catheter that is threaded from the femoral artery to the aorta and the
arterial tree up to the internal carotid artery. The ophthalmic artery derives from the internal
carotid artery and the catheter is faced to the ophthalmic artery with chemotherapy release
directly into the artery. This powerful method can be used for small or large tumors, unilateral
or bilateral cases, and as primary or secondary treatment.

1. Shields CL, Kaliki S, Shah SU, et al. Minimal exposure (one or two cycles) of intra-arterial
chemotherapy in the management of retinoblastoma. Ophthalmology 2012;119(1):188–192.
2. Shields CL, Manjandavida FP, Pieretti G, et al. Intra-arterial chemotherapy for retinoblastoma
in 70 eyes: Outcomes based on the International Classification of Retinoblastoma.
Ophthalmology 2014;121:1453–1460.

Figure 18.67. Small macular retinoblastoma.

Figure 18.68. Following only two doses of intra-arterial chemotherapy, there was complete tumor regression.

988
Figure 18.69. Large retinoblastoma with total retinal detachment.

Figure 18.70. Following three doses of intra-arterial chemotherapy, complete tumor regression is noted.

Figure 18.71. Massive retinoblastoma with total retinal detachment and vitreous seeding.

989
Figure 18.72. Following four doses of intra-arterial chemotherapy, complete tumor regression was achieved.

990
• RETINOBLASTOMA: INTRA-ARTERIAL CHEMOTHERAPY FOR
SECONDARY TREATMENT

Intra-arterial chemotherapy can be used as a primary or secondary treatment. This therapy is

commonly employed after failure of intravenous chemotherapy.

Shields CL, Manjandavida FP, Pieretti G, et al. Intra-arterial chemotherapy for retinoblastoma in
70 eyes: Outcomes based on the International Classification of Retinoblastoma. Ophthalmology
2014;121:1453–1460.

Figure 18.73. Small macular recurrence after intravenous chemotherapy.

Figure 18.74. Following three doses of intra-arterial chemotherapy, tumor regression was achieved.

991
Figure 18.75. Large peripheral recurrence after intravenous chemotherapy.

Figure 18.76. Following four doses of intra-arterial chemotherapy, tumor regression was achieved.

Figure 18.77. Massive subretinal seed recurrence after intravenous chemotherapy.

992
Figure 18.78. Following five doses of intra-arterial chemotherapy, tumor regression was achieved.

993
• RETINOBLASTOMA: INTRAVENOUS PLUS INTRA-ARTERIAL
CHEMOTHERAPY FOR ADVANCED BILATERAL RETINOBLASTOMA

More advanced bilateral retinoblastoma, including bilateral groups D and E, is often started on
intravenous chemotherapy for treatment of the eyes and prevention of metastatic disease.
However, intra-arterial chemotherapy is also given in some cases to protect from local ocular
recurrence.

Shields CL, Kaliki S, Al-Dahmash S, et al. Management of advanced retinoblastoma with

intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina
2013;33(10):2103–2109.

Figure 18.79. Massive bilateral retinoblastoma classified as group E in both eyes.

Figure 18.80. Following intravenous plus intra-arterial chemotherapy, complete tumor regression was
achieved with return of vision.

994
Figure 18.81. Massive bilateral retinoblastoma classified as group E in the right eye of a child.

Figure 18.82. Following intravenous plus intra-arterial chemotherapy, complete tumor regression was
achieved and retinal folds were noted surrounding the fovea.

Figure 18.83. Massive bilateral retinoblastoma classified as group E in the left eye of the same child as in
Figure 18.81.

995
Figure 18.84. Following intravenous plus intra-arterial chemotherapy, complete tumor regression was
achieved and the fovea was flat with visual potential.

996
• RETINOBLASTOMA: INTRAVITREAL CHEMOTHERAPY FOR
VITREOUS SEEDING

Recurrent vitreous seeds can be challenging to treat, but with intravitreal chemotherapy, this
problem has generally been controlled. The injection should be carefully performed in a region
where there are few or no seeds to avoid dragging seeds through the entry site. Cryotherapy
upon withdrawal of the needle is a safety feature to prevent metastasis.

Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or recurrent
retinoblastoma vitreous seeds: Preliminary results. JAMA Ophthalmol 2014;132(3):319–25.

Figure 18.85. The chemotherapy is delivered through the pars plana at 3.0 mm from the limbus.

Figure 18.86. After injection, the needle is withdrawn through a cryotherapy ice ball to protect from tumor
seeding.

997
Figure 18.87. Vitreous seed recurrence overlying regressed retinoblastoma.

Figure 18.88. Following intravitreal chemotherapy, vitreous seeds resolved.

Figure 18.89. Large clump of active vitreous seed recurrence overlying regressed retinoblastoma.

998
Figure 18.90. Following intravitreal chemotherapy, vitreous seeds resolved.

999
• CHEMOREDUCTION, SUBCONJUNCTIVAL CARBOPLATIN, AND
EXTERNAL BEAM RADIATION FOR ADVANCED RETINOBLASTOMA

More advanced retinoblastoma with larger tumors or with vitreal subretinal seeds may require
more aggressive management with CRD, local subconjunctival carboplatin, and low-dose
external beam radiation. We give 1 cc of subconjunctival carboplatin (20 mg/cc). The dose of
EBR ranges from 2,800 to 4,000 cGy depending on the radiation oncologist. Examples are
shown before and after such treatment.

Figure 18.91. Multifocal retinoblastoma with tumors nasal and temporal to the optic disc.

Figure 18.92. The same area 9 months later, showing excellent type 1 tumor regression.

1000
Figure 18.93. Sizeable retinoblastoma inferonasal to the disc in the right eye, with a total secondary retinal
detachment.

Figure 18.94. The same area 6 months later, showing excellent type 1 tumor regression.

Figure 18.95. Extensive retinoblastoma prior to treatment.

1001
Figure 18.96. The same area, 1 month later. At this early stage, there is still evidence of viable tumor, and
longer follow-up and consolidation treatment are almost always necessary.

1002
• RETINOBLASTOMA: ENUCLEATION AND HARVESTING OF FRESH
TUMOR TISSUE

Enucleation is generally preferred for most cases of advanced unilateral retinoblastoma and for
many cases of bilateral retinoblastoma when there is no hope for salvageable vision in the
affected eye. In performing enucleation, it is important to obtain a long section of optic nerve
because the main route of extension of the tumor is via the optic nerve to the central nervous
system. In addition, it is often desirable to harvest fresh tumor tissue for genetic analysis and
other studies.

Figure 18.97. The eye has been removed with a long section of optic nerve. The end of the optic nerve is being
sectioned with a blade and will be submitted separately for histopathologic study before the globe is opened.
This prevents artifact tumor seeding on the optic nerve.

Figure 18.98. Diagram showing the base of the tumor (shaded) and the planned area for scleral trephine
opening, which should straddle the margin of the tumor (dashed circle). The dashed line below depicts the site
of sectioning the optic nerve.

1003
Figure 18.99. Corneal trephine (8 mm diameter) being used to make a circular area in the sclera near the
equator and straddling the margin of the tumor.

Figure 18.100. The opening has been made, and fresh white tumor tissue is being harvested.

Figure 18.101. The tissue has been harvested, and the globe has been fixed in formalin. The pathologist
draws two parallel dashed lines so that the main part of the tumor will be in the main pupillary-optic nerve
section and the scleral window will be in the minor calotte.

1004
Figure 18.102. Histopathologic section, showing that the specimen is still well oriented in spite of opening the
globe prior to fixation.

1005
• RETINOBLASTOMA: APPEARANCE OF PROSTHESIS FOLLOWING
ENUCLEATION IN YOUNGER CHILDREN

When enucleation is done for retinoblastoma, a prosthesis is designed and fitted by an ocularist
to provide the best cosmetic result possible. It is sometimes difficult to tell which eye was
enucleated when a good prosthesis is fitted.

Figure 18.103. Leukocoria in an infant with retinoblastoma.

Figure 18.104. Appearance after enucleation and prosthesis, showing excellent cosmetic appearance.

1006
Figure 18.105. Right prosthesis.

Figure 18.106. Left prosthesis.

Figure 18.107. Right prosthesis.

Figure 18.108. Left prosthesis.

1007
• RETINOBLASTOMA: APPEARANCE OF THE PROSTHESIS
FOLLOWING ENUCLEATION IN OLDER CHILDREN

Figure 18.109. Right prosthesis.

Figure 18.110. Left prosthesis.

Figure 18.111. Left prosthesis.

1008
Figure 18.112. Right prosthesis.

Figure 18.113. Left prosthesis.

Figure 18.114. Left prosthesis.

1009
 CHAPTER 19

LESIONS THAT CAN SIMULATE

RETINOBLASTOMA

LESIONS SIMULATING RETINOBLASTOMA

Several conditions can resemble retinoblastoma by causing a white fundus lesion

and/or by causing leukocoria (1–27). The clinician should be familiar with these
conditions and the features that serve to differentiate them clinically from
retinoblastoma. Many simulating lesions are other tumors, like astrocytic
hamartoma, medulloepithelioma, and combined hamartoma, and they are covered
mainly in other chapters; they are briefly mentioned here in the context of their
similarities to retinoblastoma. This chapter describes primarily some nonneoplastic
conditions that can simulate retinoblastoma. These conditions are classified as
follows:
A. Hereditary conditions
1. Norrie disease
2. Congenital retinoschisis
3. Incontinentia pigmenti
4. Dominant exudative vitreoretinopathy
B. Developmental abnormalities
1. Persistent hyperplastic primary vitreous (PHPV), persistent fetal vasculature
(PFV)
2. Congenital cataract
3. Coloboma
4. Retina dysplasia
5. Congenital retinal fold
6. Myelinated nerve fibers
7. Morning glory syndrome
C. Inflammatory disorders
1. Ocular toxocariasis
2. Congenital toxoplasmosis
3. Congenital cytomegalovirus retinitis

1010
 4. Herpes simplex retinitis
5. Peripheral uveoretinitis
6. Metastatic endophthalmitis
7. Orbital cellulitis
D. Tumors
1. Retinal astrocytic hamartoma
2. Medulloepithelioma
3. Glioneuroma
4. Choroidal hemangioma
5. Retinal capillary hemangioma
6. Combined retinal hamartoma
7. Leukemia
E. Miscellaneous
1. Coats disease
2. Retinopathy of prematurity
3. Rhegmatogenous retinal detachment
4. Vitreous hemorrhage
This comprehensive list does not reflect the frequency of these lesions in a clinical
practice. In a series of 2,775 patients referred with the diagnosis of possible
retinoblastoma, 2,171 (78%) proved on our evaluation to have retinoblastoma and
604 (22%) proved to have simulating lesions (1) (Table 19.1). The three conditions
that most closely simulated retinoblastoma were PHPV Coats disease (40%), PFV
(26%), and vitreous hemorrhage (5%) (1). The frequency of PFV as a simulator is
greatest in young children at median age of 1 year whereas the median age of Coats
disease as a simulator is 4 years old. The specific clinical features that help to
differentiate these conditions are discussed in detail in the literature (1–27) and are
summarized in the following table and plates.

Table 19.1 Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604

patients

1011
Selected References
Series/Reviews
1. Shields CL, Schoenfeld E, Kocher K, et al. Lesions simulating retinoblastoma
(pseudoretinoblastoma) in 604 cases. Ophthalmology 2013;120:311–316.
2. Shields JA, Parsons HM, Shields CL, et al. Lesions simulating retinoblastoma. J
Pediatr Ophthalmol Strabismus 1991;28:338–340.
3. 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.

1012
 4. Shields JA, Shields CL, Parsons HM. Review: Differential diagnosis of
retinoblastoma. Retina 1991;11:232–243.
5. Kogan L, Boniuk M. Causes for enucleation in childhood with special reference
to pseudogliomas and unsuspected retinoblastoma. Int Ophthalmol Clin
1962;2:507–514.
6. Robertson DM, Campbell RJ. An analysis of misdiagnosed retinoblastoma in a
series of 726 enucleated eyes. Mod Probl Ophthalmol 1977;18:156–159.
7. Margo CE, Zimmerman LE. Retinoblastoma: the accuracy of clinical diagnosis in
children treated by enucleation. J Pediatr Ophthalmol Strabismus 1983;20:227–
229.

Coats Disease
8. Ridley ME, Shields JA, Brown GC, et al. Coats’ disease. Evaluation of
management. Ophthalmology 1982;89:1381–1387.
9. Shields JA, Shields CL. Differentiation of Coats’ disease and retinoblastoma. J
Pediatr Ophthalmol Strabismus 2001;38:262–266.
10. 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.
11. 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.
12. Shields JA, Shields CL. Review: Coats disease. The 2001 LuEsther Mertz
Lecture. Retina 2002;22:80–91.

Persistent Fetal Vasculature

13. Goldberg MF. Persistent fetal vasculature (PFV): An integrated interpretation of
signs and symptoms associated with persistent hyperplastic primary vitreous
(PHPV). Edward Jackson Memorial Lecture. Am J Ophthalmol 1997;124:587–
626.
Inflammatory Conditions
14. Shields JA. Ocular toxocariasis. A review. Surv Ophthalmol 1984;28:361–381.
15. Shields JA, Shields CL, Eagle RC Jr, et al. Endogenous endophthalmitis
simulating retinoblastoma. A report of six cases. The 1993 Seslen Lecture.
Retina 1995;15:213–219.

Imaging
16. Shields JA, Michelson JB, Leonard BC, et al. B-scan ultrasonography in the
diagnosis of atypical retinoblastomas. Can J Ophthalmol 1976;11:42–51.

Case Reports
17. Borne MJ, Shields JA, Shields CL, et al. Bilateral viral endophthalmitis
simulating retinoblastoma. Arch Ophthalmol 1994;112:1280–1281.
18. 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.
19. Shields JA, Shields CL, Ehya H, et al. Atypical retinal astrocytic hamartoma
diagnosed by fine-needle biopsy. Ophthalmology 1996;103:949–952.
20. Shields JA, Shields CL, Eagle RC Jr, et al. Calcified intraocular abscess
simulating retinoblastoma. Am J Ophthalmol 1992;114:227–229.

1013
21. Shields JA, Eagle RC Jr, Fammartino J, et al. Coats’ disease as a cause of
anterior chamber cholesterolosis. Arch Ophthalmol 1995;113:975–977.
22. Shields CL Zahler J, Falk N, et al. Neovascular glaucoma from advanced Coats
disease as the initial manifestations of facioscapulohumeral dystrophy in a 2-
year-old child. Arch Ophthalmol 2007;125:840–842.
23. Ganesh A, Kaliki S, Tibbetts M, et al. Coats like retinopathy in an infant with
preclinical facioscapulohumeral dystrophy. J AAPOS 2012;16:204–206.
24. Patel AK, Murphy M, Shields CL. Anterior chamber cholesterolosis in Coats
disease. Arch Pediatr Adolesc Med 2011;165:1131–1132.
25. Shields CL, Eagle RC Jr, Shah R, et al. Multifocal hypopigmented retinal
pigment epithelial lesions in a child with incontinentia pigmenti. Retina
2006;26:328–333.
26. Steigel E, Say EA, Carter BC, et al. Simultaneous FZD4 and LRP5 mutation in
autosomal dominant familial exudative vitreoretinopathy. Retin Cases Brief Rep
2013; 7(1):26–28.
27. Patel AK, Murphy M, Shields CL. Picture of the month: Anterior chamber
cholesterolosis in Coats disease. Arch Pediatr Adolesc Med 2011;165:1131–1132.

1014
• COATS DISEASE SIMULATING RETINOBLASTOMA
Coats disease is an idiopathic condition characterized by congenital retinal telangiectasia,
usually seen unilaterally in young males. It can cause intraretinal and subretinal exudation and
retinal detachment. Coats disease can simulate retinoblastoma by producing a localized macular
lesion (exudation, not tumor) or a total retinal detachment that can simulate the exophytic
variant of retinoblastoma. Unlike retinoblastoma, Coats disease shows irregular, light bulb–type
telangiectasia in the peripheral fundus and yellow intraretinal and subretinal exudation. The
retinal vessels tend to course over the detachment and do not dip into it as they do in
retinoblastoma.

1. 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.
2. 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.
3. Shields JA, Shields CL. Differentiation of Coats’ disease and retinoblastoma. J Pediatr
Ophthalmol Strabismus 2001;38:262–266.

Figure 19.1. Macular exudation in Coats disease. Such exudation, remote from the peripheral lesion, is almost
never seen with untreated retinoblastoma, but it is very characteristic of Coats disease.

Figure 19.2. More extensive macular exudation in Coats disease.

1015
Figure 19.3. Peripheral retinal telangiectasia and retinal detachment in Coats disease. Irregular caliber blood
vessels as seen here are rarely seen with retinoblastoma.

Figure 19.4. Total retinal detachment secondary to Coats disease. Note that the subretinal material is yellow,
suggesting the accumulation of lipid. The subretinal material in exophytic retinoblastoma is usually more of a
white-gray color.

Figure 19.5. Fluorescein angiogram of Coats disease with total retinal detachment, showing the characteristic
telangiectasia.

1016
Figure 19.6. B-scan ultrasonogram of Coats disease, showing the total funnel-shaped retinal detachment but
no mass as is generally seen with retinoblastoma.

1017
• ADVANCED COATS DISEASE SIMULATING RETINOBLASTOMA:
CLINICAL AND FLUORESCEIN ANGIOGRAPHIC FEATURES

In general, children with Coats disease tend to have a yellow pupillary reflex (xanthocoria) in
the affected eye, and those with retinoblastoma tend to have a white pupillary reflex
(leukocoria). However, there are cases in which the differential diagnosis may be difficult based
on the color of the pupillary reflex. Hence, ophthalmoscopy, ultrasonography, fluorescein
angiography, and possibly other studies are useful to establish a definitive diagnosis.

1. Shields JA, Shields CL. Review: Coats disease. The 2001 LuEsther Mertz Lecture. Retina
2002;22:80–91.
2. Shields JA, Shields CL. Differentiation of Coats’ disease and retinoblastoma. J Pediatr
Ophthalmol Strabismus 2001;38:262–266.

Figure 19.7. Xanthocoria (yellow pupillary reflex) in a child with Coats disease in the left eye.

Figure 19.8. Xanthocoria in a child with Coats disease in the right eye.

1018
Figure 19.9. Fundus appearance of total retinal detachment secondary to Coats disease. Note the yellow
subretinal material and telangiectasias of the retina vessels inferiorly.

Figure 19.10. Fluorescein angiography of the lesion shown in Figure 19.9, better depicting the retinal
telangiectasia.

Figure 19.11. Clinical appearance of advanced retinal detachment secondary to Coats disease.

1019
Figure 19.12. Fluorescein angiography of the lesion shown in Figure 19.11, better depicting the retinal
telangiectasia.

1020
• COATS DISEASE: CLINICOPATHOLOGIC CORRELATION
Like retinoblastoma, Coats disease can produce a total retinal detachment and neovascular
glaucoma and require enucleation of the affected eye. In some cases, enucleation is done
because the possibility of retinoblastoma cannot be absolutely excluded. In the case cited here,
the diagnosis of Coats disease was evident, but enucleation was performed because of severe
ocular pain secondary to neovascular glaucoma.

Figure 19.13. Total retinal detachment and iris neovascularization secondary to Coats disease. The child had
severe pain from neovascular glaucoma.

Figure 19.14. B-scan ultrasonogram, showing total retinal detachment with condensed retina posterior to the
lens but no evidence of a mass posteriorly.

1021
Figure 19.15. Section of the enucleated eye, showing total retinal detachment and yellow exudation filling the
subretinal space.

Figure 19.16. Low-magnification photograph of the sectioned eye, showing total retinal detachment and
homogeneous eosinophilic exudation filling the subretinal space.

Figure 19.17. Photomicrograph of thickened detached retina, showing large dilated retinal blood vessels and
marked retinal thickening due to intraretinal exudation. (Hematoxylin–eosin ×50.)

1022
Figure 19.18. Photomicrograph of subretinal space showing eosinophilic exudation containing lipid-laden
macrophages and cholesterol clefts, features typical of Coats disease. (Hematoxylin–eosin ×100.)

1023
• COATS DISEASE CAUSING ANTERIOR CHAMBER
CHOLESTEROLOSIS

The anterior chamber is generally clear in patients with Coats disease. However, advanced cases
can present with hyphema secondary to iris neovascularization or anterior chamber
cholesterolosis without a history of prior hyphema. A case of the latter is shown.

1. Shields JA, Eagle RC Jr, Fammartino J, et al. Coats disease as a cause of anterior chamber
cholesterolosis. Arch Ophthalmol 1995;113:975–977.
2. Patel AK, Murphy M, Shields CL. Picture of the month. Anterior chamber cholesterolosis in
Coats disease. Arch Pediatr Adolesc Med 2011;165:1131–1132.

Figure 19.19. Abnormal pupillary reflex in the right eye of a 19-month-old boy.

Figure 19.20. Closer view of the left eye, showing yellow refractile material in the anterior chamber.

1024
Figure 19.21. Gross section of the enucleated eye, showing anterior chamber cholesterolosis and total
exudative retinal detachment with similar refractile material in the subretinal space.

Figure 19.22. Higher magnification view of anterior segment of eye shown in Figure 19.21.

Figure 19.23. Young boy with advanced Coats disease demonstrating total retinal detachment.

1025
Figure 19.24. Following several injections of bevacizumab at another institution, the anterior chamber was
filled with cholesterol.

1026
• PERSISTENT HYPERPLASTIC PRIMARY VITREOUS (PERSISTENT
FETAL VASCULATURE)

Persistent hyperplastic primary vitreous (PHPV; PFV) can also produce leukocoria and simulate
Coats disease. In contrast to retinoblastoma, it is generally present at birth in a microphthalmic
eye, and almost always is unilateral and nonfamilial. PHPV can range from mild to severe forms,
the latter often resulting in a total secondary retinal detachment and blindness. Characteristic
features of this entity include the elongated ciliary processes due to their being dragged into the
retrolental mass and a progressive cataract that can undergo spontaneous resolution. The
congenital retrolental fibrovascular tissue, dragging of ciliary processes, and secondary cataract
are almost never seen with retinoblastoma.

Figure 19.25. Cataract and posterior synechia in a microphthalmic eye with advanced persistent hyperplastic
primary vitreous (PHPV).

Figure 19.26. B-scan ultrasonogram of the patient shown in Figure 19.25. It is often difficult, using
ultrasonography in such cases, to differentiate persistent hyaloid system from a fixed retinal detachment.

1027
Figure 19.27. Anterior segment of the eye of a young man who had a blind eye since infancy. Note the dense
white cataract and the dragged ciliary processes behind the pupillary margin. The blind eye was enucleated for
cosmetic reasons.

Figure 19.28. Lens and ciliary body region in the enucleated eye shown in Figure 19.27 as seen from posterior
view. The cataract is extremely small due to spontaneous resorption of the lens, a well-known feature of the
cataract seen with persistent hyperplastic primary vitreous.

Figure 19.29. Side view of a very small cataractous lens with central dragging of the ciliary body tissue, which
adheres to the margins of the cataract. The lens is smaller because of spontaneous resorption. Note also the
subtle remnants of the hyaloid canal (vertical white line) in the vitreous immediately posterior to the cataract.

Figure 19.30. Photomicrograph of the anterior segment of the same eye, demonstrating typical central

1028
dragging of the ciliary processes to the small lens (far right).

1029
• PERSISTENT HYPERPLASTIC PRIMARY VITREOUS: CLINICAL AND
PATHOLOGIC FEATURES

Shields CL, Schoenfeld E, Kocher K, et al. Lesions simulating retinoblastoma

(pseudoretinoblastoma) in 604 cases. Ophthalmology 2013;120:311–316.

Figure 19.31. Mittendorf dot (white spot) and barely visible hyaloid artery is noted in this eye with mild persistent
fetal vasculature.

Figure 19.32. On fluorescein angiography, the hyaloid artery is visible (out of focus) as it extends from the disc
to the Mittendorf dot and onto the posterior lens surface as tunica vasculosa lentis, all features of persistent
fetal vasculature.

1030
Figure 19.33. Leukocoria of the right eye in a child with persistent hyperplastic primary vitreous. Note the slight
microphthalmia of the affected eye.

Figure 19.34. Closer view of the right eye, showing dense secondary cataract and characteristic dragging of
the ciliary processes into the retrolental mass.

Figure 19.35. Gross appearance of a sectioned eye with persistent hyperplastic primary vitreous with a total
secondary retinal detachment. When such a detachment occurs with persistent hyperplastic primary vitreous,
there is no hope for visual recovery.

1031
Figure 19.36. Low-magnification photomicrograph of persistent hyperplastic primary vitreous, showing
retrolental fibrovascular mass, secondary cataract, dragging of the ciliary processes, and anterior
displacement of the retina over the pars plana. (Hematoxylin–eosin ×3.)

1032
• FAMILIAL EXUDATIVE VITREORETINOPATHY SIMULATING
RETINOBLASTOMA

Familial exudative vitreoretinopathy can manifest with various features of mild retinal dragging,
retinal neovascularization, retinal cicatrix, traction retinal detachment, vitreoretinal fibrosis, and
phthisis bulbi. Additional anterior segment features include tunica vasculosa lentis. The main
etiology of these various features is incomplete retinal perfusion in the peripheral fundus, either
localize or for 360 degrees of the periphery. Below is a case in which a child was referred for
retinoblastoma and familial exudative vitreoretinopathy was the diagnosis, in both this child
and his brother.

Shields CL, Schoenfeld E, Kocher K, et al. Lesions simulating retinoblastoma

(pseudoretinoblastoma) in 604 cases. Ophthalmology 2013;120:311–316.

Figure 19.37. Normal-appearing right eye of child referred for possible retinoblastoma in the left eye. However,
note mild dragging of the retinal vessels temporally.

Figure 19.38. In this child’s left eye, there was extensive vitreoretinal fibrosis and no evidence of
retinoblastoma clinically or by ultrasound.

1033
Figure 19.39. Fluorescein angiography of the right eye disclosed prominent retinal nonperfusion peripherally
and mild retinal dragging, consistent with familial exudative vitreoretinopathy.

Figure 19.40. Similar nonperfusion noted superior and for the entire periphery.

Figure 19.41. The brother of child in Figures 19.37 to 19.39 showed peripheral cicatrix from undetected familial
exudative vitreoretinopathy.

1034
Figure 19.42. Fluorescein angiography disclosed nonperfusion, suggestive of familial exudative
vitreoretinopathy.

1035
• OCULAR TOXOCARIASIS SIMULATING RETINOBLASTOMA
Ocular toxocariasis results from the infestation of the eye with the second-stage larva of the
canine roundworm, Toxocara canis. It can simulate retinoblastoma either by causing a white
fundus granuloma or a diffuse endophthalmitis secondary to an underlying granuloma. The
clinical features, diagnosis, and management of this condition are discussed in the literature.
Unlike retinoblastoma, ocular toxocariasis tends to produce more severe vitreoretinal traction.

Shields JA. Ocular toxocariasis. A review. Surv Ophthalmol 1984;28:361–381.

Figure 19.43. Leukocoria and esotropia of the left eye in a child with ocular toxocariasis.

Figure 19.44. Macular granuloma secondary to ocular toxocariasis. The associated retinal traction does not
tend to occur with a comparable-sized, untreated retinoblastoma.

1036
Figure 19.45. Ocular toxocariasis with a peripheral inflammatory mass. Note the fibrillary margin of the white
lesion, suggesting vitreous traction and early cyclitic membrane formation. Such findings would be unlikely
with untreated retinoblastoma.

Figure 19.46. Wide-angle fundus photograph showing an inferior falciform fold secondary to a peripheral
granuloma in a child with ocular toxocariasis. A falciform fold would almost never occur with untreated
retinoblastoma.

Figure 19.47. Section of an enucleated eye with ocular toxocariasis. There is a total retinal detachment
associated with the dense white retinal mass.

Figure 19.48. Photomicrograph through a chorioretinal eosinophilic abscess, showing larva of Toxocara canis.
(Hematoxylin–eosin ×250.) (Courtesy of Armed Forces Institute of Pathology, Washington, DC.)

1037
• ENDOGENOUS ENDOPHTHALMITIS SIMULATING
RETINOBLASTOMA

Prior to the advent of antibiotics, endogenous endophthalmitis was more common in children
and was frequently confused clinically with retinoblastoma. Although less common today, cases
of endophthalmitis are still referred with the diagnosis of possible retinoblastoma. Examples are
cited.

Shields JA, Shields CL, Eagle RC Jr, et al. Endogenous endophthalmitis simulating
retinoblastoma. A report of six cases. The 1993 Seslen Lecture. Retina 1995;15:213–219.

Figure 19.49. Cytomegalovirus endophthalmitis simulating endophytic retinoblastoma in an infant. Note the
fluffy-white endophytic mass. The opposite eye had similar findings. Peripheral retinal signs of acute retinal
necrosis suggested a viral infection rather than retinoblastoma.

Figure 19.50. Fine-needle aspiration biopsy specimen of the lesion shown in Figure 19.49, demonstrating
large cells with inclusion bodies, characteristic of cytomegalovirus. (Papanicolaou ×400.)

1038
Figure 19.51. Diffuse vitreous cells secondary to streptococcal endophthalmitis following dental surgery. The
child was referred with diagnosis of diffuse retinoblastoma.

Figure 19.52. Fundus mass inferiorly associated with a total secondary retinal detachment. Although the
findings were atypical, enucleation was performed because of total loss of vision and because retinoblastoma
could not be excluded.

Figure 19.53. Photograph of the sectioned eye shown in Figure 19.52 showing white chorioretinal in the globe
posteriorly.

1039
Figure 19.54. Histopathologic section through the mass shown above. A necrotic abscess is present.
(Hematoxylin–eosin ×50.) Although the mass was clearly infectious, no organisms could be identified, and the
etiology was never determined.

1040
• IDIOPATHIC INTRAOCULAR ABSCESS WITH CALCIFICATION,
SIMULATING RETINOBLASTOMA

Shields JA, Shields CL, Eagle RC Jr, et al. Calcified intraocular abscess simulating
retinoblastoma. Am J Ophthalmol 1992;114:227–229.

Figure 19.55. Leukocoria and posterior synechia in the left eye of a newborn girl.

Figure 19.56. Axial computed tomography, showing a diffuse intraocular mass with foci of calcification.

Figure 19.57. Sectioned eye after enucleation, showing a white mass filling the vitreous cavity.

1041
Figure 19.58. Photomicrograph of the intraocular mass, showing extensive areas of necrosis. (Hematoxylin–
eosin ×25.)

Figure 19.59. Photomicrograph of another area, showing viable lymphocytes, eosinophils, and fibroblasts.
(Hematoxylin–eosin ×200.)

Figure 19.60. Photomicrograph, showing foci of dystrophic calcification in the same lesion. These accounted
for the dense foci seen with computed tomography. No organisms were demonstrated in spite of numerous
studies. (Hematoxylin–eosin ×75.)

1042
• INCONTINENTIA PIGMENTI SIMULATING RETINOBLASTOMA
Incontinentia pigmenti (Bloch–Sulzberger disease) is an X-linked dominant condition in which
female infants develop abnormalities of the skin, central nervous system, hair, teeth, and eyes
(affected males do not survive). About 35% of patients have ocular involvement, which is
usually characterized by bilateral geographic areas of mottling of the retinal pigment epithelium
and several other changes, including tractional retinal detachment, that can simulate
retinoblastoma.

Shields CL, Eagle RC Jr, Tabassian A, et al. Multifocal hypopigmented retinal pigment epithelial
lesions in a child with incontinentia pigmenti. Retina 2006;26:328–333.

Figure 19.61. Leukocoria and esotropia of the left eye in a young girl.

Figure 19.62. Skin changes in the area of the umbilicus, showing typical lesions of incontinentia pigmenti.

1043
Figure 19.63. The fundus shows typical linear retinal pigment epithelium alterations in the equatorial region of
the right eye inferotemporally.

Figure 19.64. Fibrovascular mass in the retrolental region of the left eye, simulating retinoblastoma.

Figure 19.65. B-scan ultrasonogram, showing a mass and tractional retinal detachment in the mid portion of
the eye.

1044
Figure 19.66. Section of the eye following enucleation, showing total retinal detachment and a retrolental
fibrovascular mass representing the gliotic retina.

1045
• MISCELLANEOUS CONDITIONS SIMULATING RETINOBLASTOMA
Several other conditions can simulate retinoblastoma clinically. Selected examples are shown.

Shields CL, Schoenfeld E, Kocher K, et al. Lesions simulating retinoblastoma

(pseudoretinoblastoma) in 604 cases. Ophthalmology 2013;120:311–316.

Figure 19.67. Congenital cataract of uncertain etiology simulating retinoblastoma.

Figure 19.68. Retinopathy of prematurity. A total retinal detachment with gliotic retina immediately behind the
lens. Extensive gliosis is not seen in the retinal detachment associated with retinoblastoma.

1046
Figure 19.69. Congenital toxoplasmic retinochoroiditis. The macular lesion was large enough to produce a
white pupillary reflex. Unlike retinoblastoma, this lesion appears flat or slightly depressed with indirect
ophthalmoscopy.

Figure 19.70. Extensive myelinated retinal nerve fibers. This was extensive enough to produce leukocoria.

Figure 19.71. Large optic disc coloboma in the right eye.

Figure 19.72. Same child as in Figure 19.71 with small coloboma in the left eye. These photographs have
same magnification, demonstrating difference in coloboma size.

1047
 CHAPTER 20

VASCULAR TUMORS OF THE RETINA AND

OPTIC DISC

RETINAL HEMANGIOBLASTOMA (CAPILLARY HEMANGIOMA)

General Considerations
Retinal vascular tumors include hemangioblastoma (capillary hemangioma),
cavernous hemangioma, racemose hemangioma, and acquired vasoproliferative
tumor. Each has different clinical features, systemic implications, complications, and
management.
Retinal hemangioblastoma can be solitary, without systemic disease, or a
component of von Hippel–Lindau (VHL) syndrome (1–36). VHL syndrome is an
autosomal-dominant condition with various combinations of retinal
hemangioblastoma, cerebellar hemangioblastoma, pheochromocytoma,
hypernephroma, pancreatic cysts, endolymphatic sac tumor, and several other
tumors and cysts (1–3). The locus for VHL gene is on chromosome 3 (3p25–26)
(7–11), and inactivation of a tumor suppressor gene appears to play a key role,
similar to the situation with regard to retinoblastoma. A patient with a retinal
hemangioblastoma should be evaluated periodically for VHL syndrome. The
incidence of VHL syndrome is about 1 in 40,000 live births, and there is an
estimated 7,000 cases in the U nited States (1). The mean age at diagnosis is 18 years
for patients with VHL and 36 years for those without VHL (3). Development of new
retinal tumors after age 40 years is rare. In a patient with a solitary
hemangioblastoma, the risk of developing VHL is 45% if the patient is <10 years of
age at diagnosis and 1% if >60 years of age (8). Hemangioblastoma may not be
unique to VHL. A similar tumor has been seen associated with Marshall–Stickler
syndrome (33).

Clinical Features
1048
Retinal hemangioblastoma is typically a reddish-pink tumor in the peripheral retina
or on the optic disc. It can occur as an exudative or tractional type. The exudative
type has intraretinal and subretinal exudation similar to Coats disease. In contrast to
Coats disease, however, it shows one or more distinct red masses with dilated,
tortuous, feeding and draining blood vessels. The tractional type of retinal
hemangioblastoma can be similar, but is also characterized by retinal gliosis,
vitreoretinal traction, vitreous hemorrhage, and tractional retinal detachment. With
either type, yellow exudation is often located in the macular area, remote from the
peripheral tumor. Spontaneous regression of the tumor rarely occurs (32).

Diagnostic Approaches
The diagnosis of retinal hemangioblastoma is usually made by the typical
ophthalmoscopic features described. Fluorescein angiography shows rapid
hyperfluorescence of the mass in the arterial phase and late hyperfluorescence, often
with leakage of dye into the vitreous. It is important to differentiate the feeding
artery and the draining vein because that information is needed in treatment, as
discussed later. Indocyanine green angiography and ultrasonography add little to the
diagnosis. Optical coherence tomography can identify the mass in the retina and
help to delineate associated changes like retinal edema and localized retinal
detachment (12,13). Computed tomography, magnetic resonance imaging, or other
imaging studies should be done to detect the central nervous system (CNS) tumors
and other systemic lesions associated with VHL.
Patients with two or more retinal hemangioblastomas carry a mutation in the
VHL gene. Patients with a single retinal hemangioblastoma may or may not carry
the germline mutation and genetic testing is critical.

Pathology
Histopathologically, retinal hemangioblastoma is composed of spindle cells, small
blood vessels, and clear stromal cells (14–16). The stromal cells are believed to be
the cells of origin of this tumor (16). However, their specific nature has not been
clarified, and they do not appear to be vascular endothelial cells. Hence the term
capillary hemangioma may not be accurate. Currently, retinal hemangioblastoma
appears to be the preferred term because of its similarity to the cerebellar
hemangioblastoma.

Management
Management of retinal hemangioblastoma depends on tumor size, location,
complications, and whether the patient has VHL syndrome (17–32). Those
associated with VHL syndrome generally appear at an earlier age, are more
aggressive, and require active treatment. Juxtapapillary or epipapillary retinal
hemangioblastomas may be more difficult to manage because of their location near
the optic disc.
Some small asymptomatic retinal hemangioblastomas can be cautiously followed
and may remain stable or, rarely, show spontaneous regression (32). Tumors with
limited retinal exudation or detachment can be managed by laser photocoagulation
or cryotherapy, and fairly good control is generally achieved (17–20). Photodynamic
therapy and thermotherapy have been found useful in some medium-sized tumors

1049
(21–23). More advanced lesions may require plaque radiotherapy or external beam
radiotherapy (24,25). Surgical management with endoresection of the tumor or
ligature of the feeding vessels have been attempted (26–28). Repair of traction
retinal detachment is often necessary.
The use of vascular endothelial growth factor (VEGF) inhibitors has been studied
fairly extensively with intermediate results (29–31). The results indicate that these
oral or injectable medications lead to reduction in cystoid macular edema and
subretinal fluid with little improved vision and no apparent change in tumor size.
The true value of VEGF inhibitors has not yet been established.

Selected References
Series Reviews
1. Singh AD, Shields CL, Shields JA. von Hippel-Lindau disease. Surv Ophthalmol
2001;46:117–142.
2. Niemelä M, Lemeta S, Sainio M, et al. Hemangioblastomas of the retina: impact
of von Hippel-Lindau disease. Invest Ophthalmol Vis Sci 2000;41(7):1909–1915.
3. 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.
4. McCabe CM, Flynn HW Jr, Shields CL, et al. Juxtapapillary capillary
hemangiomas. Clinical features and visual acuity outcomes. Ophthalmology
2000;107:2240–2248.
5. Ling H, Cybulla M, Schaefer O, et al. When to look for Von Hippel-Lindau
disease in gastroenteropancreatic neuroendocrine tumors? Neuroendocrinology
2004;80:39–46.
6. Wong WT, Agrón E, Coleman HR, et al. Clinical characterization of retinal
capillary hemangioblastomas in a large population of patients with von
Hippel-Lindau disease. Ophthalmology 2008;115(1):181–188.

Genetics
7. Chan CC, Vortmeyer AO, Chew EY, et al. VHL gene deletion and enhanced
VEGF gene expression detected in the stromal cells of retinal angioma. Arch
Ophthalmol 1999;117:625–630.
8. Singh A, Shields J, Shields C. Solitary retinal capillary hemangioma: hereditary
(von Hippel-Lindau disease) or nonhereditary? Arch Ophthalmol 2001;119:232–
234.
9. Singh AD, Ahmad NN, Shields CL, et al. Solitary retinal capillary hemangioma:
lack of genetic evidence for von Hippel-Lindau disease. Ophthalmic Genet
2002;23:21–27.
10. Dollfus H, Massin P, Taupin P, et al. Retinal hemangioblastoma in von Hippel-
Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci
2002;43:3067–3074.
11. Knapp CM, Woodruff G, Roberts F. Ophthalmic pathology of genotypically
confirmed von Hippel Lindau disease type 1. Br J Ophthalmol 2006;90(2):242–
243.

Imaging
12. Shields CL, Mashayekhi A, Luo CK, et al. Optical coherence tomography in

1050
 children: analysis of 44 eyes with intraocular tumors and simulating conditions.
J Pediatr Ophthalmol Strabismus 2004;41:338–344.
13. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014; 34(8):1495–1512.

Pathology
14. Nicholson DH, Green WR, Kenyon KR. Light and electron microscopic study of
early lesions in angiomatosis retinae. Am J Ophthalmol 1976;82(2):193–204.
15. Ehlers N, Jensen OA. Juxtapapillary retinal hemangioblastoma (angiomatosis
retinae) in an infant: light microscopical and ultrastructural examination.
Ultrastruct Pathol 1982;3(4):325–333.
16. Chan CC, Collins AB, Chew EY. Molecular pathology of eyes with von Hippel-
Lindau (VHL) Disease: a review. Retina 2007;27(1):1–7.

Management
17. Singh AD, Nouri M, Shields CL, et al. Treatment of retinal capillary
hemangioma. Ophthalmology 2002;109:1799–1806.
18. Garcia-Arumi J, Sararols LH, Cavero L, et al. Therapeutic options for capillary
papillary hemangiomas. Ophthalmology 2000;107:48–54.
19. Shields JA. Response of retinal capillary hemangioma to cryotherapy. Arch
Ophthalmol 1993;111:551.
20. Welch RB. Von Hippel-Lindau disease: the recognition and treatment of early
angiomatosis retinae and the use of cryosurgery as an adjunct to therapy. Trans
Am Ophthalmol Soc 1970;68:367–424.
21. Parmar DN, Mireskandari K, McHugh D. Transpupillary thermotherapy for
retinal capillary hemangioma in von Hippel-Lindau disease. Ophthalmic Surg
Lasers 2000;31:334–336.
22. Schmidt-Erfurth U M, Kusserow C, Barbazetto IA, et al. Benefits and
complications of photodynamic therapy of papillary capillary hemangiomas.
Ophthalmology 2002;109:1256–1266.
23. Atebara NH. Retinal capillary hemangioma treated with verteporfin
photodynamic therapy. Am J Ophthalmol 2002;134:788–790.
24. Raja D, Benz MS, Murray TG, et al. Salvage external beam radiotherapy of
retinal capillary hemangiomas secondary to von Hippel-Lindau disease: visual
and anatomic outcomes. Ophthalmology 2004;111:150–153.
25. Kreusel KM, Bornfeld N, Lommatzsch A, et al. Ruthenium-106 brachytherapy
for peripheral retinal capillary hemangioma. Ophthalmology 1998;105:1386–
1392.
26. Kwan AS, Ramkissoon YD, Gregor ZJ. Surgical management of retinal capillary
hemangioblastoma associated with retinal detachment. Retina 2008;28(8):1159–
1162.
27. Khurshid GS. Transvitreal endoresection of refractory retinal capillary
hemangioblastoma after feeder vessel ligation. Ophthalmic Surg Lasers Imaging
Retina 2013;44(3):278–280.
28. Farah ME, U no F, Hofling-Lima AL, et al. Transretinal feeder vessel ligature in
von Hippel-Lindau disease. Eur J Ophthalmol 2001;11:386–388.
29. Aiello LP, George DJ, Cahill MT, et al. Rapid and durable recovery of visual

1051
 function in a patient with von Hippel-Lindau syndrome after systemic therapy
with vascular endothelial growth factor receptor inhibitor su5416.
Ophthalmology 2002;109:1745–1751.
30. Girmens JF, Erginay A, Massin P, et al. Treatment of von Hippel-Lindau retinal
hemangioblastoma by the vascular endothelial growth factor receptor inhibitor
SU 5416 is more effective for associated macular edema than for
hemangioblastomas. Am J Ophthalmol 2003;136:194–196.
31. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular
endothelial growth factor therapy with pegaptanib for advanced von Hippel-
Lindau disease of the retina. Retina 2007;27(2):150–158.
32. Milewski SA. Spontaneous regression of a capillary hemangioma of the optic
disc. Arch Ophthalmol 2002;120:1100–1101.

Case Reports
33. Shields JA, Shields CL, Deglin E. Retinal capillary hemangioma in Marshall-
Stickler syndrome. Am J Ophthalmol 1997;124:120–122.
34. Othmane IS, Shields C, Singh A, et al. Postpartum cerebellar herniation in von
Hippel-Lindau syndrome. Am J Ophthalmol 1999;128:387–389.
35. Fine HF, Shields JA, Fisher YL, et al. Optic disc hemangioblastoma (capillary
hemangioma) with ipsilateral oculodermal melanocytosis. Jpn J Ophthalmol
2008; 52(3):233–234.
36. Salazar PF, Shields CL, Materin MA, et al. Endolymphatic sac tumor as the
initial manifestation of von Hippel-Lindau syndrome. Retin Cases Brief Rep
2008;2:332–334.

1052
• RETINAL HEMANGIOBLASTOMA
Retinal hemangioblastoma is found most often in the sensory retina away from the optic disc. It
appears as a reddish-pink intraretinal tumor with a dilated, tortuous feeding retinal artery, and a
similar draining vein. It can assume an exudative form, a tractional form, or a combination of
the two.

Figure 20.1. Small retinal hemangioblastoma with minimal surrounding exudative retinal detachment.

Figure 20.2. Retinal hemangioblastoma with typical intraretinal exudation. The red lesion is almost the same
color as the background fundus, but it is better identified by the dilated vessels that feed and drain the mass. In
this case, the yellow exudation is mostly inferior to the vascular lesion.

1053
Figure 20.3. Larger, inferiorly located retinal hemangioblastoma with secondary exudative retinal detachment.

Figure 20.4. Early tractional form of retinal hemangioblastoma. The tumor is obscured by overlying fibrosis in
the vitreous, but the dilated blood vessels suggest its presence. In this case, the traction is relatively minor.
There is mild scattered retinal exudation more posteriorly.

Figure 20.5. “Free-floating” retinal hemangioblastoma. Vitreous traction, usually associated with a posterior
vitreous detachment, has blanched the tumor and pulled it into the overlying vitreous cavity anterior to the
retina. The retinal feeder vessels are intact here, but they can bleed, leading to vitreous hemorrhage in such
cases.

1054
Figure 20.6. Combined exudative and tractional type of retinal hemangioblastoma. Note the traction on the
retinal blood vessels and the yellow intraretinal and subretinal exudation.

1055
• RETINAL HEMANGIOBLASTOMA: WIDE-ANGLE IMAGING
Wide-angle fundus photography provides a broad view of retinal hemangioblastoma and helps
to delineate the extent of exudation, retinal detachment, and vitreous traction.

Figure 20.7. Small retinal hemangioblastoma located posterior to the equator temporally in the left eye of a
teenaged boy with von Hippel–Lindau syndrome. Note that the small lesion is fed by an artery from the inferior
vascular arcade and drained by a vein into the superior arcade.

Figure 20.8. Retinal hemangioblastoma in the superior fundus of the left eye in a teenaged girl with von
Hippel–Lindau syndrome. Note the dilated retinal artery and vein that supply and drain the mass and the
remote yellow exudation in the foveal region.

1056
Figure 20.9. Bilobed retinal hemangioblastoma located immediately inferonasal to the optic disc in a 55-year-
old man with no findings of von Hippel–Lindau syndrome. The patient has been followed for 2 years with no
change in the lesion. He has 20/50 vision due to subretinal fluid and mild cystoid foveal edema.

Figure 20.10. Yellow-colored retinal hemangioblastoma located between the equator and the ora serrata
superotemporally in the left eye. Note the feeder blood vessels and sparse exudation. There is vitreous traction
on the lesion that may account for the yellow color due to blanching of blood vessels in the lesion.

Figure 20.11. Tractional form of retinal hemangioblastoma located near the equator inferotemporally in the left
eye. Note the vitreous traction band between the lesion and the posterior pole and the retinal and preretinal
fibrosis that partly precludes a view of the tumor. The patient had enucleation of the opposite eye as a young
child for complications of retinal hemangioblastoma, and her mother had von Hippel–Lindau syndrome.

Figure 20.12. Fairly large retinal hemangioblastoma located between the equator and the ora serrata nasal in
the left eye. There is a total exudative, nonrhegmatogenous retinal detachment secondary to the tumor. There

1057
appears to be a second small hemangioblastoma adjacent to the optic disc in the area of traction.

1058
• RETINAL HEMANGIOBLASTOMA (NODULAR) OF THE OPTIC NERVE
In some instances, a retinal hemangioblastoma can lie partly or entirely over the optic disc. In
such cases, the prominent feeding and draining blood vessels are less apparent. It can assume a
nodular or sessile growth pattern. This form has the same relationship to VHL syndrome as the
peripheral type.

Figure 20.13. Nodular retinal hemangioblastoma overlying the superior margin of the optic disc. (Courtesy of
William Hagler, MD.)

Figure 20.14. Nodular retinal hemangioblastoma overlying the nasal margin of the optic disc in a 33-year-old
woman with no evidence of von Hippel–Lindau syndrome. Note the subtle retinal traction and subtle retinal
exudation in the papillomacular bundle.

1059
Figure 20.15. Nodular retinal hemangioblastoma overlying the inferonasal margin of the optic disc in an
African-American teenaged male who had no systemic or genetic evidence of von Hippel–Lindau syndrome.
There was no yellow exudation at this time, but optical coherence tomography showed very shallow subretinal
fluid in the foveal area, accounting for 20/30 visual acuity.

Figure 20.16. The same lesion shown in Figure 20.15, 3 years later. The lesion has shown slow enlargement,
but vision is 20/40 at this time. The lesion showed no regression after systemic and periocular corticosteroids,
and further treatment had not been decided on at that time.

Figure 20.17. Multinodular retinal hemangioblastoma at the optic disc with surrounding exudative retinopathy.

Figure 20.18. Retinal hemangioblastoma on the nasal margin of the optic disc in a patient with von Hippel–
Lindau syndrome. Note the second, more peripheral retinal hemangioblastoma inferiorly that has been treated
elsewhere with surrounding laser photocoagulation.

1060
• RETINAL HEMANGIOBLASTOMA (SESSILE) OF THE OPTIC NERVE
Sessile retinal hemangioblastoma may have indistinct margins and be more difficult to recognize
than the nodular variant.

Figure 20.19. Subtle retinal hemangioblastoma on the inferotemporal margin of the optic disc with secondary
circinate retinal exudation in a middle-aged woman without von Hippel–Lindau syndrome. Note the yellow
circinate exudation peripheral to the lesion and the clear area between the lesion and the exudation.

Figure 20.20. Sessile retinal hemangioblastoma over superior margin of optic. Note the larger feeding blood
vessel and the intraretinal exudation in the foveal area (to the left).

1061
Figure 20.21. Sessile retinal hemangioblastoma covering the optic disc and producing a dense circinate
exudation.

Figure 20.22. Two retinal hemangioblastomas in the posterior pole of the left eye. Note the sessile lesion on
the superior margin of the optic disc and a second lesion inferior to the fovea with retinal feeder and draining
blood vessels. Two distinct lesions like this are virtually pathognomonic of von Hippel–Lindau syndrome.

Figure 20.23. Retinal hemangioblastoma of the optic disc in a 5-year-old child with von Hippel–Lindau
syndrome. There is subretinal serous fluid in the macular area but no yellow exudation. This patient was seen
a number of years ago, and no treatment was given.

Figure 20.24. Appearance of the lesion shown in Figure 20.23, 6 years later, when the patient was referred to
us. The lesion had enlarged dramatically, and there is a total secondary exudative retinal detachment. Several
attempts to reattach the retina were unsuccessful, and enucleation was eventually necessary.

1062
• RETINAL HEMANGIOBLASTOMA: FLUORESCEIN ANGIOGRAPHY
AND OPTICAL COHERENCE TOMOGRAPHY

Fluorescein angiography of retinal hemangioblastoma has typical of rapid filling, often in the
prearterial phase with late staining and leakage. Optical coherence tomography allows
assessment of subretinal fluid and intraretinal edema as well as localization of the
hemangioblastoma within the retina.

Figure 20.25. Fluorescein angiography of retinal hemangioblastoma inferiorly showing filling of the feeding
artery. The draining vein (to the left) appears dark at this time but filled rapidly in the next 2 seconds.

Figure 20.26. The same lesion in the recirculation phase, showing fading fluorescence of the prominent artery
and vein and hyperfluorescence of the mass.

1063
Figure 20.27. Fluorescein angiogram of a juxtapapillary retinal hemangioblastoma in the laminar venous
phase showing rapid filling and staining.

Figure 20.28. Same lesion as above, note the intense hyperfluorescence of the mass.

Figure 20.29. Juxtapapillary retinal hemangioblastoma with exudative maculopathy.

1064
Figure 20.30. Optical coherence tomography of the fovea (top) demonstrating subretinal and intraretinal fluid.
Optical coherence tomography of the tumor (bottom) showing the exophytic optically dense mass in the outer
retina surrounded by intraretinal fluid.

1065
• RETINAL HEMANGIOBLASTOMA: ASSOCIATION WITH VON HIPPEL–
LINDAU SYNDROME

The VHL syndrome is characterized by various combinations of retinal hemangioblastoma,

cerebellar and spinal cord hemangioblastoma, pheochromocytoma, hypernephroma,
endolymphatic sac tumors, and a variety of other vascular and cystic lesions in various parts of
the body. The genetic defect has been localized on the short arm of chromosome 3. Presented
here is the case of a young boy with sporadic VHL syndrome who developed endolymphatic sac
tumor at age 6 years and multiple bilateral retinal hemangioblastomas at age 12 years, findings
that are pathognomonic of VHL syndrome. He later developed massive, aggressive
hemangioblastomas with proliferative vitreoretinopathy in both eyes.

Figure 20.31. Fundus of the right eye, showing two subtle superior retinal hemangioblastomas. These could
be overlooked on a cursory examination.

Figure 20.32. Fundus of the left eye, showing two subtle superior retinal hemangioblastomas. These could
also be easily overlooked.

1066
Figure 20.33. Fluorescein angiography of the right eye, showing hyperfluorescence of the two retinal
hemangioblastomas.

Figure 20.34. Fluorescein angiography of the left eye, showing hyperfluorescence of the two retinal
hemangioblastomas. Several other tumors were detected in this eye.

Figure 20.35. Appearance of the tumors in the left eye after laser photocoagulation, showing chorioretinal
scars.

1067
Figure 20.36. Axial computed tomogram of another patient with von Hippel–Lindau syndrome, showing a cystic
mass in the cerebellum. Note the opaque, phthisical right globe due to prior complications of longstanding
retinal detachment from retinal hemangioblastomas.

1068
• RETINAL HEMANGIOBLASTOMA: CLINICOPATHOLOGIC
CORRELATION

In some cases, aggressive retinal hemangioblastoma may not be controlled, and enucleation of
the affected eye may be necessary because of pain, secondary glaucoma, or phthisis bulbi. The
fellow eye must be followed closely in all cases.

Figure 20.37. Fundus drawing of a red optic disc mass and secondary retinal detachment in a 4-year-old girl
with a negative family history for von Hippel–Lindau syndrome.

Figure 20.38. Fundus photograph of the ill-defined optic disc mass shown in Figure 20.37. Note the retinal
detachment inferiorly. After unsuccessful attempts at retinal detachment repair, the blind, painful eye was
enucleated.

1069
Figure 20.39. Grossly sectioned eye, showing a mass over the optic disc, total retinal detachment, and a
silicone encircling band from the retinal detachment surgery.

Figure 20.40. Histopathology of the tumor, showing a vascular mass composed of capillary caliber vessels
and intervascular stromal cells with foamy cytoplasm. (Hematoxylin–eosin ×150.)

Figure 20.41. The patient’s opposite eye was entirely normal until 3 years after the initial diagnosis, at which
time a peripheral retinal hemangioblastoma developed and preretinal macular fibrosis occurred, requiring
surgical peeling of the preretinal membrane. The patient continues to have limited vision in the remaining eye.

1070
Figure 20.42. Peripheral fundus photograph of the eye shown in Figure 20.41, showing dilated retinal blood
vessels and retinovitreal fibrous tissue over the peripheral vascular tumor.

1071
• RETINAL HEMANGIOBLASTOMA IN OLDER PATIENTS AND IN A
PATIENT WITH MARSHALL–STICKLER SYNDROME

Retinal hemangioblastoma can occur as a sporadic lesion or as a part of VHL syndrome. It is

usually diagnosed in the first two decades of life, particularly in patients with the VHL gene. In
some cases, it can occur in older individuals with no personal or familial evidence of VHL
syndrome. A similar retinal tumor has also been observed in association with Marshall–Stickler
syndrome, an autosomal-dominant condition characterized by typical facies, arthropathy,
cataracts, myopia, and retinal detachment.

Shields JA, Shields CL, Deglin E. Retinal capillary hemangioma in Marshall–Stickler syndrome.
Am J Ophthalmol 1997;124:120–122.

Figure 20.43. Solitary retinal hemangioblastoma in a 65-year-old woman with no von Hippel–Lindau
syndrome.

Figure 20.44. Solitary retinal hemangioblastoma in a 62-year-old man with no von Hippel–Lindau syndrome.

1072
Figure 20.45. Fluorescein angiogram of the lesion shown in Figure 20.44, demonstrating typical features of a
retinal hemangioblastoma.

Figure 20.46. Fundus photograph of the lesion shown in Figure 20.44 after 9 years, revealing enlargement of
the lesion. It was treated with plaque radiotherapy.

Figure 20.47. Superior retinal hemangioblastoma in a 31-year-old man with Marshall–Stickler syndrome but
no von Hippel–Lindau syndrome.

1073
Figure 20.48. Fluorescein angiogram of the lesion shown in Figure 20.47, depicting the hyperfluorescent
mass and dilated feeding artery and draining vein.

1074
• RETINAL HEMANGIOBLASTOMA: LASER PHOTOCOAGULATION
If small retinal hemangioblastomas can be controlled with laser photocoagulation, the
complications of exudative maculopathy and retinal detachment can be reversed or prevented.
It usually requires from one to three laser treatments about 2 to 3 months apart to achieve
satisfactory results. The technique of laser photocoagulation is reported in the literature and
briefly illustrated here.

Figure 20.49. Progressively growing small retinal hemangioblastoma in a 42-year-old man.

Figure 20.50. Appearance of the lesion shown in Figure 20.49 immediately after photocoagulation. The more
superior feeding arteriole is closed, but the inferior draining vein is still patent. The artery was retreated and the
vain was closed on a subsequent laser treatment.

1075
Figure 20.51. Retinal hemangioblastoma superotemporal to the foveal region in a 5-year-old boy. Note the
circinate exudation that extended into the fovea, causing a visual decrease to 20/100.

Figure 20.52. Appearance of the lesion after laser photocoagulation, showing resolution of the exudation.
Visual acuity returned to 20/30.

Figure 20.53. Small retinal hemangioblastoma on the superior margin of the optic disc with foveal exudation.
The tumor was treated with surface laser photocoagulation.

1076
Figure 20.54. Appearance 3 years later, showing resolution of the foveal exudation. The vision acuity improved.
There is still some circinate exudation inferiorly.

1077
• RETINAL HEMANGIOBLASTOMA: CRYOTHERAPY
Cryotherapy can be employed for somewhat larger peripherally located retinal
hemangioblastomas. A triple freeze–thaw technique is generally used, waiting at least 2 to 3
months before giving a second treatment if necessary. A successfully treated case is shown.

Figure 20.55. Pedunculated retinal hemangioblastoma near the temporal equator in the right eye.

Figure 20.56. Fluorescein angiogram in the venous phase.

1078
Figure 20.57. Late fluorescein angiogram, showing marked hyperfluorescence of the tumor and leakage of dye
into the vitreous.

Figure 20.58. Same eye, showing yellow intraretinal exudation in the foveal region.

Figure 20.59. Appearance of a peripheral tumor after double freeze–thaw cryotherapy. The tumor has
disappeared entirely.

Figure 20.60. Appearance of the macular area 10 months after initial cryotherapy, showing marked resolution
of the macular exudation. It eventually resolved completely.

1079
• RETINAL HEMANGIOBLASTOMA: CRYOTHERAPY
Following successful treatment of a retinal capillary hemangioma, the size and configuration of
the retinal blood vessels may return to normal.

Shields JA. Response of retinal hemangioblastoma to cryotherapy. Arch Ophthalmol

1993;111:551.

Figure 20.61. Dilated tortuous retinal blood vessels inferiorly in a 13-year-old girl.

Figure 20.62. The dilated vessels go to a red retinal tumor inferiorly at the equator.

1080
Figure 20.63. Remote macular exudation in the same patient. Visual acuity was 20/200.

Figure 20.64. Area shown in Figure 20.62, showing disappearance of the tumor after cryotherapy.

Figure 20.65. Area shown in Figure 20.61, showing that the retinal vessels have returned to normal size and
distribution after cryotherapy of the tumor.

Figure 20.66. Macular area after destruction of the tumor with cryotherapy. Note that the macular exudation
seen in Figure 20.63 has disappeared and retinal pigment epithelial alteration are present. The vision
returned to 6/6 (20/20) and has remained normal for 23 years since treatment.

1081
• RETINAL HEMANGIOBLASTOMA: PHOTODYNAMIC THERAPY
Some retinal hemangioblastomas can be treated with photodynamic therapy with a technique
similar to that used for age-related macular degeneration. A case is depicted showing clinical
and ocular coherence tomography findings before and after treatment.

Figure 20.67. Retinal hemangioblastoma in temporal macular region with exudative retinopathy.

Figure 20.68. Optical coherence tomography demonstrating intraretinal and subretinal fluid and the edge of the
hemangioblastoma (top) as well as an image through the hemangioblastoma showing the mass as optically
dense in the outer retina.

Figure 20.69. Following several sessions of photodynamic therapy with antivascular endothelial growth factor,

1082
the tumor shows regression and the exudation is resolving.

Figure 20.70. Following therapy, optical coherence tomography demonstrates flat, thinned retina (top) with
dense mass (top and bottom).

Figure 20.71. Retinal hemangioblastoma along the superior arcade in a teenaged girl with von Hippel–Lindau
syndrome. Note the small tumors immediately adjacent to the main lesion.

Figure 20.72. Following photodynamic therapy, tumor regression was noted.

1083
 RETINAL CAVERNOUS HEMANGIOMA

General Considerations
Retinal cavernous hemangioma is a benign vascular tumor that is usually diagnosed
in children or young adults (1–30). It can occur as an isolated solitary tumor or as a
component of an oculoneurocutaneous syndrome that has an autosomal-dominant
hereditary pattern and is also associated with similar CNS vascular abnormalities
and several types of cutaneous vascular malformations. A patient with solitary or
multiple retinal cavernous hemangiomas should generally be evaluated for such
cutaneous and CNS lesions. The latter may cause intracranial hemorrhage with small
strokes, oculomotor palsies, and related signs and symptoms (8,9). Liver
hemangiomas have also been identified in a family with this syndrome.
Patients with retinal and CNS cavernous hemangiomas can manifest a mutation in
one of the cerebral cavernous malformations (CCM) genes including CCM/KRIT1,
CCM2/MGC4607, and CCM3/PDCD10 (7). CCM3 is related to a higher risk for
cerebral hemorrhage in childhood.

Clinical Features
Clinically, retinal cavernous hemangioma usually appears as a solitary, reddish-blue
sessile tumor in the peripheral retina. Less often, it is located in a juxtapapillary or
epipapillary position. In contrast to retinal hemangioblastoma, it does not produce
significant retinal exudation, and it usually has its epicenter along the course of a
retinal vein without a dilated retinal feeding artery. It is often associated with white
fibroglial tissue that can occur spontaneously or can be secondary to small
hemorrhages near the tumor surface. A frequent complication is secondary gliosis
and vitreoretinal traction that can lead to foveal ectopia and visual loss (1–6).
Although retinal cavernous hemangioma is usually relatively small and localized, it
can occasionally be very large and cause major complications, including severe
vitreous hemorrhage and retinal detachment (11,12). We observed one patient with
an extensive retinal cavernous hemangioma that apparently extended anteriorly to
the iris root and presented with a hyphema and vitreous hemorrhage (11).
Although retinal cavernous hemangioma is usually considered to be the only
ocular manifestation of this autosomal-dominant condition, other rarely reported
ocular features include choroidal hemangioma and ocular melanocytosis (21).

Diagnostic Approaches
With fluorescein angiography, retinal cavernous hemangioma has a very typical, if
not pathognomonic, pattern. In the vascular filling phases, the tumor remains
hypofluorescent. In the late venous phase, the saccular aneurysms begin gradually to
fill with fluorescein. Eventually, the upper half of the vascular spaces fills with
fluorescein, whereas the lower half remains hypofluorescent due to the presence of
blood inferiorly. There is minimal, if any, late leakage of dye. This plasma blood
and fluorescein–blood interface is very characteristic of retinal cavernous
hemangioma and quite different from what occurs in retinal hemangioblastoma and
other retinal vascular lesions.

1084
Pathology
Histopathologically, retinal cavernous hemangioma is composed of a
conglomeration of otherwise normal retinal veins, sometimes forming a distinct
sessile or slightly elevated mass in the retina. The secondary retinal gliosis has been
found by electron microscopy to be composed of glial filaments (10,11).

Management
Most retinal cavernous hemangiomas are relatively stationary and require no
treatment. The main complication is vitreous hemorrhage, which appears to be
relatively uncommon. In cases with extensive vitreous hemorrhage, membrane
peeling and removal of the blood by vitrectomy techniques may be acceptable. The
role of laser or cryotherapy in treating the tumor is not clearly established, but they
can be done in cases with recurrent hemorrhage.

Selected References
Series Reviews
1. Gass JD. Cavernous hemangioma of the retina. A neuro-oculocutaneous
syndrome. Am J Ophthalmol 1971;71:799–814.
2. Messmer E, Laqua H, Wessing A, et al. Nine cases of cavernous hemangioma of
the retina. Am J Ophthalmol 1983;95:383–390.
3. Heimann H, Damato B. Congenital vascular malformations of the retina and
choroid. Eye (Lond) 2010;24(3):459–467.
4. Bottoni F, Canevini MP, Canger R, et al. Twin vessels in familial retinal
cavernous hemangioma. Am J Ophthalmol 1990;109(3):285–289.
5. Sarraf D, Payne AM, Kitchen ND, et al. Familial cavernous hemangioma: an
expanding ocular spectrum. Arch Ophthalmol 2000;118:969–973.
6. Giuffre G. Cavernous hemangioma of the retina and retinal telangiectasis.
Distinct or related vascular malformations? Retina 1985;5:221–224.

Genetics
7. Couteulx SL, Brezin AP, Fontaine B, et al. A novel KRIT1/CCM1 truncating
mutation in a patient with cerebral and retinal cavernous angiomas. Arch
Ophthalmol 2002; 120:217–218.
Imaging
8. Schwartz AC, Weaver RG Jr, Bloomfield R, et al. Cavernous hemangioma of the
retina, cutaneous angiomas, and intracranial vascular lesion by computed
tomography and nuclear magnetic resonance imaging. Am J Ophthalmol
1984;98:483–487.
9. Pancurak J, Goldberg MF, Frenkel M, et al. Cavernous hemangioma of the
retina. Genetic and central nervous system involvement. Retina 1985;5:215–220.
Pathology
10. Messmer E, Font RL, Laqua H, et al. Cavernous hemangioma of the retina.
Immunohistochemical and ultrastructural observations. Arch Ophthalmol
1984;102:413–418.
11. Shields JA, Eagle RC Jr, Shields CL, et al. Retinal cavernous hemangioma. Fifty-
two years clinical follow up with clinicopathologic correlation. Retina

1085
 2014;34:1253–1257.

Management
12. Haller JA, Knox DL. Vitrectomy for persistent vitreous hemorrhage from a
cavernous hemangioma of the optic disk. Am J Ophthalmol 1993;116(1):106–
107.

Case Reports
13. Klein M, Goldberg MF, Cotlier E. Cavernous hemangioma of the retina: report
of four cases. Ann Ophthalmol 1975;7:1213–1221.
14. Lewis RA, Cohen MH, Wise GN. Cavernous haemangioma of the retina and
optic disc. A report of three cases and a review of the literature. Br J
Ophthalmol 1975;59:522–534.
15. Colvard DM, Robertson DM, Trautmann JC. Cavernous hemangioma of the
retina. Arch Ophthalmol 1978;96:2042–2044.
16. Goldberg RE, Pheasant TR, Shields JA. Cavernous hemangioma of the retina. A
four-generation pedigree with neuro-oculocutaneous involvement and an
example of bilateral retinal involvement. Arch Ophthalmol 1979;97:2321–2324.
17. Moffat KP, Lee MS, Ghosh M. Retinal cavernous hemangioma. Can J Ophthalmol
1988;23:133–135.
18. Mansour AM, Jampol LM, Hrisomalos NF, et al. Case report. Cavernous
hemangioma of the optic disc. Arch Ophthalmol 1988;106:22.
19. Yamaguchi K, Yamaguchi K, Tamai M. Cavernous hemangioma of the retina in
a pediatric patient. Ophthalmologica 1988;197:127–129.
20. Backhouse O, O’Neill D. Cavernous haemangioma of retina and skin. Eye 1998;
12:1027–1028.
21. Zografos L, Gonvers M. Ocular melanocytosis and cavernous haemangioma of
the optic disc. Br J Ophthalmol 1994;78:73–74.
22. Kushner MS, Jampol LM, Haller JA. Cavernous hemangioma of the optic nerve.
Retina 1994;14:359–361.
23. Drigo P, Battistella PA, Mammi I. Familial cerebral, hepatic, and retinal
cavernous angiomas. Childs Nerv Syst 1995;11:65.
24. Isola VM. Hemangioma of the ciliary body: a case report and review of the
literature. Ophthalmologica 1996;210(4):239–243.
25. Bell D, Yang HK, O’Brien C. A case of bilateral cavernous hemangioma
associated with intracerebral hemangioma. Arch Ophthalmol 1997;115:818–819.
26. Naftchi S, la Cour M. A case of central visual loss in a child due to macular
cavernous haemangioma of the retina. Acta Ophthalmol Scand 2002;80(5):550–
552.
27. Hewick S, Lois N, Olson JA. Circumferential peripheral retinal cavernous
hemangioma. Arch Ophthalmol 2004;122(10):1557–1560.
28. Patikulsila D, Visaetsilpanonta S, Sinclair SH, et al. Cavernous hemangioma of
the optic disk. Retina 2007;27(3):391–392.
29. Chen L, Huang L, Zhang G, et al. Cavernous hemangioma of the retina. Can J
Ophthalmol 2008;43(6):718–720.
30. Velazquez-Martin JP, Domville D, Fulda E, et al. Peripheral capillary
nonperfusion and vitreolesional adhesion in retinal cavernous hemangioma.
Retina 2013;33(3):666–667.

1086
• RETINAL CAVERNOUS HEMANGIOMA: CLINICAL VARIATIONS
The clinical appearance of retinal cavernous hemangioma can vary considerably from case to
case. It can range from a small subtle cluster of aneurysms to a more massive blue-red tumor.
Fibroglial tissue in the larger lesions can cause considerable dragging of the retina.

Figure 20.73. Small retinal cavernous hemangioma in the macula.

Figure 20.74. Retinal cavernous hemangioma in the periphery with overlying vitreous fibrosis on wide-angle
imaging.

1087
Figure 20.75. Retinal cavernous hemangioma centered in the macular area.

Figure 20.76. Retinal cavernous hemangioma temporal to the macular area.

Figure 20.77. Retinal dragging secondary to retinal cavernous hemangioma. The posterior pole shows the
retinal fold extending inferotemporally from the optic disc.

1088
Figure 20.78. Large peripheral retinal cavernous hemangioma in the same eye shown in Figure 20.77. The
glial tissue on the cavernous hemangioma accounted for the retinal dragging.

1089
• RETINAL CAVERNOUS HEMANGIOMA: 52-YEAR FOLLOW-UP AND
CLINICOPATHOLOGIC CORRELATION

Large retinal cavernous hemangioma presented with hyphema at birth and was later recognized
on fundus examination. Over the 52-year course, this patient had repetitive hyphemas, cataract
extraction, secondary glaucoma, and eventual unrelenting pain, necessitating enucleation.
Clinicopathologic correlation confirmed the retinal cavernous hemangioma.

Shields JA, Eagle RC Jr, Shields CL, et al. Retinal cavernous hemangioma. Fifty-two years
clinical follow up with clinicopathologic correlation. Retina 2014;34:1253–1257.

Figure 20.79. Large peripheral retinal cavernous hemangioma with extensive vitreous hemorrhage. This
patient was born with hyphema due to anterior extension of the lesion into the ciliary body.

Figure 20.80. Fluorescein angiogram in venous phase, showing hypofluorescence of the mass and
hyperfluorescence of the cavernous spaces.

1090
Figure 20.81. Following unrelenting pain and glaucoma, the eye was enucleated. Gross appearance of
sectioned globe showing white fibrous tissue in retina anterior to the equator and red vascular tissue posterior
to the equator.

Figure 20.82. Gross appearance of the multilobulated retinal cavernous hemangioma.

Figure 20.83. Section through retinal cavernous hemangioma showing large congested blood vessels
extending for full thickness of the retina. (Hematoxylin–eosin ×10.)

1091
Figure 20.84. Higher-power view through retinal cavernous hemangioma showing blood-filled vascular
channels lined by thin endothelial cells. (Hematoxylin–eosin ×50.)

1092
• RETINAL CAVERNOUS HEMANGIOMA: FLUORESCEIN
ANGIOGRAPHY

Fluorescein angiography shows a highly characteristic pattern in cases of retinal cavernous

hemangioma. The lesion generally shows hypofluorescence in the arterial filling phases and
gradual filling of the aneurysms with fluorescein in the late venous and recirculation phases.
This is explained by the fact that the lesion lies on the venous side of the circulation and has
slow, almost stagnant, blood flow.

Figure 20.85. Retinal cavernous hemangioma along the superotemporal retinal vascular arcade in a young
woman who also had a similar vascular lesion in brain and maldevelopment of one arm and hand. She had a
cerebrovascular accident at age 30 years.

Figure 20.86. Fluorescein angiogram in the laminar venous phase, showing general hypofluorescence of the
mass.

1093
Figure 20.87. Late angiogram, showing typical hyperfluorescence of the superior and hypofluorescence of the
inferior aspect of the aneurysms.

Figure 20.88. Large globular retinal cavernous hemangioma that resembles a retinal hemorrhage.

Figure 20.89. Early angiogram, showing hypofluorescence of the lesion shown in Figure 20.88.

1094
Figure 20.90. Late angiogram, showing hyperfluorescence of the aneurysms, which is quite different from the
persistent hypofluorescence that would be seen with a hemorrhage alone.

1095
• RETINAL CAVERNOUS HEMANGIOMA WITH INVOLVEMENT OF THE
OPTIC DISC

1. Drummond JW, Hall DL, Steen WH Jr, et al. Cavernous hemangioma of the optic disc. Ann
Ophthalmol 1980;12:1017–1018.
2. Patikalsila D, Visaetsilpanonta S, Sinclair SH, et al. Cavernous hemangioma of the optic disc:
a case report. Retina 2007;27:391–392.

Figure 20.91. Retinal cavernous hemangioma affecting the temporal half of the optic disc. (Courtesy of Jerry
Drummond, MD.)

Figure 20.92. Fluorescein angiogram in the vascular filling phase of the patient in Figure 20.91, showing
hypofluorescence of the lesion. (Courtesy of Jerry Drummond, MD.)

1096
Figure 20.93. Late-phase angiogram of the same patient, showing characteristic hyperfluorescence of the
aneurysms. (Courtesy of Jerry Drummond, MD.)

Figure 20.94. Massive retinal cavernous hemangioma centered in the optic disc.

Figure 20.95. Fluorescein angiogram in the venous phase of the lesion shown in Figure 20.94. Note the
hypofluorescence of the lesion, in contrast to the early hyperfluorescence seen with retinal
hemangioblastoma.

1097
Figure 20.96. Late fluorescein angiogram of the same lesion, showing late hyperfluorescence of the
aneurysms with a fluorescein–blood interface that is characteristic of cavernous hemangioma.

1098
• FAMILIAL RETINAL CAVERNOUS HEMANGIOMA ASSOCIATED WITH
CENTRAL NERVOUS SYSTEM AND CUTANEOUS VASCULAR
ANOMALIES

Retinal cavernous hemangiomatosis is often a part of a familial oculoneurocutaneous syndrome

with similar vascular lesions in the CNS and skin.

Goldberg RE, Pheasant TR, Shields JA. Cavernous hemangioma of the retina. A four-generation
pedigree with neuro-oculocutaneous involvement and an example of bilateral retinal
involvement. Arch Ophthalmol 1979;97:2321–2324.

Figure 20.97. Middle-aged woman presenting with right oculomotor nerve palsy. Note the failure of infraduction
of the right eye. In view of the familial findings described in what follows, it was believed that the nerve palsy
was secondary to hemorrhage from a small intracranial vascular anomaly.

Figure 20.98. Superior fundus of the patient shown in Figure 20.97, demonstrating subtle retinal aneurysms.

1099
Figure 20.99. Late fluorescein angiogram of the eye shown in Figure 20.98, demonstrating typical venous
aneurysms.

Figure 20.100. Right fundus of the patient’s daughter, showing subtle retinal cavernous hemangioma.

Figure 20.101. Left fundus of the patient’s daughter, showing more conspicuous retinal cavernous
hemangioma.

1100
Figure 20.102. Subtle cutaneous hemangioma in the patient’s daughter.

1101
 RETINAL RACEMOSE HEMANGIOMA

General Considerations
Retinal racemose (cirsoid) hemangioma is not a true neoplasm. Instead, it is a
benign retinal arteriovenous (AV) communication that can occur as an isolated
solitary lesion or as a component of the Wyburn–Mason syndrome (1–15). A patient
with retinal racemose hemangioma should generally be evaluated and followed for
similar AV communications in the midbrain, mandible, maxilla, orbit, and other
predisposed areas. We have seen excess bleeding after dental surgery that eventually
led to detection of the retinal lesion as a component of the Wyburn–Mason
syndrome.

Clinical Features
Archer and associates divided retinal AV communications into three groups: Group
1 is characterized by the interposition of an arteriolar or abnormal capillary plexus
between the large communicating vessels; group 2 is typified by direct AV
communication without the interposition of capillary or arteriolar elements; group
3 includes more complex AV communications associated with severe visual loss (1).
By strict definition, the lesions are not true neoplasms, and they are not localized,
balloonlike dilations as seen with aneurysms. The lesion is characterized clinically
by a dilated retinal artery that communicates directly with dilated retinal vein,
usually without an intervening capillary bed. The abnormal blood vessels are
generally uniformly dilated, but focal aneurismal dilations of the affected vessels are
occasionally seen. It can range from a simple AV communication to a more complex
mass of vascular channels. The lesion can show a changing pattern if followed for
years (7). On rare occasions, it can produce vitreous hemorrhage or branch retinal
vein obstruction (10,13).

Diagnostic Approaches
The most useful ancillary study for retinal racemose hemangioma is fluorescein
angiography. It demonstrates the AV communication with rapid transit and no
appreciable leakage of fluorescein. MRI can be performed to rule out similar
vascular changes in the brain and periocular region, as seen with the Wyburn–Mason
syndrome. Optical coherence tomography shows an irregular retinal surface with
optical densities corresponding to the large blood vessels (12).

Pathology
Histopathologically, retinal racemose hemangioma consists of large dilated,
otherwise normal, vascular channels in the sensory retina. A clinicopathologic
correlation of a retinal racemose hemangioma from a rhesus monkey has been
reported (6).

Management
Most retinal racemose hemangiomas require no treatment. Rare complications

1102
include vitreous hemorrhage and branch retinal vein obstruction, both of which
should be managed like other cases of vitreous hemorrhage and vascular
obstruction, based on the clinical situation. If the blood does not resolve, it can be
removed by vitrectomy techniques.

Selected References
Series Reviews
1. Archer DB, Deutman A, Ernest JT, et al. Arteriovenous communications of the
retina. Am J Ophthalmol 1973;75:224–241.

Case Reports
2. Bech K, Jenson OA. Racemose haemangioma of the retina; two additional cases,
including one with defects of the visual fields as a complication of
arteriography. Acta Ophthalmol (Copenh) 1958;36(4):769–781.
3. Cameron ME, Greer CH. Congenital arteriovenous aneurysm of the retina: a
post mortem report. Br J Ophthalmol 1968;52:768–772.
4. Hoyt WF, Cameron RB. Racemose angioma of the mandible, face, retina, and
brain: report of case. J Oral Surg 1968;26:596–601.
5. Bernth-Petersen P. Racemose haemangioma of the retina. Report of three cases
with long term follow-up. Acta Ophthalmol (Copenh) 1979;57:669–678.
6. Bellhorn RW, Friedman AH, Henkind P. Racemose (cirsoid) hemangioma in
rhesus monkey retina. Am J Ophthalmol 1972;74:517–522.
7. Augsburger JJ, Goldberg RE, Shields JA, et al. Changing appearance of retinal
arteriovenous malformation. Graefes Clin Exp Ophthalmol 1980;215:65–70.
8. Mansour AM, Wells CG, Jampol LM, et al. Ocular complications of
arteriovenous communications of the retina. Arch Ophthalmol 1989;107: 232–
236.
9. Bloom PA, Laidlaw A, Easty DL. Spontaneous development of retinal ischaemia
and rubeosis in eyes with retinal racemose angioma. Br J Ophthalmol
1993;77:124–125.
10. Shah GK, Shields JA, Lanning R. Branch retinal vein obstruction secondary to
retinal arteriovenous communication. Am J Ophthalmol 1998;126: 446–448.
11. Goh D, Malik NN, Gilvarry A. Retinal racemose haemangioma directly
communicating with a intramuscular facial cavernous haemangioma. Br J
Ophthalmol 2004; 88:840–842.
12. Materin MA, Shields CL, Marr BP, et al. Retinal racemose hemangioma. Retina
2005;25:936–937.
13. Papageorgiou KI, Ghazi-Nouri SM, Andreou PS. Vitreous and subretinal
haemorrhage: an unusual complication of retinal racemose haemangioma. Clin
Exp Ophthalmol 2006;34:176–177.
14. Yang C, Liu YL, Dou HL, et al. U nilateral hemi-central retinal vein obstruction
associated with retinal racemose angioma. Jpn J Ophthalmol 2009;53(4):435–
436.
15. Panagiotidis D, Karagiannis D, Tsoumpris I. Spontaneous development of
macular ischemia in a case of racemose hemangioma. Clin Ophthalmol
2011;5:931–932.

1103
• RETINAL RACEMOSE HEMANGIOMA: CLINICAL FEATURES
Retinal racemose hemangioma (AV communication) can range from a simple communication to
a more complex array of intertwining blood vessels.

Figure 20.103. Dilated retinal artery and vein superior to the optic disc in a young child.

Figure 20.104. Fundus photograph of the area slightly peripheral to the area shown in Figure 20.103,
demonstrating the arteriovenous communication.

1104
Figure 20.105. Slightly more complex retinal racemose hemangioma.

Figure 20.106. Complex retinal racemose hemangioma with a sclerotic white appearance to some of the
retinal vessels. (Courtesy of Robert Kalina, MD.)

Figure 20.107. Complex racemose hemangioma in a 10-year-old girl with Wyburn–Mason syndrome. She was
subsequently found have a similar complex vascular anomaly in the maxilla after having prolonged bleeding
from dental treatment. A few years later, she developed hemorrhage from a similar lesion in the midbrain.

Figure 20.108. Wide-angle fundus photograph of the lesion shown in Figure 20.107, demonstrating the full
extent of the vascular anomaly.

1105
• RETINAL RACEMOSE HEMANGIOMA: FLUORESCEIN
ANGIOGRAPHY

In most instances, the blood vessels in a retinal racemose hemangioma fill rapidly with
fluorescein, but they do not tend to leak the dye.

Figure 20.109. Montage of a large arteriovenous communication in the superotemporal fundus. (Courtesy of
Robert Kalina, MD.)

Figure 20.110. Montage of a fluorescein angiogram of the patient shown in Figure 20.109. (Courtesy of Robert
Kalina, MD.)

1106
Figure 20.111. Retinal racemose hemangioma in the macular area of a 35-year-old man.

Figure 20.112. Arterial phase of the lesion shown in Figure 20.111.

Figure 20.113. Early venous phase of the lesion shown in Figure 20.111.

1107
Figure 20.114. Close up the angiogram of the vessels shown in Figure 20.113, demonstrating the complex
nature of the vascular lesion.

1108
• RETINAL RACEMOSE HEMANGIOMA: ADVANCED CASE WITH
FLUORESCEIN ANGIOGRAPHY AND OPTICAL COHERENCE
TOMOGRAPHY

A case is depicted of advanced retinal racemose hemangioma in a teenaged male, showing

fluorescein and optical coherence tomography findings. He had normal cutaneous examination
and cranial MRI studies showed no evidence of Wyburn–Mason syndrome.

Materin MA, Shields CL, Marr BP, et al. Retinal racemose hemangioma. Retina 2005;25:936–937.

Figure 20.115. Appearance of the disc and macular area of the affected left eye in a 13-year-old boy.

Figure 20.116. The same eye, showing similar vascular changes nasal to the optic disc.

1109
Figure 20.117. Fluorescein angiogram of the macular region in the full venous phase. Note that the abnormal
retinal blood vessels are filled with fluorescein, but there is no leakage of dye.

Figure 20.118. Late fluorescein angiogram, showing mild intraretinal leakage from small blood vessels in the
foveal region.

Figure 20.119. Optical coherence tomography, showing marked disruption of the retina due to the presence of
large abnormal blood vessels in the retina.

1110
Figure 20.120. Wide-angle fundus photograph of the lesion, showing the full extent of abnormal blood vessels.

1111
• RETINAL RACEMOSE HEMANGIOMA COMPLICATED BY BRANCH
RETINAL VEIN OBSTRUCTION

In rare instances, retinal racemose hemangioma can be complicated by a branch retinal vein
obstruction. The precise mechanism is unclear.

Shah GK, Shields JA, Lanning R. Branch retinal vein obstruction secondary to retinal
arteriovenous communication. Am J Ophthalmol 1998;126:446–448.

Figure 20.121. Superotemporal enlarged blood vessels in the right eye of a 12-year-old girl with 20/30 vision.

Figure 20.122. A more peripheral view, showing arteriovenous communication.

1112
Figure 20.123. Fluorescein angiogram in the venous phase.

Figure 20.124. Fluorescein angiogram in the recirculation phase.

Figure 20.125. Appearance 9 years later, when the patient developed sudden worsening of vision in the
affected right eye. Note the hemorrhagic retinopathy along the course of the vascular anomaly.

1113
Figure 20.126. Fluorescein angiogram, showing hypofluorescence of the retinal hemorrhages in the
distribution of the vascular anomaly.

1114
 VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS

General Considerations
Retinal vasoproliferative tumor is a term applied to a vascular fundus lesion that has
received a good deal of attention in the recent literature (1–36). In our original
report of 12 cases, we used the term presumed acquired retinal hemangioma to
characterize this condition and discussed those features that differentiate it from
retinal hemangioblastoma (capillary hemangioma), choroidal melanoma, and other
fundus lesions (1). Because of the possibility that this condition is not necessarily a
primary retinal vascular mass, in our later report on 103 tumors we coined the term
vasoproliferative tumor of the ocular fundus (VPTOF), which might be preferable.
We realized that the features of this condition were variable from case to case, and
we divided this lesion into primary and secondary types (2). Although there are
usually no major ocular associations, a tumor compatible with this diagnosis has
been reported with Waardenburg syndrome (5) and familial aniridia (12).

Clinical Features
The patient with a retinal vasoproliferative tumor may be asymptomatic or have
painless visual impairment. The ophthalmoscopic features of VPTOF vary from case
to case, but, in general, the lesion appears as an elevated, reddish-pink mass in the
pre-equatorial region, usually inferotemporally. However, we have observed this
lesion in all quadrants and even in the posterior fundus. It usually has a retinal
feeding artery and draining vein. These vessels are of retinal origin and are slightly
enlarged but are not so dilated and tortuous as those seen with the retinal
hemangioblastoma associated with VHL syndrome. The VPTOF characteristically
produces exudation that usually extends from the peripheral lesion toward the
posterior pole. The exudation is usually continuous with the mass and is not usually
in the macular area remote from the tumor as often seen with retinal
hemangioblastoma. However, preretinal macular gliosis can occur remote from the
lesion. Other common features are subretinal and vitreal hemorrhage, pigment
proliferation, and atrophy of the retinal pigment epithelium (1,2,6).
The primary type of VPTOF is characteristically a unilateral, solitary lesion in the
fundus inferotemporally. About half of the affected patients have systemic
hypertension, but no other specific abnormalities have been identified. It differs
from retinal capillary hemangioma in that it occurs in middle-aged or older
individuals, does not have markedly dilated and tortuous feeding and draining
vessels, is usually more peripherally located, and is not associated with VHL
syndrome. It differs from choroidal melanoma in that it produces exudation and has
a retinal blood supply. Some patients have elevated serum lipids.
The secondary type of VPTOF occurs in eyes that have certain predisposing ocular
lesions. In our series of 103 tumors, the main predisposing lesions were
intermediate uveitis (28%), retinal pigmentary dystrophy (“retinitis pigmentosa”)
(21%) (3), ocular toxocariasis (7%), toxoplasmic retinitis (7%), coloboma (7%), and
traumatic chorioretinopathy (7%). We have more recently seen this lesion is
association with cases of Coats disease (11), familial exudative vitreoretinopathy,
chronic retinal detachment from any cause, and other entities associated with ocular

1115
trauma or inflammation. Some secondary VPTOFs are bilateral or multifocal, and
they have no specific distribution in the fundus. In addition, some secondary
VPTOFs are more diffuse and ill defined compared to the more localized primary
lesion. The diffuse variant of secondary VPTOF may be similar to Coats disease, but
it lacks the characteristic telangiectasia that is seen in Coats disease.
In some instances, VPTOF can gradually undergo spontaneous regression without
treatment. We have observed this in both the primary and secondary variations.

Diagnostic Approaches
Fluorescein angiography shows rapid filling of the tumor through the mildly dilated
retinal feeder artery and subsequent fluorescence to the lesion. However, the filling
with fluorescein is not as rapid as that seen with retinal hemangioblastoma. There is
usually leakage of dye into the subretinal space and overlying vitreous.
U ltrasonography generally shows higher internal reflectivity as compared to a
comparable-sized melanoma.

Pathology
There are a few reports on the histopathology of VPTOF. Cases that have come to
histopathologic examination have usually undergone prior treatment such as laser
photocoagulation, cryotherapy, and other techniques. Hence, the basic pathology has
been obscured by secondary retinal pigment epithelial changes and gliosis. Some
believe that it is primarily a glial proliferation with secondary vascular changes (9).
We also believe that it represents a reactive process containing retinal blood vessels,
glial cells, and retinal pigment epithelial cells (9). Most tumors probably have a
variable combination of these three components.

Management
Management varies from case to case. Asymptomatic lesions may be observed and
may be stable for years or even regress spontaneously. Those with progressive
exudation or vitreous hemorrhage may be managed by cryotherapy, which can
sometimes induce dramatic tumor regression. Smaller lesions without extensive
exudation or retinal detachment can be treated with laser photocoagulation. If the
vitreous hemorrhage does not resolve in a few months, vitrectomy to remove the
blood combined with laser photocoagulation or cryotherapy may be warranted. For
cases that do not respond to these treatments, we and others have had successful
control with plaque brachytherapy (14). Photodynamic therapy may be an effective
treatment in some smaller lesions. Removal of the mass by local resection is an
additional option in selected cases.

Selected References
Series Reviews
1. Shields CL, Kaliki S, Al-Dahmash SA, et al. Vasoproliferative tumors of the
ocular fundus. Comparative clinical features of primary versus secondary tumors
in 334 cases. Arch Ophthalmol 2012;131(3):328–334.
2. Shields JA, Decker WL, Sanborn GE, et al. Presumed acquired retinal
hemangiomas. Ophthalmology 1983;90:1292–1300.

1116
 3. 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.
4. Heimann H, Bornfeld N, Vij O, et al. Vasoproliferative tumours of the retina. Br
J Ophthalmol 2000;84:1162–1169.
5. Damato B. Vasoproliferative retinal tumour. Br J Ophthalmol 2006;90:399–400.
6. Shields JA, Pellegrini M, Kalaki S, et al. Retinal vasoproliferative tumors in 6
patients with Neurofibromatosis Type 1. JAMA Ophthalmol 2014;132:190–196.
7. Rennie IG. Retinal vasoproliferative tumours. Eye (Lond) 2010;24:468–471.
8. Shields JA, Reichstein D, Mashayekhi A, et al. Retinal vasoproliferative tumors
in ocular conditions of childhood. J AAPOS 2012;16:6–9.
9. 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.

Pathology
10. Smeets MH, Mooy CM, Baarsma GS, et al. Histopathology of a vasoproliferative
tumor of the ocular fundus. Retina 1998;18:470–472.
11. Irvine F, O’Donnell N, Kemp E, et al. Retinal vasoproliferative tumors: surgical
management and histological findings. Arch Ophthalmol 2000;118:563–569.
12. Hiscott P, Mudhar H. Is vasoproliferative tumour (reactive retinal glioangiosis)
part of the spectrum of proliferative vitreoretinopathy? Eye (Lond)
2009;23:1851–1858.
13. 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 2012;155(3):593–608.
14. Shields JA, Shields CL. Reactive retinal astrocytic tumors (so-called
vasoproliferative tumors): histopathologic, immunohistochemical, and genetic
studies of four cases. Am J Ophthalmol 2013;156:202–203.

Management
15. Blasi MA, Scupola A, Tiberti AC, et al. Photodynamic therapy for
vasoproliferative retinal tumors. Retina 2006;26(4):404–409.
16. Chan RP, Lai TY. Photodynamic therapy with verteporfin for vasoproliferative
tumour of the retina. Acta Ophthalmol 2010;88(6):711–712.
17. Barbezetto IA, Smith RT. Vasoproliferative tumor of the retina treated with
PDT. Retina 2003;23(4):565–567.
18. Manjandavida FP, Shields CL, Kaliki S, et al. Cryotherapy-induced release of
epiretinal membrane associated with retinal vasoproliferative tumor: Analyis of
16 cases. Retina 2014;34:1644–1650.
19. Anastassiou G, Bornfeld N, Schueler AO, et al. Ruthenium-106 plaque
brachytherapy for symptomatic vasoproliferative tumours of the retina. Br J
Ophthalmol 2006; 90:447–450.
20. Cohen V, Shields CL, Demirci H, et al. Iodine plaque brachytherapy for
vasoproliferative tumor of the retina in 30 eyes. Arch Ophthalmol
2008;126(9):1245–1251.
21. Kitei PM, Say EA, Shields CL, et al. Management of Retinal Vasoproliferative
Tumor Associated with ROP by Plaque Brachytherapy. J Pediatr Ophthalmol
Strabismus 2011; 48, Online: e10–e12.

1117
22. Nickerson SJ, Al-Dahmash SA, Shields CL, et al. Retinal vasoproliferative tumor
with total retinal detachment managed with plaque radiotherapy. Oman J
Ophthalmol 2012;5:53–54.
23. Yeh S, Wilson DJ. Pars plana vitrectomy and endoresection of a retina
vasoproliferative tumor. Arch Ophthalmol 2010;128(9):1196–1199.

Case Reports
24. Medlock R, Shields JA, Shields CL, et al. Retinal hemangioma-like lesions in
eyes with retinitis pigmentosa. Retina 1991;10:274–277.
25. McCabe CM, Mieler WF. Six-year follow-up of an idiopathic retinal
vasoproliferative tumor. Arch Ophthalmol 1996;114:617.
26. Lafaut BA, Meire FM, Leys AM, et al. Vasoproliferative retinal tumors
associated with peripheral chorioretinal scars in presumed congenital
toxoplasmosis. Graefes Arch Clin Exp Ophthalmol 1999;237:1033–1038.
27. Rundle P, Shields JA, Shields CL, et al. Vasoproliferative tumour of the ocular
fundus associated with Waardenburg’s syndrome. Eye 2000;14:105–106.
28. Pollack AL, McDonald HR, Johnson RN, et al. Peripheral retinoschisis and
exudative retinal detachment in pars planitis. Retina 2002;22:719–724.
29. Jain K, Berger AR, Yucil YH, et al. Vasoproliferative tumours of the retina. Eye
2003;17:364–368.
30. Tranos P, Clare G, Sullivan P. Vasoproliferative tumor of the retina after
spontaneous reattachment of rhegmatogenous retinal detachment. Retina
2006;26:475–476.
31. Au AK, Shields CL, Kalina R, et al. Bilateral vasoproliferative retinal tumors in a
patient with autosomal dominant aniridia. Retin Cases Brief Rep 2007;1:249–
250.
32. Mori K, Ohta K, Murata T. Vasoproliferative tumors of the retina secondary to
ocular toxocariasis. Can J Ophthalmol 2007;42:758–759.
33. Chow CC, Blair MP, Shapiro MJ. Acquired vasoproliferative retinal tumor: a
late sequel of retinopathy of prematurity. Arch Ophthalmol 2011;129:1234–
1235.
34. 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.
35. Murthy R, Honavar SG. Secondary vasoproliferative retinal tumor associated
with U sher syndrome type 1. J AAPOS 2009;13:97–98.
36. Hood CT, Janku L, Lowder CY, et al. Retinal vasoproliferative tumor in
association with neurofibromatosis type 1. J Ped Ophthalmol Strabismus
2010;20:1–3.

1118
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS. PRIMARY
TYPE: CLINICAL FEATURES

The primary type of VPTOF usually is located in the inferior aspect of the fundus between the
equator and the ora serrata.

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.

Figure 20.127. Characteristic vasoproliferative tumor of the ocular fundus inferiorly in a 65-year-old man,
showing a pink-yellow lesion with adjacent intraretinal hemorrhage and exudation.

Figure 20.128. Characteristic vasoproliferative tumor of the ocular fundus inferiorly with adjacent circinate
exudation in a 40-year-old man.

1119
Figure 20.129. Vasoproliferative tumor of the ocular fundus inferiorly with adjacent intraretinal hemorrhage in a
30-year-old woman.

Figure 20.130. Posterior pole of the same eye shown in Figure 20.129, demonstrating the preretinal macular
gliosis that frequently occurs with vasoproliferative tumor of the ocular fundus.

Figure 20.131. Response of vasoproliferative tumor of the ocular fundus to cryotherapy. Pretreatment
appearance of a relatively large VPTOF inferiorly in a 46-year-old man.

1120
Figure 20.132. Appearance of the same lesion shown in Figure 20.131, demonstrating marked regression of
the mass after double freeze–thaw cryotherapy.

1121
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS. PRIMARY
TYPE: WIDE-ANGLE IMAGING

Primary VPTOF can sometimes produce extensive exudation. In contrast to the remote macular
exudation seen with retinal hemangioblastoma, the exudate from this peripheral lesion tends to
form a solid wall that can often progress toward the macular region. In addition, primary
vasoproliferative tumor also incites remote foveal changes in the form of surface wrinkling
retinopathy and/or a foveal hole.

Figure 20.133. Wide-angle image of exudation from vasoproliferative tumor of the ocular fundus located
posterior to the ora serrata inferotemporally in a 22-year-old woman. The vascular mass is difficult to visualize,
but it is located immediately inferior to the localized hemorrhage at the 8 o’clock meridian.

Figure 20.134. Wide-angle image of the right eye of a 36-year-old woman. The elongated vascular mass can
barely be seen in the photograph from 6 to 9 o’clock. In this case, the exudation shows signs of spontaneous
resolution. There is a small foveal hole.

1122
Figure 20.135. Extensive exudation secondary to vasoproliferative tumor of the ocular fundus located inferiorly
in the left eye of a 56-year-old woman. The mass at 6 o’clock is difficult to see clearly because of overlying
vitreous cellular reaction.

Figure 20.136. Vasoproliferative tumor of the ocular fundus with chronic exudation located near the equator
temporally in an 82-year-old man. This differs from peripheral exudative hemorrhagic chorioretinopathy, which
develops from choroidal vascular changes and does not have such retinal blood vessels that feed and drain
the lesion.

Figure 20.137. Vasoproliferative tumor of the ocular fundus located inferotemporally in the left eye of a 48-year-
old woman. In this instance, there are concentric arcs of exudation and localized retinal detachment between
the lesion and the optic disc. Note the somewhat dilated and tortuous retinal blood vessels that feed and drain
the mass.

1123
Figure 20.138. Vasoproliferative tumor of the ocular fundus located inferiorly and temporally in the left eye of a
39-year-old woman. In this case, the lesion has undergone subretinal and preretinal fibrosis/gliosis that has
led to retinal dragging.

1124
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS. PRIMARY
TYPE: CLINICOPATHOLOGIC CORRELATION

Figure 20.139. Vasoproliferative tumor of the ocular fundus near the equator inferiorly, with exudation and
proliferation of the retinal pigment epithelium.

Figure 20.140. Fluorescein angiogram in the recirculation phase, showing hyperfluorescence of the mass.

Figure 20.141. A-scan ultrasonogram, showing high internal reflectivity in the mass.

1125
Figure 20.142. B-scan ultrasonogram, showing a dome-shaped retinal mass with acoustic solidity.

Figure 20.143. Clinical appearance of the lesion about 2 years later, showing definite growth and increased
vascularity and vitreous hemorrhage, causing a poor view of the mass. Despite several applications of
cryotherapy, the blind eye became painful and was enucleated.

Figure 20.144. Histopathology, showing benign spindle cells and epithelial cells. It was uncertain whether the
lesion was truly a vascular mass. The proliferated retinal pigment epithelial cells raised the possibility of a
primary tumor of the pigment epithelium.

1126
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS:
SECONDARY TYPE

Figure 20.145. Secondary vasoproliferative tumor of the ocular fundus (VPTOF) in a 25-year-old man with
bilateral intermediate uveitis (pars planitis) with typical pars plana exudates in both eyes. The patient also had
a small VPTOF in the opposite eye.

Figure 20.146. Vasoproliferative tumor of the ocular fundus in a patient with familial pigmentary dystrophy of the
retina (retinitis pigmentosa). The patient had multiple similar lesions in both eyes.

1127
Figure 20.147. Inferior secondary vasoproliferative tumor of the ocular fundus arising from a presumed
Toxocara granuloma.

Figure 20.148. Peripheral vasoproliferative tumor of the ocular fundus in a patient who had a typical scar of
retinal toxoplasmosis in the posterior pole.

Figure 20.149. Secondary vasoproliferative tumor of the ocular fundus in a patient with Coats disease.

Figure 20.150. Right eye of a 23-year-old woman with the diffuse bilateral type of vasoproliferative tumor of the
ocular fundus (VPTOF) with vitreous cellular reaction and hemorrhage. The left eye had identical findings. The
precise etiology was undetermined, but it was classified as a secondary VPTOF possibly from idiopathic
ocular inflammation.

1128
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS:
SECONDARY TYPE ASSOCIATED WITH NEUROFIBROMATOSIS
TYPE 1

Recent observations have recognized that patients with systemic neurofibromatosis type 1 are
at risk for vasoproliferative tumors with related exudative retinopathy and visual loss.

Shields JA, Pellegrini M, Kalaki S, et al. Retinal vasoproliferative tumors in 6 patients with
neurofibromatosis type 1. JAMA Ophthalmol 2014;132:190–196.

Figure 20.151. Patient with neurofibromatosis type 1 and vasoproliferative tumor inferiorly producing massive
exudation.

Figure 20.152. Ultrasonography disclosing the echogenic mass and subretinal fluid.

1129
Figure 20.153. Patient with neurofibromatosis type 1 and vasoproliferative tumor superotemporally with a
peripheral tract of subretinal exudation.

Figure 20.154. Fluorescein angiography confirms staining of the mass.

Figure 20.155. Patient with neurofibromatosis type 1 and vasoproliferative tumor inferiorly with surrounding
exudative retinopathy.

1130
Figure 20.156. Fluorescein angiography confirms staining and leakage of the mass.

1131
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS:
TREATMENT WITH LASER PHOTOCOAGULATION, CRYOTHERAPY,
OR PLAQUE RADIOTHERAPY

Depending on the clinical circumstances, VPTOF can be managed by observation, laser

photocoagulation, cryotherapy, or plaque radiotherapy. Examples of treatment for symptomatic
lesions are shown.

Figure 20.157. Inferotemporal primary vasoproliferative tumor of the ocular fundus in a 38-year-old woman.
There are subtle peripheral myelinated retinal nerve fibers, which are probably coincidental, along the
inferotemporal vascular arcade.

Figure 20.158. The same lesion shown above, 6 months after laser photocoagulation, showing resolution of
the vascular lesion.

1132
Figure 20.159. Vasoproliferative tumor of the ocular fundus inferiorly in the left eye of a 45-year-old woman.

Figure 20.160. The lesion shown above 6 months after cryotherapy. The lesion has largely resolved and there
is less exudation.

Figure 20.161. Primary vasoproliferative tumor of the ocular fundus inferotemporally and with exudative
maculopathy with edema and reduced visual acuity.

1133
Figure 20.162. Following plaque radiotherapy the tumor showed involution and fibrosis and the maculopathy
resolved, returning 20/25 visual acuity.

1134
• VASOPROLIFERATIVE TUMOR OF THE OCULAR FUNDUS:
TREATMENT WITH PHOTODYNAMIC THERAPY OR CRYOTHERAPY

Photodynamic therapy is used for VPTOF when the tumor is postequatorial and relatively small.
Occasionally one session is sufficient. This method causes involution of the vascular mass with
subsequent resorption of the subretinal and intraretinal fluid. Cryotherapy is useful for tumors
anterior to the equator. In some cases, the cryotherapy causes release of epiretinal membrane.

Manjandavida FP, Shields CL, Kaliki S, Shields JA. Cryotherapy-induced release of epiretinal
membrane associated with retinal vasoproliferative tumor: Analyis of 16 cases. Retina
2014;34:1644–1650.

Figure 20.163. Retina vasoproliferative tumor with exudative retinopathy.

Figure 20.164. Following photodynamic therapy, complete tumor regression and resolution of retinopathy are
noted.

1135
Figure 20.165. Retina vasoproliferative tumor with premacular epiretinal membrane.

Figure 20.166. Optical coherence tomography demonstrating the epiretinal membrane.

Figure 20.167. Following cryotherapy, the tumor and exudation has resolved.

Figure 20.168. Following cryotherapy, the epiretinal membrane has released, leaving normal foveal contour.

1136
 CHAPTER 21

GLIAL TUMORS OF THE RETINA AND OPTIC

DISC

SOLITARY CIRCUMSCRIBED RETINAL ASTROCYTIC

PROLIFERATION

General Considerations
Tumors and pseudotumors that originate from retina glial cells include solitary
circumscribed retinal astrocytic proliferation, retinal astrocytic hamartoma usually
seen with tuberous sclerosis complex (TSC), and acquired retinal astrocytoma
(1–11). Reactive gliosis (focal or massive gliosis) from a variety of causes is common
in the eye and can rarely simulate a tumor, but is not discussed further in this atlas
of intraocular tumors.

Clinical Features
Solitary circumscribed retinal astrocytic proliferation generally occurs in an eye with
clear media and no prior ocular insults. This tumor appears ophthalmoscopically as
a solitary, white-yellow, superficial retinal lesion (1,10). This lesion appears as a
well-defined round mass and resides most often in the postequatorial region.
Although this lesion can simulate retinal astrocytic hamartoma, solitary
circumscribed retinal astrocytic proliferation typically occurs in older patients with
no history of TSC.

Diagnostic Approaches
The diagnosis can be suspected on the basis of lack of symptoms and previous
ocular history as well as characteristic ophthalmoscopic findings. With fluorescein
angiography, this tumor is relatively hypofluorescent. With ultrasonography, this

1137
lesion usually shows medium to high internal reflectivity and acoustic solidity with
a dome-shaped appearance. Optical coherence tomography (OCT) shows the lesion
as an abruptly elevated, optically dense mass with intense posterior shadowing.

Pathology
The histopathology of this condition has not been described. We speculate that it is
composed of glial cells in the superficial retina and the pathogenesis is unknown.

Management
Solitary circumscribed retinal astrocytic proliferation is suspected clinically based on
typical ophthalmoscopic features and management is periodic observation. Growth
has not been demonstrated in cases that we have followed. Interventional therapy
has not been required.

Selected References
Series/Review
1. Shields JA, Bianciotto CG, Kivela T, et al. Solitary circumscribed retinal
astrocytic proliferation. The 2010 Jonathan W. Wirtschafter lecture. Arch
Ophthalmol 2011;129(9):1189–1194.

Pathology
2. Rodrigues MM, Bardenstein D, Wiggert B, et al. Retinitis pigmentosa with
segmental massive retinal gliosis. An immunohistochemical, biochemical, and
ultrastructural study. Ophthalmology 1987;94:180–186.

Case Reports
3. Ryan H. Massive retinal gliosis. Trans Ophthalmol Soc Aust 1954;14:77–83.
4. Green WR. Bilateral Coats’ disease. Massive gliosis of the retina. Arch
Ophthalmol 1967;77:378–383.
5. Ganley JP, Streeten BW. Glial nodules of the inner retina. Am J Ophthalmol
1971; 71:1099–1103
6. Yanoff M, Zimmerman LE, Davis RL. Massive gliosis of the retina. Int
Ophthalmol Clin 1971;11:211–229.
7. Berger B, Peyman GA, Juarez C, et al. Massive retinal gliosis simulating
choroidal melanoma. Can J Ophthalmol 1979;14:285–290.
8. Nowinski T, Shields JA, Augsburger JJ, et al. Exophthalmos secondary to
massive intraocular gliosis in a patient with a colobomatous cyst. Am J
Ophthalmol 1984; 97:641–643.
9. Khawly JA, Matthews JD, Machemer R. Appearance and rapid growth of retinal
tumor (reactive astrocytic hyperplasia?). Graefes Arch Clin Exp Ophthalmol
1999; 237:78–81.
10. Demirci H, Shields JA, Shields CL, et al. Spontaneous disappearance of
presumed retinal astrocytic hyperplasia. Retina 2002;22:237–239.
11. Gelisken F, Inhoffen W, Rohrbach JM, et al. Massive retinal gliosis: a late
complication of retinal detachment surgery. Graefes Arch Clin Exp Ophthalmol
2004;242:255–258.

1138
• SOLITARY CIRCUMSCRIBED RETINAL ASTROCYTIC
PROLIFERATION

Pseudoneoplastic (reactive) gliosis of the retina can assume a variety of clinical and
histopathologic appearances. Focal gliosis is generally a dense yellow-white or gray lesion that
is different from most astrocytic hamartomas of TSC.

Shields JA, Bianciotto CG, Kivela T, et al. Solitary circumscribed retinal astrocytic proliferation.
The 2010 Jonathan W. Wirtschafter lecture. Arch Ophthalmol 2011;129(9):1189–1194.

Figure 21.1. Solitary circumscribed retinal astrocytic proliferation. This yellow-white superficial retinal nodule in
a healthy 51-year-old man has been stable for several years. The etiology is unknown.

Figure 21.2. Fluorescein angiogram in the late venous phase of the lesion shown in Figure 21.1, revealing
fairly intense hyperfluorescence of the lesion. The fluorescence of the lesion began in the early venous phase.

1139
Figure 21.3. Optical coherence tomography of the lesion shown in Figure 21.1. Note the shadowing of the
deep retina and choroid due to the highly reflective, superficial lesion.

Figure 21.4. Presumed reactive gliosis of the retina (solitary circumscribed retinal astrocytic proliferation)
located superior to the optic disc in the right eye of a 45-year-old woman. The optic disc has a congenital
abnormality, perhaps a mild variant of coloboma.

Figure 21.5. Mass of reactive gliosis located in peripheral fundus of an eye enucleated for chronic discomfort
many years after surgery for congenital cataract followed by numerous complications.

1140
Figure 21.6. Histopathology, showing a mass composed of well-differentiated glial cells. (Hematoxylin–eosin
×100.)

1141
RETINAL ASTROCYTIC HAMARTOMA

General Considerations
Retinal astrocytic hamartoma is a benign retinal tumor that is composed of glial
cells, predominantly astrocytes (1–36). It is believed to be congenital in most cases,
but it can become clinically apparent sometime after birth. It does not metastasize.
It is frequently associated with TSC, a syndrome that includes various combinations
of low-grade intracranial astrocytoma, cutaneous angiofibromas (“adenoma
sebaceum”), cutaneous depigmented macules, cardiac rhabdomyoma, renal
angiomyolipoma, and other hamartomas. In those cases that are part of TSC, various
genetic alterations have been identified on chromosomes 9 and 16. Some patients
have only the retinal tumor without additional findings of TSC. It is undetermined
whether they represent a separate entity or a forme fruste, or partial expression, of
TSC. An identical fundus tumor is occasionally seen in patients with
neurofibromatosis type 1.

Clinical Features
Ophthalmoscopically, retinal astrocytic hamartoma can show considerable variation
from case to case. The two most common variations are the noncalcified tumor and
the calcified tumor. The noncalcified variant appears as a gray-yellow, sessile lesion
in the inner aspect of the sensory retina. It can be transparent and fairly flat,
sometimes suggesting retinal gliosis. Slightly larger lesions have a gray-yellow color
and may cause retinal traction. The calcified variant may have minimal calcification
or may be totally calcified. The characteristic feature is glistening yellow spherules
of calcification. This glistening calcification differs from the duller, chalky
calcification that characterizes retinoblastoma. Many lesions show both calcified and
noncalcified components. Occasionally depigmented spots at the level of the RPE
are noted in patients with TSC and astrocytic hamartoma (4).
In contrast to retinoblastoma, astrocytic hamartoma does not usually develop
prominent retinal feeding and draining blood vessels (7). It often is associated with
mild to moderate retinal traction, a finding not usually seen with a comparable-
sized untreated retinoblastoma. Occasionally, the tumor appears as a deep retinal
lesion that is usually noncalcified and can resemble subretinal fibrosis.
Although astrocytic hamartoma is usually a relatively stable lesion, it can show
progressive growth and exhibit locally malignant behavior. We have seen cases that
showed progressive growth, exudative retinal detachment, and neovascular
glaucoma, ultimately requiring enucleation (5). Extraocular extension into the
orbital and epibulbar tissues has been recognized in these cases.

Diagnostic Approaches
Retinal astrocytic hamartoma, particularly the calcified variant, usually shows
autofluorescence (18). Fluorescein angiography of the typical lesion shows a
characteristic network of small blood vessels in the venous phase with fairly intense
late staining. In the case of a calcified lesion, ultrasonography shows a calcified
plaque as might be seen with choroidal osteoma or calcified retinoblastoma. OCT

1142
can be used to document the superficial location of the lesion and its highly
reflective features (9–17). Cytopathologic study of fine-needle aspiration biopsy
(FNAB) can be employed to make the diagnosis in atypical cases (7).

Pathology
Histopathologically, astrocytic hamartoma is usually composed of elongated fibrous
astrocytes that have small uniform nuclei and interlacing cytoplasmic processes.
Areas of calcification may be present, often in the form of calcospheres. Some larger
tumors may contain moderately pleomorphic gemistocytic astrocytes. The less
common, locally invasive variant is generally located on the optic disc and has large,
poorly differentiated cells similar to the subependymal astrocytomas that are seen in
the brain in some patients with TSC (5).
Management
The majority of astrocytic hamartomas are small, extrafoveal, stationary lesions,
with little or no tendency to grow or cause complications. However, they should be
followed periodically because some can show progressive growth, exudative retinal
detachment, and neovascular glaucoma. When a lesion is growing and is suspected
to have potential for such proliferation, then treatment is warranted. Depending on
the circumstances, laser photocoagulation, cryotherapy, or vitrectomy and retinal
detachment surgery may be necessary. Most cases of the giant cell variant have come
to enucleation because of neovascular glaucoma. However, we believe that if such a
tumor is detected early, treatment with irradiation or other methods might possibly
achieve tumor control and avoid enucleation.

Selected References
Series/Review
1. Shields JA, Shields CL. Glial tumors of the retina. The 2009 King Khaled
Memorial Lecture. Saudi J Ophthalmol 2009;23(3-4):197–201.
2. Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis.
Arch Ophthalmol 1976;94:1277–1280.
3. Zimmer-Galler IE, Robertson DM. Long-term observation of retinal lesions in
tuberous sclerosis. Am J Ophthalmol 1995;119:318–324.
4. Shields CL, Reichstein DA, Bianciotto CG, et al. Retinal pigment epithelial
depigmented lesions associated with tuberous sclerosis complex. Arch
Ophthalmol 2012;130:387–390.
5. Shields JA, Eagle RC Jr, Shields C, et al. Aggressive retinal astrocytomas in 4
patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc
2004;102:139–147.
6. Destro M, D’Amico DJ, Gragoudas ES, et al. Retinal manifestations of
neurofibromatosis. Diagnosis and management. Arch Ophthalmol 1991;109:662–
666.
7. Shields CL, Schoenberg E, Kocher K, et al. Lesions simulating retinoblastoma
(pseudoretinoblastoma) in 604 cases: results based on age at presentation.
Ophthalmology 2013;120(2):311–316.
8. Shields JA, Bianciotto CG, Kivela T, et al. Solitary circumscribed retinal
astrocytic proliferation. The 2010 Jonathan W. Wirtschafter lecture. Arch
Ophthalmol 2011;129(9):1189–1194.

1143
Imaging
9. Shields CL, Mashayekhi A, Luo CK, et al. Optical coherence tomography in
children: analysis of 44 eyes with intraocular tumors and simulating conditions.
J Pediatr Ophthalmol Strabismus 2004;41:338–344.
10. Mennel S, Meyer CH, Eggarter F, et al. Autofluorescence and angiographic
findings of retinal astrocytic hamartomas in tuberous sclerosis. Ophthalmologica
2005;219:350–356.
11. Shields CL, Materin MA, Shields JA. Review of optical coherence tomography
for intraocular tumors. Curr Opin Ophthalmol 2005;16(3):141–154.
12. Shields CL, Benevides R, Materin MA, et al. Optical coherence tomography of
retinal astrocytic hamartoma in 15 cases. Ophthalmology 2006;113(9):1553–
1557.
13. Chanana B, Kumar V. Imaging findings in tuberous sclerosis with multiple
retinal astrocytic hamartomas. J Pediatr Ophthalmol Strabismus 2011;48(2):127–
128.
14. Xu L, Burke TR, Greenberg JP, et al. Infrared imaging and optical coherence
tomography reveal early-stage astrocytic hamartomas not detectable by
fundoscopy. Am J Ophthalmol 2012;153(5):883–889.
15. Goel N, Pangtey B, Bhushan G, et al. Spectral-domain optical coherence
tomography of astrocytic hamartomas in tuberous sclerosis. Int Ophthalmol
2012;32(5):491–493.
16. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014;34:1495–512.
17. Pichi F, Serafino M, Giuliari GP, et al. Retinal astrocytic hamartoma: Spectral
domain optical coherence tomography classification and correlation with
tuberous sclerosis complex. J AAPOS 2013;17(1):e27.
18. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumors. Curr
Opin Ophthalmol 2013;24(3):222–232.
Pathology
19. Shields JA, Shields CL, Ehya H, et al. Atypical retinal astrocytic hamartoma
diagnosed by fine-needle biopsy. Ophthalmology 1996;103:949–952.
Case Reports
20. Trincao R, Cunha-Vaz JG, Pires JM. Astrocytic hamartoma of the optic disc in
localized ocular neurofibromatosis (von Recklinghausen’s disease).
Ophthalmologica 1973;167:465–469.
21. Reeser FH, Aaberg TM, Van Horn DL. Astrocytic hamartoma of the retina not
associated with tuberous sclerosis. Am J Ophthalmol 1978;86:688–698.
22. Kroll AJ, Ricker DP, Robb RM, et al. Vitreous hemorrhage complicating retinal
astrocytic hamartoma. Surv Ophthalmol 1981;26:31–38.
23. Coppeto JR, Lubin JR, Albert DM. Astrocytic hamartoma in tuberous sclerosis
mimicking necrotizing retinochoroiditis. J Pediatr Ophthalmol Strabismus
1982;19:306–313.
24. Bec P, Mathis A, Adam P, et al. Retinitis pigmentosa associated with astrocytic
hamartomas of the optic disc. Ophthalmologica 1984;189:135–138.
25. U lbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina.

1144
 Differentiation of sporadic tumors from phakomatosis-associated tumors. Arch
Pathol Lab Med 1984;108:160–163.
26. Drewe RH, Hiscott P, Lee WR. Solitary astrocytic hamartoma simulating
retinoblastoma. Ophthalmologica 1985;190:158–167.
27. Jost BF, Olk RJ. Atypical retinitis proliferans, retinal telangiectasis, and vitreous
hemorrhage in a patient with tuberous sclerosis. Retina 1986;6:53–56.
28. Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in
tuberous sclerosis. Retina 1993;13:155–159.
29. Ettl A, Philipp W, Mayer U . Retinal phakomata associated with cerebral
astrocytoma. An incomplete form of Bourneville-Pringle disease?
Ophthalmologica 1993;206:209–213.
30. Mullaney PB, Jacquemin C, Abboud E, et al. Tuberous sclerosis in infancy. J
Pediatr Ophthalmol Strabismus 1997;34:372–375.
31. 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;
Erratum. Ophthalmology 2000;107:413.
32. 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.
33. Kiratli H, Turkcuoglu P, Bilgic S. Gyrate atrophy associated with astrocytic
hamartoma of the optic disc. Retina 2004;24:976–977.
34. Inoue M, Hirakarta A, Iizuka N, et al. Tractional macular detachment associated
with optic disc astrocytic hamartoma. Acta Ophthalmol 2009;87(2):239–240.
35. Veronese C, Pichi F, Guidelli SG et al. Cystoid changes within astrocytic
hamartomas of the retina in tuberous sclerosis. Retinal Cases & Brief Reports
2011;5:113–116.
36. Lonngi M, Gold AS, Murray TG. Combined bevacizumab and triamcinolone
acetonide injections for macular edema in a patient with astrocytic hamartomas
and tuberous sclerosis. Ophthalmic Surg Lasers Imaging Retina 2013;44(1):85–90.

1145
• RETINAL ASTROCYTIC HAMARTOMA, NONCALCIFIED TYPE:
CLINICAL AND PATHOLOGIC FEATURES

Retinal astrocytic hamartoma is often noncalcified. In cases that lack the typical calcification,
the appearance can suggest other diagnoses such as early retinoblastoma, myelinated nerve
fibers, granuloma, or other conditions. However, there are features that serve to differentiate
these conditions. Close examination for extraocular signs of TSC can also facilitate the
diagnosis.

Figure 21.7. Typical noncalcified astrocytic hamartoma adjacent to the optic disc in a 43-year-old woman with
tuberous sclerosis complex. The lesion had been present since early childhood.

Figure 21.8. Sessile, transparent astrocytic hamartoma inferior to the optic disc in a 12-year-old girl with no
tuberous sclerosis complex.

1146
Figure 21.9. Subtle sessile, noncalcified astrocytic hamartoma in the superonasal juxtapapillary regions in the
left eye of a 12-year-old girl.

Figure 21.10. Three epipapillary noncalcified astrocytic hamartomas in the blonde fundus of the left eye of a
child with tuberous sclerosis.

Figure 21.11. Atypical presumed astrocytic hamartoma inferonasal to the optic disc. The lesion was producing
vitreous seeding. The diagnosis was confirmed by fine-needle aspiration biopsy. The inset shows spindle-
shaped cells. (Papanicolaou ×400.) Immunohistochemistry showed positive reaction to glial fibrillary acidic
protein, supporting the diagnosis of astrocytic tumor.

1147
Figure 21.12. Histopathology of a noncalcified astrocytic hamartoma showing a mass of closely packed
fibrous astrocytes arising in the nerve fiber layer of the retina. (Hematoxylin–eosin ×20.) (Courtesy of the Armed
Forces Institute of Pathology, Washington, DC.)

1148
• RETINAL ASTROCYTIC HAMARTOMA: CALCIFIED TYPE
The calcified variant of retinal astrocytic hamartoma can be partially calcified or, less often,
totally calcified. Some, but not all, affected patients have nonocular signs of TSC.

Figure 21.13. Totally calcified astrocytic hamartoma superior to the optic disc in the right eye. This lesion is very
typical of the astrocytic hamartoma of tuberous sclerosis complex, but this patient had no clinical
manifestations of TSC.

Figure 21.14. Small calcified astrocytic hamartoma nasal to the optic disc in the left eye. Note the subtle,
noncalcified component surrounding the central nodule.

Figure 21.15. Partly calcified, highly typical, astrocytic hamartoma inferior to the fovea in the left eye in an adult

1149
woman with no other signs of tuberous sclerosis complex. Note again the more apparent noncalcified
component surrounding the central nodule.

Figure 21.16. Almost totally calcified astrocytic hamartoma on the superonasal margin of the optic disc. Note
the straightening of the surrounding retinal vessels due to retinal traction induced by the lesion. (Courtesy of
Peter Reed Pavan, MD.)

Figure 21.17. Venous phase fluorescein angiogram of the lesion shown in Figure 21.16, demonstrating the
fine vascularity that is typical of astrocytic tumors in the vascular filling phases of angiography. (Courtesy of
Peter Reed Pavan, MD.)

Figure 21.18. Late recirculation phase of the lesion shown in Figure 21.16, showing moderate
hyperfluorescence of the lesion. (Courtesy of Peter Reed Pavan, MD.)

1150
• RETINAL ASTROCYTIC HAMARTOMA: CALCIFIED TYPE, CLINICAL
AND PATHOLOGIC FEATURES

Retinal astrocytic hamartoma can be calcified from birth, or it can become gradually calcified
after birth. It can superficially simulate calcified retinoblastoma, but it has a glistening yellow
calcification as compared to the dull, chalky-white calcification seen with retinoblastoma.

Figure 21.19. Small calcified astrocytic hamartoma superonasal to the optic disc.

Figure 21.20. Small calcified astrocytic hamartoma inferotemporal to the fovea in the right eye.

1151
Figure 21.21. Typical calcified astrocytic hamartoma nasal to the optic disc. Note the sessile, noncalcified
component of the tumor superior to the more evident calcified lesion.

Figure 21.22. More elevated astrocytic hamartoma adjacent to the optic disc.

Figure 21.23. Atypical diffuse multifocal retinal astrocytic hamartoma with foci of calcification.

Figure 21.24. Pathology of a calcified astrocytic hamartoma that occurred on the optic disc. Note the astrocytic
tumor (to the left), dense calcification (to the right), and the basophilic whorls (psammoma bodies).
(Hematoxylin–eosin ×20.) (Courtesy of the Armed Forces Institute of Pathology, Washington, DC.)

1152
• RETINAL ASTROCYTIC HAMARTOMA: STANDARD AND WIDE-
ANGLE IMAGING

Figure 21.25. Calcified retinal astrocytic hamartoma superior to the fovea in the right eye of a 25-year-old
woman. The patient had no clinical evidence of tuberous sclerosis complex.

Figure 21.26. Closer view of the lesion in Figure 21.25, showing the typical calcified nodules.

Figure 21.27. Calcified retinal astrocytic hamartoma inferior to the fovea in the left eye of a 40-year-old woman.

1153
The patient had no clinical evidence of tuberous sclerosis complex.

Figure 21.28. Closer view of the lesion shown in Figure 21.27.

Figure 21.29. Minimally calcified astrocytic hamartoma superotemporal to the fovea of the right eye in a 21-
year-old man. He has been followed for 16 years, and the lesion has remained stable. He has a similar lesion
in the right eye, which has also remained stable.

Figure 21.30. Closer view of the lesion shown in Figure 21.29. Even though the patient had lesions in both
eyes, he had no other clinical evidence of tuberous sclerosis complex, but genetic studies could not be done.

1154
• RETINAL ASTROCYTIC HAMARTOMA: FLUORESCEIN
ANGIOGRAPHY

Fluorescein angiography shows rather typical features with astrocytic hamartoma. In the
vascular filling phases, the tumor shows a network of fine blood vessels, and in the late
angiograms, there is fairly intense late staining of the mass.

Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in tuberous sclerosis.
Retina 1993;13:155–159.

Figure 21.31. Calcified astrocytic hamartoma in a young patient with no tuberous sclerosis complex.

Figure 21.32. Fluorescein angiogram of the lesion shown in Figure 21.31 in the early venous phase,
demonstrating mild hyperfluorescence of the lesion. Note that the blood vessels seem to bypass the lesion
and do not dip into the lesion as seen with retinoblastoma.

1155
Figure 21.33. Late angiogram, showing relatively intense hyperfluorescence of the lesion with slight leakage of
dye into the vitreous.

Figure 21.34. Multifocal noncalcified astrocytic hamartoma in a young boy with tuberous sclerosis complex.

Figure 21.35. Fluorescein angiography depicts hyperfluorescence of the three epipapillary tumors.

1156
Figure 21.36. Additional tumors that are not clinically apparent are discovered inferiorly in the same eye.

1157
• RETINAL ASTROCYTIC HAMARTOMA: OPTICAL COHERENCE
TOMOGRAPHY

OCT can be used to document the retinal location and highly reflective features of retinal
astrocytic hamartoma. This lesion classically arises in the nerve fiber layer and expands this
layer to form a tumor. Calcification causes a “moth-eaten” appearance on OCT, but even
without calcification, the lesion can appear “moth-eaten” from cavitation.

Figure 21.37. Calcified astrocytic hamartoma superior to the foveola in the right eye.

Figure 21.38. Optical coherence tomography showing the “moth-eaten” appearance with shadowing
corresponding to foci of calcification.

Figure 21.39. Noncalcified astrocytic hamartoma superotemporal to the right optic disc.

1158
Figure 21.40. Optical coherence tomography demonstrating lesion in the nerve fiber layer and with early
cavitation.

Figure 21.41. Noncalcified astrocytic hamartoma superotemporal to the right optic disc.

Figure 21.42. Optical coherence tomography demonstrating a “moth-eaten” appearance without shadowing
that probably represent cavitation.

1159
• TUBEROUS SCLEROSIS COMPLEX: EXTRAOCULAR FEATURES
TSC (Bourneville disease) is the syndrome most often associated with retinal astrocytic
hamartoma. It has a variety of ocular, cutaneous, neurologic, and systemic manifestations,
including various combinations of low-grade intracranial paraventricular astrocytoma,
cutaneous angiofibromas (“adenoma sebaceum”), depigmented cutaneous macules, “ash leaf
sign” cardiac rhabdomyoma, renal angiomyolipoma, and other hamartomas. Some examples are
shown.

Figure 21.43. Subtle facial angiofibromas (“adenoma sebaceum”) in the ocular region of a 12-year-old boy.

Figure 21.44. Histopathology of cutaneous angiofibroma, showing spindle-shaped cells and collagen in
dermis with mild sebaceous gland hyperplasia. (This accounts for the misnomer “adenoma sebaceum.”)
(Hematoxylin–eosin ×10.)

1160
Figure 21.45. Cutaneous nonpigmented macule (“ash leaf sign”) on the leg of the patient shown in Figure
21.43.

Figure 21.46. Fundus of the patient shown in Figure 21.43. Note the two subtle astrocytic hamartomas. One is
superonasal to the optic disc, and the other is superotemporal to the foveola.

Figure 21.47. Periungual angiofibromas of the fingernail, a characteristic feature of tuberous sclerosis
complex.

Figure 21.48. Coronal magnetic resonance imaging of the patient shown in Figure 21.43, depicting an
intracranial paraventricular astrocytoma.

1161
• RETINAL ASTROCYTIC HAMARTOMA: ATYPICAL VARIATIONS
Most astrocytic hamartomas are located in the nerve fiber layer, but some can extend full
thickness retinal and involve deeper layers. Some are obvious whereas others are nearly
imperceptible, best detected by OCT. Exudation is occasionally found.

Figure 21.49. Atypical multifocal peripheral retinal astrocytic hamartomas in a young man.

Figure 21.50. Optical coherence tomography demonstrating the noncalcified lesion on the inner surface of the
retina.

Figure 21.51. Barely visible flat diffuse retinal astrocytic hamartoma along the superotemporal vessels,
preceding the first venous bifurcation. The lesion imparts a “ground glass” appearance to the retina. This child
has established tuberous sclerosis complex.

1162
Figure 21.52. Optical coherence tomography (horizontal orientation) through the flat lesion demonstrating the
minimal thickening of the nerve fiber layer.

Figure 21.53. Atypical circumpapillary astrocytic hamartoma in a child with tiny retinal hemorrhages and mild
macular exudation. This lesion has remained stable over several years.

Figure 21.54. Ultrasonography demonstrating calcification deep within the mass.

1163
• RETINAL ASTROCYTIC HAMARTOMA: AGGRESSIVE TUMOR IN
PATIENTS WITH TUBEROUS SCLEROSIS COMPLEX

In some instances, retinal astrocytic hamartoma can show pronounced growth and produce a
total retinal detachment and neovascular glaucoma, often requiring enucleation. Our group has
reported four such cases.

Shields JA, Eagle RC Jr, Shields C, et al. Aggressive retinal astrocytomas in 4 patients with
tuberous sclerosis complex. Arch Ophthalmol 2005;123:856–863.

Figure 21.55. Fundus photograph of a young child, showing a bilobed nodular mass arising from the retina
and overlying the optic nerve. The eye later developed neovascular glaucoma and pain and required
enucleation.

Figure 21.56. Gross appearance of the sectioned globe of the eye shown in Figure 21.55, disclosing exophytic
retinal mass and total retinal detachment.

1164
Figure 21.57. Gross appearance of the sectioned globe from another young child with a similar history,
showing exophytic retinal mass and total retinal detachment.

Figure 21.58. Plump spindle cells with intensely eosinophilic cytoplasm and ovoid nuclei. (Hematoxylin–eosin
×100.)

Figure 21.59. In another area of the tumor, there are larger round or ovoid cells that have abundant pale
eosinophilic cytoplasm with peripheral vacuolization, and round nuclei with nucleoli. They resemble cells that
comprise subependymal giant cell astrocytoma of the brain in patients with tuberous sclerosis complex.
(Hematoxylin–eosin ×100.)

1165
Figure 21.60. Calcospherites. Typical multilaminated, basophilic calcium deposits seen in all four tumors.
(Hematoxylin–eosin ×100.)

1166
• RETINAL ASTROCYTIC HAMARTOMA: EXTRAOCULAR EXTENSION
IN A PATIENT WITH TUBEROUS SCLEROSIS COMPLEX

Although astrocytic hamartoma associated with TSC is usually a benign, relatively stationary
lesion, it can rarely show progressive growth and evolve into a low-grade malignancy. A
clinicopathologic correlation of such a case is depicted.

Gunduz K, Eagle RC Jr, Shields JA, et al. Invasive giant cell astrocytoma of the retina in a
patient with tuberous sclerosis. Ophthalmology 1999;106:639–642.

Figure 21.61. White mass in the right eye in a female infant. On the basis of findings in this eye,
retinoblastoma was initially suspected.

Figure 21.62. More typical sessile, noncalcified, astrocytic hamartomas, and retinal pigment epithelial
alterations in the left eye of the same patient.

1167
Figure 21.63. Coronal computed tomogram of the head, showing two paraventricular calcified astrocytomas
typical of tuberous sclerosis complex (TSC). Based on the ocular and cranial findings, a diagnosis of TSC was
made. No treatment was given to either eye, and the parents were noncompliant with further appointments.

Figure 21.64. Appearance of the right eye at age 10 years. The mass shown in Figure 21.61 had progressed to
fill the entire globe and extend extrasclerally.

Figure 21.65. Section of the enucleated eye, showing a mass filling the vitreous cavity and extending through
the cornea and sclera anteriorly.

1168
Figure 21.66. Histopathology, showing large astrocytes with atypical nuclei and abundant cytoplasm.
(Hematoxylin–eosin ×200.)

1169
• RETINAL ASTROCYTIC HAMARTOMA: ATYPICAL TUMOR
DIAGNOSED BY FINE-NEEDLE ASPIRATION BIOPSY

FNAB is not generally recommended in the diagnosis of astrocytic hamartoma. However, in

atypical cases, it may prove to be a valuable diagnostic method. A case is cited.

Shields JA, Shields CL, Ehya H, et al. Atypical retinal astrocytic hamartoma diagnosed by fine
needle biopsy. Ophthalmology 1996;103:949–952.

Figure 21.67. Drawing showing a yellow macular tumor in a male infant with a secondary bullous retinal
detachment (shown in blue) and peripheral alterations in the retinal pigment epithelium.

Figure 21.68. Fundus photograph of a light red-yellow lesion in the macular area.

1170
Figure 21.69. Late fluorescein angiogram, showing hyperfluorescence of the mass.

Figure 21.70. B-scan ultrasonogram, showing a retinal mass in the posterior pole with acoustic solidity and a
secondary retinal detachment. The parents insisted on a biopsy to exclude retinoblastoma.

Figure 21.71. Cytopathology of fine-needle aspiration biopsy specimen showing characteristic spindle cells.
(Papanicolaou ×150.)

1171
Figure 21.72. Immunohistochemical stain for glial-fibrillary acidic protein, showing positive cytoplasmic
staining for glial cells. (×150.)

1172
 ACQUIRED RETINAL ASTROCYTOMA

General Considerations
Retinal astrocytic hamartoma accounts for the great majority of true glial tumors of
the sensory retina, and in most instances, it is associated with other signs of TSC.
The typical case that is unassociated with clinically evident TSC may represent a
forme fruste of TSC in which only the ocular features are manifest. Occasionally,
however, the retina can spawn an acquired astrocytoma in somewhat older
individuals who have no clinical manifestations of TSC (1–13). We choose to call
this lesion an acquired retinal astrocytoma, as opposed to the congenital astrocytic
hamartoma of TSC. Most such tumors appear to be different from a clinical
standpoint, but their histopathology is quite similar. They may represent the retinal
equivalent of a low-grade central nervous system astrocytoma.

Clinical Features
Acquired retinal astrocytoma appears as a solitary mass that arises in the sensory
retina. It typically is yellow and has abundant intrinsic vascularity that is best
visualized with fluorescein angiography. U nlike the typical congenital astrocytic
hamartoma, it generally lacks clinically evident calcification, is more likely to
exhibit slowly progressive growth, and is unassociated with TSC. Intraretinal
exudation and secondary retinal detachment usually occur as the tumor enlarges.
Astrocytoma has been observed in an eye with congenital hypertrophy of the retinal
pigment epithelium, although this seems to be coincidental (11).

Diagnostic Approaches
Fluorescein angiography characteristically shows small, well-defined fine blood
vessels in the tumor in the vascular filling phases and rather intense, diffuse late
staining. Retinal feeder vessels can be apparent, but they are not dilated and
tortuous like those seen with retinoblastoma and retinal hemangioblastoma.
U ltrasonography discloses a noncalcified retinal mass with high internal reflectivity.

Pathology
Histopathologically, acquired retinal astrocytoma is composed of mature glial cells,
similar to the case of astrocytic hamartoma. However, the acquired tumors do not
tend to have the extensive calcification that characterizes many astrocytic
hamartomas. Some tumors have large, round cells with glassy eosinophilic
cytoplasm (gemistocytes) similar to an equivalent tumor in the brain. Pleomorphic
xanthoastrocytoma, also similar to the brain counterpart, has also been reported in
the retina (10).

Management
In most reported cases, the affected eye has been enucleated because of growth and
secondary glaucoma and/or because of suspicion that the lesion is a choroidal
melanoma. If astrocytoma is diagnosed at an early point, then photodynamic

1173
therapy, cryotherapy, or radiotherapy can control the tumor and minimize
complications (4–6).

Selected References
Series Reviews
1. Shields JA, Shields CL. Glial tumors of the retina. The 2009 King Khaled
Memorial Lecture. Saudi J Ophthalmol 2009;23(3-4):197–201.
2. Shields CL, Shields JA, Eagle RC Jr, et al. Progressive enlargement of acquired
retinal astrocytoma in two cases. Ophthalmology 2004;111:363–368.
3. Cohen VM, Shields CL, Furuta M, et al. Vitreous seeding from retinal
astrocytoma in three cases. Retina 2008;28(6):884–888.
Management
4. Eskelin S, Tommila P, Palosaari T, et al. Photodynamic therapy with
verteporfin to induce regression of aggressive retinal astrocytomas. Acta
Ophthalmol 2008;86(7):794–799.
5. Shields CL, Materin MA. Marr BP, et al. Resolution of exudative retinal
detachment from retinal astrocytoma following photodynamic therapy. Arch
Ophthalmol 2008;126(2):273–274.
6. Vilaplana D, Castilla M, Poposki V, et al. Acquired retinal astrocytoma
managed with endoresection. Retina 2006;26(9):1081–1082.
Case Reports
7. Reeser FH, Aaberg TM, Van Horn DL. Astrocytic hamartoma of the retina not
associated with tuberous sclerosis. Am J Ophthalmol 1978;86:688–698.
8. Ramsay RC, Kinyoun JL, Hill CW, et al. Retinal astrocytoma. Am J Ophthalmol
1979;88:32–33.
9. 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.
10. Zarate JO, Sampaolesi R. Pleomorphic xanthoastrocytoma of the retina. Am J
Surg Pathol 1999;23:79–81.
11. Paoli D. Retinal astrocytoma associated with hypertrophy of the retinal pigment
epithelium: clinical report and follow-up. Ophthalmologica 1998;212(Suppl
1):71–73.
12. Redinova M, Barakova D, Sach J, et al. Intraocular astrocytoma without
phacomatosis. Eur J Ophthalmol 2004;14:350–354.
13. House R, Mashayekhi A, Shields JA, Shields CL. Total regression of acquired
retinal astrocytoma using photodynamic therapy. Retinal Cases & Brief Reports
2015; in press.

1174
• ACQUIRED RETINAL ASTROCYTOMA
The lesions depicted here occurred in patients without evidence of TSC and are presumably
examples of acquired retinal astrocytoma. Fluorescein angiographic features are rather typical
and differ from those for retinoblastoma, choroidal melanoma, and other fundus tumors.

Figure 21.73. Characteristic white acquired retinal astrocytoma superior to the optic disc.

Figure 21.74. Early fluorescein angiogram of the lesion shown in Figure 21.73, demonstrating the typical fine
vascularity of the lesion.

1175
Figure 21.75. Fluorescein angiogram in the recirculation phase of the lesion shown in Figure 21.73, showing
more intense hyperfluorescence of the lesion.

Figure 21.76. Solitary presumed retinal astrocytoma in a 34-year-old man.

Figure 21.77. Fluorescein angiogram in the venous phase of the lesion shown in Figure 21.76, revealing early
hyperfluorescence of the lesion with leakage of dye from some of the tumor blood vessels.

1176
Figure 21.78. Late fluorescein angiogram of the lesion shown in Figure 21.76, showing intense late staining
and slight leakage of fluorescein into the overlying vitreous.

1177
• ACQUIRED RETINAL ASTROCYTOMA: CLINICOPATHOLOGIC
CORRELATION

Figure 21.79. Wide-angle photograph, showing an amelanotic mass adjacent to the optic disc associated with
a total retinal detachment in a 35-year-old woman.

Figure 21.80. Closer view of the lesion shown in Figure 21.79, depicting the yellow tumor with associated
retinal blood vessels.

1178
Figure 21.81. A-scan ultrasonogram, showing medium to low internal reflectivity in the mass, similar to that
seen with most uveal melanomas.

Figure 21.82. B-scan ultrasonogram, showing the very typical pedunculated mass with acoustic solidity of the
lesion.

Figure 21.83. Low-magnification photomicrograph of the lesion after enucleation, showing the eosinophilic
mass arising from the sensory retina adjacent to the optic nerve.

Figure 21.84. Photomicrograph of the lesion, showing well-differentiated astrocytes. (Hematoxylin–eosin ×50.)

1179
• ACQUIRED RETINAL ASTROCYTOMA: CLINICOPATHOLOGIC
CORRELATIONS

The lesions depicted here occurred in patients without evidence of TSC and are presumably
examples of acquired retinal astrocytoma. Histopathology revealed a benign glial tumor. These
patients were not seen by the authors.

1. Ramsay RC, Kinyoun JL, Hill CW, et al. Retinal astrocytoma. Am J Ophthalmol 1979;88:32–
33.
2. Reeser FH, Aaberg TM, Van Horn DL. Astrocytic hamartoma of the retina not associated with
tuberous sclerosis. Am J Ophthalmol 1978;86:688–698.

Figure 21.85. Fundus photograph of a pedunculated retinal lesion inferior to the optic disc. Note the yellow
exudation in and around the tumor. (Courtesy of Robert Ramsay, MD.)

Figure 21.86. Low-magnification photomicrograph of the lesion shown in Figure 21.85 after enucleation
performed elsewhere. Note the eosinophilic lesion arising from the sensory retina. (Courtesy of Robert
Ramsay, MD.)

1180
Figure 21.87. Yellow-white fundus lesion arising temporal to the optic disc. (Courtesy of Thomas Aaberg, Sr,
MD, and Frederick Reeser, MD.)

Figure 21.88. Appearance of the lesion shown in Figure 21.87, 2 years later, demonstrating tumor growth.
(Courtesy of Thomas Aaberg, Sr, MD, and Frederick Reeser, MD.)

Figure 21.89. Gross photograph of the enucleated eye seen in Figure 21.88, showing a white mass in the
posterior pole. (Courtesy of Thomas Aaberg, Sr, MD, and Frederick Reeser, MD.)

1181
Figure 21.90. Photomicrograph of the lesion shown in Figure 21.89, revealing the closely compact glial cells.
(Courtesy of Thomas Aaberg, Sr, MD, and Frederick Reeser, MD.)

1182
• ACQUIRED RETINAL ASTROCYTOMA: PIGMENTED VARIANTS
DIAGNOSED BY FINE-NEEDLE ASPIRATION BIOPSY

On rare occasions, acquired retinal astrocytoma can be pigmented and simulate a choroidal
melanoma. However, the yellow exudation seen with this tumor would be highly unlikely with
choroidal melanoma. Epithelioma of the retinal pigment epithelium (discussed in the next
section) can be very similar clinically. FNAB can be helpful in establishing the correct diagnosis.

Figure 21.91. Fundus appearance of a partially pigmented macular mass in a 20-year-old woman.

Figure 21.92. B-scan ultrasonography of the lesion shown in Figure 21.91. It is a dome-shaped mass that is
acoustically solid.

1183
Figure 21.93. Cytopathology with immunohistochemistry of a fine-needle aspiration biopsy specimen from the
patient shown in Figure 21.91, demonstrating positive reaction to glial fibrillary acidic protein. (×200.) Markers
for epithelial cells were negative.

Figure 21.94. Nonpigmented deep retinal lesion superior to the fovea and optic disc in a 23-year-old woman
as seen in 1992.

Figure 21.95. Lesion shown in Figure 21.94 in 2002. It showed growth and acquired pigment and invaded the
retina. Atypical choroidal melanoma was a diagnostic consideration, and fine-needle aspiration biopsy was
done.

1184
Figure 21.96. Cytopathology of the lesion shown in Figure 21.95, demonstrating ovoid to round cells with
benign nuclear features. Immunohistochemistry showed positive reaction to glial fibrillary acidic protein and
negative reaction to the melanoma-specific antigen HMB-45, and epithelial markers, supporting the diagnosis
of astrocytic neoplasm.

1185
• ACQUIRED RETINAL ASTROCYTOMA: DIAGNOSED BY FINE-
NEEDLE ASPIRATION BIOPSY AND MANAGEMENT WITH
PHOTODYNAMIC THERAPY

Acquired retinal astrocytoma tends to occur in the peripapillary region and can manifest
subretinal fluid, cystoid retinal edema, and exudation. Treatment with photodynamic therapy
has been beneficial in some cases.

1. Shields CL, Materin MA. Marr BP, et al. Resolution of exudative retinal detachment from
retinal astrocytoma following photodynamic therapy. Arch Ophthalmol 2008;126(2):273–274.
2. House R, Mashayekhi A, Shields JA, et al. Total regression of acquired retinal astrocytoma
using photodynamic therapy. Retinal Cases & Brief Reports 2015; in press.

Figure 21.97. Juxtapapillary retinal astrocytoma in a young man with symptoms of visual loss.

Figure 21.98. Fluorescein angiography shows relatively slow fluorescence of the mass.

1186
Figure 21.99. Optical coherence tomography demonstrates the optically dense intraretinal mass and
subretinal and intraretinal fluid and dense exudation in the fovea.

Figure 21.100. Fine-needle aspiration biopsy yielded cells that were positive for glial fibrillary acid protein
(GFAP) stain, suggestive of a glial tumor, namely astrocytoma.

Figure 21.101. One session of photodynamic therapy caused involution of the mass over 1 year.

Figure 21.102. Optical coherence tomography demonstrated dramatic reduction of the dense mass and
resolution of fluid. Posterior vitreous separation is noted.

1187
 PART 3

TUMORS OF THE PIGMENT EPITHELIUM,

NONPIGMENTED EPITHELIUM, AND
LYMPHOMA/LEUKEMIA

1188
 CHAPTER 22

TUMORS AND RELATED LESIONS OF THE

PIGMENT EPITHELIUM

SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL

PIGMENT EPITHELIUM

General Considerations
Tumors and related lesions of the retinal pigment epithelium (RPE) include
congenital hypertrophy of the RPE (CHRPE), hyperplastic RPE lesions associated
with familial adenomatous polyposis (FAP), congenital simple hamartoma, torpedo
maculopathy, combined hamartoma, pseudocancerous reactive hyperplasia, benign
epithelioma (adenoma), and malignant epithelioma (adenocarcinoma). CHRPE is
further divided into solitary and multifocal variants, the latter also known as
congenital grouped pigmentation or “bear tracks.”
Solitary CHRPE is a well-known fundus condition that has been the subject of
considerable attention in the ophthalmic literature (1–28). Although it is believed to
be congenital, the median age at diagnosis is 45 years (1). This late diagnosis may
be because the condition is generally asymptomatic and located in midperipheral or
peripheral fundus and may remain undetected on routine fundus examination. It is
usually a solitary lesion that, unlike choroidal nevus and melanoma (4), has no
recognized predilection for race.
The term CHRPE has also been applied to a somewhat different multifocal fundus
condition that has a high association with FAP and bowel cancer (15,16), a subject
to be discussed later. That choice of terminology is unfortunate because the typical
solitary CHRPE apparently is not associated with an increased incidence of FAP or
gastrointestinal malignancy (17).

Clinical Features

1189
A review of 330 cases of solitary CHRPE provided additional information regarding
this condition (1). It appears clinically as a well demarcated flat to minimally
elevated fundus plaque that can range from a black homogeneous lesion to a
completely depigmented lesion (1–28). As mentioned earlier, most are located in
the midperipheral or peripheral fundus. Only 2% are found in the macular or
peripapillary region. The lesion is predominately pigmented in 88% and
nonpigmented in 12% of cases. The median largest basal diameter is 4.5 mm. Well-
defined depigmented foci, called lacunae, are present in 43% of the pigmented
CHRPE. Most solitary CHRPE lesions have a typical depigmented ring or “halo”
around the margin. The lacunae show enlargement in 32% of cases after a mean
follow-up of 5 years (1). The majority of solitary CHRPE show slightly increased
diameter, as observed in 74% to 83% of cases followed more than 5 years in two
reported series (1,3).
Concerning differential diagnosis, the large lesions, particularly those in the
peripheral fundus, can appear similar to choroidal melanoma. The peripheral
lesions generally give the false impression ophthalmoscopically that they are quite
elevated. In a series of 330 cases, the referral diagnosis was choroidal nevus in 26%,
choroidal melanoma in 15%, and nonspecified fundus lesions in 48%. The correct
diagnosis of CHRPE was submitted in only 9% of cases. The clinical features
described here are different from those of nevus or melanoma, and the diagnosis
readily can be made by the experienced observer.
Recent reports have provided further information about the potential of solitary
CHRPE to spawn a nodular growth pattern (18,19). In perhaps 1% of cases, such a
nodular growth develops in the area of CHRPE. The nodular growth gradually
acquires a retinal feeding artery and draining vein and produces yellow intraretinal
exudation and exudative retinal detachment (19). This pattern is identical to the
adenoma of the RPE to be described subsequently. In one case that was managed by
eye wall resection, the growing amelanotic nodular lesion arising from solitary
CHRPE proved to be a low-grade malignant epithelioma (adenocarcinoma) of the
RPE (19). The subject is discussed later under the section on epitheliomas of the
RPE.

Diagnostic Approaches
Fluorescein angiography and indocyanine green angiography generally show
blockage of fluorescence throughout most of the sequence. Characteristically, there is
persistent hypofluorescence of the pigmented areas and transmission of choroidal
fluorescence through the depigmented areas throughout the angiography sequence.
U ltrasonography is nondiagnostic, but in many cases, it shows the lesion to be about
0.5 to 1 mm thick. Visual field results range from a mild relative scotoma to an
absolute field defect, usually depending on the size of the lesion. Optical coherence
tomography (OCT) shows overlying retinal thinning, loss of photoreceptors, and
moderate relative shadowing of the underlying choroid, but the findings are
nondiagnostic (5–9). Autofluorescence shows lack of lipofuscin with a dark
appearance (10). The lesion cannot generally be detected with CT or MRI.

Pathology
Histopathologically, the RPE cells in CHRPE are taller and more densely packed

1190
with spherical melanosomes as compared to the normal RPE, which has smaller,
more elliptically shaped melanosomes. There appears to be a combination of
cellular hyperplasia and hypertrophy. There is overlying atrophy of the
photoreceptors (11,12).

Management
The management of solitary CHRPE is simple periodic observation. If a small
nodular growth should evolve, it can often be observed for a period of time because
progression is very slow and does not usually affect the patient’s vision. If such a
nodule produces exudation or subretinal fluid, laser photocoagulation or
cryotherapy can be considered to stop the progression of the leakage. If such a
growth should produce surface wrinkling retinopathy in the macular region,
vitrectomy and membrane peeling should be considered. The prognosis for CHRPE
is generally excellent.

Selected References
Series Reviews
1. 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.
2. Gass JD. Focal congenital anomalies of the retinal pigment epithelium. Eye
1989;3:1–18.
3. Chamot L, Zografos L, Klainguti G. Fundus changes associated with congenital
hypertrophy of the retinal pigment epithelium. Am J Ophthalmol
1993;115:154–161.
4. Shields JA, Mashayekhi A, Ra S, Shields CL. Pseudomelanomas of the posterior
uveal tract: the 2006 Taylor R. Smith Lecture. Retina 2005;25(6):767–771.

Imaging
5. Shields CL, Materin MA, Shields JA. Review of optical coherence tomography
for intraocular tumors. Curr Opin Ophthalmol 2005;16:141–154.
6. Shields CL, Materin MA, Walker C, et al. Photoreceptor loss overlying
congenital hypertrophy of the retinal pigment epithelium by optical coherence
tomography. Ophthalmology 2006;113:661–665.
7. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr
Opin Ophthalmol 2013;24(3):222–232.
8. Fung AT, Pellegrini M, Shields CL. Congenital hypertrophy of the retinal
pigment epithelium: Enhanced depth imaging optical coherence tomography in
18 cases. Ophthalmology 2014;121(1):251–256.
9. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014; 34(8):1495–1512.
10. Shields CL, Pirondini C, Bianciotto C. et al. Autofluorescence of congenital
hypertrophy of the retinal pigment epithelium. Retina 2007;27:1097–1100.

Pathology
11. Lloyd WC III, Eagle RC, Shields JA, et al. Congenital hypertrophy of the retinal

1191
 pigment epithelium: electron microscopic and morphometric observations.
Ophthalmology 1990;97:1052–1060.
12. Parsons MA, Rennie IG, Rundle PA, et al. Congenital hypertrophy of retinal
pigment epithelium: a clinico-pathological case report. Br J Ophthalmol
2005;89(7):920–921.

Case Reports
13. Buettner H. Congenital hypertrophy of the retinal pigment epithelium. Am J
Ophthalmol 1975;79(2):177–189.
14. Purcell JJ, Shields JA. Hypertrophy with hyperpigmentation of the retinal
pigment epithelium. Arch Ophthalmol 1975;93:1122–1126.
15. Traboulsi EI, Maumenee IH, Krush AJ, et al. Pigmented ocular fundus lesions in
the inherited gastrointestinal polyposis syndromes and in hereditary
nonpolyposis colorectal cancer. Ophthalmology 1988;95:964–969.
16. Traboulsi EI. Ocular manifestations of familial adenomatous polyposis (Gardner
syndrome). Ophthalmol Clin North Am 2005;18:163–166.
17. Shields JA, Shields CL, Shah P, et al. Lack of association between typical
congenital hypertrophy of the retinal pigment epithelium and Gardner’s
syndrome. Ophthalmology 1992;99:1705–1713.
18. Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital
hypertrophy of the retinal pigment epithelium. Arch Ophthalmol 2000;118:637–
641.
19. Shields JA, Shields CL, Eagle RC Jr, et al. Adenocarcinoma arising from
congenital hypertrophy of retinal pigment epithelium. Arch Ophthalmol
2001;119:597–602.
20. Paoli D. Retinal astrocytoma associated with hypertrophy of the retinal pigment
epithelium: clinical report and follow-up. Ophthalmologica 1998;212:71–73.
21. van der Torren K, Luyten GP. Progression of papillomacular congenital
hypertrophy of the retinal pigment epithelium associated with impaired visual
function. Arch Ophthalmol 1998;116:256–257.
22. Sharma MC, Blake CR, Weinstein R, et al. Peripapillary congenital hypertrophy
of the retinal pigment epithelium. Ophthalmic Surg Lasers Imaging 2004;35:174–
175.
23. Trichopoulos N, Augsburger JJ, Schneider S. Adenocarcinoma arising from
congenital hypertrophy of the retinal pigment epithelium. Graefes Arch Clin
Exp Ophthalmol 2005;28:1–4.
24. Meyer CH, Rodrigues EB, Mennel S, et al. Grouped congenital hypertrophy of
the retinal pigment epithelium follows developmental patterns of pigmentary
mosaicism. Ophthalmology 2005;112:841–847.
25. Shields JA, Eagle RC, Shields CL, et al. Malignant transformation of congenital
hypertrophy of the retinal pigment epithelium. Ophthalmology 2009;116:2213–
2216.
26. Zucchiatti I, Battaglia Parodi M, Pala M, et al. Macular congenital hypertrophy
of the retinal pigment epithelium: a case report. Eur J Ophthalmol
2010;20(3):621–624.
27. Boldrey EE, Schwartz A. Enlargement of congenital hypertrophy of the retinal
pigment epithelium. Am J Ophthalmol 1982;94(1):64–66.
28. Arepalli S, Kaliki S, Shields JA, et al. Growth of congenital hypertrophy of the

1192
retinal pigment epithelium over 22 years. J Ped Ophthalmol Strabism 2012;
49:e73–e75.

1193
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: CLINICAL VARIATIONS

Solitary CHRPE can show considerable variation in color, size, and shape.

Figure 22.1. Small solitary congenital hypertrophy of the retinal pigment epithelium with a homogeneous black
color in a 54-year-old man.

Figure 22.2. Slightly larger solitary congenital hypertrophy of the retinal pigment epithelium in a 17-year-old
man. Note the black central portion and the slightly less pigmented peripheral area.

1194
Figure 22.3. Solitary congenital hypertrophy of the retinal pigment epithelium, showing a depigmented lacuna
and marginal light halo in a 28-year-old man. Note that the margin is slightly irregular but smooth.

Figure 22.4. Juxtapapillary solitary congenital hypertrophy of the retinal pigment epithelium (RPE) in a 40-year-
old man, showing similar features to the more peripheral lesion shown in Figure 22.3. This is a very unusual
location for congenital hypertrophy of the RPE.

1195
Figure 22.5. Solitary congenital hypertrophy of the retinal pigment epithelium located near the equator inferiorly
in a middle-aged woman. Note the subtle lacunae in the lesion.

Figure 22.6. Large solitary congenital hypertrophy of the retinal pigment epithelium (RPE) in a 17-year-old man.
He was referred for enucleation because of suspected choroidal melanoma, but the enucleation was
canceled when the lesion was diagnosed as congenital hypertrophy of the RPE.

1196
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: WIDE-ANGLE IMAGING OF
PREDOMINANTLY PIGMENTED LESIONS

Figure 22.7. Small congenital hypertrophy of the retinal pigment epithelium located in the midperipheral fundus
inferiorly.

Figure 22.8. Small congenital hypertrophy of the retinal pigment epithelium located between the equator and
the ora serrata inferiorly.

1197
Figure 22.9. Medium-sized congenital hypertrophy of the retinal pigment epithelium located near the equator
temporally.

Figure 22.10. Medium-sized congenital hypertrophy of the retinal pigment epithelium (CHRPE) located near the
equator inferiorly. Note the characteristic lacunae. There is a small pigmented nodule in the center of the
lesion. The central nodule arising from CHRPE is discussed subsequently in the section on epithelioma of the
RPE.

1198
Figure 22.11. Medium-sized congenital hypertrophy of the retinal pigment epithelium located near the equator
inferonasally.

Figure 22.12. Large congenital hypertrophy of the retinal pigment epithelium located near the equator nasally.

1199
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: WIDE-ANGLE IMAGING OF
PREDOMINANTLY NONPIGMENTED LESIONS

In some instances, solitary congenital hypertrophy of the RPE seems to lose its pigmented
appearance and appear predominantly amelanotic. This may correspond with coalescence of the
depigmented lacunae. Examples are shown.

Figure 22.13. Medium-sized congenital hypertrophy of the retinal pigment epithelium located near the ora
serrata superonasally.

Figure 22.14. Medium-sized congenital hypertrophy of the retinal pigment epithelium located near the equator

1200
superonasally.

Figure 22.15. Large congenital hypertrophy of the retinal pigment epithelium located near the equator
temporally.

Figure 22.16. Large congenital hypertrophy of the retinal pigment epithelium located near the equator
inferotemporally.

1201
Figure 22.17. Montage showing medium-sized congenital hypertrophy of the retinal pigment epithelium located
near the equator inferonasally.

Figure 22.18. Large congenital hypertrophy of the retinal pigment epithelium located between the equator and
the ora serrata inferotemporally. Note that the normal choroidal blood vessels can be seen through the lesion.

1202
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: FLUORESCEIN ANGIOGRAPHY AND
HISTOPATHOLOGY

Lloyd WC III, Eagle RC, Shields JA, et al. Congenital hypertrophy of the retinal pigment
epithelium: electron microscopic and morphometric observations. Ophthalmology
1990;97:1052–1060.

Figure 22.19. Solitary congenital hypertrophy of the retinal pigment epithelium, showing characteristic
depigmented lacunae in a 46-year-old woman. The patch of myelinated retinal nerve fibers over the lesion is
probably coincidental.

1203
Figure 22.20. Arterial-phase fluorescein angiogram of the lesion shown in Figure 22.19, demonstrating early
hypofluorescence of the lesion.

Figure 22.21. Full venous phase, showing hypofluorescence of the areas of pigmentation and transmission
hyperfluorescence in the areas of depigmentation.

Figure 22.22. Late phase, showing a continued similar pattern of fluorescence.

1204
Figure 22.23. Pathology of normal retinal pigment epithelium (RPE) for comparison to congenital hypertrophy
of the RPE. (Hematoxylin–eosin ×100.)

Figure 22.24. Pathology of congenital hypertrophy of the retinal pigment epithelium (RPE) from the same eye
shown in Figure 22.23. Note that the RPE cells are slightly taller and more densely pigmented as compared to
normal RPE cells. (Hematoxylin–eosin ×100.)

1205
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: AUTOFLUORESCENCE AND OPTICAL
COHERENCE TOMOGRAPHY CORRELATIONS

With OCT, CHRPE typically shows retinal thinning and loss of photoreceptors in the overlying
sensory retina. On autofluorescence, the pigmented part tends to block light, and the lacunae
tend to transmit light from underlying scleral autofluorescence.

1. Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of congenital hypertrophy of

the retinal pigment epithelium. Retina 2007;27:1097–1100.
2. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr Opin
Ophthalmol 2013;24(3):222–232.
3. Fung AT, Pellegrini M, Shields CL. Congenital hypertrophy of the retinal pigment epithelium:
Enhanced depth imaging optical coherence tomography in 18 cases. Ophthalmology
2014;121:251–256.

Figure 22.25. Solitary congenital hypertrophy of the retinal pigment epithelium inferotemporal to the macula.

1206
Figure 22.26. Autofluorescence of the lesion shown in Figure 22.25, demonstrating hypoautofluorescence of
the flat mass.

Figure 22.27. Solitary congenital hypertrophy of the retinal pigment epithelium superotemporal to the macula
with lacunae.

1207
Figure 22.28. Optical coherence tomography of the lesion shown in Figure 22.27, revealing
hypoautofluorescence of the mass and slight hyperautofluorescence of the intrinsic lacunae.

Figure 22.29. Solitary congenital hypertrophy of the retinal pigment epithelium temporal to the macula.

Figure 22.30. Optical coherence tomography of the lesion shown in Figure 22.29, demonstrating thin retina
with outer retinal loss and thin cleft.

1208
• SOLITARY CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM: DOCUMENTED GROWTH IN THE BASAL
DIMENSION

Figure 22.31. Small lesion superotemporal to the optic disc in the right eye of a 17-year-old woman.

Figure 22.32. Appearance of the same lesion 13 years later, showing definite increase in its diameter.

1209
Figure 22.33. Large solitary congenital hypertrophy of the retinal pigment epithelium inferotemporal to the optic
disc.

Figure 22.34. Appearance of the same lesion shown in Figure 22.33 after 2 years. Note that the lesion has
enlarged slightly and is closer to the optic disc margin and now crosses the horizontal blood vessel that was
not involved in the earlier photograph.

1210
Figure 22.35. Peripapillary solitary congenital hypertrophy of the retinal pigment epithelium involving the
macular region. (Courtesy of Gregg Luyten, MD.)

Figure 22.36. Lesion shown in Figure 22.35, several years later, demonstrating growth in the basal dimension
and now encircling the optic disc. Note the numerous lacunae that have developed. (Courtesy of Gregg Luyten,
MD.)

1211
MULTIFOCAL CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM (CONGENITAL GROUPED PIGMENTATION;
BEAR TRACKS)

General Considerations
The multifocal variant of CHRPE is also known as congenital grouped pigmentation
of the retina or “bear tracks” (1–13). It is generally a nonhereditary, sporadic
condition, but it has been observed in a mother and daughter (2). There are usually
no related ocular abnormalities, but it has been observed in the opposite eye of a
patient with persistent hyperplastic primary vitreous (12), retinoblastoma,
neurofibromatosis, and Coats disease. These findings are possibly coincidental.

Clinical Features
Multifocal CHRPE is characterized by several groups of well-delineated, flat, slate-
gray lesions that usually assume a sector distribution in the fundus. Each group
consists of 3 to 30 individual pigmented lesions that vary from 0.1 to 3 mm in
diameter, with the larger lesions located more peripherally. Each individual lesion
is similar to unifocal CHRPE, but is usually smaller than the unifocal type and does
not show the lacunae or haloes of depigmentation. The lesions are sometimes
clinically nonpigmented, in which case they have been called “polar bear tracks”
(1). These typical clinical features should serve to differentiate this condition from
the numerous other conditions that can be associated with multiple pigmented
lesions in the fundus. Retinal electrophysiologic studies are normal in multifocal
CHRPE. The lesions tend to remain stable.
As mentioned earlier, a close relationship has recently been recognized between
multiple small pigmented fundus lesions and FAP and Gardner syndrome,
conditions associated with familial colonic cancer. The fundus lesions have been
called CHRPE, but they are actually different from multifocal CHRPE in that they are
bilateral, have a more haphazard distribution, and often have more irregular or
jagged borders. There appears to be no association with the typical forms of CHRPE
described here and these cancer syndromes (4). This subject is discussed further in
the next section.

Diagnostic Approaches
Imaging with fluorescein angiography demonstrates hypofluorescence. OCT shows a
flat lesion with focal outer retinal atrophy (6,7). These lesions are
hypoautofluorescent on fundus autofluorescence (8,9).

Pathology
The histopathology of multifocal CHRPE is very similar to that of solitary CHRPE
(10,11). However, light and electron microscopy have suggested that the pigment
granules retain their normal ellipsoid configuration, and hypertrophy and
hyperplasia were not significant features (10,11).

Management
1212
Multifocal CHRPE requires no treatment and can be observed as part of routine
ocular examination. The prognosis is excellent.

Selected References
Series Reviews
1. Gass JD. Focal congenital anomalies of the retinal pigment epithelium. Eye
1989;3:1–18.
2. Renardel de Lavalette VW, Cruysberg JR, Deutman AF. Familial congenital
grouped pigmentation of the retina. Am J Ophthalmol 1991;112:406–409.
3. Yoshida T, Adachi-U sami E, Kimura T. Three cases of grouped pigmentation of
the retina. Ophthalmologica 1995;209:101–105.
4. Shields JA, Shields CL, Shah P, et al. Lack of association between typical
congenital hypertrophy of the retinal pigment epithelium and Gardner’s
syndrome. Ophthalmology 1992;99:1705–1713.
5. Shields CL, Reichstein DA, Bianciotto CG, et al. Retinal pigment epithelial
depigmented lesions associated with tuberous sclerosis complex. Arch
Ophthalmol 2012; 130:387–390.

Imaging
6. Fung AT, Pellegrini M, Shields CL. Congenital hypertrophy of the retinal
pigment epithelium: Enhanced depth imaging optical coherence tomography in
18 cases. Ophthalmology 2014;121:251–256.
7. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014;34(8):1495–1512.
8. Shields CL, Pirondini C, Bianciotto C, et al. Autofluorescence of congenital
hypertrophy of the retinal pigment epithelium. Retina 2007;27:1097–1100.
9. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr
Opin Ophthalmol 2013;24(3):222–232.
Pathology
10. Shields JA, T’so MO. Congenital group pigmentation of the retina.
Histopathologic description and report of a case. Arch Ophthalmol
1975;92:1153–1155.
11. Regillo CD, Eagle RC Jr, Shields JA, et al. Histopathologic findings in
congenital grouped pigmentation of the retina. Ophthalmology 1993;100:400–
405.

Case Reports
12. Fujii M, Hayasaka S, Setogawa T. Persistent hyperplastic primary vitreous in
the right eye and congenital grouped pigmentation of the retina in the left.
Ophthalmologica 1989;198:135–139.
13. Shields CL, Eagle RC Jr, Shah R, et al. Multifocal hypopigmented retinal
pigment epithelial lesions in a child with incontinentia pigmenti. Retina
2006;26:328–333.

1213
• MULTIFOCAL CONGENITAL HYPERTROPHY OF THE RETINAL
PIGMENT EPITHELIUM

Multifocal CHRPE is also known as congenital grouped pigmentation of the retina or “bear
tracks.” Other than being multifocal, it is similar clinically and histopathologically to solitary
CHRPE. Like the solitary form, it can be deeply pigmented or nonpigmented, but the
depigmented variant is less common. It often assumes a sector distribution, with the small
lesions located closer to the optic disc and large lesions toward the peripheral fundus.

Regillo CD, Eagle RC Jr, Shields JA, et al. Histopathologic findings in congenital grouped
pigmentation of the retina. Ophthalmology 1993;100:400–405.

Figure 22.37. Typical multifocal congenital hypertrophy of the retinal pigment epithelium in a 1-year-old boy.

1214
Figure 22.38. Nonpigmented congenital hypertrophy of the retinal pigment epithelium, sometimes called “polar
bear tracks,” in a 10-year-old girl.

Figure 22.39. Sector multifocal congenital hypertrophy of the retinal pigment epithelium in a young boy. There
was no family history of colon cancer.

1215
Figure 22.40. Multifocal congenital hypertrophy of the retinal pigment epithelium in a 2-year-old child with
retinoblastoma. The opposite eye had similar lesions and was managed by enucleation, providing an
opportunity to study the lesions pathologically.

Figure 22.41. Gross photograph of the retinal pigment epithelium in the enucleated fellow eye of the patient
seen in Figure 22.39, showing foci of hyperpigmentation.

1216
Figure 22.42. Electron microscopy of one of the lesions shown in Figure 22.41, demonstrating the large,
densely packed melanosomes in the cytoplasm of the retinal pigment epithelium cells. (×4000.) (Courtesy of
Ralph C. Eagle, Jr, MD.)

1217
RETINAL PIGMENT EPITHELIAL HAMARTOMAS ASSOCIATED WITH
FAMILIAL ADENOMATOUS POLYPOSIS AND GARDNER SYNDROME

General Considerations
This condition has a strong association with FAP, an autosomal-dominant condition
in which almost 100% of patients develop colon cancer (1–22). It is unfortunate
that the term CHRPE was used to describe this fundus condition by those who first
made this association (1,6), because neither solitary nor multifocal CHRPE is
associated with an increased incidence of colon cancer (11). To minimize confusion,
we choose to call this condition “retinal pigment epithelial hamartomas associated
with familial adenomatous polyposis” (RPEH-FAP). Others term this condion as
“pigmented ocular fundus lesions” (4). About 70% of patients with FAP have these
characteristic fundus lesions, which represent the hallmark of a life-threatening
familial cancer (1–10).
Many ophthalmologists have used the term Gardner syndrome to describe the
association of these fundus lesions with bowel cancer. However, Gardner syndrome
is defined as FAP plus extracolonic manifestations, including osteomas, desmoid
tumors, cutaneous cysts, and several other tumors. Hence, all patients with Gardner
syndrome have FAP, but patients with FAP do not necessarily have Gardner
syndrome. There is also a close relationship between RPEH-FAP and central nervous
system gliomas (Turcot syndrome) (8).

Clinical Features
RPEH-FAP has characteristic ophthalmoscopic features. U nlike solitary CHRPE, the
lesions are multiple and bilateral and their margins are often less well defined.
U nlike multifocal CHRPE, they are randomly dispersed and do not have a sector
distribution, and they have irregular depigmented margins, sometime forming a fish-
tail, comma, or comet configuration. Some have proposed that the presence of four
or more such lesions is diagnostic of FAP, but some patients have many more, even
hundreds of lesions bilaterally. In some cases, the RPE lesions are pinpoint, best
found with fluorescein angiography (19).

Pathology and Pathogenesis

Histopathologically, RPEH-FAP has been identified to have one of three basic
configurations: a monolayer of hypertrophic cells, a mound of RPE cells interposed
between the RPE basement membrane of the inner collagenous layer of Bruch’s
membrane, or a multilayered mound of hyperplastic cells (13). It is believed to
indicate a generalized defect in melanogenesis. The gene for FAP has been identified
on the long arm of chromosome 5 (5q21) (10).

Management
The management of RPEH-FAP is periodic observation only. However, the almost
universal development of colon cancer in affected patients warrants close scrutiny
for and early management of that malignancy. Affected patients, particularly those
with a family history of colon cancer, should have periodic colonoscopy and

1218
removal of suspicious polyps.

Selected References
Series/Reviews
1. Blair NP, Trempe CL. Hypertrophy of the retinal pigment epithelium associated
with Gardner’s syndrome. Am J Ophthalmol 1980;90:661–667.
2. Lewis RA, Crowder WE, Eierman LA, et al. The Gardner syndrome. Significance
of ocular features. Ophthalmology 1984;91:916–925.
3. Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and importance of
pigmented ocular fundus lesions in Gardner’s syndrome. N Engl J Med
1987;316:661–667.
4. Traboulsi EI, Maumenee IH, Krush AJ, et al. Pigmented ocular fundus lesions in
the inherited gastrointestinal polyposis syndromes and in hereditary
nonpolyposis colorectal cancer. Ophthalmology 1988;95:964–969.
5. 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.
6. Traboulsi EI, Maumenee IH, Krush AJ, et al. Congenital hypertrophy of the
retinal pigment epithelium predicts colorectal polyposis in Gardner’s syndrome.
Arch Ophthalmol 1990;108:525–526.
7. Heinemann MH, Baker RH, Miller HH, et al. Familial polyposis coli: the
spectrum of ocular and other extracolonic manifestations. Graefes Arch Clin Exp
Ophthalmol 1991;229:213–218.
8. Munden PM, Sobol WM, Weingeist TA. Ocular findings in Turcot syndrome
(glioma-polyposis). Ophthalmology 1991;98:111–114.
9. 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.
10. Ruhswurm I, Zehetmayer M, Dejaco C, et al. Ophthalmic and genetic screening
in pedigrees with familial adenomatous polyposis. Am J Ophthalmol
1998;125:680–686.
11. Shields JA, Shields CL, Shah PG, et al. Lack of association among typical
congenital hypertrophy of the retinal pigment epithelium, adenomatous
polyposis, and Gardner syndrome. Ophthalmology 1992;99:1709–1713.

Imaging
12. Tzu JH, Cavuoto KM, Villegas VM, et al. Optical coherence tomography
findings of pigmented fundus lesions in familial adenomatous polyposis.
Ophthalmic Surg Lasers Imaging 2013;21:1–2.

Pathology
13. 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.
Case Reports
14. Whitson WE, Orcutt JC, Walkinshaw MD. Orbital osteoma in Gardner’s
syndrome. Am J Ophthalmol 1986;101:236–241.

1219
15. Kunikata H, Abe T, Yoshida M, et al. The characteristics of congenital
hypertrophy of retinal pigment epithelium in Turcot’s syndrome.
Ophthalmologica 2000;214:374–375.
16. Aiello LP, Traboulsi EI. Pigmented fundus lesions in a preterm infant with
familial adenomatous polyposis. Arch Ophthalmol 1993;111:302–303.
17. Krush AJ, Traboulsi EI, Offerhaus JA, et al. Hepatoblastoma, pigmented ocular
fundus lesions and jaw lesions in Gardner syndrome. Am J Med Genet
1988;29:323–332.
18. Rossato M, Rigotti M, Grazia M, et al. Congenital hypertrophy of the retinal
pigment epithelium (CHRPE) and familial adenomatous polyposis (FAP). Acta
Ophthalmol Scand 1996;74:338–342.
19. Ganesh A, Kaliki S, Levin AV, et al. Epiretinal membrane and retinal pigment
epithelial lesions in a young child lead to detection of de novo APC gene
mutation. Arch Ophthalmol 2012;130(8):1071–1073.
20. McKay DL. Congenital hypertrophy of the retinal pigment epithelium and
familial adenomatous polyposis. Aust N Z J Ophthalmol 1993;21:3–6.
21. Romania A, Zakov ZN, McGannon E, et al. Congenital hypertrophy of the
retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology
1989;96:879–884.
22. Romania A, Zakov ZN, Church JM, et al. Retinal pigment epithelium lesions as
a biomarker of disease in patients with familial adenomatous polyposis. A
follow-up report. Ophthalmology 1992;99:911–913.

1220
• RETINAL PIGMENT EPITHELIAL HAMARTOMAS ASSOCIATED WITH
FAMILIAL ADENOMATOUS POLYPOSIS

Multifocal lesions of hypertrophy and hyperplasia of the RPE are known to be a hallmark of
patients with FAP and Gardner syndrome, familial conditions that predispose the patient to
colorectal cancer. Gardner syndrome consists of FAP with extracolonic manifestations, like
desmoid tumors, osteomas, and other benign tumors. Examples of RPEH-FAP are shown.

1. Ganesh A, Kaliki S, Levin AV, et al. Epiretinal membrane and retinal pigment epithelial
lesions in a young child lead to detection of de novo APC gene mutation. Arch Ophthalmol
2012;130(8):1071–1073.
2. Whitson WE, Orcutt JC, Walkinshaw MD. Orbital osteoma in Gardner’s syndrome. Am J
Ophthalmol 1986;101;236–241.

Figure 22.43. Two typical lesions in the macular region.

1221
Figure 22.44. Typical fundus lesion in a patient with familial adenomatous polyposis. (Courtesy of Norman
Blair, MD.)

Figure 22.45. Multifocal retinal pigment epithelial lesions in a baby subsequently discovered to have familial
adenomatous polyposis following our examination and genetic testing.

1222
Figure 22.46. Fluorescein angiography of patient in Figure 22.45 demonstrating early hypofluorescence of the
lesions that persists into the late phases.

Figure 22.47. Sections of colon, showing numerous polyps in a patient who also had typical fundus lesions.
(Courtesy of James Bolling, MD.)

1223
Figure 22.48. Coronal computed tomogram, showing orbital osteoma as part of Gardner syndrome. (Courtesy
of James Orcutt, MD.)

1224
 PSEUDONEOPLASTIC REACTIVE HYPERPLASIA OF THE RETINAL
PIGMENT EPITHELIUM

General Considerations
The RPE has a marked propensity to undergo reactive hyperplasia as a result of
ocular insults such as inflammation or trauma. In most instances, RPE hyperplasia is
small and typical and does not pose a diagnostic problem. On occasion, such RPE
proliferation can simulate a pigmented neoplasm such as choroidal or ciliary body
melanoma or true neoplasms of the RPE (1–11).

Clinical Features
Pseudoneoplastic reactive hyperplasia of the RPE can assume a number of clinical
appearances. It can appear as a diffuse or sessile lesion or as a nodular mass. Its
dark black color and associated signs of prior inflammation or trauma can help to
differentiate the lesion from choroidal melanoma. Secondary retinal detachment is
uncommon. Even though this lesion is relatively stable, a few cases have been
observed in which small focal areas of RPE hyperplasia have shown evolution into a
nodular tumor that transgresses the retina into the vitreous cavity. In rare instances,
presumed reactive hyperplasia of the RPE can even extend extrasclerally (11).

Pathology
Microscopically, pseudoneoplastic reactive hyperplasia of the RPE consists of a
proliferation of RPE cells forming either a relatively flat sheet of pigment or a
distinct mass. A typical feature is the benign proliferation of RPE cells that elaborate
excess basement membrane material. This appears as acellular periodic acid-Schiff–
positive material that can become so extensive that the residual RPE cells can be
separated by abundant amounts of this substance (5,6).

Management
The management of pseudoneoplastic reactive hyperplasia of the RPE is generally
simple periodic observation. Major progression or complications are quite unusual.

Selected References
Series Reviews
1. Shields JA, Shields CL, Slakter J, et al. Locally invasive tumors arising from
hyperplasia of the retinal pigment epithelium. Retina 2001;21:487–492.
2. 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.
3. Kurz GH, Zimmerman LE. Vagaries of the retinal pigment epithelium. Int
Ophthalmol Clin 1962;2:441–464.
4. Jampel HD, Schachat AP, Conway B, et al. Retinal pigment epithelial
hyperplasia assuming tumor-like proportions. Report of two cases. Retina
1986;6:105–112.

1225
Pathology
5. T’so MO, Albert DM. Pathologic condition of the retinal pigment epithelium.
Arch Ophthalmol 1972;88:27–38.
6. Frayer WC. Reactivity of the retinal pigment epithelium: an experimental and
histopathologic study. Trans Am Ophthalmol Soc 1966;64:586–639.

Case Reports
7. Loeffler KU , Kivelä T, Borgmann H, et al. Malignant tumor of the retinal
pigment epithelium with extraocular extension in a phthisical eye. Graefes Arch
Clin Exp Ophthalmol 1996;234(Suppl 1):S70–S75.
8. 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(4):525–528.
9. Olsen TW, Frayer WC, Myers FL, et al. Idiopathic reactive hyperplasia of the
retinal pigment epithelium. Arch Ophthalmol 1999;117:50–54.
10. Heegaard S, Larsen JN, Fledelius HC, et al. Neoplasia versus hyperplasia of the
retinal pigment epithelium. A comparison of two cases. Acta Ophthalmol Scand
2001; 79:626–633.
11. Shields JA, Green WR, McDonald PR. U veal pseudomelanoma due to post-
traumatic pigmentary migration. Arch Ophthalmol 1973;89:519–522.

1226
• PSEUDONEOPLASTIC REACTIVE HYPERPLASIA OF THE RETINAL
PIGMENT EPITHELIUM

Reactive hyperplasia of the RPE can range from a small focal nodule in the macular area that is
presumed to be congenital to larger, more irregular forms.

Figure 22.49. Reactive hyperplasia of the retinal pigment epithelium of uncertain etiology located adjacent to
the foveola.

Figure 22.50. Reactive hyperplasia of the retinal pigment epithelium nasal to the optic disc. The diagnosis was
uncertain, but congenital retinal toxoplasmosis was suspected.

1227
Figure 22.51. Focus of idiopathic reactive hyperplasia of the retinal pigment epithelium near the ora serrata
temporally in the left eye.

Figure 22.52. Focal reactive hyperplasia of the retinal pigment epithelium inferiorly in an eye with a
longstanding retinal detachment and subretinal fibrosis.

1228
Figure 22.53. Reactive hyperplasia of the retinal pigment epithelium after ocular trauma in a 66-year-old
woman.

Figure 22.54. Histopathology of hyperplasia of the retinal pigment epithelium. Note that the irregular pigment
proliferation has caused an elevated nodule beneath the retina that can clinically simulate a choroidal
melanoma. (Hematoxylin–eosin ×20.)

1229
• HYPERPLASIA AND MIGRATION OF THE PIGMENT EPITHELIUM
SIMULATING A UVEAL MELANOMA WITH EXTRAOCULAR
EXTENSION

Occasionally, the retinal pigment epithelium can undergo massive proliferation and migration,
simulating a uveal melanoma. Such a case is depicted.

Shields JA, Green WR, McDonald PR. Uveal pseudomelanoma due to post-traumatic pigmentary
migration. Arch Ophthalmol 1973;89:519–522.

Figure 22.55. Bilobed pigmented ciliary body mass in an 11-year-old girl. The diagnosis of ciliary body
“hemorrhage” was made elsewhere, and an attempt was made to drain the blood through a limbal incision.

1230
Figure 22.56. Following attempted intraocular biopsy elsewhere, there was progressive migration of pigment
into the epibulbar tissue. The clinical diagnosis was changed to ciliary body melanoma with extraocular
extension, and an epibulbar biopsy was done.

Figure 22.57. Histopathology, showing a peculiar proliferation of retinal pigment epithelium cells. The lesion
was observed periodically. (Hematoxylin–eosin ×150.)

Figure 22.58. Appearance of the epibulbar area 4 years later. Note that the epibulbar pigmentation has entirely
resolved.

1231
Figure 22.59. View of the ciliary body area at same time as the photograph shown in Figure 22.58. Note that
the intraocular component has markedly decreased in size.

Figure 22.60. Appearance 21 years later, when the patient was 32 years old. Note that the epibulbar tissues
remain normal. Only a flat area of pigmentation was seen in the ora serrata region.

1232
 CONGENITAL SIMPLE HAMARTOMA OF THE RETINAL PIGMENT
EPITHELIUM

General Considerations
Congenital simple hamartoma of the RPE is a term that we have chosen for a rather
typical pigmented fundus lesion (1–9). Earlier, we called this lesion congenital focal
hyperplasia of the RPE, but we now prefer the term congenital simple hamartoma
of the RPE. We believe that the lesion is most congenital as a small mass composed
of proliferating RPE cells and hence should be classified as a hamartoma. It is
presumably composed exclusively of RPE cells and hence would be a simple rather
than a complex or combined hamartoma.

Clinical Features
Congenital simple hamartoma of the RPE appears clinically as a distinct solitary
nodule that protrudes through the sensory retina, sometimes into the vitreous cavity.
Most reported cases have been <1 mm in diameter and 1 to 2.5 mm in thickness
and have been located in the central macular region, usually in the fovea, adjacent
to the foveola. It is possible that similar lesions could exist in the peripheral fundus
but are not recognized or appreciated clinically. Based on a clinical series of five
cases, associated features include minimally dilated retinal feeding artery and
draining retinal vein (100%), adjacent mild retinal traction (80%), yellow retinal
exudation (20%), and vitreous pigmented cells (20%). Fluorescein angiography
shows early and persistent hypofluorescence of the lesion (3).

Diagnostic Approaches
Congenital simple hamartoma has typical ophthalmoscopic and biomicroscopic
features. The lesion is generally hypofluorescent with fluorescent angiography
throughout the angiogram. It is generally too small to resolve with ultrasonography.
OCT demonstrates an abruptly elevated solid mass within the retina and extending
as a dome into the vitreous cavity with complete optical shadowing (4–7).

Pathology
The pathology of congenital simple hamartoma of the RPE is not known. We
speculate that it is a benign nodule composed of proliferating RPE cells, but
histopathology has not been clearly established.

Management
The management of congenital simple hamartoma of the RPE is only periodic
observation. Most lesions have remained relatively stable after being first
recognized.

Selected References
Series Reviews

1233
 1. Laqua H. Tumors and tumor-like lesions of the retinal pigment epithelium.
Ophthalmologica 1981;183:34–38.
2. Gass JD. Focal congenital anomalies of the retinal pigment epithelium. Eye
1989;3:1–18.
3. Shields CL, Shields JA, Marr BP, et al. Congenital simple hamartoma of the
retinal pigment epithelium. A study of five cases. Ophthalmology
2003;110:1005–1011.
Imaging
4. Shields CL, Materin MA, Karatza E, et al. Optical coherence tomography (OCT)
of congenital simple hamartoma of the retinal pigment epithelium. Retina
2004; 24:327–328.
5. Shields CL, Mashayekhi A, Luo CK, et al. Optical coherence tomography in
children. Analysis of 44 eyes with intraocular tumors and simulating conditions.
J Pediatr Ophthalmol Strabismus 2004;41:338–344.
6. Shukla D, Ambatkar S, Jethani J, et al. Optical coherence tomography in
presumed congenital simple hamartoma of retinal pigment epithelium. Am J
Ophthalmol 2005; 139:945–947.
7. López JM, Guerrero P. Congenital simple hamartoma of the retinal pigment
epithelium: optical coherence tomography and angiography features. Retina
2006;26(6):704–706.

Case Reports
8. Souissi K, El Afrit MA, Kraiem A. Congenital retinal arterial macrovessel and
congenital hamartoma of the retinal pigment epithelium. J Pediatr Ophthalmol
Strabismus 2006;43(3):181–182.
9. Gotoh M, Yoshikawa H, Kagimoto HT, et al. Congenital simple hamartoma of
the retinal pigment epithelium in an Asian. Jpn J Ophthalmol 2008;52(2):144–
145.

1234
 TORPEDO MACULOPATHY

General Considerations
Torpedo maculopathy is a presumed congenital condition affecting the eye at the
level of the RPE with focal, well-circumscribed atrophy or hyperplasia in a torpedo
configuration (1–7). This lesion tends to occur in the temporal macular region, just
temporal to the foveola.

Clinical Features
This unusual congenital condition is characterized by a torpedo-shaped focal loss of
RPE in the temporal macular region, pointing toward the foveola. Speculation on
the origin of this feature states that it might be a focal defect in ocular development
at the time of the fetal bulge.

Diagnostic Approaches
By ultrasonography, the lesion is flat. By OCT, there is often a cleft of subretinal
empty space with photoreceptor retraction. Autofluorescence fundus imaging is
dark, implying loss of retinal pigment epithelial cells.

Pathology
The pathology of this condition has not been investigated.

Management
There are no associated syndromes with this condition and the management is
observation.

Selected References
Series Reviews
1. Golchet PR, Jampol LM, Mathura JR, et al. Torpedo maculopathy. Br J
Ophthalmol 2010;94:302–306.
2. Shields CL, Guzman J, Shapiro M, et al. Torpedo maculopathy occurs at the site
of the fetal “bulge.” Arch Ophthalmol 2010;128(4);499–501.
3. Rigotti M, Babighian S, Carcereri De Prati E, et al. Three cases of a rare
congenital abnormality of the retinal pigment epithelium: Torpedo
maculopathy. Ophthalmologica 2002;216:226–227.

Pathology
4. Streeten BW. Development of the human retinal pigment epithelium and the
posterior segment. Arch Ophthalmol 1969;81:383–394.

Case Reports
5. Roseman RL, Gass JD. Hypopigmented nevus of the retinal pigment epithelium
in the macula. Arch Ophthalmol 1992;110:1358–1359.
6. Mahieu L, Mathis A. “Torpedo” maculopathy. J Fr Ophtalmol 2003;26:533.

1235
7. Angioï-Duprez K, Maalouf T. Torpedo maculopathy. J Fr Ophtalmol
2000;23:200.

1236
• CONGENITAL SIMPLE HAMARTOMA OF THE RETINAL PIGMENT
EPITHELIUM AND TORPEDO MACULOPATHY

Figure 22.61. Congenital simple hamartoma of the retinal pigment epithelium in the fovea of the right eye in a
child.

Figure 22.62. Fluorescein angiogram of the lesion shown in Figure 22.61 demonstrating hypofluorescence of
the lesion.

1237
Figure 22.63. Congenital simple hamartoma of the retinal pigment epithelium in the perifoveal region.

Figure 22.64. Optical coherence tomography of the lesion shown in Figure 22.63, demonstrating an optically
dense mass with abrupt shadowing posteriorly.

1238
Figure 22.65. Torpedo maculopathy of the right eye in an asymptomatic patient. (Courtesy of Michael Shapiro,
MD.)

Figure 22.66. Torpedo maculopathy of the left eye in an asymptomatic patient. (Courtesy of Lisa Fogel, MD.)

1239
 COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT
EPITHELIUM

General Considerations
Combined hamartoma of the retina and RPE is a fundus lesion that also has rather
characteristic but variable clinical features (1–41). It is generally believed to be
congenital and nonhereditary, and the etiology is uncertain. There are systemic
associations in some patients with this condition (28–41).

Clinical Features
The most characteristic ophthalmoscopic finding is an ill-defined gray retinal mass
that demonstrates tortuous or straightened retinal blood vessels, probably due to
secondary retinal traction from excessive glial tissue on the surface of the lesion. It is
characteristically located on or adjacent to the optic disc, but it is commonly seen in
extrapapillary areas of the fundus. It can vary widely in size, ranging from a small
lesion 1 mm in diameter to a mass lesion >10 mm in diameter. Visual acuity is
variable, depending on the tumor size and location and the amount of retinal
traction. Most patients that come to clinical attention are young children found to
have poor vision on school examination. Tumors located in the macular area can
lead to strabismus and amblyopia. Foveal ectopia secondary to traction can also be
a cause of amblyopia.
In either location, the abnormal tortuous retinal blood vessels show characteristic
straightening as they pass anterior to the lesion toward the peripheral fundus. A
peripheral lesion can cause retinal dragging, creating a “dragged disc” appearance.
Combined hamartoma can be associated with peripheral retinal ischemia and
secondary peripheral neovascularization. Combined hamartoma is generally a stable
lesion, but excessive glial proliferation can lead to retinal traction and visual loss.
Other complications, such as retinal exudation and vitreous hemorrhage, are rather
uncommon. Almost all sporadic cases have been unilateral, although bilaterality has
been recognized and is generally suggestive of underlying systemic syndrome such as
neurofibromatosis type 2 (41).
For several years, a lesion somewhat similar to combined hamartoma has been
recognized as a component of neurofibromatosis type 2 (41). It has also been
recognized recently in patients with neurofibromatosis type 1 (36). It is uncertain
whether the areas of retinal gliosis seen in patients with neurofibromatosis are the
same as a classic combined hamartoma. Isolated case reports have described an
association with Gorlin syndrome (33), optic neuritis (32), juvenile nasopharyngeal
angiofibroma (37), and the branchio-oculo-facial syndrome (38–40).
The main tumors to be included in the differential diagnosis are retinoblastoma in
children and choroidal melanoma in adults. The gliosis and traction that are so
typical with combined hamartoma are not generally seen with these other
neoplasms. The most important nonneoplastic condition in the differential diagnosis
is primary or secondary retinal gliosis. In our experience, there are occasionally
atypical cases in which the differentiation between severe vitreous traction
maculopathy (surface wrinkling retinopathy) and combined hamartoma can be
difficult.

1240
Diagnostic Approaches
Fluorescein angiography shows markedly abnormal retinal blood vessels in the mass
and gradual late staining of the lesion. Indocyanine green angiography is nonspecific
and shows mild patchy hyperfluorescence in the late phase. OCT shows an irregular
lesion with vitreoretinal traction into a “sawtooth” or “folded” pattern that replaces
full-thickness retinal tissue (5–10).

Pathology
Histopathologically, combined hamartoma is located mostly in the sensory retina or
optic disc tissue and is composed of an admixture of pigment epithelial cells,
proliferating blood vessels, and glial tissue. The proliferating RPE cells may assume
a tubular arrangement (11).

Management
There is no highly effective method for treating combined hamartoma. Amblyopic
therapy may be helpful in some young children. Vitrectomy and membrane peeling
can be helpful in cases with vitreous hemorrhage and preretinal gliosis (12–18), but
is generally not useful if the lesion involves full thickness of the retina. Laser
photocoagulation can be employed for the rare neovascular membrane that can
develop.

Selected References
Series/Reviews
1. Gass JD. An unusual hamartoma of the pigment epithelium and retina
simulating choroidal melanoma and retinoblastoma. Trans Am Ophthalmol Soc
1973;71:171–185.
2. Schachat AP, Shields JA, Fine SL, et al. Combined hamartoma of the retina and
retinal pigment epithelium. Ophthalmology 1984;91:1609–1615.
3. Cosgrove JM, Sharp DM, Bird AC. Combined hamartoma of the retina and
retinal pigment epithelium: the clinical spectrum. Trans Ophthalmol Soc UK
1986;105:106–113.
4. 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(12):2246–2252.

Imaging
5. Ting TD, McCuen BW 2nd, Fekrat S. Combined hamartoma of the retina and
retinal pigment epithelium: optical coherence tomography. Retina 2002;22:98–
101.
6. Shields CL, Mashayekhi A, Luo CK, et al. Optical coherence tomography in
children. Analysis of 44 eyes with intraocular tumors and simulating conditions.
J Pediatr Ophthalmol Strabismus 2004;41:338–344.
7. Shields CL, Mashayekhi A, Dai VV, et al. Optical coherence tomography
findings of combined hamartoma of the retina and retinal pigment epithelium
in 11 patients. Arch Ophthalmol 2005;123:1746–1750.
8. Huot CS, Desai KB, Shah VA. Spectral domain optical coherence tomography of

1241
 combined hamartoma of the retina and retinal pigment epithelium. Ophthalmic
Surg Lasers Imaging 2009;40(3):322–324.
9. Arepalli S, Pellegrini M, Ferenczy SR, et al. Combined hamartoma of the retina
and retinal pigment epithelium. Findings on enhanced depth imaging optical
coherence tomography (EDI-OCT) in 8 eyes. Retina 2014;34(11):2202–2207.
10. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014; 34(8):1495–1512.

Pathology
11. McDonald HR, Abrams GW, Burke JM, et al. Clinicopathologic results of
vitreous surgery for epiretinal membranes in patients with combined retinal
and retinal pigment epithelial hamartomas. Am J Ophthalmol 1985:100:806–
813.

Management
12. Sapperfield DL, Gitter KA. Surgical intervention for combined retinal–retinal
pigment epithelial hamartoma. Retina 1990;10:119–124.
13. Stallman JB. Visual improvement after pars plana vitrectomy and membrane
peeling for vitreoretinal traction associated with combined hamartoma of the
retina and retinal pigment epithelium. Retina 2002;22:101–104.
14. Mason JO 3rd. Visual improvement after pars plana vitrectomy and membrane
peeling for vitreoretinal traction associated with combined hamartoma of the
retina and retinal pigment epithelium. Retina 2002;22:824–825.
15. Inoue M, Noda K, Ishida S, et al. Successful treatment of subfoveal choroidal
neovascularization associated with combined hamartoma of the retina and
retinal pigment epithelium. Am J Ophthalmol 2004;138:155–156.
16. Cohn AD, Quiram PA, Drenser KA, et al. Surgical outcomes of epiretinal
membranes associated with combined hamartoma of the retina and retinal
pigment epithelium. Retina 2009;29(6):825–830.
17. Zhang X, Dong F, Dai R, et al. Surgical management of epiretinal membrane in
combined hamartomas of the retina and retinal pigment epithelium. Retina
2010;30(2):305–309.
18. Bruè C, Saitta A, Nicolai M, et al. Epiretinal membrane surgery for combined
hamartoma of the retina and retinal pigment epithelium: role of multimodal
analysis. Clin Ophthalmol 2013;7:179–184.
Case Reports
19. Kahn D, Goldberg MF, Jednock N. Combined retinal–retina pigment epithelial
hamartoma presenting as a vitreous hemorrhage. Retina 1984;4:40–43.
20. Font RL, Moura RA, Shetlar DJ, et al. Combined hamartoma of sensory retina
and retinal pigment epithelium. Retina 1989;9:302–311.
21. Palmer ML, Carney MD, Combs JL. Combined hamartomas of the retinal
pigment epithelium and retina. Retina 1990;10:33–36.
22. Mason JO 3rd, Kleiner R. Combined hamartoma of the retina and retinal
pigment epithelium associated with epiretinal membrane and macular hole.
Retina 1997; 17:160–162.
23. Blumenthal EZ, Papamichael G, Merin S. Combined hamartoma of the retina

1242
 and retinal pigment epithelium: a bilateral presentation. Retina 1998;18:557–
559.
24. Theodossiadis PG, Panagiotidis DN, Baltatzis SG, et al. Combined hamartoma of
the sensory retina and retinal pigment epithelium involving the optic disk
associated with choroidal neovascularization. Retina 2001;21:267–270.
25. Moschos M, Ladas ID, Zafirakis PK, et al. Recurrent vitreous hemorrhages due to
combined pigment epithelial and retinal hamartoma: natural course and
indocyanine green angiographic findings. Ophthalmologica 2001;215:66–69.
26. Helbig H, Niederberger H. Presumed combined hamartoma of the retina and
retinal pigment epithelium with preretinal neovascularization. Am J Ophthalmol
2003; 136:1157–1159.
27. Cebulla CM, Flynn HW Jr. Calcification of combined hamartoma of the retina
and retinal pigment epithelium over 15 years. Graefes Arch Clin Exp Ophthalmol
2013; 251(5):1455–1456.

Association with Syndromes

28. Sivalingam A, Augsburger J, Perilongo G, et al. Combined hamartoma of the
retina and retinal pigment epithelium in a patient with neurofibromatosis type
2. J Pediatr Ophthalmol Strabismus 1991;28:320–322.
29. Destro M, D’Amico DJ, Gragoudas ES, et al. Retinal manifestations of
neurofibromatosis. Diagnosis and management. Arch Ophthalmol 1991;109:662–
666.
30. Bouzas EA, Parry DM, Eldridge R, et al. Familial occurrence of combined
pigment epithelial and retinal hamartomas associated with neurofibromatosis 2.
Retina 1992;12:103–107.
31. Kaye LD, Rothner AD, Beauchamp GR, et al. Ocular findings associated with
neurofibromatosis type II. Ophthalmology 1992;99:1424–1429.
32. Ticho BH, Egel RT, Jampol LM. Acquired combined hamartoma of the retina
and pigment epithelium following parainfectious meningoencephalitis with
optic neuritis. J Pediatr Ophthalmol Strabismus 1998;35:116–118.
33. De Potter P, Stanescu D, Caspers-Velu L, et al. Photo essay: combined
hamartoma of the retina and retinal pigment epithelium in Gorlin syndrome.
Arch Ophthalmol 2000;118:1004–1005.
34. Kutsche K, Glauner E, Knauf S, et al. Cloning and characterization of the
breakpoint regions of a chromosome 11;18 translocation in a patient with
hamartoma of the retinal pigment epithelium. Cytogenet Cell Genet
2000;91:141–147.
35. Tsai P, O’Brien JM. Combined hamartoma of the retina and retinal pigment
epithelium as the presenting sign of neurofibromatosis-1. Ophthalmic Surg
Lasers 2000;31:145–147.
36. Vianna RN, Pacheco DF, Vasconcelos MM, et al. Combined hamartoma of the
retina and retinal pigment epithelium associated with neurofibromatosis type-1.
Int Ophthalmol 2001;24(2):63–66.
37. Fonseca RA, Dantas MA, Kaga T, et al. Combined hamartoma of the retina and
retinal pigment epithelium associated with juvenile nasopharyngeal
angiofibroma. Am J Ophthalmol 2001;132:131–132.
38. Demirci H, Shields CL, Shields JA. New ophthalmic manifestations of branchio-
oculo-facial syndrome. Am J Ophthalmol 2005;139:362–364.

1243
39. Badami A, Bianciotto CG, Shields CL, et al. Combined hamartoma of the retina
and retinal pigment epithelium in a child with branchial cleft cysts. J Pediatr
Ophthalmol Strabism 2012;49, Online: e9–e11.
40. Kadaba P, Arepalli S, Shields JA, et al. Combined hamartoma of retina and
retinal pigment epithelium in branchio-oto-renal syndrome. J AAPOS
2014;18:201–203.
41. Firestone B, Shields CL, Arias JD, et al. Bilateral combined hamartomas of the
retina and retinal pigment epithelium as the presenting feature of
neurofibromatosis type 2 (Wishart type). J Ped Ophthalmol Strabism 2014;51.

1244
• COMBINED HAMARTOMA OF RETINA AND RETINAL PIGMENT
EPITHELIUM: JUXTAPAPILLARY TYPE AND HISTOPATHOLOGY

Most combined hamartomas are located over or adjacent to the optic disc but many occur in an
extrapapillary location. In some cases, the diagnosis must remain presumptive, and it is possible
that some lesions diagnosed as combined hamartoma may be a result of ocular insults such as
inflammation or trauma.

Schachat AP, Shields JA, Fine SL, et al. Combined hamartoma of the retina and retinal pigment
epithelium. Ophthalmology 1984;91:1609–1615.

Figure 22.67. Small combined hamartoma on the superonasal margin of the optic disc in a 40-year-old man.

1245
Figure 22.68. Slightly larger combined hamartoma surrounding the superior half of the optic disc in a 45-year-
old man.

Figure 22.69. Combined hamartoma inferotemporal to the optic disc in a 32-year-old man. In this case, there
is a small amount of intraretinal exudation in the foveal area. Note the retinal traction temporal to the lesion.

Figure 22.70. Combined hamartoma temporal to the optic disc in a 19-year-old woman. In this case, there is
extensive gliosis over the lesion that obscures its pigmentation.

1246
Figure 22.71. Extensive combined hamartoma over and around the optic disc. This was noted shortly after birth
in a boy and has been followed for about 16 years without appreciable change.

Figure 22.72. Histopathology of combined hamartoma, showing thickened sensory retina adjacent to the optic
disc with intraretinal pigment, excessive blood vessels, and a glial membrane of the inner surface of the
lesion. (Hematoxylin–eosin ×10.) (Courtesy of the Armed Forces Institute of Pathology, Washington, DC.)

1247
• COMBINED HAMARTOMA OF RETINA AND RETINAL PIGMENT
EPITHELIUM: EXTRAPAPILLARY TYPE

Extrapapillary combined hamartoma can be located in the posterior fundus or as peripheral as

the equator. It can cause significant secondary dragging of the sensory retina. The illustrations
in the following plates show the retinal dragging in all cases.

Figure 22.73. Inferior dragging of the sensory retina in a 3-year-old boy evaluated for visual loss and found to
have a combined hamartoma inferiorly causing the dragging.

Figure 22.74. Curvilinear combined hamartoma along the inferior vascular arcade in the patient shown in
Figure 22.73. Contraction of the white glial tissue on the tumor surface accounts for the retinal dragging.

1248
Figure 22.75. Combined hamartoma in the equator inferonasally in the left eye of a 15-year-old girl. Note that in
the area peripheral to the lesion (to the left), the retinal vessels become straighten and attenuated.

Figure 22.76. Posterior fundus of the eye shown in Figure 22.75. Note the dragging of the inferonasal retinal
blood vessels in a nasal direction.

1249
Figure 22.77. Similar peripheral combined hamartoma in a 6-year-old boy.

Figure 22.78. Similar peripheral combined hamartoma in a 30-year-old man. A choroidal melanoma would be
unlikely to show such traction.

1250
• COMBINED HAMARTOMA OF RETINA AND RETINAL PIGMENT
EPITHELIUM: WIDE-ANGLE IMAGING AND ASSOCIATION WITH
NEUROFIBROMATOSIS AND BRACHIO-OCULO-FACIAL SYNDROME

1. Demirci H, Shields CL, Shields JA. New ophthalmic manifestations of branchio-oculo-facial

syndrome. Am J Ophthalmol 2005;139:362–364.
2. Kadaba P, Arepalli S, Shields JA, et al. Combined hamartoma of the retina and retinal
pigment epithelium in branchio-otic syndrome. J AAPOS 2014 Apr;18(2):201–203.
3. Firestone B, Shields CL, Arias JD, et al. Bilateral combined hamartomas of the retina and
retinal pigment epithelium as the presenting feature of neurofibromatosis type 2 (Wishart
type). J Ped Ophthalmol Strabism 2014;51:e33–36.

Figure 22.79. Large circumpapillary lesion with marked retinal traction in a 12-year-old boy.

1251
Figure 22.80. Montage of a combined hamartoma temporal to the foveal region in a young child. Note again the
severe traction, which would not occur with a comparable-sized melanoma.

Figure 22.81. Two-year-old child with retinal pigment epithelial hyperplasia and atrophy with subtle epiretinal
membrane in the right eye.

1252
Figure 22.82. Same child with advanced epiretinal membrane (combined hamartoma) with retinal dragging in
the left eye causing marked reduction in visual acuity.

Figure 22.83. Abdominal magnetic resonance imaging disclosing multiple paraspinal neuromas (arrows) in
child shown in Figures 22.81 to 22.82, consistent with diagnosis of neurofibromatosis type 2.

1253
Figure 22.84. Combined hamartoma in superior peripheral fundus in an 11-year-old girl. The patient also had
an orbital dermoid cyst and clinical findings compatible with the branchio-oculo-facial syndrome.

1254
• COMBINED HAMARTOMA OF RETINA AND RETINAL PIGMENT
EPITHELIUM: FLUORESCEIN ANGIOGRAPHY

Fluorescein angiography of combined hamartoma shows rather characteristic features.

Figure 22.85. Combined hamartoma temporal to the optic disc in a 30-year-old man.

Figure 22.86. Venous-phase fluorescein angiogram of the lesion shown in Figure 22.85, demonstrating
central hypofluorescence and hyperfluorescence due to early leakage from abnormal blood vessels in the
pigmented lesion.

1255
Figure 22.87. Late angiogram showing ill-defined hyperfluorescence of the lesion.

Figure 22.88. Larger combined hamartoma surrounding the optic disc. Note the scattered yellow retinal
exudation, which is a little more excessive than that usually seen with this condition.

1256
Figure 22.89. Full venous-phase fluorescein angiogram. Note that some of the blood vessels in the region of
the lesion are tortuous, but the blood vessels peripheral to the lesion are straightened due to retinal traction at
the location of the lesion.

Figure 22.90. Late angiogram, showing a rather typical pattern of mild hyperfluorescence.

1257
• COMBINED HAMARTOMA OF RETINA AND RETINAL PIGMENT
EPITHELIUM: OPTICAL COHERENCE TOMOGRAPHY
CORRELATIONS

OCT is a valuable tool for showing preretinal traction associated with combined hamartoma and
may be helpful in making surgical decisions regarding membrane peeling in affected patients
with visual loss. It depicts the extent of involvement of the sensory retina by the lesion and the
location and extent of associated glions.

1. Shields CL, Mashayekhi A, Dai VV, et al. Optical coherence tomography findings of combined
hamartoma of the retina and retinal pigment epithelium in 11 patients. Arch Ophthalmol
2005;123:1746–1750.
2. 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.
3. Arepalli S, Pellegrini M, Ferenczy SR, et al. Combined hamartoma of the retina and retinal
pigment epithelium: Findings on enhanced depth imaging optical coherence tomography in
8 eyes. Retina 2014;34(11):2202–2207.

Figure 22.91. Combined hamartoma inferonasal to the optic disc appearing as a gray lesion in the retina.

1258
Figure 22.92. Optical coherence tomography showing irregularly thickened inner retina with suggestion of
vitreoretinal traction.

Figure 22.93. Combined hamartoma in the macular region with overlying vitreoretinal fibrosis and surrounding
retinal pigment epithelial hyperplasia.

Figure 22.94. Optical coherence tomography showing marked folding of the retina and preretinal fibrosis with
focal vitreous adhesion.

1259
Figure 22.95. Combined hamartoma in the macular region with epiretinal fibrosis and retinal striae.

Figure 22.96. Optical coherence tomography showing the “sawtooth” pattern with “mini-folds” and full-
thickness retinal folding classified as “maxi-folds.”

1260
EPITHELIOMA (ADENOMA) OF THE IRIS PIGMENT EPITHELIUM

General Considerations
True tumors can occasionally develop in the pigment epithelium of the iris (IPE),
ciliary body (CPE), or retina (RPE). Tumors arising in these layers have often been
called adenomas and adenocarcinomas, depending on whether they had benign or
malignant histopathologic features. Because they arise from neuroepithelium and do
not usually form glandular structures, we prefer to use the terms benign and
malignant epithelioma of the pigment epithelia, respectively, rather than adenoma
or adenocarcinoma. Benign and malignant tumors of the pigment epithelia are often
indistinguishable from one another clinically and histopathologically. However, the
differentiation is a moot point because metastasis from pigment epithelial
epithelioma is extremely rare, if it even occurs. Hence, we have chosen to group
them together under the term epithelioma of the pigment epithelium. However,
there are some clinical and histopathologic differences among the tumors that arise
from the IPE, CPE, and RPE. Hence, they are discussed separately based on their
clinical features and anatomic site of origin. This section covers epithelioma of the
IPE (1–24).

Clinical Features
The age range at diagnosis is 11 to 85 years (mean 60 years), and there is no
predisposition for gender (1). The patient is almost always referred because of
suspected iris or ciliary body melanoma. Epithelioma of the IPE is solitary and
unilateral, and 80% are located in the peripheral iris, although it can also originate
near the pupillary margin. Clinically, it is abruptly elevated, dark gray to black in
color, and has a smooth but sometimes multinodular surface. It typically causes
thinning or complete effacement of the overlying iris stroma but, unlike melanoma,
it does not originate in the iris stroma.

Differential Diagnosis
The main lesions in the differential diagnosis of epithelioma of the IPE include iris
nevus, iris or ciliary body melanoma, and cyst of the IPE (2,8). These conditions are
discussed in more detail elsewhere in this book. The uniform black color, site of
origin behind the iris, abruptly elevated margin, and lack of sentinel blood vessels
should be useful in making the diagnosis of epithelioma of the IPE.

Diagnostic Approaches
Although it was previously believed to be difficult or impossible to differentiate
epithelioma of the IPE from iris melanoma, nevus, or melanocytoma, the typical
features should suggest the correct diagnosis. In contrast to iridociliary cyst, it
typically blocks light with transillumination. U ltrasound biomicroscopy can help in
determining the extent of the lesion and help to exclude an iris cyst or cavitary
ciliary body melanoma (9). However, epithelioma of the IPE can sometimes show
small cysts with ultrasound biomicroscopy.

1261
Pathology
Histopathologically, reported cases of epithelioma of the IPE have had rather
consistent features. Low-magnification microscopy shows a deeply pigmented tumor
that appears to arise from adjacent normal IPE. It tends to compress the iris stroma,
but it does not usually infiltrate the stroma. It is characterized cytologically by
irregular cords and tubules of well-differentiated pigment epithelial cells separated
by connective tissue septae. Cystoid spaces that contain melanophages occasionally
are found within the tumor. Rarely, epithelioma of the IPE has been classified as
malignant, based on local invasiveness and cellular pleomorphism.

Management
Epithelioma of the IPE generally has an indolent clinical course. However, it can
occasionally show slow growth and induce the same anterior segment complications
as iris or ciliary body melanoma (2,8). If the diagnosis is suspected clinically and the
lesion is asymptomatic, we generally recommend only observation. In our
experience, between 10% and 15% eventually require surgical removal, usually by
iridocyclogoniectomy, if growth or progressive tumor seeding is demonstrated. The
tumor was managed by iridocyclogoniectomy in 2 of our 20 reported cases and
observation in 18, and all of the latter were stable with follow-up from 6 months to
9 years (1).

Selected References
Series Reviews
1. Shields JA, Shields CL, Mercado G, et al. Adenoma of the iris pigment
epithelium. A report of 20 cases. The 1998 Pan-American Lecture. Arch
Ophthalmol 1999;117:736–741.
2. Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based
on patient age at presentation. Ophthalmology 2012;119:407–414.
3. Asbury MK. Epithelial tumors of the iris. Am J Ophthalmol 1944;27:1094–1104.
4. Laval J. Benign pigment epithelium tumor of the iris. Arch Ophthalmol
1952;48:66–74.
5. Ashton N. Primary tumours of the iris. Br J Ophthalmol 1964;48:650–668.
6. Morris DA, Henkind P. Neoplasms of the iris pigment epithelium. Am J
Ophthalmol 1968;66:31–41.
7. Duke JR, Dunn SN. Primary tumors of the iris. Arch Ophthalmol 1958;59:204–
214.
8. Shields JA, Sanborn GE, Augsburger JJ. The differential diagnosis of malignant
melanoma of the iris. Ophthalmology 1983;90:716–720.

Imaging
9. Bianciotto CG, Shields CL, Romanelli M, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118:1297–1302.

Case Reports
10. Vrabec F, Soukup F. Malignant epithelioma of the pigmented epithelium of the
human iris. Am J Ophthalmol 1963;56:403–409.

1262
11. Bujara K, von Domarus D, Demeler U . Adenoma of the iris pigment epithelium.
Ophthalmologica 1978;177:336–340.
12. Offret H, Saraux H. Adenoma of the iris pigment epithelium. Arch Ophthalmol
1980;98:875–883.
13. Shields JA, Sanborn GE, Augsburger JJ, et al. Adenoma of the iris pigment
epithelium. Ophthalmology 1983;90:735–739.
14. Tso MO, Goldberg MF, Sugar J. Nodular adenomatosis of iris pigment
epithelium. Am J Ophthalmol 1985;100:87–95.
15. Shields CL, Shields JA, Cook GR, et al. Differentiation of adenoma of the iris
pigment epithelium from iris cyst and melanoma. Am J Ophthalmol
1985;100:678–681.
16. Doro S, Werblin TP, Haas B, et al. Fetal adenoma of the pigmented ciliary
epithelium associated with persistent hyperplastic primary vitreous.
Ophthalmology 1986; 93:1343–1450.
17. Rennie IG, Parsons MA, Palmer CA. Congenital adenoma of the iris and ciliary
body: light and electron microscopic observations. Br J Ophthalmol
1992;76:563–566.
18. Isola V, Battaglia Parodi M, Calderini S. Benign adenoma of the iris pigment
epithelium: clinical and iris fluorescein angiographic features. Ophthalmologica
1994;208:172–174.
19. Spraul CW, d’Heurle D, Grossniklaus HE. Adenocarcinoma of the iris pigment
epithelium. Arch Ophthalmol 1996;114:1512–1517.
20. Cursiefen C, Schlötzer-Schrehardt U , Holbach LM, et al. Adenoma of the
nonpigmented ciliary epithelium mimicking a malignant melanoma of the iris.
Arch Ophthalmol 1999;117(1):113–116.
21. Shields JA, Eagle RC Jr, Shields CL, et al. Progressive growth of benign
adenoma of the pigment epithelium of the ciliary body. Arch Ophthalmol
2001;119:859–861.
22. Suzuki J, Goto H, U sui M. Adenoma arising from nonpigmented ciliary
epithelium concomitant with neovascularization of the optic disk and cystoid
macular edema. Am J Ophthalmol 2005;139:188–190.
23. Elizalde J, U bia S, Barraquer RI. Adenoma of the nonpigmented ciliary
epithelium. Eur J Ophthalmol 2006;16(4):630–633.
24. Singh AD, Rundle PA, Longstaff S, et al. Iris pigment epithelial adenoma:
resection and repair. Eye (Lond) 2006;20(3):385–386.

1263
• EPITHELIOMA (ADENOMA) OF THE IRIS PIGMENT EPITHELIUM
1. Shields JA, Sanborn GE, Augsburger JJ, et al. Adenoma of the iris pigment epithelium.
Ophthalmology 1983;90:735–739.
2. Shields CL, Shields JA, Cook GR, et al. Differentiation of adenoma of the iris pigment
epithelium from iris cyst and melanoma. Am J Ophthalmol 1985;100:678–681.

Figure 22.97. Epithelioma of the iris pigment epithelium (IPE) in the peripheral iris in a 63-year-old woman.

Figure 22.98. Gonioscopic view of the lesion shown in Figure 22.97. Note the white strands of residual iris
stroma over the lesion.

1264
Figure 22.99. Multinodular pigmented tumor in the peripheral portion of the anterior chamber seen initially in a
teenaged boy. The lesion was followed, and it showed slow progression and induced secondary glaucoma
from seeding of pigment into the trabecular meshwork.

Figure 22.100. Histopathology of the tumor shown in Figure 22.99 after removal by iridocyclectomy, showing
cords of proliferating pigment epithelium. After tumor removal by iridocyclectomy, the intraocular pressure
returned to normal, and the patient has had 20/20 vision for 25 years since the surgery.

1265
Figure 22.101. Pigmented tumor posterior to the iris as seen with the slit lamp in a 30-year-old African-
American man. The lesion was also removed by iridocyclectomy.

Figure 22.102. Photomicrograph of the lesion shown in Figure 22.101, revealing cords of proliferating pigment
epithelial cells. In this particular section, the IPE (top) is intact, but it was apparent in other sections that the
tumor arose from the IPE. (Hematoxylin–eosin ×150.)

1266
• EPITHELIOMA (ADENOMA) OF THE IRIS AND CILIARY BODY
PIGMENT EPITHELIUM: CLINICOPATHOLOGIC CORRELATION OF A
GROWING LESION

Shields JA, Eagle RC Jr, Shields CL, et al. Clinicopathologic reports, case reports, and small case
series: progressive growth of benign adenoma of the pigment epithelium of the ciliary body.
Arch Ophthalmol 2001;119:1859–1861.

Figure 22.103. Black iris mass nasally in the left eye of a 74-year-old white woman. She had undergone
cataract surgery in the same eye 3 years earlier, at which time no iris lesion was observed. The lesion was
diagnosed as adenoma or iris pigment epithelium, and it was observed periodically.

Figure 22.104. Appearance of the lesion 3 years later, showing definite enlargement of the mass. A smaller
ciliary body component was identified at this time.

1267
Figure 22.105. Gross appearance of the deeply pigmented mass after removal by partial lamellar
iridocyclectomy.

Figure 22.106. Low-magnification photomicrograph of the same lesion, showing cords of deeply pigmented
epithelial cells. The normal central portion of the iris is seen to the left. (Hematoxylin–eosin ×10.)

1268
Figure 22.107. Higher-magnification view of cords and islands of pigment epithelial cells. (Hematoxylin–eosin
×75.)

Figure 22.108. Bleached preparation of the same tumor, showing the cells in better detail. Note the distinct
bundles of cells surrounded by basement membrane. The cells have abundant granular cytoplasm and
uniform nuclei. (Hematoxylin–eosin ×150; bleached.)

1269
EPITHELIOMA (ADENOMA) OF THE CILIARY BODY PIGMENT
EPITHELIUM

General Considerations
Benign and malignant epithelioma (adenoma) can also originate from the ciliary
body pigment epithelium (CPE) (1–19). It generally has somewhat different clinical
and histopathologic features than epithelioma of the IPE and RPE and ciliary body
melanoma.

Clinical Features
In our series of eight patients with this uncommon tumor, the mean age at diagnosis
was 51 years (range 8 to 73 years) (1). The lesion was unilateral and solitary, with
no predilection for gender or race. The referring diagnosis was ciliary body
melanoma in seven cases and cyst in one. No patient was referred with the correct
diagnosis of epithelioma or adenoma of the CPE, but the diagnosis was strongly
suspected on the basis of our clinical examinations.
Clinically, epithelioma of the CPE is usually dark brown to black in color. It is
typically dome shaped, with abruptly elevated margins, but it does not assume a
true mushroom configuration. It often has a mossy, corrugated surface. Even though
it is usually benign cytologically, it can grow slowly and produce subluxation of the
lens, invasion of the anterior chamber, secondary glaucoma, vitreous hemorrhage,
and retinal detachment, similar to ciliary body melanoma.
There have been occasional reports of tumors of the CPE in young children. These
generally have occurred in eyes with other congenital malformations and probably
represent unusual congenital rather than acquired lesions.

Diagnostic Approaches
Fluorescein angiography is more difficult to perform on adenoma of the CPE
because of its occult location behind the iris. However, it usually shows
hypofluorescence in the filling phases and mild late staining of the lesion.
U ltrasonography reveals high internal reflectivity with A-scan and acoustic solidity
with B-scan. U ltrasound biomicroscopy can delineate the solid mass from simulating
cystic lesions (3). Transillumination shows blockage of light by the tumor.
Diagnostic fine-needle aspiration biopsy can disclose pigment epithelial cells
compatible with a tumor of the pigment epithelium (4).

Pathology
Grossly, epithelioma of the CPE is a dark brown to black and is dome shaped, with
abruptly elevated margins. Microscopically, the pedunculated mass arises from a
small base. The tumor generally rests on the inner surface of the ciliary body and
does not involve its stroma. Stromal involvement suggests local malignant
transformation.
A characteristic microscopic feature is the presence of numerous round or oval
clear vacuoles encompassed by cells whose cytoplasm is replete with large,
spherical melanosomes. The vacuoles contain a hyaluronidase-resistant acid

1270
mucopolysaccharide. This microcystic pattern of epithelioma of the CPE differs from
one of the RPE, which reveals more epithelial cords and lacks the microcystic
features.
In some areas, the cells are less pigmented and have features of large epithelial
cells with uniform central nuclei and slightly prominent nucleoli. There may be
mild nuclear atypia, but mitotic figures are rare. Based on cytologic features and
degree of local invasiveness, the tumor is classified as either a benign epithelioma or
malignant epithelioma of the CPE.

Management
The treatment of epithelioma of the CPE varies with the size and extent of the
tumor (1,5,6). Because the tumor has usually been suspected clinically to be a ciliary
body melanoma, it has often been managed as a melanoma. It is possible that some
epitheliomas of the CPE have been treated with radioactive plaques with the
presumed diagnosis of melanoma. However, the sensitivity of this tumor to
radiotherapy is not clearly established. A small asymptomatic lesion in which the
diagnosis of epithelioma is strongly suspected can be managed by periodic
observation. If the tumor is larger and the eye has useful vision, it is best treated by
surgical resection (5,6). Larger tumors with secondary glaucoma and other
complications may require enucleation. The prognosis for vision depends on the
size of the tumor, and the prognosis for life is excellent.

Selected References
Series Reviews
1. Shields JA, Shields CL, Gunduz K, et al. Adenoma of the ciliary body pigment
epithelium. The 1998 Albert Ruedemann Sr. Memorial Lecture. Part 1. Arch
Ophthalmol 1999;117:592–597.
2. Shields CL, Shields JA, Shields MB, et al. Prevalence and mechanisms of
secondary intraocular pressure elevation in eyes with intraocular tumors.
Ophthalmology 1987;94(7):839–846.

Imaging
3. Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118(7):1297–1302.

Pathology
4. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected
intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.

Management
5. Shields JA, Shields CA. Surgical approach to lamellar sclerouvectomy for
posterior uveal melanomas: the 1986 Schoenburg lecture. Ophthalmic Surg
1988;19:774–780.
6. Shields JA, Shields CL, Shah P, et al. Partial lamellar sclerouvectomy for ciliary
body and choroidal tumors. Ophthalmology 1991;98:971–983.

1271
Case Reports
7. Streeten BW, McGraw JL. Tumor of the ciliary pigment epithelium. Am J
Ophthalmol 1972;74:420–429.
8. Wilensky JT, Holland MG. A pigmented tumor of the ciliary body. Arch
Ophthalmol 1974;92:219–220.
9. Naumann G, Volcker HE, Lerche W. Adenom des pigmentierten ciliarepithels.
Klinische, histochemische und elektronenmikroskopische befunde und literatur-
ubersicht. Graefes Arch Clin Exp Ophthalmol 1976;198:245–258.
10. Chang M, Shields JA, Wachtel DL. Adenoma of the pigmented epithelium of
the ciliary body simulating a malignant melanoma. Am J Ophthalmol
1979;88:40–44.
11. Dryja TP, Zakov ZN, Albert DM. Adenocarcinoma arising from the epithelium
of the iris and ciliary body. Int Ophthalmol Clin 1980;20:177–190.
12. Papale JJ, Akiwama K, Hirose T, et al. Adenocarcinoma of the ciliary body
pigment epithelium in a child. Arch Ophthalmol 1984;102:100–103.
13. Lieb WE, Shields JA, Eagle RC, et al. Cystic adenoma of the pigmented ciliary
epithelium: clinical, pathological and immunohistochemical findings.
Ophthalmology 1990;97:1489–1493.
14. Campochiaro PA, Gonzalez-Fernandez F, Newman SA, et al. Ciliary body
adenoma in a 10-year-old girl who had a rhabdomyosarcoma. Arch Ophthalmol
1992;110:681–683.
15. Greenburg PB. Haik BG, Martin PC. A pigmented adenoma of the ciliary
epithelium examined by magnetic resonance imaging. Am J Ophthalmol
1995;120:679–681.
16. Rennie IG, Faulkner MK, Parsons MA. Adenoma of the pigmented ciliary
epithelium. Br J Ophthalmol 1997;78:484–485.
17. Shields JA, Eagle RC Jr, Shields CL, et al. Progressive growth of benign
adenoma of the pigment epithelium of the ciliary body. Arch Ophthalmol
2001;119:1859–1861.
18. Dinakaran S, Rundle PA, Parsons MA, et al. Adenoma of ciliary pigment
epithelium: a case series. Br J Ophthalmol 2003;87(4):504–505.
19. Elizalde J, U bia S, Barraquer RI. Adenoma of the nonpigmented ciliary
epithelium. Eur J Ophthalmol 2006;16(4):630–633.

1272
• EPITHELIOMA (ADENOMA) OF THE CILIARY BODY PIGMENT
EPITHELIUM

Although epithelioma of the CPE is generally pigmented, it can sometimes have areas that lack
pigmentation.

Figure 22.109. Epithelioma of the ciliary body pigment epithelium (CPE) in a 73-year-old woman. Adenoma of
the CPE was a primary diagnostic consideration, but melanoma could not be excluded.

Figure 22.110. Photomicrograph of the resected lesion, showing its characteristic pedunculated shape and
small base. Numerous small cysts are present throughout the mass. (Hematoxylin–eosin ×15.)

1273
Figure 22.111. Ultrasound biomicroscopy of the ciliary body mass in an African-American woman. Clinical
photographs were not successful due to cortical cataract in the quadrant of the lesion. Epithelioma of the ciliary
body pigment epithelium was the leading clinical diagnosis.

Figure 22.112. Low-magnification photomicrograph of the lesion shown in Figure 22.111 following removal by
partial lamellar iridocyclectomy. Note the variable pigmentation in the round, well-circumscribed mass.

1274
Figure 22.113. Photomicrograph of the same lesion, showing alternating areas of pigmented and
nonpigmented cells. (Hematoxylin–eosin ×50.)

Figure 22.114. Photomicrograph of the same lesion, showing epithelial cells with only minimal pigmentation.
(Hematoxylin–eosin ×100.)

1275
• EPITHELIOMA (ADENOMA) OF THE CILIARY BODY PIGMENT
EPITHELIUM WITH POSTERIOR EXTENSION INTO THE RETINAL
PIGMENT EPITHELIUM

Some adenomas appear to arise in the CPE and extend posteriorly into the RPE. Such a tumor
can be resected by partial lamellar cyclochorioretinectomy. A clinicopathologic correlation of
such a case is shown.

Lieb WE, Shields JA, Eagle RC, et al. Cystic adenoma of the pigmented ciliary epithelium.
Clinical, pathological and immunohistochemical findings. Ophthalmology 1990;97:1489–1493.

Figure 22.115. Fundus photograph of a peripheral, pigmented, hemorrhagic mass in a 52-year-old man. There
is overlying vitreous hemorrhage.

1276
Figure 22.116. Late fluorescein angiogram, showing ill-defined, patchy hyperfluorescence of the mass.

Figure 22.117. B-scan ultrasonogram, showing an abruptly elevated mass with acoustic solidity.

1277
Figure 22.118. Low-magnification photomicrograph, showing the mass after removal by cyclochoroidectomy.

Figure 22.119. Microscopic appearance of the tumor. Note the pigmented cells with numerous clear cystic
spaces. (Hematoxylin–eosin ×200.)

1278
Figure 22.120. Fundus appearance of the resected area after 2 years, showing clear margins without tumor
recurrence.

1279
EPITHELIOMA (ADENOMA) OF THE RETINAL PIGMENT EPITHELIUM

General Considerations
An acquired neoplasm that arises from the RPE has features that are generally
different from choroidal melanoma and from neoplasms of the IPE or CPE (1–37). It
can be benign or malignant, but even the more malignant variants rarely, if ever,
exhibit regional or distant metastasis. Because their clinical features and
management are similar, benign and malignant types are discussed collectively here
under the term epithelioma of the RPE.

Clinical Features
Epithelioma of the RPE is generally diagnosed in adulthood, with a mean age of 53
years (range 28 to 79 years). U nlike uveal melanoma, this tumor appears to have no
predilection for race. It may have a slight predilection for females (1). Although
adenoma of the RPE usually occurs in an otherwise normal eye, it is also seen in
eyes that had prior insults like inflammation or trauma. In such instances, the
epithelioma may arise from a prior reactive hyperplasia of the RPE.
Epithelioma of the RPE is usually solitary and unilateral and begins as a small,
deep retinal tumor that is dark brown to black in color. It usually grows very slowly
and invades the overlying sensory retina, at which time it often acquires a retinal
feeding artery and draining vein, both of which can become dilated and tortuous,
similar to those seen with the retinal hemangioblastoma. Yellow intraretinal
exudation can slowly accumulate and eventually reach the subretinal space,
producing intraretinal and subretinal yellow exudation, a finding that would be
extremely rare with choroidal melanoma. In rare instances in which the tumor
remains untreated, it may fill the globe and extend through the sclera to involve the
orbital soft tissues (28). In some instances, epithelioma of the RPE has arisen from
solitary CHRPE (4).

Diagnostic Approaches
In our series, all patients were referred with the diagnosis of suspected choroidal
melanoma (1). Transillumination generally reveals partial to complete blockage of
light by the tumor. Fluorescein angiography can document the retinal feeder vessels
and show early hypofluorescence and late minimal hyperfluorescence of the tumor,
without visibility of choroidal vessels. U ltrasonography typically demonstrated the
tumor to be abruptly elevated and to have medium to high internal reflectivity and
acoustic solidity. Cytologic evaluation of diagnostic fine-needle aspiration biopsy
reveals cells compatible with a pigment epithelial tumor (9).

Pathology
Microscopically, epithelioma of the RPE is composed of a neoplastic proliferation of
RPE cells forming cords or tubules. Most cases show well-differentiated cells, but
others may be poorly differentiated. There is frequently tumor invasion of the
overlying sensory retina and underlying choroid. Tumors in the anterior portion of
the RPE often show microcysts, similar to epithelioma of the CPE, and those in the

1280
posterior portion of the RPE have a glandular or tubular configuration.

Management
Treatment of epithelioma of the RPE must necessarily vary from case to case. We
believe that a small, asymptomatic lesion can be safely observed. If the tumor is
located anterior to the equator and shows growth, we have preferred local resection
by partial lamellar sclerouvectomy (10) or plaque radiotherapy. If it is located
posterior to the equator and begins to produce exudative retinal detachment, then
laser treatment, thermotherapy, or cryotherapy can be attempted. Plaque
radiotherapy can be used for medium-sized or larger tumors in eyes with good
vision. If vitreoretinal traction is contributing to visual loss, then vitrectomy with
intraocular gas to reattach the retina can be employed in conjunction with the
aforementioned modalities.

Selected References
Series Reviews
1. 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.
2. Greer CH. Epithelial tumours of the retinal pigment epithelium. Trans
Ophthalmol Soc UK 1952;72:265–277.
3. Laqua H. Tumors and tumor-like lesions of the retinal pigment epithelium.
Ophthalmologica 1981;183:34–38.
4. Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital
hypertrophy of the retinal pigment epithelium. Arch Ophthalmol 2000;118:637–
641.
5. Shields JA, Shields CL, Gunduz K, et al. Adenoma of the ciliary body pigment
epithelium: the 1998 Albert Ruedemann, Sr, memorial lecture, Part 1. Arch
Ophthalmol 1999;117:592–597.
6. Shields JA, Mashayekhi A, Ra S, et al. Pseudomelanomas of the posterior uveal
tract. The 2006 Taylor Smith Lecture. Retina 2005;25:767–771.
7. Shields CL, Manalac J, Das C, et al. Choroidal melanoma. Clinical features,
classification, and top 10 pseudomelanomas. Curr Opin Ophthalmol
2014;25(3):177–185.

Pathology
8. Tso MO, Albert DM. Pathologic conditions of the retinal pigment epithelium.
Arch Ophthalmol 1972;88:27–38.
9. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected
intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.

Management
10. Shields JA, Shields CL, Shah P, et al. Partial lamellar sclerouvectomy for ciliary
body and choroidal tumors. Ophthalmology 1991;98:971–983.

Case Reports
11. Theobald GD, Floyd G, Kirk HQ. Hyperplasia of the retinal pigment

1281
 epithelium. Simulating a neoplasm: report of two cases. Am J Ophthalmol
1958;45:235–240.
12. Fair JR. Tumors of the retinal pigment epithelium. Am J Ophthalmol
1958;45:495–505.
13. Blodi FC, Reuling FH, Sornson ET. Pseudomelanocytoma at the optic
nervehead: an adenoma of the retinal pigment epithelium. Arch Ophthalmol
1965;73:353–355.
14. Garner A. Tumours of the retinal pigment epithelium. Br J Ophthalmol
1970;54:715–723.
15. deHaan AB. Tumour of the pigment epithelium. Ophthalmologica 1971;163:26.
16. Font RL, Zimmerman LE, Fine BS. Adenoma of the retinal pigment epithelium.
Am J Ophthalmol 1972;73:544–554.
17. Minckler D, Allen AW. Adenocarcinoma of the retinal pigment epithelium.
Arch Ophthalmol 1978;96:2252–2254.
18. Chamot L, Zografos L. Tumeurs et pseudo-tumeurs de l’epithelium pigmentaire.
J Fr Ophthalmol 1984;7:825–836.
19. Jampel HD, Schachat AP, Conway B, et al. Retinal pigment epithelial
hyperplasia assuming tumor-like proportions: a report of two cases. Retina
1986;6:105–112.
20. Ramahefasolo S, Coscas G, Regenbogen L, et al. Adenocarcinoma of retinal
pigment epithelium. Br J Ophthalmol 1987;71:516–520.
21. Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented adenoma of the optic
nerve head simulating a melanocytoma. Ophthalmology 1992;99:1705–1708.
22. Shields JA, Eagle RC Jr, Barr CC, et al. Adenocarcinoma of the retinal pigment
epithelium arising from a juxtapapillary histoplasmosis scar. Arch Ophthalmol
1994;112:650–653.
23. Fan JT, Robertson DM, Campbell RJ. Clinicopathologic correlation of a case of
adenocarcinoma of the retinal pigment epithelium. Am J Ophthalmol
1995;119:243–245.
24. Finger PT, McCormick SA, Davidian M, et al. Adenocarcinoma of the retinal
pigment epithelium: a diagnostic and therapeutic challenge. Graefes Arch Clin
Exp Ophthalmol 1996;234:S22–S27.
25. Loeffler KU , Kivela T, Borgmann H, et al. Malignant tumor of the retinal
pigment epithelium with extraocular extension in a phthisical eye. Graefes Arch
Clin Exp Ophthalmol 1996;234:S70–S75.
26. 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.
27. Loose IA, Jampol LM, O’Grady R. Pigmented adenoma mimicking a
juxtapapillary melanoma. A 20-year follow-up. Arch Ophthalmol 1999;117:120–
122.
28. Shields JA, Shields CL, Eagle RC Jr, et al. Adenocarcinoma arising from
congenital hypertrophy of the retinal pigment epithelium. Arch Ophthalmol
2001;119:597–602.
29. Shields JA, Melki T, Shields CL, et al. Epipapillary adenoma of retinal pigment
epithelium. Retina 2001;21:76–78.
30. Shields JA, Materin M, Shields CL, et al. Adenoma of the retinal pigment
epithelium simulating a juxtapapillary choroidal neovascular membrane. Arch

1282
 Ophthalmol 2001;119:289–292.
31. Heegaard S, Larsen JN, Fledelius HC, et al. Neoplasia versus hyperplasia of the
retinal pigment epithelium. A comparison of two cases. Acta Ophthalmol Scand
2001; 79:626–633.
32. Sommacal A, Campbell RJ, Helbig H. Adenocarcinoma of the retinal pigment
epithelium. Arch Ophthalmol 2003;121:1481–1483.
33. Heindl LM, Naumann GO, Kruse FE, et al. Aggressive metastasizing
adenocarcinoma of the retinal pigment epithelium with trisomy 21. Br J
Ophthalmol 2008;92(3):389–391.
34. Shields JA, Eagle RC Jr, Shields CL, et al. Malignant transformation of
congenital hypertrophy of the retinal pigment epithelium. Ophthalmology
2009;116(11):2213–2216.
35. Palamar M, Shields CL, Marr BP, et al. Retinal pigment epithelial tumor in a
young Asian female. Eur J Ophthalmol 2009;19(3):487–489.
36. Wei W, Mo J, Jie Y, Li B. Adenoma of the retinal pigment epithelium: A report
of 3 cases. Can J Ophthalmol 2010;45(2):166–170.
37. Cupp DG, McCannell TA. Macular pucker in association with RPE adenoma: A
report of a case and review of the literature. Semin Ophthalmol 2013;29:199–
201.

1283
• BENIGN EPITHELIOMA (ADENOMA) OF THE RETINAL PIGMENT
EPITHELIUM: FLUORESCEIN ANGIOGRAPHY AND
ULTRASONOGRAPHY

Fluorescein angiography and ultrasonography may provide help in differentiating a neoplasm of

the RPE from choroidal melanoma. With angiography, the RPE tumor is more likely to have
retinal feeding and draining vessels and tends to be less hyperfluorescent than most melanomas.
With ultrasonography, it tends to show higher internal reflectivity than melanoma.

Figure 22.121. Abruptly elevated, deeply pigmented, oval-shaped mass near the equator of the eye in a 47-
year-old woman.

1284
Figure 22.122. Early fluorescein angiogram, showing hypofluorescence of the mass and the slightly prominent
retinal feeder vessel.

Figure 22.123. B-scan ultrasonogram, showing a pedunculated mass with acoustic solidity. Because of
progression, the lesion was eventually removed surgically by a partial lamellar sclerouvectomy.

Figure 22.124. Histopathology of the lesion shown in Figure 22.123, demonstrating proliferation of pigment
epithelial cells and typical microcysts that characterize some epitheliomas of the peripheral retinal pigment
epithelium and most epitheliomas of the ciliary body pigment epithelium.

1285
Figure 22.125. Fundus appearance of a black retinal mass with retinal feeder vessels and surrounding retinal
exudation. This is highly suggestive of an epithelioma of the RPE, and choroidal melanoma would be unlikely
to show such yellow exudation.

Figure 22.126. Cytopathology of a fine-needle biopsy of the lesion shown in Figure 22.125. The deeply
pigmented cells were compatible with epithelial cells and bleached preparations, and immunohistochemistry
supported the diagnosis of benign epithelioma or retinal pigment epithelium. Based on results of
cytopathology, the patient is being followed, without treatment.

1286
• EPITHELIOMA (ADENOMA) OF RETINAL PIGMENT EPITHELIUM IN
AFRICAN-AMERICAN PATIENTS

In some patients, particularly African Americans, an adenoma of the RPE can become highly
elevated, invade the sensory retina, assume a dilated retinal feeding artery and draining vein,
and produce an exudative retinal detachment. Two such cases are illustrated. Both patients
declined enucleation after plaque radiotherapy failed to control the tumor, and the affected eye
became phthisical in both instances.

Figure 22.127. Fundus drawing of presumed epithelioma of the retinal pigment epithelium in a 28-year-old
African-American man. The b lue area depicts a secondary retinal detachment.

1287
Figure 22.128. Fundus photograph of the posterior fundus of the same eye, showing dilated retinal blood
vessels and retinal exudation.

Figure 22.129. Fundus photograph of more peripheral area showing the black pedunculated tumor and the
dilated, tortuous feeding and draining blood vessels, and the yellow retinal exudation.

Figure 22.130. Fundus drawing of epithelioma of the retinal pigment epithelium in a 31-year-old African-
American woman.

1288
Figure 22.131. Fundus photograph of the same patient, showing dilated retinal blood vessels and retinal
exudation and a deeply pigmented retinal tumor.

Figure 22.132. Fundus photograph of a more peripheral area, showing the black pedunculated tumor with
surrounding retinal exudation.

1289
• EPITHELIOMA (ADENOMA) OF RETINAL PIGMENT EPITHELIUM
SIMULATING A MELANOCYTOMA

In some instances, an adenoma of the RPE can occur on the optic disc and clinically simulate a
melanocytoma.

Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented adenoma of the optic nerve head
simulating a melanocytoma. Ophthalmology 1992;99:1705–1708.

Figure 22.133. Fundus photograph of a pigmented juxtapapillary lesion in an 86-year-old woman. Based on
the clinical appearance, the lesion was believed to be a melanocytoma when evaluated a number of years
ago. Today, tumor of the retinal pigment epithelium would most likely be suspected.

1290
Figure 22.134. Fluorescein angiogram in the venous phase, showing hypofluorescence of the lesion.

Figure 22.135. Fluorescein angiogram in the late phase, showing continued hypofluorescence of the lesion.

Figure 22.136. The patient died of an unrelated cause, and the eye was obtained and studied postmortem.
Gross photograph shows the pigmented lesion adjacent to the optic disc.

1291
Figure 22.137. Histopathology, showing the pigmented mass causing elevation of the optic nerve head.
(Hematoxylin–eosin ×20.)

Figure 22.138. Histopathology, showing cords of pigment epithelial cells with moderate connective tissue
stroma. (Hematoxylin–eosin ×100.)

1292
• EPITHELIOMA (ADENOMA) OF RETINAL PIGMENT EPITHELIUM
SIMULATING MELANOMA

Illustrated is a clinicopathologic correlation of an intraocular tumor that prompted enucleation

because choroidal melanoma was a diagnostic consideration. In retrospect, the dark-black color
and surrounding yellow exudation are more suggestive of a neoplasm of the RPE rather than
melanoma. Melanocytoma, also a diagnostic consideration, would also be unlikely to produce
such extensive circinate exudation.

Shields JA, Melki T, Shields CL, et al. Epipapillary adenoma of the retinal pigmented epithelium.
Retina 2001;21:76–78.

Figure 22.139. Pedunculated black mass overlying the optic disc in a 45-year-old man with 20/30 vision in the
affected eye. He was informed 23 years earlier that he had a small “nevus” adjacent to his optic disc. Note the
yellow circinate exudation around the mass.

1293
Figure 22.140. Fluorescein angiogram in the venous phase, showing hypofluorescence of the mass.

Figure 22.141. Late fluorescein angiogram, revealing continued hypofluorescence of the central portion of the
mass and surrounding hyperfluorescence corresponding to subretinal fluid. A fine-needle aspiration biopsy
was advised but not done because the patient was fearful of melanoma and requested enucleation.

1294
Figure 22.142. Gross section of the enucleated eye, showing an elevated black mass in the posterior pole with
surrounding yellow exudation.

Figure 22.143. Histopathology of tumor, showing cords of pigmented epithelial cells resting on a basement
membrane. (Hematoxylin–eosin ×200.)

1295
Figure 22.144. Bleached section, better showing the epithelial nature of the benign tumor cells. It was
interpreted as a benign epithelioma (adenoma) of the RPE. (Hematoxylin–eosin ×200; bleached.)

1296
• EPITHELIOMA OF RETINAL PIGMENT EPITHELIUM SIMULATING A
CHOROIDAL NEOVASCULAR MEMBRANE

Epithelioma of the RPE can sometimes be nonpigmented and resemble a choroidal neovascular
membrane.

Shields JA, Materin M, Shields CL, et al. Adenoma of the retinal pigment epithelium simulating a
juxtapapillary choroidal neovascular membrane. Arch Ophthalmol 2001;119:289–292.

Figure 22.145. Amelanotic thickening of the retina temporal to the optic disc and mild hyperemia of the optic
disc in a 79-year-old man. The patient was treated elsewhere with laser 13 years earlier for a presumed
juxtapapillary choroidal neovascular membrane.

1297
Figure 22.146. Fluorescein angiogram in the venous phase, showing reticular hyperfluorescence in the central
portion of the lesion with surrounding hyperfluorescence.

Figure 22.147. Late angiogram, showing hyperfluorescence of the lesion secondary to leakage of dye into the
surrounding retinal tissue.

Figure 22.148. B-scan ultrasonogram, showing an elevated mass measuring 2 mm in thickness. The vision
had deteriorated to finger counting, and the patient elected enucleation when informed of a slight possibility of
malignant neoplasm.

1298
Figure 22.149. Histopathology, showing a dome-shaped mass deep to the atrophic retina. (Hematoxylin–eosin
×10.)

Figure 22.150. Appearance of cells forming epithelial cords resting on a delicate basement membrane.
(Periodic acid-Schiff ×200.) Immunohistochemistry revealed the cells to be cytokeratin positive and HMB-45
negative, supporting the diagnosis of epithelioma of the RPE, rather than melanoma.

1299
• MALIGNANT EPITHELIOMA (ADENOCARCINOMA) OF RETINAL
PIGMENT EPITHELIUM DIAGNOSED BY FINE-NEEDLE ASPIRATION
BIOPSY

Another case of nonpigmented malignant epithelioma of the RPE is shown.

Shields JA, Eagle RC Jr, Barr CC, et al. Adenocarcinoma of the retinal pigment epithelium arising
from a juxtapapillary histoplasmosis scar. Arch Ophthalmol 1994;112:650–653.

Figure 22.151. Fundus photograph of an amelanotic dome–shaped tumor adjacent to the optic disc and
exudative retinal detachment in a 69-year-old woman with ocular histoplasmosis syndrome. The lesion had
shown progressive growth and was diagnosed as a choroidal melanoma by several retinal specialists.
Because of progressive tumor growth and visual loss, fine-needle aspiration biopsy was performed.

1300
Figure 22.152. Cytology of a fine-needle aspiration biopsy specimen, showing a cluster of tumor cells.
(Papanicolaou ×250.)

Figure 22.153. Immunohistochemical stain for cytokeratin showing immunoreactivity in the tumor cells.
Cytopathology and immunohistochemistry suggested a malignant tumor of the pigment epithelium. Because
of progressive growth of the tumor and poor vision, the patient chose to have enucleation. (CAM 52 cytokeratin
×200.)

Figure 22.154. Gross photograph of the sectioned globe, showing an elevated mass in the posterior pole.
Note the extensive yellow exudation throughout a wide area of the fundus.

1301
Figure 22.155. Low-magnification photomicrograph, showing the tumor occupying the prepapillary region.
Note that the choroid is not affected by the tumor. (Hematoxylin–eosin ×25.)

Figure 22.156. Photomicrograph, showing cords of mildly anaplastic tumor cells with moderate nuclear
pleomorphism and prominent nucleoli. (Hematoxylin–eosin ×200.)

1302
• EPITHELIOMA (ADENOMA) OF THE RETINAL PIGMENT EPITHELIUM
ARISING FROM CONGENITAL HYPERTROPHY OF THE RPE

Although CHRPE was traditionally believed to be a stationary lesion, it is now known to

occasionally show slow growth and spawn an elevated mass, believed to be an epithelioma of
the RPE.

Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital hypertrophy of the
retinal pigment epithelium. Arch Ophthalmol 2000;118:637–641.

Figure 22.157. Typical congenital hypertrophy of the retinal pigment epithelium in the fundus inferiorly in a 66-
year-old man. Note the depigmented lacunae and the small black nodule in the center of the lesion.

1303
Figure 22.158. Fluorescein angiogram of the lesion shown in Figure 22.157. Note the retinal feeder vessel that
supplies the central nodule.

Figure 22.159. Focal nodule arising from congenital hypertrophy of the retinal pigment epithelium in a 54-year-
old woman. Note that the nodular growth is already associated with slight yellow retinal exudation.

Figure 22.160. The same lesion shown in Figure 22.159 after 8 years, revealing enlargement of the nodule
and accumulation of extensive yellow exudation. The peripheral asymptomatic lesion in this elderly woman
was eventually treated with a radioactive plaque. There was an initial favorable response, but she was later
lost to follow-up.

1304
Figure 22.161. Focal elevated nodule arising from equatorial congenital hypertrophy of the retinal pigment
epithelium in an African-American woman.

Figure 22.162. The same lesion shown in Figure 22.161 after 8 years, demonstrating marked enlargement of
the nodule with surrounding exudation and acquisition of a visible retinal blood supply. After 10 years, the
nodule had grown slightly but the patient remained asymptomatic.

1305
• MALIGNANT EPITHELIOMA (ADENOCARCINOMA) OF RETINAL
PIGMENT EPITHELIUM ARISING FROM CONGENITAL
HYPERTROPHY OF THE RPE

In rare instances, a malignant epithelioma has been documented to arise from CHRPE. Like
benign epithelioma of the RPE, such a lesion is generally low grade and has no known tendency
to metastasize. Such a case is depicted.

Shields JA, Shields CL, Eagle RC Jr, et al. Adenocarcinoma arising from congenital hypertrophy
of the retinal pigment epithelium. Arch Ophthalmol 2001;119:597–602.

Figure 22.163. Fundus drawing in January 1997, showing a fleshy yellow mass arising in an area of
congenital hypertrophy of the retinal pigment epithelium in a middle-aged woman.

1306
Figure 22.164. Fundus photograph in January 1997.

Figure 22.165. Fundus drawing in late 1999, showing a fleshy-yellow mass arising in an area of congenital
hypertrophy of the retinal pigment epithelium and invading the overlying vitreous and producing subretinal
exudation. The lesion was removed by partial lamellar cyclochoroidectomy.

1307
Figure 22.166. Appearance of a sectioned gross specimen, showing an amelanotic mass with a deeply
pigmented central area.

Figure 22.167. Microscopic appearance of tumor cells. Note the epithelial appearance of the cells and
cytoplasmic pigment and thick basement membranes. (Hematoxylin–eosin ×200.)

1308
Figure 22.168. Monolayer of deeply pigmented epithelial cells, consistent with congenital hypertrophy of the
retinal pigment epithelium (CHRPE), near the base of the tumor. Note the abrupt transition between the
CHRPE and the overlying mass. (Hematoxylin–eosin ×250.) The lesion was interpreted by ophthalmic
pathologists as a low-grade adenocarcinoma malignant epithelioma arising from the CHRPE.

1309
• PRESUMED EPITHELIOMA (ADENOMA) OF RETINAL PIGMENT
EPITHELIUM ARISING FROM A LASER SCAR

Nodular tumors can also develop from areas of focal hyperplasia of the RPE. These unusual
tumors tend to grow through the sensory retina and actually cause a characteristic tumor-
induced retinal hole. Depicted is such a tumor that developed from RPE hyperplasia at the site
of laser treatment for central serous retinopathy.
It was diagnosed as benign tumor of the RPE from cytopathology of a fine-needle aspiration
biopsy specimen.

Shields JA, Shields CL, Slakter J, et al. Locally invasive tumors arising from hyperplasia of the
retinal pigment epithelium. A report of two cases. Retina 2001;21:487–492.

Figure 22.169. Fundus appearance in 1982 shortly after laser photocoagulation elsewhere for central serous
chorioretinopathy in a young adult male. Indirect laser treatment was apparently done just temporal to the
prominent foveal scar.

1310
Figure 22.170. Fundus in 1984, showing a tiny focus of retinal pigment epithelium hyperplasia, presumably
arising at the site of laser treatment.

Figure 22.171. Appearance in 1996, showing a black tumor that has extended through the sensory retina and
produced a full-thickness retinal hole with the tumor apposed to the posterior vitreous face. Note the retinal
pigment epithelium degeneration around the pigmented nodule.

1311
Figure 22.172. Late fluorescein angiogram, showing a central area of hypofluorescence and surrounding
transmission of choroidal fluorescence through the areas of retinal pigment epithelium atrophy.

Figure 22.173. B-scan ultrasonogram, showing highly reflectivity echoes near the anterior surface of the tumor.
This became denser in subsequent studies and was interpreted as osseous metaplasia of the retinal
pigment epithelium confined to the area of the lesion.

1312
Figure 22.174. Cytopathology of a fine-needle aspiration biopsy specimen. Special studies confirmed them to
be epithelial cells compatible with retinal pigment epithelium origin. The patient was still being followed in
2006, with finger counting vision and very slow growth and increasing calcification of the mass seen by
ultrasonography.

1313
• PRESUMED EPITHELIOMA (ADENOMA) OF THE RETINAL PIGMENT
EPITHELIUM ARISING FROM AN INFLAMMATORY SCAR

Shields JA, Shields CL, Slakter J, et al. Locally invasive tumors arising from hyperplasia of the
retinal pigment epithelium. A report of two cases. Retina 2001;21:487–492.

Figure 22.175. Irregular, flat hyperplasia of the retinal pigment epithelium in the foveal area of a 20-year-old
woman with visual loss. The diagnosis of the ophthalmologist at that time was possible retinal toxoplasmosis.

Figure 22.176. The same lesion when the patient was 46 years old. Note the dome-shaped black nodule,
which has produced a full-thickness, tumor-induced retinal hole similar to that in Figure 22.171.

1314
Figure 22.177. Fluorescein angiogram in the venous phase, showing uniform hypofluorescence of the lesion.
Note that a retinal blood vessel disappears from view as it enters the lesion, confirming the superficial location
of the lesion.

Figure 22.178. Late fluorescein angiogram, showing central hypofluorescence with surrounding
hyperfluorescence due to retinal pigment epithelium alterations. Note the similarity to Figure 22.179.

1315
Figure 22.179. B-scan ultrasonogram, showing a dome-shaped mass with slight acoustic hollowness but no
choroidal excavation.

Figure 22.180. Cytopathology of a fine-needle aspiration biopsy specimen. Special studies confirmed them to
be epithelial cells compatible with retinal pigment epithelium origin.

1316
• MALIGNANT EPITHELIOMA OF THE RETINAL PIGMENT
EPITHELIUM: AGGRESSIVE VARIANT

In some cases, malignant epithelioma of the RPE can become highly aggressive and fill the
globe and extend into the extraocular tissues.

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.

Figure 22.181. External photograph of the right eye, showing pannus and complete opacification of the cornea
in 77-year-old woman. The eye had been blind for several years.

Figure 22.182. Photograph 1 year later, showing proptosis of the right eye and a hemorrhagic mass in the
inferior aspect of the conjunctiva.

1317
Figure 22.183. Axial computed tomography scan demonstrating proptosis of the right globe and linear
calcification along the eye wall. There is a massive lesion filling the globe and orbit. Note the intraocular bone
echoes, which represent osseous metaplasia of the retinal pigment epithelium.

Figure 22.184. Gross photograph of the sectioned globe, showing thin-walled posterior staphyloma filled with
a mixture of blood and hemorrhagic tumor tissue protruding from the posterior aspect of the eye (right). Lightly
colored necrotic tumor fills the vitreous cavity (left).

1318
Figure 22.185. Photomicrograph, showing cords of nonpigmented neoplastic cells with linear basement
membrane. (Hematoxylin–eosin ×200.)

Figure 22.186. Photomicrograph, showing cords of low-grade malignant cells. (Hematoxylin–eosin ×300.)
Although debatable, most ophthalmic pathologists believed that the lesion arose from the retinal pigment
epithelium rather than the nonpigmented ciliary epithelium.

1319
 CHAPTER 23

TUMORS OF THE NONPIGMENTED CILIARY

EPITHELIUM

CONGENITAL NEOPLASMS (MEDULLOEPITHELIOMA)

Several neoplasms and related lesions can originate in the nonpigmented ciliary
epithelium (NPCE). Zimmerman classified these lesions into congenital and acquired
types (1,2). We use the following modification of Zimmerman’s classification:
I. Congenital
A. Glioneuroma
B. Nonteratoid medulloepithelioma (diktyoma)
1. Benign
2. Malignant
C. Teratoid medulloepithelioma
1. Benign
2. Malignant
II. Acquired
A. Pseudoepitheliomatous hyperplasia
1. Reactive
2. Age-related (Fuchs adenoma; coronal adenoma)
B. Benign epithelioma
1. Solid
2. Papillary
3. Pleomorphic
C. Malignant epithelioma
1. Solid
2. Papillary
3. Pleomorphic

1320
Some, like glioneuroma, are exceedingly rare. We have only seen one case that may
have met criteria for that diagnosis, but this rare tumor is not discussed here. The
acquired tumors have generally been called “adenomas.” However, because they are
tumors derived from neuroepithelium, we prefer to call them neuroepithelioma or,
simply, epithelioma of the NPCE.

Congenital Neoplasms of the Nonpigmented Ciliary Epithelium

(Intraocular Medulloepithelioma)

General Considerations
The most important congenital tumor of the NPCE is medulloepithelioma, a
nonhereditary, embryonal neoplasm generally diagnosed in the first decade of life
(1–50). On occasion, the tumor is not recognized until adulthood (40,50). It arises
from the medullary epithelium, or inner layer of the optic cup, prior to its
differentiation into its adult derivatives. It most commonly occurs in the ciliary
body, where it presumably arises from the anterior lip of the optic cup. However,
medulloepithelioma has occasionally been recognized in the optic nerve
(30–33,41,43).

Clinical Features
An early clinical feature is a “lens coloboma,” which is actually a notch in the lens
due to congenital absence of zonule in the quadrant of the tumor. Examination of
the adjacent ciliary body reveals a rather typical fleshy, pink-to-tan mass. Clear cysts
are often present within the mass. The cysts may become a prominent part of the
tumor and may even break free from the mass to float freely in the anterior
chamber or vitreous cavity (12). Rarely, a medulloepithelioma may be pigmented
(34–36).
A characteristic neoplastic cyclitic membrane can develop, sometimes suggesting
the diagnosis of persistent hyperplastic primary vitreous (PHPV) (1). Secondary
glaucoma occurs in 60% of cases and is most often due to iris neovascularization
and secondary angle closure (1,5,6). Retinal detachment is a common complication.
There is often a long delay in diagnosis and sometimes misdirected therapy. Patients
have often undergone cataract surgery, glaucoma surgery, and vitreous surgery while
the underlying tumor remained unsuspected.
Extraocular extension with orbital invasion is an uncommon complication of
medulloepithelioma (1). Central nervous system extension has rarely been
recognized. It can be fatal due to progressive intracranial growth of the neoplasm.
Tumors that demonstrate extraocular extension, a very rare occurrence, can
metastasize to regional lymph nodes and systemic sites.
Medulloepithelioma of the optic nerve generally presents with visual loss and an
elevated amelanotic mass in the posterior pole, obscuring a view of the optic disc.
In that location, the tumor can show slow growth and cause secondary exudation or
retinal detachment (30–33,41,43).

Diagnostic Approaches
Fluorescein angiography shows early hyperfluorescence and gradual late staining of
the mass. U ltrasonography reveals a mass pattern with acoustic solidity and high

1321
internal reflectivity (8). Areas of cartilage within the mass can produce echoes very
similar to those with dystrophic calcification seen with retinoblastoma (8–10).

Pathology
Medulloepithelioma can be classified histopathologically into nonteratoid and
teratoid types, and both can be cytologically benign or malignant. In our experience
more than 80% of intraocular medulloepitheliomas are cytologically malignant. The
nonteratoid type consists purely of cells that resemble ciliary epithelium and is
sometimes called a diktyoma, derived from the Greek word meaning “fish net.” The
teratoid type demonstrates heteroplastic elements such as cartilage,
rhabdomyoblasts, and brain. Cysts found in both types contain a hyaluronidase-
sensitive mucopolysaccharide, identical to vitreous, that is secreted by the tumor
cells, forming secondary cysts (1–3,14–19). Recurrent medulloepithelioma tends to
have more malignant histopathologic features. Melanin granules are occasionally
present in the cytoplasm, which explains why some tumors are clinically
pigmented. Eyes with medulloepithelioma are often found to have degrees of
persistence of the hyaloid system, another developmental abnormality (1,3).

Management
Although most eyes with medulloepithelioma require enucleation, a small,
circumscribed medulloepithelioma can be managed by iridocyclectomy. Plaque
radiotherapy is an option for localized or recurrent tumor, but its role has not been
clearly defined (21,23). Because deaths have occurred only in patients with
advanced extrascleral extension, orbital exenteration should be considered if there is
extensive orbital involvement. The role of irradiation and chemotherapy for
intraocular medulloepithelioma is not established.

Selected References
Large Series
1. Kaliki S, Shields CL, Eagle RC Jr, et al. Ciliary body medulloepithelioma:
analysis of 41 cases. Ophthalmology 2013;120(12):2552–2559.
2. Zimmerman LE. The remarkable polymorphism of tumors of the ciliary
epithelium. The Norman McAlister Gregg Lecture. Trans Aust Coll Ophthalmol
1970;2:114–125.
3. Broughton WI, Zimmerman LE. A clinicopathologic study of 56 cases of
intraocular medulloepitheliomas. Am J Ophthalmol 1978;85:407–418.
4. Canning CR, McCartney AC, Hungerford J. Medulloepithelioma (diktyoma). Br
J Ophthalmol 1988;72:764–767.
5. Shields JA, Eagle RC Jr, Shields CL, et al. Congenital neoplasms of the
nonpigmented ciliary epithelium (medulloepithelioma). Ophthalmology
1996;103:1998–2006.
6. Singh A, Singh AD, Shields CL, et al. Iris neovascularization in children as a
manifestation of underlying medulloepithelioma. J Pediatr Ophthalmol
Strabismus 2001;38:224–228.
7. 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

1322
 2011;95(7):1001–1005.

Imaging
8. Shields JA, Eagle RC, Shields CL, et al. Fluorescein angiography and
ultrasonography of malignant intraocular medulloepithelioma. J Pediatr
Ophthalmol Strabismus 1996;33:193–196.
9. Garcia-Feijoo J, Encinas JL, Mendez-Hernandez C, et al. Medulloepithelioma of
the ciliary body: ultrasonographic biomicroscopic findings. J Ultrasound Med
2005; 24:247–250.
10. Vajaranant TS, Mafee MF, Kapur R, et al. Medulloepithelioma of the ciliary
body and optic nerve: clinicopathologic, CT, and MR imaging features.
Neuroimaging Clin N Am 2005;15(1):69–83.
11. Sosinska-Mielcarek K, Senkus-Konefka E, Jaskiewicz K, et al. Intraocular
malignant teratoid medulloepithelioma in an adult: clinicopathological case
report and review of the literature. Acta Ophthalmol Scand 2006;84:259–262.
12. Zhou M, Xu G, Bojanowski CM, et al. Differential diagnosis of anterior chamber
cysts with ultrasound biomicroscopy: ciliary body medulloepithelioma. Acta
Ophthalmol Scand 2006;84:137–139.
13. Ayres B, Brasil OM, Klejnberg C, et al. Ciliary body medulloepithelioma:
clinical, ultrasound biomicroscopic and histopathologic correlation. Clin
Experiment Ophthalmol 2006;34(7):695–698.

Pathology
14. Kivela T, Tarkkanen A. Recurrent medulloepithelioma of the ciliary body.
Immunohistochemical characteristics. Ophthalmology 1988;95:1565–1575.
15. Desai VN, Lieb WE, Donoso LA, et al. Photoreceptor cell differentiation in
intraocular medulloepithelioma: an immunohistopathologic study. Arch
Ophthalmol 1990;108:481–482.
16. Lloyd WC 3rd, O’Hara M. Malignant teratoid medulloepithelioma: clinical-
echographic-histopathologic correlation. JAAPOS 2001;5:395–397.
17. Babu N, Dey P. Medulloepithelioma of ciliary body diagnosed by fine needle
aspiration cytology. Cytopathology 2003;14:93–94.
18. Singh G, Gupta R, Kakkar A, et al. Fine needle aspiration cytology of metastatic
ocular medulloepithelioma. Cytopathology 2011;22(5):343–345.
19. 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.
Management
20. Davidorf FH, Craig E, Birnbaum L, et al. Management of medulloepithelioma of
the ciliary body with brachytherapy. Am J Ophthalmol 2002;133:841–843.
21. Cassoux N, Charlotte F, Sastre X, et al. Conservative surgical treatment of
medulloepithelioma of the ciliary body. Arch Ophthalmol 2010;128(3):380–381.
22. Ramasubramanian A, Shields CL, Kytasty C, et al. Resection of intraocular
tumors (partial lamellar sclerouvectomy) in the pediatric age group.
Ophthalmology 2012;119(12):2507–2513.
23. Papastefanou VP, Cohen VM. Ciliary-body adenoma of the non-pigmented
epithelium with rubeosis iridis treated with plaque brachytherapy and
bevacizumab. Eye (Lond) 2012;26(10):1388–1390.

1323
Case Reports
24. Shields JA, Shields CL, Schwartz RL. Malignant teratoid medulloepithelioma of
the ciliary body simulating persistent hyperplastic primary vitreous. Am J
Ophthalmol 1989;107:296–298.
25. Hennis HL, Saunders RA, Shields JA. Malignant teratoid medulloepithelioma of
the ciliary body. J Clin Neuroophthalmol 1990;10:291–292.
26. Husain SE, Husain N, Boniuk M, et al. Malignant nonteratoid
medulloepithelioma of the ciliary body in an adult. Ophthalmology
1998;105:596–599.
27. Quiones Tapia D, Serrano de la Iglesia JM. Malignant nonteratoid
medulloepithelioma. Ophthalmology 1999;106:211.
28. Jumper MJ, Char DH, Howes EL Jr, et al. Neglected malignant
medulloepithelioma of the eye. Orbit 1999;18:37–43.
29. Lumbroso L, Desjardins L, Coue O, et al. Presumed bilateral
medulloepithelioma. Arch Ophthalmol 2001;119:449–450.
30. Reese AB. Medulloepithelioma (dictyoma) of the optic nerve. Am J Ophthalmol
1957;44:4–6.
31. Green WR, Iliff WJ, Trotter RR. Malignant teratoid medulloepithelioma of the
optic nerve. Arch Ophthalmol 1974;91:451–454.
32. O’Keefe M, Fulcher T, Kelly P, et al. Medulloepithelioma of the optic nerve
head. Arch Ophthalmol 1997;115:1325–1327.
33. Chavez M, Mafee MF, Castillo B, et al. Medulloepithelioma of the optic nerve. J
Pediatr Ophthalmol Strabismus 2004;41:48–52.
34. Pe’er J, Hidayat AA. Malignant teratoid medulloepithelioma manifesting as a
black epibulbar mass with expulsive hemorrhage. Arch Ophthalmol
1984;102:1523–1527.
35. Gopal L, Babu EK, Gupta S, et al. Pigmented malignant medulloepithelioma of
the ciliary body. J Pediatr Ophthalmol Strabismus 2004;41:364–366.
36. Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented medulloepithelioma of the
ciliary body. Arch Ophthalmol 2002;120:207–210.
37. Font RL, Rishi K. Diffuse retinal involvement in malignant nonteratoid
medulloepithelioma of ciliary body in an adult. Arch Ophthalmol
2005;123(8):1136–1138.
38. Kanavi MR, Soheilian M, Kamrava K, et al. Medulloepithelioma masquerading
as chronic anterior granulomatous uveitis. Can J Ophthalmol 2007;42(3):474–
476.
39. Al-Salam S, Algawi K, Alashari M. Malignant non-teratoid medulloepithelioma
of ciliary body with retinoblastic differentiation: a case report and review of
literature. Neuropathology 2008;28(5):551–556.
40. Pushker N, Khuraijam N, Sen S, et al. Medulloepithelioma of the ciliary body
associated with massive intravitreal hemorrhage in an adult. Can J Ophthalmol
2008;43(2):253–254.
41. Lindegaard J, Heegaard S, Toft PB, et al. Malignant transformation of a
medulloepithelioma of the optic nerve. Orbit 2010;29(3):161–164.
42. Alkatan H, Al-Amry M, Al-Hussain H, et al. Medulloepithelioma of the ciliary
body: the delay in diagnosis and frequent initial mismanagement. Can J
Ophthalmol 2011;46(5):431–438.
43. Corrêa ZM, Augsburger JJ, Spaulding AG. Medulloepithelioma of the optic

1324
 disc. Hum Pathol 2011;42(12):2047–2051.
44. Sharma P, Shields CL, Turaka K, et al. Ciliary body medulloepithelioma with
neoplastic cyclitic membrane imaging with fluorescein angiography and
ultrasound biomicroscopy. Graefes Arch Clin Exp Ophthalmol 2011;249(8):1259–
1261.
45. Lewis DA, Nehls S, Rowe J, et al. Ciliary body medulloepithelioma in a 10-
year-old boy. Arch Ophthalmol 2012;130(7):881.
46. Saunders T, Margo CE. Intraocular medulloepithelioma. Arch Pathol Lab Med
2012;136(2):212–216.
47. Earl JB, Minckler DS, Lee TC, et al. Malignant teratoid medulloepithelioma
with retinoblastic and rhabdomyoblastic differentiation. J AAPOS
2013;17(3):328–331.
48. Ramasubramanian A, Correa ZM, Augsburger JJ, et al. Medulloepithelioma in
DICER1 syndrome treated with resection. Eye (Lond) 2013;27(7):896–897.
49. Laird PW, Grossniklaus HE, Hubbard GB. Ciliary body medulloepithelioma
associated with pleuropulmonary blastoma. Br J Ophthalmol 2013;97(8):1079,
1086–1087.
50. Ali MJ, Honavar SG, Vemuganti GK. Ciliary body medulloepithelioma in an
adult. Surv Ophthalmol 2013;58(3):266–272.

1325
• CILIARY BODY MEDULLOEPITHELIOMA: CLINICAL AND GROSS
PATHOLOGIC FEATURES

Ciliary body medulloepithelioma can have a variety of clinical manifestations, depending on the
size and extent of the tumor at the time of diagnosis.

Figure 23.1. Typical lens notch or “coloboma” in a 4-year-old girl.

Figure 23.2. Appearance of the same eye shown in Figure 23.1 with scleral depression, showing a fleshy-
white ciliary body mass. The tumor was removed by iridocyclectomy and was found to be a benign nonteratoid
medulloepithelioma.

1326
Figure 23.3. Retrolenticular neoplastic membrane in a young girl. A ciliary body medulloepithelioma was
detected temporally.

Figure 23.4. Intravenous fluorescein angiography of the neoplastic membrane in Figure 23.3 demonstrating
the large caliber vessels within neoplastic tissue emanating from the tumor and growing along the anterior
hyaloid face.

1327
Figure 23.5. Characteristic tumor-induced cyclitic membrane secondary to another ciliary body
medulloepithelioma.

Figure 23.6. Gross pathology of the eye seen in Figure 23.5 following enucleation. Note the irregular, cystic
ciliary body mass, subluxation of the cataractous lens, and the secondary total retinal detachment.

1328
• MALIGNANT TERATOID MEDULLOEPITHELIOMA:
CLINICOPATHOLOGIC CORRELATION

Hennis HL, Saunders RA, Shields JA. Malignant teratoid medulloepithelioma of the ciliary body.
J Clin Neuroophthalmol 1990;10:291–292.

Figure 23.7. Inferotemporal medulloepithelioma in a 6-year-old boy. Note the fleshy-white lesion with a cyst
near the surface.

Figure 23.8. Gross appearance of the lesion after successful removal by iridocyclectomy.

1329
Figure 23.9. Photomicrograph of the lesion, showing a vitreous-filled cyst near the surface. (Hematoxylin–
eosin ×40.)

Figure 23.10. Area of the tumor showing tubules and acini of proliferating epithelial cells and extracellular
mesenchyme-like tissue. (Hematoxylin–eosin ×150.)

1330
Figure 23.11. Another area of the same tumor showing closely compact cells with malignant features.
(Hematoxylin–eosin ×200.)

Figure 23.12. Another area of the same tumor showing tissue compatible with brain. The tumor was classified
histopathologically as a malignant teratoid medulloepithelioma. (Hematoxylin–eosin ×150.)

1331
• MALIGNANT TERATOID MEDULLOEPITHELIOMA:
CLINICOPATHOLOGIC CORRELATION

Although most ciliary body medulloepitheliomas are difficult to demonstrate with fundus
photography and ultrasonography, the case depicted here was successfully demonstrated with
those techniques. The clinical and ultrasonographic findings suggested a possible diagnosis of
retinoblastoma.

Shields JA, Eagle RC, Shields CL, et al. Fluorescein angiography and ultrasonography of
malignant intraocular medulloepithelioma. J Pediatr Ophthalmol Strabismus 1996;33:193–196.

Figure 23.13. Clinical photograph of a superonasal mass in the right eye of a 7-year-old girl. Note the chalky
gray-white areas in the tumor and the gray neoplastic cyclitic membrane.

Figure 23.14. Fluorescein angiogram, showing fine blood vessels that are leaking fluorescein in the tumor.

1332
Figure 23.15. B-scan ultrasonogram, showing the pedunculated mass with dense echoes. These persisted at
lower sensitivities. Although the fluorescein angiogram and ultrasonogram suggested retinoblastoma, the
diagnosis of medulloepithelioma was made, and the eye was enucleated.

Figure 23.16. Gross photograph of the sectioned globe, showing the white ciliary body mass. Note the
retrolental cyclitic membrane and the faint hyaloid blood vessel passing from the tumor toward the optic disc.

1333
Figure 23.17. Area of the tumor showing tubules and acini of proliferating epithelial cells. (Hematoxylin–eosin
×100.)

Figure 23.18. Area of the tumor showing foci of hyaline cartilage. It was the foci of cartilage that accounted for
the chalky gray areas seen clinically, the hypofluorescent foci seen with angiography, and the dense echoes
seen ultrasonographically. (Hematoxylin–eosin ×100.)

1334
• CILIARY BODY MEDULLOEPITHELIOMA SIMULATING PERSISTENT
HYPERPLASTIC PRIMARY VITREOUS

In many instances, ciliary body medulloepithelioma can masquerade as or produce a congenital

cataract or glaucoma, or it can be confused with PHPV. There is a positive association of
medulloepithelioma with PHPV.

Shields JA, Shields CL, Schwartz RL. Malignant teratoid medulloepithelioma of the ciliary body
simulating persistent hyperplastic primary vitreous. Am J Ophthalmol 1989;107:296–298.

Figure 23.19. Leukocoria due to cataract in an infant.

Figure 23.20. Appearance of the same eye after three operations elsewhere for presumed persistent
hyperplastic primary vitreous. The anterior chamber is filled with red-yellow material, and the blind, painful eye
was enucleated.

1335
Figure 23.21. Section of the enucleated eye, showing an irregular ciliary body mass that extends into the
posterior segment and produces a retinal detachment. Note the large hemorrhagic cavity in the ciliary body
portion of the tumor.

Figure 23.22. Low-magnification photograph, showing triangular-shaped ciliary body mass with foci of
cartilage and exudative retinal detachment.

1336
Figure 23.23. Photomicrograph of a large focus of hyaline cartilage lined by skeletal muscle. (Hematoxylin–
eosin ×50.)

Figure 23.24. Another area of the same tumor, showing atypical, closely packed epithelial cells with malignant
features. (Hematoxylin–eosin ×200.) The final diagnosis was malignant teratoid medulloepithelioma.

1337
• PIGMENTED MALIGNANT MEDULLOEPITHELIOMA OF THE CILIARY
BODY

In rare instances, a medulloepithelioma can be pigmented clinically and histopathologically. A

clinicopathologic correlation of such a case is shown.

Shields JA, Eagle RC Jr, Shields CL, et al. Pigmented medulloepithelioma of the ciliary body.
Arch Ophthalmol 2002;120:207–210.

Figure 23.25. A 3-year-old girl with leukocoria in the right eye. Note the black lesion seen in the pupil
inferotemporally.

1338
Figure 23.26. Pigmented ciliary body mass and a vascularized cyclitic membrane inferotemporally. There is a
coincidental congenital iris nevus superior to the lesion. The mass was removed by iridocyclectomy.

Figure 23.27. Gross appearance of the resected mass, showing normal iris and sclera above and a mass
with a deeply pigmented center.

Figure 23.28. Pseudoacini and cords of pigmented epithelial cells comprised the bulk of the tumor centrally.
(Hematoxylin–eosin ×100.)

1339
Figure 23.29. Histopathology of the resected tumor, showing the pigmented neuroepithelial tubules in the
superficial area of the tumor (left) and the nonpigmented sarcomatoid area (right). (Hematoxylin–eosin ×50.)

Figure 23.30. Colloidal iron stain discloses large amounts of mucopolysaccharide surrounding the
neuroepithelial elements. (Colloidal iron ×100.) This vitreous material is seen with pigmented
medulloepithelioma but not with primary epithelioma of the pigment epithelium.

1340
• AGGRESSIVE MALIGNANT CILIARY BODY MEDULLOEPITHELIOMA
IN AN ADULT

There is a variant of embryonal medulloepithelioma that has its clinical onset in adulthood and
tends to be highly aggressive and can exhibit extrascleral and orbital invasion. It differs from
adult-acquired epithelioma of the nonpigmented ciliary epithelium in that it has heteroplastic
elements histopathologically, similar to a congenital teratoid medulloepithelioma.

Figure 23.31. Face view of 54-year-old African-American woman, showing a mass in the anterior segment of
the left eye. Prior to the detection of the mass, the patient had undergone cataract surgery, followed several
months later by placement of an Ahmed valve for unexplained glaucoma.

Figure 23.32. Closer view of the left eye, showing an iris mass and an epibulbar nodule. A biopsy elsewhere
was interpreted as mucin-secreting adenocarcinoma, compatible with a metastasis. However, systemic

1341
evaluation failed to detect a primary neoplasm, and the patient as referred for enucleation.

Figure 23.33. Appearance of glaucoma valve exposed at the time of enucleation. The cornea and anterior
chamber are to the right.

Figure 23.34. Gross appearance of the anterior segment of enucleated eye, showing a white ciliary body mass
with extrascleral extension, to the left. The cornea is above.

1342
Figure 23.35. Histopathology in poorly differentiated areas of the tumor, showing malignant large, round cells.
These cells showed positive immunoreactivity to desmin and muscle-specific actin, confirming that they
represented rhabdomyoblasts, a common finding in embryonal medulloepithelioma. (Hematoxylin–eosin
×250.)

Figure 23.36. Low-magnification view, showing positive histochemical stain for mucin. This substance was
sensitive to hyaluronidase. (Alcian blue ×20.)

1343
• MEDULLOEPITHELIOMA OF THE OPTIC NERVE AND SYNDROMES
RELATED TO MEDULLOEPITHELIOMA

In rare instances, medulloepithelioma can affect the optic disc and retrobulbar portion of the
optic nerve. Because it is the same histopathologically as the ciliary body lesion, it is included
here.
Other considerations include the pleuropulmonary blastoma family cancer syndrome that can
be associated with medulloepithelioma. This cancer predisposition syndrome, resulting from a
mutation in the DICER1 gene, leads to germline cancers of the lung, pleura, nonpigmented
ciliary epithelium, and other sites.

1. O’Keefe M, Fulcher T, Kelly P, et al. Medulloepithelioma of the optic nerve. Arch Ophthalmol
1997;115:1325–1327.
2. Kramer G, Arepalli S, Shields CL, et al. Ciliary body medulloepithelioma association with
pleuropulmonary blastoma in a familial tumor predisposition syndrome. J Pediatri
Ophthalmol Strabism 2014;51:e48–e50.

Figure 23.37. Fundus montage of medulloepithelioma at the optic disc, showing a fleshy mass involving the
disc and extending into the surrounding retina. Note the intraretinal exudation and the extensive exudative
retinal detachment. (Courtesy of Deepak Edward, MD.)

1344
Figure 23.38. Axial magnetic resonance imaging in T1-weighted image with contrast enhancement of the
lesion shown in Figure 23.37, revealing an enhancing mass at the optic disc with extension into the
retrobulbar aspect of the optic nerve for about 25 mm. (Courtesy of Deepak Edward, MD.)

Figure 23.39. Section of the enucleated eye for the lesion shown in Figure 23.37. Note the white intraocular
mass with contiguous involvement of the optic nerve. (Courtesy of Deepak Edward, MD.)

1345
Figure 23.40. Photomicrograph of the lesion shown in Figure 23.39. Left: Hematoxylin–eosin stain, showing
strands of embryonal neuroepithelium typical of medulloepithelioma (×100). Right: Positive
immunohistochemical stain for neuron-specific enolase, showing poorly differentiated neuronal cells in the
mass (×100). (Courtesy of Deepak Edward, MD.)

Figure 23.41. White retrolental fibrous neoplastic cyclitic membrane in a young child arising from
medulloepithelioma.

1346
Figure 23.42. Ultrasound biomicroscopy disclosed a relatively small, cystic mass of the ciliary body consistent
with medulloepithelioma. This child was subsequent discovered to have related pleuropulmonary blastoma.

1347
 AGE-RELATED HYPERPLASIA OF THE NONPIGMENTED CILIARY
EPITHELIUM (CORONAL ADENOMA; FUCHS ADENOMA)

General Considerations
Age-related hyperplasia of the nonpigmented ciliary epithelium (ARH-NPCE;
coronal adenoma; Fuchs adenoma) is a peculiar, small intraocular mass that is found
in an occult location in the pars plicata of the ciliary body (1–7). Although it is
extremely common, it generally remains undetected clinically and only rarely
assumes clinical significance. It appears to represent an unusual proliferation of the
NPCE that is associated with aging of the ciliary body (2).

Clinical Features
ARH-NPCE is a small lesion in the ciliary body and is rarely seen clinically.
However, in selected cases, it might be possible to visualize the small,
circumscribed, homogeneous, yellow-white mass in the pars plicata, using indirect
ophthalmoscopy with scleral indentation or gonioscopy with a three-mirror lens. It
can be solitary or multiple and is usually confined to one ciliary process. When it is
seen clinically, it is usually large and can be confused clinically with a ciliary body
melanoma, epithelioma of the NPCE, or other neoplasm (7). On occasion, it can
erode through the iris and appear as a mass in the anterior chamber angle (4). It can
also induce a sector cortical cataract (3).

Pathology
Grossly, ARH-NPCE appears as a distinct white mass in the pars plicata. It is
generally confined to one ciliary process. Microscopically, it is composed of
convoluted sheets or tubes of nonpigmented ciliary epithelium, separated by
eosinophilic periodic acid-Schiff–positive extracellular material (7). In some cases,
the basement membrane material becomes so extensive that the tumor cells are seen
as small strands or islands of epithelial cells. Electron microscopy shows
intercellular interdigitations with numerous desmosomes and other features
consistent with cells of the NPCE. The extracellular material demonstrates type IV
collagen and laminin, also consistent with NPCE.

Diagnostic Approaches
As mentioned earlier, ARH-NPCE is not likely to be seen on routine ocular
examination. In rare cases in which it is seen clinically, the aforementioned clinical
features should prompt consideration of the diagnosis. The white color is unlike that
in ciliary body melanoma, but the lesion might be impossible to differentiate from a
true-acquired epithelioma of NPCE. With the advent of high-resolution ultrasound
biomicroscopy of the anterior segment, it is expected that larger ARH-NPCEs will be
recognized more often. Aspiration cytology has been proposed as a diagnostic
adjunct in some cases (6).

Management

1348
No treatment is usually necessary when ARH-NPCE is suspected clinically. Larger
lesions that become clinically apparent or extend through the iris can be removed
surgically by iridocyclectomy because melanoma or other neoplasms are diagnostic
considerations (7). However, iridocyclectomy can be a difficult procedure with
potential complications and should not generally be done for small, asymptomatic,
stationary lesions that are likely to be benign. In such cases, a period of observation
rather than immediate surgery is often more advisable.

Selected References
1. Zimmerman LE. The remarkable polymorphism of tumors of the ciliary
epithelium. The Norman McAlister Gregg Lecture. Trans Aust Coll Ophthalmol
1970;2:114–125.
2. Iliff WJ, Green WR. The incidence and location of Fuch’s adenoma. Arch
Ophthalmol 1972;88:249–254.
3. Bronwyn-Bateman J, Foos RY. Coronal adenomas. Arch Ophthalmol
1979;97:2379–2384.
4. Zaidman GW, Johnson BL, Salamon SM, et al. Fuch’s adenoma affecting the
peripheral iris. Arch Ophthalmol 1983;101:771–773.
5. Brown HH, Glasgow BJ, Foos RY. U ltrastructural and immunohistochemical
features of coronal adenomas. Am J Ophthalmol 1991;112:34–40.
6. Glasgow BJ. Intraocular fine needle aspiration biopsy of coronal adenomas.
Diagn Cytopathol 1991;7:239–242.
7. Shields JA, Shields CL, Eagle RC, et al. Age-related hyperplasia of the
nonpigmented ciliary body epithelium (Fuchs adenoma) simulating a ciliary
body malignant neoplasm. Arch Ophthalmol 2009;127:1124–1125.

1349
• AGE-RELATED HYPERPLASIA OF THE NONPIGMENTED CILIARY
BODY EPITHELIUM (CORONAL ADENOMA; FUCHS ADENOMA)

Age-related hyperplasia of the nonpigmented ciliary body epithelium (NPCE) is a benign

proliferation of epithelial cells with elaboration of basement membrane material that is more
common with increasing age. It is not usually seen clinically, but it is often discovered on
pathologic examination of eyes of older individuals.

Zaidman GW, Johnson BL, Salamon SM, et al. Fuchs adenoma affecting the peripheral iris. Arch
Ophthalmol 1983;101:771–773.

Figure 23.43. Close-up view of a grossly sectioned eye enucleated for an unrelated choroidal melanoma. Note
the white nodule replacing a ciliary process (above).

Figure 23.44. Another eye with a similar view, showing a white nodule on the edge of a ciliary process.

1350
Figure 23.45. Histopathology of age-related hyperplasia of the nonpigmented ciliary body epithelium, showing
a linear arrangement of epithelial cells separated by abundant basement membrane material. (Hematoxylin–
eosin ×20.)

Figure 23.46. Histopathology of age-related hyperplasia of the nonpigmented ciliary body epithelium, showing
histopathology similar to that shown in Figure 23.45. The basement membrane is accentuated with the
periodic acid-Schiff stain. (Periodic acid-Schiff ×25.)

1351
Figure 23.47. Age-related hyperplasia of the nonpigmented ciliary body epithelium presenting through the iris
root. (Courtesy of Gerald Zaidman, MD and Bruce Johnson, MD.)

Figure 23.48. Goniophotograph, showing the lesion in anterior chamber angle. The lesion was removed
surgically, and the diagnosis of age-related hyperplasia of the nonpigmented ciliary body epithelium was
established. Curiously, the lesion appears pigmented, perhaps because it is covered by iris pigment
epithelium. (Courtesy of Gerald Zaidman, MD and Bruce Johnson, MD.)

1352
• AGE-RELATED HYPERPLASIA OF THE NONPIGMENTED CILIARY
BODY EPITHELIUM (CORONAL ADENOMA; FUCHS ADENOMA)

Age-related hyperplasia of the nonpigmented ciliary epithelium is rarely seen clinically. On

occasion, however, it may become large enough to produce clinically recognizable changes. A
clinicopathologic correlation of such a case is shown.

Figure 23.49. Anterior segment of the right eye of a 54-year-old woman. In this view, one can barely see a ciliary
body mass pushing the peripheral iris forward on the nasal side (to the right in photograph).

Figure 23.50. The same eye on left gaze with the pupil dilated. Note the dense cortical cataract caused by the
ciliary body mass.

1353
Figure 23.51. Ultrasound biomicroscopy, showing the solid ciliary body mass (to the right).

Figure 23.52. Direct view of the tumor after a scleral flap has been raised to remove the mass by
iridocyclectomy.

1354
Figure 23.53. Low-magnification view of histopathology of the lesion. Note the well-circumscribed eosinophilic
mass with good margins. The iris and sclera can be seen above. (Hematoxylin–eosin ×10.)

Figure 23.54. Histopathology, showing cords of mature nonpigmented ciliary epithelium with abundant
extracellular basement membrane. (Hematoxylin–eosin ×50.)

1355
ACQUIRED EPITHELIOMA OF THE NONPIGMENTED CILIARY BODY
EPITHELIUM

General Considerations
In contrast to medulloepithelioma, which is congenital, acquired epithelioma of the
nonpigmented ciliary body epithelium (NPCE) appears in adulthood and arises
from fully differentiated NPCE (1–19). It can also be benign or malignant
histopathologically. Both benign and malignant types are clinically similar and are
only locally invasive and rarely exhibit metastasis. Hence, they are discussed
collectively under acquired epithelioma of the NPCE.

Clinical Features
Acquired epithelioma of the NPCE usually is nonpigmented, yellow to light tan in
color, and has an irregular surface that directly impinges on the vitreous cavity
(1–19). Mild intraocular inflammatory signs and small cysts in the tumor are often
present, and an adjacent cortical cataract is often seen. The tumor can be highly
vascular and have small satellite deposits in the overlying vitreous. Vitreous
hemorrhage is an occasional presenting feature of this neoplasm. Inflammation and
secondary glaucoma are often seen with larger tumors (14,19). On rare occasions,
this tumor can show extrascleral extension (10) and even lead to a phthisical eye.

Pathology
The histopathologic differentiation of benign from malignant epithelioma of the
NPCE depends on cytologic features and degree of local invasiveness, and many
cases have borderline features, making the precise categorization difficult (1,2,4,5).
Of nine cases that were reported by the authors, seven were classified as benign and
two were malignant (2).
Acquired tumors of the NPCE have been divided into solid, papillary, and
pleomorphic types (1). Most are composed of a variable combination of these three
patterns (4). A consistent feature is the presence of moderately well differentiated
epithelial cells that rest on prominent periodic acid-Schiff–positive basement
membrane. Some tumors contain large quantities of extracellular hyaluronidase-
sensitive acid mucopolysaccharide, identical to vitreous. Smooth muscle
differentiation has rarely been identified in epithelioma of the NPCE (5).

Diagnostic Approaches
Awareness of epithelioma of the NPCE and recognition of its clinical features are
important in making the clinical diagnosis. In recent years, we have made the
correct clinical diagnosis in most cases based on the aforementioned clinical features
(2). Ancillary studies are helpful in confirming the suspected diagnosis. In contrast
to ciliary body melanoma, a tumor of the NPCE usually transmits light. With
fluorescein angiography, it shows considerable vascularity, progressive
hyperfluorescence, and late staining, and with ultrasonography it has an abrupt
margin and acoustic solidity with B-scan and high internal reflectivity with A-scan.
U ltrasound biomicroscopy could be useful in showing tumor extent (3).

1356
Management
More than 20 years ago, most cases of acquired neoplasms of the NPCE were
managed by enucleation, usually because they were believed to be ciliary body
melanoma. However, it now seems that local resection by partial lamellar
sclerouvectomy is an effective treatment (2,6–8). In some cases, it is feasible to
remove the tumor and the cataract in the same operation. The role of irradiation is
undetermined. The visual prognosis is usually good, and the systemic prognosis is
excellent (2).

Selected References
Series/Reviews
1. Zimmerman LE. The remarkable polymorphism of tumors of the ciliary
epithelium. The Norman McAlister Gregg Lecture. Trans Aust Coll Ophthalmol
1970;2:114–125.
2. Shields JA, Eagle RC Jr, Shields CL, et al. Acquired neoplasms of the
nonpigmented ciliary epithelium (adenoma and adenocarcinoma). The 1995 F.
Phinizy Calhoun Lecture. Ophthalmology 1996;103:2007–2016.

Imaging
3. Bianciotto C, Shields CL, Guzman JM, et al. Assessment of anterior segment
tumors with ultrasound biomicroscopy versus anterior segment optical
coherence tomography in 200 cases. Ophthalmology 2011;118:1297–1302.

Pathology
4. Laver NM, Hidayat AA, Croxatto JO. Pleomorphic adenocarcinomas of the
ciliary epithelium. Immunohistochemical and ultrastructural features of 12
cases. Ophthalmology 1999;106:103–110.
5. Shields JA, Eagle RC Jr, Shields CL. Adenoma of nonpigmented ciliary
epithelium with smooth muscle differentiation. Arch Ophthalmol 1999;117:117–
119.

Management
6. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for
posterior uveal melanomas. The 1986 Schoenberg Lecture. Ophthal Surg
1988;19:774–780.
7. Shields JA, Shields CL, De Potter P. Local resection of intraocular tumors. Curr
Opin Ophthalmol 1993;4:62–67.
8. Ramasubramanian A, Shields CL, Kytasty C, et al. Resection of intraocular
tumors (partial lamellar sclerouvectomy) in the pediatric age group.
Ophthalmology 2012;119:2507–2513.
Case Reports
9. Shields JA, Augsburger JJ, Wallar PH, et al. Adenoma of the nonpigmented
epithelium of the ciliary body. Ophthalmology 1983;90:1528–1530.
10. Rodrigues M, Hidayat A, Karesh J. Pleomorphic adenocarcinoma of ciliary
epithelium simulating an epibulbar tumor. Am J Ophthalmol 1988;106:595–
600.
11. Grossniklaus HE, Zimmerman LE, Kachmer ML. Pleomorphic adenocarcinoma

1357
 of the ciliary body. Ophthalmology 1990;97:763–768.
12. McGowan HD, Simpson ER, Hunter WS, et al. Adenoma of the nonpigmented
epithelium of the ciliary body. Can J Ophthalmol 1991;26:328–333.
13. Grossniklaus HE, Lim JI. Adenoma of the nonpigmented ciliary epithelium.
Retina 1994;14:452–456.
14. Biswas J, Neelakantan A, Rao BS. Adenoma of nonpigmented epithelium of the
ciliary body presenting as anterior uveitis and glaucoma: a case report. Ind J
Ophthalmol 1995;43:137–140.
15. Murphy MF, Johnston PB, Lyness RW. Adenoma of the non-pigmented
epithelium of the ciliary body. Eye 1997;11:419–420.
16. Cursiefen C, Schlotzer-Schrehardt U , Holbach LM, et al. Adenoma of the
nonpigmented ciliary epithelium mimicking a malignant melanoma of the iris.
Arch Ophthalmol 1999;117:113–116.
17. Dinakaran S, Rundle PA, Parsons MA, et al. Adenoma of ciliary pigment
epithelium: a case series. Br J Ophthalmol 2003;87:504–505.
18. Suzuki J, Goto H, U sui M. Adenoma arising from nonpigmented ciliary
epithelium concomitant with neovascularization of the optic disk and cystoid
macular edema. Am J Ophthalmol 2005;139:188–190.
19. Bae JH, Kwon JE, Yang WI, et al. Adenoma of the nonpigmented ciliar
epithelium presenting with recurrent iridocyclitits: unique expression of glial
fibrillary acidic protein. Graefes Arch Clin Exp Ophthalmol 2011;249:1747–1749.

1358
• BENIGN EPITHELIOMA (ADENOMA) OF THE NONPIGMENTED
CILIARY BODY EPITHELIUM: CLINICAL FEATURES

Acquired epithelioma of the NPCE is generally an amelanotic ciliary body mass that can have
variable clinical features. It frequently causes an adjacent cataract that can preclude a clear
view of the lesion. Fluorescein angiography is difficult to perform because of the hidden
location of the lesion in most cases. In all of the cases shown here, the differentiation between
benign and malignant lesions could not be made clinically, and the diagnosis was confirmed
histopathologically following surgical resection.

Shields JA, Eagle RC Jr, Shields CL. Adenoma of the nonpigmented ciliary epithelium with
smooth muscle differentiation. Arch Ophthalmol 1999;117:117–119.

Figure 23.55. Inferior epithelioma of nonpigmented ciliary body epithelium in a 39-year-old man. This lesion is
atypical in that it has a very smooth surface.

1359
Figure 23.56. Wide-angle fundus photograph of the lesion in Figure 23.55, showing that it transmits light. The
eye was enucleated and the diagnosis was confirmed.

Figure 23.57. Superior malignant epithelioma of the nonpigmented ciliary body epithelium in a 58-year-old
African-American patient, showing the margin of the lesion and an adjacent secondary cataract and
subluxation of the lens.

1360
Figure 23.58. Fluorescein angiogram of the lesion shown in Figure 23.57, demonstrating nonspecific
hyperfluorescence of the lesion. Following removal by iridocyclectomy, the lesion proved histopathologically to
be an epithelioma of the nonpigmented ciliary body epithelium with unusual areas of smooth muscle
differentiation.

Figure 23.59. Dense cataract overlying a faintly visualized adenoma of the nonpigmented ciliary body
epithelium in a 45-year-old woman.

1361
Figure 23.60. B-scan ultrasonogram of the lesion shown in Figure 23.59. Note that the lesion has abrupt
margins and is markedly pedunculated. Histopathologically, the resected lesion was an epithelioma of the
nonpigmented ciliary body epithelium.

1362
• BENIGN EPITHELIOMA (ADENOMA) OF THE NONPIGMENTED
CILIARY BODY EPITHELIUM: CLINICOPATHOLOGIC CORRELATION

Epithelioma of the NPCE is sometimes a white, fluffy tumor with numerous cystic spaces that
contain an acid mucopolysaccharide characteristic of vitreous. The patient shown here had
local resection of a large tumor with removal of a dislocated lens at the time of surgery and had
excellent vision 7 years later.

Shields JA, Eagle RC Jr, Shields CL, et al. Acquired neoplasms of the nonpigmented ciliary
epithelium (adenoma and adenocarcinoma). Ophthalmology 1996;103:2007–2016.

Figure 23.61. Superior ciliary body mass in a 31-year-old woman.

1363
Figure 23.62. Gross view of the tumor after removal by partial lamellar iridocyclectomy.

Figure 23.63. Side view of the lesion, showing the scleral base and friable appearance of the white lesion.

1364
Figure 23.64. Photomicrograph, showing cords of bland epithelial cells and cystic spaces. (Hematoxylin–eosin
×150.)

Figure 23.65. Low-magnification view of the lesion stained for mucin, showing marked positivity within the
numerous cystic spaces. This was a hyaluronidase-sensitive acid mucopolysaccharide identical to vitreous.
(Alcian-blue ×10.)

1365
Figure 23.66. Appearance of the anterior segment several years later, showing a large sector iridectomy. The
posterior fundus was normal. A cosmetic contact lens was used to cover the defect.

1366
• BENIGN EPITHELIOMA (ADENOMA) OF THE NONPIGMENTED
CILIARY BODY EPITHELIUM: CLINICOPATHOLOGIC CORRELATION
AND TREATMENT

A dense cortical cataract near the lens equator is a common finding in a patient with a
neoplasm of the NPCE.

Shields JA, Augsburger JJ, Shah H, et al. Adenoma of the nonpigmented epithelium of the
ciliary body. Ophthalmology 1983;90:1528–1530.

Figure 23.67. Dense cortical cataract in a 41-year-old man.

1367
Figure 23.68. The same lesion shown in Figure 23.67 with the eye rotated, showing a light brown mass
adjacent to the dense cortical cataract.

Figure 23.69. Removal of the lesion by partial lamellar iridocyclectomy.

The limbus-hinged scleral flap is being developed.

Figure 23.70. Low-magnification photomicrograph, showing a well-circumscribed lesion. (Hematoxylin–eosin

×10.)

1368
Figure 23.71. Photomicrograph of the tumor, showing characteristic cords of proliferating nonpigmented ciliary
epithelium. (Hematoxylin–eosin ×150.)

Figure 23.72. Photomicrograph, showing characteristic positive staining for mucin. (Alcian blue ×150.)

1369
• BENIGN EPITHELIOMA (ADENOMA) OF THE NONPIGMENTED
CILIARY BODY EPITHELIUM: ULTRASOUND BIOMICROSCOPY

Epithelioma of the NPCE is difficult to detect clinically in many cases. Ultrasound

biomicroscopy can be helpful in demonstrating the lesion. We have recently observed that UBM
will help to locate the lesion on the vitreous side of the pigment epithelium, which is different
from ciliary body melanoma or other stromal neoplasms.

Figure 23.73. Thinning of the iris inferotemporally due to a ciliary body mass in a 41-year-old woman.

Figure 23.74. Ultrasound biomicroscopy of the lesion shown in Figure 23.73, depicting a ciliary body mass
with a slight dislocation of the posterior chamber intraocular lens.

1370
Figure 23.75. Gross photograph of the tumor after removal by partial lamellar iridocyclochoroidectomy. Inset
shows the histopathology, with cords of nonpigmented epithelial cells. (Hematoxylin–eosin ×200.) Visual
acuity was 20/70 after 1 year of follow-up.

Figure 23.76. Ciliary body mass pushing through the iris inferiorly and presenting in the anterior chamber in a
67-year-old woman.

1371
Figure 23.77. Ultrasound biomicroscopy of the lesion shown in Figure 23.76, demonstrating a pedunculated
ciliary body mass.

Figure 23.78. Gross photograph of the tumor after removal by partial lamellar iridocyclectomy. Note that wide
margins were obtained at the time of surgery. Inset shows the histopathology, with cords of nonpigmented
epithelial cells and abundant basement membrane. (Periodic acid-Schiff ×200.) The visual acuity was 20/40 at
1 year after surgery.

1372
• PLEOMORPHIC ADENOCARCINOMA OF THE NONPIGMENTED
CILIARY BODY EPITHELIUM: CLINICOPATHOLOGIC CORRELATIONS

Pleomorphic adenocarcinoma of the NPCE can be localized in the globe or it can exhibit
extraocular extension. Even though it is cytologically malignant and may exhibit aggressive local
behavior, the tumor does not have a tendency to metastasize.

Figure 23.79. Ciliary body mass causing inferior compression of the iris stroma in a 50-year-old woman.

Figure 23.80. Low-magnification photomicrograph of the mass after removal by partial lamellar
iridocyclectomy. (Hematoxylin–eosin ×5.)

1373
Figure 23.81. Photomicrograph, showing a solid pattern of abnormal epithelial cells. (Hematoxylin–eosin
×150.)

Figure 23.82. Elderly man with amelanotic iris mass, presumed to be a metastasis but there was no primary
cancer detected.

1374
Figure 23.83. After several years, the mass filled the globe and lead to completely disorganized globe, no light
perception, and pain.

Figure 23.84. Following enucleation, the gross examination disclosed the entire globe filled with a yellow-white
mass and histopathologic evaluation revealed a diagnosis of adenocarcinoma of the nonpigmented ciliary
body epithelium.

1375
 CHAPTER 24

INTRAOCULAR LYMPHOID TUMORS AND

LEUKEMIAS

INTRAOCULAR LYMPHOID TUMORS

Introduction to Intraocular Lymphoid Lesions

Tumors derived from lymphoid cells can sometimes develop in the eye and affect
the uveal tract, retina, vitreous, or optic disc (1–13). The several classifications of
lymphoid malignancies that have been used in recent years are beyond the scope of
this book. The Revised European American Lymphoma Classification has been
popular and applied to intraocular lymphomas (2). Intraocular lymphoid tumors
range from benign, relatively stable lesions to highly aggressive malignancies that
can produce blindness and even death from associated brain or visceral disease.
Specific intraocular lymphoid and lymphoplasmacytic tumors to be discussed in this
section include uveal benign reactive lymphoid hyperplasia (BRLH), malignant
lymphoma, and plasmacytoma.
BRLH is an idiopathic infiltration of the uveal tract by benign lymphocytes and
plasma cells. It has rather characteristic clinical and histopathologic features. Most
have considered it to be a benign reactive immunologic process, and evolution into
malignant lymphoma is very uncommon.
The great majority of intraocular lymphomas are non-Hodgkin large-cell
lymphomas comprising malignant lymphocytes of B-cell lineage. There are two
general types of intraocular lymphoma: the uveal type and the retinovitreal type.
The uveal type is generally associated with visceral or nodal lymphoma and rarely

1376
with central nervous system (CNS) lymphoma. It is generally found in
immunocompetent patients. The retinovitreal type is closely related to primary CNS
lymphoma (PCNSL) and, when it appears initially in the eye, it has been called
primary intraocular lymphoma (PIOL). This is not an ideal term because a primary
lymphoma can also occur in the uveal tract, without any association with the CNS. It
has a predilection to develop in immunocompromised patients, but it is also seen in
patients who are presumably immunocompetent. Of all patients with intraocular
lymphoma, approximately 60% have the PCNS lymphoma, 15% have the uveal
form, about 5% have both types simultaneously, and 20% have no demonstrable
extraocular lymphoma.
Benign or malignant plasmacytomas can rarely occur in the uveal tract. Both types
can appear as an isolated solitary lesion, with no demonstrable systemic
associations, or as a component of multiple myeloma. Other lymphoid malignancies
that can rarely involve the intraocular structures include Hodgkin disease,
angiotropic large-cell lymphoma, T-cell lymphoma (mycosis fungoides), and adult
T-cell leukemia/lymphoma. These rare forms are similar to the two more common
forms with regard to ocular presentations, and are not illustrated in this atlas.

Selected References
Small Series
1. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin
Ophthalmol 2002;13:411–418.
2. Nussenblatt RB, Chan CC, Wilson WH, et al. CNS and ocular lymphoma
workshop group. International central nervous system and ocular lymphoma
workshop: recommendations for the future. Ocul Immunol Inflamm 2006;14:139–
144.
3. Grossniklaus HE, Martin DF, Avery R, et al. U veal lymphoid infiltration. Report
of four cases and clinicopathologic review. Ophthalmology 1998;105:1265–
1273.
4. Coupland SE, Foss HD, Hidayat AA, et al. Extranodal marginal zone B cell
lymphomas of the uvea: an analysis of 13 cases. J Pathol 2002;197:333–340.

Pathology
5. Elner VM, Hidayat AA, Charles NC, et al. Neoplastic angioendotheliomatosis. A
variant of malignant lymphoma immunohistochemical and ultrastructural
observations of three cases. Ophthalmology 1986;93:1237–1245.
6. Kohno T, U chida H, Inomata H, et al. Ocular manifestations of adult T-cell
leukemia/lymphoma. A clinicopathologic study. Ophthalmology
1993;100:1794–1799.
7. 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.

Case Reports
8. Keltner JL, Fritsch E, Cykiert RC, et al. Mycosis fungoides. Intraocular and
central nervous system involvement. Arch Ophthalmol 1977;95:645–650.
9. Jensen OA, Johansen S, Kiss K. Intraocular T-cell lymphoma mimicking a ring
melanoma. First manifestation of systemic disease. Report of a case and survey

1377
 of the literature. Graefes Arch Clin Exp Ophthalmol 1994;232:148–152.
10. Towler H, de la Fuente M, Lightman S. Posterior uveitis in Hodgkin’s disease.
Aust N Z J Ophthalmol 1999;27:326–330.
11. Yahalom C, Cohen Y, Averbukh E, et al. Bilateral iridociliary T-cell lymphoma.
Arch Ophthalmol 2002;120:204–207.
12. Levy-Clarke GA, Buggage RR, Shen D, et al. Human T-cell lymphotropic virus
type-1 associated T-cell leukemia/lymphoma masquerading as necrotizing
retinal vasculitis. Ophthalmology 2002;109:1717–1722.
13. Mori A, Deguchi HE, Mishima K, et al. A case of uveal, palpebral, and orbital
invasions in adult T-cell leukemia. Jpn J Ophthalmol 2003;47:599–602.

1378
 BENIGN REACTIVE LYMPHOID HYPERPLASIA OF THE UVEA

General Considerations
BRLH is an idiopathic condition characterized by infiltration of the uveal tract by
benign lymphocytes and plasma cells. There is controversy regarding its benign
nature, and some cases originally classified as BRLH have been reclassified as well-
differentiated small-cell lymphoma (1–57). In our experience, transformation into
lymphoma is extremely uncommon. It has rarely been associated with Waldenstrom
macroglobulinemia. In some cases, BRLH or low-grade lymphoma can have
multisystem manifestations, a condition called Castleman syndrome. U veal
involvement has been observed with this syndrome.

Clinical Features
U veal BRLH affects mainly adults and is usually unilateral (1–8). It can occur in the
iris, ciliary body, or choroid and can simultaneously involve the conjunctiva and
orbit. In the iris, it appears either as a circumscribed mass or as a diffuse amelanotic
thickening of the iris stroma. In the ciliary body, it presents as an amelanotic mass
that can push the iris forward, simulating a ring melanoma and causing angle
closure glaucoma. Choroidal BRLH appears as one or more circumscribed yellow-
orange lesions that range from minimally elevated to dome shaped (8). Choroidal
BRLH also manifests as numerous small yellow lesions that may be similar to
birdshot choroidopathy, multifocal choroiditis, or sarcoidosis. These focal lesions
can eventually coalesce to produce a diffuse thickening of the choroid. We have also
seen cases that appear as a diffuse red-orange lesion in the posterior pole,
remarkably similar to the diffuse choroidal hemangioma seen with Sturge–Weber
syndrome. The vitreous is usually clear, with no evident inflammatory or tumor
cells. A secondary, nonrhegmatogenous retinal detachment with clear serous
subretinal fluid is often present. Spontaneous tear of the RPE is a rare complication
(34).
U veal BRLH may be similar clinically to lymphoma, metastasis, localized or
diffuse amelanotic choroidal melanoma, uveal effusion syndrome, posterior scleritis,
birdshot choroidopathy, choroidal sarcoidosis, diffuse choroidal hemangioma, and
other solitary, multifocal or diffuse yellow-orange fundus lesions. A clinical history
and ocular examination, systemic evaluation, and selected laboratory studies can
help in differentiating uveal BRLH from these entities.

Diagnostic Approaches
A simple, crucial diagnostic step in evaluating a patient with a fundus mass that
could be BRLH or lymphoma is to carefully check the conjunctiva and look for the
classic pink infiltration that characterizes either a benign or a malignant lymphoid
tumor. Such a “salmon patch” infiltration is often subtle and located in the
conjunctival fornix. This finding should prompt the clinician to perform biopsy of
the conjunctival lesions rather than the intraocular lesion. The histopathology of the
uveal and conjunctival components is generally similar or identical.
Fluorescein angiography of BRLH shows no specific features and may be similar

1379
to that for metastasis or lymphoma or choroidal inflammation. Like these other
choroidal lesions, they are relatively hypofluorescent in the early vascular filling
phases and show moderate late staining beginning in the venous or recirculation
phase.
U ltrasonography shows a diffuse thickening of the choroid with medium to low
internal reflectivity, similar to choroidal melanoma. However, a classic ultrasound
finding that is seen in many cases is an ovoid echolucent epibulbar mass, usually
posterior to the sclera. Even though it is strongly suggestive of a lymphoid tumor,
extraocular extension of an amelanotic choroidal melanoma, and other tumors can
produce a similar pattern.
In cases in which the diagnosis is uncertain and there is no evidence of an
episcleral mass to biopsy, a uveal biopsy can be performed (14–25). This can be
done by fine-needle aspiration biopsy (FNAB), transvitreal biopsy with a vitrectomy
instrument, or an eye wall biopsy. The first two of these yield scanty material for
diagnosis and may or may not show only representative cells. Eye wall biopsy
provides a tissue diagnosis, but the surgery is more difficult and with more
complications. In general, FNAB is quicker and easier to perform and often yields a
correct diagnosis (15,16).

Pathology
Gross examination of enucleated eyes shows a diffuse, amelanotic uveal mass. The
epibulbar component, if present, is evident on gross evaluation. Histopathologically,
uveal BRLH is characterized by a localized or diffuse replacement of the uveal
stroma by an infiltration of benign lymphocytes and plasma cells. It can be confined
to one portion of the uvea, or it can diffusely affect the entire uveal tract. It is most
pronounced in the posterior choroid. In some cases, germinal centers are present in
the lesion. Intranuclear inclusions, called Dutcher bodies, are often seen.
Immunohistochemistry and polymerase chain reaction can be used to further
categorize the condition as a low-grade proliferation of B-lymphocytes.

Management
The management of suspected uveal BRLH should be determined by the clinical
findings. The patient should have a systemic evaluation to exclude lymphoma and
myeloma. If the involvement is small and the patient is asymptomatic, periodic
observation may be justified. Sometimes this condition can remain stationary for
months or years. A larger, symptomatic lesion with secondary retinal detachment or
other complications can be managed initially by a standard course of oral
corticosteroids with tapering of the medication. In general, corticosteroids bring
about some improvement. Whole-eye irradiation, usually 20 to 25 Gray of external
beam in divided doses, is often necessary if corticosteroids fail to control the disease.
The response of BRLH to irradiation appears to be favorable.
The visual prognosis depends on the extent of the disease, but most patients with
less advanced disease have a fairly good visual outcome. The systemic prognosis for
uveal BRLH is generally good, and evolution into systemic lymphoma appears to be
very rare.

Selected References

1380
Series/Reviews
1. Ryan SJ, Zimmerman LE, King FM. Reactive lymphoid hyperplasia. An unusual
form of intraocular pseudotumor. Trans Am Acad Ophthalmol Otolaryngol
1972;76:652–671.
2. Coupland SE, Damato B. U nderstanding intraocular lymphomas. Clin
Experiment Ophthalmol 2008;36(6):564–578.
3. Fuller ML, Sweetenham J, Schoenfield L, et al. U veal lymphoma: a variant of
ocular adnexal lymphoma. Leuk Lymphoma 2008;49(12):2393–2397.
4. Kanavi MR, Soheilian M, Bijanzadeh B, et al. Diagnostic vitrectomy (25-gauge)
in a case with intraocular lymphoma masquerading as bilateral granulomatous
panuveitis. Eur J Ophthalmol 2010;20(4):795–798.
5. Vosganian GS, Boisot S, Hartmann KI, et al. Primary intraocular lymphoma: a
review. J Neurooncol 2011;105(2):127–134.
6. Arcinue CA, Hochberg F, Neumann R, et al. Diagnostic criteria for primary
ocular lymphoma. Ophthalmology 2013;120(3):646–646.e2.
7. Davis JL. Intraocular lymphoma: a clinical perspective. Eye (Lond)
2013;27(2):153–162.
8. Mashayekhi A, Shukla SY, Shields JA, et al. Choroidal lymphoma: Clinical
features and association with systemic lymphoma. Ophthalmology
2014;121:342–351.

Imaging
9. Desroches G, Abrams GW, Gass JD. Reactive lymphoid hyperplasia of the uvea.
A case with ultrasonographic and computed tomographic studies. Arch
Ophthalmol 1983;101:725–728.
10. Chang TS, Byrne SF, Gass JD, et al. Echographic findings in benign reactive
lymphoid hyperplasia of the choroid. Arch Ophthalmol 1996;114:669–675.
11. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of
iris tumors in 100 consecutive cases. Technique and complications.
Ophthalmology 2006;113:2080–2086.
12. Shields CL, Arepalli S, Pellegrini M, et al. Choroidal lymphoma appears with
calm, rippled, or undulating topography on enhanced depth imaging optical
coherence tomography in 14 cases. Retina 2014;34(7):1347–1353.
13. Shields CL, Pellegrini M, Ferenczy SR, et al. Enhanced depth imaging optical
coherence tomography (EDI-OCT) of intraocular tumors. From placid to seasick
to rock and rolling topography. The 2013 Francesco Orzalesi Lecture. Retina
2014; 34(8):1495–1512.

Pathology/Cytology
14. Scherfig E, Prause JU , Jensen OA. Transvitreal retinochoroidal biopsy. Graefes
Arch Clin Exp Ophthalmol 1989;227:369–373.
15. Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
16. Cheung MK, Martin DF, Chan CC, et al. Diagnosis of reactive lymphoid
hyperplasia by chorioretinal biopsy. Am J Ophthalmol 1994;118:457–462.
17. Rutzen AR, Ortega-Larrocea G, Dugel PU , et al. Clinicopathologic study of
retinal and choroidal biopsies in intraocular inflammation. Am J Ophthalmol
1995; 119(5):597–611.

1381
18. Grossniklaus HE, Martin DF, Avery R, et al. U veal lymphoid infiltration. Report
of four cases and clinicopathologic review. Ophthalmology 1998;105:1265–
1273.
19. Gündüz K, Shields JA, Shields CL, et al. Transscleral choroidal biopsy in the
diagnosis of choroidal lymphoma. Surv Ophthalmol 1999;43(6):551–555.
20. 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.
21. Lim LL, Suhler EB, Rosenbaum JT, et al. The role of choroidal and retinal
biopsies in the diagnosis and management of atypical presentations of uveitis.
Trans Am Ophthalmol Soc 2005;103:84–91.
22. Coupland SE, Joussen A, Anastassiou G, et al. Diagnosis of a primary uveal
extranodal marginal zone B-cell lymphoma by chorioretinal biopsy: case report.
Graefes Arch Clin Exp Ophthalmol 2005;243(5):482–486.
23. Gonzales JA, Chan CC. Biopsy techniques and yields in diagnosing primary
intraocular lymphoma. Int Ophthalmol 2007;27(4):241–250.
24. Levy-Clarke GA, Greenman D, Sieving PC, et al. Ophthalmic manifestations,
cytology, immunohistochemistry, and molecular analysis of intraocular
metastatic T-cell lymphoma: report of a case and review of the literature. Surv
Ophthalmol 2008;53(3):285–295.
25. Lee BS, Frankfort BJ, Eberhart CG, et al. Diagnosis of intravascular lymphoma
by a novel biopsy site. Ophthalmology 2011;118(3):586–590.

Management
26. Nakauchi Y, Takase H, Sugita S, et al. Concurrent administration of intravenous
systemic and intravitreal methotrexate for intraocular lymphoma with central
nervous system involvement. Int J Hematol 2010;92(1):179–185.
27. Taoka K, Yamamoto G, Kaburaki T, et al. Treatment of primary intraocular
lymphoma with rituximab, high dose methotrexate, procarbazine, and
vincristine chemotherapy, reduced whole-brain radiotherapy, and local ocular
therapy. Br J Haematol 2012;157(2):252–254.
28. Teckie S, Yahalom J. Primary intraocular lymphoma: treatment outcomes with
ocular radiation therapy alone. Leuk Lymphoma 2013;55(4):795–801.

Case Reports
29. Gass JDM. Retinal detachment and narrow angle glaucoma secondary to
inflammatory pseudotumor of the uveal tract. Am J Ophthalmol 1967;64:612–
621.
30. Shields JA, Augsburger JJ, Gonder JR, et al. Localized benign lymphoid tumor
of the iris. Arch Ophthalmol 1981;99:2147–2148.
31. Jakobiec FA, Sacks E, Kronish JW, et al. Multifocal static creamy choroidal
infiltrates. An early sign of lymphoid neoplasia. Ophthalmology 1987;94:397–
406.
32. Gittinger JW Jr. Ocular involvement in Castleman’s disease. Response to
radiotherapy. Ophthalmology 1989;96:1646–1649.
33. Duker JS, Shields JA, Eagle RC. Ocular lymphoid hyperplasia. Arch Ophthalmol
1989;107:446–447.
34. Matsuo T, Matsuo N, Shiraga F, et al. Retinal pigment epithelial tear in reactive
lymphoid hyperplasia of uvea. Ophthalmologica 1990;200:46–54.

1382
35. Jensen OA, Johansen S, Kiss K. Intraocular T-cell lymphoma mimicking a ring
melanoma. First manifestation of systemic disease. Report of a case and survey
of the literature. Graefes Arch Clin Exp Ophthalmol 1994;232(3):148–152.
36. Verity DH, Graham EM, Carr R, et al. Hypopyon uveitis and iris nodules in non-
Hodgkin’s lymphoma: ocular relapse during systemic remission. Clin Oncol (R
Coll Radiol) 2000;12(5):292–294.
37. Yahalom C, Cohen Y, Averbukh E, et al. Bilateral iridociliary T-cell lymphoma.
Arch Ophthalmol 2002;120(2):204–207.
38. Lobo A, Larkin G, Clark BJ, et al. Pseudo-hypopyon as the presenting feature in
B-cell and T-cell intraocular lymphoma. Clin Experiment Ophthalmol
2003;31(2):155–158.
39. Ahmed M, Androudi S, Brazitikos P, et al. 360 degrees iris-ciliary body B-cell
lymphoma masquerading as post-cataract uveitis. Semi Ophthalmol 2004;19(3–
4):127–129.
40. Coupland SE, Anastassiou G, Bornfeld N, et al. Primary intraocular lymphoma
of T-cell type: report of a case and review of the literature. Graefes Arch Clin
Exp Ophthalmol 2005;243(3):189–197.
41. Fackler TK, Bearelly S, Odom T, et al. Acute lymphoblastic leukemia
presenting as bilateral serous macular detachments. Retina 2006;26(6):710–712.
42. Candoni A, Simeone E, Bandello F, et al. Leukaemic infiltration of the retina at
onset of Philadelphia-positive acute lymphoblastic leukaemia revealed by
stratus optical coherence tomography. Br J Haematol 2006;133(5):455.
43. Gupta G, Larson RA, Jampol LM. Chronic lymphocytic leukemia masquerading
as uveitis. Retina 2007;27(9):1311–1312.
44. Lin FC, Chen JT, Horng CT. Bilateral central retinal artery occlusion associated
with leukemic optic neuropathy. Can J Ophthalmol 2007;42(5):759–760.
45. Calfa CJ, Lossos IS, Ruiz P, et al. Ocular involvement as the initial manifestation
of T-cell chronic lymphocytic leukemia. Am J Ophthalmol 2007;144(2):326–329.
46. Huynh TH, Johnson MW, Hackel RE. Bilateral proliferative retinopathy in
chronic myelogenous leukemia. Retina 2007;27(1):124–125.
47. Stacy RC, Jakobiec FA, Schoenfield L, et al. U nifocal and multifocal reactive
lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa. Am J
Ophthalmol 2010;150(3):412–426.
48. Kim J, Chang W, Sagong M. Bilateral serous retinal detachment as a presenting
sign of acute lymphoblastic leukemia. Korean J Ophthalmol 2010;24(4):245–
248.
49. Almousa R, Nga ME, Sundar G. Marginal zone B-cell orbital lymphoma with
intracranial involvement. Ophthal Plast Reconstr Surg 2010;26(3):205–206.
50. Sangave A, Faia LJ, Yeh S, et al. A case of rapid progression and vision loss in a
patient with primary intraocular lymphoma. Ocul Immunol Inflamm
2010;18(2):99–100.
51. Angioi K, Bodaghi B, Kaminsky P, et al. Intravascular lymphoma mimicking a
Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm 2011;19(2):132–134.
52. Gregory ME, Chadha V, Roberts F, et al. Bilateral central retinal artery occlusion
in a patient with primary central nervous system lymphoma. Graefes Arch Clin
Exp Ophthalmol 2011;249(8):1269–1270.
53. Chinta S, Rani PK, Manusani U . Bilateral exudative retinal detachment as a
presenting sign of acute lymphoblastic leukemia. Middle East Afr J Ophthalmol

1383
 2012; 19(4):410–412.
54. Goel N, Pangtey B, Thakar M, et al. Chronic myeloid leukemia presenting with
bilateral central retinal vein occlusion and massive retinal infiltrates. J AAPOS
2012;16(4):406–408.
55. Bajenova NV, Vanderbeek BL, Johnson MW. Change in choroidal thickness
after chemotherapy in leukemic choroidopathy. Retina 2012;32(1):203–205.
56. Chan TS, Gill H, Leung AY, et al. U veitis as the initial manifestation of diffuse
large B-cell lymphoma. Am J Hematol 2012;87(2):198–200.
57. Salomão DR, Pulido JS, Johnston PB, et al. Vitreoretinal presentation of
secondary large B-cell lymphoma in patients with systemic lymphoma. JAMA
Ophthalmol 2013;131(9):1151–1158.

1384
• UVEAL BENIGN REACTIVE LYMPHOID HYPERPLASIA
Uveal BRLH is a benign lesion in which the uveal tract is infiltrated by a combination of
lymphocytes and plasma cells. Because it can simultaneously involve the conjunctiva, careful
external ocular examination may suggest the diagnosis of the intraocular lesion.

1. Shields CL, Shields JA, Carvalho C, et al. Conjunctival lymphoid tumors: Clinical analysis of
117 cases and relationship to systemic lymphoma. Ophthalmology 2001;108:979–984.
2. Mashayekhi A, Shukla SY, Shields JA, et al. Choroidal lymphoma: Clinical features and
association with systemic lymphoma. Ophthalmology 2014;121:342–351.

Figure 24.1. Peripheral iris involvement with a localized mass in a 33-year-old woman. The lesion was excised
by iridocyclectomy, and proven histopathologically to be BRLH.

1385
Figure 24.2. Histopathology of uveal benign reactive lymphoid hyperplasia, showing mature lymphocytes, one
of which, near the center of the photomicrograph, has an intranuclear inclusion (Dutcher body). (Periodic acid-
Schiff ×200.)

Figure 24.3. Localized choroidal involvement with BRLH near the temporal equator of the right eye in a 49-year-
old man.

Figure 24.4. Characteristic lymphoid infiltration of the conjunctiva in the same eye shown in Figure 24.3. A
conjunctival biopsy revealed benign lymphoid infiltration.

1386
Figure 24.5. Appearance of the fundus lesion shown in Figure 24.3 after 2,000 cGy of ocular irradiation,
demonstrating excellent response.

Figure 24.6. Appearance of the conjunctival lesion after the irradiation, showing excellent response.

1387
• UVEAL BENIGN REACTIVE LYMPHOID HYPERPLASIA: CLINICAL AND
PATHOLOGIC FEATURES

Figure 24.7. Multiple subtle yellow choroidal lesions in left eye of a 65-year-old woman. The small lesions are
difficult to visualize with photography. Note the red-orange color to the posterior choroid.

1388
Figure 24.8. More pronounced peripheral fundus lesions located inferiorly in the same eye shown in Figure
24.7. The lesions are very similar to those seen with birdshot or sarcoid choroidopathy.

Figure 24.9. Conjunctiva of the same eye shown in Figures 24.7 and 24.8. Note the salmon patch infiltration.
This is seen with lymphoid infiltration but not with birdshot choroidopathy. This is very helpful in clinical
diagnosis.

Figure 24.10. Histopathology of the lesion shown in Figure 24.9, demonstrating uniform small lymphocytes.

1389
Figure 24.11. Grossly sectioned eye with BRLH. Note the marked thickening of the entire posterior uvea and
the perineural infiltration adjacent to the optic nerve in the orbit. (Courtesy of the Armed Forces Institute of
Pathology, Washington, DC.)

1390
Figure 24.12. Low-power photograph of a pathology slide of an eye with uveal benign reactive lymphoid
hyperplasia. The lesion has a dark-blue color characteristic of lymphoid tumor. (Courtesy of the Armed Forces
Institute of Pathology, Washington, DC.)

1391
• UVEAL BENIGN REACTIVE LYMPHOID HYPERPLASIA: DIAGNOSTIC
STUDIES AND TREATMENT

A case is shown with clinical appearance, fluorescein angiography, ultrasonography, magnetic

resonance imaging, and response to irradiation.

Figure 24.13. Wide-angle fundus photograph showing diffuse thickening of the entire posterior aspect of the
choroid in the left eye. This is subtle in the photograph, but was quite elevated when viewed with binocular
indirect ophthalmoscopy. The fundus has a diffuse orange color, resembling a diffuse choroidal hemangioma.

1392
Figure 24.14. Closer view of the area nasal to the disc, showing the choroidal thickening and red-orange color
to the fundus. Note also the hyperemia of the disc.

Figure 24.15. Fluorescein angiography focused on the region nasal to the optic disc, showing very subtle
hyperfluorescence of the choroidal infiltration and subtle horizontal choroidal folds inferiorly.

Figure 24.16. B-scan ultrasonogram, showing choroidal thickening with low to medium internal reflectivity.
Note the echolucent area posterior to the sclera within the orbital fat. This nodule of orbital involvement is a

1393
common and typical finding in uveal benign reactive lymphoid hyperplasia but can also be seen with
extrascleral extension of diffuse uveal melanoma and in true malignant lymphoma of the choroid.

Figure 24.17. Axial magnetic resonance imaging in T1-weighted image with contrast, showing diffuse,
irregular, hyperintense thickening of the choroid.

Figure 24.18. Appearance of the same eye 2 years after external beam irradiation, showing resolution of the
choroidal infiltration. There is some peculiar subretinal fibrosis temporal to the optic disc.

1394
• UVEAL BENIGN REACTIVE LYMPHOID HYPERPLASIA
MASQUERADING AS BIRDSHOT CHOROIDITIS OR SARCOIDOSIS

Uveal reactive lymphoid hyperplasia can cause a clinical appearance very similar to “birdshot
choroidopathy” or choroidal sarcoidosis. The finding of a salmon-colored lesion in the
conjunctiva suggests lymphoid hyperplasia, and a biopsy can confirm the diagnosis and exclude
sarcoidosis and birdshot choroidopathy. A bilateral case is illustrated.

Figure 24.19. Wide-angle fundus photograph of the right eye in a 60-year-old man, showing numerous
discrete yellow-orange deposits in the choroid.

1395
Figure 24.20. Identical findings in the left eye.

1396
Figure 24.21. Closer view of the posterior pole in the right eye, showing macular edema and concentration of
the focal choroidal lesions inferior to the optic disc.

Figure 24.22. Posterior pole of the left eye, showing similar changes. The patient was referred for a choroidal
biopsy to exclude sarcoidosis and birdshot choroidopathy.

Figure 24.23. Salmon-colored lesion found in the superior fornix of the right eye. A conjunctival biopsy rather

1397
than a choroidal biopsy was done, and the diagnosis of reactive lymphoid hyperplasia was confirmed.

Figure 24.24. Histopathology, showing well-differentiated lymphocytes compatible with mucosal-associated

lymphoid tissue (MALT) lymphoma.

1398
• UVEAL BENIGN REACTIVE LYMPHOID HYPERPLASIA: WIDE-ANGLE
IMAGING, ULTRASONOGRAPHY, AND MAGNETIC RESONANCE
IMAGING

Figure 24.25. Fundus appearance of the left eye of a 66-year-old man with benign reactive lymphoid
hyperplasia of the choroid. There is a diffuse red-orange choroidal thickening and a secondary retinal
detachment inferiorly with shifting subretinal fluid.

1399
Figure 24.26. B-scan ultrasonogram, showing diffuse thickening of the choroid and secondary retinal
detachment. Also note the small echolucent area posterior to the sclera, which represents simultaneous
adjacent orbital involvement.

Figure 24.27. Benign reactive lymphoid hyperplasia of the choroid in the right eye of a 44-year-old man. The
pigment epithelial alterations suggest that the lesion and the retinal detachment are beginning to resolve.

1400
Figure 24.28. Axial magnetic resonance imaging in T1-weighted image with gadolinium enhancement and fat
suppression, showing a diffuse enhancing lesion of the choroid with orbital involvement posterior to the
sclera.

Figure 24.29. Resolving benign reactive lymphoid hyperplasia with secondary retinal pigment epithelium
proliferation. The inferotemporal mass resembles a ciliochoroidal detachment as seen with uveal effusion
syndrome. However, it was a solid lymphocytic infiltration of the peripheral choroid and ciliary body.

1401
Figure 24.30. Axial magnetic resonance imaging in T1-weighted image with gadolinium enhancement and fat
suppression, showing a diffuse enhancing lesion of the left choroid. Uveal effusion mostly involves the
peripheral choroid and ciliary body and is less likely to cause thickening of posterior choroid.

1402
UVEAL LYMPHOMA

General Considerations
Systemic lymphoma usually involves lymph nodes and viscera, particularly liver,
spleen, gastrointestinal tract, and lung, and it can occasionally appear in the uveal
tract (1–15). In this section, we will refer to it as uveal lymphoma. U veal lymphoma
is speculated to be a form of metastatic lymphoma from a nonocular primary site,
although some cases appear to develop primarily in the uveal tract, either with or
without systemic involvement. The systemic lymphoma can precede the uveal
involvement, or it can be detected after the diagnosis of uveal lymphoma. As
mentioned, a solitary uveal lymphoma will sometimes have no demonstrable
association with systemic lymphoma, and needle biopsy or eye wall biopsy may be
necessary to differentiate the lesions from amelanotic choroidal melanoma or
metastatic carcinoma (5–7). Although most cases represent uveal infiltration by non-
Hodgkin B-cell lymphoma, the uvea rarely can be involved by T-cell lymphoma,
Hodgkin disease, and other rare forms of lymphoma.

Clinical Features
Clinically, uveal lymphoma has features that are very similar or identical to those
described previously for uveal BRLH, so the features will not be repeated here. The
uveal tumor typically appears different from the confluent, greasy-yellow lesions
that occupy the subretinal pigmented epithelium in the vitreoretinal form, and it is
important to differentiate the two because of their different prognoses. U veal
lymphoma is usually unilateral, but bilateral involvement is not rare. It can
sometimes occur as a solitary mass rather than multiple lesions. In such instances, it
can resemble amelanotic choroidal nevus, melanoma, metastatic carcinoma,
osteoma, hemangioma, posterior scleritis, uveal effusion syndrome, sarcoidosis,
birdshot choroidopathy, and other neoplastic and inflammatory conditions. In
contrast to BRLH, uveal involvement by malignant lymphoma is often more
aggressive and can cause more extensive uveal involvement.
Iris lymphoma, either of B-cell or T-cell lineage, can be indolent or very
aggressive. The aggressive variant can produce marked iris thickening and a tumor-
induced pseudohypopyon or hyphema. There is often a peculiar tendency for the
anterior uvea, with some cases causing massive involvement of the iris and ciliary
body, with minimal involvement of the choroid (3). We have seen lymphoma of the
ciliary body and iris cause thickening of the anterior uvea and a blind, painful eye
(9).
It is possible that the development of uveal lymphoma, particularly in the iris,
may herald a relapse of previously controlled systemic lymphoma, and it should
prompt more thorough systemic evaluation for tumor relapse.

Diagnostic Approaches
As mentioned earlier, many patients with uveal lymphoma have a history of
systemic non-Hodgkin B-cell lymphoma. The diagnostic approaches and results of
ancillary studies are similar to those described for BRLH. We have found that FNAB

1403
can be helpful in the diagnosis of uveal lymphoma and can usually differentiate
lymphoma from other lesions in the differential diagnosis (7). If adequate material
is obtained with FNAB, immunohistochemistry can be done to help to elucidate the
nature of the lymphoma. In most cases, the diagnosis can be made with less
aggressive methods, but eye wall biopsy can also provide an ample specimen to
make a diagnosis in cases that are more difficult (5,6).

Pathology
Histopathologically, choroidal lymphoma is a usually a proliferation of malignant
B-lymphocytes. It can be well differentiated or poorly differentiated. In contrast to
BRLH, it is more likely to be monomorphic and monoclonal, although there is great
variation. Immunohistochemistry and flow cytometry may be helpful in specific
categorization of this lesion.

Management
If the patient with a yellow choroidal mass has known systemic lymphoma and is
receiving chemotherapy, then the uveal disease can be followed without further
treatment, and it generally shows a favorable response to the systemic
chemotherapy. Such a favorable response seen with ophthalmoscopy may reflect an
otherwise unapparent systemic response in nonocular tissues. If the patient has no
history of systemic lymphoma, then an evaluation should be undertaken to exclude
the previously mentioned neoplastic and inflammatory conditions that can have
similar clinical features. If no systemic disease is found, then FNAB and
cytopathologic studies can be performed to confirm or rule out lymphoma.
Lymphoma confined to the uveal tract can be treated with whole-eye irradiation
(3,000 to 4,000 cGy) or plaque radiotherapy if the lesion is solitary and localized.
The prognosis varies with the degree of systemic involvement.

Selected References
Series/Reviews
1. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin
Ophthalmol 2002;13:411–418.
2. Coupland SE, Foss HD, Hidayat AA, et al. Extranodal marginal zone B cell
lymphomas of the uvea: an analysis of 13 cases. J Pathol 2002;197:333–340.
3. Mashayekhi A, Shields CL, Shields JA. Iris involvement by lymphoma: a review
of 13 cases. Clin Experiment Ophthalmol 2013;41(1):19–26.
4. Mashayekhi A, Shukla SY, Shields JA, Shields CL. Choroidal lymphoma:
Clinical features and association with systemic lymphoma. Ophthalmology
2014;121:342–351.

Pathology/Cytology
5. Scherfig E, Prause JU , Jensen OA. Transvitreal retinochoroidal biopsy. Graefes
Arch Clin Exp Ophthalmol 1989;227:369–373.
6. Rutzen AR, Ortega-Larrocea G, Dugel PU , et al. Clinicopathologic study of
retinal and choroidal biopsies in intraocular inflammation. Am J Ophthalmol
1995;119:597–611.
7. Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected

1404
 intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.
Case Reports
8. Leff SR, Shields JA, Augsburger JJ, et al. U nilateral eyelid, conjunctival, and
choroidal tumors as initial presentation of diffuse large cell lymphoma. Br J
Ophthalmol 1985;69:861–864.
9. Duker JS, Shields JA, Ross M. Intraocular large cell lymphoma presenting as
massive thickening of the uveal tract. Retina 1987;7:41–45.
10. Jakobiec FA, Sacks E, Kronish JW, et al. Multifocal static creamy choroidal
infiltrates. An early sign of lymphoid neoplasia.Ophthalmology 1987;94:397–
406.
11. Gunduz K, Shields JA, Shields CL, et al. Transcleral choroidal biopsy in the
diagnosis of choroidal lymphoma. Surv Ophthalmol 1999;43:551–555.
12. Verity DH, Graham EM, Carr R, et al. Hypopyon uveitis and iris nodules in non-
Hodgkin’s lymphoma: ocular relapse during systemic remission. Clin Oncol (R
Coll Radiol) 2000;12:292–294.
13. Yahalom C, Cohen Y, Averbukh E, et al. Bilateral iridociliary T-cell lymphoma.
Arch Ophthalmol 2002;120:204–207.
14. Lobo A, Larkin G, Clark BJ, et al. Pseudo-hypopyon as the presenting feature in
B-cell and T-cell intraocular lymphoma. Clin Exp Ophthalmol 2003;31:155–158.
15. Mori A, Deguchi HE, Mishima K, et al. A case of uveal, palpebral, and orbital
invasions in adult T-cell leukemia. Jpn J Ophthalmol 2003;47:599–602.

1405
• UVEAL LYMPHOMA: RESPONSE TO RADIOTHERAPY
The uveal form of intraocular lymphoma can occur in the iris, ciliary body, or choroid or
subretinal space. It can have a variety of clinical presentations, can be diagnosed by fine-needle
biopsy or eye wall resection, and also responds favorably to radiotherapy. Shown here is a single
case of fine-needle biopsy proven choroidal lymphoma without systemic disease that responded
to external beam radiotherapy.

Arias JD, Kumar N, Fulco EAM, et al. Seasick choroid: a finding on enhanced depth imaging
spectral domain optical coherence tomography (EDI-OCT) of choroidal lymphoma. Retina Cases
and Brief Reports 2013;7(1):19–22.

Figure 24.31. Montage image depicting the extensive, diffuse uveal thickening from choroidal non-Hodgkin
lymphoma.

1406
Figure 24.32. Following biopsy and radiotherapy, the tumor has completely regressed.

Figure 24.33. B-scan ultrasonography demonstrating the thick choroidal mass with extrascleral component.

Figure 24.34. Following radiotherapy, the ultrasound has returned to normal with no evidence of mass.

1407
Figure 24.35. Optical coherence tomography (OCT) showing the dramatic “seasick” appearance with massive
thickening of the choroid with tumor, overlying subretinal fluid, and intraretinal edema.

Figure 24.36. Following radiotherapy, the OCT has returned to normal.

1408
• UVEAL LYMPHOMA: OPTICAL COHERENCE TOMOGRAPHY OF
CALM, RIPPLED OR SEASICK APPEARANCE

Shields CL, Arepalli S, Pellegrini M, et al. Choroidal lymphoma appears with calm, rippled, or
undulating topography on enhanced depth imaging optical coherence tomography in 14 cases.
Retina 2014;34:1347–1353.

Figure 24.37. Yellow thin, patchy choroidal lymphoma.

1409
Figure 24.38. OCT reveals calm, flat thickening of the uvea. Note the outer choroidal infiltration with lymphoma
and obliteration of choroidal vessels.

Figure 24.39. Diffuse yellow choroidal infiltration with lymphoma.

Figure 24.40. OCT reveals rippled topography from slightly thicker lymphoma.

1410
Figure 24.41. Diffuse yellow choroidal infiltration with lymphoma and overlying retinal striae.

Figure 24.42. OCT reveals “seasick” topography from thick choroidal infiltration with lymphoma.

1411
• UVEAL LYMPHOMA: AGGRESSIVE FORM
In some instances, lymphoma can cause massive thickening of the uveal tract and lead to a
blind, painful eye. A patient with massive infiltration of the iris and ciliary body by non-Hodgkin
B-cell lymphoma is depicted.

Duker JS, Shields JA, Ross M. Intraocular large cell lymphoma presenting as massive thickening
of the uveal tract. Retina 1987;7:41–45.

Figure 24.43. Facial photograph of a 46-year-old woman who was noted a few weeks earlier to have an
unexplained thickening of the iris. She subsequently developed a blind, painful right eye.

Figure 24.44. Close-up view of the affected eye at the time of referral, showing marked epibulbar injection,

1412
corneal edema, and diffuse hyphema.

Figure 24.45. Section of the enucleated eye, showing marked amelanotic thickening of the uvea, mostly the iris
and ciliary body.

Figure 24.46. Photomicrograph of the iris and ciliary body region. Note the thickening of the iris and ciliary body
by a diffuse mass, which also abuts the lens equator. (Hematoxylin–eosin ×20.)

1413
Figure 24.47. Photomicrograph of the peripheral choroidal region, showing replacement of the choroid by
lymphoma. Note that the overlying retinal pigment epithelium is intact. (Hematoxylin–eosin ×100.)

Figure 24.48. Histopathology of the tumor, showing malignant lymphoma cells. (Hematoxylin–eosin ×200.)

1414
• UVEAL LYMPHOMA: AGGRESSIVE FORM PRESENTING WITH
PAINFUL SECONDARY GLAUCOMA

In some instances, lymphoma can cause massive thickening of the uveal tract and lead to a
blind, painful eye. Another patient with massive lymphomatous infiltration of the iris and ciliary
body is depicted.

Figure 24.49. A 72-year-old man presented with an acute onset of blind, painful left eye. His medical history
was unremarkable.

Figure 24.50. Close-up view of the affected left eye, showing epibulbar injection and hyphema.

1415
Figure 24.51. Gross appearance of the sectioned eye, showing a massive replacement of the ciliary body by a
white mass. Half of the choroid (to the left) is also thickened by the tumor.

Figure 24.52. The iris and ciliary body replaced by a basophilic mass that has obliterated the anterior chamber
angle. (Hematoxylin–eosin ×25.)

1416
Figure 24.53. Posterior choroid thickened by a basophilic mass. (Hematoxylin–eosin ×20.)

Figure 24.54. Photomicrograph of a uveal tumor, showing highly anaplastic lymphoma. (Hematoxylin–eosin
×250.)

1417
• UVEAL LYMPHOMA: AGGRESSIVE FORM WITH ORBITAL
INVOLVEMENT

In some instances, a patient with uveal and orbital lymphoma can create diagnostic difficulty.
Depicted is a patient who underwent unsuccessful retinal detachment surgery in which no
retinal break was identified. She subsequently developed an orbital mass that aroused suspicion
of uveal melanoma with extraocular extension, and she was referred for orbital exenteration. A
lymphoid tumor was discovered to be the cause of both the retinal detachment and the orbital
mass, and the patient was treated successfully with ocular radiotherapy.

Figure 24.55. Fundus photograph done elsewhere of the thickened choroid. An overlying retinal detachment
prompted surgery.

1418
Figure 24.56. Fundus appearance several months later when larger intraocular masses became apparent.
The vitreous has precluded a clear fundus view.

Figure 24.57. Axial magnetic resonance imaging in T1-weighted image, showing continuous uveal and orbital
mass.

1419
Figure 24.58. Axial magnetic resonance imaging in T2-weighted image, showing the same mass.

Figure 24.59. Epibulbar surface examination found at referral, showing a diffuse, minimally elevated mass in
the bulbar conjunctiva compatible with lymphoid infiltration.

1420
Figure 24.60. B-scan ultrasonogram, showing a diffuse choroidal and episcleral tumor. The extrascleral
component of the lymphoma shows low internal reflectivity that extends posteriorly around the thickened optic
nerve sheath.

1421
 UVEAL PLASMACYTOMA

General Considerations
Plasmacytoma is a neoplasm composed of plasma cells that can range from benign
to malignant. It is best known as an osseous malignancy that is part of multiple
myeloma, but it can occur as a solitary extramedullary plasmacytoma (SEMP).
Intraocular plasmacytoma is a form of SEMP that can be confined to the uveal tract
or can occur as part of multiple myeloma. Reported cases have involved the uveal
tract, and it can occur in the iris, ciliary body, or choroid (1–12).

Clinical Features
U veal plasmacytoma has clinical features that may be identical to those of
lymphoma or choroidal metastasis. It can occur in the iris, ciliary body, or choroid.
It generally appears as a yellow-pink mass, often with secondary retinal detachment.
The lesion can be solitary or multiple.

Diagnostic Approaches
Because uveal plasmacytoma has no unique features, the diagnostic evaluation is the
same as for other amelanotic uveal lesions. Fluorescein angiography and
ultrasonography may be of some benefit in distinguishing it from amelanotic
melanoma, but the findings can be identical to those of lymphoma or metastatic
carcinoma. If the diagnosis of plasmacytoma is suspected, the patient should
undergo a complete systemic evaluation to confirm the diagnosis and rule out
lymphoma, myeloma, or monoclonal gammopathy. If the patient has known
multiple myeloma and the diagnosis is suspected clinically, FNAB can be used to
confirm the diagnosis. If the patient has no myeloma, the unsuspected diagnosis has
been made on cytopathology of FNAB (12).

Pathology
Histopathologically, uveal plasmacytoma is composed predominantly of sheets of
plasma cells. Depending on the degree of cellular differentiation, it can be classified
as benign or malignant. It differs from BRLH, which was discussed previously, and is
composed of lymphocytes with an admixture of plasma cells.

Management
There is little information about the specific treatment for uveal plasmacytoma. The
management is presumed to be similar to that for uveal lymphoma and should
include an evaluation of multiple myeloma or other lymphoproliferative diseases
and irradiation or chemotherapy as done for uveal lymphoma. The prognosis varies,
and patients with frank multiple myeloma have a relatively poor prognosis. The
solitary plasmacytoma is generally expected to have a better prognosis.

Selected References
Series/Reviews

1422
 1. Adkins JW, Shields JA, Shields CL, et al. Plasmacytoma of the eye and orbit. Int
Ophthalmol 1997;20:339–343.
2. Knapp AJ, Gartner S, Henkind P. Multiple myeloma and its ocular
manifestations. Surv Ophthalmol 1987;31:343–351.
3. Orellana J, Friedman AH. Ocular manifestations of multiple myeloma,
Waldenstrom’s macroglobulinemia and benign monoclonal gammopathy. Surv
Ophthalmol 1981;26:157–169.
Case Reports
4. Maisel JM, Miller F, Sibony PA, et al. Multiple myeloma presenting with ocular
inflammation. Ann Ophthalmol 1987;19:170–174.
5. Bowman Z, Peiffer RL Jr, Bouldin TW. Pathogenesis of ciliary-body cysts
associated with multiple myeloma. Ann Ophthalmol 1988;20:292–295.
6. Sandberg HO, Westby RK, Arnesen K. Plasmacytoma of the uvea in a case of
multiple myeloma. Acta Ophthalmol (Copenh) 1989;67:329–332.
7. Brody JM, Butrus SI, Ashraf MF, et al. Multiple myeloma presenting with
bilateral exudative macular detachments. Acta Ophthalmol Scand 1995;73:81–
82.
8. Wong VA, Wade NK. POEMS syndrome: an unusual cause of bilateral optic disk
swelling. Am J Ophthalmol 1998;126:452–454.
9. Honavar SG, Shields JA, Shields CL, et al. Extramedullary plasmacytoma
confined to the choroid. Am J Ophthalmol 2001;131:277–278.
10. Tranos PG, Andreou PS, Wickremasinghe SS, et al. Pseudohypopyon as a
feature of multiple myeloma. Arch Ophthalmol 2002;120:87–88.
11. Morgan AE, Shields JA, Shields CL, et al. Presumed malignant plasmacytoma of
the choroid as the first manifestation of multiple myeloma. Retina 2003;23:867–
868.
12. Shields CL, Chong WH, Eyha H, et al. Sequential bilateral solitary
extramedullary plasmacytoma of the ciliary body. Cornea 2007;26:759–761.

1423
• CHOROIDAL PLASMACYTOMA
A case is depicted in which cytologic study of an FNAB of atypical choroidal mass made the
diagnosis of a plasmacytoma. The tumor responded dramatically to radiotherapy. Several years
later, the patient developed a monoclonal gammopathy.

1. Adkins JW, Shields JA, Shields CL, et al. Plasmacytoma of the eye and orbit. Internat
Ophthalmol 1977;20:339–343.
2. Honavar SG, Shields JA, Shields CL, et al. Extramedullary plasmacytoma confined to the
choroid. Am J Ophthalmol 2001;131:277–278.

Figure 24.61. Fundus drawing, showing two large choroidal masses in the right eye of a systemically healthy
77-year-old woman.

1424
Figure 24.62. Wide-angle fundus photograph showing the two masses. The red-orange color of the lesions is
similar to the background color of the fundus.

Figure 24.63. B-scan ultrasonogram, showing the two masses with acoustic solidity.

1425
Figure 24.64. Cytology of fine-needle aspiration biopsy, showing mature plasma cells. (Papanicolaou ×300.)

Figure 24.65. Appearance of the macular area after 3,000 cGy of ocular irradiation, showing disappearance of
the macular mass.

1426
Figure 24.66. B-scan ultrasonogram after irradiation, showing marked flattening of the tumors.

1427
• CILIARY BODY PLASMACYTOMA
Shields CL, Chong WH, Ehya H, et al. Sequential bilateral solitary extramedullary plasmacytoma
of the ciliary body. Cornea 2007;26:759–761.

Figure 24.67. Mass behind the iris, invading the anterior chamber, in an adult woman.

Figure 24.68. Ultrasound biomicroscopy shows a solid ciliary body mass.

1428
Figure 24.69. Cytopathology of fine-needle aspiration biopsy, showing neoplastic plasma cells. (Papanicolaou
×200.)

Figure 24.70. Surgeon’s view of a radioactive plaque placed over the lesion.

1429
Figure 24.71. Appearance later, showing normal-appearing iris with posterior synechia that was present
previously.

Figure 24.72. Ultrasound biomicroscopy after plaque radiotherapy, showing complete resolution of the mass.

1430
 PRIMARY VITREORETINAL AND CENTRAL NERVOUS SYSTEM
LYMPHOMA

General Considerations
Primary vitreoretinal and central nervous system lymphoma (PVRCNSL) is an
unusual variant of lymphoma that affects the brain, meninges, and often the
intraocular structures (1–39). If the eye is involved first, it is called vitreoretinal
lymphoma (VRL) (1,12), which is the term that we will employ here whether or not
the CNS is affected.
Historically, this disease was called microgliomatosis, reticulum cell sarcoma, and
histiocytic lymphoma because the cell of origin was debated. It was eventually
learned that the disease was due to a proliferation of B-lymphocytes, and these
terms were abandoned. This disease very frequently involves the optic nerve, retina,
and vitreous (1–39). It accounts for about 65% of cases of intraocular lymphoma
and is bilateral in about 90% of cases (37). In about 80% of patients who develop
VRL, the ocular findings are the initial manifestations of the disease. PIOL often
occurs in elderly patients (mean age 60 years) who are apparently
immunocompetent. However, it has an increased incidence in patients who are
immunosuppressed from medications or in patients with acquired
immunodeficiency syndrome. In immunosuppressed patients, the disease has a more
aggressive clinical course and carries a worse prognosis.

Clinical Features
There are several clinical variations of VRL. It usually presents as patchy yellow
retinal lesions and secondary cells in the vitreous cavity. In some cases, the vitreal
cells predominate and the retinal involvement is not evident clinically. The vitreal
cells are characteristically arranged in clumps, but they can sometimes be fine and
evenly dispersed. The presence of vitreal cells suggests an inflammatory process, and
the malignancy is often misdiagnosed initially as retinitis, vitreitis, or uveitis and is
referred to as a “masquerade syndrome,” a term used to describe a malignant
condition that simulates a benign process. Specifically, the condition can be initially
diagnosed as an inflammatory process such as cytomegalovirus retinitis, acute retinal
necrosis, retinal toxoplasmosis retinitis, and several other inflammatory conditions.
In other instances, it may simulate choroidal metastatic carcinoma, amelanotic
choroidal melanoma, or other neoplasms.
VRL primarily affects the retina and/or the optic disc. Retinal involvement is
characterized by retinal thickening by a yellow infiltration and vitreal cells. In some
cases, the retinal vessels show sheathing, suggesting the diagnosis of a retinal
vasculitis or frosted branch angiitis (angiocentric lymphoma). Infiltration of the
optic nerve head can lead to optic disc hyperemia and edema.
A highly characteristic and well-known feature, seen in many cases, is a round or
geographic greasy-yellow mass under the retinal pigment epithelium (8,10,35).
These multiple masses tend to become confluent and appear as a diffuse, greasy-
yellow infiltration. This represents neoplastic detachments of the RPE by a mass of
necrotic malignant B-lymphocytes. This is initially homogeneously yellow, but later
shows characteristic brown clumps of RPE proliferation on the surface of the mass.

1431
Diagnostic Approaches
If VRL is suspected on the basis of ocular examination, it is important to confirm the
diagnosis by neurologic evaluation, lumbar puncture with spinal fluid studies, and
imaging studies of the brain, usually by computed tomography or magnetic
resonance imaging. The detection of CNS lymphoma would support the diagnosis of
concurrent VRL rather than an inflammatory process.
It must be stressed that the best method of diagnosing early VRL is with
ophthalmoscopy, which is far superior to MRI or CT in detection of early
vitreoretinal involvement. Standard diagnostic approaches such as fluorescein
angiography and ultrasonography are of only minimal value and do not reveal
specific features that differentiate VRL from other inflammatory or neoplastic
processes. The diagnosis is usually made by cytologic evaluation of FNAB or
vitrectomy specimens that reveal the lymphoma cells (15–23). If the vitreous
infiltration is not marked, more tissue can be obtained by FNAB of the sub-RPE
mass. The material should be processed by standard cytopathology techniques, and
the specimen should be reviewed by a cytopathologist or ocular pathologist who
has experience with ocular specimens. Although the diagnosis is not usually difficult
for cytopathologists experienced with ocular specimens, immunopathology methods
can sometimes be applied to vitreous biopsy specimens to confirm the diagnosis
and characterize the lymphocytes (14).

Pathology
Several years ago, there was uncertainty about the nature of cells that infiltrate the
retina, vitreous, and sub-RPE space in cases of VRL. As mentioned earlier, this
condition was historically called microgliomatosis, reticulum cell sarcoma, and
histiocytic lymphoma. Recent techniques of flow cytometry and
immunohistochemistry have identified the cells in most cases to be malignant B-cell
lymphocytes (13–24).
Histopathologically, the retina is diffusely infiltrated by large malignant
lymphocytes of B-cell lineage. Similar cells are seen in the sub-RPE space, vitreous,
and occasionally the retinal blood vessels. A characteristic feature on both
histopathology and cytopathology is extensive necrosis of the tumor cells. This is
particularly true of cells in the vitreous and sub-RPE space, where their blood
supply is compromised. Although most cases show the tumor cells to be B-
lymphocytes, similar clinical and histopathologic features can be occasionally
identified in the eye with cutaneous T-cell lymphoma (mycosis fungoides) and other
rare forms of lymphoma.

Management
Once the diagnosis of VRL is established, management depends on the extent of the
disease. When the tumor is confined to the eye without demonstrable brain
involvement, ocular radiation, usually 3,500 to 4,000 cGy in 200-cGy fractions, or
intravitreal chemotherapy, is given to the affected eye (12,25–29). In most cases,
there is bilateral involvement, and both eyes are often treated, depending on clinical
circumstances. For concurrent brain involvement, cranial radiation in similar doses
is generally advisable. This is generally combined with systemic chemotherapy or
intrathecal methotrexate in appropriate doses. Although it is controversial, we do

1432
not advocate prophylactic irradiation to uninvolved eyes in patients with CNS
lymphoma. However, close ocular follow-up is necessary, and irradiation can be
instituted as soon as ocular involvement becomes evident. Some favorable results
have been achieved with intravitreal injection of methotrexate and rituximab
(26–28).
Although a few patients appear to be cured after appropriate treatment, the
prognosis is much worse if there is extensive CNS involvement. Close monitoring of
affected patients is warranted.

Selected References
Series/Reviews
1. Nussenblatt RB, Chan CC, Wilson WH, et al. CNS and Ocular Lymphoma
Workshop Group. International Central Nervous System and Ocular Lymphoma
Workshop: recommendations for the future. Ocul Immunol Inflamm
2006;14:139–144.
2. Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory
investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology
1987;94:1631–1639.
3. Char DH, Ljung BM, Miller T, et al. Primary intraocular lymphoma (ocular
reticulum cell sarcoma) diagnosis and management. Ophthalmology
1988;95:626–630.
4. Ridley ME, McDonald HR, Sternberg P Jr, et al. Retinal manifestations of ocular
lymphoma (reticulum cell sarcoma). Ophthalmology 1992;99:1153–1160.
5. Buettner H, Bolling JP. Intravitreal large-cell lymphoma. Mayo Clin Proc 1993;
68:1011–1015.
6. Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular–central nervous system
lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology
1999;106:1805–1810.
7. Gill MK, Jampol LM. Variations in the presentation of primary intraocular
lymphoma: case reports and a review. Surv Ophthalmol 2001;45:463–471.
8. Buggage RR, Chan CC, Nussenblatt RB. Ocular manifestations of central nervous
system lymphoma. Curr Opin Oncol 2001;13:137–142.
9. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin
Ophthalmol 2002;13:411–418.
10. Gass JD, Sever RJ, Grizzard WS, et al. Multifocal pigment epithelial
detachments by reticulum cell sarcoma: a characteristic funduscopic picture.
Retina 2003;23:135–143.
11. Chan CC, Wallace DJ. Intraocular lymphoma: update on diagnosis and
management. Cancer Control 2004;11:285–295.
12. Sagoo MS, Mehta H, Swampillai AJ, et al. Primary intraocular lymphoma. Surv
Ophthalmol 2013;59(5):503–516.

Pathology/Cytology
13. Kaplan HJ, Meredith TA, Aaberg TM, et al. Reclassification of intraocular
reticulum cell sarcoma (histiocytic lymphoma). Immunologic characterization of
vitreous cells. Arch Ophthalmol 1980;98:707–710.
14. Wilson DJ, Braziel R, Rosenbaum JT. Intraocular lymphoma.
Immunopathologic analysis of vitreous biopsy specimens. Arch Ophthalmol

1433
 1992;110:1455–1458.
15. Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of
suspected intraocular tumors. The 1992 U rwick Lecture. Ophthalmology
1993;100:1677–1684.
16. Pavan PR, Oteiza EE, Margo CE. Ocular lymphoma diagnosed by internal
subretinal pigment epithelium biopsy. Arch Ophthalmol 1995;113:1233–1234.
17. Davis JL, Viciana AL, Ruiz P. Diagnosis of intraocular lymphoma by flow
cytometry. Am J Ophthalmol 1997;124:362–372.
18. Ciulla TA, Pesavento RD, Yoo S. Subretinal aspiration biopsy of ocular
lymphoma. Am J Ophthalmol 1997;123:420–422.
19. Levy-Clarke GA, Byrnes GA, Buggage RR, et al. Primary intraocular lymphoma
diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina
2001;21:281–284.
20. Levy-Clarke GA, Byrnes GA, Buggage RR, et al. Primary intraocular lymphoma
diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina
2001;21:281–284.
21. Rao M. Primary intraocular lymphoma diagnosed by fine needle aspiration
biopsy of a subretinal lesion. Retina 2002;22:512–513.
22. Coupland SE, Bechrakis NE, Anastassiou G, et al. Evaluation of vitrectomy
specimens and chorioretinal biopsies in the diagnosis of primary intraocular
lymphoma in patients with Masquerade syndrome. Graefes Arch Clin Exp
Ophthalmol 2003; 241:860–870.
23. Pleyer U , Hummel M, Stein H. Evaluation of vitrectomy specimens and
chorioretinal biopsies in the diagnosis of primary intraocular lymphoma in
patients with masquerade syndrome. Graefes Arch Clin Exp Ophthalmol
2003;241:860–870.
24. Johnston RL, Tufail A, Lightman S, et al. Retinal and choroidal biopsies are
helpful in unclear uveitis of suspected infectious or malignant origin.
Ophthalmology 2004; 111:522–528.

Management
25. Valluri S, Moorthy RS, Khan A, et al. Combination treatment of intraocular
lymphoma. Retina 1995;15:125–129.
26. Fishburne BC, Wilson DJ, Rosenbaum JT, et al. Intravitreal methotrexate as an
adjunctive treatment of intraocular lymphoma. Arch Ophthalmol
1997;115:1152–1156.
27. Velez G, Boldt HC, Whitcup SM, et al. Local methotrexate and dexamethasone
phosphate for the treatment of recurrent primary intraocular lymphoma.
Ophthalmic Surg Lasers 2002;33:329–333.
28. Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in
the management of primary central nervous system lymphoma with ocular
involvement. Ophthalmology 2002;109:1709–1716.
29. Levy-Clarke GA, Chan CC, Nussenblatt RB. Diagnosis and management of
primary intraocular lymphoma. Hematol Oncol Clin North Am 2005;19:739–749.

Case Reports
30. Gass JD, Weleber RG, Johnson DR. Non-Hodgkin’s lymphoma causing fundus
picture simulating fundus flavimaculatus. Retina 1987;7:209–214.
31. Gass JD, Trattler HL. Retinal artery obstruction and atheromas associated with

1434
 non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol
1991;109:1134–1139.
32. Brown SM, Jampol LM, Cantrill HL. Intraocular lymphoma presenting as
retinal vasculitis. Surv Ophthalmol 1994;39:133–140.
33. Matzkin DC, Slamovits TL, Rosenbaum PS. Simultaneous intraocular and orbital
non-Hodgkin lymphoma in the acquired immune deficiency syndrome.
Ophthalmology 1994;101:850–855.
34. Cohen RG, Hedges TR 3rd, Duker JS. Central retinal artery occlusion in a child
with T-cell lymphoma. Am J Ophthalmol 1995;120:118–120.
35. 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.
36. Oh KT, Polk TD, Boldt HC, et al. Systemic small noncleaved cell lymphoma
presenting as a posterior choroidal mass. Am J Ophthalmol 1998;125:560–562.
37. Towler H, de la Fuente M, Lightman S. Posterior uveitis in Hodgkin’s disease.
Aust N Z J Ophthalmol 1999;27:326–330.
38. Shah GK, Kleiner RC, Augsburger JJ, et al. Primary intraocular lymphoma seen
with transient white fundus lesions simulating the multiple evanescent white
dot syndrome. Arch Ophthalmol 2001;119:617–620.
39. To KW, Thirkill CE, Jakobiec FA, et al. Lymphoma-associated retinopathy.
Ophthalmology 2002;109:2149–2153.

1435
• PRIMARY VITREORETINAL LYMPHOMA
Primary VRL involves primarily the retina, vitreous, and optic nerve. Although it has been known
to involve the eye only, most patients have, or will develop, primary central nervous system
lymphoma as part of the same disease process. Regarding VRL, the diagnosis generally is best
confirmed by cytopathologic study of vitreous biopsy.

Figure 24.73. Slit-lamp view of anterior vitreous cells in a patient with primary vitreoretinal lymphoma. Note the
clumps of yellow-white tumor cells in the anterior vitreous. (Courtesy of Alan Cruess.)

Figure 24.74. Cranial computed tomogram, showing a large intracranial lymphoma. Patients with suspected
primary vitreoretinal lymphoma should have cranial computed tomography or magnetic resonance imaging
periodically. (Courtesy of Alan Cruess.)

1436
Figure 24.75. Fundus appearance of vitreoretinal lymphoma, showing a typical hazy view of yellow-white tumor
tissue. The retina cannot be clearly seen in such cases due to overlying vitreous involvement by the tumor.
(Courtesy of Alan Cruess.)

Figure 24.76. Cytopathology of a vitreous biopsy, showing malignant lymphoma cells. (Hematoxylin–eosin
×300.) (Courtesy of Alan Cruess.)

1437
Figure 24.77. Fundus view of optic nerve involvement with non-Hodgkin lymphoma in a 57-year-old woman.
(Courtesy of W. Richard Green, MD.)

Figure 24.78. Cross section of the optic nerve in the patient shown in Figure 24.35, demonstrating basophilic
lymphoma cells infiltrating the pial septa. (Hematoxylin–eosin ×20.) (Courtesy of W. Richard Green, MD.)

1438
• PRIMARY VITREORETINAL LYMPHOMA: WIDE-ANGLE IMAGING AND
MANAGEMENT

Figure 24.79. Right fundus of a 64-year-old man. There were only scant vitreous cells and no retinal lesions
seen.

1439
Figure 24.80. Left eye of the same patient, showing a hazy fundus view due to extensive vitreal involvement by
lymphoma cells.

1440
Figure 24.81. Clumps of yellow-white cells beneath the retinal pigment epithelium nasally in the right eye of a
71-year-old man.

Figure 24.82. Temporal fundus of the eye in Figure 24.81, showing similar lesions.

Figure 24.83. Cytopathology of a vitreous fine-needle aspiration biopsy, showing malignant lymphoma cells
with extensive necrosis, a typical finding in primary intraocular lymphoma. (Papanicolaou ×200. Insets ×400.)

1441
Figure 24.84. Appearance of the right eye shown in Figure 24.82 after external beam irradiation, demonstrating
the vitreal clumps to be smaller and more distinct, suggesting that they are no longer active.

1442
• PRIMARY VITREORETINAL LYMPHOMA: SPONTANEOUS
REGRESSION AFTER FINE-NEEDLE ASPIRATION BIOPSY

There are cases in which fine-needle aspiration biopsy of a uveal lymphoid tumor can lead to
tumor regression before treatment. We are uncertain as to why this occurs. The patient shown
here had multiple clumps of subretinal pigment epithelium lymphoma and following needle
biopsy, all the lymphomas resolved. Three months later, they recurred, and she was treated with
chemotherapy.

Fenton G, Shields CL, Horgan N, et al. Partial spontaneous regression of vitreoretinal large cell
lymphoma following fine needle aspiration biopsy. Retina Cases and Brief Reports
2008;2(2):163–166.

Figure 24.85. Wide-angle fundus image, showing large clumps of lymphoma cells beneath the retinal pigment
epithelium of a 72-year-old woman.

1443
Figure 24.86. Closer view of the lymphoma under the retinal pigment epithelium temporally.

Figure 24.87. Large clumps of subretinal pigment epithelium lymphoma inferior to the optic disc at
presentation.

1444
Figure 24.88. Following fine-needle aspiration of the large temporal tumor, there was remarkable
spontaneous clearing of subretinal pigment epithelium tumor inferiorly in right eye within 1 month. The
planned irradiation was canceled, and the patient was followed conservatively.

Figure 24.89. Another patient with intraretinal and subretinal pigment epithelium lymphoma as well as retinal
hemorrhage.

1445
Figure 24.90. Optical coherence tomography of macular lesion in Figure 24.87, demonstrating the multifocal
subretinal pigment epithelial location of the tumor.

1446
INTRAOCULAR LEUKEMIA

General Considerations
Most patients with ocular involvement by leukemia already have known systemic
disease, but rarely the ophthalmic findings can be the initial manifestation of the
systemic disorder (1–19). More than half of the patients with leukemia have related
ocular abnormalities, but <5% have true intraocular involvement by the neoplasm.
Intraocular leukemic infiltration occurs most often in children with acute
lymphoblastic leukemia. It can involve the iris, ciliary body, choroid, retina,
vitreous, or optic nerve. Ocular involvement is usually a sign of severe disease and
can be the first sign of relapse of disease that had been in remission. Although most
cases of intraocular leukemia occur in children, adult T-cell leukemia and other
types can also involve the intraocular structures.

Clinical Features
Iris leukemia can appear as a solitary mass or as diffuse iris thickening. In many
instances, the lesion is friable and can seed tumor cells into the aqueous, producing
a neoplastic pseudohypopyon. Spontaneous hyphema can also be a manifestation of
iris involvement by leukemia. Consequently, it can be misdiagnosed as
retinoblastoma, uveitis, or endophthalmitis. In the posterior segment, it appears as a
diffuse or patchy thickening of the retina and choroid, often with extensive retinal
hemorrhage, infiltration of the optic disc, and tumor cells in the vitreous. Patients
with intraocular leukemia almost always have demonstrable leukemia in peripheral
blood, bone marrow, and the CNS. Optic disc edema from leukemia must be
differentiated from true papilledema due to CNS involvement and from radiation-
induced papillopathy.

Diagnostic Approaches
The diagnosis should be suspected with any of the aforementioned findings in a
patient with known leukemia. Fluorescein angiography and ultrasonography show
no specific diagnostic changes. Diagnostic FNAB can establish the diagnosis in cases
of iris, anterior chamber, vitreous, retinal, or choroidal involvement (6,7).

Pathology
Histopathologically, intraocular leukemia is characterized by an infiltration of the
uvea, retina and optic disc, and uveal tract by leukemic blast cells with extensive
hemorrhage. The tumor cells often fill the retinal and uveal blood vessels and have
a tendency to invade deep into the optic nerve.

Management
Management is usually treatment of the systemic disease combined with ocular
irradiation, especially if optic nerve involvement threatens the patient’s vision. In
such cases, prompt ocular radiotherapy is indicated. Involvement of the iris and
optic disc often imparts a worse prognosis.

1447
Selected References
Series/Reviews
1. Brown GC, Shields JA, Augsburger JJ, et al. Leukemic optic neuropathy. Int
Ophthalmol 1981;3:111–116.
2. Guyer DR, Schachat AP, Vitale S, et al. Leukemic retinopathy. Relationship
between fundus lesions and hematologic parameters at diagnosis.
Ophthalmology 1989;96:860–864.
3. Schachat AP, Markowitz JA, Guyer DR, et al. Ophthalmic manifestations of
leukemia. Arch Ophthalmol 1989;107:697–700.
4. Reddy SC, Jackson N, Menon BS. Ocular involvement in leukemia—a study of
288 cases. Ophthalmologica 2003;217:441–445.
5. Sharma T, Grewal J, Gupta S, et al. Ophthalmic manifestations of acute
leukaemias: the ophthalmologist’s role. Eye 2004;18:663–672.

Management
6. Shields JA, Shields CL, Ehya H, et al. Fine-needle aspiration biopsy of suspected
intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.
7. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of
iris tumors in 100 consecutive cases. Technique and complications.
Ophthalmology 2006;113:2080–2086.
Case Reports
8. Finger PT, Pro MJ, Schneider S, et al. Visual recovery after radiation therapy for
bilateral subfoveal acute myelogenous leukemia (AML). Am J Ophthalmol
2004;138:659–662.
9. Kassam F, Gale JS, Sheidow TG. Intraocular leukemia as the primary
manifestation of relapsing acute myelogenous leukemia. Can J Ophthalmol
2003;38:613–616.
10. Allione A, Montanaro M, Marmont F, et al. Fungal endophthalmitis in acute
leukaemia. Br J Haematol 2004;124:257.
11. Mori A, Deguchi HE, Mishima K, et al. A case of uveal, palpebral, and orbital
invasions in adult T-cell leukemia. Jpn J Ophthalmol 2003;47:599–602.
12. Patel SV, Herman DC, Anderson PM, et al. Iris and anterior chamber
involvement in acute lymphoblastic leukemia. J Pediatr Hematol Oncol
2003;25:653–656.
13. Somervaille TC, Hann IM, Harrison, et al. Intraocular relapse of childhood
acute lymphoblastic leukaemia. Br J Haematol 2003;121:280–288.
14. Hirata A, Miyazaki T, Tanihara H. Intraocular infiltration of adult T-cell
leukemia. Am J Ophthalmol 2002;134:616–618.
15. Dadeya S, Malik KP, Guliani BP, et al. Acute lymphocytic leukemia presenting
as masquerade syndrome. Ophthalmic Surg Lasers 2002;33:163–165.
16. O’Keefe JS, Sippy BD, Martin DF, et al. Anterior chamber infiltrates associated
with systemic lymphoma: report of two cases and review of the literature.
Ophthalmology 2002;109:253–257.
17. Wallace RT, Shields JA, Shields CL, et al. Leukemic infiltration of the optic
nerve. Arch Ophthalmol 1991;109:1027.
18. Schachat AP, Jabs DA, Graham ML, et al. Leukemic iris infiltration. J Pediatr

1448
 Ophthalmol Strabismus 1988;25:135–138.
19. Yi DH, Rashid S, Cibas ES, et al. Acute unilateral leukemic hypopyon in an
adult with relapsing acute lymphoblastic leukemia. Am J Ophthalmol
2005;139:719–721.

1449
• INTRAOCULAR AND OPTIC NERVE INVOLVEMENT WITH LEUKEMIA
Intraocular findings in leukemia usually occur as retinal hemorrhages secondary to the
hematological abnormality. Occasionally, however, the iris, ciliary body, choroid, retina, and
vitreous can be directly involved with leukemic infiltration.

Wallace RT, Shields JA, Shields CL, et al. Leukemic infiltration of the optic nerve. Arch
Ophthalmol 1991;109:1027.

Figure 24.91. Salmon-colored leukemic infiltration in the superior fornix of a patient with known leukemia.

Figure 24.92. Choroidal infiltration of leukemia in patient shown in Figure 24.91.

1450
Figure 24.93. Spontaneous pseudohypopyon in a 23-year-old patient with acute lymphoblastic leukemia.
(Courtesy of Elise Torczynski, MD.)

Figure 24.94. Cytopathology of a needle biopsy of the anterior chamber material shown in Figure 24.93,
demonstrating leukemic blast cells. (Courtesy of Elise Torczynski, MD.) (Papanicolaou ×400.)

1451
Figure 24.95. Marked involvement of the optic nerve head and surrounding fundus in a 28-year-old woman with
leukemia. The differential diagnosis was leukemic infiltration and opportunistic infection. The diagnosis of
leukemia was confirmed by the study of a fine-needle aspiration specimen, and ocular radiation was given.

Figure 24.96. Appearance of the same eye after irradiation. Most of the leukemic infiltration has resolved, but
profound optic atrophy was present, and the patient had no useful vision in the affected eye.

1452
• INTRAOCULAR AND OPTIC NERVE INVOLVEMENT WITH LEUKEMIA:
CLINICOPATHOLOGIC CORRELATION

Leukemia has a tendency to affect the posterior fundus and to invade the optic nerve, causing
profound visual loss. Two cases are illustrated.

Brown GC, Shields JA, Augsburger JJ, et al. Leukemic optic neuropathy. Int Ophthalmol
1991;3:111–116.

Figure 24.97. Fluffy yellow-white, hemorrhagic, retinovitreal mass adjacent to the optic disc in a 20-year-old
man in a blast crisis from chronic myelogenous leukemia. Visual acuity was hand motions. Orbital and brain
involvement were detected with magnetic resonance imaging. (Courtesy of Franco M. Recchia, MD.)

1453
Figure 24.98. Appearance of the lesion shown in Figure 24.97, 5 weeks later, after brain and eye irradiation
and chemotherapy. There has been considerable resolution of the lesion. Visual acuity was finger counting.
(Courtesy of Franco M. Recchia, MD.)

Figure 24.99. Atypical optic disc swelling in an 8-year-old boy with 20/20 vision in the affected left eye. He
underwent chemotherapy for systemic relapse of previously diagnosed leukemia at this time.

1454
Figure 24.100. The same eye 3 months later, when he developed rapid blindness. Radiotherapy was given
without visual recovery, and the child died shortly thereafter.

Figure 24.101. Photograph of the sectioned eye obtained postmortem. Note the hemorrhagic swelling of the
optic disc and surrounding tissues.

1455
Figure 24.102. Photomicrograph of the involved retina, showing intravascular and extravascular infiltration of
leukemic blast cells. (Hematoxylin–eosin ×200.)

1456
 CHAPTER 25

SURGICAL MANAGEMENT OF INTRAOCULAR

TUMORS

SURGICAL MANAGEMENT OF INTRAOCULAR TUMORS

Surgical management of intraocular tumors has been mentioned in several parts of

this book, but specific steps have not been illustrated. Techniques illustrated here
include fine-needle aspiration biopsy (FNAB), application of radioactive plaque,
and surgical tumor removal by iridectomy, partial lamellar sclerouvectomy,
enucleation, and orbital exenteration (1–16). Laser photocoagulation and
cryotherapy are discussed elsewhere and are illustrated earlier in this book as they
apply to specific lesions.
Intraocular FNAB is a method of diagnosing selected lesions that defy an accurate
diagnosis using less invasive diagnostic modalities (1,2). It is a fairly difficult surgical
procedure that requires skill of the ocular oncologist in obtaining the cellular tissue
and avoiding complications as well as the cooperation of an experienced
cytopathologist. It should be reserved for selected cases in which an accurate
diagnosis will influence the therapeutic choice. It is performed by passing a fine
needle into the suspicious tissue and obtaining cells for special preparation and
cytologic analysis. In the case of an iris lesion, the needle is passed through the
corneoscleral limbus directly into the tumor, using the surgical microscope for better
visualization (2). For posteriorly located lesions, the needle is passed through the
pars plana and vitreous and into the tumor apex, usually using indirect
ophthalmoscopy (1). In some cases the needle is placed via the surgical microscope
for guidance. Although false results sometimes occur, it is an accurate diagnostic
procedure in most cases.
Selected iris tumors can be removed by partial iridectomy. Selected ciliary body
or choroidal tumors can be removed by techniques of partial lamellar
sclerouvectomy. This technique is used mainly for melanoma, leiomyoma, and
tumors or the pigmented or nonpigmented ciliary epithelium (3–5). Enucleation is

1457
indicated for advanced malignant tumors such as retinoblastoma and uveal
melanoma that cannot be successfully managed by other methods (6–14). A gentle
technique should be employed in all cases, and the method may vary depending on
whether the tumor is a melanoma or a retinoblastoma. Fresh tissue is often
harvested following enucleation for genetic analysis (15). Orbital exenteration,
particularly the eyelid-sparing technique, is reserved for some advanced tumors,
particularly uveal melanomas with large degrees of extraocular extension (16).
The techniques employed are subsequently illustrated and discussed in more
detail in the references cited.

Selected References
Pathology/Cytology
1. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected
intraocular tumors. The 1992 U rwick Lecture. Ophthalmology 1993;100:1677–
1684.
2. Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of
iris tumors in 100 consecutive cases. Technique and complications.
Ophthalmology 2006;113:2080–2086.

Management
3. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for
posterior uveal melanomas. The 1986 Schoenberg Lecture. Ophthalmic Surg
1988;19:774–780.
4. Shields JA, Shields CL, Shah P, et al. Partial lamellar sclerouvectomy for ciliary
body and choroidal tumors. Ophthalmology 1991;98:971–983.
5. Ramasubramanian A, Shields CL, Kytasty C, et al. Resection of intraocular
tumors (partial lamellar sclerouvectomy) in the pediatric age group.
Ophthalmology 2012;119:2507–2513.
6. Shields JA, Shields CL, De Potter P. Enucleation technique for children with
retinoblastoma. J Pediatr Ophthalmol Strabismus 1992;29:213–215.
7. Shields CL, Shields JA, De Potter P. Hydroxyapatite orbital implant after
enucleation. Experience with initial 100 consecutive cases. Arch Ophthalmol
1992;110:333–338.
8. Shields CL, Shields JA, De Potter P, et al. Lack of complications of the
hydroxyapatite orbital implant in 250 consecutive cases. Trans Am Ophthalmol
Soc 1993;91:177–189.
9. DePotter P, Shields CL, Shields JA, et al. U se of the orbital hydroxyapatite
implant in the pediatric population. Arch Ophthalmol 1994;112:208–212.
10. Edelstein C, Shields CL, DePotter P, et al. Complications of motility peg
placement for the hydroxyapatite orbital implant. Ophthalmology
1997;104:1616–1621.
11. Shields CL, U ysal Y, Marr BP, et al. Experience with the polymer-coated
hydroxyapatite implant following enucleation in 126 patients. Ophthalmology
2007;114:367–373.
12. Shah SU , Shields CL, Lally SE, et al. Hydroxyapatite orbital implant in children
following enucleation. Analysis of 531 sockets. Ophthalm Plast Reconstr Surg
2014;31(2):108–114.
13. Shields CL, Shah SU , Au A, et al. Long-term outcomes of hydroxyapatite orbital

1458
 implant in 1185 consecutive cases. 2015; in press.
14. Shields CL, Shields JA. Retinoblastoma management: Advances in enucleation,
intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin
Ophthalmol 2010;21:203–212.
15. Shields JA, Shields CL, Lally SE, et al. Harvesting fresh tumor tissue from
enucleated eyes. The 2008 Jack S. Guyton Lecture. Arch Ophthalmol
2010;128(2):241–243.
16. Shields JA, Shields CL, Suvarnamani C, et al. Orbital exenteration with eyelid
sparing: indications, technique and results. Ophthalmic Surg 1991;22:292–297.

1459
• FINE-NEEDLE ASPIRATION BIOPSY: INSTRUMENTATION AND
TECHNIQUE

The instrumentation, techniques, limitations, complications, and results for FNAB of suspected
intraocular tumors and inflammations are reported in more detail in the references cited and are
only illustrated briefly here. (Illustrations by Linda Warren.)

1. 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.

Figure 25.1. Instruments used for intraocular fine-needle aspiration biopsy.

1460
Figure 25.2. Translimbal, transaqueous approach for iris lesions, front view. The surgical microscope is
generally used for this technique.

Figure 25.3. Translimbal, transaqueous approach for iris lesions, side view.

1461
Figure 25.4. Trans–pars plana, transvitreal approach for ciliary body and choroidal lesions. Indirect
ophthalmoscopy is usually used to visualize the lesion and facilitate needle guidance. The technique requires
considerable experience.

Figure 25.5. Method used for a choroidal mass overlying a bullous retinal detachment. An equatorial
sclerotomy is performed, the choroid is cauterized, and the needle is passed obliquely through the subretinal
space. This approach avoids inducing a retinal hole.

1462
Figure 25.6. Trans–pars plana approach for fine-needle aspiration biopsy of free cells in the vitreous cavity.
This technique is most appropriate for diagnosing vitreous lymphoma or differentiating conditions such as
vitreous melanoma cells from blood cells. Standard vitrectomy techniques can also be used to make the
diagnosis in such cases.

1463
• FINE-NEEDLE ASPIRATION BIOPSY OF ANTERIOR SEGMENT
LESIONS

Examples are shown of metastasis lung cancer to the iris and a primary iris melanoma.

Shields CL, Manquez ME, Mashayekhi A, et al. Fine needle aspiration biopsy of iris tumors in
100 consecutive cases. Technique and complications. Ophthalmology 2006;113:2080–2086.

Figure 25.7. Superior iris mass in a 6-year-old boy. Fine-needle aspiration biopsy was performed.

1464
Figure 25.8. Cytopathology, showing histiocytes and a giant cell, findings compatible with juvenile
xanthogranuloma.

Figure 25.9. Two peripheral iris masses in a 63-year-old man, one superotemporally and one superonasally.

Figure 25.10. Needle being passed through the cornea just inside the limbus and directed toward the lesion at
the 11 o’clock position. Cytopathology revealed malignant cells compatible with lung cancer. Subsequent
systemic evaluation revealed an occult lung cancer.

1465
Figure 25.11. Pigmented iris lesion with tumor seeding on the iris surface in a 58-year-old man. Fine-needle
aspiration biopsy was performed.

Figure 25.12. Cytopathology of fine-needle aspiration biopsy on the lesion shown in Figure 25.11, revealing
pigmented spindle and epithelioid melanoma cells. (Papanicolaou ×200.) A radioactive plaque was applied.

1466
• FINE-NEEDLE ASPIRATION BIOPSY OF POSTERIOR SEGMENT
LESIONS

Figure 25.13. Mass inferior to the optic disc in a 49-year-old woman. The lesion appeared to have a pigmented
base, and melanoma was suspected. However, the patient had a history of breast cancer, and metastasis was
considered to be a possibility. Cytopathology revealed carcinoma, compatible with metastatic breast cancer.

Figure 25.14. Syringe and connector tubing used for fine-needle aspiration biopsy.

1467
Figure 25.15. Calipers set at 4 mm to ensure entrance through the pars plana by the 25-gauge needle.

Figure 25.16. Needle being passed through the conjunctiva, sclera, and pars plana into the vitreous cavity. The
needle is then passed through the vitreous into the tumor with indirect ophthalmoscopy guidance or surgical
microscope guidance.

1468
Figure 25.17. After tumor tissue is aspirated into the needle bore, balanced salt solution is aspirated through
the needle into the syringe. The solution is then submitted to cytopathology laboratory for studies. Some prefer
to smear the aspirated material on a slide, which is stained for cytopathologic study.

Figure 25.18. Cytopathology of an aspiration of the lesion shown in Figure 25.13, demonstrating cells
compatible with choroidal metastasis from breast cancer.

1469
• PLAQUE RADIOTHERAPY FOR INTRAOCULAR TUMORS: PLAQUE
DESIGN AND APPLICATION

Figure 25.19. Standard round, 15-mm iodine-125 plaque. The dummy plaque is to the left and the shielded
side of the active plaque is to the right.

Figure 25.20. Opposite side of the active shielded plaque, showing the iodine-125 seeds. The side shown
here is directed toward the sclera at the time of plaque application.

1470
Figure 25.21. Standard round plaque being positioned at the time of surgery.

Figure 25.22. Notched plaque for the treatment of juxtapapillary tumors.

1471
Figure 25.23. Custom-designed plaque for treating ciliary body tumors.

Figure 25.24. The plaque shown in Figure 25.23 being positioned at the time of surgery.

1472
• APPLICATION TECHNIQUE OF THE RADIOACTIVE PLAQUE
Brachytherapy, using a radioactive plaque sutured to the sclera over the base of the intraocular
tumors, is used most often for selected malignant tumors such as uveal melanoma,
retinoblastoma, and uveal metastasis. It can be used under special circumstances for
circumscribed choroidal hemangioma, retinal vascular tumors, and perhaps other intraocular
lesions. The use of radioactive plaques for these tumors is illustrated under the specific chapters
in this book.

Figure 25.25. After a conjunctival peritomy is performed and appropriate rectus muscles are isolated with
traction sutures, transscleral transillumination is performed and the shadow of the tumor is visualized; a
sterile pencil is used to make a circle around the tumor margins.

Figure 25.26. A dummy plaque without radioactive seeds is placed for suture alignment.

1473
Figure 25.27. The dummy plaque has been removed, and a radioactive iodine-125 plaque is inserted.

Figure 25.28. The radioactive plaque is sutured into proper position.

1474
Figure 25.29. Drawing showing a gold-shielded plaque sutured to the sclera.

Figure 25.30. There are a number of special considerations in plaque application for intraocular tumors. In this
case, the plaque is placed under the lateral rectus muscle because of the tumor location near the equator
temporally.

1475
• APPLICATION OF A RADIOACTIVE PLAQUE FOR A LARGE
CILIOCHOROIDAL MELANOMA

The patient should have a complete ocular examination and a detailed fundus and a large
detailed drawing done. The tumor is measured precisely with ophthalmoscopy,
transillumination, and ultrasonography. The radiation oncologist and the radiation physicists
prepare the plaque. Plaque application for larger tumors, as shown here, is more difficult to
perform. The drawing is place adjacent to the operating table at the time of surgery.

Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for large posterior uveal melanoma
(>8 mm in thickness) in 354 consecutive patients. Ophthalmology 2002;109:1838–1849.

Figure 25.31. A peritomy is developed at the limbus using scissors and forceps.

1476
Figure 25.32. Tenon’s fascia is separated from the sclera by spreading with scissors between the rectus
muscles.

1477
Figure 25.33. Two to four rectus muscles are hooked and isolated with 4-0 silk sutures to facilitate rotation of
the eye.

Figure 25.34. Transillumination is performed, and the margins of the tumor are marked with a sterile marking
pencil. In the case of a posterior tumor, only the anterior part of the tumor is marked.

1478
Figure 25.35. The 20-mm plaque is inspected, and the iodine-125 seeds are counted. They will be recounted
at the time of plaque removal.

1479
Figure 25.36. The plaque is sutured to the sclera. In this case, it was possible to suture the plaque to the
check ligaments of the rectus muscles instead of placing the needle through the sclera.

1480
• APPLICATION OF RADIOACTIVE PLAQUE FOR AN IRIS TUMOR
In our hands, plaque radiotherapy is reserved for iris melanomas that are large or too diffuse
and in which local resection by iridectomy or iridocyclectomy is not possible. It can also be
used to treat selected cases of metastatic cancer to the iris and lymphoproliferative tumors.

Shields CL, Shah S, Bianciotto CG, et al. Iris melanoma management with Iodine-125 plaque
radiotherapy in 144 patients: Impact of melanoma-related glaucoma on outcomes.
Ophthalmology 2013;120:55–61.

Figure 25.37. A case of diffuse iris melanoma. The patient had 180 degrees inferiorly of tumor invasion in the
anterior chamber angle.

Figure 25.38. Custom-designed curvilinear plaque placed on the eye to irradiate the lesion shown in Figure
25.37.

1481
Figure 25.39. A diffuse iris melanoma that is too large for local resection and had seeded tumor cells into the
anterior chamber angle for 360 degrees and onto the lens surface. Plaque radiotherapy was selected as an
alternative to enucleation.

Figure 25.40. Plaque sutured in position on the eye, completely covering the cornea.

1482
Figure 25.41. After plaque was placed, the conjunctiva was mobilized to cover the plaque for patient comfort
and the eye was patched. Antibiotic/steroid ointment was applied twice daily. For more posteriorly located
tumors in the ciliary body and choroidal, the conjunctiva is closed at the limbus and the cornea is not covered.

Figure 25.42. Appearance of the lesion shown in Figure 25.40 after 1 year. The tumor has become atrophic
and is less elevated. There is an early radiation-induced cataract. The cataract can be removed and an
intraocular lens inserted a few months later when the tumor appears to be controlled.

1483
• APPLICATION OF RADIOACTIVE PLAQUE FOR ADVANCED IRIS
MELANOMA

Figure 25.43. A plaque designed to cover an iris melanoma that extends for >180 degrees in anterior chamber
angle. The clear, plastic dummy plaque used for alignment has no radioactive seeds, and the active plaque
contains iodine-125 seeds.

Figure 25.44. Another plaque design for such lesions. In this case, the plaque does not have a central hole
and is placed directly over cornea with seeds precisely over the more peripheral iris tumor. The pupil is kept
dilated while the plaque is on the eye.

1484
Figure 25.45. Diffuse iris melanoma suitable for plaque treatment as an alternative to enucleation in selected
cases.

Figure 25.46. Design of a plaque to cover the lesion shown in Figure 25.45.

1485
Figure 25.47. The plaque is placed over the cornea and sutured into position to cover the lesion shown in
Figure 25.45.

Figure 25.48. The conjunctiva has been mobilized and placed over the plaque seen in Figure 25.47. After the
plaque is removed in 3 to 5 days, the conjunctiva will be realigned to its original position at the limbus.

1486
• REMOVAL OF AN IRIS TUMOR BY PARTIAL IRIDECTOMY
Partial iridectomy (either sector or peripheral) is used mostly for resectable iris melanoma, but
it can be used to resect other benign and malignant tumors under certain circumstances.
(Illustrations by Linda Warren.)

Figure 25.49. A limbal incision has allowed entrance into the anterior chamber. The cornea is retracted with a
suture, and the iris is being cut radially about 3 mm from the tumor.

1487
Figure 25.50. Both radial cuts have been made, and a basal iris cut is being made outside the tumor margin,
allowing tumor removal.

Figure 25.51. The sector iridectomy has been completed, and the limbal wound has been closed with
interrupted 9-0 or 10-0 nylon sutures.

Figure 25.52. In cases in which the sector iridectomy is not too large, the iris defect can be repaired with a
permanent intraocular suture (iridoplasty), creating a rounder pupil. A 10-0 prolene suture is generally used for
the pupilloplasty.

1488
Figure 25.53. Postoperative photograph of a sector defect too large to close with iridoplasty. Iridoplasty would
be extremely difficult in such a case.

Figure 25.54. Postoperative photograph of a smaller sector defect closed with iridoplasty.

1489
• REMOVAL OF AN IRIDOCILIARY TUMOR BY PARTIAL LAMELLAR
IRIDOCYCLECTOMY

This technique is useful for uveal melanoma, leiomyoma, epithelial tumors of the ciliary body,
and other selected lesions. General anesthesia is usually employed for such cases. (Illustrations
by Linda Warren.)

1. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for posterior uveal
melanomas. The 1986 Schoenberg Lecture. Ophthalmic Surg 1988;19:774–780.
2. Shields JA, Shields CL, Shah P, et al. Partial lamellar sclerouvectomy for ciliary body and
choroidal tumors. Ophthalmology 1991;98:971–983.

Figure 25.55. A conjunctival peritomy is done and appropriate rectus muscles are isolated for traction
purposes. The dashed line depicts the margins of the tumor as determined with transillumination. The solid
line shows the extent of the limbus-hinged scleral flap to be developed.

1490
Figure 25.56. A limbus-hinged scleral flap of 80% scleral thickness has been developed.

Figure 25.57. The inner scleral fibers have been incised, and the tumor is exposed.

1491
Figure 25.58. The tumor has been removed, a peripheral iridectomy has been performed to ensure a wider
margin, and the scleral wound has been closed with 9-0 interrupted nylon sutures. The conjunctiva has been
reapproximated to the limbus with 7-0 absorbable sutures.

Figure 25.59. Postoperative photograph of a sector defect after tumor removal by iridocyclectomy.

1492
Figure 25.60. Postoperative photograph of a peripheral iris defect after tumor removal by iridocyclectomy. In this
case, a full sector iridectomy was not necessary because the tumor only involved the peripheral aspect of the
iris.

1493
• REMOVAL OF A PERIPHERAL CHOROIDAL TUMOR BY PARTIAL
LAMELLAR CYCLOCHOROIDECTOMY

This technique is used for more posteriorly located tumors, including melanoma, leiomyoma,
schwannoma, and larger tumors of the ciliary body and retinal pigment epithelium. Only the
highlights of this difficult procedure are shown here, and the fine details are not illustrated.
(Illustrations by Linda Warren.)

1. Shields JA, Shields CL. Surgical approach to lamellar sclerouvectomy for posterior uveal
melanomas. The 1986 Schoenberg Lecture. Ophthalmic Surg 1988;19:774–780.
2. Shields JA, Shields CL, Shah P, et al. Partial lamellar sclerouvectomy for ciliary body and
choroidal tumors. Ophthalmology 1991;98:971–983.

Figure 25.61. A conjunctival peritomy has been performed, the rectus muscles have been isolated with traction
sutures, and the shadow of the tumor, seen with transillumination, will be marked with a sterile pen. The solid
line depicts the size of the posteriorly hinged scleral flap that will be developed.

1494
Figure 25.62. The dissected scleral flap has been reflected posteriorly, revealing the inner scleral bed.
Diathermy (not shown) is performed on the sclera around the tumor with a 5-mm margin.

Figure 25.63. A circular incision is being made through the inner scleral bed about 4 mm outside the tumor
margin but inside the area of diathermy.

1495
Figure 25.64. The inner scleral bed has been incised, revealing the tumor.

Figure 25.65. Side view of the tumor being removed, leaving intact the sensory retina and vitreous.

1496
Figure 25.66. The tumor has been removed and the scleral flap sutured into its original position with 8-0
interrupted nylon sutures. The conjunctiva is mobilized to cover the area of surgery.

1497
• ENUCLEATION
In ocular oncology, enucleation is performed mostly for advanced cases of uveal melanoma and
retinoblastoma when there is little hope for useful vision in the affected eye. It is occasionally
warranted for uveal metastasis that has produced a blind, painful eye. It is also performed for
uveal melanoma and retinoblastoma that have not been controlled following conservative
methods of treatment. In cases of intraocular tumor, a minimal manipulation enucleation
should be performed. In cases of retinoblastoma, it is important to obtain a long section of
optic nerve along with the intact globe. (Illustrations by Linda Warren.)

Shields CL, Shields JA, De Potter P. Hydroxyapatite orbital implant after enucleation. Experience
with initial 100 consecutive cases. Arch Ophthalmol 1992;110:333–338.

Figure 25.67. A conjunctival peritomy is performed at the limbus for 360 degrees.

1498
Figure 25.68. The rectus muscles are individually hooked, tagged with absorbable sutures, and cut near their
insertions. The oblique muscles are also cut at their insertions.

Figure 25.69. A hemostat is placed on the medial rectus muscle stump, the enucleation scissors are passed
along the medial wall of the orbit, and the optic nerve is cut.

1499
Figure 25.70. After hemostasis is achieved, the orbital implant is placed in the socket and the rectus muscles
are attached to the implant. Although there are a variety of orbital implants, most surgeons who perform
enucleation have recently used a hydroxyapatite or Medpore implant. We have most recently used a polymer-
coated hydroxyapatite implant.

Figure 25.71. The conjunctiva is closed with a running absorbable suture. A conformer is inserted and a
pressure patch applied.

1500
Figure 25.72. Side view showing vascularization of the hydroxyapatite implant 6 months after surgery. Depicted
also is the peg that can be used to integrate the implant to the overlying prosthesis to provide better ocular
motility although placement of the peg was met with enthusiasm in the past. Most patients are pleased with
their outcome and prefer not to have the peg placed because they are satisfied with the ocular motility.

1501
• ENUCLEATION IMPLANTS: STANDARD AND COATED
HYDROXYAPATITE IMPLANTS

Shields CL, Uysal Y, Marr BP, et al. Experience with the polymer-coated hydroxyapatite implant
following enucleation in 126 patients. Ophthalmology 2007;114:367–373.

Figure 25.73. View of scleralized hydroxyapatite implant placed into the socket immediately after enucleation.

Figure 25.74. The muscles have been sutured to the implant. The conjunctiva is being retracted to visualize a
rectus muscle attached to the implant. Tenon’s fascia and conjunctiva will be closed subsequently.

1502
Figure 25.75. Appearance of the newer polymer-coated hydroxyapatite implant. This eliminates the need for
using eye bank sclera to encase the implant. Four rectangles have been cut for approximation of the rectus
muscles, and holes are made to allow passage of the sutures on the rectus muscles. More recently, we have
used four holes instead of eight and can still align the muscles accurately.

Figure 25.76. The rectus muscles have been attached and tied to the coated implant.

1503
Figure 25.77. Tenon’s fascia has been closed over the implant using interrupted, vertically placed absorbable
sutures. The conjunctiva has not yet been closed.

Figure 25.78. The conjunctiva has been closed over Tenon’s fascia with a running 7-0 absorbable suture. A
conformer will be inserted next (see next plate).

1504
• ENUCLEATION CONFORMER AND PROSTHESIS

Figure 25.79. Transparent conformer with central hole.

Figure 25.80. Appearance of a round prosthesis with iris and pupil. This is used to replace the conforma after
the area is well healed, usually after 4 to 5 weeks.

1505
Figure 25.81. Appearance of prosthesis with tapered edges. The ocularist often labels the part that fits
superiorly.

Figure 25.82. Back side of the prosthesis in Figure 25.81, showing the smooth surface.

1506
Figure 25.83. Vertically elongated prosthesis with a special “lip” to help correct blepharoptosis and superior
sulcus defect.

Figure 25.84. Back side of the prosthesis shown in Figure 25.83. In this case, the ocularist has designed and
placed a rubber balloon reservoir that contains artificial tear solution that allows continued lubrication to
alleviate dry eye symptoms.

1507
• ENUCLEATION SOCKET AND PROSTHESIS

Figure 25.85. Full face view of a patient with a right prosthesis.

Figure 25.86. Appearance of both eyes in the patient shown in Figure 25.85 with the prosthesis in the right
socket.

1508
Figure 25.87. View of both sides with the prosthesis removed.

Figure 25.88. Closer view of the right socket with the prosthesis removed.

1509
Figure 25.89. Child who had enucleation of the left eye, showing appearance prior to fitting of the prosthesis.

Figure 25.90. Man who had enucleation of the right eye, showing appearance prior to fitting of the prosthesis.

1510
• OCULAR PROSTHESIS IN YOUNG PATIENTS FOLLOWING
ENUCLEATION

Figure 25.91. Prosthesis on the left side.

1511
Figure 25.92. Prosthesis on the right side.

1512
Figure 25.93. Prosthesis on the right side.

1513
Figure 25.94. Prosthesis on the right side.

1514
Figure 25.95. Prosthesis on the left side.

1515
Figure 25.96. Prosthesis on the left side.

1516
• OCULAR PROSTHESIS IN ADULT PATIENTS FOLLOWING
ENUCLEATION

Figure 25.97. Prosthesis on the right side.

Figure 25.98. Prosthesis on the right side.

1517
Figure 25.99. Prosthesis on the left side.

1518
Figure 25.100. Prosthesis on the left side.

1519
Figure 25.101. Prosthesis on the right side.

1520
Figure 25.102. Prosthesis on both sides. The patient had bilateral enucleation for blind, painful eyes
secondary to congenital glaucoma.

1521
• OCULAR PROSTHESIS AND PROTECTIVE POLYCARBONATE
GLASSES FOLLOWING ENUCLEATION

Figure 25.103. Prosthesis for the right eye.

1522
Figure 25.104. Patent shown in Figure 25.103 without glasses.

1523
Figure 25.105. Prosthesis for the left eye.

1524
Figure 25.106. Patient shown in Figure 25.105 without glasses.

1525
Figure 25.107. Prosthesis for the right eye.

1526
Figure 25.108. Patient shown in Figure 25.107 without glasses.

1527
• ORBITAL EXENTERATION
Orbital exenteration is most often employed for primary malignant orbital tumors or for eyelid
or conjunctival tumors that have secondarily invaded the orbit. With regard to intraocular
tumors, it is used most often for massive orbital extension of uveal melanoma, retinoblastoma,
and rarely other tumors. Because most intraocular tumors do not extend to affect the eyelids, an
eyelid-sparing exenteration can be done in the majority of cases. (Illustrations by Linda Warren.)

Figure 25.109. A suture is used to close the eyelids, and a skin incision is made either just outside the cilia
(inner dashed line) for an eyelid-sparing exenteration or in the midportion of the eyelid (outer dashed line) for
an eyelid-sacrificing exenteration.

1528
Figure 25.110. Eyelid-sparing exenteration. The skin and orbicularis muscle are undermined superiorly and
inferiorly to the bony orbital rim.

Figure 25.111. The periosteum is incised about 3 mm outside of the orbital rim, and a periosteal elevator is
used to separate the periosteum from the bone into the orbit for 360 degrees.

Figure 25.112. The enucleation scissors are inserted outside the orbital periosteum on the medial side, and
the optic nerve is cut near the orbital apex. The scissors are down and to the left. The surgeon cannot view the
optic nerve and the severing of the nerve is done by feel.

1529
Figure 25.113. After hemostasis is achieved in the orbital cavity, interrupted 5-0 nylon sutures are used to
suture the upper to the lower eyelid flap.

Figure 25.114. Side view postoperatively, showing the bare orbital cavity with the eyelids sutured together over
the defect.

1530
• ORBITAL EXENTERATION PROSTHESIS

Figure 25.115. Right-side prosthesis.

1531
Figure 25.116. Patient shown in Figure 25.115 without glasses.

1532
Figure 25.117. Patient shown in Figure 25.115 without prosthesis.

1533
Figure 25.118. Right-side prosthesis.

1534
Figure 25.119. Patient shown in Figure 25.118 without glasses.

1535
Figure 25.120. Patient shown in Figure 25.118 without prosthesis.

1536
 INDEX

Note: Figures are noted with a page number first succeeded by the notation for the
specific figure in italic numerals and tables are page numbers with “t”; for example,
figure 1 – 27 on page 3 is shown as 3:1 – 27.

A
Abscess, retinoblastoma simulated by calcification and idiopathic intraocular,
385:19.55 – 19.60
Acquired immunodeficiency syndrome (AIDS), 546
Acute lymphoblastic leukemia, 552
Adenomas, 503. See Ciliary body benign epithelioma
African-Americans
epithelioma, RPE in, 493:22.127 – 22.132
melanoma, choroidal, 126:7.157 – 7.160
Age-related hyperplasia (ARH), NPCE, 514, 516:23.43 – 23.48
clinicopathologic correlation, 517:23.49 – 23.54
electron microscopy, 514
iridocyclectomy, 514
ophthalmoscopy, 514
U BM, 514
Age-related macular degeneration (ARMD), 144
melanoma, choroidal simulated by, 196:11.1 – 11.6
AIDS. See Acquired immunodeficiency syndrome
Alcohol irrigation, congenital iris stromal cyst, 63:4.49 – 4.54
Amblyopia, 474
Amblyopic therapy, combined hamartoma, 474
Amelanotic lesion, iris nevus and, 16
Ancillary studies, acquired epithelioma NPCE, 518
Aniridia, 3
familial, VPTOF and, 418
sporadic, nephroblastoma and, 3
Anterior chamber angle, dislodged fixation IPE, 59:4.37 – 4.42
ARH. See Age-related hyperplasia
ARMD. See Age-related macular degeneration
Arteriovenous (AV) communication
iris, 278:13.127 – 13.132
racemose hemangioma and, 412
Asians, choroidal melanoma in, 126:7.161 – 7.162
Aspiration
for iris pigment epithelial cyst, 56:4.19 – 4.24
iris stromal cyst, 60
congenital, 60, 62:4.43 – 4.48
lacrimal gland cyst, 3
Aspiration cytology, ARH NPCE, 514

1537
Astrocytic proliferation, retinal, 429:21.1 – 21.6
Astrocytoma, acquired retinal, 427, 444, 445:21.73 – 21.78
clinicopathologic correlation, 446:21.79 – 21.84, 447:21.85 – 21.90
fluorescein angiography, 444, 445:21.73 – 21.78
FNAB, 448:21.91 – 21.96, 449:21.97 – 21.102
melanoma, choroidal simulated by, 448
PDT, 449:21.97 – 21.102
Atropine drops, iridectomy, 39:2.110
Autofluorescence fundus photography
melanoma, uveal, 140
AV communication. See Arteriovenous communication

B
Band keratopathy, iris melanoma and, 29:2.53
BDU MP. See Bilateral diffuse uveal melanocytic proliferation
“Bear tracks,” 453, 462, 463. See also “Polar bear tracks”
Benign reactive lymphoid hyperplasia (BRLH), 525
choroidal, 527
ciliary body, 527
fluorescein angiography, 527
FNAB, 527
ultrasonography, 527
uveal, 527, 529:24.1 – 24.6
choroiditis, birdshot and, 532:24.19 – 24.24
clinical features, 530:24.7 – 24.12
diagnostic studies, 531:24.13 – 24.18
EBRT, 531:24.18
fluorescein angiography, 531:24.15
fundus photography, 531:24.13 – 24.14
MRI, 531:24.17, 533:24.25 – 24.30
pathologic features, 530:24.7 – 24.12
sarcoidosis and, 532:24.19 – 24.24
treatment, 531:24.13 – 24.18
ultrasonography, 531:24.16, 533:24.25 – 24.30
wide-angle imaging, 533:24.25 – 24.30
Bilateral diffuse uveal melanocytic proliferation (BDU MP), 209
clinical variations, 209:11.79 – 11.84
melanoma, uveal simulated by, 210:11.85 – 11.90
neoplasms and, 209
pigmentation, 209:11.79 – 11.84
Bilateral intermediate uveitis (pars planitis), VPTOF and, 423:20.145
Biomicroscopy. See U ltrasound biomicroscopy
Biopsies. See Fine needle aspiration biopsy; Needle biopsy, lymphoma and; Wall
biopsy, lymphoma and
Blindness
lymphoid tumors, intraocular and, 525
Bloch-Sulzberger disease. See Incontinentia pigmenti
Blocked light

1538
 CHRPE and, 460
epithelioma, 482, 490
IPE epithelioma, 482
RPE epithelioma, 490
Bowel cancer
CHRPE and, 453
RPEH and, 464
Branchio-oculo-facial syndrome
retinal, hamartoma, combined, 479:22.79 – 22.84
retinal/RPE, 479:22.79 – 22.84
Brain metastasis, retinoblastoma, 325:15.67 – 15.72
Branchi-oculo-facial syndrome, combined hamartoma and, 474
Branch retinal vein obstruction, racemose hemangioma, 412
retinal, 417:20.121 – 20.126
Breast cancer metastasis
choroidal, 220:12.25 – 12.30, 221:12.31 – 12.36
iris, 216:12.1 – 12.6
optic disc, 243:12.163 – 12.168
uveal, 213
BRLH. See Benign reactive lymphoid hyperplasia
Bronchial carcinoid tumors, metastasis, 213
choroidal, 225:12.55 – 12.60
iris, 218:12.13 – 12.14
Bruch’s membrane, choroidal melanoma and rupture of, 129

C
Calcification
idiopathic intraocular abscess and retinoblastoma simulated by, 385:19.55 –
19.60
melanoma, uveal simulated by sclerochoroidal, 211:11.91 – 11.92
retinoblastoma simulated by idiopathic intraocular abscess and, 385:19.55 –
19.60
Callender classification, uveal melanoma, 129
Capillary hemangioma. See Hemangioblastoma
Carboplatin
retinoblastomachemothermotherapy, 360
retinoblastoma CRD, 361
Carcinoma
bile duct, choroidal metastasis and, 226:12.63
esophageal, choroidal metastasis and, 226:12.64 – 12.66
intraocular metastatic, 213
kidney, choroidal metastasis, 226:12.61 – 12.62
Castleman syndrome, 527
Cataract
cortical, iris nevus and, 20:2.16
retinoblastoma simulated by congenital, 387:19.67
subluxed mature, uveal melanoma simulated by, 212:11.97 – 11.98
Cavernous hemangioma, 277:13.121 – 13.126

1539
 CNS, 277:13.121 – 13.126
cutaneous, 277:13.121 – 13.126
iris, 276:13.119 – 13.120, 277:13.121 – 13.126
retinal, 389, 404 – 405
clinical variations, 407:20.73 – 20.78, 408:20.79 – 20.84
CNS associated with familial, 411:20.97 – 20.102
cutaneous vascular anomalies with familial, 411:20.97 – 20.102
familial, 411:20.97 – 20.102
fluorescein angiography, 409:20.85 – 20.90
histopathology, 408:20.79 – 20.84
optic disc involvement in, 410:20.91 – 20.96
ultrasonography, 408:20.83
Central nervous system (CNS). See also Primary CNS lymphoma
cavernous hemangioma, familial retinal associated with, 411:20.97 – 20.102
gliomas, 464
hemangiomas, cavernous
retinal, 404
lymphoma, 525
NPCE tumor extension into, 504
Charged particle irradiation, uveal melanoma, 156
Chemoreduction (CRD), retinoblastoma, 350
bilateral, 361:18.49 – 18.54
chemoreduction 363:18.61 – 18.66
EBRT and, 368:18.91 – 18.96
foveal-sparing, 363:18.61 – 18.66
macular recurrence and, 358:18.31 – 18.36
unilateral, 361:18.49 – 18.54
Chemotherapy
lymphoma, uveal, 535, 537:24.31 – 24.36
plasmacytoma, uveal, 542
retinoblastoma, 360:18.43 – 18.48
VRL, 547
Children
choroidal circumscribed, 247
endophthalmitis, endogenous in, 384
enucleation prosthesis in, 572:25.91 – 25.96
epithelioma, CPE in, 486
hemangiomas in
retinal, 404
leukemias, intraocular in, 552
melanoma, choroidal in, 125:7.151 – 7.156
Cholesterolosis, anterior chamber, 379:19.19 – 19.24
Choristoma, intraocular lacrimal gland, 3, 4, 5:1.1 – 1.6
Choroid
BRLH, 527
granuloma, melanoma simulated by, 206:11.61 – 11.66
growth and metastasis of small melanocytic lesions, risk factors for, 96
hemorrhage, choroidal melanoma simulating, 202:11.37 – 11.42

1540
iris nevus and, 15
melanocytoma, 93:6.55 – 6.60
giant diffuse variant, 94:6.61 – 6.66
localized, 82
melanoma and, 94:6.61 – 6.66
oculodermal melanocytosis and, 94:6.61 – 6.66
melanoma, 11:1.29
adjacent structures and, 115:7.91 – 7.96
advance tumor, 122:7.133 – 7.138, 123:7.139 – 7.144
ARMD simulating, 196:11.1 – 11.6
astrocytoma, acquired retinal simulating, 448
as atypical extraocular extension, 121:7.127 – 7.132
choroidal nevus and, 69 – 70, 79:5.43 – 5.48, 80:5.49 – 5.54
clinical features of, 95 – 96, 96:7.2t
clinicopathologic correlations in, 137:8.31 – 8.36
CT, 147:9.31 – 9.32
diffuse growth pattern of, 118:7.109 – 7.114
diffuse melanocytosis, oculodermal and, 13:1.39 – 1.40
diffuse tumors, 119:7.115 – 7.120, 120:7.121 – 7.126, 121:7.127 – 7.132
enucleation, 184:10.145 – 10.150, 185:10.151 – 10.156, 186:10.157 – 10.162,
187:10.163 – 10.168
extraocular extension, 121:7.127 – 7.132, 123:7.139 – 7.144
fluorescein angiography, 143:9.7 – 9.12, 144:9.13 – 9.18
FNAB, 150:9.51 – 9.54, 151:9.55 – 9.60, 152:9.61 – 9.66, 153:9.67 – 9.72
fundus autofluorescence, 149:9.43 – 9.48
genetic testing, 153:9.67 – 9.72
as glaucoma, acute, 122:7.133 – 7.138
gross features of, 133:8.7 – 8.12
growth, 96, 107:7.43 – 7.48, 161:10.7 – 10.12
hamartoma, combined and, 474
hemorrhage, choroidal simulated by, 202:11.37 – 11.42
hemorrhages, subretinal/intraretinal simulating, 200:11.25 – 11.30
ICGA, 145:9.19 – 9.24
intracranial extension of, 124:7.145 – 7.150
iris nevus and, 16
laser photocoagulation, 162:10.13 – 10.18
melanocytosis, oculodermal and, 11:1.25 – 1.26
melanocytosis and, 11:1.25 – 1.26
metastasis, 107:7.43 – 7.48, 161:10.7 – 10.12
mushroom-shaped tumors, 134:8.13 – 8.18, 143:9.7 – 9.12, 173:10.79 – 10.84
mushroom-shaped tumors with nonpigmented dome, 113:7.79 – 7.84
mushroom-shaped tumors with pigmented dome, 111:7.67 – 7.72, 112:7.73 –
7.78
necrosis, 127:7.163 – 7.168
nodular posterior scleritis simulating, 204:11.49 – 11.54
nonpigmented, 110:7.61 – 7.66
in non-whites, 126:7.157 – 7.162
observation of, 155, 160:10.1 – 10.6

1541
 OCT, 148:9.37 – 9.42
optic nerve invasion, 120:7.121 – 7.126
orbital exenteration, 188:10.169 – 10.174
overlying choroidal neovascular membrane and, 144:9.13 – 9.18
P32 test, 150:9.50
partly pigmented, 109:7.55 – 7.60
PEHCR simulating, 197:11.7 – 11.12, 198:11.13 – 11.18
pigmented, 108:7.49 – 7.54, 109:7.55 – 7.60, 111:7.67 – 7.72, 112:7.73 – 7.78
plaque radiotherapy, 168:10.49 – 10.54, 169:10.55 – 10.60, 170:10.61 –
10.66, 171:10.67 – 10.72, 173:10.79 – 10.84, 176:10.97 – 10.102
plaque radiotherapy, juxtapapillary melanoma management with, 175:10.91 –
10.96
plaque radiotherapy, side effects of, 179:10.115 – 10.120
PLSU , 183:10.139 – 10.144
pseudoangiomatous, 143
regression, 127:7.163 – 7.168
retinal arterial macroaneurysm with hemorrhage simulating, 199:11.19 – 11.24
retinal invasion by, 116:7.97 – 7.102, 117:7.103 – 7.108
RPE and, 466
sector melanocytosis, oculodermal and, 13:1.41 – 1.42
size/shape variations in, 114:7.85 – 7.90
spontaneous regression of, 96
TTT, 163:10.19 – 10.24, 164:10.25 – 10.30, 165:10.31 – 10.36, 166:10.37 –
10.42
TTT and plaque radiotherapy for, 176:10.97 – 10.102
TTT side effects for, 167:10.43 – 10.48
ultrasonography, 146:9.25 – 9.26, 146:9.29 – 9.30, 164:10.29 – 10.30
ultrasonography following plaque radiotherapy for, 178:10.109 – 10.114
visual loss caused by, 124:7.145 – 7.150
vitreal invasion by, 116:7.97 – 7.102
vitreous hemorrhage presenting in, 152:9.61 – 9.66
vortex vein varix simulating, 203:11.43 – 11.48
wide-angle imaging, 114:7.85 – 7.90
wide-angle imaging of diffuse tumors, 119:7.115 – 7.120
in young patients, 125:7.151 – 7.156
metastasis, 107:7.43 – 7.48, 161:10.7 – 10.12
neovascular membrane, 144:9.13 – 9.18
epithelioma of RPE simulating, 496:22.145 – 22.150
melanoma simulated by, 201:11.31 – 11.36
nevus simulated by, 201:11.31 – 11.36
nevus, 69 – 80
adjacent structures and effects of, 75:5.19 – 5.24
autofluorescence, 78:5.37 – 5.42
choroidal melanoma and, 69 – 70, 79:5.43 – 5.48, 80:5.49 – 5.54
clinical variations, 74:5.13 – 5.18
congenital, 69
fluorescein angiography, 70, 76:5.25 – 5.30
giant, 74:5.17 – 5.18

1542
 halo, 74:5.13 – 5.14
multifocal, 74:5.16
nonpigmented, 73:5.7 – 5.12
OCT, 70, 77:5.31 – 5.36
pigmented, 72:5.1 – 5.6
retinal detachment and, 75:5.19 – 5.20
RPE detachment and, 75:5.21 – 5.22
optic disc melanocytoma and involvement of, 86:6.13 – 6.18
plasmacytoma, 542, 544:24.61 – 24.66
FNAB, 542, 544
radiotherapy, 544
pseudomelanomas, 194:11.1t
tumors, partial lamellar cyclochoroidectomy for peripheral, 567:25.61 – 25.66
Choroidal melanotic schwannoma, 299:14.55 – 14.60
Choroidal metastasis
carcinoid tumors, 225:12.55 – 12.60
choroidal melanoma, 224:12.49 – 12.54
cutaneous melanoma, 223:12.43 – 12.48
effects on adjacent structures, 229:12.79 – 12.84
external beam radiotherapy, 240:12.145 – 12.150
fine-needle aspiration biopsy, 239:12.139 – 12.144
fluorescein angiography, 235:12.115 – 12.120
fundus autofluorescence, 238:12.133 – 12.138
kidney, bile duct, and esophageal carcinomas, 226:12.61–12.66
lung carcinoma simulating sarcoidosis, 232:12.97 – 12.102
magnetic resonance imaging, 237:12.127 – 12.132
metastasis: 236:12.121 – 12.126
mushroom-shaped, 233:12.103 – 12.108
optical coherence tomography, 238:12.133 – 12.138
orange-colored, 230:12.85 – 12.90
pathology, 231:12.91 – 12.96
photodynamic therapy, 242:12.157 – 12.162
plaque radiotherapy, 241:12.151 – 12.156
primary neoplasm, 234:12.109 – 12.114
sarcomas, 228:12.73 – 12.78
undetermined primary sites, diagnosed by fine-needle aspiration biopsy,
227:12.67 – 12.72
Choroidal neovascularization (CNV), 69
Choroidal osteoma, 282, 287
choroidal neovascularization, 287
clinical features, 285:14.1 – 14.6
decalcification, 287:14.13 – 14.18
familial occurrence, 287:14.13 – 14.18
fluorescein angiography, 288: 14.19 – 14.24
Choroiditis
birdshot, BRLH, uveal and, 532:24.19 – 24.24
helioid, 207
solitary idiopathic, melanoma, amelanotic choroidal simulated by, 207:11.67 –

1543
 11.72
Chromosome 5 (5q21), 464
CHRPE. See Congenital hypertrophy of retinal pigment epithelium
Ciliary body
benign epithelioma (adenoma), 43
BRLH, 527
lymphoma, 534
medulloepithelioma, 507:23.1 – 23.6
aggressive malignant, 512:23.31 – 23.36
pigmented malignant, 511:23.25 – 23.30
melanocytoma, 82, 92:6.49 – 6.54
melanoma, 129
cavity variant, 105:7.31 – 7.36
clinical features of, 95
dilated pupil appearance of, 103:7.19 – 7.24
extraocular extension, 106:7.37 – 7.42
FNAB, 150:9.51 – 9.54
glaucoma, secondary and, 106:7.37 – 7.42
gross features of, 132:8.1 – 8.6
iris extension, 102:7.13 – 7.18
MRI, 147:9.33 – 9.36
P32 test, 150:9.49
plaque radiotherapy, 174:10.85 – 10.90, 177:10.103 – 10.108
ring variant, 106:7.37 – 7.42
sentinel blood vessels and, 100:7.1 – 7.6
transscleral extension, 101:7.7 – 7.12
U BM, 146:9.27 – 9.28
wide-angle imaging, 104:7.25 – 7.30
plasmacytoma, 545:24.67 – 24.72
Ciliary pigment epithelium (CPE), 482
epithelioma, 486, 488:22.109 – 22.114
clinicopathologic correlation, 485:22.103 – 22.108
Ciliochoroidal
melanoma, partial lamellar cyclochoroidectomy, 180:10.121 – 10.126,
181:10.127 – 10.132
Circumscribed choroidal hemangioma
adjacent structures, 253:13.13 – 13.18
clinical features, 251:13.1 – 13.6
clinicopathologic correlation of choroidal melanoma, 259:13.49 – 13.54
clinicopathologic correlation of tumor, 258:13.43 – 13.48
computed tomography, 256:13.31 – 13.36
fluorescein, 254:13.19 – 13.24
fundus autofluorescence, 257:13.37 – 13.42
indocyanine green angiography, 254:13.19 – 13.24
laser photocoagulation 260:13.55 – 13.60
magnetic resonance imaging, 256:13.31. – 13.36
optic disc in, 258:13.43 – 13:48
photodynamic therapy, 260:13.55 – 13.60, 261:13.61 – 13.66, 262:13.67 –

1544
 13.72
plaque radiotherapy, 263:13.73 – 13.78
ultrasonography, 255:13.25 – 13.30, 256:13.31 – 13.36
wide-angle imaging, 252:13.7 – 13.12
CNS. See Central nervous system
CNV. See Choroidal neovascularization
Coats disease
advanced, retinoblastoma simulated by, 377:19.7 – 19.12
cholesterolosis, anterior chamber caused by, 379:19.19 – 19.24
CHRPE and, 462
exudation, 376
glaucoma, neovascular, 378
gliosis, pseudoneoplastic and, 427
PHPV simulating, 380
retinal detachment, 376, 378
retinoblastoma simulated by, 374, 376:19.1 – 19.6
clinicopathologic correlation of, 378:19.13 – 19.18
fluorescein angiography, 377:19.7 – 19.12
retinoblastoma simulated by advanced, 377:19.7 – 19.12
VPTOF and, 423:20.149
xanthochoria, 377:19.7 – 19.8
Cogan-Reese syndrome, 16
iris melanoma, 32:2.67 – 2.72
Coherence tomography, retinal hemangioblastoma, 403
Collaborative Ocular Melanoma Study (COMS), 156
Coloboma, 3
retinoblastoma simulated by congenital retinochoroidal, 387:19.71 – 19.72
Colonic cancer, familial, 462
Combination methods, uveal melanoma, 157
Computed tomography (CT)
hemangioma, choroidal circumscribed, 247, 238:13.33
melanoma
choroidal, 147:9.31 – 9.32
uveal, 140
osteoma, choroidal, 282, 271:14.27
VRL, 546
COMS. See Collaborative Ocular Melanoma Study
Congenital grouped pigmentation, 453, 462, 463
Congenital hypertrophy of retinal pigment epithelium (CHRPE)
benign epithelioma (adenoma), 453
epithelioma, RPE and, 498:22.157 – 22.162, 499:22.163 – 22.168
fluorescein angiography, 453, 454
ICGA, 454
malignant epithelioma (adenocarcinoma), 453
multifocal, 462, 463:22.37 – 22.42
OCT, 454
optic disc melanocytoma and, 88:6.27 – 6.28
solitary, 453 – 454

1545
 autofluorescence, 460:22.25 – 22.30
basal dimension documented growth of, 461:22.31 – 22.36
clinical correlations, 460:22.25 – 22.30
clinical variations of, 456:22.1 – 22.6
fluorescein angiography, 459:22.19 – 22.24
histopathology, 459:22.19 – 22.24
OCT, 460:22.25 – 22.30
pigmented lesions of, 457:22.7 – 22.12
predominantly nonpigmented lesions of, 458:22.13 – 22.18
predominantly pigmented lesions of, 457:22.7 – 22.12
wide-angle imaging of predominantly nonpigmented lesions of, 458:22.13 –
22.18
wide-angle imaging of predominantly pigmented lesions of, 457:22.7 – 22.12
torpedo maculopathy, 453
ultrasonography, 454
Congenital malformations, pseudoneoplastic gliosis and, 427
CPE. See Ciliary pigment epithelium
Cryotherapy
epithelioma, RPE, 490
hamartoma, astrocytic, 431
hemangioblastoma, retinal, 401:20.55 – 20.60, 402:20.61 – 20.66
hemangioma, retinal cavernous, 405
triple-freeze thaw technique, 401
VPTOF, 418, 425:20.157 – 20.162, 426:20.163 – 20.168
CT. See Computed tomography
Cutaneous vascular anomalies, familial retinal cavernous hemangioma associated
with, 411:20.97 – 20.102
Cutaneous vascular malformations, cavernous retinal hemangioma, 404
Cyclectomy, iris melanoma, 39:2.110
Cyclochoroidectomy
melanoma, ciliochoroidal, 180:10.121 – 10.126, 181:10.127 – 10.132
peripheral choroidal tumor removal with partial lamellar, 567:25.61 – 25.66
Cysts
IPE, 51 – 52
central, 51, 53:4.1 – 4.6
dislodged, 52, 58:4.31 – 4.36, 59:4.37 – 4.42
iridociliary, 52, 57:4.25 – 4.30
midzonal, 51 – 52, 55:4.13 – 4.18, 56:4.19 – 4.24, 57:4.25 – 4.30
U BM, 52, 55:4.18
iris, 51 – 67
classification, 51:4.1t
clinical variations, 51 – 52
iris pigment epithelial
midzonal, 50:3.25 – 3.30
iris stromal, 60, 60:4.3t
acquired, 60, 64:4.55 – 4.60, 66:4.67 – 4.72
acquired, natural course of, 66:4.67 – 4.72
acquired, secondary, 67:4.73 – 4.78

1546
 alcohol irrigation for congenital, 63:4.49 – 4.54
aspiration for congenital, 63:4.49 – 4.54
congenital, 60, 62:4.43 – 4.48, 63:4.49 – 4.54
cryotherapy for acquired, 66:4.72
OCT, imaging with, 65:4.61 – 4.66
U BM, imaging with, 65:4.61 – 4.66

D
Dacryops. See Lacrimal gland cysts
Decalcification, choroidal, 287:14.13 – 14.18
Diffuse choroidal hemangioma
external beam radiotherapy, 269:13.97 – 13.102
plaque radiotherapy, 269:13.97 – 13.102
Sturge – Weber syndrome, 266:13.79 – 13.84
ultrasonography and magnetic resonance imaging, 268:13.91 – 13:96
Diffuse oculodermal melanocytosis, melanoma and, 13:1.37 – 1.40
Diktyoma, 504
Dilated pupil, 103:7.19 – 7.24
Dutcher bodies, 527
Dysplastic nevus syndrome. See Familial atypical mole syndrome
Dystrophy. See Familial pigmentary dystrophy of retina (retinitis pigmentosa)

E
Ectropion iridis, congenital, 43, 48:3.13
Effusion, uveal, 205:11.55 – 11.60
Electron microscopy, ARH NPCE, 514
Endogenous endophthalmitis, retinoblastoma simulated by, 384:19.49 – 19.54
Endophthalmitis
endogenous, retinoblastoma simulated by, 384:19.49 – 19.54
melanoma simulating, uveal, 191:10.187 – 10.192
Enucleation
epithelioma, CPE, 486
gliosis, pseudoneoplastic, 427
hamartoma, astrocytic, 441
hemangioblastoma
choroidal circumscribed, 259
retinal, 398
implants, 569:25.73 – 25.78
medulloepithelioma, 504
melanocytoma, optic disc, 81 – 82
melanoma
choroidal, 184:10.145 – 10.150, 185:10.151 – 10.156, 186:10.157 – 10.162,
187:10.163 – 10.168
iris, 25, 33:2.74 – 2.75, 35:2.85 – 2.90
uveal, 156, 189:10.175 – 10.180
NPCE, acquired epithelioma, 518
prosthesis
in adults, 573:25.97 – 25.102

1547
 in children, 572:25.91 – 25.96
conformer, 570:25.79 – 25.84
protective polycarbonate glasses and, 574:25.103 – 25.108
socket, 571:25.85 – 25.90
tumors, intraocular, 555, 568:25.67 – 25.72
Episclera
melanocytosis and involvement of, 11:1.28 – 1.30
pigmentation, melanocytosis and, 12:1.33, 14:1.45
Epithelioma. See also Ciliary body benign epithelioma
acquired, NPCE, 518
benign
NPCE, 520:23.55 – 23.60
NPCE, clinicopathologic correlation, 521:23.61 – 23.66, 522:23.67 – 23.72
NPCE, treatment, 522:23.67 – 23.72
NPCE, U BM, 523:23.73 – 23.78
CPE, 486, 488:22.109 – 22.114
clinicopathologic correlation, 485:22.103 – 22.108
RPE posterior extension and, 489:22.115 – 22.120
IPE, 482, 484:22.97 – 22.102
clinicopathologic correlation, 485:22.103 – 22.108
malignant, NPCE, 524:23.79 – 23.84
RPE, 490
in African-Americans, 493:22.127 – 22.132
aggressive variant of, 502:22.181 – 22.186
choroidal neovascular membrane, 496:22.145 – 22.150
CHRPE and, 498:22.157 – 22.162, 499:22.163 – 22.168
fluorescein angiography, 490, 492:22.121 – 22.126
FNAB, 497:22.151 – 22.156
inflammatory scar and, 501:22.175 – 22.180
laser scar and, 500:22.169 – 22.174
melanocytoma simulated by, 494:22.133 – 22.138
melanoma simulated by, 495:22.139 – 22.144
plaque radiotherapy, 493
ultrasonography, 490, 492:22.121 – 22.126
Ewing’s sarcoma, metastasis, 218:12.18
External beam radiotherapy (EBRT)
BRLH, uveal, 531:24.18
hemangioma
choroidal circumscribed, 247
choroidal diffuse, 264, 269:13.97 – 13.102
Extraocular extension
melanoma
choroidal, 121:7.127 – 7.132
ciliary body, 106:7.37 – 7.42
uveal, 469:22.55 – 22.60
retinoblastoma and massive, 324:15.61 – 15.66
Exudation, 376
Coats disease, 376

1548
 VPTOF, 421

F
Facial palsy, melanocytosis and, 14:1.47
Familial adenomatous polyposis (FAP)
CHRPE and, 453
fundus lesions, multiple small pigmented and, 462
RPEH associated with, 464, 465:22.43 – 22.48
Familial atypical mole syndrome (dysplastic nevus syndrome), melanoma and
iris, 38:2.103 – 2.108
Familial exudative vitreoretinopathy simulating, retinoblastoma, 382:19.37 – 19.42
Familial pigmentary dystrophy of retina (retinitis pigmentosa), 423:20.146
FAP. See Familial adenomatous polyposis
Fine needle aspiration biopsy (FNAB)
anterior segment lesion, 558:25.7 – 25.12
astrocytoma, acquired retinal, 448:21.91 – 21.96, 449:21.97 – 21.102
BRLH, 527
epithelioma
CPE, 486
RPE, 490, 497:22.151 – 22.156
hamartoma, astrocytic, 431
retinal, 443:21.67 – 21.72
infectious fundus lesion, 208:11.78
instrumentation, 557:25.1
lacrimal gland cyst diagnosis with, 3, 4
leukemias, intraocular, 552
melanocytoma, optic disc, 82
melanoma
choroidal, 150:9.51 – 9.54, 151:9.55 – 9.60, 152:9.61 – 9.66, 153:9.67 – 9.72
ciliary body, 150:9.51 – 9.54
iris, 25, 41:2.121 – 2.126
uveal, 140
NPCE, acquired epithelioma, 518
plasmacytoma
choroidal, 544
uveal, 542
posterior segment lesion, 559:25.13 – 25.18
technique, 557:25.2 – 25.6
tumors, intraocular, 555
VRL, 546
VRL, primary, 551:24.85 – 24.90
Fluorescein angiogram, 247:12.177
Fluorescein angiography
astrocytoma, acquired retinal, 444, 445:21.73 – 21.78
BRLH, 527
BRLH, uveal, 531:24.15
choroidal nevus features on, 70, 76:5.25 – 5.30
CHRPE, 454, 459:22.19 – 22.24

1549
 epithelioma
CPE, 486
RPE, 490, 492:22.121 – 22.126
gliosis, pseudoneoplastic, 427
hamartoma
combined, 474
combined retinal/RPE, 480:22.85 – 22.90
hamartoma, astrocytic, 431
retinal, 437:21.31 – 21.36
hamartoma, congenital simple, 470
hemangioblastoma, retinal, 389 – 390, 396:20.25 – 20.30
hemangioma
cavernous, 405
retinal, cavernous, 409:20.85 – 20.90
retinal cavernous, 404 – 405
iris nevus, 16
leukemias, intraocular, 552
melanocytoma, optic disc, 87:6.19 – 6.22
melanoma
choroidal, 144:9.13 – 9.18
uveal, 139 – 140, 142:9.1 – 9.6
NPCE, acquired epithelioma, 520
NPCE tumor, 504
plasmacytoma, uveal, 542
racemose hemangioma, retinal, 412, 415:20.109 – 20.114, 416:20.115 – 20.120
retinoblastoma
Coats disease simulating, 377:19.7 – 19.12
RPE, 470
VPTOF, 418
VRL, 446
FNAB. See Fine needle aspiration biopsy
Foreign bodies, iris melanoma simulated by, 43, 47:3.7 – 3.12
Freckle, iris, 15
pigmented, 18:2.1
Fundus. See also Vasoproliferative tumor of ocular fundus
autofluorescence
choroidal melanoma, 149:9.43 – 9.48
small melanoma detection with, 107:7.44, 107:7.46 – 7.47
infectious lesions of, choroidal melanoma simulated by, 208:11.73 – 11.78
lesions
choroidal melanoma simulated by solitary infectious, 208:11.73 – 11.78
FAP and multiple small pigmented, 462
multiple small pigmented, 462
photography
BRLH, uveal, 531:24.13 – 24.14
choroidal nevus, 70

1550
Gardner syndrome, RPEH associated with, 464
Genetic studies
hemangioblastoma, retinal, 390
melanoma, uveal, 157
Glaucom
secondary
lymphoma, uveal and, 540:24.49 – 24.54
Glaucoma
hemangioblastoma, retinal, 398
medulloepithelioma, ciliary body simulating, 510:23.19 – 23.24
melanocytoma and, 15 – 16
iris, 22:2.25 – 2.30
melanocytomalytic, 22:2.25 – 2.30
melanoma and
choroidal, 122:7.133 – 7.138
ciliary body, 106:7.37 – 7.42
iris, difuse, 33:2.74
neovascular
Coats disease, 378
hamartoma, retinal astrocytic, 441
NPCE tumors and secondary, 504
secondary
melanoma, ciliary body and, 106:7.37 – 7.42
NPCE, acquired epithelioma, 518
Gliomas, CNS, 464
Gliosis
hemangioma, retinal cavernous and secondary, 405
pseudoneoplastic
enucleation, 427
fluorescein angiography, 427
retinal, 427, 429:21.1 – 21.6
ultrasonography, 427
reactive, 427
Globe compression, uveal melanoma simulated by, 212:11.99 – 11.100
Gonioscopy, ARH NPCE, 514
Gorlin syndrome, hamartoma and, 474
Granuloma
choroidal, melanoma simulated by, 206:11.61 – 11.66
iris melanoma simulated by, 43

H
Hamartoma. See also Retinal pigment epithelial hamartomas
astrocytic, 427
calcified, 431, 434:21.13 – 21.18, 435:21.19 – 21.24
cryotherapy, 431
FNAB, 431
FNAB for retinal, 443:21.67 – 21.72
laser photocoagulation, 431

1551
 noncalcified, 430, 433:21.7 – 21.12
retinal, 430 – 431
retinal, atypical variations, 440:21.49 – 21.54
retinal, calcified, 434:21.13 – 21.18
retinal, clinical features of calcified, 435:21.19 – 21.24
retinal, clinical features of noncalcified, 433:21.7 – 21.12
retinal, fluorescein angiography, 437:21.31 – 21.36
retinal, OCT, 438:21.37 – 21.42
retinal, pathologic features of calcified, 435:21.19 – 21.24
retinal, pathologic features of noncalcified, 433:21.7 – 21.12
retinal, wide-angle imaging, 436:21.25 – 21.30
retinal detachment surgery, 431
TSC and retinal, 439, 439:21.43 – 21.48, 441:21.55 – 21.60, 442:21.61 –
21.66
ultrasonography, 431
vitrectomy, 431
combined
CHRPE and, 453
clinical features, 474
retinal, 474
retinal/RPE, Branchio-oculo-facial syndrome, 479:22.79 – 22.84
retinal/RPE, extrapapillary type, 478:22.73 – 22.78
retinal/RPE, fluorescein angiography, 480:22.85 – 22.90
retinal/RPE, juxtapapillary type, 477:22.67 – 22.72
retinal/RPE, neurofibromatosis, 479:22.79 – 22.84
retinal/RPE, OCT, 481:22.91 – 22.96
retinal/RPE, wide-angle imaging, 479:22.79 – 22.84
retinoblastoma simulated by, 373
RPE, 474
congenital simple
CHRPE and, 453
fluorescein angiography of RPE, 470
RPE, 470, 473:22.61 – 22.64
ultrasonography of RPE, 470
retinoblastoma simulated by, 373
Hemangioblastoma (capillary hemangioma)
PDT, 403:20.67 – 20.72
retinal, 390, 392:20.1 – 20.6
clinicopathologic correlation, 398:20.37 – 20.42
cryotherapy, 401:20.55 – 20.60, 402:20.61 – 20.66
enucleation, 398
exudative, 390, 392:20.2, 392:20.3, 392:20.6
fluorescein angiography, 389 – 390, 396:20.25 – 20.30
free-floating, 392:20.5
gliosis, pseudoneoplastic and, 427
laser photocoagulation, 400:20.49 – 20.54
Marshall-Stickler syndrome and, 399:20.43 – 20.48
optic nerve, nodular, 394:20.13 – 20.18

1552
 optic nerve, sessile, 395:20.19 – 20.24
PDT, 390
tractional, 389, 392:20.4, 392:20.6
VHL syndrome, 389, 390, 393:20.7 – 20.9, 397:20.31 – 20.36
wide-angle imaging of, 393:20.7 – 20.12
Hemorrhage. See also Retinal arterial macroaneurysm with hemorrhage
ARMD-causing, 196
atypical, iris melanoma simulated by, 43, 48:3.16
choroidal melanoma simulated by, 200:11.25 – 11.30, 202:11.37 – 11.42
intracranial, retinal cavernous hemangioma, 404
intraretinal, choroidal melanoma simulated by, 200:11.25 – 11.30
iris melanoma simulated by, 48:3.16
NPCE, acquired epithelioma, 518
retinal arterial macroaneurysm with, 199:11.19 – 11.24
subretinal, choroidal melanoma simulated by, 200:11.25 – 11.30
vitreous
hemangioma, retinal cavernous, 404, 405
melanoma, choroidal and presenting, 152:9.61 – 9.66
racemose hemangioma, 412
Herpes infection, iris melanoma simulated by, 43
Heterochromia, 6, 8:1.7
Histiocytic lymphoma, 546
Hyperplasia. See also Age-related hyperplasia; Benign reactive lymphoid
hyperplasia; Persistent hyperplastic primary vitreous
inflammation and reactive, 466
reactive
inflammation and, 466
RPE and, 466, 468:22.49 – 22.54
RPE migration and, simulating uveal melanoma with extraocular extension,
469:22.55 – 22.60
Hyphema
cholesterolosis, anterior chamber and, 379
melanoma, iris, 29:2.51

I
ICE. See Iridocorneal syndrome
ICGA. See Indocyanine green angiography
Incontinentia pigmenti (Bloch–Sulzberger disease), 386:19.61 – 19.66
Indocyanine green angiography (ICGA)
CHRPE, 454
hamartoma, combined, 474
hemangioblastoma, retinal, 390
melanoma
choroidal, 145:9.19 – 9.24
uveal, 139 – 140
Inflammation
epithelioma, RPE and, 490
gliosis, pseudoneoplastic and, 427

1553
 NPCE, acquired epithelioma, 518
reactive hyperplasia and, 466
retinoblastoma simulated by, 373
Intraocular neoplasms, nonneoplastic conditions simulating, 193 – 212
IPE. See Iris pigment epithelium
Iridectomy
iris stromal cyst, 60
melanoma, iris, 25, 39:2.109 – 2.114, 40:2.115 – 2.120
tumors
intraocular, 555
iris, 565:25.49 – 25.54
Iridocorneal endothelial syndrome, 16
iris melanoma simulated by, 43, 46:3.1 – 3.6
Iridocorneal syndrome (ICE), 43
Iridocyclectomy
ARH NPCE, 514
iridociliary tumor removal with partial lamellar, 566:25.55 – 25.60
iris stromal cyst, 60
lacrimal gland cyst, 4, 5:1.2
medulloepithelioma, 504
melanoma, iris, 38:2.104
Iridogoniocyclectomy, iris melanoma, 39:2.109 – 2.114
Iris
ciliary body melanoma and extension in, 102:7.13 – 7.18
cysts, 51 – 67
classification, 51:4.1t
clinical variations, 51 – 52
freckle, 15
pigmented, 18:2.1
juvenile xanthogranuloma, 304:14.67 – 14.72
lymphoma, 534
melanocytoma, 15, 16, 21:2.19 – 2.24
friable, 21:2.21
glaucoma and, 22:2.25 – 2.30
growth, documented, 23:2.31 – 2.36
iris melanoma simulated by, 49:3.21
melanoma, 25
adjacent structures and, 25, 49:3.19 – 3.20
atypical clinical variations, 29:2.49 – 2.54, 30:2.55 – 2.60
bilobed, 30:2.57
bilobed ring, 29:2.49
circumscribed, 25
conditions that simulate, 43 – 50
diffuse, 25, 33:2.73 – 2.78, 37:2.97 – 2.102
distant metastasis of, 25
ectropion iridis, congenital simulating, 43, 48:3.13
enucleation, 25, 35:2.85 – 2.90
FNAB, 25, 41:2.121 – 2.126

1554
 foreign bodies simulating, 43, 47:3.7 – 3.12
hemorrhage, atypical simulating, 43, 48:3.16
hemorrhagic, 30:2.55
imaging, 34:2.79 – 2.84
iridectomy, 25, 39:2.109 – 2.114, 40:2.115 – 2.120
iridocorneal endothelial syndrome simulating, 43, 46:3.1 – 3.6
iridocyclectomy, 25, 38:2.104
iridogoniocyclectomy, 39:2.109 – 2.114
iris melanocytoma simulating, 49:3.21
Lisch nodule simulating, 49:3.19 – 3.20
metastasis and death from, 25:2.3t
mixed cell-type, 30:2.59 – 2.60
nonneoplastic conditions simulating, 44:3.1t, 48:3.13 – 3.18
nonpigmented, 28:2.43 – 2.48
optical coherence tomography, imaging with, 34:2.79 – 2.84
pedunculated, 30:2.58 – 2.59
pigmented, 27:2.37 – 2.42, 30:2.57
pigment epithelial cyst simulating, 48:3.14, 49:3.22
pigment epithelial midzonal cysts simulating, 50:3.25 – 3.30
plaque radiotherapy, 25, 36:2.91 – 2.96, 41:2.121 – 2.126, 42:2.127 – 2.132,
564:25.43 – 25.48
pupilloplasty, 40:2.115 – 2.120
retained lens material simulating, 43, 48:3.17 – 3.18
tapioca, 25, 28:2.47 – 2.48, 31:2.61 – 2.66
trabecular meshwork, 25
ultrasound biomicroscopy, imaging with, 34:2.79 – 2.84
vascular, 30:2.56
metastasis
breast cancer, 216:12.1 – 12.6
bronchial carcinoid tumors, 218:12.14
cutaneous melanoma, 217:12.7 – 12.12
Ewing’s sarcoma, 218:12.18
lung cancer, 218:12.13
small cell carcinoma, 218:12.15 – 12.16
stomach cancer, 218:12.17
nevus, 15, 16
adjacent structures and effects of, 20:2.13 – 2.18
diffuse, 16
into iris melanoma, 16:2.1t
minimally pigmented, 19:2.7 – 2.12
nonpigmented, 19:2.7 – 2.12
peripheral, 20:2.15
pigmented, 18:2.2 – 2.6
secondary cyst, 20:2.17
tapioca, 16
trans-scleral involvement, 20:2.18
tumors
iridectomy, 565:25.49 – 25.54

1555
 plaque radiotherapy, 563:25.37 – 25.42
Iris and ciliary body rhabdomyosarcomas, 295:14.43 – 14.48
Iris arteriovenous communication (Racemose Hemangioma), 278:13.127 – 13.132
Iris mammillations, 6
Iris pigment epithelium (IPE)
clinicopathologic correlation, 485:22.103 – 22.108
epithelioma, 482, 484:22.97 – 22.102
Iris pigment epithelium (IPE) cysts, 51 – 52
central, 51, 53:4.1 – 4.6
dislodged, 52, 58:4.31 – 4.36
fixation in anterior chamber angle of, 59:4.37 – 4.42
iridociliary, 52, 57:4.25 – 4.30
midzonal, 50:3.25 – 3.30, 51 – 52, 55:4.13 – 4.18, 56:4.19 – 4.24, 57:4.25 – 4.30
U BM, 52, 55:4.18
Iris stroma
cysts, 60, 60:4.3t
acquired, 60, 64:4.55 – 4.60, 66:4.67 – 4.72
acquired, natural course of, 66:4.67 – 4.72
acquired, secondary, 67:4.73 – 4.78
alcohol irrigation for congenital, 63:4.49 – 4.54
aspiration for congenital, 63:4.49 – 4.54
congenital, 60, 62:4.43 – 4.48, 63:4.49 – 4.54
cryotherapy for acquired, 66:4.72
OCT, imaging with, 65:4.61 – 4.466
U BM, imaging with, 65:4.61 – 4.466
melanoma, 25
tumors, melanocytic of, 15 – 42
Iris varix, 279:13.133 – 13.138
Iris vascular tumors and malformations
capillary, 276:13.115 – 13.120
cavernous hemangioma, 277:13.121 – 13:126
Irradiation
charged particle, uveal melanoma, 156
lymphoma, uveal, 535
plasmacytoma, uveal, 542
Ischemia
peripheral retinal, combined hamartoma and, 474

J
Juvenile nasopharyngeal angiofibroma, combined hamartoma and, 474

K
Kidney carcinoma, choroidal metastasis, 226:12.61 – 12.62
Klippel – Trenaunay – Weber syndrome, 125, 125:7.156
KRITI gene, hemangioma and mutation of, 404

L
Lacrimal gland
choristoma, intraocular, 3, 4, 5:1.1 – 1.6

1556
 ectopic tissue of, 3
Lacrimal gland cysts (dacryops), 3
iridocyclectomy, 4, 5:1.2
Lacunae, 453
Lamellar sclerouvectomy
epithelioma, RPE, 490
NPCE, acquired epithelioma, 518
Laser photocoagulation
choroidal nevus, 70
hamartoma
astrocytic, 431
combined, 474
hemangioblastoma, retinal, 400:20.49 – 20.54
melanoma
choroidal, 162:10.13 – 10.18
uveal, 155 – 156
VPTOF, 418, 425:20.157 – 20.162
Lesions
anterior segment, FNAB, 558:25.7 – 25.12
congenital, uveal tract, 3 – 14
pigment epithelium, 453 – 502
posterior segment, FNAB, 559:25.13 – 25.18
retinoblastoma-simulating, 373 – 387, 374:19.1t
uveal tract, congenital, 3 – 14
Leukemias. See also Acute lymphoblastic leukemia
intraocular, 552, 553:24.91 – 24.96
fluorescein angiography, 552
FNAB, 552
radiotherapy, 552
ultrasonography, 552
intraocular lymphoid, 525 – 554
optic nerve involvement in, 553:24.91 – 24.96
clinicopathologic correlation, 554:24.97 – 24.102
Leukocoria, 314, 385:19.55
PHPV simulating, 380
retinoblastoma and, 373
Lisch nodules, 301:14:61
iris melanoma simulated by, 49:3.19 – 3.20
Lung cancer metastasis
choroidal, 222:12.37 – 12.42, 232:12.97 – 12.102
iris, 218:12.13
optic disc, 243:12.151 – 12.156
sarcoidosis simulated by, 232:12.97 – 12.102
uveal, 213
Lymphoid tumors, intraocular, 525 – 526. See also Benign reactive lymphoid
hyperplasia
Lymphoma. See Non-Hodgkin large-cell lymphomas; Primary CNS lymphoma;
Primary intraocular lymphoma; Revised European American Lymphoma

1557
 Classification
ciliary body, 534
histiocytic, 546
intraocular, 525 – 526
iris, 534
metastatic, 534
non-Hodgkin large-cell, 525
PVRCNSL, 546 – 547
uveal, 534 – 535
aggressive form, 539:24.43 – 24.48
bilateral, 534
chemotherapy, 535, 537:24.31 – 24.36
glaucoma, secondary to, 540:24.49 – 24.54
irradiation, 535
OCT, 538:24.37 – 24.42
ophthalmoscopy, 535
orbital involvement and aggressive, 541:24.55 – 24.60
plaque radiotherapy, 535
radiotherapy, 535, 537:24.31 – 24.36
unilateral, 534
VRL, 546

M
Magnetic resonance imaging (MRI)
BRLH, uveal, 531:24.17, 533:24.25 – 24.30
melanoma
ciliary body, 147:9.33 – 9.34
uveal, 140
racemose hemangioma, retinal, 412
VRL, 546
Malignant teratoid medulloepithelioma, 508:23.7 – 23.12, 509:23.13 – 23.18
Marshall–Stickler syndrome, hemangioblastoma and, 389
retinal, 389, 399:20.43 – 20.48
Masquerade syndrome, 546
Medulloepithelioma, 504
ciliary body, 507:23.1 – 23.6
aggressive malignant, 512:23.31 – 23.36
PHPV simulating, 510:23.19 – 23.24
pigmented malignant, 511:23.25 – 23.30
malignant teratoid, 508:23.7 – 23.12, 509:23.13 – 23.18
nonteratoid, 504
NPCE tumors and, 504
optic nerve, 504, 513:23.37 – 23.42
recurrent, 504
retinoblastoma simulated by, 373
teratoid types, 504
Melanocytoma
choroidal, 93:6.55 – 6.60

1558
 giant diffuse variant, 94:6.61 – 6.66
localized, 82
melanoma and, 94:6.61 – 6.66
oculodermal melanocytosis and, 94:6.61 – 6.66
ciliary body, 82, 92:6.49 – 6.54
epithelioma of RPE simulating, 494:22.133 – 22.138
glaucoma and, 15, 16
iris, 15, 16, 21:2.19 – 2.24
friable, 21:2.21
glaucoma and, 22:2.25 – 2.30
growth, documented, 23:2.31 – 2.36
iris melanoma simulated by, 49:3.21
iris nevus and, 16
optic disc, 81 – 94, 84:6.1 – 6.6
associations, 88:6.25 – 6.30
choroidal involvement in, 86:6.13 – 6.18
CHRPE, 88:6.27 – 6.28
clinical variations, 88:6.25 – 6.30
fluorescein angiography, 87:6.19 – 6.22
juxtapapillary, 86:6.13 – 6.18
melanoma and, 81 – 82, 91:6.43 – 6.48
OCT, 87:6.23 – 6.24
retinal nerve fiber layer involvement in, 85:6.7 – 6.12
tumor necrosis in, 89:6.31 – 6.36
visual loss from central retinal vascular obstruction, 90:6.37 – 6.42
visual loss from tumor necrosis in, 89:6.31 – 6.36
optic nerve, 81 – 82
uveal, posterior, 81 – 94
Melanocytosis. See Oculodermal melanocytosis
choroidal, 11:1.29
congenital, ocular, 3, 6
external features of, 6, 8:1.7 – 1.12
fundus features of, 6, 9:1.13 – 1.18
melanoma, intracranial and, 14:1.43 – 1.48
melanoma, uveal and, 12:1.31 – 1.36
episcleral involvement in, 11:1.28 – 1.30
facial palsy and, 14:1.47
intracranial, melanocytosis and, 14:1.43 – 1.48
melanoma and
choroidal, 11:1.25 – 1.26
intracranial, 14:1.43 – 1.48
ocular
congenital, 3, 6, 12:1.31 – 1.36
episcleral pigmentation in, 12:1.33, 14:1.45
external features of congenital, 6, 8:1.7 – 1.12
fundus features of congenital, 6, 9:1.13 – 1.18
optic disc melanocytoma and, 88:6.25 – 6.26
uveal melanoma associated with, 11:1.25 – 1.30

1559
 oculodermal
choroidal melanocytoma and, 94:6.61 – 6.66
diffuse, 13:1.37 – 1.40
sector, 13:1.41 – 1.42
uveal melanoma associated with, 11:1.25 – 1.30
scleral, posterior uveal melanoma and, 129
scleral involvement in, 8:1.9 – 1.11, 11:1.28 – 1.30, 14:1.46
Melanoma. See Collaborative Ocular Melanoma Study; To Find Small Ocular
Melanoma
choroidal, 11:1.29, 129
adjacent structures and, 115:7.91 – 7.96
advance tumor, 122:7.133 – 7.138, 123:7.139 – 7.144
ARMD simulating, 196:11.1 – 11.6
astrocytoma, acquired retinal simulating, 448
as atypical extraocular extension, 121:7.127 – 7.132
in children, 125:7.151 – 7.156
choroidal neovascular membrane and, 144:9.13 – 9.18
choroidal nevus and, 69 – 70, 79:5.43 – 5.48, 80:5.49 – 5.54
choroiditis, solitary idiopathic simulating, 207:11.67 – 11.72
clinical features of, 95 – 96, 96:7.2t
clinicopathologic correlations in, 137:8.31 – 8.36
CT, 147:9.31 – 9.32
diffuse growth pattern of, 118:7.109 – 7.114
diffuse tumors, 119:7.115 – 7.120, 120:7.121 – 7.126, 121:7.127 – 7.132
enucleation, 184:10.145 – 10.150, 185:10.151 – 10.156, 186:10.157 – 10.162,
187:10.163 – 10.168
extraocular extension, 123:7.139 – 7.144
fluorescein angiography, 143:9.7 – 9.12, 144:9.13 – 9.18
FNAB, 150:9.51 – 9.54, 151:9.55 – 9.60, 152:9.61 – 9.66, 153:9.67 – 9.72
fundus autofluorescence, 149:9.43 – 9.48
genetic testing, 153:9.67 – 9.72
as glaucoma, acute, 122:7.133 – 7.138
gross features of, 133:8.7 – 8.12
growth, 96, 107:7.43 – 7.48, 161:10.7 – 10.12
hamartoma, combined and, 474
hemorrhage, choroidal simulated by, 202:11.37 – 11.42
hemorrhages, subretinal/intraretinal simulating, 200:11.25 – 11.30
ICGA, 145:9.19 – 9.24
infectious fundus lesions simulating, 208:11.73 – 11.78
intracranial extension of, 124:7.145 – 7.150
iris nevus and, 16
laser photocoagulation, 162:10.13 – 10.18
metastasis, 107:7.43 – 7.48, 161:10.7 – 10.12
mushroom-shaped tumors, 134:8.13 – 8.18, 143:9.7 – 9.12, 173:10.79 – 10.84
mushroom-shaped tumors with nonpigmented dome, 113:7.79 – 7.84,
114:7.85 – 7.90
mushroom-shaped tumors with pigmented dome, 111:7.67 – 7.72, 112:7.73 –
7.78

1560
 necrosis, 127:7.163 – 7.168
neovascular membrane, choroidal simulating, 201:11.31 – 11.36
nodular posterior scleritis simulating, 204:11.49 – 11.54
nonpigmented, 110:7.61 – 7.66, 113:7.79 – 7.84, 114:7.85 – 7.90
in non-whites, 126:7.157 – 7.162
observation of, 155, 160:10.1 – 10.6
OCT, 148:9.37 – 9.42
optic nerve invasion, 120:7.121 – 7.126
orbital exenteration, 188:10.169 – 10.174
P32 test, 150:9.50
partly pigmented, 109:7.55 – 7.60
PEHCR simulating, 197:11.7 – 11.12, 198:11.13 – 11.18
pigmented, 108:7.49 – 7.54, 109:7.55 – 7.60, 111:7.67 – 7.72, 112:7.73 – 7.78
plaque radiotherapy, 168:10.49 – 10.54, 169:10.55 – 10.60, 170:10.61 –
10.66, 171:10.67 – 10.72, 173:10.79 – 10.84, 176:10.97 – 10.102
plaque radiotherapy, juxtapapillary melanoma management with, 175:10.91 –
10.96
plaque radiotherapy, side effects of, 179:10.115 – 10.120
PLSU , 183:10.139 – 10.144
pseudoangiomatous, 143
regression, 127:7.163 – 7.168
retinal arterial macroaneurysm with hemorrhage simulating, 199:11.19 – 11.24
retinal invasion by, 116:7.97 – 7.102, 117:7.103 – 7.108
retinal vein dilation and, 117:7.103 – 7.108
RPE and, 466
size/shape variations in, 114:7.85 – 7.90
spontaneous regression of, 96
TTT, 163:10.19 – 10.24, 164:10.25 – 10.30, 165:10.31 – 10.36, 166:10.37 –
10.42
TTT and plaque radiotherapy for, 176:10.97 – 10.102
TTT side effects for, 167:10.43 – 10.48
ultrasonography, 146:9.25 – 9.26, 146:9.29 – 9.30, 164:10.29 – 10.30
ultrasonography following plaque radiotherapy for, 178:10.109 – 10.114
visual loss caused by, 124:7.145 – 7.150
vitreal invasion by, 116:7.97 – 7.102
vitreous hemorrhage presenting in, 152:9.61 – 9.66
vortex vein varix simulating, 203:11.43 – 11.48
wide-angle imaging, 114:7.85 – 7.90
wide-angle imaging of diffuse tumors, 119:7.115 – 7.120
in young patients, 125:7.151 – 7.156
ciliary body, 129
cavity variant, 105:7.31 – 7.36
dilated pupil appearance of, 103:7.19 – 7.24
extraocular extension, 106:7.37 – 7.42
FNAB, 150:9.51 – 9.54
glaucoma, secondary and, 106:7.37 – 7.42
gross features of, 132:8.1 – 8.6
iris extension, 102:7.13 – 7.18

1561
 MRI, 147:9.33 – 9.36
P32 test, 150:9.49
plaque radiotherapy, 174:10.85 – 10.90, 177:10.103 – 10.108
ring variant, 106:7.37 – 7.42
RPE and, 466
sentinel blood vessels and, 100:7.1 – 7.6
transscleral extension, 101:7.7 – 7.12
U BM, 146:9.27 – 9.28
wide-angle imaging, 104:7.25 – 7.30
ciliochoroidal
cyclochoroidectomy, 180:10.121 – 10.126, 181:10.127 – 10.132
partial lamellar cyclochoroidectomy, 180:10.121 – 10.126
plaque radiotherapy, 562:25.31 – 25.36
PLSU , 180, 182:10.133 – 10.138
uveal effusion simulating, 205:11.55 – 11.60
diffuse, 129
diffuse melanocytosis, oculodermal and, 13:1.37 – 1.40
epithelioma of RPE simulating, 495:22.139 – 22.144
iris, 6, 25
adjacent structures and, 25, 49:3.19 – 3.20
atypical clinical variations, 29:2.49 – 2.54, 30:2.55 – 2.60
bilobed ring, 29:2.49
circumscribed, 25
conditions that simulate, 43 – 50
diffuse, 25, 33:2.73 – 2.78, 37:2.97 – 2.102
distant metastasis of, 25
ectropion iridis, congenital simulating, 43, 48:3.13
enucleation, 25, 35:2.85 – 2.90
FNAB, 25, 41:2.121 – 2.126
foreign bodies simulating, 43, 47:3.7 – 3.12
hemorrhage, atypical simulating, 43
hemorrhagic, 30:2.55
imaging, 34:2.79 – 2.84
iridectomy, 25, 39:2.109 – 2.114, 40:2.115 – 2.120
iridocorneal endothelial syndrome simulating, 43, 46:3.1 – 3.6
iridocyclectomy, 25, 38:2.104
iridogoniocyclectomy, 39:2.109 – 2.114
iris melanocytoma simulating, 49:3.21
metastasis and death from, 25:2.3t
mixed cell-type, 30:2.59 – 2.60
nonneoplastic conditions simulating, 44:3.1t, 48:3.13 – 3.18
nonpigmented, 28:2.43 – 2.48
optical coherence tomography, imaging with, 34:2.79 – 2.84
pedunculated, 30:2.58 – 2.59
pigmented, 27:2.37 – 2.42, 30:2.57
pigment epithelial cyst simulating, 48:3.14, 49:3.22
pigment epithelial midzonal cysts simulating, 50:3.25 – 3.30
plaque radiotherapy, 25, 36:2.91 – 2.96, 41:2.121 – 2.126, 42:2.127 – 2.132,

1562
 564:25.43 – 25.48
pupilloplasty, 40:2.115 – 2.120
retained lens material simulating, 43, 48:3.17 – 3.18
tapioca, 25, 28:2.47 – 2.48, 31:2.61 – 2.66
trabecular meshwork, 25
ultrasound biomicroscopy, imaging with, 34:2.79 – 2.84
vascular, 30:2.56
iris nevus and, 16
malignant, 14:1.43
optic disc melanocytoma and, 91:6.43 – 6.48
melanocytoma and
choroidal, 94:6.61 – 6.66
optic disc, 81 – 82, 91:6.43 – 6.48
melanocytosis, congenital ocular and, 6
melanocytosis, oculodermal and, 11:1.25 – 1.26
melanocytosis and, 11:1.25 – 1.26
metastatic, brain, 14:1.43
nonpigmented, 129
pigmented, 129
RPE and
epithelioma of, 495:22.139 – 22.144
sector melanocytosis, oculodermal and, 13:1.41 – 1.42
uveal
BDU MP simulating, 210:11.85 – 11.90
bilateral, 12:1.33 – 1.36
cataract, subluxed mature simulating, 212:11.97 – 11.98
classification, 129
endophthalmitis simulated by, 191:10.187 – 10.192
enucleation, 189:10.175 – 10.180
fluorescein angiography, 139 – 140, 142:9.1 – 9.6
globe compression simulating, 212:11.99 – 11.100
histopathologic features of, 130:8.1t
melanocytosis, congenital ocular and, 6, 12:1.31 – 1.36
melanocytosis, ocular and, 11:1.25 – 1.30
melanocytosis, oculodermal and, 11:1.25 – 1.30
miscellaneous conditions simulating posterior, 211:11.91 – 11.96, 212:11.97 –
11.102
multifocal, 12:1.31 – 1.32
nonneoplastic conditions simulating, 193 – 212
orbital exenteration, 189:10.175 – 10.180, 190:10.181 – 10.186
plaque radiotherapy, 172:10.73 – 10.78
posterior, 95 – 127, 97:7.3t – 98:7.6t, 191:10.187 – 10.192, 211:11.91 – 11.96
posterior, cell types, 135:8.19 – 8.24, 136:8.25 – 8.30
posterior, diagnostic approaches, 139 – 153
posterior, management of, 155 – 191
posterior, pathology of, 129 – 137
retinal detachment, rhegmatogenous simulating, 211:11.93 – 11.94
retinoschisis, bullous simulating, 211:11.95 – 11.96

1563
 RPE migration and hyperplasia, simulating, 469:22.55 – 22.60
RPE simulated by, 469:22.55 – 22.60
sclerochoroidal calcification simulating, 211:11.91 – 11.92
staphyloma, scleral simulating, 212:11.101 – 11.102
Melanosis, iris, 6
Membrane peeling, combined hamartoma, 474
Metastases
iris
breast cancer, 216:12.1 – 12.6
bronchial carcinoid tumors, 218:12.14
cutaneous melanoma, 217:12.7 – 12.12
Ewing’s sarcoma, 218:12.18
lung cancer, 218:12.13
small cell carcinoma, 218:12.15 – 12.16
stomach cancer, 218:12.17
lung cancer, 213
sarcoidosis simulated by, 232:12.97 – 12.102
lung carcinoma, sarcoidosis simulated by, 232:12.97 – 12.102
melanoma
cutaneous, 213
lymphoma, 534
melanoma
brain, 14:1.43
choroidal, 161:10.7 – 10.12
Metastasis
melanoma
choroidal, 107:7.43 – 7.48
Metastatic tumors, 214
breast cancer, 216:12.1 – 12.6, 220:12.25 – 12.30
cutaneous melanoma, 217:2.7 – 12.12
iridociliary and ciliary body metastasis, 219:12.19 – 12.24
lung cancer, 222:12.37 – 12.42
miscellaneous sites, 218:12.13 – 12.18
multifocal and bilateral tumors, 221:12.31 – 12.36
Microgliomatosis, 546
Microscopy, melanoma, posterior uveal, 129
Mitomycin, iris stomal cyst, 60
MRI. See Magnetic resonance imaging
Mushroom-shaped choroidal metastasis, 233:12.103 – 12.108

N
Necrosis. See also Tumor necrosis, optic disc melanocytoma
melanoma, choroidal, 127:7.163 – 7.168
Needle biopsy, lymphoma and, 534
Neoplasms
intraocular, nonneoplastic conditions simulating, 193 – 212
NPCE congenital, 503 – 504
RPE and, 466

1564
Neovascular membrane, choroidal epithelioma of RPE simulating, 496:22.145 –
22.150
melanoma simulated by, 201:11.31 – 11.36
nevus simulated by, 201:11.31 – 11.36
Nephroblastoma, sporadic aniridia and, 3
Neuritis, optic, 474
Neurofibromatosis
CHRPE and, 462
ectropion iridis, congenital and, 49:3.19
hamartoma, combined and, 474
hamartoma, combined retinal/RPE, 479:22.79 – 22.84
Neurofibromatosis type 1 (NF1)
hamartoma, astrocytic and, 430
Neurofibromatosis type 1 with secondary, VPTOF, 424:20.151 – 20.156
Nevus. See also Familial atypical mole syndrome
choroidal, 69 – 80
adjacent structures and effects of, 75:5.19 – 5.24
autofluorescence, 78:5.37 – 5.42
choroidal melanoma and, 69 – 70, 79:5.43 – 5.48, 80:5.49 – 5.54
clinical variations, 74:5.13 – 5.18
congenital, 69
fluorescein angiography, 70, 76:5.25 – 5.30
giant, 74:5.17 – 5.18
halo, 74:5.13 – 5.14
multifocal, 74:5.16
neovascular membrane, choroidal simulating, 201:11.31 – 11.36
nonpigmented, 73:5.7 – 5.12
OCT, 70, 77:5.31 – 5.36
pigmented, 72:5.1 – 5.6
retinal detachment and, 75:5.19 – 5.20
RPE detachment and, 75:5.21 – 5.22
iris, 15, 16
adjacent structures and effects of, 20:2.13 – 2.18
diffuse, 16
iris melanoma simulated by, 43
minimally pigmented, 19:2.7 – 2.12
nonpigmented, 19:2.7 – 2.12
peripheral, 20:2.15
pigmented, 18:2.2 – 2.6
secondary cyst, 20:2.17
trans-scleral involvement, 20:2.18
magnocellular, 82
Nevus of Ota. See Oculodermal melanocytosis
NF1. See Neurofibromatosis type 1
Nodular posterior scleritis, choroidal melanoma simulated by, 204:11.49 – 11.54
Non-Hodgkin large-cell lymphomas, 525
uveal, 534
Nonneoplastic conditions, uveal melanoma simulated by, 193 – 212

1565
Nonpigmented ciliary epithelium (NPCE)
ARH, 514, 516:23.43 – 23.48
clinicopathologic correlation, 517:23.49 – 23.54
electron microscopy, 514
iridocyclectomy, 514
ophthalmoscopy, 514
U BM, 514
congenital neoplasms of, 503 – 504
epithelioma, acquired, 518
epithelioma, benign, 520:23.55 – 23.60
clinicopathologic correlation, 521:23.61 – 23.66, 522:23.67 – 23.72
treatment, 522:23.67 – 23.72
U BM, 523:23.73 – 23.78
epithelioma, malignant, 524:23.79 – 23.84
neoplastic cyclitic membrane development and, 504
tumors, 503 – 524
Non-whites, choroidal melanoma in, 126:7.157 – 7.162. See also Aferican-
Americans; Asians
NPCE. See Nonpigmented ciliary epithelium

O
OCT. See Optical coherence tomography
Ocular radiation, VRL, 547
Ocular toxocariasis, retinoblastoma simulated by, 383:19.43 – 19.48
Oculodermal melanocytosis (nevus of Ota), 10:1.19 – 1.24
Oculoneurocutaneous syndrome, hemangioma
retinal, 404
retinal cavernous and, 411
Ophthalmoscopy
ARH-NPCE, 414
lymphoma, uveal, 535
VRL, 546
Optical coherence tomography (OCT)
choroidal nevus, 70, 77:5.31 – 5.36
CHRPE, 454, 460:22.25 – 22.30
hamartoma
combined, 474
combined retinal/RPE, 481:22.91 – 22.96
retinal astrocytic, 438:21.37 – 21.42
hemangioblastoma, retinal, 390
iris nevus, 16
melanocytoma, optic disc, 87:6.23 – 6.24
melanoma
choroidal, 148:9.37 – 9.42
melanoma, uveal, 140
racemose hemangioma, retinal, 412, 416:20.115 – 20.120
small melanoma detection with, 107:7.45 – 7.46, 107:7.48
torpedo maculopathy, 472

1566
Optic disc
cavernous hemangioma, retinal and involvement of, 410:20.91 – 20.96
lymphoid tumors in, 525
melanocytoma, 81 – 94, 84:6.1 – 6.6
associations, 88:6.25 – 6.30
choroidal involvement in, 86:6.13 – 6.18
CHRPE, 88:6.27 – 6.28
clinical variations, 88:6.25 – 6.30
fluorescein angiography, 87:6.19 – 6.22
juxtapapillary, 86:6.13 – 6.18
melanoma and, 81 – 82, 91:6.43 – 6.48
OCT, 87:6.23 – 6.24
retinal nerve fiber layer involvement in, 85:6.7 – 6.12
tumor necrosis in, 89:6.31 – 6.36
visual loss from central retinal vascular obstruction, 90:6.37 – 6.42
visual loss from tumor necrosis in, 89:6.31 – 6.36
tumors
glial, 427 – 449
vascular, 389 – 426
Optic disc metastasism, 243:12.163 – 12.168
Optic nerve
hemangioblastoma, retinal of
nodular, 394:20.13 – 20.18
sessile, 395:20.19 – 20.24
leukemia and involvement of, 553:24.91 – 24.96
medulloepithelioma, 504, 513:23.37 – 23.42
melanocytoma, 81 – 82
melanoma, choroidal and invasion of, 120:7.121 – 7.126
Optic nerve involvement in
leukemia and involvement of
clinicopathologic correlation, 554:24.97 – 24.102
Optic neuritis, combined hamartoma and, 474
Orbital exenteration, 575:25.109 – 25.114
medulloepithelioma, 504
melanoma
choroidal, 188:10.169 – 10.174
uveal, 157, 189:10.175 – 10.180, 190:10.181 – 10.186
prosthesis, 576:25.115 – 25.120
tumors, intraocular, 555
Ovarian cancer, BDU MP and, 209

P
P32 test. See Radioactive phosphorus uptake test
Pain, ocular
hemangioblastoma, retinal, 398
optic disc melanocytoma, 89:6.31
Pars planitis. See Bilateral intermediate uveitis
Partial lamellar sclerouvectomy (PLSU )

1567
 melanoma
ciliochoroidal, 180, 182:10.133 – 10.138
uveal, 156
tumors, intraocular, 555
PCNSL. See Primary CNS lymphoma
PDT. See Photodynamic therapy
PEHCR. See Peripheral exudative hemorrhagic chorioretinopathy
Peripheral exudative hemorrhagic chorioretinopathy (PEHCR), choroidal melanoma
simulated by, 197:11.7 – 11.12, 198:11.13 – 11.18
Persistent hyperplastic primary vitreous (PHPV)
CHRPE and, 462
clinical features, 381:19.31 – 19.36
medulloepithelioma, ciliary body simulating, 510:23.19 – 23.24
pathologic features, 381:19.31 – 19.36
retinoblastoma simulated by, 373, 380:19.25 – 19.30
Phakomatosis pigmentovascularis, 271, 13.103 – 13.108
Photocoagulation, retinal hemangioblastoma, 390
Photodynamic therapy (PDT)
acquired retinal astrocytoma, 449:21.97 – 21.102
choroidal nevus, 70
hemangioblastoma, retinal, 390, 403:20.67 – 20.72
VPTOF, 418, 426:20.163 – 20.168
Photoreceptors, CHRPE and loss of, 460
PHPV. See Persistent hyperplastic primary vitreous
Phthisical eye, 518
Phthisis bulbi, retinal hemangioblastoma, 398
Pigment epithelial cyst
iris melanoma simulated by, 48:3.14, 49:3.22
iris nevus and, 16
Pigment epithelium. See also Ciliary pigment epithelium; Congenital hypertrophy
of retinal pigment epithelium; Iris pigment epithelium; Retinal pigment
epithelial
lesions, 453 – 502
tumors of, 453 – 502
Pinealoblastoma
pineal cyst simulating, 332:15.109 – 15.114
retinoblastoma and, 312 – 313, 332:15.109 – 15.114
PIOL. See Primary intraocular lymphoma
Plaque brachytherapy
diffuse iris melanoma with, 37:2.97 – 2.102
melanoma, uveal, 156
VPTOF, 418
Plaque radiotherapy
application technique for, 561:25.19 – 25.30
epithelioma, RPE, 490, 493
juxtapapillary melanoma management with, 175:10.91 – 10.96
lymphoma, uveal, 535
medulloepithelioma, 504

1568
 melanoma
choroidal, 168:10.49 – 10.54, 169:10.55 – 10.60, 170:10.61 – 10.66,
171:10.67 – 10.72, 173:10.79 – 10.84
ciliary body, 174:10.85 – 10.90, 177:10.103 – 10.108
ciliochoroidal, 562:25.31 – 25.36
iris, 25, 36:2.91 – 2.96, 41:2.121 – 2.126, 42:2.127 – 2.132, 564:25.43 – 25.48
uveal, 172:10.73 – 10.78
plaque design/application for, 560:25.19 – 25.24
side effects
melanoma, choroidal, 179:10.115 – 10.120
melanoma, uveal, 172:10.73 – 10.78
TTT combined with, choroidal melanoma, 176:10.97 – 10.102
tumors
intraocular, 555, 560:25.19 – 25.24
iris, 563:25.37 – 25.42
ultrasonography following, choroidal melanoma, 178:10.109 – 10.114
VPTOF, 425:20.157 – 20.162
Plasmacytoma, 525. See also Solitary extramedullary plasmacytoma
benign, 525
choroidal, 544:24.61 – 24.66
radiotherapy, 544
ciliary body, 545:24.67 – 24.72
malignant, 525
uveal, 542
FNAB, 542, 544
PLSU . See Partial lamellar sclerouvectomy
“Polar bear tracks,” 462
Polycarbonate glasses, 574:25.103 – 25.108
Primary CNS lymphoma (PCNSL), 525
Primary intraocular lymphoma (PIOL), 525
Primary vitreoretinal and central nervous system lymphoma (PVRCNSL), 546 – 547
Prosthesis
enucleation
in adults, 573:25.97 – 25.102
in children, 572:25.91 – 25.96
conformer, 570:25.79 – 25.84
protective polycarbonate glasses and, 574:25.103 – 25.108
socket, 571:25.85 – 25.90
orbital exenteration, 576:25.115 – 25.120
Pupil
iris nevus and effects on, 20:2.13 – 2.14
melanoma, ciliary body through dilated, 103:7.19 – 7.24
Pupilloplasty, iris melanoma, 40:2.115 – 2.120
PVRCNSL. See Primary vitreoretinal and central nervous system lymphoma

R
Racemose hemangioma, retinal
branch retinal vein obstruction and, 412, 417:20.121 – 20.126

1569
 clinical features, 414:20.103 – 20.108
fluorescein angiography, 412, 415:20.109 – 20.114, 416:20.115 – 20.120
MRI, 412
OCT, 412, 416:20.115 – 20.120
retinal, 390, 412
Radioactive phosphorus uptake test (P32 test), melanoma
choroidal, 150:9.50
ciliary body, 150:9.49
uveal, 140
Radiotherapy. See also Plaque radiotherapy
epithelioma, CPE, 486
leukemia, intraocular, 552
lymphoma, uveal, 535, 537:24.31 – 24.36
plasmacytoma, choroidal, 544
Reactive hyperplasia
pseudocancerous, CHRPE and, 453
pseudoneoplastic, RPE and, 466, 468:22.49 – 22.54
Retained lens material, iris melanoma simulated by, 43, 48:3.17 – 3.18
Reticulum cell sarcoma, 546
Retina. See also Branch retinal vein obstruction; Congenital hypertrophy of retinal
pigment epithelium; Familial pigmentary dystrophy of retina
acquired vasoproliferative tumors, 389
astrocytic proliferation, 429:21.1 – 21.6
astrocytoma, acquired, 427, 444, 445:21.73 – 21.78
clinicopathologic correlation, 446:21.79 – 21.84, 447:21.85 – 21.90
fluorescein angiography, 444, 445:21.73 – 21.78
FNAB, 448:21.91 – 21.96, 449:21.97 – 21.102
melanoma, choroidal simulated by, 448
PDT, 449:21.97 – 21.102
cavernous hemangioma, 404 – 405
clinical variations, 407:20.73 – 20.78, 408:20.79 – 20.84
CNS associated with familial, 411:20.97 – 20.102
cutaneous vascular anomalies with familial, 411:20.97 – 20.102
fluorescein angiography, 409:20.85 – 20.90
histopathology, 408:20.79 – 20.84
optic disc involvement in, 410:20.91 – 20.96
ultrasonography, 408:20.83
gliosis, pseudoneoplastic, 427, 429:21.1 – 21.6
hamartoma, astrocytic, 430 – 431
atypical variations, 440:21.49 – 21.54
calcified, 434:21.13 – 21.18, 435:21.19 – 21.24
clinical features of calcified, 435:21.19 – 21.24
clinical features of noncalcified, 433:21.7 – 21.12
fluorescein angiography, 437:21.31 – 21.36
FNABl, 443:21.67 – 21.72
noncalcified, 433:21.7 – 21.12
OCT, 438:21.37 – 21.42
pathologic features of calcified, 435:21.19 – 21.24

1570
 pathologic features of noncalcified, 433:21.7 – 21.12
TSC and, 439, 439:21.43 – 21.48, 441:21.55 – 21.60, 442:21.61 – 21.66
wide-angle imaging of, 436:21.25 – 21.30
hamartoma, combined, 474
branchio-oculo-facial syndrome, 479:22.79 – 22.84
extrapapillary type, 478:22.73 – 22.78
fluorescein angiography, 480:22.85 – 22.90
histopathology, 477:22.67 – 22.72
juxtapapillary type, 477:22.67 – 22.72
neurofibromatosis, 479:22.79 – 22.84
OCT, 481:22.91 – 22.96
wide-angle imaging, 479:22.79 – 22.84
hemangioblastoma, 389, 392:20.1 – 20.6
clinicopathologic correlation, 398:20.37 – 20.42
cryotherapy, 401:20.55 – 20.60, 402:20.61 – 20.66
enucleation, 398
exudative, 390, 392:20.2, 392:20.3, 392:20.6
fluorescein angiography, 389 – 390, 396:20.25 – 20.30
free-floating, 392:20.5
gliosis, pseudoneoplastic and, 427
laser photocoagulation, 400:20.49 – 20.54
Marshall–Stickler syndrome and, 389, 399:20.43 – 20.48
optic nerve, nodular, 394:20.13 – 20.18
optic nerve, sessile, 395:20.19 – 20.24
PDT, 390, 403:20.67 – 20.72
tractional, 390, 392:20.4, 392:20.6
VHL syndrome and, 389 – 390, 393:20.7 – 20.9, 397:20.31 – 20.36
wide-angle imaging, 393:20.7 – 20.12
hemorrhage, choroidal melanoma simulated by, 200:11.25 – 11.30
ischemia, peripheral, 474
lymphoid tumors in, 525
melanoma
choroid invasion of, 116:7.97 – 7.102, 117:7.103 – 7.108
racemose hemangioma, 389, 412
branch retinal vein obstruction and, 412, 417:20.121 – 20.126
clinical features, 414:20.103 – 20.108
fluorescein angiography, 412, 415:20.109 – 20.114, 416:20.115 – 20.120
MRI, 412
OCT, 412, 416:20.115 – 20.120
tumors
glial, 427 – 449
vascular, 389 – 426
vasoproliferative, 418
xanthoastrocytoma, pleomorphic, 444
Retinal arterial macroaneurysm with hemorrhage, 199:11.19 – 11.24
Retinal detachment
choroidal nevus and, 75:5.19 – 5.20
Coats disease, 376, 378

1571
 hamartoma, astrocytic and, 441
melanoma, posterior uveal and, 129
NPCE tumors and, 504
rhegmatogenous, uveal melanoma simulated by, 211:11.93 – 11.94
surgery for, 431
Retinal dragging, 478
Retinal metastasis, 244:12.169 – 12.174
Retinal nerve fiber
melanocytoma, optic disc and involvement in, 85:6.7 – 6.12
retinoblastoma simulated by extensive, 387:19.70
Retinal pigment epithelial hamartomas (RPEH)
FAP associated with, 464, 465:22.43 – 22.48
Gardner syndrome associated with, 464
Retinal pigment epithelium (RPE), 482. See also Congenital hypertrophy of retinal
pigment epithelium
choroidal nevus and detachment of, 75:5.21 – 5.22
CPE epithelioma and posterior extension of, 489:22.115 – 22.120
epithelioma, 490
in African-Americans, 493:22.127 – 22.132
aggressive variant of, 502:22.181 – 22.186
choroidal neovascular membrane, 496:22.145 – 22.150
CHRPE and, 499:22.163 – 22.168
fluorescein angiography, 490, 492:22.121 – 22.126
FNAB, 497:22.151 – 22.156
inflammatory scar and, 501:22.175 – 22.180
laser scar and, 500:22.169 – 22.174
melanocytoma simulated by, 494:22.133 – 22.138
melanoma simulated by, 495:22.139 – 22.144
plaque radiotherapy, 493
ultrasonography, 490, 492:22.121 – 22.126
hamartoma, combined, 474
extrapapillary type, 478:22.73 – 22.78
fluorescein angiography, 480:22.85 – 22.90
histopathology, 477:22.67 – 22.72
juxtapapillary type, 477:22.67 – 22.72
OCT, 481:22.91 – 22.96
wide-angle imaging, 479:22.79 – 22.84
hamartoma, congenital simple of, 470, 473:22.61 – 22.64
fluorescein angiography, 470
ultrasonography, 470
hyperplasia and migration of, simulating uveal melanoma with extraocular
extension, 469:22.55 – 22.60
reactive hyperplasia, pseudoneoplastic and, 466, 468:22.49 – 22.54
torpedo maculopathy, 472, 473:22.65 – 22.66
Retinal vascular obstruction, optic disc melanocytoma and central, 90:6.37 – 6.42
Retinitis pigmentosa. See Familial pigmentary dystrophy of retina
Retinoblastoma, 311 – 334
cavitary variant and clinicopathologic correlations, 347:17.13

1572
 chemothermotherapy, 360:18.43
CHRPE and, 462
Coats disease simulating, 373, 374, 376:19.1 – 19.6
advanced, 377:19.7 – 19.12
clinicopathologic correlation of, 378:19.13 – 19.18
coloboma, congenital retinochoroidal simulating, 387:19.71 – 19.72
congenital aggressive type, 325:15.67
congenital cataract simulating, 387:19.67
diffuse growth pattern, 321:15.43 – 15.48
endophthalmitis, endogenous simulating, 384:19.49 – 19.54
endophytic growth pattern, 320:15.37 – 15.42
exophytic growth pattern, 319:15.31 – 15.36
external beam radiotherapy, 354:18.7 – 18.12
familial exudative vitreoretinopathy simulating, 382:19.37 – 19.42
fluorescein angiography, 338:16.1
hamartoma, combined and, 474
high-risk pathology features, 348:17.19.
idiopathic intraocular abscess with calcification simulating, 385:19.55 – 19.60
incontinentia pigmenti simulating, 386:19.61 – 19.66
inflammation simulating, 373
international classification, 327:15.79 – 15.90
intravitreal chemotherapy, 367:18.85 – 18.90
laser photocoagulation and cryotherapy, 353:18.1 – 18.6
lesions simulating, 373 – 387, 374:19.1t
leukocoria, 314:15.1 – 15.6
massive extraocular extension, 324:15.61
medulloepithelioma, malignant teratoid, 509
neovascular glaucoma, 322:15.49
nonneoplastic conditions simulating, 373
ocular toxocariasis simulating, 383:19.43 – 19.48
older children, 326:15.73 – 15.78
orbital cellulitis, 323:15.55
pathology and microscopic features, 346:17.7 – 17.12
pathology, gross features, 345:17.1 – 17.6
PHPV simulating, 373, 380:19.25 – 19.30
plaque radiotherapy, 355:18.18, 356:18.19
prosthesis, 370:18.103 – 18.108, 371:18.109 – 18.114
retinal nerve fibers, extensive simulating, 387:19.70
retinochoroiditis, congenital toxoplasmic simulating, 387:19.69
spontaneously regressed, 331:15.103
13q deletion syndrome, 331:15.115
toxocariasis simulating, 373, 383:19.43 – 19.48
wide-angle fluorescein angiography, 339:16.7
wide-angle imaging of tumors, 316:15.13 – 15.18, 318:15.25 – 15.30.
Retinochoroiditis, retinoblastoma simulated by congenital toxoplasmic, 387:19.69
Retinopathy, retinoblastoma simulated by prematurity, 387:19.68
Retinoschisis
bullous, uveal melanoma simulated by, 211:11.95 – 11.96

1573
Revised European American Lymphoma Classification, 525
Rhabdomyosarcoma
ciliary body, 295:14.48
iris, 295:14.43 – 14.47
uveal, 290, 294
Ring chromosome 13, retinoblastoma associated with, 334:15.121 – 15.122
RPE. See Retinal pigment epithelium
RPEH. See Retinal pigment epithelial hamartomas

S
Sarcoidosis
BRLH, uveal and, 532:24.19 – 24.24
lung carcinoma metastasis simulating, 232:12.97 – 12.102
melanoma, choroidal simulated by, 206:11.61 – 11.66
Sarcomas
intraocular metastatic, 213
metastasis, uveal, 228:12.73 – 12.78
Schwannoma
choroidal, 296
choroidal melanotic, 299:14.55 – 14.60
uveal, 278, 298:14.49 – 14.54
enucleation, 302
fluorescein angiography, 296
FNAB, 296
melanoma, choroidal and, 298
plaque radiotherapy, 296
Sclera
iris nevus and involvement of, 20:2.18
melanocytosis, posterior uveal melanoma and, 129
melanocytosis and involvement of, 8:1.9 – 1.11, 11:1.28 – 1.30, 14:1.46
melanoma, ciliary body and, 101:7.7 – 7.12
staphyloma, uveal melanoma simulated by, 212:11.101 – 11.102
Scleritis, nodular posterior, 204:11.49 – 11.54
Sclerochoroidal calcification, uveal melanoma simulated by, 211:11.91 – 11.92
Sector oculodermal melanocytosis, melanoma and, 13:1.41 – 1.42
SEMP. See Solitary extramedullary plasmacytoma
Sentinel blood vessels, ciliary body melanoma and, 100:7.1 – 7.6
Slit lamp biomicroscopy, retinoblastoma, 335
Small cell carcinoma
lung, BDU MP and, 209
metastases, iris, 218:12.15 – 12.16
Solitary extramedullary plasmacytoma (SEMP), 542
Spindle A cells, iris melanoma and, 25
Spindle B cells, iris melanoma and, 25
Staphyloma, scleral, 212:11.101 – 11.102
Sturge–Weber syndrome, 527
Surgical procedures
hemorrhage, choroidal after, 202

1574
 retinal detachment, 431
tumors, intraocular, 555 – 576
Surgical resection, CPE epithelioma, 486
Synechia, 385:19.55
Systemic treatment, uveal melanoma, 157

T
Tapioca nevi, 16
TFSOM. See To Find Small Ocular Melanoma
Thermotherapy
epithelioma, RPE, 490
melanoma, uveal, 156
To Find Small Ocular Melanoma (TFSOM), 155
Torpedo maculopathy
CHRPE and, 453
OCT, 472
RPE, 472, 473:22.65 – 22.66
ultrasonography, 472
Toxocaria canis
toxocariasis caused by, 383
VPTOF from, 423:20.147 – 20.148
Toxocariasis, retinoblastoma simulated by, 373, 383:19.43 – 19.48
Transillumination
epithelioma
CPE, 486
RPE, 490
IPE, 482
melanoma, uveal, 139
Transmission of light, IPE cysts and
midzonal, 52
peripheral, 52
Transpupillary thermotherapy (TTT)
choroidal nevus, 70
melanoma
choroidal, 163:10.19 – 10.24, 164:10.25 – 10.30, 165:10.31 – 10.36,
166:10.37 – 10.42, 167:10.43 – 10.48, 176:10.97 – 10.102
uveal, 156
plaque radiotherapy combined with, 176:10.97 – 10.102
side effects, 167:10.43 – 10.48
Transretinal feeder vessel ligation, retinal hemangioblastoma, 389
Trauma, ocular
epithelioma, RPE and, 490
gliosis, pseudoneoplastic and, 427
reactive hyperplasia and, 466
TSC. See Tuberous sclerosis complex
TTT. See Transpupillary thermotherapy
Tuberculosis, choroidal melanoma
simulated by, 206:11.65 – 11.66

1575
Tuberous sclerosis complex (TSC), 430
astrocytoma, acquired retinal and, 444
hamartoma, astrocytic and, 439
retinal, 439:21.43 – 21.48, 441:21.55 – 21.60, 442:21.61 – 21.66
Tumor necrosis, optic disc melanocytoma, 89:6.31 – 6.36
Tumors. See also Specific tumors
acquired vasoproliferative, retinal, 389
choroidal, peripheral, partial lamellar cyclochoroidectomy, 567:25.61 – 25.66
glial
optic disc, 427 – 449
retinal, 427 – 449
intraocular
enucleation, 568:25.67 – 25.72
miscellaneous, 451 – 576
plaque radiotherapy, 560:25.19 – 25.24
surgical management of, 555 – 576
intraocular lymphoid, 525
iridociliary, partial lamellar iridocyclectomy, 566:25.55 – 25.60
iris
iridectomy, 565:25.49 – 25.54
plaque radiotherapy, 563:25.37 – 25.42
iris stroma, melanocytic, 15 – 42
NPCE, 503 – 524
fluorescein angiography, 504
ultrasonography, 504
optic disc
glial, 427 – 449
vascular, 389 – 426
pigment epithelium, 453 – 502
retinal
glial, 427 – 449
vascular, 389 – 426
vascular
optic disc, 389 – 426
retinal, 389 – 426
Turcot syndrome, 464

U
U BM. See U ltrasound biomicroscopy
U ltrasonography
astrocytoma, acquired retinal, 444
BRLH, 527
BRLH, uveal, 531:24.16, 533:24.25 – 24.30
choroidal nevus, 70
CHRPE, 454
epithelioma
CPE, 486
RPE, 490, 492:22.121 – 22.126

1576
 gliosis, pseudoneoplastic, 427
hamartoma
astrocytic, 431
RPE and congenital simple, 470
hemangioblastoma, retinal, 390
hemangioma
retinal cavernous, 408:20.83
leukemia, intraocular, 552
malignant teratoid medulloepithelioma, 508:23.7 – 23.12
melanoma
choroidal, 146:9.25 – 9.26, 146:9.29 – 9.30, 164:10.29 – 10.30
uveal, 140
NPCE
acquired epithelioma, 518
tumors, 504
plaque radiotherapy followed by, choroidal melanoma, 178:10.109 – 10.114
plasmacytoma, uveal, 542
RPE, 470
torpedo maculopathy, 472
VRL, 446
U ltrasound biomicroscopy (U BM)
epithelioma, IPE, 482
IPE cyst, peripheral, 55:4.18
iris nevus, 16
melanoma
ciliary body, 146:9.27 – 9.28
uveal, 140
NPCE, benign epithelioma, 523:23.73 – 23.78
U vea
fibrous histiocytoma, 306, 307:14.79 – 14.80
tumors
fibrous, 281 – 307
histiocytic, 281 – 307
osseous, 281 – 307
vascular, 247
U vea. See Bilateral diffuse uveal melanocytic proliferation
BRLH, 527, 529:24.1 – 24.6
choroiditis, birdshot and, 532:24.19 – 24.24
clinical features, 530:24.7 – 24.12
diagnostic studies, 531:24.13 – 24.18
EBRT, 531:24.18
fluorescein angiography, 531:24.15
fundus photography, 531:24.13 – 24.14
MRI, 531:24.17, 533:24.25 – 24.30
pathologic features, 530:24.7 – 24.12
sarcoidosis and, 532:24.19 – 24.24
treatment, 531:24.13 – 24.18
ultrasonography, 531:24.16, 533:24.25 – 24.30

1577
 wide-angle imaging, 533:24.25 – 24.30
effusion of, ciliochoroidal melanoma simulated by, 205:11.55 – 11.60
lesions, congenital, 3 – 14
lymphoma, 534 – 535
aggressive form, 539:24.43 – 24.48
bilateral, 534
chemotherapy, 535, 537:24.31 – 24.36
glaucoma, secondary to, 540:24.49 – 24.54
irradiation, 535
OCT, 538:24.37 – 24.42
ophthalmoscopy, 535
orbital involvement and aggressive, 541:24.55 – 24.60
plaque radiotherapy, 535
radiotherapy, 535, 537:24.31 – 24.36
unilateral, 534
melanocytoma, 81 – 94
diffuse, 82
melanocytosis, congenital ocular and, 6, 12:1.31 – 1.36
melanocytosis, ocular and, 11:1.25 – 1.30
melanocytosis, oculodermal and, 11:1.25 – 1.30
melanoma
BDU MP simulating, 210:11.85 – 11.90
bilateral, 12:1.33 – 1.36
cataract, subluxed mature simulating, 212:11.97 – 11.98
classification, 129
endophthalmitis simulated by, 191:10.187 – 10.192
enucleation, 189:10.175 – 10.180
fluorescein angiography, 139 – 140, 142:9.1 – 9.6
globe compression simulating, 212:11.99 – 11.100
histopathologic features of, 130:8.1t
miscellaneous conditions simulating posterior, 211:11.91 – 11.96, 212:11.97 –
11.102
multifocal, 12:1.31 – 1.32
nonneoplastic conditions simulating, 193 – 212
orbital exenteration, 189:10.175 – 10.180, 190:10.181 – 10.186
plaque radiotherapy, 172:10.73 – 10.78
posterior, 95 – 127, 96:7.1t, 191:10.187 – 10.192, 211:11.91 – 11.96
posterior, cell types, 135:8.19 – 8.24, 136:8.25 – 8.30
posterior, diagnostic approaches, 139 – 153
posterior, management of, 155 – 191
posterior, pathology of, 129 – 137
retinal detachment, rhegmatogenous simulating, 211:11.93 – 11.94
retinoschisis, bullous simulating, 211:11.95 – 11.96
RPE migration and hyperplasia, simulating, 469:22.55 – 22.60
sclerochoroidal calcification simulating, 211:11.91 – 11.92
staphyloma, scleral simulating, 212:11.101 – 11.102
non-Hodgkin large-cell lymphomas, 534
plasmacytoma, 542

1578
 chemotherapy, 542
fluorescein angiography, 542
FNAB, 542
irradiation, 542
ultrasonography, 542
posterior, melanocytoma, 81 – 94
posterior, melanoma, 95 – 127
American Joint Commission on Cancer (AJCC) classification, 97:7.4t – 98:7.6t
prognosis of, 97:7.3t
U veal hemangiopericytoma, 272, 273:13.109 – 13.114
U veal leiomyoma
clinical variations, 292:14.31 – 14.36
clinicopathologic correlation, 293:14.37 – 14.42
U veal neurofibroma, 301:14.61
U veal schwannoma (Neurilemoma), 298:14.49 – 14.54
U veal tract
hemangiopericytoma, 272
lymphoid tumors in, 525
U veal juvenile xanthogranuloma, 302
U veitis. See Bilateral intermediate uveitis

V
Varix, iris, 279:13.133 – 13.138
melanoma, iris simulated by, 279
Vascular endothelial growth factor (VEGF), retinal hemangioblastoma, 390
Vasoproliferative tumor
acquired, retinal, 418
retinal, 418
Vasoproliferative tumor of ocular fundus (VPTOF), 418
cryotherapy, 418, 425:20.157 – 20.162, 426:20.163 – 20.168
fluorescein angiography, 418
laser photocoagulation, 418, 425:20.157 – 20.162
PDT, 418, 426:20.163 – 20.168
plaque brachytherapy, 418
plaque radiotherapy, 425:20.157 – 20.162
primary type, 418
clinical features, 420:20.127 – 20.132
clinicopathologic correlation, 422:20.139 – 20.144
wide-angle imaging, 421:20.133 – 20.138
secondary, 418, 423:20.145 – 20.150
with neurofibromatosis type 1, 424:20.151 – 20.156
vitrectomy, 418
VEGF. See Vascular endothelial growth factor
VHL. See Von Hippel–Lindau syndrome
Visual acuity, retinal/RPE hamartoma, 474
Visual impairment, VPTOF and, 418
Visual loss. See also Blindness
ARMD-causing, 196

1579
 melanoma, choroidal, 124:7.145 – 7.150
optic disc melanocytoma
central retinal vascular obstruction and, 90:6.37 – 6.42
tumor necrosis and, 89:6.31 – 6.36
Vitreal metastasis, 244:12.169 – 12.174
Vitrectomy
hamartoma
astrocytic, 431
combined, 474
Vitrectomy hamartoma
VPTOF, 418
Vitreoretinal lymphoma (VRL), 546
chemotherapy, 547
CT, 546
fluorescein angiography, 546
FNAB, 546
MRI, 546
ocular radiation, 547
ophthalmoscopy, 546
primary, 549:24.73 – 24.78
FNAB, 551:24.85 – 24.90
management, 550:24.79 – 24.84
wide-angle imaging, 550:24.79 – 24.84
ultrasonography, 546
Vitreoretinal traction, retinal cavernous hemangioma and, 404
Vitreous cavity
lymphoid tumors in, 525
melanoma, choroid invasion of, 116:7.101 – 7.102
Von Hippel–Lindau syndrome (VHL), hemangioblastoma and, 389 – 390
retinal, 393:20.7 – 20.9, 397:20.31 – 20.36
Vortex vein varix, choroidal melanoma simulated by, 203:11.43 – 11.48
VPTOF. See Vasoproliferative tumor of ocular fundus
VRL. See Vitreoretinal lymphoma

W
Waardenburg syndrome, VPTOF and, 418
Wall biopsy, lymphoma and, 534
Wide-angle imaging
BRLH, uveal, 533:24.25 – 24.30
fluorescein angiography, retinoblastoma, 335, 339:16.7 – 16.12
hamartoma, combined retinal/RPE, 479:22.79 – 22.84
hemangioblastoma, retinal, 393:20.7 – 20.12
hemangioma, choroidal circumscribed, 252:13.7 – 13.12
melanoma, ciliary body, 104:7.25 – 7.30
retinoblastoma, 302, 339:16.7 – 16.12
large tumor, 318:15.25 – 15.30
medium-sized tumor, 317:15.19 – 15.24
small tumor, 316:15.13 – 15.18

1580
 spontaneously arrested, 330:15.101 – 15.102
spontaneously regressed, 330:15.97 – 15.98
VPTOF, primary type, 421:20.133 – 20.138
VRL, primary, 550:24.79 – 24.84
Wyburn–Mason syndrome, retinal racemose hemangiomas and, 412

X
Xanthoastrocytoma, retinal pleomorphic, 444
Xanthochoria, Coats disease, 377:19.7 – 19.8

Z
Zimmerman classification, NPCE tumor, 503

1581
目录
Title Page 3
Copyright 4
Dedication 6
Foreword 1 7
Foreword 2 9
Preface 10
Acknowledgments 12
Contents 14
PART 1 Tumors of the Uveal Tract 17
Chapter 1 Congenital Uveal Lesions 18
Intraocular Lacrimal Gland Choristoma 18
Congenital Ocular Melanocytosis 25
Chapter 2 Melanocytic Tumors of Iris Stroma 54
Iris Nevus 54
Iris Melanoma 79
Chapter 3 Conditions That Simulate Iris Melanoma 137
Conditions That Simulate Iris Melanoma 137
Chapter 4 Iris Cysts 156
Iris Cysts 156
Iris Stromal Cysts 183
Chapter 5 Choroidal Nevus 205
Choroidal Nevus 205
Chapter 6 Melanocytoma of the Optic Disc and Posterior Uvea 243
Melanocytoma of the Optic Disc and Posterior Uvea 243
Chapter 7 Posterior Uveal Melanoma: Clinical Features 291
Clinical Features of Posterior Uveal Melanoma 291
Chapter 8 Posterior Uveal Melanoma: Pathology 406
Pathology of Posterior Uveal Melanoma 406
Chapter 9 Posterior Uveal Melanoma: Diagnostic Approaches 430
Posterior Uveal Melanoma: Diagnostic Approaches 430

1582
 Chapter 10 Posterior Uveal Melanoma: Management 474
Posterior Uveal Melanoma: Management 474
Chapter 11 Nonneoplastic Conditions That Can Simulate Posterior
577
Uveal Melanoma and Other Intraocular Neoplasms
Nonneoplastic Conditions That Can Simulate Posterior Uveal
577
Melanoma and Other Intraocular Neoplasms
Chapter 12 Metastatic Tumors to the Uvea, Retina, and Optic Disc 631
Metastatic Tumors to the Intraocular Structures 631
Chapter 13 Vascular Tumors and Malformations of the Uvea 720
Circumscribed Choroidal Hemangioma 720
Diffuse Choroidal Hemangioma 760
Phakomatosis Pigmentovascularis 775
Uveal Hemangiopericytoma 778
Iris Vascular Tumors and Malformations 782
Chapter 14 Osseous, Myogenic, Neurogenic, Fibrous, and
797
Histiocytic Tumors of the Uvea
Choroidal Osteoma 797
Myogenic Tumors of the Uvea 819
Uveal Rhabdomyosarcoma 827
Uveal Schwannoma (Neurilemoma) 832
Uveal Neurofibroma 841
Uveal Juvenile Xanthogranuloma and Langerhans’ Cell
845
Histiocytosis
Fibrous Histiocytoma, Primitive Neuroectodermal Tumor,
855
and Other Histiocytic Tumors of the Uvea
PART 2 Tumors of the Retina and Optic Disc 858
Chapter 15 Retinoblastoma: Introduction, Genetics, Clinical
859
Features, Classification
Retinoblastoma: Introduction, Genetics, and Clinical
859
Features
Chapter 16 Retinoblastoma: Diagnostic Approaches 920
Retinoblastoma: Diagnostic Approaches 920
Chapter 17 Retinoblastoma: Pathology 935
Retinoblastoma: Pathology 935
Chapter 18 Management of Retinoblastoma 947

1583
 Management of Retinoblastoma 947
Chapter 19 Lesions That Can Simulate Retinoblastoma 1010
Lesions Simulating Retinoblastoma 1010
Chapter 20 Vascular Tumors of the Retina and Optic Disc 1048
Retinal Hemangioblastoma (Capillary Hemangioma) 1048
Retinal Cavernous Hemangioma 1084
Retinal Racemose Hemangioma 1102
Vasoproliferative Tumor of the Ocular Fundus 1115
Chapter 21 Glial Tumors of the Retina and Optic Disc 1137
Solitary Circumscribed Retinal Astrocytic Proliferation 1137
Retinal Astrocytic Hamartoma 1142
Acquired Retinal Astrocytoma 1173
PART 3 Tumors of the Pigment Epithelium,
1188
Nonpigmented Epithelium, and Lymphoma/Leukemia
Chapter 22 Tumors and Related Lesions of the Pigment Epithelium 1189
Solitary Congenital Hypertrophy of the Retinal Pigment
1189
Epithelium
Multifocal Congenital Hypertrophy of the Retinal Pigment
1212
Epithelium (Congenital Grouped Pigmentation; Bear Tracks)
Retinal Pigment Epithelial Hamartomas Associated with
1218
Familial Adenomatous Polyposis and Gardner Syndrome
Pseudoneoplastic Reactive Hyperplasia of the Retinal
1225
Pigment Epithelium
Congenital Simple Hamartoma of the Retinal Pigment
1233
Epithelium
Torpedo Maculopathy 1235
Combined Hamartoma of the Retina and Retinal Pigment
1240
Epithelium
Epithelioma (Adenoma) of the Iris Pigment Epithelium 1261
Epithelioma (Adenoma) of the Ciliary Body Pigment
1270
Epithelium
Epithelioma (Adenoma) of the Retinal Pigment Epithelium 1280
Chapter 23 Tumors of the Nonpigmented Ciliary Epithelium 1320
Congenital Neoplasms (Medulloepithelioma) 1320
Age-related Hyperplasia of the Nonpigmented Ciliary

1584
 Epithelium (Coronal Adenoma; Fuchs Adenoma)
Acquired Epithelioma of the Nonpigmented Ciliary Body
1356
Epithelium
Chapter 24 Intraocular Lymphoid Tumors and Leukemias 1376
Intraocular Lymphoid Tumors 1376
Benign Reactive Lymphoid Hyperplasia of the Uvea 1379
Uveal Lymphoma 1403
Uveal Plasmacytoma 1422
Primary Vitreoretinal and Central Nervous System
1431
Lymphoma
Intraocular Leukemia 1447
Chapter 25 Surgical Management of Intraocular Tumors 1457
Surgical Management of Intraocular Tumors 1457
Index 1537

1585