Basic Sciences Review for Medical Licensure

Developed at
The University of Oklahoma College of Medicine

Suitable Reviews for:

United States Medical Licensing Examination
(USMLE), Step 1
 Pathology
Fourth Edition

John H. Holliman

Springer Science+Business Media, LLC

John H. Holliman, M.D.
Department of Pathology
College of Medicine
Health Sciences Center
The University of Oklahoma
Oklahoma City, OK 73190
USA

Library of Congress Cataloging-in-Publication Data

Holliman, John H.
Pathology I John H. Holliman. - 4th ed.
p. cm. - (Oklahoma notes)
ISBN 978-0-387-94390-9 ISBN 978-1-4612-0813-6 (eBook)
DOI 10.1007/978-1-4612-0813-6
1. Pathology-Outlines, syllabi, etc. 1. Title. II. Series.
[DNLM: 1. Pathology-examination questions. 2. Pathology-
outlines. QZ 18.2 J739p 1995]
RB32.H65 1995
616.07 '076-dc20
DLC
for Library of Congress 94-47452
Printed on acid-free paper.

© 1995, 1992, 1988, and 1987 Springer Science+Business Media New York
Originally published by Springer-Verlag New York, Inc in 1995
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987654321
ISBN 978-0-387-94390-9
"The time has come," the Walrus said,
"To talk of many things:
Of shoes-and ships-and sealing wax-
Of cabbages-and kings-
And why the sea is boiling hot-
And whether pigs have wings."

- Lewis Carroll
 Preface to the
()~~

In 1973, the University of Oklahoma College of Medicine instituted a requirement

for passage ofthe Part 1 National Boards for promotion to the third year. To assist
students in preparation for this examination, a two-week review of the basic
sciences was added to the curriculum in 1975. Ten review texts were written by
the faculty: four in anatomical sciences and one each in the other six basic sci-
ences. Self-instructional quizzes were also developed by each discipline and ad-
ministered during the review period.
The first year the course was instituted the Total Score performance on National
Boards Part I increased 60 points, with the relative standing of the school chang-
ing from 56th to 9th in the nation. The performance of the class since then has
remained near the national candidate mean. This improvement in our own stu-
dents' performance has been documented (Hyde et al: Performance on NBME
Part I examination in relation to policies regarding use of test. J. Med. Educ. 60:
439-443, 1985).
A questionnaire was administered to one of the classes after they had completed
the Boards; 82% rated the review books as the most beneficial part of the course.
These texts were subsequently rewritten and made available for use by all stu-
dents of medicine who were preparing for comprehensive examinations in the
Basic Medical Sciences. Since their introduction in 1987, over 300,000 copies
have been sold. Obviously these texts have proven to be of value. The main reason
is that they present a concise overview of each discipline, emphasizing the content
and concepts most appropriate to the task at hand, i.e., passage of a comprehen-
sive examination covering the Basic Medical Sciences.
The recent changes in the licensure examination that have been made to create a
Step l/Step 2/Step 3 process have necessitiated a complete revision of the Okla-
homa Notes. This task was begun in the summer of 1991 and has been on-going
over the past 3 years. The book you are now holding is a product of that revision.
Besides bringing each book up to date, the authors have made every effort to make
the tests and review questions conform to the new format of the National Board
of Medical Examiners. Thus we have added numerous clinical vignettes and ex-
tended match questions. A major revision in the review of the Anatomical Sci-
ences has also been introduced. We have distilled the previous editions' content to
the details the authors believe to be of greatest importance and have combined the
four texts into a single volume. In addition a book about neurosciences has been
added to reflect the emphasis this interdisciplinary field is now receiving.
I hope you will find these review books valuable in your .preparation for the
licensure exams. Good Luck!

Richard M. Hyde, Ph.D.

Executive Editor
 Preface

These notes were developed as a synopsis of general and systemic pathology in

order to present to those students who are preparing for national examinations a
relatively concise review of the discipline. These notes are not intended to replace
the many fine textbooks of pathology whose scope, detail, and mission are more
suited to the in depth study of pathology. Rather, these notes are intended to serve
as "memory joggers" to rekindle and refresh the recall of salient features of various
disease processes and to point out to the students possible areas of weakness
which they may need to address in more detail by referring to one of the standard
textbooks of pathology.

Hopefully, the notes will allow a systematic review of the material in a reasonable
amount of time. Some major topics in Pathology (genetic diseases, immunologic
disorders, and infectious diseases) are covered in other areas of our curriculum
and are therefore only touched upon briefly in these notes. You may wish to refer
to other titles in the Oklahoma Notes series for more detailed discussions of these
areas.

The first portion of the notes reviews some of the basic principles and patterns of
disease. The remainder of the notes reviews disorders that result when these
principles and patterns are applied to individual organs or tissues. There are two
self assessment exams at the end of the notes containing questions that have
previously been used on local exams and, although I have tried to filter them out;
may contain wording that is not presented in the notes. If so, please refer to your
standard pathology textbooks.

Most "disease" results from deviation of normal cell/tissue structure and function.
A thorough understanding of what can induce these changes, how these changes
evolve to produce signs and symptoms, and how you may be able to intervene in
this process will enable you to take better care of your patients. And that's why
we're here, isn't it?

I would like to acknowledge the faculty of the Department of Pathology whose

ideas and suggestions have helped me compile this edition and to give a special
thanks to my chairman, Fred G. Silva, M.D., for giving me the opportunity and
time to complete this project. Lastly, thanks to my wife, Claudia, for her unflag-
ging support and patience.

J.H.H.
 Contents

Preface to the Oklahoma Notes vii

Preface ix

General Pathology
Principles of Cell/Tissue Injury........................... ...... .............. ...... ................ 1
Principles of Fluid Balance and Hemodynamics ......................................... 13
Principles of Host Defense ................................................ .......... ........ .......... 20
Principles of Infectious Disease ............ .......... .................... ................ .......... 31
Principles of Wound Healing and Tissue Repair .......................................... 34
Principles of Neoplasia .................................................................................. 38

Systemic Pathology
Cardiovascular System .................................................................................. 47
Congestive Heart Failure ........................................................................... 47
Congenital Heart Disorders ....................................................................... 48
Arteriosclerosis .......................................................................................... 51
Ischemic Heart Disease/Coronary Heart Disease ...................... ............... 56
Valvular Heart Disease ............................................................................... 61
Myocardial Heart Disease .......................................................................... 65
Pericardial Heart Disease .......................................................................... 68
Cardiac Neoplasms .................................................................................... 69
Vascular Disease ........................................................................................ 69
Respiratory Tract ........................................ ................................................... 76
Upper Respiratory Tract ............................................................................ 77
Developmental Anomalies ......................................................................... 78
Atelectasis .................................................................................................. 78
Respiratory Distress of the Newborn ........................................................ 79
Circulatory Disorders ................................................................................. 79
InflammatorylInfectious Disorders ................................ ........................... 81
Chronic Obstructive Pulmonary Disease ................ ................ .................. 85
Restrictive Lung Disease ............................................................................ 88
Respiratory Tract Neoplasia ...................................................................... 90
Pleura and Pleural Cavity.......................................................................... 91
HematopoieticlLymphoreticular Systems ..................................................... 93
Basic Laboratory Hematology ................ ............ ....................................... 93
Hemostasis ................................................................................................. 96
Coagulation Disorders .................................................... ~.......................... 98
Anemia ....................................................................................................... 102
Acute Leukemia ......................................................................................... 105
Myelodysplastic Syndromes ...................................................................... 107
xii Contents

Myeloproliferative Disorders ............................ ......................................... 108

Lymphoproliferative Disorders ................................................................. 109
Immunosecretory Disorders ...................................................................... 109
Malignant Lymphomas ................................. ............................................. 111
Histiocytoses .............................................................................................. 115
Thymic Disorders ........................ ............................................................... 116
Endocrine System .......................................................................................... 118
General Principles ...................................................................................... 118
Pituitary ...................................................................................................... 118
Thyroid ................................................... .................................................... 122
Parathyroid ................................................................................................. 128
Adrenal Cortex ........................................................................................... 129
Diffuse Endocrine System ......................................................................... 133
Breast 138
Inflammatory Disease ................................................................................ 139
Fibrocystic Change .................................................................................... 139
Benign and Borderline Neoplasia .............................................................. 140
Malignant Neoplasia .................................................................................. 141
Genital Tract .................................................................................................. 145
Developmental Disorders ........................................................................... 146
Sexually TransmittedlInfectious Diseases ................................................. 146a
Vulva/Vagina .............................................................................................. 147
Penis ........................................................................................................... 148
Cervix ......................................................................................................... 149
Uterus ......................................................................................................... 152
Fallopian Tubes .......................................................................................... 155
Ovary .......................................................................................................... 156
Testis .......................................................................................................... 161
Prostate ....................................................................................................... 163
Placental Disorders .................................................................................... 165
Urinary Tract ................................................................................................. 167
CongenitallDevelopmental Disorders ........................................................ 168
Glomerular Disease ....................................... ............................................. 169
Pyelonephritis ............................................................................................ 172
Hypertension .............................................................................................. 172
Acute Renal Failure ................................................................................... 173
Chronic Renal Failure ................................................................................ 174
Renal Neoplasms ........................................................................................ 174
Renal Manifestations of Systemic Disease ................................................ 175
Urinary Bladder ......................................................................................... 176
Head and Neck ............................................................................................... 178
Oral CongenitallDevelopmental Disorders ................................................ 178
Oral Cysts ........................................................................ ........................... 179
Oral Infectious/Inflammatory Disorders ................................................... 180
Oral Trauma ............................................................................................... 181
Oral Manifestations of Dermatologic Disease ........................................... 182
Oral Neoplasia ............................................................................................ 182
Salivary Glands .................... ................... ....... ............................... ............. 184
Gastrointestinal Tract .................................................................................... 185
Esophagus .............................................. ........ ............................... ............. 185
Stomach ............... ........ ........................... .................. ................ ... ............... 188
Small Bowel/Colon/Rectum .... ........ ..... .................. .................................... 192
 Contents xiii

Liver, Biliary Tract and Exocrine Pancreas .................................................. 203

Bilirubin Metabolism/Jaundice .................................................................. 203
Drug Induced Disease ..... ....... ...................................... .............................. 206
Circulatory Disorders .. ............ ................................................ ................... 207
Portal Hypertension ............... ..... ..... .......................................................... 208
Inflammatory Disease ................................................................................ 209
Cirrhosis ..................................................................................................... 213
Hepatic Neoplasia ...................................................................................... 216
Reye's Syndrome ........................................................................................ 217
Hepatic Failure ........................................................................................... 218
Gallbladder and Biliary Tract .................................................................... 219
Exocrine Pancreas 222
Skin 224
Eczema and Acute Non-Infectious Inflammatory Dermatoses ................ 224
Infectious Inflammatory Disorders ........................................................... 227
Papulosquamous Disease ........................................................................... 230
Vesiculobullous Disease ............................................................................. 231
Non-Neoplastic Disorders of Skin Appendages ........................................ 233
Drug Eruptions .... ...... ........... ........ ....... ................ ....................................... 234
Connective Tissue (autoimmune) Disorders ............................................. 235
Epithelial Tumors and Tumor-Like Conditions ........................................ 236
Dermal Tumors and Tumor-Like Conditions ............................................ 238
Melanocytic Tumors and Tumor-Like Conditions .................................... 240
Lymphomas and Pseudolymphomas .................. ................ ..... .................. 241
Bone and Joint ................................................................................................ 243
Congenital Disorders ............... ......... ..... ............ ..... ........... ........................ 243
Metabolic Bone Disorders ......................................................................... 243
Bone Neoplasia 244
Joint Disorders 245
Neuromuscular System ................................................................................. 246
Cellular Components and Reaction to Injury......................... ................... 246
Malformations of the Central Nervous System ......................................... 248
Nonspecific CNS Reaction to Injury .............................. ........................... 250
Traumatic Injury ........................................................................................ 251
Vascular Disease ........................................................................................ 252
Infectious Disease 254
Dementia and Degenerative Disease ......................................................... 257
Demyelinating Disease ............................................................................... 258
Nutritional and Toxic Disease ..................................... .............................. 259
Metabolic Disease 259
Neoplastic Disease ....................................................... .............................. 260
Skeletal Muscle . ...... ................................................................................... 265
Self Assessment Exam A 266
Self Assessment Exam B 273
 PRINCIPLES OF CELL/TISSUE INJURY

STEADY STATES

The viability of a cell is dependent on its ability to produce energy, to manufacture essential proteins, to maintain
its structural integrity and, in most cases, to replicate. Interference with any of these functions can affect the entire
cell and may be reflected by structural, biochemical, or molecular changes within the cell which may ultimately be
expressed as clinical signs and symptoms of "disease". "Health", therefore, depends on the ability of cells to
maintain structural and functional stability (a steady state) in the face of a constantly changing microenvironment,
a process termed homeostasis.

ALTERED STEADY STATES

Substantial alteration of the cellular microenvironment, whether due to normal (physiologic) processes or to
abnormal (pathologic) processes, may produce an "altered" steady state. The degree of "alteration" is dependent
on the type, intensity, and duration of the environmental change and the innate ability of that particular celito
withstand change. In general, those cells that are highly specialized are more susceptible to injury than are lesser
specialized cells. Depending on these factors, the cell (or the tissue composed of these cells) may be acutely but
reversibly altered (degenerations), chronically but reversibly altered (adaptations), or simply irreversibly altered
(cell death).

MORPHOLOGIC RESPONSES TO ALTERED STEADY STATES

I. "DEGENERATION" - An acute injury or change in the microenvironment, if not severe enough to result
in cell death, may transiently but reversibly alter cellular morphology and/or function. Whether due to
interference with normal control mechanisms or interruption of metabolic pathways, acute reversible
injuries (degenerations) are often manifested by excessive accumulation of various substances within the
cell cytoplasm.. Although intracellular accumulations do not always indicate preceding cell injury, they can
nevertheless (depending on the nature and extent of the accumulations) interfere with the normal
functioning of the cell. Accumulated substances may include:

A. WATER - Cellular swelling is the first morphologic change to occur after injuries that interfere with
cell membrane permeability and the regulation of intracellular fluid volume and ionic
concentrations. Due to the increased water, the cell appears enlarged with a pale cytoplasm but a
nonnally positlOned nucleus. Hydropic change (vacuolar degeneration) is an exaggerated state of
 cellular swelling where segments of swollen distended endoplasmic reticulum appear in the
cytoplasm as clear vacuoles and may displace the nucleus to the periphery of the cell. Concomitant
compression of the microvasculature by the enlarged swollen cells may also contribute to further
cell injury.
B. LIPIDS - Fatty change refers to an absolute increase in lipids within parenchymal cells (most often
seen in the liver and heart). With any interruption of normal cellular lipid uptake, synthesis,
metabolism or excretion, clear lipid vacuoles appear in the cytoplasm. As the vacuoles coalesce
or enlarge, they displace the nucleus to the periphery of the cell. To distinguish fat vacuoles from
water vacuoles, their lipid nature can be confirmed with special stains for fat (Sudan Black, Oil
Red 0). Intracellular accumulation of lipids may simply represent non-specific injury to the cell,
but it also occurs in specific disease states such as atherosclerosis, lipid storage diseases, alcoholic
liver disease, etc. Fatty ingrowth is a separate, usually asymptomatic, process in which lipids
accumulate within stromal connective tissue cells that lie between parenchymal cells (most
frequently seen in the pancreas and heart).
C. GLYCOGEN - Glycogen infiltration involves an increase in intracellular glycogen due to abnormal
glucose or glycogen metabolism. Glycogen is also stored as clear vacuoles in the cytoplasm
(hepatocytes tend to accumulate glycogen in a perinuclear indentation that gives the appearance
of nuclear vacuoles) and can be distinguished from water and lipids by the use of special stains
(P AS, etc.). It also occurs in hyperglycemic states, glycogen storage diseases, etc.
D. PROTEINS - Accumulations of protein appear as homogeneous, glassy, pink-staining hyaline
(hyaline degeneration). The term "hyaline" only refers to the histologic appearance of the
protein and not to its specific chemical composition. Intracellular hyaline may be seen as small
granules in the cytoplasm of the renal proximal tubule epithelium indicating proteinuria; as Ru.ssell
bodies in plasma cells indicating increased immunoglobulin synthesis; as inclu.sion bodies in a
variety of cells indicating viral infection, and as Mallory bodies (altered prekeratin intennediate
filaments) in liver cells indicating alcohol damage. Hyaline may also be deposited extracellularly -
in the connective tissue of old scars, in arteriolar walls in patients with hypertension, along the
alveolar septal walls (hyaline membranes) in patients with Respiratory Distress Syndromes, in
various neoplasms, etc.
E. PIGMENTS - Endogenous or exogenous pigments may accumulate within cells because of increased
synthesis, impaired excretion, phagocytosis, etc. The presence of intracellular pigment mayor may
not in itselfbe injurious, but excessive accumulation of exogenous pigments (carbon, iron, silica,
ink, etc) may reflect environmental contamination, and excessive accumulation of endogenous
pigments may reflect an underlying disease or metabolic disorder. Common endogenous pigments
include:

1. LIPOFUSCIN (LIPOCHROME) - This finely granular yellow-brown, "wear and tear" pigment
indicates chronic free radical injury (lipid peroxidation) of cell membranes. It frequently
becomes more apparent with the aging of a cell and tends to be deposited in perinuclear
cytoplasmic lysosomes. Although it does not appear to interfere with cell function, when
extensive it may impart a brown discoloration to the tissue ("brown atrophy" of the heart
and liver).
2. MELANIN - This is a brown-black pigment that is produced by melanocytes and in a
somewhat different form in specific areas of the brain (neuromelanin). Cells containing
large amounts of melanin are usually an indication of some disorder of melanocytes.
3. HEMOSIDERIN - This is a granular gold-brown iron-bearing (ferric ion) pigment derived
from the breakdown of hemoglobin. Hemosiderin-laden cells (usually macro phages) are
frequently found around areas of hemorrhage or chronic congestion, but hemosiderin may
also be found in a variety of parenchymal cells in systemic disorders such as hemosiderosis

2
 and the more severe hemochromatosis which is one of the most common inherited
(autosomal recessive - linked to the HLA region of chromosome 6) metabolic
abnormalities.
4. BILIRUBIN - This is a green-brown pigment that is also a breakdown product of
hemoglobin (porphyrin rings) but, unlike hemosiderin, does not contain iron. It is the major
pigment of bile, and can accumulate in fluid and tissue whenever there is a disturbance in
bile metabolism or excretion.

II. ADAPTATION - Repeated sublethal injury or a chronic alteration in the cellular microenvironment may
chronically but reversibly alter cellular morphology and/or function (adaptation). Adaptive changes
frequently involve processes governed by those genes that mediate cell growth and differentiation (proto-
oncogenes) and, at a biochemical level, there are numerous strategies (use of alternate biochemical
pathways, induction of new metabolic products, alteration of cellular receptors, etc.) that enable cells to
adjust to an altered environment. Some of these adaptive responses are reflected by morphologic changes
at the gross and/or light microscopic level. Unless the environmental alterations are extreme, these coping
mechanisms may allow the tissues to maintain viability for extended periods of time. Like many other
biologic processes, however, in some instances "adaptive" responses may ultimately prove to be
destructive.

A. ATROPHY - This is a decrease in the size (or in some instances the number) of individual cells that
had previously been of normal size. Like many adaptive responses, this can result from either
normal (physiologic) or abnormal (pathologic) changes in the cellular environment. Pathologic
atrophy results from a variety of conditions that restrict either oxygenation, nutrition, or stimulation
(neural or endocrine) of the cell. Cellular organelles (mitochondria, endoplasmic reticulum, etc.)
are decreased in number due to either increased catabolism (as illustrated by increased numbers
of autophagic vacuoles and residual bodies) or decreased synthesis of cell constituents. Grossly,
atrophic tissue is smaller than normal. (Hypoplasia refers to an organ or tissue that never reached
full size and is a developmental disorder rather than an adaptive response.)
B. HYPERTROPHY - This is an increase in the size of individual cells in response to an increased
functional demand. Generally, this involves an increase in structural components of those cells that
are not commonly considered capable of mitotic division (striated muscle cells) when they must
work against increased resistance. These cells only have a limited capacity to enlarge, however, and
progressive or persistently increased resistance will ultimately result in cell failure. Grossly,
hypertrophic tissue is larger and heavier than normal.
C. HYPERPLASIA - This is an increase in the number of cells usually in response to increased hormonal
or growth factor stimulation. Since hyperplasia and hypertrophy are both designed to increase the
functional capabilities of a tissue, both may occur concurrently in some instances (the gravid
uterus), and since hyperplasia necessitates increased mitotic division, it is not surprising that
hyperplasia and neoplasia may sometimes be closely associated. Grossly, hyperplastic tissue is
increased in volume.
D. METAPLASIA - This is a substitution of one mature cell type for another mature cell type. In most
instances, metaplasia is a process in which a new harsher environment induces a change to a more
protective tissue type. On the negative side however, the normal function of the original tissue is
lost and in some instances, persistence of the adverse environment may ultimately induce non-
adaptive dysplastic or neoplastic transformation of the metaplastic tissue.
E. DYSPLASIA - This is an atypical (but still potentially reversible) growth of cells that is usually
induced by chronic irritation or stimulation. Varying degrees of cytologic and nuclear atypia are
present including alteration in the shape and size of the cell and/or nucleus, loss of cell orientation,

3
 and increased mitoses. Similar, but more exaggerated, changes (anaplasia) are observed in
malignant cells and, indeed, dysplasia is generally regarded as a potential precursor to cancer.
F. NEOPLASIA - This is a permanent abnormal growth of cells which exceeds and is uncoordinated
with the growth of normal cells and which represents a destructi ve form of adaptation. Unlike the
preceding adaptive changes, neoplasia is irreversible.

III. CELL DEATH - Cell death occurs when the altered steady state induces sufficient biochemical
disturbances to cause permanent, irreparable damage to the cell. The line between reversibly and
irreversibly injured cells, however, may at times be quite indistinct. The morphologic changes caused by
the deterioration of an irreversibly injured cell in living tissue is termed necrosis. Necrosis is the result of
cellular changes brought about by either endogenous degradative enzymes liberated from disintegrating
cellular lysosomes (autolysis) or exogenous degradative enzymes released from invading leukocy1es
(heterolysis)' Depending on environmental conditions and the type of cell involved, there is a variable time
lag between the moment of biochemical cell death and the time the morphologic changes of necrosis begin
to appear. Therefore, it could be said that all necrotic cells are dead, but not all dead cells are necrotic.

A MORPHOLOGIC INDICATIONS OF NECROSIS

I. EOSINOPHILIA OF THE CYTOPLASM - This is due in part to loss of the normal cytoplasmic
basophilia and results from the disaggregation of polysomes and denaturation of
cytoplasmic proteins.
2. DENSE CONDENSATION OF THE NUCLEAR CHROMATIN (pyknosis) - This is followed by
either fragmentation (karyorrhexis), dissolution (karyolysis), or extrusion from the cell.
Although it is irreparable damage to the cell membrane that actually spells doom for the
cell, these Iluclear challges are the dtifillitive morphologic evidellce of irreversible illjury
ami cell death.

B. PATTERNS OF NECROSIS - The pattern in which necrotic changes progress within a tissue depends
in part on the type of injury, the tissue involved, and the environment surrounding the dying cell(s).
Identification of these different morphologic patterns of necrosis can give some clue as to the
etiology of the insult.

I. COAGULATION NECROSIS - This is the most common pattern of necrosis, is due to

inadequate oxygenation of cells, and is generally the result of a reduction in blood flow
(ischemia) to the tissue. Although nuclear material disappears, denaturation of the
endogenous degradative enzymes prevents cellular digestion. This allows preservation of
faded, "ghost-like" cellular outlines and underlying tissue architecture. Eventually, the dead
cells are removed by the action of exogenous proteolytic enzymes and phagocytic
"scavengers", and the tissue is replaced either by regeneration of new tissue or, more likely,
by scar.
2. LIQUEFACTION NECROSIS - This pattern results when proteolytic digestion of dead cells
(either by endogenous or exogenous catalytic enzymes) is not delayed by enzyme
denaturation. This is characteristic of tissues injured by bacterial infections which attract
large numbers of neutrophils (creating an abscess) and ischemic destruction of brain tissue.
3. GANGRENOUS NECROSIS - This refers to ischemic coagulation necrosis which may
subsequently desiccate and mummifY (dry gangrene) or which may develop a secondary
saprophytic infection (often by anaerobic bacteria) and subsequent liquefaction of the
necrotic tissue by neutrophilic enzymes (wet gangrene). This frequently occurs in the skin
and subcutaneous tissues of the lower extremities as a common complication of the

4
 peripheral vascular disease associated with uncontrolled diabetes mellitus, but it can also
occur in the appendix, bowel, gallbladder, etc.
4. CASEOUS NECROSIS - This is a form of necrosis in which the preservation of the underlying
tissue outlines is lost and replaced by a granular, amorphous, acellular substance which on
gross examination resembles cottage cheese. It is encountered principally in infectious
diseases involving mycobacteria and fungi and may be seen in association with a
specialized form of chronic inflammation known as granulomatous inflammation.
5. FAT NECROSIS

a. Enzymatic fat necrosis - This is produced by lipolytic activity on fat cells. It is

seen when pancreatic lipases are released into abdominal fatty tissues (usually
during the course of pancreatitis). The lipases convert triglycerides to free fatty
acids which complex with calcium to form calcium soaps. Grossly this produces
white chalky deposits in fatty tissue.
b. Traumatic fat necrosis - This is produced by traumatic rupture of fat cells with
subsequent phagocytosis of the lipid material by macro phages. Seen most
frequently in female breast tissue, traumatic fat necrosis histologically does not
have the enzymatically "digested" appearance seen with enzymatic fat necrosis.

6. FIBRINOID NECROSIS - This is characteristically associated with immune complex

formation and refers to smudgy, amorphous, eosinophilic material (consisting of
immunoglobulins, fibrinogen, and complement) usually deposited in or around the walls
of small blood vessels. Although not usually grossly apparent, the histologic appearance
resembles fibrin deposits - hence the term fibrinoid (fibrin-like).
7. APOPTOSIS - This refers to a distinctive form of cell death which usually involves
individual cells or small groups of cells. It is felt to be due to sudden. extensive
endonuclease mediated DNA damage which may represent "pre-programmed" cell death
or, in some instances, a pathologic destruction initiated by T -killer lymphocytes or
chemical mediators (TNF-a). The nuclear chromatin condenses and then disperses into
a condensed cytoplasm which becomes progressively eosinophilic. The entire cell may then
fragment and be subsequently phagocytized.

C. CALCIFICATION

I. DYSTROPHIC CALCIFICATION - This refers to the deposition of calcium salts, often in

necrotic tissue, in the face of normal serum calcium levels. Within dying cells, calcium
accumulates in the irreparably damaged mitochondria but extracellular calcium deposits
also develop utilizing membrane bound vesicles as a nidus for propagation. Histologically,
calcium may appear as small concentrically laminated spheres (psammoma bodies) or as
variably sized amorphous basophilic deposits.
2. METASTATIC CALCIFICATION - This refers to the deposition of calcium in normal tissues
of patients with high serum calcium levels. The histologic appearance is similar to
dystrophic calcification but the distribution is generally more widespread.

5
 MAJOR MECHANISMS OF CELLITISSUE INJURY

As previously mentioned, the "health" of a cell is dependent upon production of energy, synthesis of essential
proteins, maintenance of structural integrity, and ability to replicate. Any process interfering with these functions,
therefore, is potentially injurious to the cell.

I. METABOLIC INJURY

A. HYPOXIA/ANOXIA - Whether due to poor O2 saturation of the blood (hypoxemia) or insufficient

vascular supply (ischemia), oxygen deficiency (hypoxia) interferes with mitochondrial oxidative
phosphorylation and the production of ATP. In general, those cells that have high metabolic activity
are most sensitive to the effects ofhypoxiaJanoxia. To maintain energy production, the anaerobic
glycolytic pathway is triggered which reduces cellular glycogen and increases cellular lactic acid.
The resulting drop in pH causes clumping of the nuclear chromatin (which may ultimately lead to
nuclear pyknosis). The loss of ATP interferes with the energy-dependent sodium pump in the
plasma membrane, and the resulting influx of sodium, calcium, and water causes cellular swelling.
Additionally, the buildup of lactate, inorganic phosphates, etc creates an increased intracellular
osmotic pressure which also contributes to the swelling. The porous cell membranes also allow
c~10plasmic enzymes to leak into the extracellular space and circulation (where their identification
by laboratory tests may help in diagnosis). Ultrastructurally, cytoskeletal damage may be apparent.
"Blebs" may develop indicating damage to the plasma membrane, and the appearance of "myelin
figures" indicate cell and organelle membrane damage. The endoplasmic reticulum dilates due to
the accumulation of water, ribosomes become detached from the rough endoplasmic reticulum,
and polysomes dis aggregate thereby interfering with protein production. At this point, although the
exact biochemical mechanisms are unknown, if oxygen deprivation continues, the cell becomes
irreversibly injured. Initially, mitochondria condense but at this point begin to develop amorphous
densities consisting of precipitated lipids, proteins and calcium. The increase in cytoplasmic
calcium may activate the endogenous calcium-dependent phospholipases which then begin to break
down the cell membranes (leading to further permeability changes that result in additional calcium
influx from the extracellular space and perpetuation of the membrane damage). Synthesis of
replacement phospholipids is hampered by the lack of ATP production in the injured mitochondria
which now show internal vacuolization. Other mechanisms (breakdown of the cytoskeleton, free
radical formation, accumulation of catabolic products, etc) may also contribute to additional
plasma and/or organelle membrane damage. Ultimately, the lysosomal membranes become porous
releasing degradative enzymes into the cytoplasm, and cellular digestion occurs.
B. FREE RADICAL FORMATION - Free radicals are extremely unstable and reactive chemicals which
are able to provoke inappropriate disulfide bonding of proteins, peroxidation of lipids, and damage
to DNA. Partial reduction of oxygen to create superoxides (02), hydroxyl ions (OH), and hydrogen
peroxide (H20 2) is an important (but not the only) source of free radicals within the cell. Free
radicals can also be created by ionizing radiation, metabolism of drugs, or as bypro ducts of normal
metabolism. They are inactivated by spontaneous decay, by naturally occurring antioxidants
(superoxide dismutase, Vit. E, etc), or by interaction with specific enzymes. However, in reacting
with other substances (especially in peroxidation of lipids), additional free radicals may be formed
which can initiate a chain of autocatalytic events leading to irreversible cell injury.

6
II. PHYSICAL INJURY

A. RADIATION - The type of radiation, dosage, mode of delivery, and the oxygenation of the tissues
all influence the effect of radiation.

1. IONIZING RADIATION - High levels of ionizing radiation will produce acute cell death,
while low levels may produce genetic mutations or loss of reproductive ability without
causing overt cell death. Ionizing radiation causes cellular injury by the transfer of radiant
energy which may, through radiolysis of intracellular water, induce the formation offree
radicals (esp. hydroxyl ions). It also disrupts molecular bonding in DNA that can result in
single or double stranded breaks. This may lead to mutations, inhibit cell division, or alter
the ability to divide or to maintain normal homeostasis by interfering with the regulation
and/or structure of the protein products of the genes. It is not surprising that morphologic
alterations of the nucleus (giant cells, bizarre pleomorphism, etc) may become apparent
by light microscopy and mimic changes seen in neoplastic cells. Indeed, radiation may
actually induce certain neoplasms. Tissues vary in their sensitivity to ionizing radiation. In
general, cells with a low natural turnover rate are most radioresistant while those with a
high natural turnover are most radiosensitive.

a. Local effects

(1) Cellular changes - Depending on the tissues involved, acute radiation

injury may be manifested as an acute dermatitis, pneumonitis, enteritis,
etc. Chronic complications include development of neoplasms (primarily
sarcomas) even after an interval often years or more.
(2) Vascular changes - Striking changes may also be observed in the
vasculature of irradiated tissue. Acutely, the vessels may dilate,
thrombose, or rupture. Over time, however, reactive endothelial cell
proliferation and mural scarring may lead to narrowing or even
obliteration of the vessel lumens causing tissue ischemia. The chronic
effects of radiation injury, therefore, might include interstitial fibrosis of
various tissues, strictures of hollow organs, etc.

b. Systemic effects (whole body radiation syndromes)

(1) Hematopoietic syndrome (200-500 rads) - Radiation injury to

hematopoietic precursors results in development of a pancytopenia within
a few weeks of exposure. Bleeding and infection are the major
complications.
(2) GI syndrome (500-1000 rads) - Destruction of the gastrointestinal
epithelium results in the development of nausea, vomiting, and severe
diarrhea within several days of exposure. This may lead to severe
metabolic disturbances, vascular collapse, sepsis, and death.
(3) Cerebral syndrome (>2500 rads) - Vascular endothelial damage results
in cerebral edema, convulsions, coma, and death within hours of
exposure.

7
 2. NON-IONIZING RADIATION

a. Ultraviolet rays - These penetrate the skin only superficially and induce injury
after a latent period of several hours (sunburn). Systemic symptoms include fever,
headache, nausea, vomiting. Repeated exposure causes progressive pigmentation
and skin thickening and increases the risk of developing various cutaneous
malignancies.
b. Infrared rays - These can produce heat and, in overdoses, may cause thermal
bums, edema, and vesiculation of the skin.
c. Microwaves - These can also release energy in the form of heat.

B. TEMPERATURE - Cell injury and/or cell death result if tissue is maintained at a temperature greater
than 15°C below or more than 5°C above normal body temperature. The severity of injury is
related to the duration of the exposure.

1. HYPOTHERMIA

a. Localized hypothermia - Cooling of tissue damages vascular endothelium and

increases vascular permeability leading to edema and blister formation. Prolonged
cooling may also cause extensive ischemic injury due to poor blood perfusion of
surrounding tissue. In addition to the vascular damage, freezing of tissue interferes
with ionic concentrations due to crystallization of intracellular water, denatures
proteins, and physically disrupts cell membranes leading to cell death (frostbite).
In frozen tissue, the effects of the vascular damage may not appear until the tissue
is reperfused as it thaws.
b. Systemic hypothermia - If compensatory mechanisms (increased BMR,
shivering, etc) are overwhelmed, continued dissipation of internal core heat leads
to metabolic depression, mental confusion, lethargy, and coma. Vascular collapse
and cardiac arrhythmias are major causes of death.

2. HYPERTHERMIA

a. Localized hyperthermia (bums) - Heating of tissue causes vasodilation and

increased vascular permeability leading to edema and blister formation. If severe
enough, the cells show nuclear swelling with disruption of nuclear membranes and
coagulation of intracellular proteins. The clinical significance of cutaneous bums
depends on the depth and the surface area covered. Third degree (full thickness)
bums are the most severe and destroy not only the epidermis but the underlying
dermis and dermal appendages which prevents re-epithelialization. First and
second degree (partial thickness) bums leave basal epithelium or at least some of
the dermal appendages intact (from which epithelial cells can be regenerated).
Inhalation of superheated air can cause similar injury throughout the respiratory
tract. Complications of bums include shock (loss of circulating blood volume),
hemoconcentration, electrolyte imbalance, and infection (responsible for over 50%
of deaths).
b. Systemic hyperthermia - This results from either increased heat production
(increased BMR, increased muscular activity, etc), decreased heat loss (peripheral
vasoconstriction, interference with sweating mechanisms, etc), or alteration of the
"set point" of the hypothalamic regulatory centers (macrophage release of

8
 interleukin-l in infections. etc). Compensatory peripheral vasodilation leads to
pooling of blood and hypotension. Excessive sweating may lead to severe fluid
and electrolyte imbalances which could induce shock.

C. ELECTRICITY - Electricity can cause cell injury or death either due to interruption of neural
transmissions of the cardiac conduction/respiratory control systems or by the generation of heat.
Electrothermal injury occurs when the body completes a circuit between two conductors. The
outcome of electrothermal injury depends on the conduction path through the body (usually the
most direct path between contact pomts), the current, the duration of flow, the amperage, and the
electrical resistance of the tissue in that conduction path. Tissues with relatively low water content
(primarily skin) have increased resistance and are most likely to be affected by production of heat
(electrical bums) and, although not always present, these bums may be the only morphologic
evidence of fatal electrocutions.
D. ATMOSPHERIC PRESSURE - The degree of injury depends on the magnitude, direction, rate, and
duration of pressure change. In general, increased pressure is tolerated better than decreased
pressure. A sudden decrease in pressure (as seen in rapid ascents in scuba diving accidents)
produces free gas bubbles as nitrogen is released from solution in the plasma. These can then act
as emboli with variable clinical results (Caisson disease). The decreased pressure of high altitude
leads to hypoxia and alteration of vascular permeability which in some cases can lead to death from
pulmonary and/or cerebral edema. Up to a point, slow increases in pressure are tolerated fairly
well, but rapid increases in pressure (blast injuries) may produce considerable damage due to the
variable densities and compressibility of tissues. Tearing, lacerations, and rupture (esp of air-filled
tissues or organs) may produce significant morbidity.
E. MECHANICAL TRAUMA - This results when sufficient outside force is applied to body tissues to
disrupt their structure or function. The type of injury sustained is determined by the amount of
force, the rate at which it is applied, the surface area of the tissues involved, and the type of tissue.
Mechanical il1iury produces wounds such as abrasions (loss of superficial cells as the result of
friction or crushing), contusions (disruption of blood vessels produced by blunt force), lacerations
(the tearing of tissue resulting from excessive stretching), incisions (cuts produced by a sharp
instrument), and avulsions (tearing away of body parts).

III. CHEMICAL / DRUG INJURY - This is an important cause of cell injury and cell death and can cause
tissue damage by a wide variety of pathways. Chemicals can stimulate, suppress, or disrupt normal cellular
fimction, alter membrane permeability, etc. Although some chemicals cause direct damage, the toxicity of
many other chemicals may be related to the induction of intracellular free radicals. Chemicals and drugs
can be inhaled, ingested, or absorbed through the skin and can adversely affect critical biochemical
pathways, molecular components, or cell organelles. The effects depend in part on their eventual
distribution within the body, their metabolism, and their mode of excretion. Drugs that produce consistent
and predictable cell or tissue injury generally act by immune suppression or to direct toxicity by the drug
and/or its metabolites. The severity of injury is generally dose-dependent. Unpredictable drug injuries
usually are not dose-dependent and generally are related to immunologic reactions (hypersensitivity, etc).
Age, genetic constitution, underlying disease, nutritional status, and other factors all influence the
susceptibility to specific injuries by drugs or environmental chemicals.

A. ALCOHOLS

1. ETHYL ALCOHOL - This is the most frequently abused chemical in the U.S. It interferes
with mitochondrial fimction and is metabolized by the inducible microsomal P-450 oxidase
pathway and by alcohol and acetaldehyde dehydrogenases. A metabolite, acetaldehyde, has

9
 been implicated as the mediator of chronic injury. Acutely, ethanol acts as a functional
CNS depressant and produces reversible changes to the stomach (acute gastritis) and liver
(fatty change). Death can result from respiratory depression or cardiac arrhythmias.
Chronic changes are seen primarily the liver (cirrhosis), stomach (gastritis, ulcers), nervous
system (peripheral neuropathies), and heart (dilated, congestive cardiomyopathy). Other
associated disorders include esophageal cancer, pancreatitis, etc.
2. METHYL ALCOHOL - This is metabolized by the liver to formaldehyde and formic acid.
Acute poisoning produces acidosis, visual disturbances (including blindness), severe
abdominal pain, and convulsions. Cerebral and brain stem edema may result in death. The
most characteristic lesion is retinal ganglion cell necrosis but pancreatic necrosis and other
changes may also be seen.

B. ORGANIC SOLVENTS

I. ETHYLENE GLYCOL - This is a constituent of antifreeze and various solvents and cleaning
agents. It is metabolized by the liver to oxalic acid (among other products). Early
symptoms are those of inebriation. Metabolic acidosis develops which is followed by
congestive heart failure and pulmonary edema. Acute tubular necrosis of the kidney
produces acute renal failure. Birefringent calcium oxalate crystals can be seen in renal
tubules and in urine.
2. CARBON TETRACHLORIDE - This is distributed to the liver where it initially acts on the
endoplasmic reticulum to block protein synthesis. Free radical formation also occurs.
Morphologically, CCl 4 produces a centrilobular (zone 3) hepatic necrosis.
3. BENZENE - Widely used as an industrial solvent, bemzene primarily affects the bone
marrow to produce an aplastic anemia. There is also an increased risk of subsequent acute
non-lymphocytic leukemias.

C. INSECTICIDES - These are absorbed across skin, ingested, or inhaled.

1. CHLORINATED HYDROCARBONS (chlordane, DDT, etc) - These can enter the food chain,
accumulate in fat stores, and may slowly reach toxic levels. They initially cause CNS
hyperexcitability, delirium and convulsions followed by CNS depression, paralysis, coma,
and death.
2. ORGANOPHOSPHATES (malathion, parathion, etc) - These inhibit acetylcholinesterase
thereby allowing accumulation of acetylcholine at the neuromuscular junctions. Signs may
include muscle twitching and paralysis with death often related to cardiac arrhythmias and
respiratory depression.

D. HEAVY METALS

I. LEAD - Although widely used in industry, the major sources of lead are paint (pre-1977),
auto exhaust (from leaded gasolines), food (from contamination or leaded containers or
cookware), and water (from leaded or soldered pipes). Lead is absorbed across the GI
tract or by inhalation and is cleared through the kidneys and biliary tract. All individuals
are lead contaminated to some extent, but for a variety of reasons children are more
sensitive to the toxic effects oflead than are adults. Although inhaled lead is almost totally
absorbed in both children and adults, ingested lead is more readily absorbed by children.
Once absorbed, the majority of lead is deposited in bone (particularly around the
epiphyses), teeth, hair, and nails. A portion remains in the blood (mostly associated with

10
 el)'t:hrocytes) and the remainder is distributed in soft tissues (kidney, brain, bone marrow,
etc). The buildup oflead is cumulative and prolonged or repeated exposure to even small
amounts can lead to lead poisoning. The reservoir of lead in the bone is slowly released
into the blood and can contribute to long term elevations in blood lead levels. Lead is even
more readily mobilized from the bone stores during periods of stress or illness.
2. MERCURY - Mercury inhibits multiple enzyme systems (oxidative phosphorylation,
cytochrome c oxidase) and also combines with sulfhydryl groups in the cell membrane. It
can be inhaled, ingested, or absorbed through the skin and mucous membranes. It is
excreted primarily through the urine and feces. Organic mercurial compounds are more
readily absorbed across GI and respiratory tract than inorganic forms because of increased
lipid solubility. Inhalation of mercuric vapors tends to have neuropsychiatric effects
(depression, irritability, insomnia) while the effects of organic mercury (Minamata
disease) are primarily sensorimotor (paresthesias, constriction of visual fields, hearing loss,
ataxias, abnormal reflexes, etc). Morphologically, there is cerebral (esp calcarine cortex)
and cerebellar (esp granular cell layer) atrophy and gliosis. Inorganic mercury is more
likely to cause renal damage with acute poisoning causing proximal tubular epithelial
necrosis and acute renal failure. Chronic poisoning induces a membranous
glomerulonephritis and proteinuria.
3. ARSENIC - Arsenic is ubiquitous in the soil. The major route of arsenic exposure is through
naturally or commercially contaminated food and water. Most cases of arsenic poisoning,
however, are related to accidental ingestion of arsenic containing pesticides - especially
by children. Arsenic can be absorbed across the respiratory or GI tract and inhibits
sulfhydryl enzyme systems. It is rapidly metabolized by the liver and excreted in the urine
but can accumulate in the liver, spleen, kidney, lungs, and GI tract. Long term storage is
primarily in the skin, hair and nails. Acutely, arsenic ingestion results in a necrotizing,
hemorrhagic gastroenteritis with nausea, vomiting, abdominal pain and bloody diarrhea
leading to fluid loss and hypotension. Hepatic necrosis and acute renal tubular necrosis
may also ensue. Death is usually due to cardiovascular collapse and hypovolemic shock.
With chronic exposure, axonal destruction leads to peripheral sensorimotor neuropathies
which in some instances may simulate Guillain-Barre syndrome. There may also be hair
loss, GI disturbances, patchy hyperpigmentation of the skin, and hyperkeratoses of the
palms and soles which may progress to squamous cell carcinoma. Chronic inhalation
exposure has been associated with respiratory cancers.
4. IRON (ferrous sulfate) - Iron is a mitochondrial poison and accidental iron poisoning is
relatively common in children. Acute overdose causes lethargy and restlessness and leads
to hemorrhagic gastroenteritis with abdominal pain, hematemesis, bloody diarrhea, and
shock. Hepatic necrosis and liver failure may supervene. With survival, late sequelae
include hepatic cirrhosis and bowel obstruction from severe scarring of the GI tract.

E. MISCELLANEOUS

1. CY ANIDE - This exists in many forms, the most common of which are hydrogen cyanide
(a gas) and the cyanide salts (potassium cyanide, sodium cyanide, etc). Cyanogenic
glycosides that release HCN after ingestion are found in many fruits and vegetables.
Automobile exhaust is the largest source of airbome cyanide but cigarette smoke and other
manufacturing processes also contribute. Water contamination occurs through industrial
discharges. Many nitrogen containing substances (plastics, textiles, etc) will release HCN
when burned, and this can be a significant contributor to morbidity and mortality in smoke
inhalation victims. Cyanide can be inhaled, ingested, or absorbed through the skin and

11
 mucous membranes. Once absorbed, it is distributed throughout the body and exerts its
toxic effects by combining with the ferric iron in cytochrome oxidase and blocking cellular
oxygen utilization. Cellular conversion to anaerobic respiration produces a severe
metabolic acidosis and energy dependent homeostatic mechanisms are disrupted. Cyanide
is detoxified primarily by the liver and excreted in the urine as thiocyanate. In acute
poisoning, the primary effects are on the CNS resulting in respiratory and cardiac
depression leading to hypotension and shock. Chronic exposure leads to a variety of
neurologic abnormalities (demyelinating neuropathies, Parkinson-like signs, optic atrophy
and visual disturbances), EKG abnormalities, and goiters. Ability to smell the bitter
almond odor is genetically inherited and present in about 60-80% of the population.
2. CARBON MONOXIDE - This gas has a greater affinity (200x) for hemoglobin than does
oxygen and also interferes with the release of O2 from oxyhemoglobin. Acute poisoning
produces "cherry red" discoloration of skin due to accumulated carboxyhemoglobin in the
superficial cutaneous capillaries. There may also be morphologic changes of systemic
hypoxia (petechial hemorrhages, etc). If death is not immediate, there may be hemorrhagic
necrosis of the basal ganglia and lamellar necrosis of cortical gray matter. Diagnosis is
determined by elevated blood carboxyhemoglobin levels.
3. POLYCHLORINATED BIPHENYLS (PCB) - These were used in industry until 1977 when
production was banned. These compounds are structurally similar to DDT but are
essentially indestructible and are permanent in the environment. In humans, they have been
associated with chloracne, visual disturbances, and impotence.

IV. BIOLOGIC INJURY - This includes a wide spectrum of microbial organisms from viruses to higher
fonns of parasites. These can induce cell injury through direct cytopathic or cytotoxic effects or indirectly
through inflammatorylimmunologic host defense mechanisms.
V. NUTRITIONAL INJURY - Nutritional imbalances may interfere with the ability to maintain cell structure
and function and includes such disorders as marasmus, kwashiorkor, vitamin and mineral deficiencies, and
obesity.
VI. GENETIC INJURY - Genetic damage may interfere with the ability to maintain normal cell homeostasis
by altering the regulation and/or structure of the protein products of the genes.
VII. INFLAMMA TORY/IMMUNOLOGIC INJURY - Although these host defense mechanisms are crucial
to the well-being of the organism, either excessive or inadequate expression may result in cell injury and
death.

12
 FLUID BALANCE AND HEMODYNAMICS

I. EDEMA - This refers to the accumulation of excess fluid in cells or tissues. Intracellular edema is
generally a reflection of cellular injury and altered cell membrane permeability while interstitial edema (the
extracellular, extravascular fluid compartment) may reflect a disturbance in the normal hemodynamic
forces that control fluid balance or indicate endothelial injury and increased vascular permeability.
Interstitial edema may be a regional process involving a localized area or it may be a diffuse process
involving all tissues of the body (anasarca).

A. PATHOGENESIS - The normal exchange offluid between plasma and interstitial tissues is dependent
on opposing forces which usually are fairly well balanced. The osmotic pressure of the interstitial
fluid (primarily influenced by the sodium content) and the hydrostatic pressure of the intravascular
fluid tend to draw water out of the vasculature while the oncotic pressure of the intravascular fluid
(primarily influenced by the albumin content of the plasma) draws water back into the vasculature.
Under normal conditions, the major force on the arteriolar side of the capillary bed is the
hydrostatic pressure of the intravascular fluid which forces fluid into the interstitial tissue, and on
the venous side of the capillary bed, the major force is the oncotic pressure of the intravascular
fluid which pulls water back into the intravascular space. Any excess fluid remaining in the
interstitial tissue is borne off by the lymphatic channels and ultimately returned to the intravascular
space via the thoracic duct. Interstitial edema, therefore, can result from any of the following
mechanisms:

I. INCREASED OSMOTIC PRESSURE OF THE INTERSTITIAL FLUID - This can lead to a

generalized edema resulting from an increased total body sodium due to excessive salt
intake, increased renal tubular sodium absorption, decreased renal tubular sodium
excretion, or reduced renal perfusion (triggering the renin-angiotensin-aldosterone system).
2. DECREASED ONCOTIC PRESSURE OF THE PLASMA PROTEIN - This may also produce a
generalized edema generally resulting from a decrease in albumin concentration. This may
be due to a failure of albumin synthesis (liver disease, malnutrition) or excessive albumin
loss (glomerulopathy, enteropathy), etc.
3. INCREASED HYDROSTATIC PRESSURE OF THE INTRAVASCULAR FLUID - This leads to a
localized edema and usually involves increased hydrostatic pressure within the venous
system (rather than the arterial system) resulting from interference with or obstruction of
venous blood flow.
4. OBSTRUCTION OF LYMPHATIC DRAINAGE (lymphedema) - This also produces a localized
edema and is usually the result of lymphatic obstruction by cancer, scarring (post-
inflammatory, post-radiation, etc), parasitic disease (filaria), or lymphadenectomy.

13
 5. INCREASED ENDOTHELIAL PERMEABILITY - This produces a localized edema and is the
result of inflammation, immunologic reactions, or other tissue injury.

B. TYPES OF EDEMA FLUID

1. TRANSUDATE - This is a protein-poor « 3 gmldl) fluid which has a specific gravity

<1.012. It develops from imbalances in the normal hemodynamic forces and is
frequently seen with congestive heart failure (increased intravascular hydrostatic pressure,
etc), liver disease (decreased albumin synthesis, obstruction to portal venous flow, etc),
renal disease (excessive loss of albumin, excessive salt retention, etc), and GI disorders
(protein malabsorption, protein-losing enteropathies, etc).
2. EXUDATE - is a protein-rich (> 3 gmldl) fluid which has a specific gravity> 1.020. It
generally is the result of endothelial damage and alteration of vascular permeability
and is seen with inflammatory/immunologic disorders, etc.

c. COMMON DISORDERS ASSOCIATED WITH EDEMA - The clinical significance of edema depends on
the severity, location, rapidity of development, and underlying cause.

1. CONGESTWE HEART FAILURE - This refers to a clinical condition manifested by numerous

signs and symptoms that arise when the heart is no longer able to maintain normal cardiac
output. The signs and symptoms of heart failure are generally due to hypoxic and
congestive effects on organs and tissues other than the heart itself

a. Left-sided heart failure - This occurs when the left ventricle is unable to
maintain adequate cardiac output. Ultimately, the increased hydrostatic pressure
that is created is transmitted "backward" to the pulmonary venous circulation.
Acutely, transudative fluid escapes the septal capillaries and causes edematous
thickening of the alveolar septi (this produces dyspnea and also reduces lung
compliance). When the capacity of the interstitial lymphatics to drain the excess
fluid is surpassed, the transudate subsequently seeps into the alveolar sacs
producing pulmonary edema which may be auscultated as pulmonary rates.
Additionally, renal hypoperfusion resulting from the decreased cardiac output.
causes sodium and water to be retained via activation of the renin-angiotensin
system and the action of aldosterone on the renal tubules. This added fluid burden
intensifies the pulmonary edema and pleural effusions may develop. On a chronic
basis, there may be small capillary hemorrhages and diapedesis of red cells into
the alveolar spaces. These red cells are phagocytosed by alveolar macro phages,
the hemoglobin is broken down to hemosiderin (a brown pigment), and the
hemosiderin-laden macrophages ("heartfailure" cells) characteristic of chronic
pulmonary congestion are thereby formed. Over time, there is also irreversible
fibrous thickening of the alveolar walls contributing to the grossly appreciated
"brown induration". Although a decreased cardiac output may cause neurologic
symptoms (restlessness, irritability) due to cerebral hypoxia, the clinical
manifestations of left heart failure are primarily pulmonary in origin and include
easy fatigability, shortness of breath (SOB) or dyspnea on exertion (DOE),
paroxysmal nocturnal dyspnea (PND), orthopnea, and cough.
b. Right-sided heart failure - This occurs when the right side of the heart is unable
to overcome an increase in pulmonary arterial pressures (pulmonary
hypertension). This is most frequently the result of pre-existing left heart failure

14
 but may also be due to other causes. The increased hydrostatic pressure in the
right side of heart is transmitted "backward" into the systemic venous return and
clinically results in:

(1) Engorgement and distention of neck veins - This may lead to cerebral
congestion and hypoxia resulting in irritability, restlessness, and stupor.
(2) Passive congestion of the liver - Acute congestion is retlected by
engorgement of hepatic central veins and sinusoids. Chronic congestion
of the central veins and sinusoids, however, results in hypoxia and atrophy
of centrilobular hepatocytes and fatty change of peripheral periportal
hepatocytes. This imparts a mottled red-brown and yellow-tan appearance
known as "nutmeg liver". Long standing chronic congestion may induce
a centrilobular fibrosis known as cardiac sclerosis.
(3) Portal hypertension - This may result in ascites (accumulation oftluid
within the peritoneal cavity due to increased hydrostatic pressure within
the portal venous system) and congestive splenomegaly (chronic
congestion of the splenic sinusoids leads to fibrous thickening of the
sinusoidal walls and an enlarged, firm spleen).
(4) Dependent pitting edema - This is an interstitial edema in subcutaneous
tissue that is most pronounced in the dependent portions of the body.
(5) Increased body weight - In addition to other factors, congestive hypoxia
of the kidneys activates the renin-angiotensin system with retention of
sodium and water which adds to the interstitial tluid accumulation.

2. LIVER DISEASE (cirrhosis, hepatocellular damage) - Hepatic injury may result in decreased
synthesis of plasma protein, increased hydrostatic pressure and pooling of blood in portal
venous circulation, hepatic lymphatic obstruction, etc.
3. RENAL DISEASE (glomerulopathy, tubular dysfunction) - This may result in loss of plasma
protein, increased sodium retention, etc.
4. GI DISEASE (starvation, malabsorption, enteropathy) - This may result in plasma protein
deficiencies', etc.
5. INFLAMMATORY/IMMUNOLOGIC DISORDERS (infections, hypersensitivities, etc) - These
can result in vascular endothelial damage or increased vascular permeability creating
localized exudates.

II. HYPEREMIA - This refers to increased blood flow through dilated arteries, arterioles, and capillary
beds. Clinically, this results in increased warmth and redness in affected tissue. Basically, hyperemia is a
reflexive mechanism (neurally and/or chemically mediated) designed to allow greater blood flow to areas
ofintlammation, to tissues needing more oxygen, or as a mechanism of heat dissipation.
III. CONGESTION - This refers to pooling of blood in veins, venules, and capillaries usually due to impaired
venous drainage. Clinically, it results in a bluish discoloration of tissue (cyanosis) due to accumulation of
reduced hemoglobin. Since impaired venous drainage also leads to increased hydrostatic pressure, edema
is a common accompaniment of congestion.

A. ACUTE CONGESTION - produces a heavier, bloodier organ or tissue which mayor may not lead to
clinical signs and symptoms.

15
 B. CHRONIC CONGESTION - leads to impaired tissue oxygenation and may result in "degeneration"
or necrosis of the affected tissue. The effects of chronic passive congestion are most often seen in
the lungs, liver, and spleen.

IV. HEMORRHAGE - This refers to active bleeding into extravascular tissues or spaces resulting from
disruption of the integrity of vascular walls.

A. DEFINITIONS - Hemorrhages into skin, mucous membranes, or serosal surfaces are usually referred
to as petechiae (pin-point), purpura « 1.0 cm), or ecchymoses (> than 1.0 cm); extravascular
blood clots are hematomas; blood in body cavities are referenced to the location (hemothorax,
hemopericardium, hemoperitoneum, hemarthroSiS, etc); blood from the nose is epistaxis; coughing
of blood from lungs is hemoptysis; vomiting of blood is hematemesis; dark "tarry" blood in the
stool is melena; bright red blood in stool is hematochezia, etc.
B. CLINICAL SIGNIFICANCE - is dependent on:

1. AMOUNT - A small volume of blood loss may be insignificant, a large volume of blood loss
may be fatal.
2. LOCATION - A large hemorrhage into soft tissue may be insignificant, a small hemorrhage
into the brainstem may be fatal.
3. RATE OF LOSS - Chronic blood loss allows compensatory mechanisms to develop and is
tolerated better than acute blood loss.

V. HEMOSTASIS - This refers to the body's intrinsic ability to slow down or stop hemorrhage. This is
accomplished by forming an intravascular blood coagulum (thrombus) as the result of a complex
interaction between the vascular wall, the blood platelets, and the circulating coagulation and
anticoagulation factors. Although the terms are often used synonymously, a blood clot actually refers to
the formation of an extravascular blood coagulum or a postmortem intravascular coagulum formed only
from the plasma coagulation factors. Normal hemostasis involves a delicate balance between factors that
promote blood coagulation and thrombus stabilization and factors that inhibit blood coagulation and
promote thrombus dissolution.
VI. THROMBOSIS - Although the formation of thrombi may be appropriate and life-saving, it may also be
inappropriate and life threatening.

A. PREDISPOSING FACTORS - VIRCHOW'S TRIAD

1. ALTERATION OF VASCULAR ENDOTHELIUM - Atherosclerosis, diabetes, hypertension,

bacterial toxins, chemical agents, immunologic reactions, etc may initiate thrombus
formation.
2. ALTERATION OF BLOOD FLOW - Stasis or turbulence will disrupt the normal laminar flow
of blood and bring platelets in direct contact with the endothelium, allow increased
concentration of activated coagulation factors, inhibit ingress of coagulation inhibitors,
promote endothelial damage, and allow propagation of pre-existing thrombi.
3. ALTERATIONS OF BLOOD COMPONENTS - The presence of procoagulants (as seen in
systemic lupus, various neoplasms, etc) or deficiencies of anticoagulants (antithrombin III,
protein C, protein S) may lead to hypercoagulability and inappropriate thrombosis.

16
 B. APPEARANCE

1. ARTERIAL THROMBI - These form most frequently in areas of atherosclerotic damage to

the vessel wall or, in the heart, over areas of previous myocardial infarction. Cardiac and
aortic thrombi tend to be firmly attached to the underlying vessel wall (mural thrombi) and
are generally nonocclusive while thrombi in smaller arteries (coronary, cerebral, femoral)
may be occlusive. As arterial thrombi develop (particularly those in the heart and large
arteries where there is high blood flow), they tend to develop alternating layers offibrin
and aggregated platelets (lines ofZahn) which grossly gives the thrombus a grey laminated
appearance (white thrombus).
2. VENOUS THROMBI - These usually form in areas of blood stasis; are typically found in the
deep leg veins, superficial leg veins, and less commonly in periprostatic, periovarian, and
periuterine pelvic venous plexi; and are frequently occlusive. Since they develop in areas
of stasis, there is less tendency to develop lines of Zahn and a greater tendency for red
blood cells to become trapped in the developing thrombus which grossly creates a dark
red-blue appearance (red thrombus).
3. CAPILLARY THROMBI - These are usually due to local endothelial damage. They generally
consist of platelets and fibrin and are not grossly visible.
4. POSTMORTEM CLOTS - These may occasionally be difficult to differentiate from
antemortem thrombi (especially venous thrombi) but in general, post-mortem clots form
a perfect cast of the vessel in which they form, do not contain lines of Zahn, are not firmly
attached to the vessel wall, have a "currant-jelly" and/or "chicken fat" appearance, and do
not break apart easily.

C. SEQUELAE

1. THROMBOLYSIS AND/OR ORGANIZATION - Neutrophils and monocytes trapped in a

thrombus will degrade and phagocytize fibrin and cell debris. Lysosomal enzymes from
neutrophils and platelets will digest the coagulum and lead to softening - especially
centrally where there is no dilutional effect. Fibroblasts and endothelial cells from the
underlying vascular wall infiltrate the thrombus, and a combination of fibrinolytic activity
and endothelial proliferation may reestablish vascular flow (recanalization) through an
occlusive thrombus. Eventually fibroblastic contraction will shrink the thrombus and it may
become incorporated into the wall of the vessel.
2. CONTINUED DEVELOPMENT
3. FRAGMENTATION AND/OR DETACHMENT

D. CLINICAL SIGNIFICANCE - The clinical manifestations of thrombosis vary greatly depending on the
size, number, location, rapidity of development, and availability of collateral circulation.

VII. INFARCTION - This refers to the process of tissue necrosis secondary to an abrupt reduction in tissue
oxygenation. Except for the brain where liquefactive necrosis develops, anoxia results in coagulation
necrosis. In general, those tissues that are more highly specialized and/or are more metabolically active,
are most sensitive to the effects of hypoxia/anoxia. Infarcts are usually the result of interference with the
arterial blood supply to a tissue but, in some instances, they may be due to obstruction of venous drainage
or conditions that decrease the oxygen carrying capacity of blood. Slowly developing vascular occlusions,
however, are less prone to cause infarction since collateral circulation may develop around the obstruction.

17
 A. APPEARANCE - In those tissues that have a single blood supply without significant anastomoses
(kidney, spleen, heart, etc), occlusion of an artery will result in coagulation necrosis of the tissues
supplied by that artery. Since blood perfusion of the tissue is interrupted, the tissue becomes pale
(pale infarct). Tissues that have a single blood supply with rich anastomoses (small bowel) or that
have a dual blood supply (lung, liver) are somewhat protected against abrupt hypoxia due to the
additional blood source. Ifnecrosis does occur, however, the alternate blood source may bleed into
the necrotic tissue creating a red (hemorrhagic) infarct. Infarcts that result from venous
obstruction also tend to be hemorrhagic. The brain is also somewhat protected against infarction
due to its "parallel" blood supply provided by the Circle of Willis, but when infarcts do occur, there
is liquefactive necrosis of the tissue. Grossly, infarcts tend to be wedge-shaped with the apex
located close to the point of obstruction. Initially, they are somewhat ill-defined but become
progressively demarcated with time. Through the reparative process, infarcted tissue will
eventually be replaced by scar tissue.
B. CLINICAL SIGNIFICANCE - The effects of an infarct depends on the location and size. A small
infarct of the myocardium may be clinically insignificant while a small infarct of the brainstem may
be fatal. On the other hand, a large infarct of the cerebral cortex may result only in neurologic
deficits while a large infarct of the myocardium may cause sudden death.

VIII. EMBOLIZATION - This refers to the process in which a free-floating mass (embolus) is carried through
the vascular system to a point distant to its site of origin or entry. The vast majority of emboli are fragments
of a preexisting thrombus (thromboembolus) but other material such as air, fat, atherosclerotic plaque,
amniotic fluid, tumor cells, bone marrow, bacteria., foreign objects, etc can act as emboli if they gain access
to the circulation. Emboli will impact and occlude vessels when the diameter of the vessel becomes smaller
than the diameter of the embolus. When this occurs, infarction of tissue distal to the point of impact may
occur. Thromboemboli, like thrombi, may also undergo lysis or organization.

A. SYSTEMIC (ARTERIAL) EMBOLI - 80-85% arise from mural thrombi in the left ventricle or left
atrial appendage of the heart but valve vegetations, aortic mural thrombi, fragments of
atherosclerotic plaque, etc. may also embolize. Depending on the size of the embolus and its site
of impaction, it mayor may not cause infarction. Major sites of impaction include lower
extremities, brain, kidney, and spleen.
B. PULMONARY (VENOUS) EMBOLI - These are the third most common cause of sudden death (after
myocardial infarct and stroke). More than 95% arise from thrombi in the deep leg veins (popliteal.
femoral, iliac), travel through enlarging venous channels, through the right heart, and into the
pulmonary arteries. Although rare, if a right-to-Ieft shunt is present in the heart (patent foramen
ovale, atrial or ventricular septal defect), a venous embolus can gain access into the systemic
circulation (paradOXical embolus). Clinical significance depends on the size and number of emboli
as well as the general cardiovascular status of the patient. Details of the effects of pulmonary
emboli will be discussed with the pulmonary section.
C. FAT EMBOLI - These most frequently occur after long-bone trauma when marrow fat is exposed
to the venous circulation. Fat emboli larger than 20ll are filtered in the lung while smaller
aggregates may pass through the lung and lodge in brain and/or kidneys. This may give rise, 1-3
days after the trauma, to a clinical syndrome of progressive respiratory distress, CNS impairment
(restlessness, confusion, incontinence, coma) and possible renal dysfunction that is related to the
mechanical and chemical effects of fat in the circulation.
D. AIR EMBOLI - These may originate from abortion procedures, traumatic pneumothorax, Caisson's
disease, etc. Smaller air bubbles may block microvasculature while larger amounts (100 cc) may
cause "air lock" in the right heart.

18
IX. SHOCK - This can simply be defined as the inadequate perfusion and resultant hypoxia of body tissues.

A. ETIOLOGY

1. HYPOVOLEMIC - Acute loss of blood or fluid from the circulation may be due to
hemorrhage, bums, vomiting, diarrhea," third-spacing", etc.
2. CARDIOGENIC - The inability of the heart to maintain adequate output may be due to
myocardial infarcts, cardiac tamponade, pulmonary emboli, etc.
3. VASCULAR

a. Neuro2enic - The inability to maintain peripheral vascular muscle tone with

subsequent pooling of blood may be due to CNS injury, drugs, etc.
b. Septic (endotoxic) - This leads to peripheral vascular pooling and is usually due
to severe gram negative bacterial infections. It may also complicated by direct
toxic damage to cells and disseminated intravascular coagulation.
c. Anaphylactic - Hypersensitivity reactions may lead to widespread vasodilatation
and increased capillary permeability resulting in peripheral vascular pooling and
hypovolemia.

B. PATHOGENESIS

Reduced Blood Volume Decreased Blood Return to Heart

Pooling of blood and Decreased Cardiac Output

loss of fluid into tissue

Arteriolar dilatation with Decreased Blood Flow

increased capillary and
venule permeability

Lactic acidosis <== Decreased Oxygen to Tissues

C. CLINICAL SIGNS AND SYMPTOMS

1. DECREASED CARDIAC OUTPUT AND PERIPHERAL ARTERIOLAR VASOCONSTRICTION

(HYPOVOLEMIC/CARDIOGENIC SHOCK) - produces cool clammy skin and compensatory
tachycardia.
2. INCREASED CARDIAC OUTPUT WITH PERIPHERAL ARTERIOLAR DILATATION AND
INCREASED VASCULAR PERMEABILITY (SEPTIC SHOCK) - produces warm moist skin.
3. REDUCED BLOOD VOLUME - produces hypotension, weak thready pulse.
4. LACTIC ACIDOSIS - produces hyperventilation, obtundation, restlessness.
5. RENAL RETENTION OF SALT AND WATER (compensatory attempt to increase blood
volume) - results in oliguria.

19
 PRINCIPLES OF HOST DEFENSE

The two major defense mechanisms of the body against potentially injurious events are the inflammatory
I'esponse and the immunologic response. The cells involved in host defense are, in general, initially derived
from the bone marrow and circulate through the peripheral bloodstream and lymphatic system or are "fixed" at
certain sites throughout the body.

MAJOR CELLULAR PARTICIPANTS IN HOST DEFENSE

I. POL YMORPHONUCLEAR LEUKOCYTES (GRANULOCYTES) - These are white blood cells

containing an irregular lobulated nucleus and large cytoplasmic granules.

A. NEUTROPHILS or "POLYS" (50-65% of circulating white blood cells) - These cells can phagocytize
and destroy bacteria and other minute particulate matter, elaborate chemotactic factors, and
produce digestive enzymes to degrade and "mop up" necrotic cellular debris. Small cytoplasmic
granules contain lysozyme, collagenase, alkaline phosphatase, etc. while larger granules contain
acid hydrolases, myeloperoxidase, and neutral proteases (elastase, etc).
B. EOSINOPHILS (1-5% of circulating white blood cells) - These produce major basic protein (MBP)
which is toxic to both parasites and epithelial cells. When the eosinophil is bound to antigen, these
are released and contribute to the destruction of parasites. Eosinophils can phagocytize antigen-
antibody complexes, and they also contain histaminases which can dampen the effects of the
allergic hypersensitivity reaction.
C. BASOPHILS (1 % of circulating white blood cells) - These contain granules which also contain MBP
and lysophospholipase in addition to serotonin, heparin, and histamine. They carry surface
receptors for IgE immunoglobulins and, like neutrophils and monocytes, with the proper stimulus
can produce and secrete platelet activating/actor (P AF) which can cause vasodilation, increased
permeability of venules, and synthesis of arachidonic acid metabolites.

II. MONONUCLEAR LEUKOCYTES

A. LYMPHOCYTES (30-40% of circulating white blood cells) - are key mediators in the humoral and
cell-mediated immune responses. They can synthesize chemical mediators (lymphokines) that are
involved in lymphocyte recruitment and proliferation as well as other aspects of
inflammation/immunology.

20
 1. T-LYMPHOCYTES (T-CELLS) - These comprise the majority (X5%) of circulating
lymphocytes in the peripheral blood. These are the lymphocytes that have been
"programmed" by passage through the thymus gland where, through the process of gene
rearrangement, each T-lymphocyte acquires a unique DNA sequence for its surface T-cell
antigen receptor. Here, they also acquire the ability to recognize the major
histocompatibility complex (MHC) antigens. Released from the thymus, they circulate in
the blood and also populate the paracortical regions of lymph nodes and parts of the
splenic white pulp. Based on differences in cell surface proteins, functionally distinct
subpopulations ofT-cells (T-killer cells, T-suppressor cells, T-helper cells, and T-memory
cells) have been identified. These cells mediate the cellular immune response as well as
regulate the activity of other T -lymphocytes, B-lymphocytes and macrophages.

a. T-killer cells - These are directly cytotoxic and act by binding to "foreign" cells
and lysing the cell membrane through the action of various secreted lymphokines.
They are important in transplant rejections and in destroying virally infected cells
and tumor cells.
b. T-helper cells - These augment antibody production by stimulating B-cell
proliferation and differentiation into plasma cells.
c. T-suppressor cells - These dampen antibody production against a specific antigen
by inhibiting B-cell proliferation or by restraining T -helper cell activity.

2. B-LYMPHOCYTES (B-CELLS) - These comprise about 15% of circulating lymphocytes and

represent lymphocytes that have been "programmed" in the bone marrow. When faced
with an antigenic challenge, these cells, with the help ofT -cells, mature into plasma cells
capable of producing antibodies (immunoglobulins) directed against that specific antigen.
or they become B-memory cells. Plasma cells, however, are tissue-based and do not
circulate in the peripheral blood. Like T -cells, gene rearrangement of the immunoglobulin
genes allows for extensive antigen specificity.
3. NATURAL KILLER (NK) CELLS - These have some surface marker similarities to T-cells
but are felt to be distinct from other lymphocyte classes. Similar in function to T -killer
cells, they are able to destroy tumor cells and virally infected cells without prior activation
and therefore are important in tumor surveillance and viral diseases.

B. MONOCYTES (4-8% of circulating white blood cells) - These are the major source of tissue
macrophages. When these cells leave the circulation and enter tissue, they are termed histiocytes
when they are in the resting state and macrophages when reacting to a stimulus. These cells act to
phagocytize larger particulate matter and are also capable of pinocytosis of soluble material. They
have surface receptors similar to those of the neutrophils (Fe, C3 b) in addition to receptors for
interferon and interleukin-2. They can be "activated" (by gamma interferon, etc) and "deactivated"
(by transforming growth factor B, etc) according to their microenvironment. They "process" and
present antigens to T- and B-Iymphocytes and secrete numerous monokines (acid hydrolases,
neutral proteases, chemotactic factors, arachidonic acid metabolites, free radicals, complement
components, growth promoting factors, etc.) that are important in both the inflammatory and
immune host defenses.

III. PLA TELETS - These are derived from bone marrow megakaryocytes and enclose electron dense granules
that contain vasoactive amines and Ca++; alpha granules that contain platelet derived growth factor and
coagulation proteins; and lysosomes that contain acid hydrolases.

21
IV. MAST CELLS - These are tissue-bound cells that secrete mediators important in the early inflammatory
response (esp. IgE mediated reactions) and are located primarily around small blood vessels and serous
membranes. They also contain chemotactic factors for eosinophils.

PRINCIPLES OF INFLAMMATION

The inflammatory host defense reaction may be evoked by any insult or injury (physical, biologic, chemical) to
the body tissues and involves vascular, neurologic, and cellular responses to a variety of chemical mediators.
The inflammatory process is designed to eliminate or at least neutralize the injurious agent and prepare the
tissue for repair. Although inflammation is an ongoing process, only occasionally does it become severe enough
to be clinically evident. Like other self-protective mechanisms, exuberance of the inflammatory response can
itself result in significant tissue damage.

I. ACUTE INFLAMMATION - This is a defensive action by the host that affords an immediate response
to tissue injury. Regardless of the injurious agent, the acute inflammatory response consists of a well-
orchestrated series of events which rapidly mobilizes host defenses to mitigate the severity of the injury.
A variety of diseases characterized by recurrent infection are the result of defects at various points in this
complex process. Local manifestations of acute inflammation include heat (calor), redness (rubor),
swelling (tumor), pain (dolor), and loss of function (functio laesa).

A. VASCULAR RESPONSE TO INJURY

1. VASOCONSTRICTION - In order to retard blood loss and promote coagulation after tissue
injury, often there is an immediate, but transient, constriction of arterioles. This may be an
adrenergic neurogenic response.
2. VASODILATION - Soon after, in the area of injury, arterioles rapidly dilate and the
precapillary sphincters of nonfunctioning capillary beds are relaxed thereby allowing an
increased volume and rate of blood flow (hyperemia) through the tissue. Mediated by
histamine, this results in the clinically appreciated heat and redness of inflammation.
3. PERMEABILITY CHANGES - As hyperemia develops, the vessels become increasingly
permeable allowing the escape of fluid and proteins into the interstitium of the tissues
which, in part, acts as a dilutional agent against toxins or antigens and results in the
clinically appreciated swelling. Patterns of altered permeability include:

a. Immediate-transient response (occurs in response to mild injury) - An increase

in permeability ofvenules begins 1-10 minutes after onset of injury and lasts 15-
30 minutes. This increase in permeability appears to be mediated primarily by
serotonin (released from platelets) and histamine (released from mast cells).
Venular endothelial cells (which normally are continuous and held together by
tight cellular junctions) have a high concentration of surface receptors for
histamine. When stimulated, they contract allowing fluid leakage into interstitial
tissue. This response can be inhibited with anti-histamines.
b. Delayed-prolonged response (occurs in response to moderate injury) - Here, the
immediate-transient response is followed by a period of low permeability but then,
anywhere from 2-10 hours later, a second increase in permeability occurs. This
second increase in permeability involves both venules and capillaries and is felt

22
 to be due to direct injury to the endothelial cells, although endothelial contraction
does not appear to be as significant.
c. Immediate-sustained response (occurs in response to severe injury) - This
involves an immediate increase in the permeability ofvenules, capillaries, and/or
arterioles, apparently mediated by direct physical damage to the vessel walls.
Most clinically significant injuries result in this immediate sustained response.

B. HEMOCONCENTRATION AND STASIS - As fluid escapes into the surrounding tissue, the
concentration of cellular elements remaining inside the vessels increases. The normal laminar flow
of blood is disrupted and the red blood cells tend to clump together in the center of the vessel while
the white blood cells fall to the outer margins and begin to line the endothelial surface, a process
called margination.
C. ADHESION - As the blood flow slows down because of the loss of fluid from the vessels, the
marginating white blood cells begin to "stick" to the endothelial lining and to each other.
Activation, expression, or induction of bonding sites (adhesion molecules) between the endothelial
cells and leukocytes is likely the result of cytokines (interleukin-l, tissue necrosis factor) that are
released by monocyte/macrophages and which act on the endothelial cells and/or leukocytes. This
results in adherence ofleukocytes to the endothelium of the vessel wall which eventually becomes
lined with leukocytes, a process called pavementing. Cytokines can also induce the synthesis of
prostacyclin (PGI 2) and platelet activating factor (P AF).
D. EMIGRATION - This is the process by which the motile leukocytes escape from blood vessels by
squeezing through widened endothelial cell junctions into the perivascular interstitial tissue. Soon
after injury, large numbers of neutrophils and monocytes escape from the venules. Later, another
wave of white blood cells, this time principally monocytes, escape from both the venules and
capillaries.
E. CHEMOTAXIS - This is the unidirectional migration of cells toward an attractant, usually a chemical
substance, along a concentration gradient. Once released from the vasculature, leukocytes migrate
toward injury sites as specific surface membrane receptors recognize various chemotactic agents.
Neutrophils have surface receptors for bacterial products, CSa, arachidonic acid metabolites
(leukotriene B4), kallikrein, etc. while chemotactic products that attract monocyte/macrophages
include various lymphokines, platelet-derived growth factor, CSa, etc. Binding of these receptors
ultimately leads to an increase in intracellular Ca++ which activates contractile elements of the
cytoskeleton. As the chemotactic gradient increases, Ca++ influx persists and membrane
phospholipids are converted to arachidonic acid metabolites. There is also degranulation of storage
vesicles and formation of free radicals within the leukocytes.
F. AGGREGA TlON - The types of cells that aggregate at a site of injury depends somewhat on the
causative agent of that injury and may reflect a sequential release of cell-specific chemotactic
factors. In general, with acute inflammation (especially bacterial infection), neutrophils arrive at
the site of injury first. Later, the slower moving macro phages and lymphocytes arrive. In viral and
rickettsial infections, however, lymphocytes are the predominant inflammatory cell, and in allergic
hypersensitivity reactions and parasitic infections, eosinophils may predominate.
G. PHAGOCYTOSIS - This is a clearing mechanism characteristic of neutrophils and macro phages and
involves three stages:

1. RECOGNITION AND ATTACHMENT - This may require serum derived opsonins, including
complement fragments (especially C3 b) and specific subtypes ofIgG, to coat the surface
of the "inductee". These opsonins are recognized and bound by receptors on the leukocyte
membrane.

23
 2. ENGULFMENT - This occurs by pseudopodial extensions of the cell cytoplasm which
completely enclose the foreign particle. Fusion of this phagosome with one or more
cytoplasmic lysosomes forms a phagolysosome which is a necessary prelude to
intracellular killing and degradation. Attachment of lysosomes to an incompletely engulfed
phagosome, however, may lead to discharge of degradative enzymes into the extracellular
tissue inadvertently causing further tissue damage.
3. KlLLINGAND/oRDEGRADATION - Strong antimicrobial activity is provided by the H 20 r
myeloperoxidase-halide system of neutrophils. Granules containing myeloperoxidase are
emptied into phagolysosomes and react with H 20 2 and Cl- to form OCI- (hypochlorite)
which is lethal to susceptible organisms. Myeloperoxidase deficient phagocytes (such as
macrophages) can also destroy organisms, albeit at a slower rate, by the production of free
radicals, high concentrations of H 20 2 , etc. Other intracellular granules contain products
(lysozyme, lactoferrin, MBP, etc) which can also serve to destroy susceptible organisms.
Acid hydrolases contribute to the ultimate degradation of bacteria and other particles
within the phagolysosome.

Lysosomal enzymes, free radicals, and arachidonic acid metabolites may all be released into the
extracellular space during phagocytosis. Although this can intensifY or perpetuate the inflammatory
response, it may also cause considerable tissue injury through endothelial damage, inactivation of
antiproteases (alpha-I antitrypsin, alpha-2 macroglobulins, etc), and inactivation of antioxidants.

II. CHEMICAL MEDIA TORS - Mediators constitute the bridge between injury and host inflammatory
responses. There are a multitude of mediators that act independently or by interaction with others.
Mediators can be preformed cellular products (histamine, serotonin, lysosomal enzymes, etc), synthesized
cellular products (P AF, arachidonic acid metabolites, cytokines, etc), constituents of plasma (products of
the coagulation, complement, and kinin systems), or products of tissue injury. Some of the more important
mediators are:

A. VASOACTIVE AMINES (action is short-lived)

I. HISTAMINE - Important in the immediate-transient increased permeability response

associated with tissue injury and in IgE-mediated hypersensitivity, it is present within
granules of mast cells, basophils, and platelets, and its release is triggered by numerous
factors.
2. SEROTONIN (5-hydroxytryptamine) - Found primarily in platelets, its release occurs when
platelets aggregate following contact with collagen, ADP, thrombin, or antigen-antibody
complexes. Platelet activating factor (P AF), produced by endothelial cells and a variety
of inflammatory cells, also causes release during IgE-mediated reactions.

B. PLASMA PROTEASES

I. COMPONENTS OF THE KININ SYSTEM - These are produced, in part, by activation of

clotting factor XII (Hageman factor). Activated factor XII (prekallikrein activator)
converts inactive plasma prekallikrein into the active proteolytic enzyme, kallikrein. Kalli-
krein (which can activate additional Hageman factor) cleaves high molecular-weight
kininogen (HMWK) to produce bradykinin. Bradykinin is a potent mediator of increased
vascular permeability. It also induces vascular dilation and pain.
2. COMPONENTS OF THE COMPLEMENT SYSTEM - C3a and C5a (anaphyla toxins) are the
primary permeability-increasing components of complement and act by releasing histamine

24
 from mast cells and platelets. C5a also increases surface expression of leukocyte adhesion
molecules, is chemotactic to neutrophils and monocytes, and initiates arachidonic acid
metabolism. C3b is an opsonin and recognizes neutrophil, macrophage and eosinophil
receptors. C5b6789, the membrane attack complex (MAC), causes membrane lysis of the
cell to which it is attached.
3. COMPONENTS OF THE COAGULATION AND FIBRINOLYTIC SYSTEMS - These sustain and
amplify the inflammatory response by interacting with both the complement and kinin
systems.

C. ARACHIDONIC ACID METABOLITES (prostaglandins and leukotrienes) - Once unbound from its
esterified state in the membrane phospholipids (by a variety of mechanisms including
phospholipase A activation), arachidonic acid is metabolized by either the cyclooxygenase pathway
(producing prostaglandins) or the lipoxygenase pathway (producing leukotrienes). Important
products of the cyclooxygenase pathway (which can be inhibited by aspirin and nonsteroidal anti-
inflammatory drugs) include prostacyclin (PGI 2), thromboxane (TXA2), PGE], andfree radicals.
Prostaglandins 12 and E2 act as vasodilators. In addition, prostaglandin E2 may be responsible at
least in part for some of the pain and fever seen in inflammation. TXA2, however, is a potent
vasoconstrictor. Of the lipoxygenase pathway products, leukotrienes C4, D 4, and E4 cause
vasoconstriction and increase vascular permeability. Leukotriene B4 is a potent chemotactic agent
for leukocytes
o. REVIEW OF CHEMICAL MEDIATORS

VASODILA TION histamine, bradykinin, prostaglandins 12 and E2

INCREASED VASCULAR histamine, serotonin, anaphylatoxins (C5a, C3a), bradykinin,

PERMEABILITY leukotrienes (C4, 04, E4), platelet activating factor.

CHEMOTAXIS C5a, leukotriene B4, lymphokines, bacterial products.

FEVER TNF, interleukin-l, PGE2.

PAIN PGE2, bradykinin.

TISSUE DAMAGE free radicals, lysosomal enzymes.

III. PA TTERNS OF ACUTE INFLAMMATION - The clinical appearance of inflammatory lesions and their
exudates may provide clues to the underlying etiology.

A. CAT ARRHAL INFLAMMATION - This is associated with a profuse secretion of watery or mucoid
fluid from a mucous membrane. Example: runny nose.
B. SEROUS INFLAMMATION - This is often the result of mild injury and consists of the extravasation
of an exudate derived from serum or the mesothelial cells lining body cavities. Example: cutaneous
blisters.
C. FIBRINOUS INFLAMMATION - This results in a fibrin-rich exudate which forms shaggy fibrin strands
that may ultimately produce adhesions. Example: "Bread and butter" pericarditis.
o. SEROSANGUINOUS OR HEMORRHAGIC INFLAMMATION - This occurs with highly virulent or
fulminating infections where extensive vascular damage occurs resulting in the extravasation of red
blood cells. Example: meningococcal septicemia.

25
 E. SUPPURATIVE (PURULENT) INFLAMMATION - This indicates the presence of pus which consists
of tissue breakdown products, neutrophils, and in most cases microorganisms. Example: furuncles,
carbuncles.

I. ABSCESS - This is a localized collection of pus associated with liquefaction necrosis of

tissue.
2. EMPYEMA - This is a localized collection of pus in a natural anatomic cavity (usually
pleural cavity).

F. ULCERATIVE INFLAMMATION - This refers to a localized sloughing of inflammatory and necrotic

debris from cutaneous or mucosal surfaces. Example: decubitus ulcer, peptic ulcer.
G. GANGRENOUS INFLAMMATION - This implies enzymatic and bacterial decomposition
(putrefaction) of necrotic (usually ischemic coagulation necrosis) tissue. Example: Gangrene
associated with diabetic peripheral vascular disease.
H. MEMBRANOUS OR PSEUDOMEMBRANOUS IN FLAM MA TION - This refers to the formation of
"membranes" composed of matted fibrin, mucus, and inflammatory cells on focally necrotic
epithelial surfaces. Example: pseudomembrane of diphtheria or clostridia infections.

IV. MANIFESTA TIONS OF ACUTE INFLAMMATION

A. SYSTEMIC MANIFESTATIONS - These may include fever (effects of prostaglandin E2 and

endogenous pyrogens such as interleukin-I and tissue necrosis factor produced and released by
activated macrophages), shaking chills, weakness, muscle aching, etc.
B. LABORATORY FINDINGS - Any inflammation of clinical significance is usually reflected by an
increase in the total number of leukocytes circulating in the peripheral blood (normal =
6,OOO-8,OOO/ml. blood) which is called leukocytosis. Leukocytosis may be accompanied by
increased percentage of immature neutrophils in the peripheral blood ("left sh(ft',). Extreme
elevations of the white blood cell count are referred to as leukemoid reactions and may approach
the leukocyte counts encountered in some leukemias. There is also increased hepatic synthesis of
"acute phase proteins" (C-reactive protein, complement, fibrinogen, etc.) induced by the action
of the monokines interleukin-I and TNF-a. The erythrocyte sedimentation rate increases (due to
polyclonal hypergammaglobulinemia and hyperfibrinogenemia which decreases the red cell zeta
potential and promotes rouleaux formation), and blood becomes hypercoagulable. These findings,
however, only indicate the probable existence of inflammation. They do not reflect where the
inflammation is occurring or what the etiological agent might be.

v. CHRONIC INFLAMMATION - This may arise following an acute inflammatory reaction in which the
inciting agent is not destroyed or with repetitive bouts of acute inflammation. Alternatively, however,
chronic inflammation may begin as a low grade, smoldering response to persistent infection by organisms
with low virulence, prolonged exposure to nondegradable but toxic substances (silica in the lung), or
autoimmune reactions (rheumatoid arthritis) without ever showing the classical signs of acute
inflammation. In any event, the host response is more of an immunologic response than an acute
inflammatory response. It should be noted, however, that in some instances, acute and chronic
inflammation may coexist for long periods of time (i.e. chronic osteomyelitis).

A. CHRONIC INFLAMMATION - This is characterized by a proliferative (fibroblastic) response rather

than the exudative response seen in acute inflammation. Histologically, the inflammatory cells are
primarily mononuclear (macrophages, lymphocytes, and plasma cells) rather than the
polymorphonuclear cells that are seen in acute inflammation, and there is overlap with the

26
 developing immunologic response to injury. Chemotactic mediators (lymphokines) attract and then
immobilize additional mononuclear cells at the site of injury. They are interspersed among the
proliferating fibroblasts and capillanes that are preparing for tissue repair. Chronic inflammation
is often associated with subsequent scarring and deformity of the involved tissues.
B. GRANULOMATOUS INFLAMMATION - This refers to a specific pattern of chronic inflammation
which may occur in response to a variety of agents (esp. mycobacteria, foreign bodies, fungi)
which are indigestible or have low antigenicity. They may also be seen in various "immunologic"
disorders (sarcoidosis, primary biliary cirrhosis, etc). Granulomas are the pathologic hallmark of
this pattern of chronic inflammation and consist of small, nodular (1-2 mm) collections of modified
(perhaps by lymphokines) macrophages known as epithelioid cells. These are almost invariably
surrounded by a rim of fibroblasts and mononuclear cells, principally lymphocytes. There mayor
may not be central caseous necrosis. Giant cells (formed by a syncytium or fusion of epithelioid
cells) are often, but not always, found within the granuloma.

PRINCIPLES OF IMMUNOLOGY

The immunologic response may be evoked by any substance (antigen) which the body perceives as "foreign".
The ability of an antigen to evoke an immune response is determined by its size, shape, solubility, and chemical
structure. The immunologic response results in the formation of antibodies (humoral immune re.sponse) and/or
reactive cells (cellular immune re5ponse) that are directed against specific regions (epitopes) of the antigenic
molecule. The cells of the immune system are initially "programmed" by the central lymphoid organs (thymus
and bone marrow) and then circulate throughout the vascular and lymphatic systems or take up residence in
peripheral lymphoid organs and tissues (lymph nodes, spleen, mucosal associated lymphoid tissue, etc). These
peripheral organs and tissues function, in part, to identifY and process antigens so that an immune response can
be mounted against them. The lymph nodes monitor the lymphatic system, the spleen monitors the blood, and
the mucosal associated lymphoid tissue (MALT) monitors substances traversing the various mucous
membranes. As with the inflammatory response, however, exuberance of the immune response can result in
significant unintended tissue damage.

I. IMMUNE REPONSES

A. HUMORAL IMMUNE RESPONSE - This is the process in which an antigen evokes the production of
circulating antibodies (immunoglobulins) to that antigen. The basic structure of an immunoglobulin
is four polypeptide chains, two heavy chains and two light chains held together by disulfide bonds.
Each immunoglobulin has a portion composed of a constant sequence of amino acids (F J and a
portion composed of a variable sequence (F ab). The variable sequence allows antigen specificity,
and the constant sequence directs the biologic activity. The constant sequence of the heavy chains
subdivides the immunoglobulin into one of five classes.

1. IgM - This is the class of immunoglobulins first formed in response to an antigenic

challenge and is comprised offive basic immunoglobulin structural units held together by
a short polypeptide chain (J chain). It is effective in agglutinating antigen, activating
complement, and lysing cell walls.
2. IgG - This comprises over 85% of the circulating antibodies and is the only
immunoglobulin which can cross the placenta from mother to fetus. Several subtypes with
slightly different biologic function exist.

27
 3. IgA - This is present in the blood but is also secreted onto surface membranes (secreto!)'
IgA) to help protect against invasion by antigens.
4. IgE - This mediates allergic reactions and is found bound to mast cells primarily in and
around respirato!)' and intestinal mucosa.
5. IgD - This comprises a small percentage of circulating antibodies, and its function is
unknown. It may playa role in the development and maturation of the immune system.

B. CELLULAR IMMUNE RESPONSE - This is the process in which an antigen evokes the production of
"activated" killer T-Iymphocytes sensitized to that specific antigen. These lymphocytes playa major
role in cell-mediated immune responses such as graft and tumor rejection, delayed hypersensitivity
reactions, and immunity to certain microbiologic antigens (TB, fungi, etc.). In addition to their
cytotoxic effects, these cells also secrete various lymphokine mediators that enhance the number
of "activated" lymphocytes both in the area of antigenic challenge and throughout the body. They
also act to attract, retain, and enhance the phagocytic activity of macro phages in the area while
serving as chemotactic agents for other inflammato!), cells.

II. REACTION TO ANTIGEN - Certain antigens, termed thymus-independent antigens, will stimulate only
the B-cell (humoral) response and result in the production of primarily IgM antibodies. Other antigens
primarily stimulate the T-cell (cell-mediated) response and, in the presence of interleukin-l, result in the
production of sensitized T -lymphocytes. Most antigens, however, stimulate both T and B-cells. The initial
B-cell (humoral) response results in the production ofIgM antibodies which first appear after a lag time
of about several days, reach a peak at about two weeks, and then decline. The more antigen-specific IgG
antibodies appear around day 10, reach a higher peak and remain at a high level for a longer period of time
than the IgM, antibodies. The T-cells may interact to regulate the B-cell response. T-helper cells can
enhance the B-cell response and T -suppressor cells can suppress the B-cell response. T -cells also enable
the activated B-cells, during their maturation into plasma cells, to switch from the initial IgM antibody
production to IgG antibody production. The complement cascade is activated, in most instances, by
reaction ofCI with an antigen-antibody complex. The bypro ducts of the cascade act variously to promote
vascular permeability, phagocytosis, chemotaxis of inflammato!)' cells, and lysis of cell membranes.
III. IMMUNOLOGIC MEMORY - The T and B-memo!)' cells that are produced after the first exposure to
an antigen allow the immune response, upon subsequent exposure to that antigen, to react more rapidly
and to produce greater quantities of antibody (primarily IgG) and/or "activated" T -cells than occurs with
the initial response.
IV. IMMUNOLOGIC COMMUNICATION - The major histocompatibility complex (MHC) is a sequence
of genes on the short arm of chromosome 6 that codes for various antigens (HLA) that are expressed on
the cell surface. These genes are polymorphic in that there are numerous combinations of different alleles
at each gene locus that allows each individual a close to unique set of antigens. Class I antigens (HLA-A,
HLA-B, HLA-C) are present on all nucleated cells and platelets and are important in recognition of self,
non-self, and virally infected cells. Class II antigens (HLA-D) are expressed on B-cells, antigen
processing/presenting cells, and some activated T -cells and are important in cell to cell interactions
regarding regulation of immune responses. It becomes apparent therefore that surface immunoglobulins,
class I and II histocompatibility anitgens, T-cell receptors, T -helper and T -suppressor cell markers, etc
allow for intimate and complex cell-to-cell interactions that regulate immune responsiveness.
V. DISORDERS RELATED TO THE IMMUNE SYSTEM

A. IMMUNE DEFICIENCY DISEASES

1. THYMIC APLASIA (DiGeorge's syndrome) - This results from emb!)'ologic failure of the
third and fourth pharyngeal pouches, and therefore the thymus (and parathyroid glands),

28
 to develop. These persons are unable to develop aT-lymphocyte immune response and
therefore lack cellular immunity. In addition, because of the lack of T -helper cells,
antibody production may be impaired as well. These persons are especially vulnerable to
viral and fungal infections.
2. INFANTILE AGAMMAGLOBULINEMIA (Bruton'S agammaglobulinemia) - This is a sex-
linked recessive disease in which there IS failure of B-cell maturation and therefore failure
of the humoral immune response. These persons have very small quantities of
immunoglobulin in their serum and are vulnerable to severe bacterial infections.
3. ALYMPHOCYTIC AGAMMAGLOBULINEMIA (Swiss Type agammaglobulinemia, severe
combined immunodeficiency disease) - This is an autosomal recessive inherited disease
in which there is a defect in the lymphocyte stem cell population. There is a marked
decrease in the number oflymphocytes and thymic hypoplasia. Therefore, there is neither
a humoral nor a cellular immune mechanism. Unless bone marrow transplantation is
successful, these persons usually die early in childhood from recurrent severe infections.
4. ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) - This is the result of lymphocyte
(primarily T-helper cells) destruction by the human immunodeficiency virus. This
interferes with both humoral and cellular immunity and these patients are therefore
susceptible to a wide variety of infections.

B. HYPERSENSITIVITY REACTIONS - As mentioned previously, occasionally the immune response may

be injurious to the host. These responses are termed hypersensitivity reactions and can be divided
into four categories depending on the mechanism of tissue damage involved. The first three are
immediate hypersensitivity reactions and involve the humoral immune response. The fourth is
a delayed hypersensitivity reaction and involves the cell mediated immune response.

1. TYPE I (anaphylaxis/atopy) - In this reaction, antigen reacts with IgE antibodies that have
previously been bound to the surface membrane of mast cells. This causes the release of
histamine and other chemotactic chemicals from the mast cell granules initiating the typical
allergic response. This occurs most commonly in tissues exposed to extemal antigens
(skin, respiratory tract, GI tract). Allergic asthma, urticaria (hives), food allergies,
hayfever, and anaphylaxis are a few of the diseases mediated by this mechanism.
2. TYPE II (cytotoxic/cytolytic hypersensitivity) - In this reaction, circulating antibodies attack
antigens that are bound to, or are a component of, another cell's membrane. Antigen-
antibody interaction promotes phagocytosis of the target cell by macro phages or,
aitematively, it may activate the complement cascade and result in cell lysis. Autoimmune
hemolytic anemias, hemolytic disease of the newborn, blood transfusion reactions,
Goodpasture's syndrome, and certain drug reactions are mediated by this mechanism.
3. TYPE III (immune complex disease) - Antigen normally reacts with antibody to form an
antigen-antibody (immune) complex which is rapidly cleared from the circulation and
tissue spaces by phagocytic cells. Under certain conditions, these complexes may not be
eliminated and become deposited in tissue (especially organs that filter the circulation such
as the kidneys) where they trigger the formation of chemical mediators (via activation of
complement, etc) that promote and enhance phagocytosis, acute inflammatory reactions,
and tissue destruction. Systemic lupus erythematosus (SLE), other "autoimmune" diseases,
serum sickness, and the Arthus reaction are diseases mediated by this mechanism.
4. TYPE IV (delayed hypersensitivity, cell-mediated hypersensitivity) - In this reaction,
antigen reacts not with circulating antibodies, but with specifically "activated" T-
lymphocytes. The resultant release of lymphokines enhances the inflammatory response
to the antigen (delayed hypersensitivity). Alternatively, there may be direct T -lymphocyte

29
 mediated target cell destruction. TB skin tests, certain aspects of graft rejection, and some
"autoimmune" diseases are mediated by this mechanism.

C. TRANSPLANT/GRAFT REJECTION - Rejection involves both humoral and cell-mediated

mechanisms. Sensitized lymphocytes react to the foreign graft proteins and release lymphokines
chemotactic for macro phages and neutrophils. T -cells directly target the foreign cells and help
augment B-cell antibody production.
D. AUTOIMMUNE DISEASE - As mentioned earlier, these diseases appear to result from an immune
response mounted against the body's own tissue. They range from tissue specific diseases such as
autoimmune hemolytic anemia, rheumatoid arthritis, and Hashimoto's thyroiditis to systemic
diseases such as systemic lupus erythematosus (SLE) and progressive systemic sclerosis
(scleroderma). Most of these diseases have demonstrable circulating autoantibodies and/or
sensitized T -cells which may be directed against almost any circulating or tissue antigen which is
recognized as "foreign." These may be specific cell surface antigens, immunoglobulins, DNA, etc.

30
 PRINCIPLES OF INFECTIOUS DISEASE

I. RELA TIONSHIPS OF ORGANISMS - All organisms must compete for survival (nutrients,
environment, etc.) and must therefore establish some type of relationship to each other. This can be
commensal in which one organism can supply the needs of another without itself being harmed, ,symbiotic
in which each organism supplies the needs for the other without harm to either, or pathogenic in which one
organism will obtain its needs at the expense of another organism. "Clinical disease" results only when a
microorganism evokes sufficient anatomic and/or functional damage to the host in the course of obtaining
the necessary requirements for its survival.
II. HOST DEFENSE MECHANISMS

A. MECHANICAL BARRIERS

1. SKIN - Unbroken skin presents an impenetrable barrier to external organisms. In addition,

the normal acidic pH of the skin is unfavorable to many microorganisms.
2. INTERNAL SURFACES - Generally, surfaces which have high flow rates of secretions,
excretions, or mucus (lower respiratory tract, upper urinary tract, biliary system, etc) are
sterile while those surfaces that have a relatively low flow rates usually develop a surface
flora which under normal circumstances is in equilibrium with its environment and does
not invade below the surface (upper respiratory tract, colon).

B. CHEMICAL BARRIERS

1. pH - Although the value may vary, most organisms can only survive within a narrow pH
range.
2. MUCIN - Secreted by various body membranes, mucin traps bacteria before they can reach
the cell surface.
3. SECRETORY IgA - This is elaborated locally by various membranes and can neutralize
microorganisms before they get a chance to invade tissue.
4. LYSOZYME - This is an enzyme found in almost all tissue but has a high concentration in
tears, saliva, and intestinal mucus. It can kill certain types of bacteria.
5. INTERFERON - This is a protein that will inhibit viral replication and which can be
produced by most cells in response to appropriate stimulation.

C. HOST INFLAMMATORY RESPONSE - acute, chronic, granulomatous

D. HOST IMMUNOLOGIC RESPONSE - humoral, cell-mediated

31
III. DISTURBANCES IN HOST DEFENSE - Infectious disease is ultimately due to failure of the host
defense mechanisms to exclude microorganisms from the internal tissues of the body or failure to eliminate
or neutralize the injurious effects of those organisms in their attempt to grow and replicate. The severity
of disease is related to the number of infective organisms, to the virulence (aggressiveness) of those
organisms, and to the status of the host defense mechanisms. Factors which can interfere with host defense
mechanisms, therefore increase the susceptibility of the host to infectious disease and include hereditary
or acquired inununodeficiency diseases; drugs (steroids or other immunosuppressants, antibiotics, alcohol);
acute or chronic debilitating disease; old age; etc.
IV. INNOCULATION - This refers to the introduction of organisms into the body. Once an organism gains
entrance to the body, there is a "decisive period" before internal defense mechanisms become activated.
During this period, if the organisms are destroyed, the infection is resolved; if the organisms are not
destroyed but prevented from multiplying, a latent or smoldering infection ensues; and if the organism is
able to multiply, overt infection results.
V. VIRULENCE - This indicates the potential of an organism to induce disease. Factors which determine
the virulence of an organism include the ability to:

A. FIND A PORTAL OF ENTRY (area where organisms may gain access to the body)
B INVADE THE TISSUE - Various organisms can elaborate extracellular enzymes, termed aggressins,
which facilitate invasion.

I. LEUKOCIDINS - These are enzymes which act to neutralize or destroy the phagocytic
macro phages and neutrophils.
2. CLUMPING FACTORS - These allow some organisms to cluster together so that higher
concentrations of leukocidins are built up. Coagulase converts fibrinogen to fibrin, and
fibrin clots in the surrounding blood vessels seal off the area from circulating antibodies.
These organisms tend to result in focal infection with abscess formation.
3. SPREADING FACTORS - These enable some organisms to disseminate rapidly.
Hyaluronidase (dissolves tissue ground substances), kinase (aids in fibrinolysis), and
collagenase (dissolves collagen) create a fluid environment that tends to inhibit
phagocytosis.

C. RESIST HOST DEFENSE MECHANISMS

1. STRUCTURAL PROPERTIES - Many organisms can elaborate capsules which inhibit the
intimate contact of leukocytes that is necessary for phagocytosis.
2. FUNCTIONAL PROPERTIES - Organisms that can mutate and alter the structure of native
antigens can render the immune response ineffective.

D. ELABORATE TOXIC PRODUCTS

I. EXOTOXINS - These are produced by living organisms and can cause cellular and tissue
damage in remote areas.
2. ENDOTOXINS - These may be released by dying organisms and can cause systemic effects
(fever, shock, DIe) when absorbed into the blood stream.

E. INDUCE HYPERSENSITIVITY REACTIONS

32
VI. REQUIREMENTS FOR GROWTH - The nature of the disease that a specific organism can produce
depends greatly on that organism's requirements for growth and replication.

A. EXTRACELLULAR PARASITES - These usually evoke an acute inflammatory response and a

humoral immune response.
B. INTRACELLULAR PARASITES (whetherjacultative or obligate) - These usually evoke a chronic
inflammatory response and a cell-mediated immune response. When organisms live inside a host
cell, they are also more resistant to antibiotic drugs.
C. PREFERENTIAL LOCALIZATION OF ORGANISMS

1. SPECIES SPECIFIC - Some organisms are able to live and reproduce in only one species of
host.
2. TISSUE SPECIFIC - Some organisms are able to live and reproduce in only certain types of
tissue.

VII. CLINICAL MANIFESTATIONS OF INFECTIOUS DISEASE

A. INCUBA TION PERIOD - With all infectious diseases there is a time lag between invasion and the
development of clinical symptoms. This time lag varies with the etiological agent and is usually
specific for that agent.
B. LOCAL REACTIONS - The "classical" signs of inflammation, i.e. swelling, heat, pain, redness, loss
of function.
C. SYSTEMIC REACTIONS

1. MALAISE
2. INCREASED FATIGUE
3. MUSCLE ACHES AND PAINS
4. DECREASED BLOOD VOLUME (as fluid leaks into the tissues from the circulation during
the inflammatory response) - This results in increased heart rate (tachycardia), increased
breathing (tachypnea), and decreased urine output (oliguria).
5. FEVER/CHILLS - Increased metabolic demands and increased catabolism results in loss of
nutrients and loss of weight. There is also increased insensible water loss via sweating
(diaphoresis), tachypnea, etc.

33
 PRINCIPLES OF WOUND HEALING AND
TISSUE REPAIR

As a continuation of the inflammatory process, wound healing is a phenomenon consisting of sequentially

controlled steps which result in the replacement of dead tissue with regenerated cells and/or scar tissue. If the injury
did not involve structural damage to the tissue, regeneration of new cells can restore original function (resolution).
In most instances, however, there is at least some degree of connective tissue scarring and functional impairment
of the involved tissue (organization). Understanding of the injury-repair process is important to be able to facilitate
those factors that promote wound healing and minimize those factors that inhibit wound healing.

I. REPAIR BY REGENERATION - Effective repair by regeneration is dependant on the regenerative

capacity of each cell type.

A. LABILE CELLS - These are cells which multiply continuously throughout life to replace other cells
that are lost through normal physiological processes (all epithelial surfaces, ducts, lymphoid and
hematopoietic tissue, etc). These cells are continuously in the cell cycle and replacement of
damaged cells is relatively rapid.
B. PERMANENT CELLS - These are cells that do not have the ability to regenerate. These include
striated and cardiac muscle cells (there is still a question whether or not these cells can regenerate
to a limited degree under special circumstances, but in any case, they cannot regenerate to any
clinically significant degree) and neurons (neurons of the peripheral nervous system are capable
of regenerating axons along the lines of the destroyed axon as long as the cell body is not damaged,
but neurons of the central nervous system cannot regenerate).
C. ST ABLE CELLS - These are cells which retain the ability to regenerate but do not do so under
normal circumstances (hepatocytes, renal tubular epithelial cells, glandular parenchymal cells,
endothelial cells, mesenchymal cells, etc). These cells are in the Go phase of the cell cycle and the
mechanism(s) by which these cells are stimulated to reenter the cell cycle and proliferate is not
entirely known. Current hypotheses include:

1. STiMULA TlON BY GROWTH FACTORS - Growth factors are polypeptide proteins which
attach to cell membrane receptor sites on various types of cells and either promote DNA
replication (progression factors) or "prime" the cell for DNA replication (competence
factors).

a. Epidermal growth factor (EGF) - This is a progression factor which enhances

epidermal proliferation and stimulates, at least in culture, division of fibroblasts.
EGF has been isolated from human urine.

34
 b. Transforming growth factor a (TGFa) - This has essentially the same
properties as EGF.
c. Platelet-derived growth factor (PDGF) - This is a competence factor found in
the alpha granules of platelets and stimulates migration and proliferation of
fibroblasts, smooth muscle cells, and monocytes.
d. Fibroblast growth factor (FGF) - In addition to the same stimulatory activity as
platelet-derived growth factor, this will stimulate proliferation of endothelial cells
and promote angiogenesis.
e. Macrophage-derived growth factors - Macrophages can be induced to secrete
a variety of growth factors as well as growth inhibitors.

2. LOSS OF CONTACT INHIBITION - This appears to stimulate cell division by unknown cell
interactions.
3. DECREASE IN CELLULAR DENSITY - This also appears to stimulate cell division by
unknown cell interactions.

II. REPAIR BY SCAR FORMATION - The repair of injured tissue generally involves, to some extent, the
production (by fibroblasts) of collagen to produce a scar that will replace structurally damaged tissue.

A. COLLAGEN SYNTHESIS - Approximately eleven different forms of collagen have been identified
and each has a distinctive distribution in the various tissues of the body. Types I, II, and III are
fibrillar in structure and found in interstitial spaces with Type I being the predominant collagen in
skin, bone, and most organs. Types IV - XI are non-fibrillar (amorphous) and in addition to an
interstitial presence are also found as a constituent of basement membranes. The basic collagen
molecule (tropocollagen) is a coiled left-handed helix composed of three polypeptide alpha chains
which may be biochemically identical or biochemically (and genetically) distinct. It is the
biochemical character of the three alpha chains which determines the collagen type. Like any
protein, synthesis of collagen begins with translation of ON A and transcription on the ribosomes
of the "activated" fibroblasts to form the alpha chains of procollagen. Before excretion from the
cell by the golgi apparatus, procollagen is modified in the endoplasmic reticulum by hydroxylation
of proline and lysine (hydroxyproline and hydroxylysine are prominent components of collagen)
utilizing vitamin C as a cofactor. The hydroxylysyl residues are glycosylated and disulfide bonds
are formed to help produce the coiled or helical nature of the molecule. As the procollagen is
secreted from the fibroblast, it is made insoluble by enzymatic (procollagen peptidase) cleavage
of N- and C- terminal "noncollagen" peptides. These immature collagen molecules then
spontaneously aggregate and are "cross-linked" by oxidation of the lysyl and hydroxylysyl residues
by the enzyme lysyl oxidase (which contains copper). This enzyme also produces the cross linking
of the elastic fibers (also secreted by fibroblasts) which provide elastic recoil to tissue.
B. HEALING BY FIRST INTENTION (primary union) - This refers to the repair process involved with
surgical incisions where the margins of the wound are closely coapted by sutures or other methods.
There is very little loss of tissue substance and a minimal amount of inflammatory exudate and
necrotic debris. The process can be exemplified by the healing of a cutaneous surgical incision.

At first, the increased vascular permeability resulting from the inflammatory response initiated by
the tissue injury produces a fibrin-rich exudate (or a blood clot) which fills the space between
wound margins. As this dehydrates, it forms a surface scab which, among other things, seals the
wound against invasion by microorganisms. Beneath the scab, in response to stimulatory factors,
surface epithelial cells from the wound margins begin to migrate toward the midline within 24
hours of the injury, and by 48 hours a tenuous single layered epithelium covers the surface of the

35
 wound. Further proliferation and differentiation of the epithelial cells subsequently occurs (which
on the skin surface produces the characteristic stratified squamous epithelium) but once re-
epithelialization is complete, the cells cease their proliferation possibly due to a variety of growth
inhibitors (transforming growth factor 13, ex interferon, prostaglandin E 2 , heparin) that are also elab-
orated during the inflammatory and repair process.

Within the first twenty four hours, polymorphonuclear leukocytes accumulate at the margins of the
wound as part of the acute inflammatOIY response to the tissue injury. Fibrin strands, formed from
the inflammatory exudate and coated by plasma fibronectins, are chemotactic for macrophages and
fibroblasts and also act as "scaffolding" to facilitate the influx of these cells to the area of injury.
By the second day, fibroblasts from the healthy wound margins are "activated" (increased cell size
due to increase in the rough endoplasmic reticulum), perhaps by growth factors derived from
platelets (PDGF), macrophages (interleukin-l), or damaged tissue. They begin to infiltrate the
injured area and, in addition to collagen and elastic fibers, they also secrete ground substance
(glycosaminoglycans, proteoglycans, glycoproteins) and additional fibronectins.

Macrophages begin to replace the neutrophils around the third day and, in addition to cleaning up
cellular debris along the wound margins, they secrete factors which act in concert with the
fibronectins secreted by the fibroblasts to promote angiogenesis and neovascularization of the
wound. Endothelial cells proliferate and develop a lumen, but are "leaky" and allow protein and
fluid to escape into the surrounding tissue. This enhances the inflammatory edema but also supplies
nutrients to the metabolically active macro phages and fibroblasts. This combination of neo-
vascularity, "activated" fibroblasts and mixed inflammatory infiltrate (mostly macrophages)
embedded in an edematous ground substance is termed granulation tissue and is generally present
by the fifth day. From this point, the fibroblasts continue to secrete collagen and other ground
substances. As the inflammatory infiltrate subsides and the collagen becomes more abundant, the
vessels are slowly crowded out to produce a relatively acellular, avascular scar.
e. HEALING BY SECOND INTENTION (secondary union) - This refers to the repair process involved
when there is sufficient loss of tissue to prevent coaptation of the wound margins (abscesses,
ulcers, infarctions, etc.). Generally, there is extensive inflammatory exudate and necrotic debris that
must be removed before healing can occur.

In this situation, there is a slow, gradual buildup of granulation tissue beginning at the margins of
the wound and growing inward at a rate of approximately 0.1 - 0.2 mm/day. The exposed
granulation tissue is subject to trauma, and due to the delicate nature of the newly formed
capillaries, is prone to bleed. Migration of surface epithelium can progress only so far as the
underlying granulation tissue and therefore it takes longer for the wound to be isolated from the
surrounding environment increasing the likelihood of infection.

Wound contraction is a phenomenon that occurs in secondary union. Since the wound margins
cannot be coapted, myofibroblasts (fibroblasts containing myofilaments) at the edges of the wound
contract and can significantly reduce the volume of the area that must be filled with granulation
tissue and subsequent scar. Although usually advantageous, wound contraction can occasionally
be deleterious in that it may lead to disfiguring scars, "frozen" joints, etc.
D. DEVELOPMENT OF WOUND STRENGTH - As soon as granulation tissue is established and
fibroblasts begin to secrete new collagen, the tensile strength of a wound begins to increase
although not in a linear fashion. Much like the repair of bone fractures, there is resorption and
remodeling of collagen as it is deposited, but the total collagen content of a wound increases faster
than the tensile strength of a wound. Tensile strength depends as much on the type of collagen

36
 deposited as the amount. Early in wound healing, type III collagen (which has a relatively low
tensile strength) is secreted, but as the scar matures and the collagen is remodeled, Type I collagen
(which has a greater tensile strength) becomes predominant. Although opinions vary, after
approximately 100 days, seventy to ninety percent of the original tissue strength is restored, but a
scar is never as strong as the original tissue and, of course, is non-functional in terms of
parenchymal function.
E. ABERRATIONS OF CONNECTIVE TISSUE PROLIFERATION

1. EXUBERANT GRANULATION (proud flesh) - This refers to the excessive buildup of

granulation tissue which protrudes above the surface of the wound and prevents re-
epithelialization.
2. KELOID FORMATION - This refers to a buildup of excessive amounts of collagen leading
to disfiguring scars. Although the cause is unknown, there does seem to be a genetic
predisposition to forming keloid scars.

III. REQUIREMENTS FOR PROPER WOUND HEALING

A. ADEQUATE BLOOD SUPPLY - This is an essential factor in order to combat infection and meet the
requirements of metabolically active tissue.
B. ADEQUATE NUTRITION - Protein deficiency interferes with collagen synthesis and the proper
formation of ground substance; Vitamin C deficiency interferes with the production and tensile
strength of collagen; and zinc deficiency interferes with DNA and RNA synthesis.
e. ADEQUATE CLEANSING - The removal of dead tissue and foreign debris is necessary to prevent
infection and will expedite the healing process.
D. PROTECTION FROM TRAUMA - Granulation tissue is easily disrupted and repeated trauma or
movement retards the healing process.

37
 PRINCIPLES OF NEOPLASIA

Neoplasia refers to a "new growth" of abnormal tissue (usually derived from a single cell precursor) that serves
no physiologic function and, for the most part, is independent of normal restraints on orderly growth. Normally,
cells do not replicate unless they are stimulated by exogenous growth factors released in response to physiologic,
pathologic, or reparative demands. Neoplastic cells, however, are characterized by the ability to replicate in the
absence of these exogenous growth factors. Although inherited genetic influences unquestionably playa direct role
in the development of certain neoplasms, epidemiologic evidence suggests that 75-90% of human neoplasia is due
to environmental factors. Indeed, tissues most directly exposed to the environment (skin, respiratory tract,
gastrointestinal tract, etc) tend to show higher rates of neoplastic transformation. Evidence also suggests that
neoplastic transformation is a progressive process involving multiple steps and that in the majority of cases,
neoplastic transformation involves somatic mutations of the cellular DNA. It appears, therefore, that neoplasia is,
in essence, a "genetic" disease in that the fundamental cellular changes occur at the level of DNA but that these
changes are induced by environmental factors.

I. NOMENCLATURE - "Tumors" are denoted by the suffix "-oma". This usually indicates a neoplastic
process but occasionally may be applied to a non-neoplastic mass (hematoma, granuloma, xanthoma, etc).
An unmodified suffix generally denotes a benign neoplasm while for malignant neoplasms, the suffix is
modified to either carcinoma (referring to epithelial malignancies) or sarcoma (referring to
mesenchymaVconnective tissue malignancies). Notable exceptions include, but are not limited to, the terms
melanoma (malignant neoplasm ofmelanocytes), lymphoma (malignant neoplasm oflymphoid tissue), and
glioma (malignant neoplasms of supporting tissue of the eNS). A teratoma is a neoplasm which contains
cells from more than one germ cell layer and may be benign or malignant while a hamartoma is a non-
neoplastic "tumor" that represents abnormal overgrowth or differentiation of cells native to the tissue of
origin. Prefixes generally denote the cell of origin, microscopic architectural growth patterns, and/or gross
features.

A. PREFIXES INDICATING CELL OR TISSUE OF ORIGIN - These include squamous (squamous

epithelium), adeno- (glandular epithelium), transitional (transitional epithelium),fibro- (fibrous
connective tissue), leiomyo- (smooth muscle), rhabdomyo- (skeletal muscle), /ipo- (adipose
tissue), chondro- (cartilage), osteo- (bone), hemangio- (blood vessel), lymphangio- (lymphatic
vessel), etc.
B. PREFIXES INDICATING ARCHITECTURAL GROWTH PATTERN - These includefollicular (forming
follicles), cyst (forming cystic spaces), papillary (forming "nipple-like" projections), villous
(forming shaggy, "finger-like" projections), cribr~form (pierced by small holes), etc.
C. PREFIXES INDICATING GROSS FEATURES - These include scirrhous (hard), medullary (soft,
resembling marrow), colloid (gelatinous, mucinous), etc.

38
II. FEA TURES OF BENIGN AND MALIGNANT NEOPLASMS - The distinction between benign and
malignant tumors is based on their microscopic appearance and clinical behavior. Although there may be
similarities between benign and malignant tumors, differences generally relate to:

A. CELLULAR DIFFERENTIATION - This refers to the extent to which neoplastic cells resemble their
cell of origin. In general, benign neoplasias are well differentiated (i.e. closely resemble their cell
of origin) and retain functional capabilities. Malignant cells, however, may range from complete
lack of differentiation (anaplasia) to well differentiated. Anaplasia is characterized by cellular and
nuclear pleomorphism (due to alterations in the cell cytoskeleton); increased nuclear/cytoplasmic
ratio; increased nuclear chromatin which is frequently "clumped" along an irregular nuclear
membrane; large nucleoli; bizarre mitoses; loss of cellular orientation; and to some degree, loss
of normal functional capacity.
B. RATE OF GROWTH - This tends to parallel the degree of differentiation of the neoplastic cells.
Benign neoplasias generally show slow growth or may, on occasion, spontaneously regress. In
relative tenns, malignant neoplasms tend to grow more rapidly and rarely cease growth or regress.
C. MODE OF GROWTH - Benign neoplasms grow by expansion and tend to compress the surrounding
tissue into a "capsule" that separates the tumor from normal tissue. Malignant tumors, however,
grow by infiltration and invasion of the surrounding tissue and are not confined by a capsule.
D. METASTASIS - This refers to spread of a neoplasm to points that are not contiguous with the
primary lesion. Benign tumors do not metastasize, but all malignant neoplasms have
metastatic potential (although they do not all do so). In general, metastases occur via:

1. LYMPHATIC DISSEMINATION - This is the most common route of metastasis, especially of

epithelial neoplasms (carcinomas) and follows the natural lymphatic drainage of the site
of malignancy. Regional lymph nodes may be enlarged due to metastatic tumor or to
immune reaction to the presence of tumor products.
2. HEMATOGENOUS DISSEMINATION - This is characteristic of connective tissue neoplasms
(sarcomas). Carcinomas, however, are also spread by a hematogenous route since there
are vascular-lymphatic anastomoses. Invasion and metastases are more likely to occur via
the venous system (as opposed to the arterial system) due to its thin walled structure.
3. TRANSCOELOMIC SEEDING - This may occur with malignancies that involve coelomic
(peritoneal, pleural) surfaces.
4. TRAUMATIC SEEDING - Excessive manipulation or cutting into malignant tumors may
detach and carry small portions of the tumor to other sites.

III. CLINICAL SIGNIFICANCE OF NEOPLASIA

A. ANA TOMIC LOCATION - Both benign and malignant neoplasms may cause significant morbidity
or kill patients by virtue of their anatomic position (pituitary adenomas, craniopharyngiomas,
meningiomas, etc). Even small tumors may cause sudden death by interfering with vital functions
(brain stem, conduction system of heart, etc).
B. LOCAL EFFECTS - Both benign and malignant neoplasms may cause compression of surrounding
structures. Malignant neoplasms, however, are more prone to infarction, necrosis, hemorrhage,
ulceration, and infection. They may also stimulate excessive production of connective tissue
(desmoplaSia).
C. SYSTEMIC EFFECTS - Some tumors (benign or malignant) may produce hormones or hormone-like
substances that can have systemic effects (hypercalcemia, Cushing's syndrome, SIADH, etc). Other

39
 effects may relate to hypercoagulability. thrombocytopenia, migratory thrombophlebitis, cachexia,
sepsis, electrolyte imbalances, etc.

IV. FEATURES OF MALIGNANT CELLS - Malignant transformation requires that cells acquire an
extensive variety of traits that are not present in their normal state. In tissue culture, neoplastic cells appear
to be freed from normal regulatory controls and have an increased rate of stem cell renewal. Their growth
is no longer inhibited by the presence of neighboring cells (i.e. loss of contact inhibition). Unlike normal
cells, they do not require attachment to a hard surface to proliferate (anchorage independent growth). They
require fewer, if any, exogenous growth factors and in general are immortal (i.e. cell lines can be kept alive
indefinitely). They can develop invasive properties (probably related to cytoskeletal changes or production
of enzymes induced by oncogene activation) and metastatic potential. When injected into other animals,
these cells will produce neoplasms (transplantibility).
V. PROTO-ONCOGENES, ONCOGENES, AND ANTI-ONCOGENES - The numerous changes that
have to occur to transform a normal cell into a malignant cell suggests that there may be changes in a
smaller number of "regulators" each of which directs multiple parameters of cell function (pleiotropy).
Specific genetic information that was capable of transforming normal cells into neoplastic cells was first
identified in small DNA viruses and RNA tumor viruses (retroviruses) that were known to produce cancer
in animals. These genetic segments were called viral oncogenes (v-one). It was discovered, however, that
the retroviral segments were not of viral origin but were very similar to genetic sequences found in normal
cellular DNA implying that they had at some point in the past been incorporated into the ancestral viral
genome while the virus was replicating within an infected neoplastic cell. Additionally, since these viruses
rarely cause human cancer, it was postulated that something other than viral oncogenes may also be
responsible for neoplastic transformation. This meant that a normal cell must contain genetic information
that could potentially transform that cell into a neoplastic cell under appropriate conditions. These naturally
occurring cellular genetic segments were termed proto-oncogenes and, surprisingly, were found in almost
all life forms and coded for almost identical protein products indicating that, under normal circumstances,
they must playa fundamental role in normal cell physiology (probably related to regulation of cell division
and differentiation). Through transfection (gene transfer) experiments, it was shown that genetic material
from a neoplastic cell could transform a normal cell into a neoplastic cell, and the genetic sequences
capable of inducing transformation were termed cellular oncogenes (c-onc). These were found to be
similar in structure to normal gene sequences (proto-oncogenes) and may have arisen through simple
somatic mutation of the proto-oncogenes. Proto-oncogenes, therefore, have the potential of being
converted (through mutation, retroviral transduction, increased expression, etc) to oncogenes that can
promote excessive or inappropriate cell proliferation.

A. PROTO-ONCOGENE FUNCTION - Cell division frequently involves the interaction of a messenger

(growth factor, etc) with cell membrane receptors, transduction of that signal through the cell
membrane to a second messenger, transmission by the second messenger to the nucleus, and
initiation of DNA transcription and replication. This complex biochemical pathway is in part
mediated by the protein products encoded by cellular proto-oncogenes. Classes of proto-oncogenes
functioning in this regard include:

1. GROWTH FACTOR PROTEINS (sis, int-2) - The sis gene codes for the beta chain of PDGF.
2. GROWTH FACTOR RECEPTOR PROTEINS (erbB, fms) - The erbB gene codes for a protein
similar to the epidermal growth factor receptor while thefms gene codes for macrophage
colony stimulating factor.
3. GTP-BINDING PROTEINS (ras family) - This group of genes codes for p21 proteins that
bind to GTP and modulate transmembrane signals.

40
 4. PROTEIN TYROSINE KINASES (src, abl) - Among other things, the src gene increases the
production of second messengers for a variety of growth factors.
5. DNA-BINDING PROTEINS (myc family) - This group of genes codes for proteins that bind
directly to DNA and are probably involved in DNA synthesis.
6. TRANSCRIPTION REGULATORS (jos, jun) - regulate the transcription of DNA.

B. EFFECTS OF ONCOGENE ACTIVATION - Like the protein products of normal proto-oncogenes, the
protein products of oncogenes are involved in the regulatory pathways that control cellular division
and differentiation and are capable of transforming nonnal cells into neoplastic ones. As with c-sis,
oncogenes may code for large amounts of growth-promoting factors to which the cell can respond
(autocrine stimulation) or they may impart growth autonomy by deregulating genes that encode
growth factors. They may encode for defective receptors (v-erbB) that transmit stimulatory signals
in the absence of a growth factor, or through overexpression of growth factor receptor sites (c-
HER2Ineu), they may render tumor cells excessively sensitive to low levels of growth factors that
are below the threshold for stimulating normal cells. They may also encode proteins that enter the
nucleus and directly stimulate cellular growth. The ras family of oncogenes appear to influence cell
shape and motility. They can also induce cells to secrete a number of growth-stimulating factors.
C-src modifies the cytoskeletal protein, vinculin, which anchors actin filaments to the cell
membrane and also allows expression of otherwise tightly regulated growth factor genes. The myc
family seems to make cells more responsive to growth factors controlling cell proliferation and
appears to confer immortality to the cell line.
C. MECHANISMS OF ONCOGENE ACTIVATION - Like all other genes, each proto-oncogene is
composed of a regulatory and a structural region. Changes in either region could produce an active
oncogene. Structural mutations could lead to synthesis of a protein that has aberrant structure and
function whereas regulatory changes could lead to inappropriately high levels of a growth-inducing
protein.

1. STRUCTURAL CHANGES

a. Point mutations - Alteration of a single base pair may alter the protein product
of a proto-oncogene. Point mutations probably occur randomly throughout the
proto-oncogenes, but only those occurring at certain critical "hot spots" produce
oncogenic activation. Point mutations are best exemplified by the ras oncogenes.
10-15% of oncogenes isolated from human tumors (40% of colon cancers) have
been shown to be "hot spot" ras mutants (point mutations at position 12, 13, or
61). Point mutations are not observable by karyotypic analysis.
b. Insertions and deletions - These will also result in altering the protein product of
a proto-oncogene. If large enough, insertions or deletions may be observed on
karyotypic analysis.

2. REGULATORY CHANGES - With regulatory changes, mutations affect the amount of protein
product rather than the structure. This can occur through chromosomal translocation or
gene amplification.

a. Chromosomal translocations - Proto-oncogenes may become activated either

because they are placed next to strong promoter/enhancer sequences or because
translocation removes them from the influence of normal regulatory control
sequences. Translocation can also affect the biochemical functions of proto-
oncogenes by fusion with new genetic sequences. The c-abl oncogene in chronic

41
 myelogenous leukemia (Philadelphia chromosome) results from a translocation,
t(9;22), that encodes a protein different from the normal protein. The c-myc
oncogene in Burkitt's lymphoma, t(8,14), stimulates DNA synthesis. Major gene
rearrangements such as translocations can be observed in karyotypic studies.
b. Gene amplification - This produces many copies of an oncogene and therefore
increases the amount of protein products. In karyotypic studies, gene amplification
can be observed as homogeneously staining regions (HSR) if they stay associated
with the chromosome or as double minutes (DM) if they break loose and replicate
as extrachromosomal material. The myc oncogenes are amplified in
neuroblastomas and small cell carcinomas of the lung; HER21neu is amplified in
breast cancers: and erbB is amplified in malignant melanomas.

D. ANTI-ONCOGENES - Although it is felt that many neoplasms arise from multiple "spontaneous"
somatic mutations of cellular DNA, it is well established that the development of certain tumors
(retinoblastoma, Wilms' tumor, etc) are in some instances related to heritable factors. Since
activated oncogenes are not transmitted in the germ line, this implies that some form of cancer
susceptibility genes must exist which, in and of themselves, do not produce neoplasia but that could
affect the regulation of cell growth, the effectiveness of the immune surveillance mechanisms, the
ability to repair DNA damage, or the manner in which potentially carcinogenic compounds are
metabolized. Since the expression of these genes (particularly the growth suppressor genes) serve
to protect the cell from the events leading to neoplastic transformation, they are referred to as anti-
oncogenes. The protein products of the anti-oncogenes modulate the activity of proto-oncogenes
or their protein products, and in the absence of this regulation, neoplasia may arise. Since it is
much easier to destroy or inactivate a gene than it is to amplify or potentiate gene expression, it is
conceivable that these anti-oncogenes may play an even more important role in neoplastic
transformation than the oncogenes. The p53 anti-oncogene on the short arm of chromosome 17
becomes more active after DNA damage and has an inhibitory effect on cell mitosis so that
mutated DNA will not be replicated. In its absence, the cell may continue to reproduce
incorporating the DNA mutation into the genome of the cell line. Mutations and inactivation of the
p53 gene are seen in numerous human malignancies (esp. astrocytoma of the brain and carcinoma
of the colon).

1. INHERITED MUTATION - Heterozygous mutations of an anti-oncogene allele may be

inherited and could be a predisposing risk factor for the development of neoplasia since
that individual has inherited only one, rather than two, copies of the active anti-oncogene.
Loss or inactivation of the corresponding locus (loss of heterozygosity) by somatic
mutation may then result in overt neoplastic development. Loss of heterozygosity has been
identified on the short arm of chromosome 3 in renal cell carcinomas and small cell
carcinomas of the lung; on the short arm of chromosome II in Wilms' tumor of the kidney;
on the long arm of chromosome 13 in retinoblastoma, and ductal carcinoma of the breast,
etc. Additionally, if an inactive allele is inherited, it is present in all cells and there is,
therefore, a greater tendency to develop multiple tumors. Many of the autosomal dominant
neoplasia syndromes (multiple endocrine neoplasia syndromes, familial polyposis coli, Von
Recklinghausen's disease, etc) appear to be the result of inheriting at least one inactive anti-
oncogene allele.
2. SOMATIC MUTATION - Somatic mutation and inactivation of an anti-oncogene allele may
also occur, but the chances of inactivating both alleles in a single cell are much less than
the chance of inactivating one allele. When this does occur, however, the subsequent

42
 neoplasia would be much more likely to be solitary than multiple as seen with the inherited
neoplasia syndromes.

E. NEOPLASTIC TRANSFORMATION - DNA transfection experiments have shown that no single

oncogene will transform normal cells into neoplastic cells. It appears that more than one oncogene
may be involved, with each oncogene supplying some of the fimctions required to convert a normal
cell into a neoplastic one. Sequential activation of oncogenes (or suppression of anti-oncogenes)
may be reflected in the gradual transition of normal cells to neoplastic cells through stages of
dysplasia or preneoplasia. And, since cell replication is central to neoplastic transformation, it is
also not surprising that preexisting regenerative and/or hyperplastic conditions are occasionally
associated with subsequent neoplasia.

VI. CARCINOGENIC AGENTS

A. CHEMICALS - From studies with known chemical carcinogens, it appears that transformation of
a normal cell to a neoplastic cell occurs in two stages: initiation and promotion. Contact with either
an initiator or promotor alone is insufficient to produce transformation, however two or more dif-
ferent chemicals may act synergistically to induce cell transformation (cocarcinogenesis). The
carcinogenicity of chemical agents appears to be dose dependent so that multiple fractional doses
over time have the same transforming potential as a comparable one-time dose. Although some
chemical compounds such as alkylating agents (primarily cancer chemotherapy drugs) and
acylating agents act on cells directly, most chemical substances (procarcinogens) require metabolic
activation for conversion into ultimate carcinogens, and a variety of factors (age, sex, nutritional
status, etc) may modifY the carcinogenic effect of a chemical by affecting its metabolism. Most of
the known carcinogens are metabolized by cytochrome P-450-dependent mono-oxygenases in the
liver.

1. INITIATORS - These are chemical substances which can produce permanent changes in the
genetic make-up of a cell but which, by themselves, are unable to induce neoplastic
transformation. Initiators tend to get converted either directly or through a metabolic
descendant into substances that react with DNA to cause strand breaks, to alter
methylation, or to hinder DNA repair. For DNA changes to become permanent and
initiation to occur, the carcinogen-altered cells must be able to undergo at least one
replicative cell cycle. Initiated cells, however, do not have growth autonomy nor do they
have unique, readily identifiable genotypic or phenotypic markers.
2. PROMOTORS - These are chemical substances that can induce neoplastic transformation
in a previously initiated cell, but cannot cause neoplastic transformation in and of
themselves. Instead of altering the DNA, their action seems to involve an altered expres-
sion of the genetic information in the cell. Promoters seem to induce clonal proliferation
of initiated cells by altering the regulation of mitosis and to produce alterations in their
differentiation and maturation pathways.

B. RADIATION - Ionizing radiation may directly ionize critical cellular macromolecules or interact with
cellular water to produce free radicals that mediate cellular damage by breaking or altering
chemical bonds. It can inactivate enzymes, alter proteins, and cause chromosomal breakage,
translocations, and point mutations. It can also inhibit cell-mediated immunity. The ability of
ionizing radiation to induce neoplastic transformation, however, appears to correlate best with its
ability to induce genetic mutation within the cell.

43
 C. VIRUSES - Although not numerous, both DNA and RNA viruses have been found associated with
human neoplasia (carcinoma of the uterine cervix, hepatocellular carcinoma). Through the process
of transduction and insertional mutagenesis, viruses may directly rearrange the structure or alter
the expression of the host cell genome. This may activate cellular oncogenes or, conversely,
inactivate anti-oncogenes (one of the characteristics of most DNA tumor viruses). In order to be
transformed, however, the host cell must survive the viral infection and be able to reproduce.

VII. TUMOR GROWm - The propensity of tumor cells to reproduce is a distinguishing feature of neoplasia
and may be the result of genetic alterations (oncogene activation, anti-oncogene suppression, etc) that direct
the cell to replicate rather than to continue to differentiate. Evidence suggests that most tumors are of
monoclonal origin i.e. a single cell from normal or preneoplastic tissue becomes neoplastic at a specific
level of differentiation and the clonal derivatives of that cell produces the neoplasm. In most tumors there
appears to be an increase in the proportion of stem cells undergoing replication and a corresponding
decrease in the proportion progressing to full end-stage maturation. Although a greater number of mitotic
figures are generally seen in neoplastic tissue, these usually represent abnormal mitoses and reflect a larger
pool of dividing cells rather than implying that tumor cells divide more rapidly than normal cells.

A. GROWTH FRACTION (GF) - This refers to the proportion of cells within a tumor population that are
in the proliferating pool. The rate of tumor growth depends upon the growth fraction and the
degree of imbalance between cell production and cell loss. Most tumors have a low GF and
proliferation only slightly exceeds cell loss. The growth fraction of a tumor has a profound effect
on its susceptibility to chemotherapy. Most cancer drugs act primarily on dividing cells, therefore
those tumors which have a high growth fraction are most vulnerable. Slow growing tumors which
have a high proportion of cells outside the cell cycle respond less favorably and harbor cells which
can potentially reenter the cycle at a later time.
B. ANGIOGENESIS - Tumor growth is dependent upon vascularization. Without it, neoplastic growth
will stop at approximately one millimeter diameter due to the limited diffusion capacity of oxygen
and solutes. Angiogenic factors which include fibrinogen and various substances produced by the
tumor cells (angiogenin, fibroblast growth factor, etc) promote and control the neovascularization
of the expanding cell mass. The neovasculature, however, tends to be abnormal due to loose
endothelial junctions. Hemorrhage into tumors is not uncommon and, in the case of malignant
tumors, this may even help assist the tumor cells to spread to other sites. Hypoxia in the tumor
environment also significantly impairs the biologic effect of radiation therapy and some forms of
chemotherapy which are oxygen dependent. Circulating hormones can also influence the growth
rate of hormonally responsive tissues.
C. DOUBLING TIME - As tumor size increases, the time it takes for a tumor to double in volume also
increases (i.e. growth rate slows down) due to diminished blood supply, competition for
metabolites, and other factors that lead to a decrease in the growth fraction and an increase in cell
loss. As tumors enlarge, an increasing proportion of tumor cells drop out of the mitotic cycle either
because of necrosis or by entering into prolonged G] periods or the Go phase of the cell cycle. Even
though the doubling time slows down as tumors enlarge, by the time a solid tumor is clinically
detected it has already completed a major portion of its life cycle. The earlier a tumor is identified,
the greater the chance of successful radiation and/or chemotherapy.

VIII. CLONAL EVOLUTION AND HETEROGENEITY - Although tumors probably arise monoclonally,
by the time they have reached clinical detection, the cell population is heterogeneous in respect to
morphologic appearance, karyotype, degree of differentiation, invasiveness, metastatic capabilities, etc
implying that tumors can undergo clonal evolution as they develop, probably related to DNA instability
and the high rate of random mutation in neoplastic cells. Dedifferentiated cells are more likely to have

44
 characteristics that enable them to spread (i.e. increased motility, decreased adhesiveness, decreased
anchorage dependence, etc). Clonal evolution, like the progression of preneoplasia to neoplasia, appears
to involve a sequence of oncogene activations that, over time, leads to more highly malignant cells i.e.,
those that have a survival advantage due to their growth rate, invasiveness, drug resistance, etc. By the time
most malignant neoplasms have become clinically detectable, it is likely that they have evolved several
sub clones with metastatic potential. This implies that the earlier a cancer can be identified, the less likely
it is that more aggressive subclones have developed.
IX MECHANISMS OF TUMOR INVASION AND METASTASIS - An important feature of malignant
cells is their ability to invade surrounding tissue and ultimately to spread to distant sites. Only certain cells
within a tumor develop a high invasive and/or metastatic potential, and these tend to be cell clones with
a high mutation rate. There is emerging evidence that oncogene activation is involved in conferring
metastatic potential on tumor cells by enabling the cell to attach to, degrade, and penetrate basement
membranes and interstitial connective tissue.

A. BASEMENT MEMBRANE DISSOLUTION AND STROMAL INVASION - Tumor cells appear to bind to
structural glycoproteins such as the laminin and fibronectins which are embedded in basement
membranes and connective tissue. Since laminin adheres tightly to the type IV collagen of the base-
ment membrane, neoplastic cells may evolve mechanisms to secrete laminin or, alternatively, to
produce tumor membrane receptors that binds native laminin. Once secured to the basement
membrane, tumor cells then secrete proteases, such as type IV collagenase, to dissolve the
basement membrane. They are then free to attach to stromal fibronectin with additional release of
proteases. The ability of tumor cells to digest ground substance (collagen, glycoproteins,
proteoglycans, and elastin) by the production of proteases is correlated with invasive potential. It
is also likely that cancer cells interact with host fibroblasts and other mesenchymal cells and
stimulate them to secrete additional collagenases. As previously mentioned, tumor derived growth
factors as well as breakdown products of the connective tissue ground substance have angiogenic
and tumor chemotactic activities which promote neovascularization and recruitment of additional
tumor cells. The loose endothelial junctions of these new vessels make it relatively easy for tumor
cell to gain access to the circulation.
B. LYMPHATIC!vASCULAR INVASION AND DISSEMINATION - Invasive properties also allow tumor
cells to penetrate existing vessels. Since lymphatic channels lack a basement membrane, they are
easily invaded while the walls of venules and veins put up little resistance as well. Hemorrhage and
necrosis also promote the release of tumor cells into the circulation. Once in the circulation,
however, tumor cells are vulnerable to hemodynamic factors that cause cell trauma, to
immunologic recognition and attack (particularly by natural killer cells), and to other adverse
conditions. Fewer than one in a thousand tumors cells released into the blood stream will ultimately
metastasize. In the circulation, tumor cells tend to aggregate in clumps. Clumps of five to ten
tumor cells appear more effective in producing metastases than either single cells or larger clumps.
Some clumps adhere to platelets or produce a procoagulant which may form "shields" of
precipitated fibrin to ward off immunologic recognition. These procoagulants may partly explain
some of the hypercoagulable states seen in patients with disseminated cancer.
C. SITES OF METASTASIS - Regional spread of tumors is primarily influenced by the anatomy of
regional lymphatics. Since the capillary and lymphatic systems are interconnected, however,
hematogenous spread can be expected in the face of demonstrated lymph node metastases. The
distribution of distant metastasis, however, is not indiscriminate. Metastases from a variety of
malignant tumors display preferences for some tissue sites over others. This may reflect a given
tumors' ability to respond to tissue-specific chemotactic factors or to adhere to tissue-specific
endothelial cells and invade tissue-specific stroma. Metastatic deposits, like primary tumors, are

45
 clonal in origin and the survival and growth of the metastatic lesion generally depends on the same
factors that enable growth of the primary lesion.

X. TUMOR ANTIGENS

A. TUMOR SPECIFIC ANTIGENS - This refers to antigens that are found on neoplastic cells and not on
normal cells. In animals, each tumor induced by a given chemical carcinogen frequently carries its
own unique tumor antigen while all tumors produced by a given virus share a common antigen.
These tumor-specific antigens can activate host immunologic destruction of cancer cells in animals
but whether this occurs in humans to any significant extent is not known.
B. TUMOR ASSOCIA TED ANTIGENS - These are antigens found in normal cells but which are present
in higher concentration in tumor cells. Examples include differentiation antigens (beta HCG) which
are expressed at certain stages of a cell's maturation and oncofetal antigens (CEA, AFP) which are
expressed during embryonic development but normally repressed during adult life.

XI. GRADING AND STAGING OF MALIGNANT NEOPLASMS

A GRADING - This refers to a microscopic pathologic determination of tumor aggressiveness based

on the degree of differentiation of the neoplastic cells and the number of mitoses. Most tumors are
graded from I (low grade, well differentiated) through IV (high grade, undifferentiated). Many
malignant neoplasms progress to a higher grade over time as less differentiated clones of cells
become dominant. In general, the lower the grade the better the prognosis.
B. STAGING - This refers to a clinical and pathologic determination of tumor aggressiveness based
on the size of the neoplasm, the presence or absence of regional lymph node involvement, and the
presence or absence of distant metastases. This is the basis of the TNM (tumor size, node
involvement, metastasis) staging system. Alternatively, some tumors are staged numerically from
I (localized tumor) through IV (distant metastases). In general, the smaller the tumor and the more
localized it is, the better the prognosis.

XII. LABORA TORY METHODS OF DIAGNOSING CANCER - Standard methods of diagnosis of

neoplasia include light microscopy and electron microscopy of tissue biopsies. However, newer techniques
(gene amplification by the polymerase chain reaction with DNA probes, immunohistochemistry with
monoclonal antibodies, flow cytometry, etc) make it possible to detect a variety of activated oncogenes in
biopsy specimens and allow much greater precision in diagnosis with even smaller amounts of tissue.

46
 CARDIOVASCULAR SYSTEM

HEART FAILURE

I. CONGESTIVE HEART FAILURE (CHF) - This refers to a clinical syndrome manifested by many signs
and symptoms that arise when the heart is no longer able to maintain normal cardiac output. In 1990, CHF
was responsible for approximately 38,000 deaths in the u.s. and, despite better diagnosis and management,
has shown a rising mortality with a poor long-term prognosis. [See discussion of CHF hemodynamics on
page 14]

A. ETIOLOGY - CHF is generally related to loss of myocardial contractility (loss of muscle mass,
infiltration or replacement of myocardial tissue, etc.), increased resistance to cardiac outflow
(hypertension, valvular stenosis, etc.), inadequate ventricular filling (tamponade, "stiff'
myocardium, etc.), or increased ventricular blood volume (intracardiac shunts, valvular
insufficiency, high output states, etc.).
B. COMPENSATORY MECHANISMS - These include increased heart rate, increased contractility of
muscle fibers, hypertrophied muscle fibers, and dilatation of ventricles (to increase stroke volume
and contractile force according to Starling's law). These compensatory mechanisms, however, are
an additional burden on the compromised heart, and ultimately, the heart will decompensate.
C. CLINICAL MANIFESTATIONS - Symptoms do not develop until there is failure of the compensatory
mechanisms. The signs and symptoms of heart failure are generally due to hypoxic and congestive
effects on organs and tissues other than the heart itself

II. LEFT-SIDED HEART FAILURE - This occurs when the left ventricle is unable to maintain adequate
cardiac output. It is usually secondary to ischemic heart disease, systemic hypertension, or valvular disease.
III. RIGHT-SIDED HEART FAILURE - This occurs when the right side of the heart is unable to overcome
an increase in pulmonary arterial pressures (pulmonary hypertension). This is generally due to an extension
of pre-existing left heart failure but may also be due to other causes such as interference with pulmonary
venous outflow (left heart failure, mitral stenosis, etc.), chronically increased pulmonary blood flow (A-V
fistulas, congenital left-to-right shunts, etc.), a decrease of the cross-sectional area of the pulmonary
vascular bed (multiple small emboli, vasculitis, etc.), pulmonary parenchymal disease (causing hypoxemia,
acidosis, and pulmonary vasoconstriction), or interference with the chest "bellows" (kyphoscoliosis, etc.).

A. COR PULMONALE - This term refers to right ventricular failure due to pulmonary arterial
hypertension resulting from primary parenchymal or vascular disease of the lungs. This is usually
reflected structurally by hypertrophy and/or dilatation of the right ventricle and right atrium.

47
 I. ACUTE COR PULMONALE - This refers to sudden right ventricular failure usually resulting
from large pulmonary emboli. In addition to physical obstruction of the right ventricular
outflow, other factors (bronchoconstriction, hypoxemia, neural reflexes, etc.) contribute
to the clinical manifestations of wheezing, dyspnea, tachypnea, etc. Acute cor pulmonale
is one of the major causes of sudden death.
2. CHRONIC COR PULMONALE - This generally arises in the setting of primary pulmonary
hypertension (an unusual progressive disease of unknown etiology which generally appears
in young women) or chronic pulmonary parenchymal disease (emphysema, chronic
bronchitiS, etc.). Until decompensation occurs, the increased pulmonary arterial pressures
induce right ventricular hypertrophy and dilatation.

IV. HIGH OUTPUT FAILURE - This is seen in conditions that increase blood volume (iatrogenic fluid
overload, sodium retention, etc), increase the venous return to the heart (hyperthyroidism, etc), or decrease
the peripheral vascular resistance (A-V fistula, sepsis, etc).

CONGENITAL HEART DISORDERS

I. EMBRYOGENESIS - The development of the cardiovascular system is mandatory in early gestation in

order to supply oxygen and essential nutrients to, and remove waste products from, the rapidly developing
tissues. Approximately 21 days after conception, the heart can be identified as a simple tubular organ which
then matures and differentiates into the recognizable four chambered heart. In the adult heart, the circula-
tory pattern can essentially be divided into two systems: the right-Sided pulmonary circulation and the left-
sided systemiC circulation. Deoxygenated systemic venous blood returns to the right side of the heart where
it is pumped through the pulmonary circuit to become oxygenated. The oxygenated blood then retums to
the left side of the heart where it is pumped through the systemic arterial circulation to the tissues of the
body. Since, in the fetus, the lungs are not functional, oxygenated blood is supplied by the mother via the
placenta. This blood, admixed with fetal systemic venous blood, returns to the right side of the heart and,
instead of circulating through the pulmonary circuit, needs to be transferred to the left side of the heart so
that it can be pumped into the systemic arterial circulation. This is accomplished by a "right-to-Ieft'shunt.
This shunt must always be present during the development of the heart in order to direct the maternally
derived oxygenated blood into the left-sided systemic arterial circulation. At birth, however, these shunts
need to be closed in order to establish the normal adult circulatory blood flow. Abnormalities in the
sequential development of the heart and great vessels occur in approximately I % of infants and may result
in clinically significant disturbances in the normal circulatory patterns. Environmental (intrauterine rubella
infection, drugs, etc.) as well as genetic (Down's syndrome, Turner's syndrome, Marfan's syndrome, etc.)
factors can be contributory influences.

A. RIGHT-TQ-LEFTSHUNTS (truncus arteriosus, transposition of the great vessels, tetralogy of Fallot,

tricuspid atresia) - In general, right-to-Ieft shunts divert non-oxygenated blood away from the
pulmonary circuit and into the systemic circulation, reducing the oxygen saturation of the arterial
blood. This results in cyanosis (a bluish discoloration of the skin due to accumulation of reduced
hemoglobin in capillary beds and seen most readily around the lips and nailbeds) at or soon after
birth. Chronic cyanotic conditions may be reflected by polycythemia and digital clubbing.
B. LEFT-TQ-RIGHTSHUNTS (atrial septal defect, ventricular septal defect, patent ductus arteriosus)-
In general, left-to-right shunts divert oxygenated blood from the systemic circulation (including the
myocardial circulation) and into the pulmonary circulation, depriving the systemic tissues of
oxygen. The heart will attempt to compensate for the resulting hypoxia by increasing cardiac output

48
 which may lead to left ventricular hypertrophy and dilatation. Myocardial hypertrophy, however,
increases the oxygen demand of an already oxygen-poor myocardium. Hypoxia, acidosis, and the
additional volume demands on the right side of the heart and the pulmonary circulation result in
smooth muscle hypertrophy of the pulmonary arterioles and increased pulmonary circulatory
resistance (pulmonary hypertension). The increased pulmonary resistance is transmitted back to
the right ventricle which responds by hypertrophy. Eventually, right sided pressures may exceed
left sided pressures and a "reversal" of the shunt to a right-to-Ieft shunt occurs (Eisenmenger's
syndrome) favoring the late development of cyanosis (cyanose tardive).
C. OBSTRUCTIVE ANOMALIES (aortic coarctation, valvular stenosis or atresia) - These are physical
barriers to blood flow and generally do not cause cyanosis.

II. DEVELOPMENTAL SEQUENCES - Although the processes involved in developing a normal four-
chambered heart from a single tubular structure will be outlined separately, it should be remembered that
each of these developmental sequences is proceeding at approximately the same time.

A. DEVELOPMENT OF RIGHT AND LEFT ATRIOVENTRICULAR (A-V) CANALS - The partitioning of the
original tubular heart into a common atrium and a common ventricle is effected by the inward
growth of tissue (endocardial cushions) from the anterior and posterior aspects of the tube. The
endocardial cushions eventually meet and fuse leaving a communication on either side between the
common atrium and common ventricle. These communications (the right and left A-V canals) will
eventually become the tricuspid and mitral valve. If the endocardial cushions do not fuse, a
common A-V canal results. If the endocardial cushions are displaced to one side or the other, there
will be a structural narrowing and functional stenosis of one valve in addition to the possible
structural enlargement and functional incompetence of the other.
B. FORMATION OF THE INTERATRIAL SEPTUM (lAS) - The septum primum is a thin, crescent shaped
membrane which grows downward from the dorsocranial portion of the atrium. The opening
between the leading edge of this membrane and the endocardial cushion is the ostium primum,
which allows a right-to-left shunt from the right atrium to the left atrium. As the septum primum
grows downward to eventually fuse with the endocardial cushions, the ostium primum grows
gradually smaller and a new right-to-left shunt must be formed. This is accomplished by the
degeneration of the superior portion of the septum primum to create a new opening - the ostium
secundum. At this time, a second membrane (septum secundum) develops to the right of the
septum primum and grows downward to also fuse with the endocardial cushions. This septum_
however, does not develop completely but leaves an opening (foramen ovale) in its center. In the
fetus, blood entering the right atrium from the superior vena cava (deoxygenated blood from the
upper body) primarily traverses the tricuspid valve into the right ventricle. Blood entering the right
atrium from the inferior vena cava (deoxygenated blood from the lower body and oxygenated
blood from the placenta), however, primarily flows through the foramen ovale and ostium
secundum directly into the left atrium. After birth when ventilation occurs, vasodilation of the
pulmonary arterioles causes decreased pulmonary vascular resistance and removal of the low
pressure placental circulation causes increased systemic vascular resistance. The left atrial
pressures suddenly become greater than the right atrial pressures and the lower portion of the
septum primum acts as a flap valve to seal off the foramen ovale and completely separate the right
and left atria. Any abnormalities in this complex developmental sequence may lead to the
formation of an atrial septal defect (ASD). These occur more frequently in females and
morphologically fall into three categories:

1. OSTIUM PRIMUM DEFECT (5%) - This is a low septal defect and may be associated with
deformed valves. This is the form most commonly seen with Down's syndrome.

49
 2. OSTIUM SECUNDUM DEFECT (90%) - This is the most common form of ASO and is
located in the area of the fossa ovale. It may be associated with other congenital defects.
Cor triloculare biventricularum is essentially a large secundum defect.
3. SINUS VENOSUS (5%) - This is a high septal defect near the superior vena cava and may
be associated with anomalous pulmonary venous return.

Early, ASOs may be clinically asymptomatic although there may be a pulmonic murmur due to
increased flow. With time, they may lead to pulmonary hypertension, right atrial hypertrophy, right
ventricular hypertrophy, and reversal of the shunt.
C. DEVELOPMENT OF AORTA AND PULMONARY ARTERY - The aorta and pulmonary artery both arise
from a common channel, the truncus arteriosus. Ridges develop from either side of the truncus
and fuse to form an aorticopulmonary septum which divides the truncus arteriosus into two
channels. As it develops, it spirals as it approaches the endocardial cushions and directs blood from
the left ventricle into the aorta and blood from the right ventricle into the pulmonary artery. The
spiraling of this septum is why, in the normal heart, the aorta and pulmonary artery appear to twist
around each other. If the septum fails to develop, there is a single artery leaving the heart - a
perSistent truncus arteriosus. Clinically there is early cyanosis. Pulmonary hypertension and right
ventricular hypertrophy ultimately develop. Often associated with other developmental defects of
the heart, the prognosis is generally poor. If the septum develops but does not spiral, a
transposition of the great vessels occurs where blood from the left ventricle flows into the
pulmonary artery and blood from the right ventricle flows into the aorta. Transposition is a major
cause of congestive heart failure and death in early infancy. It is seen three times more frequently
in males and is often associated with maternal diabetes mellitus. Postnatal survival requires the
concurrent presence of an ASO (95%), POA (60%), or VSO (30%).
O. FORMATION OFTHE INTERVENTRICULAR SEPTUM - The interventricular septum is formed by two
components. One is a muscular septum which begins at the apex of the heart and grows upward
to fuse with the second component, or membranous septum, which consists of the endocardial
cushions and proximal portion of the spiral (aorticopulmonary) septum. Any disturbance of the
proper fusion of any or all of these elements may lead to a ventricular septal defect (VSO), the
most common congenital anomaly of the heart. Although often associated with other
cardiovascular defects, approximately one third occur as isolated defects. Most VSOs involve the
membranous septum (90%). Small defects « 0.5 cm.) may be asymptomatic but cause loud sys-
tolic munnurs and a palpable thrill. They may spontaneously close, but if not, a left-to-right shunt
will eventually produce, as in moderate sized defects, pulmonary hypertension and right ventricular
hypertrophy. Ultimately there will be reversal to a right-to-Ieft shunt with cyanosis, digital clubbing,
and polycythemia. Small and moderate size defects also predispose patients to the development
of infective endocarditis. Large defects may cause problems from birth culminating rapidly in
cardiac failure and death.

III. BICUSPID AORTIC VALVE - This is a relatively common defect and is generally asymptomatic
although it does predispose to infective endocarditis and dystrophic calcification.
IV. PA TENT DUCTUS ARTERIOSUS (PDA) - In utero, the ductus arteriosus (the embryologic
communication between aorta and pulmonary artery) functions as a right-to-Ieft shunt and diverts the
majority of the pulmonary artery blood flow away from the nonfunctional lungs and into the aorta. Normal-
ly, functional closure of the ductus arteriosus occurs within 24 hours after birth with subsequent fibrosis
resulting in anatomic closure. A high incidence of patent ductus arteriosus in premature infants and those
with respiratory distress syndrome suggest that increasing O2 tension may be the trigger that initiates
closing. The incidence of PO A is greater in females and clinically causes a "machine murmur" and possible
systolic thrill. The left-to-right shunt results in pulmonary hypertension and right ventricular hypertrophy.

50
 Subsequent right-to-Ieft shunts produce a "differential cyanosIs" \\ith cyanosIs of the lower extremities and,
due to bypassing of the aortic arch branches, a pink upper body.
V. COARCTATION (narrowing of the aorta) - This is relatively common. more frequent in males, and often
accompanied by other developmental abnormalities (bicuspid aortic valve. berry aneurysms, etc.) It may
occur anywhere but most frequently the narrowing is distal to the ductus arteriosus (postductal) rather than
proximal (preductal).

A. POSTDUCTAL (ADULT FORM) - The ductus is usually closed in this form of coarctation and most
patients are asymptomatic until adulthood. The upper extremities exhibit increased blood pressure
but the lower extremities show decreased blood pressure and diminished peripheral pulses
predisposing to intermittent claudication of the calf muscles. Substantial collaterals (internal mam-
maries, intercostals) may develop to shunt blood around the narrowing, and these may be noted
on physical examination or x-ray (notching of lower rib margins). Eventually, left ventricular
hypertrophy and congestive heart failure will develop, and there is an increased risk of hypertensive
stroke and dissection or rupture of the aorta proximal to the coarctation.
B. PREDUCTAL(INFANTILE FORM) - These infants manifest evidence of heart failure at or soon after
birth. The ductus is usually patent, and the prognosis depends on ability of PDA to supply blood
to the post-coarctation aorta The hypoplastic left heart syndrome may be an exaggerated form in
which there is stenosis of the proximal aorta, atresia or stenosis of the left heart valves, and
hypoplasia of the left ventricle.

VI. TETRALOGY OF FALLOT - This is the most common congenital cyanotic heart disease and is
characterized by 1) right ventricular outflow obstruction (infundibular narrowing, pulmonary valve stenosis,
etc.); 2) right ventricular hypertrophy; 3) ventricular septal defect; and 4) dextroposition (overriding) of
the aorta. The incidence is slightly greater in males, and the clinical symptoms depend on the degree of
outflow obstruction. Blood is shunted to the aorta via the VSD, and cyanosis usually develops shortly after
birth. Murmurs occur secondary to the outflow obstruction, and the clinical manifestations include dyspnea,
growth retardation, digital clubbing, etc. Although not immediately life threatening, surgery is
recommended as soon as possible.

ARTERIOSCLEROSIS

Arteriosclerosis encompasses a group of vascular disorders which are characterized by thickening and loss of
elasticity of arterial walls. There are three major types of arteriosclerosis: arteriolosclerosis (in which there is
concentric, obstructive hyaline thickening and/or hyperplastic proliferation of cells in the walls of arterioles and
small arteries), Monckeberg's medial calc~fzc sclerosis (in which there is concentric, non-obstructive medial
calcification of small and medium-sized muscular arteries), and atherosclerosis (in which there is formation of
asymmetric, obstructive fibrofatty intimal plaques in medium-sized muscular and large elastic arteries). The
most common type of arteriosclerosis, by far, is atherosclerosis, and these two terms are often used
interchangeably. Atherosclerosis is a slow progressive disease characterized by the formation of atherosclerotic
plaques, elevated intimal lesions consisting of an acellular lipid core and fibrous cap. Although the mortality
figures for coronary heart disease and strokes have fallen over the last 20 years, fifty percent of all deaths in the
U.S. are related to cardiovascular disease most of which, in tum, are related to atherosclerosis.

I. RISK FACTORS - The etiology of atherosclerosis is not completely understood. Based on

epidemiological studies, however, there are definite risk factors associated with the development of
clinically significant disease. These risk factors tend to have a cumulative rather than additive effect, but

51
 even some individuals with no history of risk factors develop significant disease, so there is some degree
of individual variability. Major risk factors include hyperlipidemia, hypertension, cigarette smoking,
and diabetes mellitus. Minor risk factors are physical inactivity, stress and behavior patterns, obesity, and
long term oral contraceptive use. Other non-alterable factors include age (atherosclerotic plaques can be
observed in almost every individual over 40 years of age and become increasingly clinically significant with
advancing age), gender (males develop more severe disease than pre-menopausal females but females
develop plaques at a more rapid rate post-menopausally), genetic predisposition (Whites tend to develop
more severe disease than Blacks), etc.
II. PLASMA LIPIDS - Lipids are primarily derived from 1) exogenous dietary cholesterol and triglycerides
that are absorbed across the intestinal mucosa; 2) endogenous cholesterol and triglycerides that are
synthesized in the liver; and 3) free fatty acids derived from adipose tissue. Cholesterol and triglycerides
are insoluble in blood and are, therefore, complexed with various polypeptides (apoproteins) and polar
lipids (phospholipids) to form soluble lipoproteins. The major apoproteins are A (AI, All), B (B48, B 100),
C (CI, CII, CIII) and E, and each has a unique function (enzyme cofactors, enzyme inhibitors, lipid transfer
proteins, ligands for specific cellular receptors, etc). It is the specific combination of apoproteins that
determines the lipoprotein activity and directs the ultimate metabolic fate of its associated lipid.

A. LIPOPROTEIN CLASSIFICATIONS

1. CHYLOMICRONS (apo E, A, CII, B48) - These primarily transport dietary triglycerides and,
to a lesser extent, dietary cholesterol and are normally found in the blood only after eating.

2. BETA LIPOPROTEINS (apo BI00) - These are also known as "low density lipoprotein"
(LDL), primarily transport endogenous cholesterol as cholesteryl ester, and is the major
plasma cholesterol carrier (approximately 70% of the total plasma cholesterol). The
majority of cholesterol used by the adrenal cortex in the production of the steroid
hormones are derived from LDL.
3. PRE-BETA LIPOPROTEINS (apo E, CII, BI00) - These are also known as "very low density
lipoprotein" (VLDL), are assembled in the liver, and primarily transport endogenously
produced hepatic triglycerides to the peripheral adipose and muscle tissue.
4. ALPHA LIPOPROTEINS (apo A, E, CII) - Theses are also known as "high density
lipoprotein" (HDL) , primarily transport endogenous cholesterol acquired from
extrahepatic peripheral tissues, and returns it to the liver.

B. REGULATION OF LIPID LEVELS - Among other metabolic functions, cholesterol is vital for the
Synthesis of cellular membranes, steroid hormones, and bile acids. 93 % of the body cholesterol is
therefore located intracellularly to provide substrate for these metabolic functions while 7% is
circulating as plasma cholesterol.

1. PLASMA TRANSPORT - Chylomicrons and VLDL are transported to peripheral adipose and
muscle tissue where, in the presence of insulin, they are "stripped" oftriglycerides by the
lipoprotein lipase (LPL) of capillary endothelial cells liberating fatty acids into the tissue.
Chylomicron "remnants", now relatively cholesterol rich, are picked up by apo E receptors
on hepatocytes and incorporated into the cell. The VLDL "remnants", also known as
intermediate density lipoproteins (fDL) (apo B 100, E) may be cleared by hepatocyte
receptors that recognize the apo B 100 and apo E subunits, or they may be directly
converted to LDL (apo B 100) by alteration of the apoprotein on the lipoprotein coat
(removal of apo E).

52
 2. PLASMA CLEARANCE OF LDL

a. Receptor pathway (major clearance mechanism) - Hepatocytes (as well as

smooth muscle cells, lymphoid cells, fibroblasts, endothelial cells, etc.) have
specific surface membrane receptors that recognize apo B 100 (in addition to
receptors for apo E) and therefore bind LDL. The LDL is cleared from the plasma
by incorporation into the cell and subsequent hydrolysis by lysosomal enzymes into
amino acids and free cholesterol. The free cholesterol then has several functions:
1) it is used for membrane synthesis or other metabolic functions; 2) it regulates
further uptake of plasma cholesterol by decreasing the number of cell surface LDL
receptors; and 3) it inhibits endogenous cellular production of cholesterol by
suppression of the microsomal enzyme 3-hydroxy-3-methylglutaryl CoA reductase
(HMG-CoA-reductase). In hepatocytes, the cholesterol can be used for bile acid
synthesis or other metabolic functions and any excess cholesterol can be excreted
directly into the bile. In extrahepatic cells, however, excess free cholesterol
activates the enzyme acyl coAcholesterol transferase (ACA7) to re-esterifY and
store the cholesterol. There is, however, a limited storage capacity for cholesterol
within the cytoplasm. In addition to binding unesterified cholesterol that results
from normal turnover or damage to cell membranes, HDL may be able to extract
excess cholesterol from the cells, transfer it to LDL via the IDL intermediary, and
clear it through the liver.
b. Phagocytic (receptor-independent) pathway - Cells of the monocyte/phagocyte
reticuloendothelial system have receptors for "modified" LDL and normally clears
approximately one third of the plasma LDL but will increase in activity as the
plasma LDL levels increase. Unlike the cells of the receptor pathway, however,
these cells do not have the regulatory mechanisms to control the accumulation of
excessive intracellular cholesterol. High levels of plasma LDL from whatever
cause may therefore lead to the development of xanthomas (nodular aggregates
of lipid-laden macrophages).

C. HYPERLIPIDEMIA - The incidence of coronary artery disease increases when the total plasma chol-
estero I levels exceed 200 mg/dl (or the cholesterol levels associated with LDL > 130 mg/dL).
There is a linear relationship between the serum cholesterol concentration and the amount of
intimal surface covered by raised atherosclerotic plaque. Once 60% of the intimal surface is
involved, the risk of coronary heart disease is greatly increased. The higher the plasma cholesterol
levels, therefore, the younger the age when coronary heart disease becomes symptomatic.

1. GENETIC FACfORS - Certain types of familial hyperlipidemias occur as a result of genetic

defects in the control of cholesterol synthesis and are among the most frequently
encountered Mendelian disorders. The synthesis of LDL receptors is controlled by a pair
of autosomal genes. Approximately 1 in 500 persons is heterozygous negative for this
gene, and these individuals have fewer hepatic LDL receptors which means that LDL
clearance is delayed and that more IDL is converted to LDL. This increases the plasma
levels of cholesterol approximately twofold. The much more rare homozygous negative
individuals have plasma cholesterol levels approximately five times normal and very early
development of clinically significant atherosclerosis. Genetic defects in the production of
specific apoproteins have also been identified. Multifactorial hyperlipidemic disorders also
occur as well as hyperlipidemias secondary to other primary disorders.

53
 2. DIETARY FACTORS - The vast majority of cases of hypercholesterolemia, however, are due
to dietary excess or a combination of dietary and genetic factors. The major contributors
to hypercholesterolemia are:

a. Excessive caloric intake (particularly in overweight individuals) - This results in

increased hepatic VLDL synthesis (and secondarily an increased serum LDL) and
may lead to hypertriglyceridemia and hypercholesterolemia. Obesity (as well as
smoking, anabolic steroids, and progestational agents) decreases HDL levels.
b. Excessive dietary cholesterol - This will suppress hepatic LDL receptors and
raise plasma cholesterol levels, but not in a linear relationship. Dietary cholesterol
also induces postprandial increases in unusual lipoproteins (beta-VLDL) which
may be atherogenic.
c. Saturated fatty acids - These increase plasma cholesterol (mainly LDL-C) by
suppressing the activity of the hepatic LDL receptors. Monounsaturated fatty
acids, carbohydrates, and polyunsaturated fatty acids (in descending order) should
be substituted for saturated fatty acids. Although monounsaturated fatty acids do
not lower cholesterol, they do not increase triglycerides nor decrease HDL as do
the carbohydrates. Polyunsaturated fatty acids do not increase plasma cholesterol
levels but may decrease HDL, potentiate carcinogenesis, and promote
. .
mununosuppreSSlon.

D. RISK ASSESSMENT

1. PLASMA CHOLESTEROL - Initial screening for atherosclerotic risk involves measurement

of total serum cholesterol. In middle aged adults (>40), a value between 200 mg/dl and
240 mg/dl is considered borderline and overt hypercholesterolemia is considered to be a
plasma cholesterol >240 mg/dl.
2. LDL-C/HDL-C RATIO - If cholesterol levels are high, the cholesterol associated with HDL
(HDL-C) can be measured and the cholesterol associated with LDL (LDL-C) can be
calculated using the Friedwald formula:

LDL-C = total cholesterol- (HDL-C + [triglyceride/5])

Triglyceride/5 is an estimate of the cholesterol associated with VLDL. As mentioned,

elevated levels of serum LDL-C (> 160 mg/dl) are directly related to the development of
clinically significant atherosclerosis while elevated levels of HDL-C seem to have a
protective effect. Therefore, the ratio ofLDL-CIHDL-C can give a rough estimate of the
risk of coronary heart disease. Favorable ratios are 4.5: 1 or lower.
3. APO AllAPO B RATIO - The ratios of the various apolipoproteins are also predictive of a
patient's risk of developing coronary disease. As serum apo AI decreases and/or apo B
increases, the severity of atherosclerosis increases.

BEWARE THE FAT, SEDENTARY, CHAIN-SMOKING, AGGRESSIVE, HYPERTENSIVE

DIABETIC WHO COMPENSATES FOR HIS/HER MISERABLE EXISTENCE BY GORGING
ON CHICKEN FRIED STEAK SMOTHERED IN WHITE CREAM GRAVY!

54
III. PA THOGENESIS - No single theory of pathogenesis has been developed which incorporates all of the
observed and experimental data. Although some feel that the primary dysfunction relates to the "neoplastic"
proliferation of smooth muscle cells in the intima, many others feel that the atherogenic process is a
response to vascular endothelial damage. Injury to the endothelium (either functional or physical) by normal
hemodynamic stress, hypertension, cigarette smoking, chronic hyperlipidemia, etc. results in an increased
permeability of the vessel to plasma constituents at the site of injury. As LDL (and to a lesser extent VLDL)
penetrates into the intima, it is partially oxidized to a form that is, among other properties, chemotactic to
blood borne monocytes and T-lymphocytes. The monocytes migrate into the intima where they differentiate
into macrophages with receptors that recognize the partially oxidized LDL. The LDL is incorporated into
the macro phages as intracellular lipid to create the '~foam cells" that are characteristic of early
atherosclerotic lesions (fatty streaks). Additionally, the macrophages may also elaborate secretory products
that further oxidize LDL, thereby enhancing its uptake.
At this stage, these lesions may be reversible if the endothelial injury abates. If it does not, however,
uncontrolled intracytoplasmic lipid accumulation eventually causes cell death, rupture, and the formation
of an extracellular lipid pool. Platelets adhere to the areas of endothelial injury, aggregate, and release
platelet derived growth factor (which can also be synthesized by macrophages, endothelial cells, and
smooth muscle cells) which stimulates migration of smooth muscle cells from the media to the intima
where they undergo a monoclonal proliferation that contributes to the elevation of the developing plaque.
Other plasma constituents, growth factors, and cytokines may also stimulate smooth muscle cell prolifera-
tion. Since these also have membrane receptors for LDL, they may incorporate lipid and contribute to the
pool of "foam cells". In addition, the smooth muscle cells elaborate the extracellular components of the
plaques (collagen, elastic fibers, and proteoglycans).

IV. MORPHOLOGY

A. FATTY STREAKS - As mentioned, these are probably reversible lesions and mayor may not
represent precursor lesions of adult atherosclerotic plaques. Grossly these appear as multiple,
essentially flat, yellow streaks on the intimal surface. Microscopically, within the intima, there are
elongated smooth muscle cells and ovoid macrophages) both of which contain intracytoplasmic
lipid droplets (,~foam cells") embedded in variable amounts of extracellular lipid, collagen, and
elastic fibers. These lesions appear in the aorta of all children by the age of one year and are most
prominent in the thoracic aorta, especially the thoracic root - an area where significant adult
atherosclerotic plaques are seldom found. They are, however, also seen in the proximal portions
of the coronary arteries by the age of 10 years, and this location does correspond to areas of adult
atherosclerotic plaques .
. B. ATHEROSCLEROTIC PLAQUES

1. GROSS - Atherosclerotic plaques appear as multifocal asymmetric white to white-yellow

elevations of the intimal surface which may coalesce to form even larger plaques. The
firmness of a plaque varies from hard (fibrous plaques which contain a large amount of
collagen) to soft (atheromatous plaques which contain abundant lipid material) but most
have a firm fibrous cap overlying a softer core of atheromatous and necrotic debris.
Plaques tend to be most severe in the abdominal aorta, particularly in areas of vascular
branching. Prominent extra-aortic sites include the proximal coronary arteries, popliteal
arteries, descending thoracic aorta, carotid arteries, and the Circle of Willis.
2. MICROSCOPIC - Within the intima, there are varying numbers of smooth muscle cells and
blood borne macrophages, an accumulation of connective tissue fibers and matrix, and
deposition of extracellular lipids (primarily cholesterol). Typically, a plaque will have a
necrotic central area containing free cholesterol, crystallized cholesteryl esters (cholesterol

55
 clefts), fibrin, plasma protein, and cellular debris embedded within extracellular proteogly-
cans, elastic fibers, and collagen. Overlying this is a fibrous cap composed of collagen
produced by variable numbers of smooth muscle cells. As plaques increase in size, a
neovascularization develops which allows access of additional plasma lipids to the plaque
as well as serving as a potential source of hemorrhage.
3. COMPLICATIONS - "Simple" plaques may evolve into clinically significant "complicated"
plaques when one or more of the following occurs:

a. Thrombus formation - Thrombi may be superimposed on the roughened,

irregular endothelium overlying the plaque. Herein lies the danger of sudden
occlusion of a vessel (especially medium sized muscular arteries), either by rapid
expansion of a mural thrombus or by embolization, with resultant infarction of its
dependent tissues. Even without thrombus formation, plaques may lead to simple
tissue atrophy as a result of chronic hypoperfusion and ischemia.
b. Ulceration - Ulceration of the fibrous cap exposes the necrotic core material to
the circulation risking induction of a mural thrombus and/or embolization of the
cholesterol and grummous debris.
c. Hemorrhage - Bleeding into the plaques may produce sudden expansion of the
plaque with occlusion of the vessel or rupture of the fibrous cap leading to emboli
and/or thrombus formation.
d. Dystrophic calcification - This increases vascular rigidity and noncompliance.
e. Medial weakening - This occurs from pressure atrophy and loss of elasticity
predisposing to aneurysm formation and potential rupture.

V. CLINICAL SIGNIFICANCE - Generally, this is related to the physical obstruction to blood flow, the risk
of thrombosis, and alteration of the normal activity of endothelial cells. Although atherosclerosis can occur
in any of the large and medium sized arteries, clinical symptoms are generally related to the hemodynamic
effects on the heart, brain, kidney, small bowel, and lower extremities.

ISCHEMIC HEART DISEASE (IHD)/CORONARY HEART DISEASE (CHD)

Although mortality rates are currently declining, IHD is responsible for approximately 30% of the total deaths in
the U.S. and 75% of the deaths due to heart disease. Basically, it results from an imbalance between the availability
of oxygen and the metabolic demand of the heart. Clinically, this imbalance is manifested as angina pectoriS or,
when excessive, as myocardial infarct.

1. REVIEW OF THE CORONARY VASCULATURE

A. LEFT CORONARY ARTERY branches into the:

I. LEFT ANTERIOR DESCENDING - This artery supplies the anterior surface of the left
ventricle. It often extends over the apex to supply a variable amount of the inferior surface.
Septal perforating branches supply the anterior 2/3 of the interventricular septum and
diagonal branches supply the lateral anterior left ventricular wall.
2. LEFT CIRCUMFLEX - This artery follows the left atrioventricular groove and gives off the
marginal artery which supplies the lateral wall of the left ventricle.

56
 B. RIGHT CORONARY ARTERY - This runs in the right atrioventricular groove, gives off the SA nodal
and A V nodal arteries and branches into the:

1. POSTERIOR DESCENDING artery which supplies the posterior 1/3 of the interventricular
septum.
2. POSTERIOR LEFT VENTRICULAR branch which supplies a variable area of the posterior left
ventricular wall.

C. DOMINANCE - In a minority of persons, the circumflex artery will give off the AV nodal artery and
extend to become the posterior descending artery. These persons are said to have a "left dominant"
coronary system as opposed to the more common "right dominant" coronary artery.

II. FACTORS AFFECTING OXYGENATION OF THE MYOCARDIUM

A. REDUCED CORONARY BLOOD FLOW

l. ATHEROSCLEROTIC NARROWING - Narrowing of the subepicardial coronary trunks is

responsible for >90% of the cases ofIHD. Although 2: 75% stenosis of the cross sectional
area is required to significantly affect the blood flow to the intramural arteriolar bed, a -
50% stenosis may have clinical impact under conditions of increased myocardial demand
for 02' As previously mentioned, the presence of atherosclerotic plaques predisposes to
the development of thrombi (potentially occlusive) due to alterations of the endothelial
surface and changes in the hemodynamic flow. Vasoactive mediators released by platelets
(serotonin, thromboxane A2, etc.) may induce additional lumenal compromise from
vasoconstriction. Soft atheromatous plaques are also prone to ulceration of the endothelial
surface and lipid material released into the circulation from the plaque is an additional
trigger for thrombus formation. Hemorrhage into the plaque may result in expansion in
size and/or rupture of the plaque.
2. HEMODYNAMIC ALTERATIONS - Normally, the perfusion of the coronary arteries is
dependent on the pressure differential between the coronary ostia and the coronary sinus.
Left coronary blood flow is maximal during diastole and depends on the aortic diastolic
pressure. In systole, there is compression of intramural arteries and increased resistance
to blood flow, as well as partial obstruction of the coronary ostia by the aortic valve cusps
and the Venturi effect on the coronary ostia of blood ejected into the aorta. Any condition,
therefore, which decreases pressure at the coronary ostia during diastole (hypotension,
aortic regurgitation, etc.) or increases pressure at the coronary sinus (tricu5pid
regurgitation, right heart failure, etc.) will reduce coronary flow.
3. SMALL VESSEL DISEASE - Diseases involving the intramural vessels (systemic lupus,
polyarteritis nodosa, radiation damage, diabetes, emboli, etc) may also reduce the blood
supply to the myocardium.

B. INCREASED METABOLIC DEMAND - Conditions which result in tachycardia and/or hypermetabolic

states (infection, exercise, pregnancy, hyperthyroidism, etc.) increase metabolic demands and
decrease the time of diastole. Conditions which induce myocardial hypertrophy (hypertension,
valvular disease, etc.) increases not only metabolic demand but the compressive forces on the
intramural vessels as well.
C. DECREASED SATURATED HEMOGLOBIN AVAILABILITY - This may be due to conditions such as
anemia, pulmonary disease, right-to-Ieft shunts, carboxyhemoglobin, etc.

57
III. ACUTE ISCHEMIC HEART DISEASE

A. ANGINA PECTORIS - Basically this is a clinical syndrome resulting from transient ischemic
myocardial injury and manifested by paroxysmal attacks of substernal or precordial chest
discomfort often described as a pressure, constriction, or heaviness which may extend into the
neck, left jaw, left shoulder, and left arm. The hearts of patients with any of the clinical forms of
angina pectoris may show patchy myocardial necrosis or fibrosis, atrophic myofibers,
subendocardial myocytolysis, or old scars indicative of previous myocardial infarcts, but as a rule
morphologic changes are minor and may even be absent.

1. ST ABLE ANGINA (most common) - This refers to chest discomfort precipitated by

exertion and relieved by rest and/or nitroglycerin. It may also be precipitated by emotional
stress, cold weather, and heavy meals. These patients usually have severe atherosclerotic
coronary disease which prevents an increase in coronary blood flow as the metabolic
demand of the myocardium is increased. During attacks, ECG may show ST segment
depression indicative of transmural ischemia.
2. VARIANT (PRlNZMETAL) ANGINA - This refers to paroxysmal chest discomfort at rest due
to vasospasm of coronary vessels which mayor may not have concurrent significant
atherosclerotic disease. The attacks often occur at night and are commonly accompanied
by arrhythmias but generally are relieved by nitroglycerin or calcium channel blockers. The
ischemia, therefore, results from decreased coronary flow rather than increased myocardial
demand. In this instance the ST segment may be elevated even though necrosis does not
occur.
3. UNSTABLE ANGINA (most ominous) - This refers to prolonged discomfort, discomfort at
rest in a patient with previous stable angina, or more severe discomfort than usual on
exertion. Most patients have severe atherosclerotic coronary disease with possible
superimposed vasospasm or platelet microthrombi.

B. ACUTE MYOCARDIAL INFARCTION - Acute infarction causes 60% of the deaths related to ischemic
heart disease and is due to irreversible myocardial damage resulting from inadequate oxygenation
of myocardial fibers. The majority of cases reveal severe underlying coronary artery disease, and
the myocardial injury, in most instances, is due either to occluded or markedly reduced blood flow
rather than increased metabolic demand. Although the clinical symptoms are often dependant on
the site of the infarct and its severity, typically there is a severe persistent chest pain unrelieved by
rest or nitroglycerin and accompanied by nausea, vomiting, and diaphoresis.

1. TRANSMURAL INFARCT - This involves the full thickness of the ventricular wall and is
greater than 2.5 cm in diameter. The majority of patients have severe multi vessel coronary
atherosclerotic disease. Arteriographic studies of patients with acute MI have shown that
85% have thrombosis over a complicated (ulcerated or fissured) plaque in the area which
corresponds to the myocardial damage. This also implies prior platelet activation,
aggregation, and release of vasoconstrictive substances. The percentage of patients with
demonstrable thromboses decreases over time suggesting that there is some spontaneous
thrombolytic activity.

a. Characteristics - Infarcts are usually single but recurrent infarcts or progressive

(expanding) infarcts may also occur.

58
 (1) Location - The vast majority affect the left ventricle with or without
involvement of the interventricular septum. Localization of the infarct is
usually dependent on the site of coronary occlusion. Occlusion of the left
anterior descending coronary is most common followed by the right
coronary and left circwnflex. Isolated right ventricular or atrial infarcts are
rare.
(2) Size - This is dependent on the severity and duration of ischemia and the
collateral circulation to the ischemic area. If significant collateral circula-
tion has developed due to gradual stenosis of the coronaries, complete
occlusion of the vessel may not induce infarction. On the other hand, if the
collateral vessel becomes occluded, a paradoxical infarct may develop in
which the infarcted myocardial tissue is not normally in the distribution of
the occluded vessel.

b. Microscopic appearance - The initial changes to the irreversibly injured

myocardial cells (nuclear chromatin condensation, cytoplasmic eosinophilia) begin
around 6-12 hours after the event. If the region is reperfused, increased
intracellular Ca++ and free radicals may increase tissue damage (reperfuston
injury). In dying myofibers, the influx of Ca++ may produce hypercontraction of
the sarcomeres, seen as transverse eosinophilic banding (contraction bands) which
is one of the earliest light microscopic findings of myofiber death. Even if not
reperfused, nuclear pyknosis, blurring of the cross striations, and myocytolysis
develop over the next several days with an increasing inflammatory infiltrate.
Neutrophils begin to subside after about 5-7 days and, by 10-14 days, prominent
granulation tissue is present at the margins of the infarct. Progressive collagen-
ization occurs over the next several months.
c. Gross appearance - No gross abnormality until 12-24 hrs when the infarcted area
begins to show a grey-brown pallor which progresses to a soft, yellow-brown
region of necrosis with an irregular hyperemic border. Maximum softening is
present at 5-8 days. Granulation tissue appears at the edges of the infarct within
10-14 days and the lesion becomes grey-white in color as scarring develops.
d. Complications

(1) Cardiac arrhythmia (90%) - This is the most frequent complication

within the first week post-infarct and is due to increased vagal tone and
ischemia of the conduction system.
(2) Left ventricular dysfunction (> 50%) - This may lead to congestive
failure or cardiogenic shock.
(3) Mural thrombosis and embolization (15-20%). Ventricular mural
thrombi may develop over the area of infarct with the risk of subsequent
thromboemboli.
(4) Rupture « 5%)

(a) Left ventricular wall - This may lead to a rapidly developing

cardiac tamponade or a slower developingpseudoaneurysm.
(b) Interventricular septum - This will leads to left-to-right shunting.
(c) Papillary muscles - This leads to mitral valve dysfunction.

(5) Ventricular aneurysm (10-15%)

59
2. SUBENDOCARDIAL INFARCT - This is less common thllil the trllilsmural infarct llild involves
only the inner portion (I/3 - 112) of the myocardium. Due to increased contractility, in-
creased metabolic demllild, llild decreased vascular tone, the subendocardial myofibers are
more sensitive to perfusion deficits. Subendocardial infarcts usually result from myocardial
hypoperfusion secondary to severe coronary atherosclerosis. An occlusive thrombus Cllil
be demonstrated in less thllil 20% of cases although the true incidence may be somewhat
higher. Patients who otherwise have marginal blood perfusion of the subendocardial area,
however, might precipitate llil infarction with llily process that would decrease coronary
blood flow or increase metabolic demllild. Grossly, most commonly, there are multifocal
areas of subendocardial necrosis less thllil 1.0 cm in diameter which are separated by
normal myocardium. When precipitated by hypotension or shock, however, the
subendocardial necrosis tends to be continuous and circumferential. The microscopic
appearance is similar to the changes occurring in transmural infarctions, but on ECG there
is less of a tendency to develop Q-waves. Complications depend on the severity and extent
of subendocardial damage. Arrhythmias or mural thrombi may develop but rupture or
aneurysm formation is rare.
3. LABORATORY ASSESSMENT OF MYOCARDIAL INFARCT - The highest predictive value for
the diagnosis of myocardial infarction is obtained with serial studies of isoenzymes of CPK
and LDH performed at the onset of chest pain (for baseline comparative levels) followed
by measurements at 6-13 hours and 24-36 hours after the chest pain. Although not yet in
wide use clinically, measurements of cardiac troponin-I and troponin-T may have even
greater sensitivity and specificity.

a. CPK - The three isoenzymes of CPK are dimeric in structure, consisting of dimers
of peptide chains "M" (found primarily in muscle) and "B" (found primarily in the
brain). Accordingly these isoenzymes are called CPK.nm, CPK.nb, and CPKbb or
CPK3 , CPK2 or CPK j respectively. In the normal population, CPK2 is not
detectable in the serum. However, at 6 to 13 hours after a mild to moderate
myocardial infarct, CPK2 becomes measurable. This appearance of CPK2 is not
surprising since 40 percent of the total CPK in heart tissue is CPK2 . The remaining
CPK activity in heart tissue is CPK3. With infarction, both the CPK2 and CPK3
isoenzymes are elevated. CPK is cleared rapidly however and after 24 hours,
CPK2 has returned to normal levels.
b. LDH - Isoenzymes ofLDH consist oftetrameres of two peptide chains. "H" chains
are found primarily in heart muscle; "M" chains are found primarily in skeletal
muscle. These two distinct peptide chains are then linked together into tetrameres
giving rise to five distinct LDH isoenzymes. In the normal population, the serum
levels of LDH2 (35% of total LDH) is greater than LDH j (25% of total LDH).
However, in heart tissue LDH j is 40% of the total LDH while LDH2 is 35%. With
injury to myocardial cells a proportionately greater amount of LDH j is released
and there is reversal of the serum LDH/LDH2 ratio (a LDH/LDH2 "flip"). It is
important to note that this LDH "flip" occurs in 90 percent of patients with
myocardial infarction only if the blood sample is collected 24 hours after the onset
of chest pain.
c. Cardiac Troponins - Cardiac troponin-T is specific to myocardial cells and is
released into the serum when myocardial necrosis occurs. It begins to rise within
2 hours of injury and remains elevated for up to two weeks. Within the first five
days after an infarct, the presence of troponin-T in the serum has a sensitivity of
100%.

60
 C. SUDDEN CARDIAC DEATH « I hour after onset of symptoms) - This is usually associated with fatal
arrhythmias precipitated by an acute ischemic event. Most patients (90%) have severe coronary
disease and 50% have evidence of old infarcts but only rarely acute infarcts. Sudden cardiac death,
however, can occur without clinical or morphologic evidence of coronary disease.

IV. CHRONIC ISCHEMIC HEART DISEASE (40% of deaths from IHD) - Asymptomatic, slow,
progressive atherosclerotic coronary disease may become manifested by the insidious onset of congestive
heart failure as the cardiac reserve is slowly depleted. Most patients, however, have a past history of angina
or myocardial infarction, and the heart failure may follow a precipitating illness such as pneumonia.
Histologically, it is characterized by diffuse myocardial atrophy, spotty loss of myocardial cells
(myocytolysis), diffuse fibrosis, and possible scarring from previous infarcts.

VALVULAR HEART DISEASE

Valvular stenosis implies failure of a valve to open properly thereby creating obstruction to the forward flow of
blood. Acquired stenosis is almost always due to a primary abnormality of the cusps or leaflets. InsL!ffzciency
implies an inability of a valve to close properly and thereby allows for the backward flow of blood. Acquired
insufficiency can be due to intrinsic valve disease or damage to the valve's supporting structures (chordae tendineae,
papillary muscles, skeletal annulus, etc.). Stenosis and insufficiency may be coexistent among different valves or
within a single valve.

I. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

A. ETIOLOGY AND INCIDENCE - Rheumatic fever is a systemic immunologically mediated disease

involving visceral organs, arteries, and soft tissue but which has long term consequences regarding
heart valves. With rare exceptions, acute attacks of rheumatic fever occur a few days to several
weeks after pharyngeal infections by Group A beta-hemolytic streptococci. Although the incidence
in the U.S. has decreased because of improved living condition and antibiotic therapy, it still
persists and should be considered in the differential diagnosis of patients with acute arthropathy
and fever.
B. CLINICAL FEATURES - In addition to laboratory evidence of antecedent group A streptococcal
infection (throat culture, rapid streptococcal antigen test, elevated ASO titers, etc), the diagnosis
rests on the presence of one or more of the following clinical features (Jones Criteria):

1. MIGRATORY POLYARTHRITIS (70% of patients) - Painful, swollen joints (often affecting

the large joints of the extremities) transiently appear in different locations. This may be
accompanied by fever.
2. CARDITIS (60% of patients) - Signs and symptoms include murmurs of mitral and/or aortic
regurgitation, arrhythmias, chest pain, friction rub.
3. ERYTHEMA MARGINATUM (5% of patients but rare in adults) - This is an asymptomatic,
often subtle, maculopapular erythematous rash of the trunk and extremities. As the lesions
progressively enlarge, there is central clearing but retention of the erythematous borders.
It generally lasts only a few hours but frequently recurs.
4. SYDENHAMS CHOREA (ST. VITUS'S DANCE) (5% of patients but rare in adults) - This is an
involuntary, purposeless, writhing muscular movement, usually bilateral, developing
several months after the initial infection and is usually self-limited.

61
 5. SUBCUTANEOUS NODULES (3% of patients but rare in adults) - These are painless, mobile
masses that overlie the extensor surfaces of Joints and tendons and consist of foci of
fibrinoid necrosis surrounded by an inflammatory infiltrate.

Rheumatic fever is much more common in children than in adults (90% of first attacks occur
between 5 and 15) and at that age is more likely to involve the heart. The onset may be abrupt with
fever, tachycardia, and painful swollen joints or it may be insidious with malaise and low fever. As
the frequency of rheumatic fever decreases with age, the signs and symptoms are more likely to
be milder and related primarily to arthritis. After the initial episode, subsequent reinfection with
Streptococcal organisms may result in recurrent attacks that clinically mimic the initial attack.
C. PATHOGENESIS - Evidence indicates that symptoms are due in part to immunologic cross reactivity
between streptococcal antigens and host tissue antigens. Antibodies to cardiac muscle/smooth
muscle sarcolemmal antigens, heart valve fibroblast antigens, heart valve glycoproteins, and
neuronal antigens (subthalamic and caudate nuclei) have been identified. It is also possible that
autoantibodies to heart tissue may somehow be activated by the streptococcal infection.
D. MORPHOLOGY

I. HEART - Rheumatic fever produces a pancarditis which is more frequently seen in children
than in adults. Adults, however, are more prone to recurrent attacks.

a. Fibrinous Pericarditis - may cause a pericardial friction rub in the acute phase
but generally resolves without sequelae.
b. Myocarditis - Although most cases resolve spontaneously, myocarditis can
infrequently be severe enough to cause death during the acute illness due to
arrhythmia or ventricular dilatation and mitral insufficiency. Histologically, the
Aschoffbody is the characteristic lesion. Foci of fibrinoid necrosis develop in the
myocardial interstitium (usually around vessels) and subendocardium
accompanied at first by a scanty mononuclear infiltrate followed by the appearance
of plump modified macro phages (Anitschkow myocytes, Anitschkow cells,
caterpillar cells) some of which may be multinucleated (Aschoff giant cells).
Aschoff bodies are pathognomonic for rheumatic heart disease. Focal
thickening of the left atrial endocardium (McCallum's plaques) may appear
representing subendothelial aggregates of Aschoff bodies. As the acute attack
subsides, there is progressive fibrosis of the Aschoff bodies.
c. Endocarditis - This is the most consistent and the most crippling aspect of
rheumatic heart disease and tends to involve the valves of the left side of the heart:
mitral (40-50%), aortic and mitral (35-40%), aortic, mitral, and tricuspid (5%);
and aortic alone « 5%). Acutely, small fibrin verrucae overlie foci of fibrinoid
necrosis that develop along the closure lines of the valves (typically on the surfaces
exposed to the forward flow of blood) and occasionally on chordae. As the acute
attack subsides, valves heal with fibrous scarring and thickened, shortened,
blunted leaflets having varying degrees of commissural fusion. The mitral valve
shows a characteristic '~fish-mouth" deformity as well as shortening, thickening,
and fusion of the chordae. In addition to commissural fusion, nodular calcifica-
tions may form behind the aortic valve cusps leading to variable degrees of
stenosis and insufficiency.

62
 2. OTHER ORGANS - The histologic changes in the joints, skin, and blood vessels include foci
of fibrinoid necrosis with varying degrees of inflammatory infiltrates and often resemble
the Aschoff bodies found in the heart.

E. COMPLICATIONS - These include cardiac failure (2° to valvular disease), thrombosis and
embolization, and infective endocarditis.

II. CALCIFIC AORTIC STENOSIS - With increasing age, calcific excrescences build up in the sinuses of
Valsalva (perhaps simply due to repeated minor trauma over a lifetime) and decrease the lumenal diameter
of the valve. As the pressure gradient across the valve increases, there is increasing left ventricular
hypertrophy. Stenosis becomes critical when two thirds of the cross sectional area of the valve is
compromised or when the pressure gradient across the valve reaches 50 mmHg (it may approach 300
mmHg in severe cases). Unlike rheumatic valves, however, there is little or no commissural fusion. In
general, the clinical symptoms first appear in elderly patients, although if there were preexisting
abnormalities of the valve (such as congenital bicuspid valves), the clinical symptoms might occur at a
younger age. Symptoms (dyspnea, angina, syncope, etc.) generally are referable to left heart failure or
inadequate cardiac output. Once they appear, median survival is only 2-3 years unless the valve is replaced.
III. MITRAL ANNULUS CALCIFICATION - Nodular calcification of the mitral annulus also occurs with
increasing age but generally does not significantly alter valve function.
IV. MITRAL VALVE PROLAPSE - A common condition (5-7% of the general population, more frequent
in young women), this may in some cases be congenital in origin. It may be related to a metabolic defect
in connective tissue metabolism since there is a high (90%) incidence in patients with Marfan's syndrome.
Prolapse is characterized by enlarged mitral leaflets and/or elongated chordae. The posterior leaflet is
always involved with the anterior leaflet involved to a lesser extent. This abnormality allows for ballooning
ofleaflets during systole and may produce a midsystolic click corresponding to the snapping of an everted
leaflet. There may also be some degree of insufficiency with late systolic murmur. Eventually, possibly
from long standing trauma, the leaflets thicken as do the chordae (which may also fuse). The valve may
ultimately resemble a rheumatic valve except that there is no commissural fusion. In a minority of cases,
the tricuspid valve may also be affected. Secondarily, there may be calcification along the base of leaflets
(resembling calcified mitral annulus), superimposed infective endocarditis, or rupture of chordae. The
majority of patients are asymptomatic but death can result from complications of infective endocarditis,
from chronic congestive failure, from chordal rupture or from arrhythmia.
V. NONBACTERIAL THROMBOTIC (MARANTIC) ENDOCARDITIS - Most frequently seen in
patients dying of chronic debilitating disease, this also occurs in hypercoagulable states (such as seen with
malignancies) or with valve trauma secondary to indwelling catheters (Swan-Ganz), etc. Small sterile
platelet-fibrin thrombi develop along lines of valve closure and may, on occasion, engender systemic
arterial emboli.
VI. INFECTIVE ENDOCARDITIS - This is a potentially lethal condition characterized by the formation of
friable septic vegetations on heart valves or endocardial surfaces. The disease may affect either normal
hearts (25-50%) or those with preexisting abnormalities (50-70%); may involve highly virulent or relatively
innocuous organisms; and may have an abrupt onset with fulminant course and rapid death or an insidious
onset with protracted course and resolution. The causative organisms are predominantly bacterial (95%)
but with immunosuppression, increasing IV drug usage, and immunodeficiency diseases, more exotic
organisms such as fungi, rickettsiae, etc. are involved. Although there is considerable overlap, the disease
tends to take one of two clinical forms.

63
A. ACUTE ENDOCARDITIS (ABE)

1. PATHOGENESIS - ABE is usually caused by virulent and aggressive organisms (staph.

aureus, etc.) which directly damage the cardiac valves and induce septic thrombus forma-
tion. It is frequently seen in LV. drug users or chronic alcoholics whose hearts usually do
not have underlying abnormality or within the first few months in patients who have had
cardiac surgery. Some patients have preexisting pyogenic infections such as pneumococcal
pneumonia or abscesses. LV. drug users, who are likely to inject microorganisms directly
into blood, have a greater incidence of right-sided lesions with staph. aureus, candida, and
aspergillus being the major organisms. Cardiac surgery leaves "foreign bodies" which
might be seeded by organisms. Early infections « 2 months after surgery) are often due
to skin and airborne organisms (Staph. aureus, Staph. epidermidis, gram negative bacilli,
etc.).
2. MORPHOLOGY - Large, bulky, friable vegetations (often multiple) develop on the valve
surfaces and are prone to perforate the underlying valve, erode into the myocardium, or
fragment and embolize.
3. CLINICAL - Characteristically, there is an abrupt onset of high fever, shaking chills, and
profound weakness. Embolic phenomena also occur early and involve the brain, spleen,
myocardium, and kidneys. The resultant septic infarcts frequently develop into abscesses.
Skin and mucosal hemorrhage (which may have infective centers from which organism can
be cultured), retinal hemorrhage with central pallor (Roth spots), and linear subungual
splinter hemorrhages may occur. Cardiac decompensation occurs early as valves are
eroded or chordae rupture. Aortic ring abscesses may cause arrhythmia. Osler's nodes
(tender, purplish subcutaneous nodules) or Janeway's spots (painless hemorrhagic
maculopapular eruptions) may appear on the palms, soles, or finger and toe pads and are
probably due to immune complex mediated vasculitis. Septic arthritis and digital clubbing
may also develop. When the left heart is involved, a murmur is present in about two thirds
of the cases. The murmurs have a tendency to change in character and intensity as portions
of vegetations break off and alter the hemodynamic flow. Mortality may approach 70%.
Death is usually due to CHF (from valve dysfunction), fatal embolism, arrhythmi~ rupture
of mycotic aneurysm, or uncontrolled sepsis.

B. SUBACUTE ENDOCARDITIS (SBE) - This implies a duration of more than six weeks.

1. PATHOGENESIS - Characteristically, SBE involves hearts that have underlying congenital

or valve abnormalities (most notably left sided valves) that alter normal hemodynamic
blood flow patterns. Regurgitation and/or jet streams promote the formation of sterile
platelet-fibrin deposits. These deposits may then be seeded by blood borne organisms.
Seeding may be promoted by agglutinating antibodies which produce clumps of organisms
that tend to precipitate out in areas of "low pressure sink" (Venturi effect). These areas are
along the free margins of the atrial surface of mitral valve and ventricular surface of aortic
valve. Certain bacteria (streptococci) appear to elaborate "adhesion factors" that promote
their adherence to fibrin and platelets. Because of these deranged hemodynamic factors,
low virulence organisms (often indigenous bacteria) have potential for implanting on the
valve or endocardial surfaces. Strep. viridans, normally found in the gingival sulci, is the
predominant organism.
2. MORPHOLOGY - Valvular vegetations form along the free margins of the valves as friable,
irregular masses but tend to be less bulky than in ABE. They may undergo progressive
fibrosis, organization, and calcification; extend to adjacent endocardium or chordae; but

64
 are less likely burrow into ventricular wall. The distribution of lesions is mitral alone
(25-30%); aortic alone (25-35%); mitral and aortic (10%); tricuspid alone (10%);
prosthesis (10%); and congenital defects (10%).
3. CLINICAL - In contrast to ABE, there is usually an insidious onset with progressive
weakness, anorexia and weight loss, anemia with skin pallor, low-grade fever, and
occasional night sweats. The initial manifestation may also be due to an embolic event to
the brain, heart, spleen, or kidneys. Similar physical signs as seen with ABE may develop
(but with less frequency), and the spleen may be enlarged and tender. A cardiac murmur
is usually present but is mostly a function of the underlying valvular disorder and
infrequently changes in character. If death occurs (10-20% with Strep. viridans), it is
usually due to CHF, embolic episodes to the myocardium or brain, arrhythmias, sepsis,
and/or renal failure due to focal or diffuse glomerulonephritis.

C. LABORATORY DATA - In ABE, the leukocyte count is usually increased but with SBE the leukocyte
count is often normal. A normochromic, normocytic anemia is generally present and rheumatoid
factor may be found in up to 50% of patients but will disappear with treatment. Circulating
immune complexes may be present and hypergammaglobulinemia can generally be demonstrated.
Diagnosis ultimately rests with identification of the organism in blood. Cultures (when taken at
regular intervals) will be positive in 90%.
D. TREATMENT - High dose therapy with antibiotics appropriate to the organism are required for
prolonged periods, and valve replacement may become necessary.

MYOCARDIAL HEART DISEASE

I. HYPERTENSIVE HEART DISEASE - After ischemic heart disease, hypertensive heart disease is the
second most common cause of cardiac failure and death.

A. PATHOGENESIS - Blood pressure is governed by cardiac volume output and the outflow resistance
(determined by the peripheral arteriolar resistance, large artery compliance, and viscosity and
inertia of blood). Widespread arteriolar vasoconstriction increases resistance to left ventricular
outflow and creates a pressure overload on the left ventricle. Hypertension also predisposes to and
accelerates atherosclerosis and arteriolosclerosis which further increases peripheral resistance and
decreases vessel compliance.
B. MORPHOLOGY - The heart responds to a pressure overload by concentric hypertrophy of the
ventricle which thickens the wall, increases heart weight (without significant increase in size), and
decreases ventricular volume. In the absence of any other abnormality that might produce left
ventricular hypertrophy (ie. valve disease), this is the identifying hallmark of hypertension. As
decompensation occurs, however, the ventricle dilates (increasing heart size) and obscures the
hypertrophic changes. Microscopic changes consist mainly of increased myofiber diameter with
blunted, prominent, "box-car" nuclei. Although hypertrophied myofibers demand more oxygen,
hypertension accelerates atherosclerosis of extramural coronary arteries and arteriolosclerosis of
intramural arterioles, both of which decrease O2 availability to the myocardium. Eventually focal
atrophy and degeneration of myocytes occur and a diffuse myocardial fibrosis develops.
C. CLINICAL - Hypertension is asymptomatic except for specific symptoms associated with severe
hypertension (tinnitus, epistaxis, dizziness, etc.). As cardiac decompensation intervenes, however,
there is an insidious onset ofleft heart failure symptomatology. Untreated hypertension will result

65
 in death due to heart failure (usually within a year of initial symptoms), stroke. renmascular disease
and/or vascular complications.

II. MYOCARDITIS - This term refers to any inflammatory condition that involves the myocardium. It can
range from a fulminant disease with abrupt onset and acute cardiac failure to an asymptomatic disease
identified only by transient EKG changes (abnormality in ST and T waves).

A. ETIOLOGY - Myocarditis may be due to microbiologic agents, hypersensitivity reactions, radiation,

or unknown causes. Viral myocarditis (Coxsackie, ECHO, polio, and influenza are the most
common) comprises more than 50% of the cases and is most frequently seen in infants, pregnant
women, and immunosuppressed patients. Although there may be direct viral toxicity to the
myofibers, most of the damage is probably due to cell mediated immune response to the virally
infected cells. Isolation of the virus is difficult and diagnosis often rests on demonstrating rising
serum antibody titers. Less common causes (in the US.) include leptospira (Wei/'s disease),
trypanosomes (Chagas' disease), toxoplasma (particularly in the fetus and newborn), diphtheria,
candida, and aspergillus.
B. MORPHOLOGY - Typically, the affected cardiac chambers become dilated, flabby, and have a
mottled appearance with hemorrhagic foci. Acute infections may be focal or diffuse and show
myocardial interstitial edema with an inflammatory infiltrate characteristic of the inciting agent. The
inflammation usually resolves in 6-8 weeks, but there may be residual dilatation or hypertrophy
which may progress to chronic disease associated with myocardial fibrosis. Although rare and of
unknown etiology, giant cell myocarditis and Fiedler's myocarditis cause a granulomatous
reaction complete with giant cells, lymphocytes, plasma cells, eosinophils, and macrophages.
Possibly viral and/or immune mediated in origin, these are frequently rapidly fatal.
e. CLINICAL - When symptomatic, the clinical manifestations include tachycardia, AV conduction
blocks, low grade fever, dyspnea and malaise.

III. CARDIOMYOPATHY - This term refers to non-inflammatory disorders of the myocardium. The etiology
of some cardiomyopathies are known (secondary cardiomyopathy) but the etiology of others have yet to
be determined (primary cardiomyopathy). Nevertheless, the clinical and pathologic patterns generally fall
into one of three categories.

A. DILATED (CONGESTIVE) CARDIOMYOPATHY - This may simply represent a common end point of
a variety of previously undiagnosed cardiac diseases and can occur at any age. Some are of known
cause (alcoholic, familial, peripartum, nutritional, and post-infectious cardiomyopathies), but the
large majority must be classified as idiopathic.

1. MORPHOLOGY - These are characterized by dilatation and hypertrophy of all chambers of

the heart with impairment of ventricular contraction, low ejection fractions, high end-
systolic volumes, and congestive heart failure. There is always increased heart weight due
to ventricular hypertrophy, but grossly the hypertrophy may be obscured by the ventricular
dilatation. The myocardium shows diffuse interstitial fibrosis without evidence of
inflammation or severe coronary atherosclerosis. Due to poor contractility, mural thrombi
are prone to develop (most frequently in the left ventricle).
2. CLINICAL - Patients generally present with signs and symptoms of congestive heart failure.
Progressive heart failure usually culminates in death unless patients first succumb to
arrhythmias or the effects of systemic emboli.

66
B. HYPERTROPHIC (OBSTRUCTIVE) CARDIOMYOPATHY - This has also been referred to as
asymmetric septal hypertrophy (ASH) and idiopathic hypertrophic subaortic stenosis (IHSS). In
most instances, it probably represents an inherited condition (particularly in patients with a family
history of sudden unexplained deaths).
1. MORPHOLOGY - In most, but not all, cases the morphology is characterized by dilated
atria, disproportional hypertrophy o/the interventricular septum with myofiber disarray,
decreased ventricular volume, mitral valve thickening, endocardial thickening of left
ventricular outflow tract, and thickening of the intramural arterioles.
2. CLINICAL - The asymmetrically hypertrophied septum and left ventricle mayor may not
result in signs (systolic murmurs of aortic outflow obstruction and mitral insufficiency) and
symptoms (angina, syncope, dyspnea) of obstruction of the left ventricular outflow. If the
septal hypertrophy is more prominent in the lower portion of the IVS, obstructive
symptoms are less likely to occur than if the hypertrophy is higher in the septal wall. If
there is also thickening of the posterior ventricular wall behind the posterior leaflet of the
mitral valve, obstructive symptoms may also result from abnormal motion of the anterior
mitral valve leaflet obstructing the LV outflow tract. This additionally allows mitral
regurgitation which further compromises outflow from a ventricular chamber already
decreased in volume. In those cases where the aortic outflow tract is compromised, as the
heart begins to fail and dilate, the obstruction is relieved and the symptoms paradoxically
improve. The clinical course is variable with some patients able to be helped by medical
therapy. Others, however, develop progressive heart failure complicated by embolization
from atrial thrombi or infective endocarditis.

C. RESTRICTIVE/INFILTRATIVE CARDIOMYOPATHIES - These are rare conditions characterized by

restriction of ventricular filling. Although the pathologic process is different, the clinical signs and
symptoms are essentially the same as dilated cardiomyopathy. High venous filling pressures lead
to right and left heart failure.

1. AMYLOIDOSIS, SARCOIDOSIS, HEMOCHROMATOSIS, POMPE'S DISEASE - These all result

in diffuse infiltration of the myocardium by abnormal substances thereby restricting normal
myocardial compliance and elevating the ventricular filling pressures.
2. ENDOMYOCARDIAL FIBROSIS - This is characterized by fibrosis of the ventricular endo-
cardium and subendocardium which extends from the apex toward the inflow tract of the
right and/or left ventricle and will occasionally involve the AV valves. Contraction of
fibrous tissue decreases chamber volume and the formation of mural thrombi may further
contribute to volume decrease. With Loffler's endocarditis, there is also a circulating
eosinophilia, infiltration of visceral organs by eosinophils, and a fulminant course leading
to rapid death.
3. ENDOCARDIAL FIBROELASTOSIS - Typically in this disorder there is focal or diffuse
thickening of the left ventricular endocardium composed of fibroelastic connective tissue.
It is most frequently seen in the first two years of life and is possibly due to intrauterine
viral infection or developmental insult. It often is associated with other congenital
cardiovascular abnormalities. Depending on the extent of endocardial involvement, it may
be asymptomatic, cause aortic or mitral stenosis and/or regurgitation, or result in
progressive congestive heart failure and death.

67
 PERICARDIAL HEART DISEASE

The normal pericardium consists of a thin, delicate membrane (visceral pericardium) adherent to the epicardial
fat and a thicker fibroelastic membrane (parietal pericardium) that is adherent to surrounding mediastinal
structures. Between the two membranes is a potential space which normally contains approximately 50 m!. of
clear yellow fluid. The visceral and parietal pericardium are in continuity at the base of the heart and the
proximal portions of the great vessels lie within the pericardial space. Normally, the pericardial pressures are
equal to the right ventricular diastolic pressure.

I. ACUTE PERICARDITIS

A. SEROUS - This is usually due to a viral, or immunologically mediated inflammation of the

epicardium and pericardium resulting in a serous effusion into the pericardial space. The effusion
generally is less than 200 m!., contains few inflammatory cells, and is usually reabsorbed without
sequelae when the inciting cause is removed.
B. FIBRINOUS (most common) - This is usually non-infectious in origin and is seen after a myocardial
infarct, after trauma to the pericardium, and in various systemic disorders. It may be clinically
manifested by malaise and fever associated with a variable degree of chest pain. A loud pericardial
friction rub may be auscultated unless serous fluid accumulates and separates the parietal and
visceral pericardium. This usually resolves without sequelae but asymptomatic delicate fibrinous
adhesions between the visceral and parietal pericardium may persist.
C. PURULENT - This is seen most frequently in young males (10-40 years old) and is associated with
infectious agents (primarily bacteria and fungi). A thick creamy exudate up to 500 ml in volume
accumulates within the pericardial cavity. A friction rub is less prominent than in fibrinous
pericarditis but the patients are sicker (usually a reflection of the underlying systemic infection).
This usually organizes to produce chronic adhesive or constrictive pericarditis.
D. HEMORRHAGIC - This connotes a fibrinous or suppurative effusion admixed with blood. It is most
frequently due to TB or neoplastic involvement of the pericardium. It generally follows the same
natural history as purulent pericarditis leading to chronic adhesive or constrictive pericarditis.

II. CLINICAL MANIFESTATIONS OF PERICARDIAL FLUID ACCUMULATION

A. ACUTE (CARDIAC TAMPONADE) - Due to the relative noncompliance of the normal parietal
pericardium, a rapid accumulation of even a modest volume (I50-200 m!.) of fluid in the
pericardial space can lead to equalization of the pericardial pressure and the left and right
ventricular diastolic pressure. This will result in decreased filling of the ventricles during diastole
and therefore decreased cardiac output during systole. This can be clinically expressed as jugular
vein distension and systemic hypotension. Characteristic of, but not exclusive to, cardiac
tamponade is a condition known as pulsus paradoxus in which the systolic pressure during
inspiration falls more than 10 mmHg below the systolic pressure during expiration. This is the
result of the lowered intrathoracic pressures during inspiration and the preferential filling of the
right ventricle at the expense of the left ventricle. On auscultation, the heart sounds may sound
"distant" due to the muffling by the fluid surrounding the heart.
B. CHRONIC - Since the parietal pericardium, over time, can stretch, chronic accumulations of fluid
can reach much greater volumes (lOx acute volumes) before clinical manifestations become
apparent. When symptoms do occur, however, they tend to be similar to the symptoms of acute
tamponade but have a more gradual onset.

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III. CHRONIC (HEALED) PERICARDITIS

A. ADHESIVE PERICARDITIS -lbis is often secondary to healed suppurative pericarditis or to radiation

or cardiac surgery. The pericardial sac is obliterated with adherence of parietal pericardium to
surrounding thoracic and mediastinal structures. This inhibits cardiac contraction resulting in
increased workload, hypertrophy, and dilatation of the heart.
B. CONSTRICTIVE PERICARDITIS - This often consists of idiopathic fibrosis or fibrocalcific scarring
of the pericardium which inhibits cardiac filling during diastole and results in decreased cardiac
output. Although the signs and symptoms are similar to adhesive pericarditis, hypertrophy and
dilatation cannot occur.

IV. CLINICAL MANIFESTATIONS OF CHRONIC PERICARDITIS - Symptoms of chronic pericarditis

may appear identical to those of a restrictive cardiomyopathy. There is evidence of both right and left heart
failure although edema, either systemic or pulmonary, is not a common feature.

CARDIAC NEOPLASMS

I. PRIMARY TUMORS - In general, primary cardiac neoplasms are exceedingly rare.

A. BENIGN (80%)

1. MYXOMAS - These may occur at any age, are more frequently seen in females, and are
derived from primitive mesenchymal cells. Ninety percent are located in the atria
(approximately four times as common in the left atrium as compared to the right atrium)
and arise in the area of the fossa ovalis. They may be sessile or pedunculated and may
protrude through AV valve during diastole, creating a ball-valve effect, and obstructing
left ventricular filling.
2. RHABDOMYOMA -lbis is most frequently seen in infants and children, is often associated
with tuberous sclerosis, and may cause obstructive symptoms.
3. PAPILLARY FIBROELASTOMA - This is primarily a valvular lesion which is benign and
asymptomatic.

B. MALIGNANT (20%) - Angiosarcoma is the most frequent followed by rhabdomyosarcoma,

mesothelioma, and lymphoma.

II. METASTATIC DISEASE -lbis also is uncommon. Metastatic neoplasms most frequently found in the
myocardium originate from the lung, the breast, or a melanoma.

VASCULAR DISEASE

I. ANEURYSMS

A. ATHEROSCLEROTIC ANEURYSMS - These are the most commonly encountered aortic aneurysms
and generally occur in middle-aged to elderly males, half of whom are hypertensive. Although
atherosclerotic aneurysms may affect the thoracic aorta, the vast majority occur in the distal
abdominal aorta and lie between the renal arteries and the bifurcation into the common iliacs. They

69
 develop slowly over time and do not produce clinical symptoms until they become large enough
to compress adjacent structures (ureters, vessels), produce thromboemboli (usually to the lower
extremities), or rupture. On physical exam, however, a pulsatile abdominal mass may be palpated
or auscultated before symptoms become apparent. Abdominal x-rays, ultrasound, NMR are also
useful non-invasive diagnostic tools. Since the risk of rupture increases with the size of the
aneurysm, they should be resected if they become greater than five cm. in size. Elective resection
has a mortality rate of2-5% while resection after rupture has a mortality rate of25-50%.
B. SYPHILITIC (LUETIC) ANEURYSMS - These are a complication of tertiary syphilis and, for the most
part, are limited to the ascending aorta and aortic arch. Tertiary syphilis causes inflammation and
obliteration of vasa vasorum leading to patchy medial necrosis. Contraction of the fibrous scar
tissue that develops in areas of necrosis leads to longitudinal "tree barking" of the intimal surface.
As the aorta dilates due to the weakening of the elastic media, there is often secondary
atherosclerotic involvement of the intima. The aneurysmal dilatation of the ascending aorta may
dilate the aortic annulus resulting in aortic insufficiency manifested by a diastolic murmur and a
widened pulse pressure. Over time, this aortic regurgitation may result in a massively enlarged
heart (cor bovinum) due to concentric left ventricular hypertrophy and dilatation. Due to their
location, clinical symptoms are more common with thoracic aneurysms. Compression of lungs,
trachea or bronchi may lead to respiratory problems; compression of the esophagus may lead to
dysphagia; compression of the recurrent laryngeal nerve may lead to hoarseness; and erosion of
bony structures may lead to pain. Death is often the result of heart failure due to the aortic valve
incompetence.
C. CYSTIC MEDIAL NECROSIS - This is a chronic degenerative process of unknown etiology that
results in focal destruction of the media of the thoracic aorta. It is most likely due to a metabolic
defect in the synthesis of collagen and elastin and is frequently associated with Marfan's syndrome
(a metabolic connective tissue disorder). However, it is also seen in other conditions (hypertension)
as well as with normal aging. Microscopically, there is patchy fragmentation and degeneration of
elastic fibers, ill-defined cyst-like areas containing amorphous ground substance devoid of collagen
or elastin fibers, and foci of medial fibrosis. With the weakening of the aortic wall, aneurysmal
dilatation may ensue and, today, this disorder is responsible for the majority of thoracic aortic
aneurysms.
D. MYCOTIC ANEURYSMS - These result from weakening of a vessel wall due to local infection
(usually by bacteria or fungi). These may occur at any location and generally become symptomatic
only when they rupture.

II. AORTIC DISSECTION (DISSECTING ANEURYSM) - This occurs more commonly than rupture of
atherosclerotic aneurysms and constitutes, in most cases, a medical emergency. Most occur in middle-aged
men (40-60) but when they occur in younger individuals, the male:female ratio is about equal due to the
increased incidence of aortic dissection in pregnant women. Hypertension is frequently a predisposing
factor particularly in those patients without preexisting damage to the aortic media. The dissection is
characterized by hemorrhage between the middle and outer II3 of the media layer. Although some feel that
the precipitating event is hemorrhage secondary to rupture of diseased vessels of the vasa vasorum
(hypertensive damage), it usually arises secondary to the development of spontaneous transverse intimal
tears in either the proximal ascending aorta (Type A) or immediately distal to the origin of the left
subclavian artery (Type B). Cystic medial necrosis has also been linked to the development of dissecting
aneurysms. Areas of medial necrosis may allow the intima to buckle into the lumen where hypertensive
pressures cause shearing and tearing. Blood is then forced into the outer media where it may longitudinally
dissect both proximally and distally.

70
 A. TYPE A DISSECTIONS - These are usually seen in middle aged men. involve the ascending aorta,
and are often secondary to medial degeneration. A major cause of death is retrograde dissection,
rupture into the pericardial cavity, and cardiac tamponade.
B. TYPE B DISSECTIONS (descending aorta only) - These are less common and are usually seen in
elderly patients with atherosclerosis and hypertension. Anterograde dissection occurs with possible
rupture into pleural or peritoneal cavities but rupture is less likely than in patients with Type A.
C. CLINICAL PRESENTATION - Symptoms usually include severe, "tearing" pain in the anterior chest
which radiates into and down the back. It may simulate myocardial infarction or perforated peptic
ulcer but those patients usually have decreased blood pressure. Additional clinical signs and
symptoms can occur as the dissection involves and narrows the lumen of the vessels that branch
from the aorta (especially coronary, carotid, and renal arteries).
D. TREATMENT - Intensive antihypertensive therapy is indicated and followed, in some cases, by
surgery.

III. NON-INFECTIOUS NECROTIZING VASCULITIDES - These are characterized by necrosis and

inflammation of vessels and are probably mediated by immunologic mechanisms. Many exhibit multi-
system involvement with highly variable clinical presentations depending on which organ symptoms are
involved and the size of the vessels involved.

A. POLYARTERITIS NODOSA (PAN) - This is the prototype of systemic necrotizing vasculitis. Primarily
affecting young to middle-aged males (30-40% of patients are HBsAg +), the classic form of the
disease causes segmental necrosis of medium and small arteries within all viscera except the lungs.
Kidney, heart, liver, and GI tract are most commonly involved.

1. MORPHOLOGY - Microscopically, three stages of vascular involvement can be identified

which may exist simultaneously within the same vessel or within different vessels.

a. Acute - Segmental (non-concentric) fibrinoid necrosis of the intima may expand

to involve the entire vessel wall thickness with subsequent infiltration of the
necrotic areas and the perivascular tissues by polys and monocytes. This tends to
occur at vascular branching points and predisposes to thrombus formation as well
as aneurysm formation. Thromboses may produce infarctions, and the symptoms
depend on where the infarctions occur.
b. Healin!! - Repair by granulation tissue results in thickening and narrowing of the
lumen due to proliferation of fibroblasts and the increased numbers of macro-
phages and plasma cells. Perivascular fibrosis may produce clinically palpable
nodules.
c. Healed - Marked fibrous thickening of the vascular wall with scattered chronic
inflammatory infiltrate.

2. CLINICAL - Complaints are often non-specific and may consist of exacerbations and
remissions offever, weight loss, hypertension, hematuria, abdominal pain, cramps, melena,
myalgia, etc. Lab changes (increased ESR anemia, leukocytosis) are likewise non-specific,
but the presence of anti-neutrophil antibodies are used as a marker of disease activity.
Renal involvement occurs in 75% of patients and, if untreated, is the most common cause
of death although CVA, bowel infarcts, etc. may supervene. Fortunately, however, the
prognosis has greatly improved with the advent of steroid and cyclophosphamide therapy.

71
B. HYPERSENSITIVITY VASCULITIDES - These often produce palpable purpura as a clinical sign.

I. LEUKOCYTOCLASTICVASCULITIS - This is a hypersensitivity immune complex vasculitis

affecting small arterioles, capillary, and venules. Although most frequently confined to the
skin, it may also involve lung, brain, heart, GI, kidney, and muscle. In contrast to PAN, all
lesions are at the same stage of development and consist of polys infiltrating the vessel
wall. Although fibrinoid necrosis mayor may not be present, immunoglobulins and
complement can be found in the lesions. Extravasation of erythrocytes into surrounding
tissue and karyorrhexis of the neutrophil nuclei (leukocytoclasis) are characteristic.
Remove the antigen (drugs, tumor antigens, microorganisms, etc.) and most patients
improve, although some die of rapidly progressive (crescentic) glomerulonephritis.
2. HENOCH-SCHONLEIN PURPURA - This is a hypersensitivity vasculitis affecting the skin,
joints, kidneys and GI tract of children. IgA and complement are deposited in the vascular
walls. There is abrupt onset of fever, arthralgias, and rash. It is usually self limited but
renal failure can occur.

C. GRANULOMATOUS (GIANT CELL) ARTERITIDES

I. TAKA YASU'S ARTERITIS (pulseless disease) - This is a disease of unknown etiology that
is most frequently seen in young to middle-aged females (has been associated with HLA-
DR4) and results in a progressive segmental stenosis of the aorta (particularly aortic arch)
and the major arch arteries. The pulmonary artery may also be involved. Histologically,
there is chronic inflammation in the adventitia and often granulomatous inflammation in
the media. Subsequent fibrosis of the media and intima causes marked thickening of the
vessel and compromise ofthe vascular lumen especially at the origins of the arch vessels.
Clinical signs and symptoms are frequently referable to decreased upper body perfusion
(decreased peripheral pulses in the upper extremities, visual disturbances, and various
neurologic deficits) and may be superimposed on more general non-specific symptoms
(fever, fatigue, and malaise). Lab findings are non-specific (increased ESR).
2. TEMPORAL ARTERITIS - Probably the most common of the vasculitides, this tends to be
a disease of the elderly women (particularly those with a genetic predisposition - HLA-
DR4) characterized by focal segmental granulomatous lesions of small, medium
(especially temporal), and occasionally large (aorta) arteries.

a. Morphology - Although biopsies of the artery may be completely negative in up

to 40% of the patients exhibiting symptoms of temporal arteritis, the characteristic
findings include medial necrosis with disruption of the internal elastic lamina; non-
specific acute and chronic inflammatory infiltrate involving the entire wall
thickness; and intimal fibrosis with reduction of lumenal caliber. Thromboses
frequently develop in the affected vessels. The histologic hallmark is the presence
of granulomatous inflammation of the vessel wall, complete with giant cells.
Unfortunately, however, these are often absent.
b. Clinical - In some patients, there is an insidious flu-like onset with weight loss,
fever, anorexia, and nausea (a closely related syndrome, polymyalgia rheumatica,
presents in the same manner but with the added symptoms of proximal myalgias
and arthralgias. Some feel that this is just a different clinical expression of the
same disease). Alternatively, the onset may be abrupt with severe throbbing
headaches and tenderness and nodularity along course of the vessel. Visual
symptoms are present in 40% of patients and may produce blindness due to

72
 ophthalmic artery involvement and ischemia to optic nerve. Occasionally.
however, symptoms may be limited to claudication of the jaw and other oral
manifestations. Lab tests are non-specific (increased ESR) and the disorder usually
responds rapidly to steroids.

D. BUERGER'S DISEASE (thromboangiitis obliterans) - This is a disease of unknown etiology

(although there may be genetic predisposition and/or immunologic hypersensitivity), almost
exclusively limited to cigarette smokers, which is characterized by segmental inflammatory and
thrombotic disease of the small and medium sized arteries and veins of the extremities and which
secondarily extends to adjacent nerves eventually leading to fibrous encasement of all three. Less
often cerebral, coronary, and visceral vessels are involved. Microscopically, neutrophils are present
throughout the thickness of the wall and microabcesses may be found in the occlusive thrombi. The
clinical course will wax and wane in relationship to cigarette use. Acute episodes are characterized
by excruciating pain and eventual gangrenous necrosis of the digits.
E. WEGENER'S GRANULOMATOSIS - This is a rare disorder of unknown etiology but which may be
related to a hypersensitivity to a foreign substance. The presence of anti-neutrophil antibodies may
be used as a marker of disease activity.

1. MORPHOLOGY - Frequently seen in middle-aged males, it is manifested by:

a. Necrotizing granulomas of the upper and lower respiratory tract (nose, sinuses,
larynx, trachea, lungs) which heal by progressive fibrosis but which sometimes
cavitate.
b. Focal necrotizing vasculitis of small arteries and veins throughout the body but
particularly prominent in the lungs, kidneys, and spleen.
c. Focal necrotizing glomerulonephritis which may evolve into rapidly progressive
( crescentic) glomerulonephritis.

2. CLINICAL - The most frequent presentation involves persistent pneumonitis with bilateml
cavitary lesions, chronic sinusitis, nasopharyngeal mucosal ulcerations, and renal disease.
At one time, it was rapidly fatal but long term remission can now be expected with the use
of steroids and cyclophosphamide.

F. KAWASAKI'S DISEASE (MUCOCUTANEOUS LYMPH NODE SYNDROME) - This is a necrotizing

vasculitis seen in children. They present with fever, lymphadenopathy, and arthritis. Lab findings
include thrombocytosis. Although usually self-limiting, involvement of the coronary arteries (30%)
may result in aneurysm formation or thrombosis.
G. RA YNAUD'S DISEASE - This is characterized by vasospasm, often bilateral, of small arteries and
arterioles in the fingers and toes (less often the ears and tip of nose) of young healthy women. Cold
temperatures and emotional stress trigger the attacks which turns finger tips white then blue then
red. Usually the disorder follows a benign course but with chronic disease, intimal thickening may
occur with ulceration and necrosis of the skin.
H. RAYNAUD'S PHENOMENON - This refers to conditions which cause the same symptoms as
Raynaud's disease but which are secondary to some underlying disorder which affects structural
integrity of vessels (scleroderma, SLE, myeloma, etc.).

73
IV. PERIPHERAL VASCULAR OCCLUSION

A. ACUTE OCCLUSION - This is generally due to embolization from a mural thrombus in the heart
(post MI, RHD), embolization from atherosclerotic plaque, or acute thrombosis usually over a
preexisting atherosclerotic plaque. Clinically there is sudden pain, numbness, and pallor of the
affected tissues.
B. CHRONIC OCCLUSION - This occurs as a result of gradual buildup of atherosclerotic plaques (often
as complication of diabetes) and leads to eventual ulceration and gangrenous necrosis of the skin
and underlying tissues.

V. VARICOSE VEINS - This refers to any venous dilatation that results from chronic elevation of
intravascular hydrostatic pressure. This is most commonly seen in the superficial leg veins and becomes
more clinically apparent with increasing age, especially in females. Increased hydrostatic pressure may
simply be the result of gravitational effects or may occur distal to venous obstruction or compression.
Histologically, the wall of the vessel will vary in thickness and the valves may be deformed and
incompetent. As the vessels dilate, they become elongated and tortuous. The overall effect is to create
chronic soft tissue edema, venous stasis, and thrombosis. The skin may develop stasis dermatitis and
chronic ulcerations.
VI. NEOPLASTIC DISEASE

A. BENIGN

1. CAPILLARY HEMANGIOMA - This is composed of non-encapsulated aggregates of thin

walled capillary-like vessels lined by flattened endothelium and separated by a scant
connective tissue stroma. They range in size up to several centimeters in diameter. The
strawberry hemangioma is a congenital cutaneous lesion that initially grows rapidly but
usually regresses within 4-5 years.
2. CA VERNOUS HEMANGIOMA - This is comprised of large cavernous vessels that form a
spongy mass that can be quite large but is usually under 2-3 cm. in diameter. Occasionally,
these may occur as part of a congenital syndrome (von Hippel-Lindau disease).
3. GLOMUS TUMOR - This arises from a glomus body (which acts as a temperature sensor
and regulates arterial blood flow). These usually appear on the distal portions of the fingers
or subungually as small, firm, purplish, extremely painful nodules. The tumors contain
vascular channels and the characteristic glomus cells in the connective tissue stroma.

B. MALIGNANT

1. ANGIOSARCOMA - This often appears in the skin or subcutaneous tissues as an ill defined
fleshy mass with central necrosis and hemorrhage. There is a wide range of histologic
appearance depending on the degree of differentiation. Hepatic angiosarcomas have been
linked to environmental exposure to vinyl chloride, arsenic, and thorotrast (once used as
a radiologic dye).
2. HEMANGIOPERICYTOMA - This is generally a small tumor arising from the vascular
pericytes and may metastasize widely.
3. KAPOSI'S SARCOMA - Originally a slowly progressive, multifocal, cutaneous neoplasm of
the legs in elderly men, Kaposi's sarcoma is now seen most frequently as an aggressive,
although treatable, disseminated disease in patients with AIDS (particularly homosexual
AIDS victims).

74
VII. TRANSPLANT REJECTION - Most transplant rejections are caused by immunologic damage to the
transplanted organ's vessels. Hyperacute rejection is mediated by a Type II hypersensitivity reaction and
results in vascular thrombosis. Acute rejection appears within a few months of transplant and is
characterized by endothelial swelling, fibrinoid necrosis of the vascular wall and thrombosis. Chronic
rejection is characterized by intimal fibrosis and thickening of the vessel wall.

75
 RESPIRATORY TRACT

REVIEW OF NORMAL

I. G ROSS ANATOMY - The air conducting passages consist of the nasal cavities, paranasal sinuses,
nasopharynx, oropharynx, hypopharynx (epiglottis and larynx), and tracheobronchial tree. At the carina,
the trachea branches into the mainstem bronchi which branch into lobar bronchi which branch into
segmental bronchi which supply the intralobar bronchopulmonary segments. Further branching produces
subsegmental bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, and
alveolar sacs. The acinus represents the functional gas exchange area of the lung and is composed of a
respiratory bronchiole and its branching structures. The larger lobule is the smallest discrete portion of lung
bounded by fibrous septa and consists of a terminal bronchiole and its branching structures. A lobule may
contain 25-30 acini. The pulmonary arteries follow the airways while the pulmonary veins course through
the connective tissue septa. Lymphatic channels are present along the bronchovascular structures but are
also found in the pleura and connective tissue septa.
II. MICRO ANATOMY - With the exception of the oropharynx and portions of the nasopharynx and
hypopharynx (which are lined by squamous epithelium), the upper respiratory tract and the large airways
are lined by pseudostratified ciliated columnar epithelium interspersed with mucus-secreting goblet cells
and neuroendocrine (Kulchitsky) cells. Mucus-secreting glands lie beneath the epithelial surface, and
cartilagenous plates help maintain patency. Cartilage, submucosal glands, and goblet cells are lost at the
level of the bronchioles which are lined by ciliated cuboidal epithelium and Clara cells (which secrete a
non-mucoid watery substance that contains lysozyme and immunoglobulins). The majority of the alveolar
surface is lined by the Type I (squamous/membranous) pneumocytes which are interspersed with the
surfactant-producing Type II (cuboidal/granular) pneumocytes. In the alveolar septal wall, the alveolar
capillary basement membrane fuses with the basement membrane of the alveolar epithelial cells on one side
(the "thin" side) and is separated from the basement membrane of the alveolar epithelial cells by the
pulmonary interstitium on the other side (the "thick" side). The interstitium contains collagen, elastin, mast
cells, occasional inflammatory cells, and connective tissue cells (primarily smooth muscle and fibroblasts).
Alveolar macrophages, derived from blood monocytes, are loosely attached to the alveolar wall or lie free
within the alveolar space.
III. DEFENSE MECHANISMS - Large particulate matter> 1011 in size is filtered by nasal hairs or trapped
in the oropharynx. Smaller particles are trapped in the bronchial mucous blanket or the bronchiolar watery
secretions rich in lysozyme and secretory IgA. Particles that are 1-511 in size are accessible to the terminal
airways and alveoli where they are phagocytized by the alveolar macrophages.
IV. GAS EXCHANGE - Ventilation refers to the movement and distribution of air within the tracheobronchial
system; diffUsion is the movement of O2 and CO 2 between the alveolar space and the capillary blood; and
perfi.lsion refers to the flow and distribution of blood within the pulmonary vascular bed. Therefore,

76
 alterations in the airways, the alveoli, the blood vessels, or any combination of the three will lead to a
decreased O 2 delivery to the tissues.

UPPER RESPIRATORY TRACT

I. INFLAMMATORY DISORDERS - These are generally due to a wide variety of viruses and produce
various clinical syndromes. In addition to the local effects, systemic effects generally include chills, malaise,
myalgias, headache and fever.

A. ACUTE RHINITIS (common cold) - This is characterized by increased nasal discharge, sneezing,
nasal obstruction and sometimes watering of the eyes and slight conjunctivitis. Fever is relatively
uncommon. Principal viruses include rhinoviruses, parainfluenza I and 2, echo 28, coxsackie a,
and respiratory syncytial virus. The viruses infect the mucosal epithelial cells which are shed in a
thin mucoid nasal discharge resulting from the increased vascular permeability and mucus
production. These secretions may become superinfected with bacteria and become mucopurulent
in nature.
B. SINUSITIS - This refers to inflammation of the sinus mucosa and can develop whenever there is
interference with drainage from or aeration of the sinuses. Acute sinusitis is usually the result of
extension of a neighboring infection into the sinuses. Incomplete resolution or repeated infections
may lead to chronic sinusitis. Sinusitis may be complicated by osteomyelitis, meningitis, intra and
extracranial abscesses, etc.
C. EPIGLOTTITIS - Most commonly seen in children <2 years old, acute epiglottisis is due most
commonly to infection by the bacteria H. Influenzae and is considered a medical emergency. The
inflammatory edema of the epiglottis obstructs the opening to the larynx and produces severe
dyspnea. An inspiratory stridor is usually evident.
D. NASAL POLYPS - These are inflammatory in nature and consist of polypoid protrusions of
edematous mucosa containing a variable number of inflammatory cells. Most polyps are the result
of chronic allergies, but may also be found in patients with chronic rhinitis or sinusitis, cystic
fibrosis, and sensitivity to aspirin. The polyps are frequently multiple and may cause symptoms of
airway obstruction.
E. VOCAL CORD POLYPS (SINGER'S NODE) - These are also inflammatory in nature and are usually
the result of trauma to the cords or, less commonly, allergies.

III. NEOPLASIA

A. SQUAMOUS PAPILLOMA - This occurs in the nasal vestibule or larynx. Histologically similar to
cutaneous warts, they can seed in the same manner and most are probably related to HPV infection.
B. INVERTED PAPILLOMA - Seen more frequently in men and generally benign, this is an endophytic
proliferation of squamous cells which often presents as nasal obstruction but which may cause
epistaxis or even erode underlying bone. Without adequate surgical excision they may recur and
a small proportion may undergo malignant transformation.
C. SQUAMOUS CELL CARCINOMA

1. NASAL(NON-CUTANEOUS) - These arise from the nasal mucosa or maxillary sinus. There
is a correlation between various environmental (cigarette smoking) and occupational
(exposure to nickel ore) hazards and the development of this tumor. Local destruction is
common but distant metastases are rare.

77
 2. NASOPHARYNGEAL - Difficult to diagnose because of their location, these may either be
keratinizing, non-keratinizing, or undifferentiated. The latter two have a strong association
with Epstein-Barr virus infection.
3. LARYNGEAL - These tumors are also associated with smoking as well as alcohol abuse. If
they originate from the true vocal cords, they often produce hoarseness and are therefore
discovered early. When they arise in other areas, howeveer, they may not produce
symptoms until they are well advanced. Overall, there is a mortality rate of approximately
30%.

D. LETHAL MIDLINE GRANULOMA - In some ways similar to Wegener's granulomatosis (see

Cardiovascular notes), this relatively rare malignancy represents a peripheral T cell lymphoma
which may involve any organ but characteristicaly begins with involvement of midline structures
such as the nose, sinuses, upper respiratory tract and GI tract. The initial symptoms are those of
a rhinitis/sinusitis. The lymphomatous infiltrate ultimately may destroy midline facial features.

LOWER RESPIRATORY TRACT

I. DEVELOPMENTAL ANOMALIES

A. HYPOPLASIA - Any condition that reduces the volume of the thoracic cavity during development
will prevent the lungs from reaching full size. This is usually the result of compression
(diaphragmatic hernia, polycystic kidney disease) or decreased fetal respiratory movement as the
result of amniotic fluid deficiency (renal agenesis, bladder obstruction).
B. DIAPHRAGMATIC HERNIA - Partial or total absence of the diaphragm may result in herniation of
the abdominal contents into the thoracic cavity. Depending on the size of the defect, this may be
asymptomatic or catastrophic. In utero, diaphragmatic defects will result in pulmonary hypoplasia
due to compression of the lungs by the herniated viscera. These infants will have respiratory
difficulties at birth.
C. BRONCHOGENIC CYSTS - These represent accessory buds from the foregut which are lined by
bronchial epithelium and often have cartilage in the wall. They usually lie in the mediastinum
around the tracheal bifurcation, but they may appear in the substance of the lung. They generally
contain mucoid material and may predispose to abscess formation. They may also rupture into the
tracheobronchial tree or pleural cavity.
D. BRONCHOPULMONARY SEQUESTRATION - This represents the presence oflung tissue that has no
connection with the tracheobronchial tree and receives its blood supply usually from the aorta. It
may occur within the lung (intralobar) where it may serve as a focus of recurrent infection or it may
be external to the lung (extralobar) where it may be associated with other concurrent congenital
abnormalities.

II. ATELECTASIS - This refers to a condition of collapse or incomplete expansion of alveoli which create
areas of lung parenchyma having reduced aeration.

A. PRIMARY (ATELECTASIS NEONATORUM) - This results from the failure of lungs to ventilate at time
of birth. This may be due to birth trauma, bronchial obstruction, drugs, immaturity, CNS disorders,
etc. When placed in water, the lungs will sink since they have no air in the alveoli.
B. SECONDARY (ACQUIRED ATELECTASIS) - This results from atelectasis occurring sometime after
initial expansion and may be due to deficiency of surfactant (respiratory distress syndromes), loss

78
 of negative intrapleural pressure (chest trauma, pneumothorax), complete obstruction of an airway
(by secretions, exudates, neoplasms, or foreign bodies), direct pressure on lungs (usually by
accumulation of material in the pleural cavities), or contraction (parenchymal fibrosis). Depending
on the etiology, the distribution may be focal, segmental, or massive. The pleural surface over the
area of atelectasis has a purple-blue color and is slightly depressed. Although atelectatic lung is still
perfused normally, ventilation is decreases leading to an intrapulmonary shunt. With simple
mechanical atelectasis, if the lungs are re-expanded soon after collapse, there is little or no residual
damage. Infections, however, may develop in areas of collapse and "carn~fication" (complete
organization of tissue) can occur if the lungs remain collapsed for an extended period of time.

III. RESPIRA TORY DISTRESS OF THE NEWBORN (RDS Type I, Hyaline Membrane Disease)

A. ETIOLOGY - Immature development of the lung results in a deficiency of surfactant, the lipid
material synthesized by the Type II pneumocytes that is needed to lower the surface tension of the
alveoli and help maintain their patency during expiration. Infants at risk include those born prema-
turely, those delivered by Caesarean section, and those whose mothers are diabetic (the anti-
glucocorticoid effects of hyperinsulinism in the fetus removes the stimulatory effect of cortisol on
the production of surfactant). An amniotic fluid lecithin:sphingomyelin ratio of less than 2: 1 or the
absence of phosphatidyl glycerol in amniotic fluid indicates a high probability of the fetus
developing RDS.
B. PATHOGENESIS - Decreased surfactant increases the surface tension of the alveoli allowing them
to collapse during expiration. This then requires greater inspiratory effort to expand the atelectatic
airways (clinically manifested as nasal flaring and retraction of the ribs and sternum during
inspiration). Decreased ventilation of an already immature lung produces hypoxia, cyanosis, and
metabolic acidosis which in turn triggers vasoconstriction (decreased perfusion leads to additional
hypoxia) resulting in endothelial and epithelial injury. There is exudation of fibrin rich fluid into
the interstitium and alveolar space and the subsequent formation of hyaline membranes (fibrinous
exudate admixed with necrotic epithelial cell debris) along the respiratory bronchioles, alveolar
ducts and alveoli. This further interferes with gas exchange, perpetuates the hypoxia, and hinders
the ability of the Type II pneumocytes to produce surfactant, initiating a vicious cycle.

VI. CIRCULATORY DISORDERS

A. PULMONARY EDEMA - Extravascular fluid, initially in the interstitial space and subsequently
spilling over into the alveoli, accumulates in the alveolar space due to disturbances of the normal
hemodynamic equilibrium (congestive heart failure, myocardial infarction, hypertensive heart
disease, longstanding mitral stenosis, etc.) or microvascular injury (see Hemodynamic Disorders).
B. CHRONIC PASSIVE CONGESTION - This is associated with chronic failure of the left side of the heart
leading to brown induration of the lung (see Hemodynamic Disorders).
C. PULMONARY EMBOLUS - This relates to the impaction of a free floating mass (usually thrombus)
in the pulmonary arterial bed. The etiology includes multiple entities which would predispose to
venous thrombosis or stasis (such as surgery, immobilitylimmobilization, congestive heart failure,
pregnancy, obesity, muscular weakness, cancer, and use of oral contracep.tive or exogenous
estrogens). The pathologic change and the clinical manifestations of pulmonary emboli are
dependent on the size of the vessels in which the embolus impacts and also on the preexistent
cardiovascular status of the lung.

1. CLINICAL - Small emboli lodge in peripheral pulmonary vessels causing local congestion,
edema, and hemorrhage but produce no clinical symptoms. Recurrent showers of small

79
 emboli, however, will result in progressive reduction of the perfusable pulmonary vascular
bed and give rise to pulmonary hypertension manifested by dyspnea on exertion, anginal
pain, syncope, and venous distention of the neck veins. Occlusion of medium size
pulmonary arteries may produce a sudden onset of dyspnea, hyperventilation, and
tachycardia. Other related symptoms would be anxiety, syncope, and anterior chest pain.
Massive embolization, particularly of the saddle type, may induce the immediate
catastrophic syndrome of acute cor pulmonale (perhaps related to release of serotonin and
thromboxane A2 from platelets in the embolus mediating a sudden increase in pulmonary
artery resistance) and sudden death (perhaps related to neural reflexes that produce cardiac
arrhythmias). If not immediately fatal, these may result in shock with central chest pain,
severe dyspnea, cyanosis, tachycardia and diaphoresis (occasionally mimicking myocardial
infarct). Most clinically significant emboli, therefore, are the larger ones that originate from
thrombi in the femoral/iliac veins and not the deep calf veins.
2. DIAGNOSIS - When pulmonary emboli are clinically suspected, the best primary screening
tool is a ventilation-perfusion scan of the lung (chest x-rays are frequently normal).
Pulmonary arteriography has the best diagnostic sensitivity and specificity but is costly.
Blood gases on room air usually reveal a decreased pC02 « 40 mm Hg) secondary to
hyperventilation (respiratory alkalosis) and a decreased p02 « 80 mm Hg). There may be
a nonspecific elevation of LDH 3 .
3. TREATMENT - Most patients receive heparin anticoagulation to raise the aPTT to 1.5-2.5
times normal values. In some patients, thrombolytic therapy may be appropriate. Long
term oral anticoagulation (3-6 months or longer) is also recommended.
4. PREVENTION - This is easier and less expensive than diagnosis and treatment. In clinical
situations where venous thrombosis is likely (post-surgery, immobilization, etc), graduated
compression stockings and intermittent pneumatic compression boots may be used.
Anticoagulation with low molecular weight heparins is also effective. In some
circumstances, the placement of inferior vena cava filters may be warranted.

D. PULMONARYINFARCfION - This signifies ischemic coagulation necrosis oflung parenchyma and

is almost always due to pulmonary emboli. It is not, however, synonymous with pulmonary emboli.
Infarcts occur in only 5-10% of pulmonary emboli and generally occur in those patients in whom
there is preexisting impairment of the bronchial artery circulation.

I. MORPHOLOGY - Grossly, the lesions will vary in size from those barely visible to wedge-
shaped involvement of a large part of an entire lobe. Classically, they abut on the visceral
pleura with the apex of the wedge-shaped infarct pointing toward the hilus. The majority
of infarcts are within the lower lobes, and more frequently seen on the right. Histologically,
the infarct shows hemorrhagic coagulation necrosis. A pleural effusion may be present.
2. CLINICAL - When symptomatic, a clinical triad indicative of pulmonary infarction includes
dyspnea, hemoptysis, and pleuritic chest pain (with possible pleural friction rub). A low
grade fever and leukocytosis may be additional findings. Radiologically, a wedge-shaped
consolidation along a pleural surface is classic although not that frequently seen. Elevation
of the diaphragm may occur.

E. PULMONARY HYPERTENSION - This refers to increased pressures within the pulmonary vasculature
and is due to increased vascular resistance resulting from vascular obstruction, constriction,
obliteration, or increased flow.

80
 1. PRIMARY - Mostly a disease of young women, prolonged vasoconstrIctIOn of the
pulmonary vessels, induced by hypersensitivity to neurohormonal regulators, produces
marked thickening of the small arteries and arterioloes with hypertrophy of the media and
reduplication of the elastic membranes. Medium sized vessels also show medial
hypertrophy and the large arteries may develop uncomplicated atherosclerotic plaques.
Insidious development of pulmonary symptomatology (progressive dyspnea, weakness,
etc) culminates with death usually due to cor pulmonale.
2. SECONDARY - This form is far more common and occurs in patients with known
underlying conditions that increase pulmonary vascular pressures or resistance (congestive
heart failure, primary pulmonary disease, or recurrent emboli).

F. ADULT RESPIRATORY DISTRESS SYNDROME (ARDS, RDS Type II, Diffuse Alveolar Damage,
"Shock" Lung) - This disorder is characterized by the acute onset of dyspnea and tachypnea with
resulting tachycardia, hypoxemia refractory to therapy, and cyanosis. Mortality approaches 50%.

1. ETIOLOGY - Factors triggering this disorder involve a wide variety of mechanisms (high
altitude exposure, anaphylaxis, exposure to chemical or physical irritants, fulminating
bacterial or viral infection, drugs, oxygen toxicity, trauma, etc.) all of which have the
common denominator of widespread diffuse microvascular injury.
2. PATHOGENESIS - Diffuse injury to alveolar capillary endothelium may be produced by
direct damage to endothelial cells or mediated by leukocyte aggregation and activation.
Leukocyte-generated free radicals, lysozymes, and arachidonic acid metabolites may be
responsible for further endothelial cell damage, vasoconstriction, destruction of interstitial
elastin and collagen, and damage to both Type I and Type II epithelial cells. There is
leakage of fibrin rich exudate into alveoli, and the resultant hyaline membrane formation
(proteinaceous exudate admixed with necrotic epithelial cell debris) interferes with gas
diffusion. The loss of surfactant-producing Type II cells compounds the problem with
widespread atelectasis producing a noncompliant "stiff" lung. Enlarged, regenerating Type
II cells may become prominent along the alveolar membrane. Ultimately, if the patient
survives, interstitial fibrosis develops.

VII. INFLAMMA TORY / INFECTIOUS DISEASE

A. ACUTE BRONCHITIS - This inflammatory lesion of bronchi may be caused by viruses, irritant gases
(smoke, ammonia, sulphur dioxide, etc.), or bacteria (staph, strep. pneumonia, and hemophilus
influenza).
B. MYCOPLASMA/VIRAL PNEUMONIAS - These pneumonias are caused, respectively, by Mycoplasma
pneumoniae (primary atypical pneumonia) and a wide variety of viruses but are morphologically
and clinically similar. The pathologic lesions are peribronchiolar and, in general, interstitial (i.e.
within the alveolar walls). The alveolar walls are widened by edema and a predominately
mononuclear infiltrate. The alveolar spaces are generally free of significant cellular exudate, but
focal hyaline membranes may be present reflecting alveolar epithelial damage. When caused by
viruses, viral inclusions may be identified. Clinically, there is often a history of recent upper
respiratory tract infection, and there may be an irregular fever with myalgia and malaise. Persistent,
racking, sparsely productive cough is the hallmark of the disease. There may be a severe frontal
headache, worsened during coughing. Chest pain is substernal, pleuritic pain and effusions are
infrequent, and dyspnea and cyanosis are rare. X-rays can show nodular, patchy or perihilar
infiltrates.

81
C. BACTERIAL PNEUMONIA - Pneumonia can be caused by a wide variety of bacterial agents. The
pathologic changes depend in part on the specific agent and the host response to that agent.
Streptococcus pneumoniae (pneumococcus) is the most common etiologic agent for both lobar
and bronchopneumonias.

1. MORPHOLOGIC PATTERNS

a. Lobar pneumonia - Lobar refers to an extensive inflammatory consolidation

involving an entire lobe or large portion thereof. The lobar distribution tends to
reflect the virulence of the organism and/or the decreased effectiveness of the
patient's defense mechanisms. Four morphologic stages have classically been
described in lobar pneumonia. Antibiotic therapy, however, may abort this natural
sequence and well developed lobar pneumonia is encountered less frequently than
in the past.

(1) Congestion - This stage is characterized by rapid proliferation of bacteria

and the early stages of the inflammatory response (vascular hyperemia and
serous exudation into alveolar spaces).
(2) Red hepatization - Here, the alveolar spaces become packed with
neutrophils, extravasated red blood cells, and precipitated fibrin which
imparts a gross consistency resembling that of liver. The intense vascular
engorgement gives the lung a red appearance. Microscopically, the
alveolar infiltrate obscures the intact underlying pulmonary architecture.
(3) Grey hepatization - Disintegration of neutrophils and red cells in
combination with continued accumulation of fibrin imparts a grayish
appearance to the still firm parenchyma. Vascular engorgement is not as
prominent.
(4) Resolution - In uncomplicated cases, the exudative debris in the alveolar
spaces is digested and contraction of the fibrin away from alveolar walls
again discloses the preserved native pulmonary architecture. The clumps
of intraalveolar debris (Masson bodies) are reabsorbed or removed
restoring the pulmonary parenchyma to its normal state.

b. Bronchopneumonia - This refers to a less extensive, but possibly more

destructive, inflammatory consolidation which occurs in patches throughout a lobe
(most frequently lower lobes) or lung, typically following tracheobronchial injury
by a bronchitislbronchiolitis or as complications of systemic disorders such as
malnutrition, alcoholism, or congestive heart failure with pulmonary edema. The
inflammation is centered around the air passages and extends out into surrounding
lung parenchyma with tissue destruction, microabscess formation, and subsequent
scarfIng.

2. CLINICAL PRESENTATION - The clinical course is typified by a sudden onset, often with
shaking chills, followed by high fever. At first, cough is dry or productive of watery
sputum. At the stage of red hepatization, the sputum becomes thick, purulent, and
hemorrhagic ("rusty" sputum). The associated pleuritis manifests itself by pleuritic pain
and a friction rub, and there may be a pleural effusion. Leukocytosis of 15,000 to 40,000
is usually present. Complications include abscesses, empyema, and sepsis.

82
 3. OTHER ETIOLOGIC AGENTS

a. Staphylococcal pneumonia - This may be a complication of influenza, chronic

pulmonary disease, cystic fibrosis, or concurrent staphylococcal infection at other
sites. It is also seen more frequently in infants and young children. These
organisms tend to produce abscess cavities and pneumatoceles (air-filled
pseudo cysts) which may progress to empyema or pneumothorax
b. Gram negative pneumonias - Most gram negative pneumonias represent hospital
acquired infections. They occur in patients who have received previous extended
broad spectrum antibiotic therapy or assisted ventilation and those with
dissemination to the lungs from another source or site (urinary tract, etc).
Mortality rate of gram negative pneumonias is over 50%.

(1) Klebsiella pneumoniae - This organism tends to complicate other

underlying diseases, chiefly alcoholism. Dyspnea and cyanosis may be
quite prominent. The sputum is characteristically thick, gelatinous and
"brick red" with blood. Morphologically, abscesses are quite common and
chronic lung abscess and pleural empyema are common complications.
(2) Hemophilus influenzae - Rare in adults, this is more frequently found in
the pediatric age group especially in cases of obstructive pulmonary
disease.
(3) Pseudomonas aeruginosa - A common cause of nosocomial infection,
this organism thrives in the watery environment of humidification devices,
and patients who require assisted ventilation are especially prone to
infection. Due to involvement of blood vessels, there is often extensiv~
hemorrhage but surprisingly scant neutrophilic reaction.
(4) Enteric gram negatives - These organisms are often seeded to the lungs
from urinary tract infections. They may colonize in the pulmonary
vasculature and may form abscesses.

D. MYCOTIC PNEUMONIAS - In general, the fungi are weak antigens and can cause tissue damage
primarily by virtue of the hypersensitivity reaction by the host against the fungal proteins. Most
of the deep mycoses (histoplasmosis, coccidioidomycosis, North American blastomycosis,
cryptococcosis, etc) induce a chronic granulomatous inflammatory reaction. Candida, mucor, and
aspergillus are the major opportunistic fungal organisms and elicit an acute inflammatory response
in the debilitated patient. They typically like to invade and obstruct vessels which can result in
hemorrhagic infarcts. Pneumocystis carinii is the most common opportunistic agent producing
pneumonia in AIDS patients. The organisms proliferate in the alveolar spaces and are associated
with a characteristic "frothy-appearing" intraalveolar edema. Nocardia characteristically elicits
purulent abscess formation. Actinomycosis invokes both a chronic granulomatous response and
a purulent exudation. The fungal colonies (sulphur granules) characteristically float in a "sea of
pus."
E. PULMONARY TUBERCULOSIS - Worldwide, tuberculosis kills more adults than any other infectious
agent. Although the incidence in the U.S. declined dramatically after the introduction of effective
anti-tuberculous drugs, the incidence has been steadily rising since 1985, primarily due to the
increased numbers of immunosuppressed patients (AIDS, etc.) and the emergence of drug-resistant
strains of the mycobacterium

83
 1. PRIMARY TUBERCULOSIS - The most common route of infection is through inhalation of
contaminated aerosol droplets from an infected individual. The primary focus of infection
in the lung parenchyma is usually subpleural, most commonly in the upper portion of lower
lobe or the lower portion of the upper lobe. This focus is called the ghon focus and
typically has central caseous necrosis. The organisms may spread through the lymphatics
to produce caseous lymphadenitis in the hilar lymph nodes (which usually show more
extensive involvement than the primary focus). The combination of the subpleural lesion
and the hilar node involvement is called the primary ghon complex. In about 90% of
individuals, the only residuum of the primary infection is the presence of a fibrotic or
sometimes calcified ghon complex. Occasionally (particularly in pre-school children), a
primary infection does not run a benign course and may evolve into a tuberculous
pneumonia, erode into a bronchus with resultant bronchogenic dissemination, or
disseminate by lymphatic and hematogenous routes to isolated organs (i.e. tuberculous
meningitis) or systemically throughout the body.
2. SECONDARY TUBERCULOSIS (adult, reactivation, postprimary TB) - Due to the previous
exposure and development of hypersensitivity, reexposure to the organism or reactivation
oflatent organisms produces a prompt granulomatous tissue response often with caseous
necrosis. Since mycobacterium organisms prefer areas of high oxygen tension, reactivation
is almost invariably localized to the apices of one or both upper lobes. This focus is called
the assmannfocus. Granulomas may coalesce to form larger foci of destruction but most
eventually become encapsulated by fibrous tissue and develop areas of dystrophic
calcification. In some cases, however, the lesions may remain active, erode into
neighboring airways and cavitate. Cavitation is considered the anatomic hallmark of
secondary tuberculosis. Apical cavitary fibrocaseous tuberculosis may heal, spread by
direct extension, or be disseminated through the tracheobronchial tree, the lymphatics, or
the blood. Local complications may include massive hemoptysis due to erosion of a
pulmonary vessel, sufficient fibrosis to result in the loss of ventilating capacity, and
infection of the pleura leading to a tuberculous empyema.

F. CHEMICAL PNEUMONIA

1. ASPIRATION PNEUMONIA - Aspiration occurs most frequently in unconscious patients,

those with repeated vomiting episodes, and those with depressed cough reflexes (alcoholic
intoxication, central nervous system malfimction, acute drug intoxication, etc). The clinical
symptoms are dependent upon the volume and the nature of the aspirate. Aspiration of
liquid gastric contents causes extensive acute inflammatory reaction, pulmonary edema,
and widespread destruction of epithelium with hemorrhage and hyaline membranes. With
extensive involvement, the lung parenchyma may be almost completely destroyed. If
sufficient volume with low Ph is aspirated, a distinct clinical picture ensues 2 to 5 hours
after aspiration with the onset of cyanosis, dyspnea, tachypnea, tachycardia and shock,
bloody frothy sputum, marked pulmonary congestion and edema. X-rays show soft patchy
mottling throughout both lung fields, indistinguishable from broncho-pneumonia. Chronic
or recurrent aspiration will cause repeated bouts of tracheobronchitis and pneumonia.
Symptoms include recurrent cough and sputum production and, with time, chronic fibrosis
will ensue with resultant dyspnea and digital clubbing.
2. LIPID PNEUMONIA

a. Endogenous (golden pneumonia. cholesterol pneumonia) - This is usually seen

as a complication of an obstructive lesion of the bronchial tree. Histologically,

84
 there are large numbers of "foamy" macro phages in the alveoli containing
surfactant and lipids from degenerating cells.
b. Exogenous - This occurs when fatty or oily material is inhaled or aspirated.
Clinical symptoms may be relatively few. Occasional cough with sputum
production and dyspnea may occur. X-ray appearance may look like an interstitial
fibrosis. Occasionally, there may be a large localized mass suggestive of
granuloma or carcinoma.

G. PULMONARY ABSCESS

l. PATHOGENESIS - Aspiration is the most common cause oflung abscess with inoculation
of the lower respiratory tract by anaerobic organisms from the oral cavity. These abscesses
tend to be solitary and occur most frequently on the right side due to the shallow angle of
the right mainstem bronchus. Other causes of abscesses include bacterial pneumonia
(especially Staphylococcal and Klebsiella pneumonia), bronchial obstruction, septic
emboli, cysts or bullae, and penetrating chest wounds. In some instances, no underlying
cause can be identified (primary idiopathic or cryptogenic lung abscess).
2. PATHOLOGY - Abscesses consist oflocalized suppuration and liquefaction necrosis oflung
parenchyma, which in chronic cases (> 6 weeks duration) may elicit considerable
fibroblastic proliferation in the wall. They may be solitary or multiple and may vary in
diameter from a few millimeters to large cavities of 5-15 cm.
3. CLINICAL SYMPTOMS - Generally, there is a fever with a prominent cough, often
accompanied by copious amounts offoul smelling (esp. anaerobic organisms) or bloody
sputum. Chest pain and weight loss may also be present. X-rays may show a homogenous
density which, ifthere is communication with an airway, may reveal an air-fluid level. If
the patient does not have putrid sputum, bronchial obstruction should be suspected as the
etiology. An infected cavitated infarct could also be suspected. A solitary lung abscess has
a fatality rate of 15 -20% and with multiple hematogenously spread abscesses, the fatality
rate approaches 50%.

VIII. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) - Obstructive disease results from the
narrowing/obstruction of the tracheobronchial tree or damage to the pulmonary parenchyma. This results
in an increased compliance of the lungs (increased residual volume and total lung capacity) but a decreased
elastic recoil (decreased forced expiratory volumes).

A. CHRONIC BRONCHITIS ("blue bloaters") - This is a clinical disorder characterized by excessive

mucous secretion within the bronchial tree than cannot be explained by either a specific infection
or by infiltrative disease. It is defined as a chronic cough with sputum production for at least three
months of the year in at least two consecutive years. The major cause is cigarette smoking, but air
pollution and occupational irritants may also playa role. The major pathophysiologic disruption
is large airway obstruction.

l. PATHOGENESIS - As a defense mechanism against chronic irritation of the

tracheobronchial mucosa by cigarette smoke and/or other environmental pollutants, there
is hypertrophy and hyperplasia of the submucosal mucous glands in the large airways
o Reid Index) with the resultant hypersecretion of mucus accounting for the increase
sputum production. Squamous metaplasia and dysplasia of the surface epithelium may also
be present. Goblet cell metaplasia of small bronchi and bronchioles also leads to excessive
mucus production, decreases the number of normal ciliated cells (thereby hampering the

85
 normal clearance mechanism of the mucous blanket), and predisposes to obstruction of
these airways by mucous plugs. On inspiration, air is able to enter around the mucous
plugs, but on expiration as the bronchioles collapse around the plugs, air is trapped and
patchy atelectasis develops. This environment is also fertile ground for bacterial growth,
and these patients are predisposed to repeated bacterial infection resulting in injury and
ultimate fibrosis (bronchiolitis fibrosa obliterans) of the bronchiolar walls.
2. CLINICAL DATA - The decrease in ventilation produces a major ventilation/perfusion
mismatch and as a result, patients tend to be cyanotic. Blood gases generally reveal a
chronic hypoxemia (which produces polycythemia) and hypercapnia that causes a
respiratory acidosis. The acidosis promotes pulmonary vasoconstriction and, over time,
patients develop pulmonary hypertension with ensuing right hear failure. Chest x-rays may
be normal in appearance but, with bronchography, bronchial pits or diverticula
representing the enlarged bronchial gland ducts are pathognomonic.
3. COMPLICATIONS - Repeated infections, cor pulmonale, peptic ulcers, and respiratory
failure are the major complications.

B. EMPHYSEMA ("pink puffers") - This is defined as an abnormal, permanent, destructive lesion of

the pulmonary parenchyma which leads to an increase in the size and volume of the air spaces
distal to the terminal bronchiole. The major pathophysiologic disruption is distal airway tissue
destruction and with loss of elastic recoil rather than large airway obstruction as is seen with
chronic bronchitis. Air moves in on inspiration, but on expiration, without elastic fibers the distal
airways collapse upon themselves trapping air behind.

1. CLASSIFICATION AND PATHOGENESIS

a. Centrilobular - This pattern is characterized by destructive changes primarily to

the respiratory bronchioles. Most striking in the upper lobes, it is seen most
frequently in cigarette smokers and for that reason is often also associated with
chronic bronchitis. Particles of cigarette smoke impact in the respiratory
bronchioles and stimulate macrophages which, among other things, recruit and
activate neutrophils. Both macrophage and neutrophilic proteases are released and
unless they are inactivated by antiproteases such as alpha-I-antitrypsin, proteolytic
digestion of the alveolar walls will ensue. Unfortunately cigarette smoke also
inactivates alpha-I-antitrypsin. Additional damage results from free radical release
from neutrophils.
b. Panlobular - Most frequently seen in the lower lobes, this pattern is characterized
by uniform involvement of the acinus and is seen in patients with inherited or
acquired alpha-I-antitrypsin deficiency, especially if they also smoke.
c. Paraseptal - This pattern is characterized by destruction in the distal portion of
the acinus directly underlying the pleura or fibrous septa and sparing the
respiratory bronchiole. It tends to occur more frequently in the upper lobes, may
form large subpleural bullae or pleural blebs, and may be a cause of spontaneous
pneumothorax in young adults.
d. Irregular (scar) emphysema - This refers to focal parenchymal loss found in
almost all adult lungs, often in areas of old scars from tuberculosis, histoplasmosis,
etc.

2. MORPHOLOGY - The alveolar walls appear attenuated and broken with fragments of the
wall appearing to "float" in large distorted air spaces.

86
 3. CLINICAL - Patients usually present with a history of progressi ve dyspnea and often weight
loss. The A-P diameter of the chest is increased (barrel chest) due to the increased lung
volume, expiration is prolonged due to the lack of elastic recoil, and patients tend to exhale
through pursed lips. Since there is equivalent destruction of airways (ventilation) and
vessels (perfusion), the ventilation/perfusion mismatch is less than that of chronic
bronchitis. The patients are not cyanotic and blood gas values may even be normal. On
chest X-ray, there is increased radiolucency of the lung fields with depression and
flattening of the diaphragm.

C. BRONCHIAL ASTHMA - This disorder is characterized by an increased senSItivIty of the

tracheobronchial tree to various stimuli and is manifested by widespread but reversible narrowing
of the small airways.

1. CLASSIFICATION AND PATHOGENESIS

a. Atopic (allereic) - This form is an IgE mediated hypersensitivity reaction (Type

I) and can be triggered by a wide variety of environmental allergens. Onset
typically occurs in childhood, and there is often a family history of allergy. Serum
IgE levels are usually elevated. Upon contact with an allergen, there is an
immediate response of wheezing, edema, and increased mucus secretion due to
degranulation of sensitized mast cells and stimulation of submucosal vagal
receptors which cause bronchoconstriction. Release of various chemical mediators
of inflammation (leukotrienes, prostaglandins, chemotactic factors, etc) potentiate
the bronchoconstriction and the interstitial edema reduces overall lung
compliance. There is also a delayed response of persistent bronchospasm resulting
from the recruitment of inflammatory cells which release additional chemical
mediators (including major basic protein).
b. Non-atopic - This form is frequently triggered by upper respiratory infections
(primarily viral). The mechanism of action is unknown. IgE levels are usually
normal, and a family history is usually lacking.
c. Miscellaneous - Other causes of asthma include various drugs (including aspirin),
occupational inhalants, exercise, and emotional stress.

2. MORPHOLOGY - Mucous plugs containing desquamated epithelial cells (Curschmann's

spirals) are present in small bronchi and bronchioles. Submucosal inflammatory infiltrates
are composed chiefly of eosinophils, and Charcot-Leyden crystals (crystalloids of
eosinophil membrane proteins) may be identified in the sputum. Thickened basement
membranes and muscular hypertrophy of bronchial walls result from repeated
bronchospasm. Goblet cell metaplasia and hyperplasia of submucosal glands may also be
present.
3. COMPLICATIONS - These include status asthmaticus, respiratory failure, pneumothora\:
or pneumomediastinum, pneumonia, atelectasis, and mucoid impaction.

D. BRONCHIECTASIS - This is a permanent dilatation (cylindrical, fusiform, or saccular) of bronchi

and bronchioles resulting from inflammatory damage to their walls. It may be due to bronchial
obstruction, necrotizing pneumonia, or a variety of congenital or inherited conditions (notably
cystic fibrosis). The inflammatory reaction in the bronchial wall ultimately results in weakening,
abnormal dilatation, and fibrosis. Clinically, it is usually associated with cough and copious
production of purulent sputum. Epithelial necrosis or metaplasia further inhibits normal clearance

87
 of bronchial secretions predisposing to further infection. The lower lobes are usually involved (the
left more often than the right), but it may be bilateral in 30-40% of cases.
E. CYSTIC FIBROSIS (mucoviscidosis) - This is an inherited autosomal (chromosome 7) recessive
disorder of exocrine glands characterized by abnormally viscous secretions and, depending on the
severity of the disease, clinically manifested by pancreatic insufficiency, chronic respiratory disease,
electrolyte disturbances, infertility, and occasionally cirrhosis of the liver. The submucous glands
in the bronchial tree secrete an atypical viscous mucus which is difficult to clear and which
predisposes to obstruction and repeated infection. Mucopurulent material is frequently present
within the trachea and bronchi, and bronchiectasis is usually present. Most patients usually
succumb due to pulmonary complications of the disease.

IX. RESTRICTIVE LUNG DISEASES - In contrast to obstructive diseases, this group of disorders is
characterized by decreased total lung capacity, reduced oxygen diffusing capacity, decreased lung
compliance ("stiff" lung), and increased elasticity. The initiating events are widely varied but all probably
result in activation of alveolar macrophages (which release fibroblast stimulating factors) and recruitment
and activation of neutrophils (which cause inflammatory or immunologic damage to alveoli and small
airways). Early lesions generally show diffuse inflammatory infiltrates within the alveolar walls (alveolitis)
and peribronchiolar interstitium that ultimately cause vascular and parenchymal destruction with extensive
fibrosis.

A. PNEUMOCONIOSES - These are primarily occupational diseases caused by the inhalation of

inorganic mineral dusts (coal dust, silica, asbestos, talc, kaolin, beryllium, etc). These dusts will
elicit, to a variable degree, inflammation and pulmonary fibrosis as a host response. The more
soluble particles tend to elicit more of an inflammatory response while the more insoluble materials
tend to elicit a fibrotic response. The size, shape, and concentration of the inhaled material also has
a bearing on the resultant damage produced. In general, particles less than 2J.lm in size are able to
reach the terminal airways where the alveolar macrophage is the primary defense mechanism.
Release of chemical mediators from the macrophages and activation of leukocytes is felt to be the
mechanism of injury to the pulmonary parenchyma.

1. COAL WORKERS LUNG (black lung) - Coal dust is deposited in small airways where it is
ingested by macrophages that then migrate into the interstitium and collect around the
respiratory bronchioles. The reaction may vary from clinically asymptomatic changes to
extensive pulmonary fibrosis and centrilobular emphysema. These patients are also at
increased risk of developing tuberculosis.
2. SILICOSIS - This is due to the inhalation primarily of quartz dust. The silica particles are
ingested by alveolar macrophages which secrete fibroblast stimulating factor and proteases
but which are also destroyed by the toxic effects of the silica. The silica is released by the
irreversibly injured macrophages only to be reingested by others thereby initiating a
repetitive cycle until they become "walled off" by fibrotic nodules of whorled collagen
surrounded by lymphocytes and fibroblasts. Hilar lymphadenopathy may develop but does
not significantly interfere with pulmonary function. Occasionally, massive fibrosis can
occur which does produce symptoms of restrictive disease. Silicosis and tuberculosis are
often associated, but there appears to be no increased risk for lung cancer.
3. ASBESTOSIS - This results from the inhalation of the long, thin asbestos fibers which cause
an alveolitis and interstitial fibrosis. Asbestos fibers cannot be completely engulfed by
macrophages and may become encrusted by protein and iron (derived from the
hemoglobin released in microhemorrhages). These are called asbestos or ferruginous
bodies and can be seen around alveolar ducts and distal acinar structures primarily in the

88
 lower lobes. Fibroblast stimulating factors released by macrophages incite fibrosis. These
patients have an increased risk of developing primary lung cancer especially if they also
smoke. The pleura is also frequently thickened (benign pleural plaques), and there is an
increased incidence of malignant mesothelioma of the pleura and peritoneum.

B. CHRONIC INTERSTITIAL (NON-INFECTIOUS) PNEUMONIAS - These encompass a group of diseases

which have in common an alveolitis with subsequent fibrosis. The end result of each of these is
"honeycomb" lung characterized by multiple cystic spaces separated by dense fibrous scars. The
cystic spaces represent dilated bronchioles caused by contraction of the fibrous scars and are often
filled with mucus and cellular debris.

1. IDIOPATHIC PULMONARY FIBROSIS (Hamman-Rich syndrome, UIP, fibrosing alveoli tis) -

By definition, the etiology of this disorder is unknown. It perhaps may be immunologically
mediated and mayor may not be associated with coexistant collagen vascular disease.
Within the lung, there are a variety of changes ranging from slight inflammatory cell
infiltrates of the alveolar wall with minimal fibrosis to diffuse alveolar damage with
extensive fibrosis and alveolar collapse. It tends to occur in middle aged males and
generally is slowly progressive over a number of years.
2. DESQUAMATIVE INTERSTITIAL PNEUMONITIS (DIP) - This is characterized by the
accumulation of macro phages and desquamated epithelial cells (Type II) within the
alveolar spaces. This possibly represents an early stage of idiopathic pulmonary fibrosis,
however, these patients are more likely to benefit from steroid therapy. Mononuclear cells
infiltrate the alveolar walls. but there is little fibrosis. Progressive dyspnea may lead to
respiratory failure.
3. LYMPHOID INTERSTITIAL PNEUMONIA - This is characterized by lymphocytic infiltrates
confined to the alveolar septa. It tends to be an indolent or slowly progressive disease, but
the incidence of pulmonary lymphoma is increased in these patients.
4. PULMONARY ALVEOLAR PROTEINOSIS - This is characterized by the presence of a
proteinaceous PAS positive fluid in alveolar spaces along with necrotic Type II
pneumocytes and alveolar macrophages.
5. HYPERSENSITIVITY PNEUMONITIS (extrinsic allergiC alveolitis) - These are primarily
occupational diseases resulting from immune-mediated alveolar damage caused by
inhalation of environmental organic dusts contaminated by various antigens (animal
protein, bacterial products, fungi, thermophilic bacteria, etc). These include moldy hay
(farmer's lung), cotton dust (byssinosis), sugar cane dust (bagassosis), maple bark dust
(maple bark stripper's lung), etc. Acute attacks of dyspnea and cough follow exposure
in sensitized individuals and continued exposure may lead to progressive respiratory
failure. Treatment is therefore identification and elimination of the allergen.
6. BRONCHIOLITIS OBLITERANS AND ORGANIZING PNEUMONIA - This is characterized by
loose granulation filling the respiratory bronchioles, alveolar ducts, and alveolar spaces and
is associated with diffuse alveolar damage and mild interstitial fibrosis. The disease can
have a fulminant course, but patients may benefit from steroid therapy.

C. SARCOIDOSIS - This is a systemic disease of unknown etiology. The most widely accepted
hypothesis is that it represents an abnormal immunologic response to a variety of non-specific
agents or antigens. The incidence is higher in young adults, females, and Blacks. The classical
syndrome includes bilateral hilar lymphadenopathy, uveoparotitis, osseous lesions in the short
bones of the hands and feet, erythema nodosum, hypergamma-globulinemia, hypercalcemia and
hypercalciuria. The lung is the most frequently affected organ, involving approximately 90% of all

89
 cases, but the manifestations are variable and may include hilar lymphadenopathy (enlargement of
the lymph nodes may be so great that the designation "potato nodes" has been applied), miliary
sarcoidosis (giving a reticulonodular "snow storm" appearance by x-ray due to the multiple miliary
sarcoid lesions throughout the lung parenchyma), diffuse fibrosis (leading to symptoms of
restrictive lung disease), or "honeycombing" (end stage pulmonary disease). Microscopically, the
histology shows granulomas without central caseation, so called "hard granulomas". No organisms
are present on acid-fast stains nor can organisms be cultured from the fresh tissue. Schaumann
bodies and asteroid bodies are characteristic but not pathognomonic. In general, the presenting
symptoms in thoracic sarcoidosis include cough, dyspnea, chest pain, loss of weight, malaise or
excessive fatigue.

X. NEOPLASIA

A. BRONCHOGENIC CARCINOMA - Overall, bronchogenic carcinoma is the leading cause of cancer

deaths in the U.S. Although there is a greater incidence in men, the incidence in women is
increasing rapidly and has replaced breast cancer as the most frequent cause of cancer deaths
among women. With the exception of small cell undifferentiated carcinoma, if discovered early,
surgery may be effective but the overall 5-year survival is only about 13%. Smoking is probably
the single most important etiologic factor and is most closely associated with squamous cell
carcinomas and small cell carcinomas. The risk is proportional to the number of cigarettes smoked
daily, the duration of the habit, and the tendency to inhale. Environmental/occupational exposure
(uranium, asbestos, chromates, nickel, coal, iron, arsenic, radiation, etc) also plays a role in some
cancers.

1. CLASSIFICATION - Bronchogenic carcinomas are felt to arise from the basal cells of the
bronchial epithelium and subsequently differentiate into a variety of recognizable patterns.
It is not uncommon, however, for more than one histologic pattern to be present in the
same tumor.

a. Squamous cell carcinoma (35%) - This is primarily a central lesion and is the
cancer most closely associated with smoking, evolving from preceding dysplastic
squamous metaplasia of the bronchial epithelium. It may vary from well-
differentiated to poorly differentiated and tends to infiltrate locally before
metastasizing. The majority of patients present with signs and symptoms
attributable to bronchial obstruction: atelectasis, pneumonia and abscess
formation. Infrequently, some tumors may cavitate and simulate the appearance
of tuberculosis or infectious lung abscess.
b. Adenocarcinoma (35%) - Although central lesions do occur, the majority of
adenocarcinomas are peripheral lesions that tend to spread through submucosal
lymphatics to the hilar lymph nodes. They may remain clinically silent until signs
and symptoms of definite metastases appear. Occasionally they are associated with
focal lung scars and fibrosis. They occur in equal frequency in men and women and
are not as closely related to cigarette smoking. The histologic patterns vary but
most can be demonstrated to contain mucus-secreting cells. A relatively rare
variant of adenocarcinoma, bronchioloalveolar carcinoma, apparently arises from
bronchiolar epithelium (Type II pneumocytes, Clara cells) and characteristically
grows as cuboidal or columnar cells spreading along alveolar septa. It may present
as a peripheral mass lesion, or it may present as irregular nodules scattered
throughout one or both lungs simulating diffuse interstitial pneumonia. These

90
 patients may present with cough and chest pain and are often hypoxemic.
Although metastases are late occurrences, the overall survival is about 25%.
c. Small cell undifferentiated (oat cell) carcinoma (20%) - Almost always a
central lesion, this type of cancer occurs predominantly in men, is associated with
smoking, and progresses rapidly with wide dissemination. The cells are relatively
small with little cytoplasm, and there is no distinctive architectural growth pattern.
Thought to arise from the neuroendocrine Kulchitsky cells, these tumors are
notorious for producing hormone-like substances (ADH, ACTH, gonadotropins,
etc). Radiation and chemotherapy is more effective than surgery, but the overall
prognOSIS IS poor.
d. Large cell undifferentiated carcinoma (10%) - This tumor is comprised oflarge
pleomorphic undifferentiated cells and may represent undifferentiated squamous
cell carcinomas or adenocarcinomas.

2. CLINICAL PRESENTATION - In the course of a routine physical examination, patients with

a lung nodule may be free of symptoms. The chance for cure by surgical excision would
be greatest in these patients. When symptomatic, the usual presentation consists of chronic
cough (often with hemoptysis), chest pain, anorexia and weight loss, and dyspnea. X-ray
almost always shows an abnormal mass. Intrathoracic manifestations may include
endobronchial obstruction with secondary atelectasis, pneumonia, abscess, or
bronchiectasis; superior vena cava obstruction; extension to the pleura with or without
effusion; extension to hilar and mediastinal lymph nodes; and mediastinal extension with
involvement of the phrenic and recurrent laryngeal nerves causing a paralyzed diaphragm
and paralyzed vocal cord. Extrathoracic manifestations are generally the result of
widespread metastases or systemic syndromes resulting from ectopic hormone production
by the tumors.

B. BRONCHIAL TUMOR - These tend to occur at a younger age than other malignant neoplasms of the
lung and, like small cell undifferentiated carcinomas, arise from the neuroendocrine Kulchitsky
cells. They resemble intestinal carcinoid tumors (see GI section) and, like those tumors, can secrete
serotonin. Though originally called adenomas, they are not truly benign, but are slow growing and
locally invasive. Occurring centrally, they tend to extend into both the lumen and the bronchial wall
in a dumbbell shape. Presenting symptoms may be related to the secretion of vasoactive amines
or to bronchial obstruction due to the occluding mass. Distant metastases are unusual and the
overall prognosis is good.
e. HAMARTOMA - These lesions represent local overgrowth of normal tissue and are not true
neoplasms. They generally appear as 1-4 cm spherical or ovoid lesions in the lung periphery. The
most frequent histologic component present is hyaline cartilage.
D. METASTATIC TUMORS - Metastatic neoplasms are more common than primary neoplasms and
tend to present as multiple nodules usually in the lung periphery.

PLEURA AND PLEURAL CAVITY

I. PNEUMOTHORAX - This refers to the presence of air within the pleural cavity. It may occur
spontaneously as a complication of other pulmonary disease (emphysema, abscess, tuberculosis,
carcinoma) or as a result of traumatic damage to the lung or chest wall. Depending on the volume of air

91
 and the degree of atelectaSis that it causes, a pneumothorax may be clinically asymptomatic or it may
present as sudden onset of unilateral pleuritic pain. dyspnea, and tachypnea.

A. CLOSED PNEUMOTHORAX - This occurs when there is no free movement of air into or out of the
pleural cavity during respiration. The air in the cavity will gradually be absorbed and the lung will
re-expand.
B. OPEN PNEUMOTHORAX - This occurs when air is able to move freely into and out of the pleural
space during respiration. The lung will remain collapsed until a negative pressure can again be
established in the pleural cavity.
C. TENSION PNEUMOTHORAX - This occurs when air enters the pleural space during inspiration but
does not escape during expiration. As a result, the pressure in the pleural cavity builds up and will
force the mediastinal structures toward the opposite side. This will cause distortion and kinking of
the great veins resulting in cardiac and respiratory dysfunction. The patient will show increasing
anxiety, restlessness, and respiratory distress. This can rapidly lead to death unless the increased
pressure is released, usually by sticking a needle through the chest wall into the pleural cavity.

XIII. PLEURAL EFFUSIONS - Predisposing factors include any general condition with sodium or protein
imbalance (congestive heart failure, nephrotic syndrome), increased pressure in pulmonary capillaries
(acute left ventricular failure, pulmonary venous thrombosis), increased permeability of pleural capillaries
(inflammatory lesions), and decreased pleural lymphatic drainage (inflammation of parietal pleura, tumor
infiltration oflymphatics, etc.). The major cause of a transudative effusion is congestive heart failure, and
the major causes of an exudative effusion include pneumonia, malignant disease, tuberculosis, and
pulmonary infarction. In a patient over the age of 40 (with no history of febrile illness, no pain, and
negative tuberculin test), the most common cause is cancer, and in a patient under the age of 40, the most
common cause is tuberculosis.
XIV. MALIGNANT MESOTHELIOMA - This may be a late complication of asbestos exposure and arises
as a thick pleural mass which tends to encase the lung and invade into surrounding thoracic tissues. Patients
often develop recurrent pleural effusions and complain of dyspnea and chest pain. Histologically, the
malignant cells may have an epithelial appearance, a spindle cell appearance, or a mixture of the two.
Although the tumor usually does not metastasize until later in the disease process, the overall 5-year
survival is extremely poor.

92
 HEMATOPOIETIC/LYMPHORETI CULAR SYSTEMS

BASIC LABORATORY HEMATOLOGY

I. AUTOMATED CELL COUNTERS - Automated (as opposed to manual) differential counts have been
shown to be a reliable tool for detecting abnormal hematologic results. All automated cell counters are
basically particle counters, using preprogrammed information to classify particles as WBC, RBC, or plate-
lets. They reliably count and report abnormal numbers of normal cells, and very reliably flag the presence
of abnormal cells although it does not identify them.

A. BASIC PARAMETERS - These include directly measured WBC, RBC, Hgb, PIt, MCV (rbc size),
MPV (PIt size) and calculated HCT, MCH, MCHC, RDW, and WBC parameters. Because these
instruments are particle counters, anything that alters size, shape, or refractive index can produce
erroneous results. Platelet clumps may result in false thrombocytopenia and false leukocytosis; very
microcytic RBC or schistocytes may indicate a false thrombocytosis; nucleated RBC, platelet
clumps, and red cells resistant to lysing (i.e. sickle cells) may simulate leukocytosis; and
hyperlipemia or the presence of a warm and/or cold auto-agglutinin may cause an elevated MCV,
MCH, and MCHC.
B. WINTROBE INDICES

1. MEAN CORPUSCULAR VOLUME (MCV = HCT/RBC) - This measures the average RBC size.
Increased MCV is generally due to folic acid deficiency, Vitamin B12 deficiency, a
substantial degree of reticulocytosis, hepatic cirrhosis, and chronic alcoholism. Decreased
MCV is generally due to chronic iron deficiency, alpha or beta-thalassemia (minor), and
anemia of chronic disease.
2. MEAN CORPUSCULAR HEMOGLOBIN (MCH = HGB/RBC) - This measures the quantity of
Hgb in the average RBC. Anemias may be classified as hypochromic, normochromic, or
hyperchromic.
3. MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION (MCHC = HGB/HCT) - This
estimates the average concentration ofHgb in the average RBC.
4. RED CELL DISTRIBUTION WIDTH (RDW) -This is the range about the mean red cell size
that correlates the degree of anisocytosis. Some RBC disorders can be classified according
to the RDW and MCV.

93
 NormRDW High RDW Norm RDW High RDW NonnRDW HighRDW
Low MCV Low MCV NormMCV NOn11MCV High MCV HighMCV

Thallasemia Minor Iron deficiency Normal Early iron or folate Aplastic anemia Vit. B12 deficiency
HbH disease Hemoglobinopathy traits deficiency Myelodysplastic Immune hemolytic anemia
Hereditary Spherocytosis Sickle cell anemia syndromes Cold agglutinins

II. MANUAL DIFFERENTIAL COUNTS (TERMS AND DEFINITIONS)

A. RED BLOOD CELLS

1. HYPOCHROMASIA - This refers to less than normal amount of hemoglobin staining. The
central pallor is increased to greater than one half of the cell diameter.
2. POLYCHROMASIA - This refers to presence of large, bluish staining immature erythrocytes
(reticulocytes). Regularly increased in anemias with increased erythropoietic activity.
3. ANISOCYTOSIS - This refers to a variation in size; i.e. microcytes « 6 microns diameter),
macrocytes (> 9 microns diameter).
4. POIKILOCYTOSIS - This refers to variation in shape of the erythrocytes. The size and
hemoglobin content may vary greatly. Poikilocytosis is non-specific, but is usually
associated with severe anemia with active erythroid regeneration or extramedullary
hematopoiesis.
5. ECHINOCYTE (BURR CELL) - This refers to spiculated cells with short equally spaced
projections over the entire surface. Seen in diseases associated with uremia, pyruvate-
kinase deficiency, post-transfusion, gastric carcinoma, bleeding peptic ulcers, etc. They are
produced by rupture of the cell membrane by enlarged cytoplasmic vacuoles.
o. ACANTHOCYTE - This refers to irregularly spiculated red cells with projections of varying
length and position. They are seen in abetalipoproteinemia, alcoholic liver disease, post-
splenectomy, malabsorption states, etc.
7. SPHEROCYTE - This refers to small spherical red cells with dense hemoglobin content.
They appear hyperchromatic because of their spherical form and decreased surface to
volume ratio. They are found in hereditary spherocytosis, immune hemolytic anemia, post-
transfusion, fragmentation hemolysis, etc.
8. SCHISTOCYTE (fragmented cell) - This refers to split red cells, often half disk shape with
two or three pointed extremities. They are seen in microangiopathic hemolytic anemias
(DIC, TTP), vasculitis, renal graft rejection, prosthetic or pathological heart valve
hemolysis, severe burns, malignant hypertension, etc. They are produced by transverse
fracture of red cells across filaments of fibrin.
9. ELLIPTOCYTE (OVALOCYTE) - This refers to red cells which vary from slightly oval to
pencil or cigar shapes in which the hemoglobin appears concentrated at both ends of the
cell. They are especially prominent in thalassemia, iron deficiency anemia, myelophthisic
and megaloblastic anemias. These cells are characteristic of in hereditary elliptocytosis, in
which elliptocytes may constitute as many as 95% of all erythrocytes.
10. CODOCYTE (TARGET CELLS) - This refers to thin, flattened cells revealing peripheral and
central zones of hemoglobin with an empty intermediate zone, giving the appearance of
a target. The target cell represents an excess of cell membrane in relation to the amount
of hemoglobin. They are seen in obstructive liver disease, hemoglobinopathies (S,C),
thalassemia, iron deficiency, etc.
II. DACRYOCYTE ("TEAR DROP" CELLS) - This refers to cells that have the shape of a drop,
usually microcytic. Frequently seen in myelofibrosis and less frequently in myelophthisic
anemia and thalassemia.

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 12. ERYTHROCYTE INCLUSIONS

a. Basophilic stipplint:: - The cells have pink cytoplasm stippled with coarse blue
granules resulting from pathologic precipitation or aggregation of ribosomes. Seen
in lead poisoning, thalassemia, and states where biosynthesis of hemoglobin is
altered.
b. Howell-Jolly bodies - These are dark-violet spherical granules. They represent
nuclear fragments containing aberrant chromosomes. They are pitted from the red
cell (usually reticulocyte) as they pass through the interendothelial slits and sinuses
of the spleen. They are characteristically seen in splenectomized persons and in
those with hemolytic anemia, hyposplenism, or megaloblastic anemia.
c. Pappenheimer bodies - On Wright's stain, these appear as coarse blue granules
(1-10) present in the periphery of the red cell (whereas basophilic stippling is
distributed throughout). They stain positive for iron and EM shows the iron to be
present in lysosomes.
d. Heinz bodies - These are precipitated, oxidized, and denatured hemoglobin. They
are seen with oxidant compound staining and are rarely seen in Wright's stained
smears. Normally one per cell is seen. If more than five per cell are seen, the
patient has enzyme deficiencies, i.e. G-6-PD or abnormal hemoglobin.

B. WHITE BLOOD CELLS

1. TOXIC GRANULATIONS - These are large, dark purple staining azurophilic granules seen
in neutrophilic cells. Toxic granules suggest infection and are often accompanied by other
cellular abnormalities.
2. DOHLE BODIES - These refer to pale blue staining areas in the cytoplasm of neutrophils,
occurring either singly or in multiples, formed by parallel arrays of rough endoplasmic
reticulum. They can be found in a variety of infections, bums, trauma, pregnancy, cancer
and with certain cytotoxic drugs. With infection, Dohle bodies are often accompanied by
toxic granulation and/or vacuolization, and are transient in nature.
3. HYPERSEGMENTATION - This refers to neutrophils containing 6 or more nuclear segments.
Hypersegmented polys occur primarily in the megaloblastic anemias.
4. HYPOSEGMENTATION - Pelger-Huet anomaly is an autosomal dominant heterozygous
condition in which nuclear segmentation of most granulocytes is arrested at two lobes.
Dumb-bell or spectacle-shaped nuclei (pince-nez) with excessively clumped chromatin are
the two morphologic characteristics of Pelger-Huet granulocytes. Hyposegmented
granulocytes can be acquired (pseudo-Pelger-Huet-anomaly) in the course of chronic and
acute leukemias, myeloproliferative disorders, or following chemotherapy.
5. ABNORMAL GRANULATION - This refers to fusion of giant azurophilic granules (Chediak-
Higashi syndrome) or numerous, large reddish-purple granulation in granulocytes,
monocytes and lymphocytes (Alder Reilly anomaly).
6. AUER RODS OR BODIES - These are reddish purple, elongated, needle-like, rod-shaped or
comma-shaped cytoplasmic inclusions that occur singly or numerously in leukemic
myeloblasts or mono blasts. Occasionally these may be seen in cells beyond the blast stage
i. e. in progranulocytes of acute pro myelocytic leukemia.

III. HEMATOLOGIC STAINS FOR PERIPHERAL SMEARS AND/OR BONE MARROW - Routine
stains include the standard Wrights or Giemsa stains. Other useful stains include Prussian Blue (iron) for

95
 histiocytes and RBC precursors; Sudan Black (SBB) for myelocytic series; Myeloperoxidase (MPX) for
myelocytic series; Chloracetate Esterase (Leder) for neutrophilic series and basophils; Alpha Napthol
Acetate Esterase (ANAE) for monocytic series, and T lymphocytes; Alpha Napthol Butyrate Esterase
(NBE) for monocytic series; Methyl Green Pyronine (MGP) for RNA.

HEMOSTASIS

This refers to the body's intrinsic ability to slow down or stop hemorrhage. This is accomplished by forming an
intravascular blood coagulum (thrombus) as the result of a complex interaction between the vascular wall, the
blood platelets, and the circulating coagulation and anticoagulation factors. Although the terms are often used
synonymously, a blood clot actually refers to the formation of an extravascular blood coagulum or a postmortem
intravascular coagulum formed only from the plasma coagulation factors. Normal hemostasis involves a delicate
balance between factors that promote blood coagulation and thrombus stabilization and factors that inhibit blood
coagulation and promote thrombus dissolution.

1. COAGULATION AND THROMBUS STABILIZATION

A. ROLE OF THE VASCULAR WALL

1. ENDOTHELIAL CELLS - These are metabolically active cells that synthesize Von Willebrand
factor (VIII-VWF) which promotes platelet adherence to subendothelial fibrillary collagen.
Under appropriate stimuli, they can elaborate thromboplastin (III) to activate the extrinsic
pathway of coagulation. Coagulation factors IX and X also become more active when
bound to the endothelial membrane.
2. SUBENDOTHELIUM - This supports the metabolic activity of the endothelial cells and
produces fibrillary collagen (among other products) which promotes platelet adherence
and activation.
3. SMOOTH MUSCLE - This has the ability to constrict (reducing luminal diameter, retarding
blood loss, and enhancing platelet adherence).

B. ROLE OF THE COAGULATION FACTORS

1. INTRINSIC PATHWAY (coagulation dependent on activation of Factor XII)

Endothelial Injury
I
I
XII - - - - - Xlla
I
I
XI - - - - - - Xla
I
I
IX - IXa
I
I
VIII~ I, - PF-3
111.-- Ca++
IIII
IIII
I
X - - - - - Xa

96
 2. EXTRINSIC PATHWAY (coagulation dependent on tissue injury and release of tissue
thromboplastin. This is an important step in generating the thrombin required to initiate
coagulation).

Tissue Injury
I
I
I
VIIa ~-- VII
I
I
I ,..----ca ++
II
II
x ------~ Xa

3. COMMON PATHWAY

Xa
I
I, PF-3
V -111
III ,--ca++
1111
1111
Prothrombin (II) - - - ~ Thrombin (IIa) ----,
I I
I
I XIII XIIIa
I I
I Fibrin Cross Linked
Fibrinogen -------~ Monomer ----~ Fibrin

C. ROLE OF THE PLATELETS

1. ADHERENCE - When subendothelial fibrillary collagen is exposed to the blood, platelets

(in the presence ofVIII-VWF secreted from endothelial cells) adhere to the collagen via
the platelet membrane receptor glycoprotein 1b (GP 1b).
2. ACTIVATION - Adherence of platelets to the subendothelial fibrillary collagen induces the
release of various products stored in the alpha granules and electron dense bodies of the
platelet cytoplasm. In addition, platelet factor III (PF-3), a phospholipid, becomes
activated to serve as a binding site for cofactors V and VIII, and in the presence of Ca++
allows the coagulation sequence to continue with the eventual production of thrombin.
Thrombin activates further PF-3 receptors to produce more thrombin.
3. AGGREGATION - Activated platelets synthesize and secrete thromboxane A2 (TXA2) which
promotes platelet aggregation, acts on the vascular smooth muscle to potentiate
vasoconstriction, and promotes release of platelet factors, including ADP, which generates
more TXA2 and which further accelerates platelet aggregation to form a temporary
hemostatic plug (aspirin inhibits TXA2 synthesis and ADP release thereby inhibiting
aggregation).

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 4. CONTRACfION - Thrombin, ADP, and TXA2 cause contraction of intraplatelet actomyosin
(thrombosthenin) to form a secondary hemostatic plug and to uncover platelet membrane
receptors (glycoprotein IIb and IIIa) which serve as binding sites for fibrin monomers.
5. STABILIZATION - Thrombin also activates Factor XIII which enhances cross linking of the
fibrin monomers, thereby anchoring and stabilizing the hemostatic plug and ensnaring the
formed elements of blood (RBC and WBC).

II. ANTI COAGULA TION AND THROMBUS DISSOLUTION (FIBRINOLYSIS)

A. ROLE OF THE VASCULAR WALL

1. ENDOTHELIAL CELLS - These also produce factors essential for anti-coagulation

(prostaf.-yclin (PGI:;) , heparin suVate, thrombomodulin, tissue plasminogen activator
(tPA), etc).
2. SMOOTH MUSCLE - This also aids anti-coagulation by its ability to dilate (increasing blood
flow thereby flushing out and diluting platelets and coagulation factors).

B. ROLE OF THE ANTI-COAGULATION FACTORS - In the presence of thrombin and heparin (present
on the surface of intact endothelial cells), antithrombin III (an a 2-globulin produced in liver) has
a negative feedback effect on thrombin, inactivates Xa and to a lesser extent XIIa, XIa, and IXa.
Elaboration of prostacyclin (PG12) from endothelial cells causes vasodilation and converts ADP
into products that inhibit platelet aggregation. Excess thrombin reacts with undamaged endothelial
cells to uncover a membrane receptor (thrombomodulin) which binds and activates circulating
Protein C (produced in the liver). Activated Protein C (APC) inhibits further thrombin production
by inactivating Va and Villa.
C. ROLE OF THROMBOLYTIC (FIBRINOLYTIC) FACTORS - Excess thrombin, in the presence of
fibronectin and fibrinogen, acts on endothelial cells and monocytes trapped in the thrombus to
induce release of urokinase and tissue plasminogen activator (tPA) which converts circulating
plasminogen (produced in the liver) to plasmin. Plasmin cleaves fibrinogen and fibrin into fibrin
split products which further act to inhibit platelet aggregation, thrombin activity, and cross-linking
of fibrin strands. In the interior of the thrombus, however, thrombin acts on platelets to induce
release of inhibitors of urokinase and tissue plasminogen activator. Activated Protein C (APC) can
inhibit this release.

COAGULATION DISORDERS

I. COAGULA TION TESTS

A. BLEEDING TIME - This is a gross in vivo test that measures the adequacy of platelet function. An
incision (l0 mm. in length and 1 mm. in depth) is made in the forearm and the blood is blotted with
a piece of filter paper every 30 seconds until the bleeding stops. Normal bleeding time is
approximately 6 minutes. Platelet count is usually in the normal range.
B. MANUAL PLATELET COUNT - A blood sample is placed in a unipet device to dissolve all the
formed blood elements except platelets. The fluid is then placed in a hemocytometer and the
platelets are counted. Normal platelet count is > 200,000/ml. Most platelet counts are now
automated and performed with the CBC and verified by the manual technique when necessary.

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 C. ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT) - This measures the intrinsic coagulation
pathway (factors XII, XI, IX, VIII, X, and V). This test is useful monitoring heparin therapy and
is a two stage test.

l. STAGE I (THE TEST SYSTEM) - Take the patient's citrated platelet-poor plasma and add
"dirt" (kaolin) which activates factor XII. Let stand 3 - 5 minutes to allow the non-calcium
dependent coagulation factors (VIII, IX, XII) to be activated.
2. STAGE D (THE MARKER SYSTEM) - Add calcium and cephalin (substitute for phospholipid
of platelet membrane). Thrombin is produced and a clot will form in about 35 seconds.
If any of the stage I factors are deficient, the clotting time will be increased.

D. 50/50 (MIXING) STUDIES FOR APTT - If the aPIT is prolonged, the patient's serum can be mixed
1:1 with normal plasma. If PIT (as measured above) returns to normal, the patient is deficient in
one of the factors of the intrinsic pathway. If the PTT does not correct to normal, the patient
probably has circulating anticoagulants or inhibitors (heparin, lupus, etc).
E. PROTHROMBIN TIME (PT) - This measures the extrinsic coagulation pathway (factors II, VII, V,
and X). Tissue thromboplastin (usually from lung or brain extract) is added to patient's citrated
serum and thrombin is formed with clot formation in about 13 seconds. This is used to monitor
coumarin and warfarin therapy since factor VII is coumarin sensitive.
F. FIBRINOGEN LEVEL - A citrated plasma sample is treated with thrombin until it coagulates. The
coagulation time of the patient is compared to a standard curve to determine the fibrinogen level.
This is, at best, only a semi-quantitative assay. Normal levels range between 200 - 500 mg/dl. If
fibrinogen levels are extremely low « 100), PT and PTT may also be prolonged.
G. ADPPLATELET AGGREGATION - ADP is added to citrated platelet-rich plasma which is placed in
a spectrophotometer and the platelet aggregation is measured by the degree of change in turbidity
overtime.
H. RISTOCETIN AGGREGATION TEST - This measures the presence or activity of Von Willebrand's
Factor. Ristocetin (an antibiotic) uncovers the platelet receptors for VWF and, in the presence of
VWF, platelets will aggregate.
I. THROMBIN TIME (TT) - This measures the third stage of coagulation. Exogenous thrombin is added
to citrated plasma and the time to clot formation is measured. Normal ranges depend of the
concentration of thrombin used in the test but generally is about 20-30 seconds. It is increased in
deficiency or abnormality of fibrinogen, presence of fibrin split products (FSP), or presence of
heparin.

II. BLEEDING DISORDERS

A. COAGULATION FACTOR ABNORMALITIES - In these disorders, bleeding is often severe with

hematomas and ecchymoses developing after minor trauma.

l. CONGENITAL - These are usually characterized by single factor deficiencies.

a. Sex-linked - The defect resides on the X chromosome and therefore IS

predominantly clinically expressed in males. Depending on the degree of activity,
they may be classified as mild, moderate, or severe.

(I) Hemophilia A (Factor VIII deficiency) - Approximately 25% of patients

do not have a family history which indicates a high rate of spontaneous

99
 mutation. VIII-C is generally decreased while VIII-VWF remains
relatively normal. The degree of deficiency varies but> 50% have severe
disease. Bleeding into joint spaces (hemarthrosis) will, with time, lead to
a crippling arthropathy. Patients will have normal bleeding time, normal
platelet count, normal PT, and increased APTT.
(2) Hemophilia B (Christmas disease, Factor IX deficiency) - This disorder
has same inheritance pattern and similar symptoms but is about 20% as
common. Like hemophilia A, patients will have normal bleeding time,
normal platelet count, normal PT, and increased APTT.

b. Autosomal Dominant

(1) Von Willebrand's disease - This has an incidence of 1 in 30,000 and is

usually diagnosed in children or young adults. Characterized by easy
bruisability and bleeding with little or no bleeding into joints. Deficiency
in ability to release synthesized VIII-VWF. For unknown reasons, VIII-C
levels are also decreased. Clinically, patients will have increased bleeding
time, normal platelet count, normal PT, and normal or increased APTT.

c. Autosomal Recessive - Deficiencies of each of the coagulation factors have been

described, but most are relatively rare.

2. ACQUIRED - These are usually characterized by multiple factor deficiencies and clotting
abnormalities.

a. Vitamin K deficiency - Hepatic synthesis of factors II, VII, IX, and X are
dependent on the presence ofVitarnin K - a fat soluble vitamin ingested in the diet
and synthesized by intestinal flora. Deficiencies may occur in cases of
malnutrition, malabsorption, biliary obstruction, or drug therapy. Clinically,
patients will show normal bleeding time, normal platelet count, increased PT, and
normal or increased APTT.
b. Severe liver disease - This impairs the hepatic synthesis of II, V, VII, IX, X, and
fibrinogen. With chronic disease, patients will show normal bleeding time, normal
platelet count, and increased PT and APTT.

B. PLATELET ABNORMALITIES

1. THROMBOCYTOPENIA - This refers to a decrease in the number of platelets and is

generally characterized by bleeding from small vessels into the skin, GI tract, mucous
membranes, urinary tract, and brain. Platelet counts below 50,000/ml may impede
coagulation while levels below 20,000/ml may result in spontaneous hemorrhage.
Clinically patients will have normal to increased bleeding time, decreased platelet count,
normal PT, and normal APTT.

a. Decreased production - This can be due to diffuse bone marrow disease (aplastic
anemia, primary or metastatic tumor, etc.), megakaryocyte disorder, etc.
b. Increased utilization - This can be due to disseminated intravascular
dissemination (DIC).

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 c. Increased destruction

(1) Isoimmune thrombocytopenia

(a) Neonatal- This has a similar pathogenesis as hemolytic disease of

the newborn. A sensitized platelet antigen (PLAl) negative
mother will produce IgG antibody to the platelet antigen of the
fetus. IgG crosses the placental membrane and destroys the fetal
platelets.
(b) Post-transfusion - A sensitized platelet antigen negative patient
given platelet antigen positive platelets will destroy not only the
transfused platelets but also his own.

(2) Idiopathic thrombocytopenic purpura (ITP)

(a) Acute - This is a self limiting disease which usually affects

children following a viral infection. Platelets are probably
destroyed as "innocent bystanders".
(b) Chronic - This is a disease of adults (often premenopausal
women) which may be associated with other autoimmune
diseases. Autoantibodies (platelet associated immunoglobulins)
produced in the spleen are directed against the patient's own
platelets. Opsonized platelets are then removed by the reticulo-
endothelial system, primarily the spleen. There are decreased
numbers of platelets in the peripheral blood but an increased
number of megakaryocytes in the bone marrow. Patients usually
give a history of easy bruising and bleeding after minor trauma.
Treated with steroids and often splenectomy.

(3) Thrombotic thrombocytopenic purpura (TTP) - This disease results

from abnormal aggregation of platelets which obstruct the
microcirculation leading to a decreased platelet count, microangiopathic
hemolytic anemia, fever, transient neurologic deficits, and renal failure.
(4) Drug reaction
(5) Mechanical destruction - This may result from cardiac or other
prostheses, roughened endothelium, etc.
(6) Hypersplenism

2. FUNCfIONALABNORMALITIES (increased bleeding time, normal platelet count, normal PT,

normal APTT)

a. Congenital

(1) Defective adhesion - Bernard-Soulier syndrome (autosomal recessive)

is a defect in the platelet membrane glycoprotein, GP 1b.
(2) Defective aggregation - Thrombasthenia (autosomal recessive) is a
defect in the platelet membrane glycoproteins GPIIb and GPIIIa so that no
fibrinogen linking of platelets can occur. Incidence is about 1 in 100,000

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 and usually diagnosed in childhood. Characterized by easy bleeding and
no clot retraction.

b. Acquired

(1) Aspirin ingestion - Aspirin inhibits cyclooxygenase which suppresses

prostaglandin (thromboxane A2) synthesis for about 72 hours.
(2) Thrombocythemia - occasionally seen with myeloproliferative disorders.
Platelet count may exceed 3,000,000/ml but they may be functionally
abnormal. These patients have problems with both thrombosis and
hemorrhage.

C. VESSEL ABNORMALITIES (increased vascular fragility) - These disorders are generally manifested
by petechial hemorrhages of the skin or mucous membranes; characterized by normal bleeding
times, normal platelet counts, normal PT, normalAPTI; and usually are not severe life threatening
situations.

1. CONGENITAL

a. Ehlers-Danlos syndrome (autosomal dominant) - This causes impaired synthesis

of the collagenous vascular support.
b. Hereditary hemorrhagic telangiectasia (autosomal dominant) - This produces
variceal dilatation of small vessels which are fragile. Patients usually present with
epistaxis or GI bleeding.

2. ACQUIRED

a. Hypersensitivity vasculitis

(1) Drug reactions - Antibodies produced against drug antigens result in

immune complex deposits in vessel walls.
(2) Henoch-SchOnlein purpura - This is a generalized hypersensitivity
vasculitis of unknown cause which results in purpura, colicky abdominal
pain, polyarthralgias, and acute glomerulonephritis.

b. Scurvy (Vitamin C deficiency) - This causes impaired synthesis of the vascular

collagenous support.

ANEMIA

I. ETIOLOGIC CLASSIFICAnON - Anemia is a decrease in hemoglobin concentration. It is a symptom

of an underlying disease and, as such, requires further investigation as to its etiology.

A. IMPAIRED RBC PRODUCTION (ineffective erythropoiesis)

1. ALTERATION OF STEM CELLS (BONE MARROW FAILURE) - This may be due to a variety
of causes including myelophthisic infiltrations; hypoplasia due to aging or myelofibrosis;

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 toxic suppression/aplasia due to benzene, radioactivity, chemotherapy; congenital disorders
such as Fanconi's syndrome (autosomal recessive) and Diamond-Blackfan (autosomal
recessive); and systemic disease such as renal failure, neoplasia, septicemia, rheumatoid/-
collagen disease, chronic liver disease, or hypothyroidism.
2. ALTERATION OF ERYTHROCYTE MATURATION

a. Defective DNA synthesis - This is characterized by macro-ovalocytes (MCV >

100), hypersegmented neutrophils, and elevated LDH and bilirubin.

(l) B12 deficiency - BI2 combines with intrinsic factor in the stomach, is
absorbed in ileum, and is necessary for nucleic acid synthesis. It may be
caused by decreased intake (rare) or decreased absorption. Symptoms
may include sallow skin (grayish green/yellow), enlarged spleen,
neurologic changes (personality, tingling, incoordination, etc).
(2) Folate deficiency - Folate is absorbed in small bowel and is also
necessary for nucleic acid synthesis. Deficiencies may be caused by
decreased intake (common), increased demand, impaired absorption, or
inhibition of folate metabolism (drugs, alcohol). Symptoms are the same
as B'2 but without the neurologic symptoms.

b. Defective Hgb synthesis

(1) Iron deficiency - Iron is absorbed in the duodenum and used in heme
synthesis. Deficiencies result from chronic blood loss, decreased intake,
increased demand, or decreased absorption. The serum concentration of
iron is decreased while the concentration of transferrin (total iron binding
capacity or TIBC) is increased. The percent saturation (ratio of
[Fe]/[TIBC] x 100; normal 20-50%) is decreased. Symptoms include
general fatigue, shortness of breath, spoon nails (koilonychia), smooth
sore tongue.
(2) Thalassemia - This results from a genetic defect in the production of the
globin portion of Hgb. A deficiency of beta chains characterizes beta
thalassemia and a deficiency of alpha chains produces alpha thalassemia.
The disease presents as a spectrum of disorders ranging from
asymptomatic changes in the CBC to severe anemia in beta thalassemia
(Cooley's anemia) with early death. The test of choice for identifYing the
anemia as thalassemic is hemoglobin electrophoresis.

B. INCREASED DESTRUCTION OF RBC (hemolytic anemia)

1. INTRACORPUSCULAR (mostly genetic causes)

a. Membrane disorders

(1) Hereditary spherocytosis (autosomal dominant) - This is a disorder with

defective synthesis of RBC membrane that leads to spherical rather than
biconcave red cells. This structural abnormality is detected by the spleen
which enlarges as it removes the abnormal cells from the circulation.

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 Splenectomy will alleviate the symptoms but does not correct the
underlying problem. Osmotic fragility test is useful diagnostic test.
(2) Hereditary elliptocytosis (autosomal dominant)

b. Enzyme deficiencies

(1) Glucose-6-phosphate dehydrogenase (G6PD) (X-linked inheritance) -

This results in loss of protection against chemical oxidation and leads to
hemolysis when certain drugs are used. Heinz bodies (denatured Hgb)
may be present in the red cells.
(2) Pyruvate kinase deficiency (autosomal recessive) - An inability to
maintain normal ATP levels results in membrane abnormalities.

c. Abnormal hemoglobin (hemoglobinopathies) - Abnormal Hgb structure results

from altered amino acid sequence in globin molecule.

(1) Sickle cell anemia (autosomal recessive) - Under conditions of low

oxygen tension, the abnormal structure of the Hgb causes the cell to
"sickle". These cells can obstruct small vessels (esp. bone and spleen) to
produce abdominal and bone pain. They are also more susceptible to
destruction because of their abnormal shape.
(2) Other hemoglobinopathies - Hgb C, Hgb SC, etc. May see anisocytosis
and Howell-Jolly bodies.

2. EXTRACORPUSCULAR (mostly acquired causes) - Because the mechanism of production

of these anemias is increased destruction of circulating red cells, they will almost always
show polychromasia and basophilic stippling, both signs of reticulocytosis.

a. Antibody mediated - These include transfusion reactions, drugs, neoplasia,

autoimmune diseases, etc. Direct Coomb's positivity.
b. Mechanical destruction (microangiopathic) - This can be seen with DIC,
prosthetic valves, etc and often produces schistocytes.
c. Infections - malaria, babesia, etc.
d. Hypersplenism - Increased sequestration and destruction of RBC by the spleen.

C. ABNORMAL BLOOD LOSS - This is usually due to acute or chronic hemorrhage.

II. MORPHOLOGIC CLASSIFICATION (according to size and Hgb content)

Size Hgb Content MCV MCH MCHC Conditions

!lm3 Il1!g %

Macrocytic Normochromic 103-160 37-55 31-36 Pernicious anemia, other megaloblastic

anemias, chronic liver disease

Normocytic Normochromic 82-102 27-34 31-36 Acute blood loss, hemolytic anemia, aplastic
anemia, myelophthisic anemia,
hypoproliferative anemia

Microcytic Normochromic 70-81 27-34 31-36 Inflammatory and neoplastic diseases

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 Microcytic Hypochromic 50-81 15-26 25-30 Iron deficiency, thalassemia, lead poisoning
sideroblastic anemia

ACUTE LEUKEMIA

Acute leukemias are characterized by monoclonal proliferation of immature "blast" cells (large cells with high
N/C ratio and variable numbers of nucleoli) that fail to participate in the normal maturational process. As the
cells accumulate in number (more a function of their inability to mature rather than uncontrolled proliferation),
they spill over into the peripheral blood and may extensively infiltrate many organ systems including the lymph
nodes, liver, kidneys, spleen and heart. In spite of this, morbidity and death is rarely caused directly by the
accumulation and dissemination of leukemic cells but rather by the secondary "suppression" and decrease in the
numbers of mature granulocytes, erythrocytes and platelets which leads to the classic symptoms of acute
leukemia - anemia, infections, and hemorrhage. Acute leukemias often have an abrupt onset and are rapidly
fatal if untreated. They may initially be recognized by the presence of blast cells in the peripheral blood, but the
diagnosis rests on increased numbers of blast cells (>30%) in the bone marrow.

I. ACUTE NON-LYMPHOBLASTIC LEUKEMIAS (ACUTE MYELOGENOUS LEUKEMIAS) - These

make up approximately 60% of the acute leukemias. They arise from the myeloid stem cell line (and
include the erythrocytic and megakaryocytic lines) and tend to arise most frequently in young to middle
aged adults. Patients may initially present with pallor and petechiae. Lymphadenopathy and splenomegaly
mayor may not be present and there usually is no fever unless secondary infection is present.

A. MORPHOLOGIC (FAB) CLASSIFICATION - Based on the cell line and the degree of maturation,
ANLLiAML has been subdivided into seven subtypes. With two exceptions (M6 and M7), these
cells stain positively with myeloperoxidase (MP) and Sudan Black B (SBB). Further differentiation
can be made with the use of Nonspec~fic Esterase (NSE) , Chloracetate Esterase (CLE) , and
periodic acid Sch~ff (PAS) stains.

1. Ml (ACUTE MYELOBLASTIC LEUKEMIA WITHOUT MATURATION) - 90% or more of

nonerythroid cells in the bone marrow are blasts. (MP+, SBB+, NSE-, CLE+).
2. M2 (ACUTE MYELOBLASTIC LEUKEMIA WITH MATURATION) - 30 to 89% of nonerythroid
cells in the bone marrow are blasts. (MP+, SBB+, NSE-, CLE+).
3. M3 (ACUTE PRO MYELOCYTIC LEUKEMIA) - Abnormal promyelocytes with heavy primary
granulation of the cytoplasm are present in the bone marrow. Some may contain bundles
of Auer rods (faggot cells). This is frequently associated with DIe. (MP+, SBB+, NSE-,
CLE+).
4. M4 (ACUTE MYELOMONOCYTIC LEUKEMIA) - 20 to 80% of nonerythroid cells in the bone
marrow must be of monocytic lineage, usually promonocytes and monocytes. (MP+,
SBB+, NSE+, CLE+).
5. M5 (ACUTE MONOCYTIC LEUKEMIA) - 80% or more of nonerythroid cells in the bone
marrow must be mono blasts, promonocytes, or monocytes, and there may be
erythrophagocytosis by the leukemic monocytes. This form differs clinically from other
forms in that the gums are hypertrophied; oral and anorectal ulcers are frequently noted;
infiltrations of the skin are common (chloroma); and lymphadenopathy and splenomegaly
is common. (MP+, SBB+, NSE+, CLE-).
6. M6 (ERYTHROLEUKEMIA, DI GUGLIELMO'S SYNDROME) - These derive from the
erythrocytic line and do not stain with MP and SBB. Over half of all nucleated cells in the

105
 bone marrow are erythroblasts and greater than 30% of non erythroid cells are blasts. The
erythrocytic series shows evidence of dyserythropoiesis (irregular, lobated, or fragmented
nuclei) and are PAS (periodic acid Schiff) positive.
7. M7 (ACUTE MEGAKARYOBLASTIC LEUKEMIA) - These derive from the megakaryocytic
line and do not stain with MP and SBB. Monoclonal platelet antibodies will stain
megakaryoblasts and their abnormal platelet derivatives. This has an association with
trisomy 21.

B. PERIPHERAL BLOOD SMEAR - The smear shows a normocytic, normochromic anemia (often
severe) with a decreased reticulocyte count. Although the white blood count may be elevated, it
is usually normal or depressed. Myeloblasts are generally present, and they may contain abnormal
intracytoplasmic lysosomal structures having a rod-like appearance (Auer rods). Platelets usually
low.
C. PROGNOSIS - Remission can be achieved in the majority of patients, but most will relapse within
a relatively short time. The prognosis is least favorable in infants and the elderly or when the
disease arises as a complication of chemotherapylirradiation for other neoplasms.

II. ACUTE LYMPHOCYTIC/LYMPHOBLASTIC LEUKEMIAS (ALL) - These comprise about 40%

of the acute leukemias. They arise from the lymphocytic cell series and are the most frequent malignancy
of childhood with a peak incidence at 3-4 years of age, although there is also another rise in frequency from
middle age onward. These account for 50% of cancer deaths in children under the age of 15. Patients may
present with symptoms of bone marrow failure (pallor, lethargy, abnormal bleeding), bone and joint pain,
peripheral lymphadenopathy and splenomegaly. Although leukemic involvement of the CNS can occur with
any leukemia, it is more frequently seen with ALL. CNS manifestations are not usually present initially, but
since most chemotherapeutic drugs cannot cross the blood-brain barrier, CNS symptoms may eventuate
even though the disease is controlled in the rest of the body. CSF usually shows increased pressure and
cellularity with decreased glucose and normal protein. Symptoms may be due to increased pressure
(headache, vomiting, papilledema, lethargy), ocular disturbances (blurred vision, strabismus, diplopia),
cranial and peripheral nerve palsies, psychic and auditory disturbances, and diabetes insipidus.

A. IMMUNOLOGIC CLASSIFICATION - Most forms of ALL are comprised of cells that stain positively
for terminal deoxynucleotidyl transferase (FdT), a marker for primitive lymphoid cells. A majority
also have the common acute lymphoblastic leukemia antigen (CALLA) but lack T-cell antigens (T)
or surface Ig (SIg). Some may, however, contain cytoplasmic Ig (Clg) or immunoglobulin gene
rearrangements which identifY them as being derived from B-celllineage. 10% will consist of cells
that have definite T-cell markers while a lesser number show surface Ig characteristic of more
mature B-cells.

1. COMMON ALL (TdT+, CALLA+, Cig-) - These account for 50-70% of childhood ALL
cases. Approximately 75% of cases demonstrate Ll morphology. Significant
lymphadenopathy or hepatosplenomegaly is usually not seen at presentation. This form
responds favorably to chemotherapy. Typical sites of relapse include CNS and gonads.
2. PRE-T-CELL ALL AND T-CELL ALL (TdT+, cALLA-, T+) - These account for
approximately 15-20% of all ALL cases. It usually occurs in the adolescent or young adult
with a male predominance; presents as high WBC count> 100,000, mediastinal mass, and
marked hepatosplenomegaly. CNS is usually involved at time of diagnosis. It is resistant
to chemotherapy and carries a poor prognosis.
3. UNDIFFERENTIATED ALL (TdT+, cALLA-, T-) - This is more common in adults and shows
a poor response to chemotherapy.

106
 4. PRE B-CELLALL (TdT+, cALLA+, CIg+) - Approximately 15-20% of ALL cases, these
also responds favorably to chemotherapy.
5. B-CELL ALL (TdT-, SIg+) - These make up < 5% of all ALL cases. They have L3
morphology (Burkitt type) and are thought to represent acute leukemic presentation of
Burkitt's lymphoma.

B. PERIPHERAL BLOOD - Smears show normocytic, normochromic anemia and thrombocytopenia.

WBC may be low, normal, or high. If high, immature lymphoid cells (lymphoblasts) will be
present.
C. PROGNOSIS - Overall, remissions can be achieved in large majority of children. Disease free states
are maintained in about 50% at five years and cures are possible. Prognosis is poorer for adults and
patients with ALL showing T-cell markers.

MYELODYSPLASTIC SYNDROMES (MDS)

These are a group of related diseases characterized by unexplained failure of the marrow to produce myeloid
cells at rate appropriate to meet needs, despite a normocellular or hypercellular marrow. The diagnosis begins
with recognition of unexplained single or multiple cytopenias (iron deficiency, B12 or folate deficiency,
pyridoxine deficiency, etc. must be excluded). Morphologic evidence of dyspoiesis may be helpful in
confirming the diagnosis of MDS, but these changes may be very subtle. Increased numbers of blasts may be
seen in the bone marrow but is always less than the 30% required for a diagnosis of acute leukemia. Confusion
frequently arises due to the myriad synonyms, partial synonyms, and related terms for myelodysplastic
syndrome and/or its subtypes. These include pre-leukemia; hemopoietic dysplasia; smoldering (myeloid)
leukemia; oligoleukemia; subacute myeloid leukemia; panmyelosis; dysmyelopoietic syndrome; etc.

I. CLINICAL FEATURES - The incidence of MDS approximates that of acute leukemia. It is most
frequently seen in elderly males and is often underdiagnosed. Younger patients, however, may also develop
MDS especially after chemotherapy/radiation therapy for other malignancies. The disorder often presents
as unexplained cytopenias with paradoxical normocellular or hypercellular marrow. It frequently progresses
to another form ofMDS and/or acute leukemia and is often fatal.
II. PATHOLOGIC FEATURES - MDS is generally characterized by dyspoiesis (abnormalities of
erythropoiesis, myelopoiesis, and megakaryopoiesis).

A. DYSERYTHROPOIESIS - Peripheral bood shows normochromic, normocytic anemia; decreased

absolute reticulocyte count; nucleated RBCs and dual RBC population; anisocytosis; poikilocytosis;
macro-ovalocytes, polychromasia, and basophilic stippling. The marrow is normocellular or
hypercellular. Erythroblasts may demonstrate megaloblastic or megaloblastoid changes, nuclear
budding, karyorrhexis, multiple nuclei, and internuclear bridging. There may be vacuolated
basophilic/polychromatophilic normoblasts; ring sideroblasts; and PAS positivity in RBC
precursors.
B. DYSMYELOPOIESIS - On smear, there may be neutropenia; monocytosis; pseudo-Pelger-Huet;
hypo granular neutrophils; immature granulocytes; and decreased myeloperoxidase and alkaline
phosphatase activity. The bone marrow shows myeloid hyperplasia with partial maturation arrest;
diminished or absent secondary granules; myeloperoxidase deficient neutrophils; abnormal
granulation; irregular cytoplasmic basophilia; and increased blasts.
C. DYSMEGAKARYOCYTOPOIESIS - Smears show thrombocytopenia; micromegakaryocytes; large
atypical platelets, abnormal granulation; and vacuolization of platelets. The marrow shows

107
 micromegakaryocytes; multiple small nuclei; large mononuclear megakaryocytes; abnormal
granulation; and nuclear dysplasia.

Ill. CLASSIFICATION (FAB)

PB Blasts BM Blasts

Refractory Anemia (RA) < 1% <5%

RA with Ring Sideroblasts (RARS) < 1% <5%

(sideroblastic anemia)

RA with Excess Blasts (RAEB) 1-5% 5-20%

Chronic Myelomonocytic Leukemia (CMML) <5% <20%

RAEB in Transformation (RAEB-T) >5% 20-30%

MYELOPROLIFERA TIVE DISORDERS

These represent a group of diseases characterized by overgrowth of one or more hematologic cell lines in the
bone marrow and involve granulocytes (chronic myelogenous leukemia), erythrocytes (polycythemia vera),
megakaryocytes/platelets (essential thrombocythemia), or fibroblasts (myelofibrosis).

I. CHRONIC MYELOGENOUS (GRANULOCYTIC) LEUKEMIA (CML) - This is the second most

common leukemia and generally arises in middle aged adults. There appears to be an increased
proliferation of stem cells which, unlike acute leukemias, proceed in the maturational process to produce
excessive numbers of "mature" granulocytes (as well as metamyelocytes and occasional myeloblasts) in
the peripheral blood. All stages of maturation are present in the bone marrow. This proliferation also
involves basophils and eosinophils and increased numbers of these cells may be present in the peripheral
blood. In 90% of patients, an acquired chromosomal abnormality (Philadelphia chromosome - Ph!) can
be identified in erythroid, megakaryocytic, and granulocytic cells suggesting a multi potent myeloid stem
cell or perhaps a pluripotent stem cell origin. The chromosomal abnormality is usually a reciprocal
translocation from the long arm of chromosome 22 to the long arm of chromosome 9. Clinically, patients
present with non-specific constitutional symptoms (weakness, weight loss, fatigue, etc) or excessive
bleeding or bruising after minor trauma. WBC usually exceeds 100,000 and thrombocytosis is often
present. Although the total number of granulocytes is increased, they are functionally impaired as is
evidenced by the lack ofleukocyte alkaline phosphatase (LAP). The disease is slowly progressive and may
cause massive splenomegaly with the spleen reaching weights in excess of 5000 gm. Hepatomegaly is
generally not as striking but leukemic cells may be seen in the sinusoids. The median survival is 3-4 years
from the time of diagnosis and the terminal course of many patients is the development of "blast crisis" in
which there is a transformation into an acute leukemia phase.
II. POLYCYTHEMIA VERA - This also takes its origin from the multi potent myeloid stem cell but instead
of granulocytic dominance, there is erythrocytic dominance resulting in an increase in the red cell mass and
causing an increase in the blood volume and viscosity. The tissues subsequently become congested and
plethoric with complications due to hypertension (headache, dizziness, heart failure), thrombosis (infarction
of spleen, kidneys, heart, brain), or hemorrhage (hematemesis, melena). The bone marrow is hypercellular
with erythroid and megakaryocytic hyperplasia and, though less striking, granulocytic hyperplasia. This is

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 reflected in the peripheral blood by increased numbers of red cells, white cells, and platelets. Repeated
phlebotomy may prolong survival and, if patients live long enough, some will progress to develop bone
marrow fibrosis and extramedullary hematopoiesis (myeloid metaplasia) resulting in splenomegaly.
III. ESSENTIAL THROMBOCYTHEMIA - This is a rare disorder characterized by proliferation of
megakaryocytes with tremendous increases in circulating platelets that are morphologically abnormal.
Peripheral platelet count is usually over 1 million. Splenomegaly, hemorrhage (especially mucosal) and
thromboses are common.
IY. MYELOFIBROSIS (myeloid metaplasia with myelofibrosis) - This occurs primarily in middle-aged adults
(50-60 years old). It is characterized by fibrosis of the bone marrow and shifting of the proliferation of
myeloid elements to the spleen. This may develop as an extension of CML or PV, but it may also occur
insidiously (agnogenic myeloid metaplasia). The spleen is enlarged and may show areas of infarct. The
liver may also be enlarged and show foci of hematopoiesis. The marrow is fibrotic and hypocellular and
the peripheral blood shows abnormal red cells ("tear-drop" and nucleated RBC), immature white cells, and
abnormal platelets. Major complications are due to infection, thrombosis or hemorrhage, but a minority
of patients may develop a picture similar to AML.

L YMPHOPROLIFERA TIVE DISORDERS

These disorders are primarily of B cell origin and represent clonal expansions from the pathway for antigen
stimulated lymphocyte differentiation. They appear to arise as a maturational arrest due to molecular
derangements and give rise to the neoplastic process. This may be induced by chromosome translocations,
retroviruses, or activation of oncogenes. T cells as well can give rise to such chronic leukemias, but are rare.

I. CHRONIC LYMPHOCYTE LEUKEMIA (CLL) - This is the most common form of leukemia. Most
patients are over 60 years old and asymptomatic. If symptomatic, complaints are often non-specific but
generalized lymphadenopathy may be present. Leukemic infiltration of the hepatic portal areas may cause
hepatomegaly, and splenomegaly may be present although not to the extent seen with CML. Lymphocytosis
of peripheral blood is generally present and may reach striking levels (> 200,000). Patients are somewhat
more susceptible to bacterial infection due to low immunoglobulin levels. Autoimmune hemolytic anemia
may be associated. The course of the disease is usually indolent with median survival 4-6 years after
diagnosis. Occasionally, however, there can be a transformation to a large cell lymphoma ("Richter's
syndrome") which is a poor prognostic sign.
II. HAIRY CELL LEUKEMIA - This disorder primarily affects males, 40-60 years old, and frequently
presents with splenomegaly. Peripheral smears show cells with fine hair-like cytoplasmic projections which
show tartrate resistant acid phosphatase (TRAP) positivity. The bone marrow is packed with cells having
a "fried egg" appearance. Splenic red pulp is expanded with pseudosinuses (lakes) lined by hairy cells.
Treatment consists of splenectomy and alpha-interferon.

IMMUNOSECRETORY DISORDERS

These encompass a group of disorders that tend to occur in middle aged to elderly people and are characterized
by a monoclonal proliferation of B-cells which secrete immunoglobulins or portions of immunoglobulins
(paraproteins, M component) into the serum and generally behave in a malignant fashion. The amount of
paraprotein produced is roughly proportional to the size of the expanded population of cells. Clinical symptoms
are related to involvement of the various tissues of the body and the hyperproteinemia that is produced.

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I. MONOCLONAL GAMMOPATHIES OF UNKNOWN SIGNIFICANCE ("benign" monoclonal
gammopathies) - These occur in 1-2% of adults over 30 years of age. Ninety percent of these
gammopathies are of the IgG class and remain stable for more than 3 years. In the bone marrow, plasma
cells constitute less than 15% of the cellularity and never occur in large groups. They rarely, if ever, evolve
into overt myeloma. Monoclonal gammopathies are occasionally associated with carcinomas, lymphomas,
or leukemia. Occasionally, they are also associated with or are a complication of immune disorders.
II. MALIGNANT MONOCLONAL GAMMOPATHIES

A. MULTIPLE MYELOMA (PLASMA CELL MYELOMA) - This is the most common form of malignant
disease of plasma cells. It involves the bone marrow extensively but often involves other tissues
as well, especially late in its course. Typically, the disease occurs in middle aged to elderly males.
Patients generally present with bone pain and are found to have lytic bone lesions, fractures, and
severe osteoporosis due to the production of osteoclast activating factor by the tumor. Diagnosis
is based on clinical features, monoclonal protein spikes, and the presence of plasmacytosis (> 30%)
or multiple plasma cell aggregates in the bone marrow. Multiple myeloma usually follows a
progressive course with death occurring in 2-5 years after diagnosis. Most patients succumb to
infection, renal insufficiency, or hemorrhage.

1. PATTERNS OF IG SECRETION - Most cases show only monoclonal Ig secretion (52% IgG,
18% IgA, 11 % IgM, 1% IgD, rare IgE) or monoclonal Ig and free monoclonal light chains.
Less frequently there may be monoclonal light chains only, and rarely biclonal or
nonsecretory forms occur. Bence-Jones proteins (immunoglobulin light chains) are
excreted through the kidney and are toxic to the tubular epithelium.
2. VARIANTS

a. Plasma cell leukemia - This occurs in 2% of myeloma patients. Patients are

usually younger and are more likely to have organomegaly, less bone pain, fewer
bone lesions and less paraprotein. Survival time is also somewhat shorter than in
myeloma. 20% or more of the circulating peripheral blood cells are plasma cells.
b. Asymptomatic, indolent myeloma - 2-5% of patients who have typical features
of myeloma have a longer clinical course with a mean survival of 4-6 years. These
patients, however, occasionally lack bony lesions.

B. SOLIT ARY PLASMACYTOMA OF BONE - This lesion consists of a bone tumor histologically
identical to myeloma in the absence of other bone lesions and no evidence of paraprotein in the
serum or urine. This slow growing tumor is usually located in the vertebrae, pelvis, femur or
humerus and remains solitary for an average of 5 years before becoming disseminated.
C. EXTRAMEDULLARY PLASMACYTOMA - These are plasma cell tumors that arise outside of the
skeleton and occur in one of three clinical settings: (l) as an extraosseous extension of multiple
myeloma; (2) as an indolent, localized primary tumor; or (3) as a primary tumor that disseminates
to produce widespread disease. Most extraskeletal plasmacytomas occur in the gastrointestinal
tract, periorbital soft tissue and viscera.
D. PRIMARY MACROGLOBULINEMIA (WALDENSTROM'S MACROGLOBULINEMIA) - This represents
a proliferation of B-cells that are differentiated enough to secrete immunoglobulins but not
differentiated enough to look like plasma cells. In essence, it is a hybrid of both well differentiated
lymphocytic lymphoma (in terms of its capacity to infiltrate lymphoid organs creating
lymphadenopathy and hepatosplenomegaly) and multiple myeloma (in terms of secretion of an M
component which is generally a monoclonal IgM). Although diffuse infiltration of bone marrow
may occur, destructive skeletal lesions are not present. The increased IgM, however, causes a

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 hyperviscosity of the serum leading to a hyperviscosity syndrome (retinal hemorrhage, transient
paresis, mental confusion, congestive heart failure, and bleeding). Patients usually live only 5-6
years from the onset of symptoms.
E. HEAVY-CHAIN DISEASE (HCD) - These malignant disorders are characterized by the production of
structurally altered monoclonal proteins. These Ig's consist of only a fragment of the Ig heavy
chain. HCD's apparently result from the proliferation of mutant B lymphocytes.

REACTIVE LYMPHOID HYPERPLASIA

Lymphoid tissue undergoes reactive changes to microbiologic agents or their products, foreign material
introduced into the body, and cell debris from tissue injury, systemic diseases or neoplasia. These reactive
changes inevitably produce an enlargement of the lymphoid tissue mass. Lymphoid hyperplasia is the generic
term used to describe the histology observed and can be categorized according to microscopic architectural
patterns (diffuse, follicular, sinus, or mixed). These patterns may occasionally simulate very closely certain
architectural forms of lymphoma. In addition to histologic similarities, lymphoid hyperplasia may simulate
lymphoma both clinically and radiographically.

MALIGNANT LYMPHOMA

Lymphomas represent neoplastic proliferation of Iymphoreticular tissue generally arising in lymph nodes (but
capable of arising in any Iymphoreticular tissue) and secondarily involving extranodal sites. The vast majority of
these tumors are lymphocytic in derivation (60% B lymphocyte, 35% T lymphocyte) but rarely may arise from
mononuclear/phagocytic cells or reticulum cells. They typically present clinically as a painless enlargement of
one or more lymph node groups and/or as hepatosplenomegaly or, less frequently, as an extranodal mass.
Lymphomas are divided into two major categories: Hodgkin's disease (HD) which comprise about 40% of
cases and non-Hodgkin's lymphomas (NHL).

I. NON-HODGKIN'S LYMPHOMA (NUL) - These are primarily derived from B-cells. T -cell lymphomas
are much less common and include mycosis fungoides (and its derivative Sezary syndrome), most
lymphoblastic lymphomas, and adult T-cell leukemiallymphoma. Clinically, NHL tends to present as
painless lymphadenopathy or with symptoms referable to hepatosplenomegaly. Less frequently, there may
be systemic symptoms offever, weight loss, night sweats, etc. Cervical and axillary lymph nodes are more
frequently the initial nodes at presentation followed by inguinal, femoral, iliac, and mediastinal. On cut
surface, the involved nodes have a yellow-white color and with the more aggressive forms, the nodes tend
to be matted.

A. CLASSIFICATION SCHEMES - Like other neoplasms, lymphomas are felt to arise from a single,
transformed ancestral cell from some point along the differentiation pathway. During the course
of hemopoietic differentiation, the cells undergo both morphologic and immunologic changes. The
Rappaport classification (the oldest and most ingrained of the currently used classifications) is
based principally on the morphologic changes while the Lukes-Collins classification takes into
account not only morphology but immunological differentiation as well. This, in part, has led to
confusion in the nomenclature ofNHL and, for the clinician, confusion about the impact a specific
diagnosis will have on the patient. In an attempt at clarification, the International Working
Fonnulation was developed in 1982 which also took into consideration the biologic behavior of
the various types ofNHL.

III
 WORKING FORMULATION RAPPAPORT COUNTERPART

Low Grade

Small lymphocytic Well differentiated lymphocytic (WDLL)

Follicular, predominantly small cleaved cell Nodular poorly differentiated lymphocytic (PDLL)
Follicular, mixed, small cleaved and large cell Nodular Mixed Lymphocytic-Histiocytic

Intermediate Grade

Follicular, predominantly large cell Nodular Histiocytic

Diffuse, small cleaved cell Diffuse poorly differentiated lymphocytic (PDLL)
Diffuse, mixed small and large cell Diffuse Mixed Lymphocytic-Histiocytic
Diffuse, large cell (cleaved/non-cleaved) Diffuse Histiocytic (DHL)

High Grade

Diffuse large cell immunoblastic Diffuse Histiocytic (DHL)

Lymphoblastic (convoluted/non-convoluted) Lymphoblastic
Small non-cleaved cell (Burkitt's/non-Burkitt's) Diffuse Undifferentiated (Burkitt's/non-Burkitt's)

B. MORPHOLOGY - The neoplastic infiltrate most often completely effaces the usual lymph node
architecture and may involve the perinodal tissue. Partial involvement sometimes occurs. The
infiltrate can grow as uniform nodules or as diffuse, monotonous sheets of cytologically abnormal
cells. The infiltrate can be composed of a mixture of both normal cells and different cytologic
varieties of malignant lymphoid cells representing different stages of differentiation, activation,
and/or transformation. The histologic subtype ofNHL, then, is determined by the presence of one
or more of these cytologic varieties and their pattern of growth.
C. CELL TYPES (WORKING FORMULA nON NOMENCLA TlJRE*/RAPPAPORT NOMENCLA TlJRE**)

1. SMALL LYMPHOCYTE*/WELL DIFFERENTIATED LYMPHOCYTE** - Normal appearing, but

slightly enlarged, small lymphocytes; identical to the cells of chronic lymphocytic
leukemia; produces a diffuse tumor.
2. LARGE CELL */HISTIOCYTE** - Large cells with an open chromatin pattern in an oval or
folded nucleus which may (large non-cleaved cell) or may not (large cleaved cell) have
several distinct nucleoli; narrow rim of cytoplasm; produces diffuse and/or nodular tumors.
3. IMMUNOBLAST*/HISTIOCYTE** - Large cells which have a uniform or very pleomorphic
vesicular nucleus with an open chromatin pattern and a single, usually centrally-located,
prominent nucleolus; moderate amount of cytoplasm; produces a diffuse tumor.
4. LYMPHOBLAST*/LYMPHOBLAST** - Cells of intermediate size which are cytologically
identical to cells of acute lymphoblastic leukemia; the nuclei have finely, dispersed
"blastic" chromatin with inconspicuous nucleoli and little discernible cytoplasm; in about
half of these tumors, the nuclear contour is conspicuously convoluted; mitoses are
frequent; produces a diffuse tumor growth pattern.
5. SMALL NONCLEAVED CELC/UNDIFFERENTIATED CELL** - Cells which are intermediate
in size with nuclei that may be more or less monotonously uniform and contain finely
dispersed chromatin containing 1 to 4 distinct nucleoli usually along the nuclear rim; the
cytoplasm is moderate and in tissue section abuts sharply against that of adjacent cells in
a "molded" fashion; it produces a diffuse tumor although germinal centers may be
infiltrated by or formed by the tumor cells. Benign histiocytes (tingible body macro-
phages) characteristically stand out against the cells to give a "starry sky" appearance.

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D. SUBTYPES OF NHL WITH PROGNOSTIC SIGNIFICANCE - Despite the differences in concepts and
terminology employed by the major classification systems, histologic subtypes that are defined by
the identification of cell types in the lymphomatous infiltrates are often predictive of distinct
clinicopathologic behavior.

1. LYMPHOMAS WITH FOLLICULAR AND/OR DIFFUSE PATTERNS - The fact that certain
NHL's can have a nodular (follicular) or diffuse pattern of growth is recognized in all of
the major classification systems. The cell infiltrate may be predominantly small cleaved
cel\*/poorly differentiated lymphocytic** or predominantly large cel)*!histiocytic** or a
mixture of both. Both the architectural pattern and the cell type are important in predicting
survival. In general, patients with nodular tumors live longer than those with diffuse
tumors for a given cell type, and patients with small cell tumors live longer than
those with large cell tumors.
2. SMALL LYMPHOCYTlC'/WELL DIFFERENTIATED LYMPHOCYTIC" LYMPHOMA (5%) -
This is characterized by a diffuse effacement of the lymph node architecture. A true
nodular (follicular) pattern is never present although ill-defined proliferation centers can
be found. This tumor usually presents at a high stage (70-80% are stage IV) due to
involvement of the bone marrow and often evolves into leukemia indistinguishable from
chronic lymphocytic leukemia. In spite of the advanced stage at presentation, the prognosis
for these patients is good.
3. DIFFUSE LARGE CELL LYMPHOMAS - There are at least two major subtypes oflarge cell
lymphomas: lymphomas derived from follicular center cells and lymphomas not derived
from follicular center cells. These two groups are designated as large cel\*/histiocytic**
lymphoma and immunoblastic*!histiocytic** lymphoma, respectively. The former comprises
about 70% of the diffuse large cell lymphomas. The immunoblast type affects slightly
younger individuals (median age 51) and presents more often with low stage disease.
4. LYMPHOBLASTlC'/LYMPHOBLASTIC" LYMPHOMA - The majority of these patients are
young adolescent males (I 0-16 years) who present with large anterior mediastinal masses.
Other age groups and other nodal and extranodal sites, however, may also be affected.
Most patients either present with bone marrow involvement (stage IV disease), or it rapidly
becomes involved. This tumor typically evolves into a leukemic phase, and it responds
better to acute lymphoblastic leukemia therapy than to therapies given for other high-grade
lymphomas. Nevertheless, prognosis is poor.
5. SMALL NONCLEAVED CELL*/UNDIFFERENTIATED" LYMPHOMA - This group actually
includes three different clinicopathological entities: Burkitt's tumor; Burkitt's type; and
non-Burkitt's (pleomorphic) type. Burkitt's tumor is endemic to subtropical West Africa
and New Guinea and has a predilection for involvement of the jaws and other extranodal
sites of young children who apparently have had an early exposure to Epstein-Barr virus
(EBV) in the setting of endemic malaria that produces an immunosuppressant effect. The
nuclear antigen of EBV is identified in greater than 90% of these tumors whereas it is
found in less than 10% of the nonendemic Burkitt's type. Patients with Burkitt's type
lymphomas are younger than those with non-Burkitt's type. While there are apparent
clinical differences between these varieties of undifferentiated lymphomas, they are
grouped together because their histology is remarkably similar and their response-to-
treatment and survival are about identical. Even though bone marrow involvement is
infrequent, the majority of patients have stage IV disease often because of gastrointestinal
tract (ileum) involvement or unusual extranodal sites of disease. The median survival of
this group is the poorest observed in all NHL's.

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 E. GENERALITIES

1. CLINICAL PRESENTATION - NHL often presents in peripheral (50%) or abdominal (25%)

lymph node groups. Nodular lymphomas and diffuse small cell lymphomas (i.e., WOLL
subtype) often present as generalized, widespread disease while diffuse large cell
lymphomas (i.e., diffuse histiocytic and immunoblastic) often present as localized disease
and may involve extranodal sites (30% of cases) as a primary manifestation. The relative
frequency of involvement of extranodal primary sites in NHL (in descending order) is
stomach, small bowel, soft tissue and periorbital tissue, skin (excluding mycosis
fungo ides), colon, salivary glands, lung and bone.
2. GROSS APPEARANCE - Lymph nodes tend to be enlarged with a fleshy white, grainy cut
surface which may appear as small white nodules when the follicular growth pattern
occurs. Occasionally, foci of necrosis and hemorrhage are present. Extranodal infiltrates
tend to form similar, but larger, discrete tumor masses in the spleen, liver or soft tissues.
With NHL of small cell types (WOLL, POLL), the spleen and liver are infiltrated by an
expansion of the white pulp and portal spaces. POLL often infiltrates the bone marrow in
a paratrabecular location while diffuse lymphomas involve the marrow space in a random
fashion.
3. PROGNOSTIC CLUES - Cell types with more favorable prognosis present more often in a
nodular growth pattern while cell types with a poorer prognosis are more likely to present
in a diffuse pattern. It is not uncommon for tumors to evolve from a nodular to a diffuse
pattern often with a simultaneous change to a large cell type. When this occurs, the
prognosis becomes worse than for a diffuse large cell tumor arising de novo. Generally,
lymphomas of small cell types have an associated lymphocytosis and bone marrow
involvement more often than those of large cell types because of the increased mobility of
the small cells. Stage IV involvement by small cell types, however, has a less ominous
prognostic meaning than Stage IV involvement by large cell types.

II. HODGKIN'S DISEASE

A. CLASSIFICATION - The neoplastic cell is the diagnostic Reed-Sternberg (RS) cell. They are large
cells with abundant eosinophilic cytoplasm, "mirror image" or multilobed nuclei with prominent
eosinophilic nucleoli, and distinct irregularly thickened nuclear membranes. In addition, Hodgkin's
lymphoma demonstrates a pleomorphic, non-neoplastic inflammatory infiltrate consisting of a
variable number of lymphocytes, histiocytes, plasma cells, and eosinophils which may be a host
reaction to the presence of tumor. Although Reed-Sternberg-like cells can be seen in other
conditions, true Reed-Sternberg cells are required for the diagnosis of Hodgkin's lymphoma. The
varying nature of the non-neoplastic, pleomorphic infiltrate, however, serves as the basis for the
histological classification of Hodgkin's disease.

1. LYMPHOCYTE PREDOMINANCE (15%) - This is characterized by a large number of mature

lymphocytes admixed with variable numbers of benign histiocytes. Although there may be
poorly defined nodules, more often there is effacement of the lymph node architecture. RS
cells are scarce as are other types of inflammatory cells, areas of necrosis, or areas of
fibrosis. Usually affects males under 35 years of age, generally presents as localized
cervical lymphadenopathy at an early stage (I or II), and carries an excellent prognosis.
2. NODULAR SCLEROSIS (30-50%) - This is characterized by lacunar cells (variants of the
RS cell which are large cells with hyperlobated nuclei containing multiple small nucleoli
and abundant pale staining cytoplasm. When fixed in formalin, they tend to artificially

114
 retract from surrounding cells giving the appearance of a lacuna). Also present are
birefringent collagen bands (which may be scanty) that arise from the capsule and tend to
divide the node into circumscribed compartments. Classic RS cells are infrequent. This
form is more frequent in females (teenage and young adult) and has a predilection for
involvement of the mediastinal, supraclavicular, and lower cervical lymph nodes.
Prognosis is generally excellent.
3. MIXED CELLULARITY (20-40%) - This form contains fewer lymphocytes but there is
diffuse infiltration of eosinophils, neutrophils, plasma cells, and histiocytes. RS cells are
generally plentiful and small foci of necrosis and fibrosis (non-collagenous) may be
present. Often presents as Stage III disease with retroperitoneal involvement, and carries
an intermediate prognosis.
4. LYMPHOCYTE DEPLETION (10-15%) - These tend to arise in older males and often present
as disseminated disease (Stage III and IV) with systemic symptoms and a more aggressive
course.

B. CLINICAL PRESENTATION - Hodgkin's disease generally presents in supradiaphragmatic LN groups

(cervical, supraclavicular, mediastinal, axillary) and rarely presents in abdominal groups (most
often with lymphocyte depletion subtype) or in extranodal soft tissue. Patients may have systemic
manifestations such as fever, night sweats, weakness, weight loss, anemia, etc, especially with
disseminated disease. All forms may eventually spread to extranodal sites.
C. PROGNOSIS - WEith treatment (radiation therapy and/or chemotherapy), the overall 10 year
survival is about 65%. In general, the younger the patient and the lower the Stage at presentation,
the better the prognosis.

III. STAGING OF LYMPHOMAS - The clinical stage of the disease is an important predictor of outcome
when combined with the histologic subtyping.

Stage I Disease limited to one lymph node region.

Stage II Disease limited to two lymph node regions, on same side of diaphragm.
Stage III Disease limited to lymph nodes but on both sides of the diaphragm.
Stage IV Disease involving extranodal tissue.

A: No systemic symptoms
B: Systemic symptoms present (fever, night sweats, weight loss, etc.)

HISTIOCYTOSES
(neoplasms of tissue-based cells)

I. HISTIOCYTOSIS-X - Characteristic histology usually shows many eosinophils admixed with pale
histiocytes having "grooved" or cleaved nucleus, and on E.M., Birbeck granules are present. The
disseminated form is called Letterer-Siwe disease and affects young infants «1 yo); the multifocal form
is Hand-Schuller-Christian disease and affects young children; and the focal form is called eosinophilic
granuloma and affects older children and adults.
II. MALIGNANT mSTIOCYTOSIS - These tumors lack Birbeck granules. A related disorder is histiocytic
medullary reticulosis which is probably the same disease. This affects any age group with a predilection
for children and young adults. Patients are acutely ill with fever, weight-loss, hepatosplenomegaly, lymph

115
 node enlargement, skin rash, and pancytopenia. Histologically, there is erythrophagocytosis and
proliferation of neoplastic histiocytes within organ sinuses and into organ parenchyma. Usually, the
progression of disease is rapid and patients die within one year, but a chronic variant form has been
described. Differential diagnosis includes disseminated histiocytosis-X, atypical (viral) reactive hyperplasia,
sinus histiocytosis with massive lymphadenopathy, and hairy cell leukemia.

DISORDERS OF THE THYMUS GLAND

I. THYMIC CYSTS - These may be found anywhere along the lines of thymic descent, from the angle of
the mandible to the body of the sternum. Thymic cysts are lined by single layered epithelium, contain
accumulated fluid, cellular debris and hemorrhagic extravasation, and are characterized by finding thymic
tissue in their walls. Although some may be developmental in origin derived from the third branchial
pouch, the origin of most thymic cysts, whether mediastinal or cervical in location, appear to be from
degenerating Hassall's corpuscles or secondarily formed spaces (radiation induced, cystic degeneration of
thymoma, etc).
II. THYMIC HYPERPLASIA

A. GIANT (MASSIVE) THYMIC HYPERPLASIA - This is considered true hyperplasia and is a dramatic
enlargement of the gland through an increase in the cellular elements which remain normally
organized. Thymus glands which are histologically unremarkable can weigh in excess of 200
grams. The pathogenesis and significance of enlargement to this degree is unknown.
Lymphocytosis, presumably antigen-responsive T lymphocytes, and an expansion of the thymus-
dependent regions of lymph nodes often accompany thymic hyperplasia and resolve following
thymectomy.
B. FOLLICULAR HYPERPLASIA -This is characterized by the presence oflymphoid follicles with active
germinal centers in thymus glands which are infrequently increased in size or weight. The presence
of lymphoid follicles in the thymus gland is associated with a large number of diseases, most of
which are believed to have an autoimmune basis or secondary immune complications (myasthenia
gravis, rheumatoid arthritis, scleroderma, etc). Myasthenia gravis is the disease most commonly
associated with follicular hyperplasia, occurring in a large majority of patients with this disease.

III. THYMOMA - This designation has been restricted to neoplasms of the thymic epithelial cells. The
lymphocytic component of thymomas is not thought to be neoplastic.

A. CLINICAL PRESENTATION - In over half of the patients, thymomas are asymptomatic and are
discovered by routine radiologic examinations. In the remaining patients, symptoms from systemic
diseases associated with thymoma (primarily myasthenia gravis) or from the presence of the tumor
itself, such as cough, dyspnea, dysphagia, chest pain or superior vena cava compression, precede
the tumor's discovery.
B. GROSS APPEARANCE - Typically, thymomas occur in the anterior mediastinum as well-
encapsulated masses although they can also arise in ectopic sites such as in the neck along the route
of embryonic migration. In about 20-25% of cases, the tumor will be adherent to surrounding
tissues, and most often microscopic invasion of these tissues can be demonstrated. The cut surface
of the neoplasm usually reveals a thick fibrous capsule surrounding tumor lobules of varying sizes
that are separated by prominent, fibrous trabeculae.
C. MICROSCOPIC APPEARANCE - Most thymomas are composed of an admixture of epithelial cells
and lymphocytes, and they have been classified based on the ratio of these cell types

116
 (predominantly lymphocytic, mixed, or predominantly epithelial), but only rarely are thymomas
purely epithelial. Microcystic degeneration may be extensive in some tumors. Well-formed
Hassall's corpuscles are rarely found.
D. CLINICAL BEHAVIOR - Thymomas are extremely slow growing neoplasms which usually remain
localized for many years before invading adjacent structures. Distant metastases occur very rarely.
If complete resection is not accomplished, death from cardiorespiratory complications of tumor
invasion will result.

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 ENDOCRINE SYSTEM

GENERAL PRINCIPLES

The endocrine system consists of a variety of cells arranged both as glandular tissues and as individual cells
(neuroendocrine system) scattered throughout the body. Their primary function is to maintain body homeostasis
through the manufacture and secretion of a variety of chemical mediators (hormones). When secreted into the
circulation, hormones can exert their effects on distant sites (endocrine effects) and when diffused through
interstitial tissue, they can exert their effects on adjacent sites (paracrine effects). They may also exert their effects
on the cell of origin (autocrine effects).

In general, hormones are either amino acid deriviatives (polypeptides) or cholesterol derivatives (steroids).
Depending on the target cell, the same hormone can exert biologically different effects. The steroids and thyroid
hormones are hydrophobic, requiring transport proteins, but can easily diffuse through the plasma membranes of
target cells to bind reversibly to intracytoplasmic receptors. Ultimately, they are bound to nuclear DNA where they
act to regulate transcription of specific genes. The remainder of the hormones are hydrophilic, transported in the
circulation in low concentrations, and bind to specific receptors on the target cell plasma membrane. They effect
their action either by induction of secondary messengers (cyclic AMP , etc) or by altering the plasma membrane
permeability to specific ions. There are delicate, sometimes complex, regulatory mechanisms that control hormone
secretion by the endocrine system.

Abnormalities of endocrine organs are usually manifested by hyperfunction (abnormal stimulation, autonomous
function, ectopic production), hypofunction (congenital defect, acquired defect, end organ unresponsiveness), or
the local effects of an enlarging mass. The differentiation between benign and malignant neoplasms is often difficult
since the normal rules (mitoses, anaplasia, etc.) don't tend to apply. In many cases the best evidence of malignancy
is the existence of metastases.

PITUITARY

I. REVIEW OF NORMAL

A. EMBRYOGENESIS

1. ANTERIOR LOBE - The adenohypophysis is derived from an upward extension of Rathke's

pouch (located in the roof of mouth). The developing sella turcica of the sphenoid bone
separates the anterior lobe from its embryonic origins, but small cellular rests may remain

118
 along the line of embryologic ascent and infrequently give rise to a benign, but locally
destructive, craniopharyngioma.
2. POSTERIOR LOBE - The neurohypophysis is derived by a downward growth ofaxons from
the hypothalamus to the median eminence of the pituitary stalk (in the region of the floor
of 3rd ventricle) and the posterior pituitary. A direct connection between hypothalamus
and posterior lobe is therefore maintained via the pituitary stalk which penetrates the
diaphragma sellae, an extension of the dura which covers the roof of the sella.

B. BLOOD SUPPLY - The arterial blood is supplied by branches of the internal carotid. The majority
of blood supply, however, is via a portal system derived from capillary beds in the floor of 3rd
ventricle. These form portal veins which course along the surface of the pituitary stalk before
entering the rich vascular network of the anterior lobe. Portal communications also exist between
the anterior and posterior lobes. The portal system then drains into the cavernous sinus.
C. HISTOLOGY AND FUNCTION

1. ANTERIOR LOBE - Histologically, the cells are arranged in nests, cords, and pseudoacinar
formations separated by a rich fibrovascular network. Originally three cell types were
identified (acidophil, basophil, and chromophobe) based on staining characteristics with
routine H&E stains. The development of immunohistochemistry techniques and
monoclonal antibodies, however, has enabled further categorization into cell types
responsible for secretion of specific hormones. Acidophils are now identified as as
somatotrophs which secrete the polypeptide growth hormone (GH), and lactotrophs which
secrete the polypeptide prolactin (PRL). The basophils now consist of the corticotrophs
which secrete the polypeptide adrenocorticotropic hormone (ACTH) and the thyrotrophs
which secrete the glycoprotein thyroid stimulating hormone (TSH). Gonadotrophs secrete
the glycoprotein gonadotropins - follicular stimulating hormone (FSH) and luteinizing
hormone (LH) - and have been classified as both basophils and chromophobes. The bulk
of the chromophobes, however, consist of non-secretory cells which probably represent
other pituitary cells that are temporarily degranulated.
2. POSTERIOR PITUITARY - The posterior pituitary hormones, anti-diuretic hormone (ADH,
vasopressin) and oxytOCin, are formed in the neurons of the hypothalamus (paraventricular
and supraoptic nuclei) and conveyed, via axonal transport down the pituitary stalk, to the
posterior lobe where they are stored in the terminal axon prior to release. Histologically
the posterior pituitary consists of scattered pituicytes and the axonal extensions of the
hypothalamic neurons.

D. REGULATION

1. ANTERIOR PITUITARY - With the exception of prolactin (hypothalamic release of dopamine

acts as an inhibitor of prolactin secretion), hypothalamic releasing factors stimulate the
release of the anterior pituitary hormones. The subsequent release of hormone from the
major target organ of the pituitary hormones has a negative feedback on both the
hypothalamus and the anterior pituitary.
2. POSTERIOR PITUITARY - The serum osmolality and blood volume act as the regulatory
mechanism of ADH. Release of ADH is stimulated principally by increased serum
osmolality and decreased blood volume.

II. HYPERPITUITARISM - Although hypothalamic hypersecretion and disruption of negative feedback

loops are occasionally at fault, autonomous pituitary hypersecretion is the most common basis of

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 hyperpituitarism and is usually due to a functional, benign, monoclonal neoplasm (pituitary adenoma)
which secretes one of the polypeptide hormones (PRL, GH, ACTH). Rarely one neoplasm may secrete 2
hormones (usually PRL and GH). Adenomas tend to appear in young adults and are slightly more frequent
in males.

A. ANATOMIC FEATURES - Adenomas vary in size, but in general, are small, soft, and red-brown to
yellow-tan in appearance. Microscopically, small microadenomas may be difficult to differentiate
from focal hyperplasia. Since the tumor cells are derived from a monoclonal expansion, they
usually are similar in appearance and generally tend to closely resemble one of the normal pituitary
cell types. Some adenomas, however, may show considerable cellular pleomorphism, but overt
malignant neoplasms are rare and when they do occur, they are generally non-functional. As the
tumors enlarge, they compress the surrounding normal pituitary tissue and expand the sella
(eroding the clinoid processes). They may become locally aggressive and penetrate into adjacent
structures (base of brain, nasal sinuses, etc). They also tend to compress their own blood supply
and may become centrally necrotic. Rarely, extensive spontaneous necrosis or sudden hemorrhage
may lead to the syndrome of ''pituitary apoplexy".
B. CLINICAL FEATURES

1. PROLACTIN EXCESS - Prolactin is the most common secretory product of pituitary

adenomas. Pathologic hyperprolactinemia is defined as a consistently elevated serum
prolactin (greater than 20 ng/ml) in the absence of pregnancy or postpartum lactation. In
women this often results in anovulation, 2° amenorrhea, and galactorrhea. In men, it may
produce infertility or impotence but it may also be relatively asymptomatic and not
discovered until the tumor grows to a size that produces symptoms due to its mass effect.
2. GROWTH HORMONE EXCESS - Before puberty, an increase in growth hormone is reflected
by exaggerated skeletal growth (giantism) which is often accompanied by nerve, muscle,
and joint problems. After puberty, hypersecretion produces acromegaly (2nd most
common functional disorder of the pituitary) which involves insidious enlargement and
coarsening of the face, hands, and feet. Facial features include prominent forehead,
protruding jaw, thick lips, and enlarged tongue. Metabolic problems include hypertension,
glucose intolerance, and osteoporosis. The diagnosis should be based upon the clinical
features of the patient, the presence of elevated basal serum GH concentrations, and the
failure of serum GH concentrations to decrease following a glucose load.
3. ACTH EXCESS - Increased ACTH secretion results in Cushing's disease [see Adrenal
section].

III. HYPOPITUITARISM - Hypothalamic problems can give rise to isolated anterior lobe hormone deficits
(GH deficiency is the more common). Generally, however, hypopituitarism results from extensive
destruction of anterior lobe tissue ( > 75% before symptoms begin to appear) and leads to
panhypopituitarism (Simmond's disease).

A. CLINICAL FEATURES - Temporally, symptoms are sequentially related to deficiencies of

gonadotropins, GH, ACTH, TSH, and PRL.

1. GONADOTROPIN DEFICIENCY - In children, this may cause delayed puberty. In adult

females there may be amenorrhea, loss of secondary sex characteristics, and atrophy of the
ovaries and external genitalia; while in adult males there may be aspermia, loss of
secondary sex characteristics, and testicular atrophy.

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 2. GROWTH HORMONE DEFICIENCY - Before puberty, this can cause pituitary dwarfism
(short stature but with normal proportions) and delayed sexual maturity. After puberty, it
is generally asymptomatic.
3. ACTH DEFICIENCY - This produces symptoms of hypoadrenalism [see Adrenal section].
4. TSH DEFICIENCY - This produces symptoms of hypothyroidism [see Thyroid section].

B. CAUSES - Most frequently, events which destroy the pituitary arise from within the sella itself.
Rarely, however, suprasellar tumors (craniopharyngioma, germinoma, etc) will impinge upon and
destroy the anterior and/or posterior pituitary, usually with resulting hypopituitarism and/or
diabetes insipidus. Craniopharyngioma is usually a benign slow-growing tumor of children and
young adults. Derived from remnants of Rathke's pouch, the tumor histologically resembles
embryonic tooth enamel formation (ameloblastoma) with squamous and columnar epithelium set
in loose fibrous tissue. Calcification is common and is a useful radiologic sign. Germinomas arise
in the pineal gland from germ cells that were also embryologic "leftovers".

1. NON-FUNCTIONING ADENOMA - This is the most frequent cause of hypopituitarism. As

the neoplasm enlarges in size, there is compression of the remainder of the gland resulting
in a gradual loss offunction. For this reason, the tumors tend to be relatively large when
discovered. Histologically, the cells generally are sparsely granulated (chromophobe aden-
oma) and may be derived from undifferentiated precursor cells. Others, however, may
contain cells with a clear cytoplasm (null cell adenoma) or cells packed with mitochondria
(oncocytoma). In some instances, a functioning adenoma may undergo secretory
exhaustion, ischemic necrosis, hemorrhage, or infarction and also lead to hypopituitarism.
2. SHEEHAN'S SYNDROME - This results from an infarct of the anterior lobe secondary to
hypotension or shock. Although there may be multiple etiologies, classically, it is due to
obstetric hemorrhage and hypotension (postpartum pituitary necrosis). During pregnancy,
the pituitary doubles in size compromising the portal veins. Sudden hypotension will then
induce an infarct. Inability to lactate may be the first sign, or it may be identified when
there is failure to resume menses. Lack of energy and loss of muscle strength is also
present.
3. EMPTY SELLA SYNDROME - This refers to the absence of a pituitary gland in an otherwise
enlarged or normal sella. This may be the end result of a number of preexisting intrinsic
pituitary problems, previous surgical removal, or due to a congenital or acquired defect
in the diaphragma sella which allows hemiation of arachnoid membrane into the sella
causing pituitary atrophy under conditions of chronic increase in CSF pressure.

IV. POSTERIOR PITUITARY SYNDROMES

A. OXYTOCIN - Apparently, neither excessive nor deficient production of oxytocin has recognizable
associated clinical effects.
B. ADH - ADH is released in response to increases in osmolality of body water or a decrease in blood
volume. Together with thirst, which promotes water ingestion, ADH regulates water balance to
maintain steady-state solute concentrations within tissues.

1. EXCESS SECRETION - The syndrome of inappropriate ADH (.S'IADH) results in renal

retention of water with hypervolemia, hemodilution, and an inability to dilute urine. The
usual cause is ectopic production of ADH by various neoplasms (classically oat cell
carcinoma of the lung), but it also may be seen with meningitis, pneumonia, head trauma,
etc. Assuming normal renal and adrenal function, the features of SIADH are hyponatremia

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 with appropriately low plasma osmolality, urine osmolality greater than plasma osmolality,
and excessive renal sodium excretion in the absence of hypotension, hypovolemia and
edema forming states.
2. DEFICIENT SECRETION - Diabetes insipidus results in clinical symptoms similar to diabetes
mellitus (polyuria, polydipsia, etc.) and is generally due to posterior pituitary tissue
destruction (metastatic neoplasm, iatrogenic), disruption ofhypothalarnic-hypophyseal axis
(trauma, inflammation), or idiopathic causes. Patients with severe diabetes insipidus can
be identified by low urine osmolality, high plasma osmolality, and increased urine
concentration following administration of synthetic ADH. In some cases, there may be
sufficient ADH secretion but an end-organ unresponsiveness to the hormone (nephrogenic
diabetes insipidus).

V. MASS EFFECTS - Expanding masses (primary or metastatic neoplasm, edema, infiltration of stroma, etc)
can produce visual impairment (usually bitemporal hemianopsia) when there is expansion beyond the sella
and impingement on the optic chiasm or compression of the oculomotor nerves. Although less likely, the
mass may compress the floor of the 3rd ventricle, increase intracranial pressure, and produce headaches,
nausea, and vomiting. Radiographic evidence of an enlarging sella may precede the development of clinical
signs and symptoms.

THYROID

I. REVIEW OF NORMAL

A. EMBRYOGENESIS - The thyroid originates as a tubular evagination from the foramen cecum at root
of tongue and grows caudally anterior to the trachea. The distal portion proliferates to form the
thyroid gland while proximal portion degenerates. Aberrant locations (substernal, lingual) may
result from improper descent. Most are midline but lateral aberrations can be present in the anterior
triangle of the neck. Failure of the proximal portion to degenerate may result in a thyroglossal duct
cyst which may not become apparent until adulthood. These lie in, or close to, the midline (as
opposed to branchial cleft cysts which lie in the anterolateral neck), contain mucinous fluid, and
are lined by squamous or columnar/cuboidal epithelium overlying a lymphocytic infiltrate
containing scattered thyroid follicles. Complications include abscess formation and/or draining
sinus tracts.
B. STRucrURE - The 20-30 gram adult thyroid consists of two lateral lobes connected by an isthmus.
Microscopically, it is composed of follicles of varying size set in a fibrovascular stroma which
contains parafollicular or "e" cells that secrete calcitonin. Normally, follicles are lined by cuboidal
epithelium with apical microvilli which surround an eosinophilic thyroglobulin-containing colloid.
With increased activity, the epithelium becomes more columnar as the colloid is absorbed while
with inactivity colloid accumulates, distends the follicle, and flattens the epithelium.
C. REGULATION - Thyroid hormones are very sensitive to metabolic demands so that the thyroid is
continually increasing and decreasing its activity to meet those demands. Hypothalamic TSHRF
stimulates release of pituitary TSH which binds to specific receptors on the follicular epithelium
and stimulates production of thyroid hormones (T4 and to a lesser extent T3). During periods of
activity, thyroglobulin is taken up from the colloid by the follicular cells and undergoes proteolysis
to release T4 and a small amount ofT3 into perifollicular capillaries. Peripherally, thyroxine (T4)
is converted to T 3, which is the more metabolically potent form. A rise in serum T3 and T 4, in tum,

122
 has negative feedback on the hypothalamic and pituitary secretion of TSHRF and TSH. T 4, T3, and
TSH can be quantitatively measured by RIA procedures. The thyroid hormones circulate in blood
bound to plasma proteins, primarily thyroxine-binding globulin (TBG). The binding is so strong
that only a vel)' small amount of the circulating hormones is unbound or "free" and biologically
active. Since the assays for T4 and T3 typically measure the total hormone, changes in TBG concen-
tration may result in changes in the measured total hormone concentration but a "normal"
biologically active level is maintained. Pregnancy, estrogen therapy, and a genetically determined
increase in TBG can lead to an elevated total T4 and T3. Alternatively, total T4 and T3 levels are
decreased when plasma TBG is decreased, as may occur in liver disease, nephrotic syndrome,
androgen treatment, or a genetic defect in TBG synthesis. Although the total hormone con-
centration is increased or decreased as appropriate in order to keep the TBG about one-third
saturated, the free hormone concentration is maintained as "normal" to provide euthyroid status.

II. CLINICAL PRESENTATION

A. HYPERTHYROIDISM (thyrotoxicosis) - This is a hypermetabolic state produced by increased T4

and/or T3. Measurement of T3 by RIA appears to be a sensitive test for hyperthyroidism. The
disorder is clinically manifested by hyperkinesia, tachycardia, cardiac arrhythmias, warm moist
skin, sweating, heat intolerance, increased appetite (but decreased weight), fine oily hair, muscle
weakness and fine tremors, emotional lability, and diarrhea. Sudden release of excessive amounts
of thyroid hormone (thyroid storm) is an emergency condition manifested by fever, tachycardia,
arrhythmias, obtundation, and coma. Major causes of hyperthyroidism include Grave's disease,
toxic multinodular goiter, and toxic adenoma.
B. HYPOTHYROIDISM - This results from a deficiency of thyroid hormones and may result from
intrinsic thyroid disease (primary hypothyroidism) or from a deficiency of TSH (secondary
hypothyroidism) as a consequence of pituitary or hypothalamic disease. Rarely is hypothyroidism
due to general end-organ resistance to thyroid hormone. The measurement of serum TSH is
regarded as the most sensitive indicator of primary hypothyroidism. With thyroid failure, the
serum TSH level is increased. In the patient with clinical features compatible with hypothyroidism,
a TSH level that is not elevated suggests secondary hypothyroidism.

1. LATE CHILDHOOD OR ADULT HYPOTHYROIDISM (myxedema) - This is a hypometabolic

state manifested by insidious onset of tiredness, apathy, and lethargy. Mental faculties
become dulled and speech becomes slowed. The skin becomes rough and the hair
becomes coarse and dry. Mucopolysaccharide is deposited in connective tissue throughout
the body giving the subcutaneous tissue a "doughy" consistency. The periorbital soft tissue
becomes puffY, the tongue becomes enlarged, and the heart becomes flabby and dilated.
Increased peripheral vascular resistance and decreased cardiac output leads to narrowed
pulse pressure, and decreased perfusion of skin results in cold intolerance. Major causes
include surgical, chemical, or radiation ablation; primary idiopathic myxedema; and
Hashimoto's thyroiditis.
2. GESTATIONAL OR EARLY INFANCY HYPOTHYROIDISM (cretinism) - This can arise from
nutritional lack of iodine or from defects in thyroid hormone synthesis. A deficiency early
in fetal life will retard brain development causing severe mental retardation, spasticity, and
deaf-mutism (neurologiC cretinism). A deficiency late in pregnancy or early infancy usually
becomes manifest by feeding difficulty, somnolence, a hoarse low pitched Cl)', and failure
to thrive. If untreated, there is impaired skeletal growth, dl)' skin, and protuberant
abdomen. Later manifestations include wide set eyes, broad flat nose, enlarged tongue, and
periorbital puffmess.

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 C. MASS EFFECTS - Goitrous enlargement and encroachment on adjacent structures may produce
dysphagia, inspiratory stridor, hoarseness, dyspnea, etc.

III. THYROIDITIS

A. ACUTE INFECTIVE THYROIDITIS - This results from bacterial or fungal seeding of the gland which
may cause painful swelling but is usually self-limiting with no sequelae except focal scarring.
B. SUBACUTE GRANULOMATOUS (DEQUERVAIN'S) THYROIDITIS - This is probably viral in origin, and
typically presents in young adult females as an acute febrile "flu-like" systemic illness. There may
be sudden, painful, and diffuse (but irregular) enlargement of thyroid and/or transient
thyrotoxicosis which gradually subsides over several months. In the thyroid, microabscesses may
form early in the disease but eventually, with follicular destruction, there is a granulomatous
"foreign body" inflammatory reaction to pools of colloid. Focal scarring may be the end result, but
generally this is not clinically significant.
C. SUBACUTE OR CHRONIC LYMPHOCYTIC THYROIDITIS - Of unknown etiology, this presents as
painless mild-moderate enlargement of the thyroid and/or transient hyperthyroidism which is
usually self-limiting. There is a lymphocytic stromal infiltrate without plasma cells or germinal
centers and there may be mild fibrosis.
D. RIEDEL'S THYROIDITIS - Also of unknown etiology, this is a rare condition more commonly seen
in middle aged females and characterized by aggressive fibrosis of the thyroid parenchyma and
adjacent structures. Clinically it presents as a hard, non-tender, fixed nodule of irregular outline
which may cause stridor, dysphagia, hoarseness and dyspnea, and which may be easily confused
with cancer. Up to 50% of patients may be clinically hypothyroid.
E. HASHIMOTO'S THYROIDITIS - This characteristically presents in middle aged women as a gradual
thyroid enlargement, usually painless, associated with insidious onset of hypothyroidism.
Occasionally, some patients may go through a phase of hyperthyroidism before hypothyroid
symptoms predominate.

1. PATHOGENESIS - The disease is autoimmune in origin and has an increased incidence in

patients with other collagen-vascular disorders. Because of its association with HLA-DR5,
some feel that there is a genetic predisposition to formation of autoantibodies to follicular
cell antigens as the result of a deficiency in antigen-specific suppressor T cells. Without
these, cytotoxic (killer) T cells are free to attack follicular cell antigens while helper T cells
assist in the B cell production of autoantibodies (microsomal, thyroglobulin, and TSH-
receptor). Two forms of TSH-receptor autoantibodies may be produced: TGI (thyroid
growth immunoglobulin) and TSI (thyroid stimulating immunoglobulin). In addition,
blocking antibodies for each of these may be formed. In Hashimoto's thyroiditis, the
TSH-receptor autoantibodies may consist mostly of TGI (or TGI and TSI with TSI
blocking antibody). At any rate, there is growth of the gland but generally no
hyperfunctioning.
2. ANATOMIC FEATURES - Grossly, the gland is usually symmetrically enlarged, firm, and
rubbery. Microscopically, there is destruction of follicles (perhaps mediated by cytotoxic
T cells) and extensive infiltration of the stroma by lymphocytes, immunoblasts, plasma
cells, and macrophages. Germinal centers are often prominent and the cytoplasm of
residual non-functional follicular cells are packed with mitochondria giving an eosinophilic
granular appearance (Hurthle cells or oncocytes). Some degree of fibrosis is usually
present and rarely may be the prominent feature.

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IV. GOITERS

A. DIFFUSE TOXIC GOITER (GRAVE'S DISEASE) - This produces a symptom complex seen
predominantly in young, adult women which is characterized by hyperthyroidism, moderate thyroid
enlargement, ocular changes (proptosis, muscle weakness, diplopia, periorbital edema, lid lag), and
localized thickening of the skin over dorsum of feet and legs (pretibial "myxedema"). The ocular
changes are present in about 70% of the cases and the dermatologic changes in about 15%.

1. PATHOGENESIS - Although genetically associated with HLA-DR3, the pathogenesis is

basically same as Hashimoto's thyroiditis. In Grave's disease, both TGI (which stimulates
gland growth) and TSI (which stimulates hormone production) are produced as a result
of an antigen-specific T suppressor cell deficiency and results in an enlarged,
hyperfunctioning gland. The thyrotoxicosis itself may further depress T suppressor cell
activity and aggravate the problem. Additionally, autoantibodies that are specifically
directed against, or at least cross react with, eye-muscle antigens are apparently produced.
Subsequent lymphocytic infiltration of, and mucopolysaccharide deposition in, the
extraocular eye muscles and retro-orbital fatty tissue account for the proptosis and ocular
changes. Similar changes in the dermis and subcutaneous tissues create the pretibial
"myxedema" associated with the disorder. Although the eye problems usually regress
spontaneously, they may progress to produce blindness despite successful treatment of the
thyrotoxicosis.
2. ANATOMIC FEATURES - Grossly, there is moderate diffuse enlargement of the thyroid with
the parenchyma having a soft meaty appearance. Histologically, the classic appearance is
increased numbers of tall columnar follicular epithelial cells creating papillary infoldings
into the follicle lumen which is almost devoid of colloid material. There is an increase in
the stromal vascularity and a heavy stromal lymphocytic infiltrate which may form
lymphoid follicles. Pre-surgical drug therapy dramatically alters the histology, however,
and the classical appearance is rarely encountered in surgical specimens. Thiourea and
mercaptoimidazole block the coupling of MIT and DIT to form T3 and T4 so that serum
hormone levels decrease but TSH is increased exaggerating the hyperplasia of the follicular
cells and the scant colloid. High dose iodides, however, inhibit the proteolysis of
thyroglobulin so that colloid increases within the follicles and flattens the follicular
epithelium. Extrathyroid tissue which may show morphologic changes include the heart,
skeletal muscle, liver, and lymphoid organs.

B. DIFFUSE NONTOXIC GOITER (simple goiter, colloid goiter) - This refers to a gradual painless
enlargement of the thyroid due to compensatory hyperplasia secondary to a defect in production
or an inability to secret functional thyroid hormone. At the time of diagnosis, however, most
patients are euthyroid.

1. ETIOLOGY - Endemic goiters are generally confined to specific geographic locations and
are the result of deficient dietary iodine intake or, in some cases, regional environmental
goitrogens. Sporadic goiters are less common and typically occur in adolescent or young
adult women. They are presumed to be due to TSH stimulation of the gland but not all
patients have high serum TSH levels. Some probably arise in a marginally euthyroid patient
when there is an increased demand for thyroid hormone (pregnancy) or when environ-
mental goitrogens (foods, drugs) are introduced. Other causes include the uncommon
hereditary defects in hormone synthesis or transport, excess production ofTBG, or other
unknown (autoimmune?) mechanisms.

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 2. DEVELOPMENT - Initially, TSH stimulation causes increased follicular cell activity
reflected by increased cell mass and tall columnar epithelial cells lining colloid-depleted
follicles (hyperplastic stage). This produces moderate diffuse enlargement of the gland
which has a meaty appearance on cut surface. As a euthyroid state is reached, colloid
(generally thyroglobulin deficient) accumulates unevenly in follicles flattening the
epithelium and enlarging the gland even further (collOid involution). As the colloid
accumulates, the cut surface develops a gelatinous appearance.

C. MULTINODULAR GOITER (adenomatous goiter) - This is the end result of a long-standing diffuse
nontoxic goiter and can cause tremendous thyromegaly (up to 1500 gm). Since they are derived
from simple goiters, they are more frequently seen in females but in an older age population.
Although the goiter may be functional (toxic multinodular goiter), more frequently patients are
euthyroid, and although the entire gland is usually multinodular, the nodularity may be asymmetric
and more prominent within one lobe. Irregular scarring creates nodules of varying size which, in
tum, contain follicles of varying size and colloid content. Focal hemorrhage, calcification, and
microcysts may form. Due to the size and irregularity, these nodules can easily be clinically
confused with cancer. Clinical symptoms are generally related to local effects of increasing size
(inspiratory stridor, dysphagia, superior vena cava syndrome) and/or hyperthyroidism (not as
severe as Grave's disease and not associated with ocular or skin problems). Sudden hemorrhage
may cause acute painful enlargement.

v. SOLITARY THYROID NODULES - Although thyroid nodules are common and thyroid carcinoma is
relatively rare, there is no reliable method to distinguish non-neoplastic from neoplastic or benign from
malignant without histologic study. Slightly over 50% of clinically palpable "solitary" thyroid nodules prove
to be nodules of multinodular goiters and, of the remainder, about 3/4 are soiitary benign adenomas.

A. BENIGN NEOPLASMS - Although lipomas, hemangiomas, etc do occur, they are unusual and of little
significance. The vast majority of benign neoplasms are adenomas which become more frequent
with increasing age and usually present as small to moderate sized (less than 4 cm) discrete
nodules. They are rarely functional but they may painlessly enlarge slowly over time, enlarge
suddenly and painfully due to hemorrhage, or remain relatively static and asymptomatic. Occasion-
ally, they (as well as nodules of multinodular goiters) may undergo cystic degeneration with
replacement of the solid tissue by cell debris and a thin brown fluid representing old hemorrhage.
Almost all adenomas are derived from follicular epithelial cells and are therefore follicular
adenomas. Descriptive terms such as embryonal, fetal, simple, and colloid refer to various
histologic patterns and have little, if any, prognostic significance. Criteria for classification as an
adenoma include: (1) complete fibrous encapsulation of the nodule; (2) compression of adjacent
thyroid parenchyma; (3) different histologic appearance of the neoplastic and non-neoplastic tissue;
and (4) lack of multinodularity in the remainder of the gland. Adenomas are felt to have little, if
any, malignant potential.
B. MALIGNANT NEOPLASMS - Although a solitary nodule in a male is more likely to be malignant, the
incidence of malignancy is higher in females. Nevertheless, thyroid carcinomas are relatively
infrequent. Previous radiation exposure (especially in young females) increases the risk of
malignancy but other forms of thyroid disease (goiter, adenoma, Hashimoto's thyroiditis, Grave's
disease, etc.) do not appear to increase the risk. There has been an increase in thyroid malignancies
(primarily papillary adenocarcinomas) among children in the area around Chernobyl.

1. PAPILLARY ADENOCARCINOMA (65%) - These can arise at any age but tend to present in
young adult females as a non-tender neck mass which is very slow growing and may have

126
 been present for years. A few may be functional, but as a rule, most are not. While some
papillary carcinomas consist solely of papillary structures, many show varying proportions
of follicular elements and a few will be devoid of any papillary structure but possess
characteristic nuclear changes (ground glass or optically clear nuclei) that indicate that
the tumor will behave as a papillary carcinoma. Another useful histologic feature is the
presence of psammoma bodies, small concentric calcifications felt to represent
degenerated papillary tips, which are present in about 50% of the cases. All lesions of the
thyroid which have any element of papillary architecture should be considered
malignant Since some of these tumors are multifocal within the thyroid (intraglandular
metastases?), the diagnosis of papillary carcinoma has treatment implications in that it
becomes prudent to surgically remove the entire gland even though tumor may only be
identified within one lobe. They spread via lymphatics to regional lymph nodes and up to
20% of patients have cervical lymph node inetastases at presentation. There may also be
hematogenous spread to the lungs and bone. Nevertheless, the overall prognosis is
excellent., but the prognosis can be negatively influenced by tumor extension through the
thyroid capsule, increased age of patient, the degree of anaplasia, and the presence of
distant metastases.
2. FOLLICULAR CARCINOMA (25%) - These tend to present in middle-aged females as a firm,
irregular, nodular mass which also grows relatively slowly. It may appear grossly benign
and encapsulated or aggressive and infiltrative. Both forms tend to show central fibrosis
and areas of necrosis, hemorrhage, and cyst formation. The architecture ranges from a well
differentiated glandular pattern to sheets of anaplastic cells. The tumor tends to invade
vessels and spread hematogenously to distant organs (lung, bone, liver, etc). Although the
small, well differentiated encapsulated forms have survival rates comparable to papillary
carcinomas, the less differentiated forms tend to be more aggressive so that there is a
poorer overall prognosis.
3. UNDIFFERENTIATED CARCINOMA (10-15%) - This aggressive tumor occurs in an older
population and is a rapidly growing anaplastic tumor with progressive local invasion and
widespread metastases. The histology varies from an anaplastic spindle cell pattern to a
multinucleated giant cell pattern and may represent dedifferentiation of pre-existing low
grade carcinomas. The average survival from time of diagnosis is less than 6 months.
4. MEDULLARY CARCINOMA (5-10%) - These arise from the parafollicular ("C") cells of
neural crest origin. Most (80-90%) secrete calcitonin, but they have the capability of
secreting a wide variety of polypeptides (ACTH, prostaglandins, etc.). Medullary
carcinomas may arise sporadically or as part of genetically inherited endocrine neoplasia
syndromes. The natural history of the two forms differs but histologically both are similar.
The cells may vary from round to spindle shaped but generally will contain neurosecretory
granules and are arranged in nests surrounded by a fibrovascular stroma which character-
istically demonstrates deposition of amyloid (altered calcitonin molecules) in the tumor
stroma. Although the clinical presentations vary widely, most of the patients have some
degree of diarrhea due to calcitonin or prostaglandin secretion. The strongest predictors
of outcome include the stage and the completeness of excision.

a. Sporadic form - This is the most frequent and tends to present in middle aged
adults as a painless, relatively large solitary mass, 50% of which have metastasized
at the time of diagnosis to regional lymph nodes, lung, liver, or bone. The overall
survival, therefore is about 40% over a 10 year span.
b. Genetic form - 10-15% of the medullary carcinomas are identified in adolescents
as part of the autosomal dominant multiple endocrine neoplasia syndromes and

127
 occur in association with pheochromocytoma and other endocrine tumors. These
tend to be multicentric, bilateral, and smaller. Because of their genetic nature and
association with other endocrine tumors, they are usually identified at an early
stage so that the 10 year survival runs 60-70%.

PARATHYROID

I. REVIEW OF NORMAL - Derived from the pharyngeal pouches, the parathyroid glands tend to lie
posterior to the thyroid gland but may be found in aberrant locations. The major secretory cell is the chief
cell which is also the precursor of the clear (wasserhelle) cells, which have abundant cytoplasmic glycogen,
and the oxyphils, which have increased numbers of cytoplasmic mitochondria. Fat cells accumulate during
childhood and adolescence to comprise about one third of the volume of each gland. After secretion, PTH
(parathormone) is cleaved into an active N-terminal polypeptide chain with a short half-life and a non-
ftmctional (but more easily measured) C-tenninal polypeptide with a longer half-life. PTH maintains serum
calcium levels by regulating renal vitamin D metabolism, increasing renal calcium reabsorption and
phosphate secretion, and increasing reabsorption from the bone stores. Increasing serum calcium levels
have a negative feedback on further PTH secretion.
II. HYPERPARATHYROIDISM

A. PRIMARY HYPERPARATHYROIDISM - This condition is reflected by elevated PTH levels even in

the face of hypophosphatemia, hypercalcemia, and increased urine calcium excretion. Serum
chloride and alkaline phosphatase levels are also increased. Over time, if not recognized and
treated, this will lead to the "stones" of nephrocalcinosis and renal stones; "bones" of bone
demineralization (osteomalacia), osteitis fibrosa cystica (von Recklinghausen's disease of bone),
and "brown tumors"; "moans" of psychiatric disturbances, neurologic abnormalities, and muscle
weakness; and "groans" of peptic ulcers, pancreatitis, and abdominal pains. Hypertension,
chondrocalcinosis, and metastatic calcification of soft tissues may also occur.

1. ADENOMA - This is the most frequent cause of primary hyperparathyroidism and represents
a neoplastic monoclonal proliferation of a parathyroid cell line (generally chief cells but
occasionally clear "wasserhelle" cells or, even less likely, oxyphil cells) which produces an
encapsulated, soft, yellow-tan nodule which is almost always functional. Although multiple
adenomas may infrequently occur (more typically seen in the multiple endocrine neoplasia
syndromes), the vast majority are solitary lesions which are slightly more common in
females and tend to involve the inferior glands. The expanding neoplastic cells displace the
fat cells which are normally present and the non-neoplastic parathyroid tissue becomes
compressed at the periphery of the expanding nodule. In general, the histologic appearance
is usually innocuous but on occasion, large cells with bizarre pleomorphic nuclei can be
observed and should not be misinterpreted as malignant.
2. PRIMARY HYPERPLASIA - Hyperplasia occurs with perhaps more frequency than was
previously recognized, but the etiology has not been clearly elucidated. Most hyperplastic
glands show chief cell proliferation with occasional clusters of oxyphil cells that tend to
crowd out the native fat cells. All four glands are affected but not necessarily equally; the
superior glands tending to be affected more prominently. The less common clear cell
hyperplasias tend to be somewhat larger. Occasionally, only one gland is grossly enlarged
and may be exceedingly difficult to distinguish from an adenoma, but the differentiation
between adenoma and hyperplasia has therapeutic implications in that surgical excision of

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 an adenoma should be curative while with surgical excision of a single hyperplastic gland,
hypercalcemia will persist due to the activity of the remaining glands. If biopsy of another
parathyroid gland shows hyperplastic changes, then all glands should be identified (up to
50% of patients have anomalously located glands) with removal of3 or 3 1/2 glands.
3. CARCINOMA - This is a rare disease. The marked variability in cell morphology that is
occasionally encountered in a benign adenoma may simulate malignant change, so a
diagnosis of carcinoma should be made with caution. Generally, carcinomas are slow
growing and eventually regionally invasive. They show cytologic atypia with increased
mitoses and may demonstrate capsular or vascular invasion. Like many endocrine tumors,
however, the best criterion of malignancy is the demonstration of metastases, but distant
metastases are unusual with this neoplasm.

B. SECONDARY HYPERPARATHYROIDISM - This is due to secondary (compensatory) hyperplasia of

the glands (and elevation of serum PTH) in response to chronic hypocalcemia (usually due to
chronic renal failure) or unresponsiveness of peripheral tissue to the effects of PTH. The glands
are usually smaller than what is seen with primary hyperplasia and if the underlying cause is
corrected within a reasonable period of time, the glandular hyperplasia and associated hormonal
effects are reversible. On the other hand, if the underlying cause persists, the changes may become
irreversible (tertiary hyperparathyroidism).

III. HYPOPARA THYROIDISM - This condition is generally characterized by low PTH, hypocalcemia, and
hyperphosphatemia. On occasion, if the PTH is non-functional or ifthere is target organ unresponsiveness,
serum PTH levels may be normal or elevated. Hypoparathyroidism is most often the result of inadvertent
removal of the parathyroids during thyroidectomy or radical neck dissection. Radiation and primary hypo-
functioning (probably an autoimmune process) of the glands are less common causes. Clinical symptoms
include weakness, paresthesias, muscle cramps or tetany, cataracts, headache, and abdominal pain.
Pseudohypoparathyroidism is a familial syndrome resulting from an end-organ resistance to PTH. It is
characterized by normal or high levels of biologically active PTH in the face of hypocalcemia,
hyperphosphatemia, and elevated alkaline phosphatase. Patients may also develop skeletal and
developmental defects.
IV. MASS EFFECTS - Even the largest of parathyroid adenomas rarely cause clinical symptomatology.

ADRENAL CORTEX

I. REVIEW OF NORMAL - The adrenal cortex is derived from mesodermal cells of the urogenital ridge.
Its yellow-brown color is due to lipochrome pigments and the lipid precursors (primarily cholesterol and
cholesterol esters) of the steroid hormones.

A. ZONA GLOMERULOSA - The outer layer of the cortex consists of clusters of cuboidal cells with
dark nuclei and scanty cytoplasm containing few lipid droplets. These cells produce
mineralocorticoids (aldosterone) which act on the kidney to promote secretion of potassium and
retention sodium and water. Mineralocorticoid secretion is regulated primarily by serum potassium
levels and the renin-angiotensin system and, under normal conditions, does not respond directly
to increased ACTH to any significant extent.
B. ZONA FASCICULATA AND ZONA RETICULARIS - Although there is a histologic distinction between
these two zones, their functional activity is entertwined. The zona fasciculata, the middle layer of
the cortex, consists of columns of cells with dark nuclei and fmely vacuolated clear cytoplasm

129
 containing the lipid precursor (mainly cholesterol) of the steroid hormones. The inner layer of the
cortex, the zona reticularis contains irregular clusters of darkly staining "compact" cells with
cytoplasmic lipochrome pigment but no vacuoles. As classically taught, the cells of the zona
fasciculata produce glucocorticoids (cortisol) and those of the zona reticularis produce androgenic
steroids (testosterone). More likely, the zona fasciculata and zona reticularis work in tandem with
cells of the fasciculata providing the storage depot for the lipid precursor substances. During times
of increased production, the zona fasciculata decreases in thickness due to cytoplasmic lipid
depletion while the zona reticularis increases in thickness due to increased production demands.
The glucocorticoids act to increase appetite and promote fat deposition in the face, neck, and trunk;
increase protein breakdown and nitrogen excretion; increase gluconeogenesis in liver (but inhibit
glucose uptake by muscle); impair the inflammatory response by inhibiting leukocyte margination
and pavementing and by inhibiting phagocytes; impair the immunologic response by lysing T cells;
and interfere with water transport into cells thereby increasing extracellular fluid volume. The
androgenic steroids act to promote masculinization and inhibit feminization. Hypothalamic CRF
stimulates pituitary corticotrophs to release ACTH which causes the zona fasciculata and reticularis
to secrete glucocorticoids and androgens. The cleavage of ACTH from a larger polypeptide chain
(pro-opiomelanocortin) also liberates melanotropins; therefore increased ACTH production from
the pituitary causes not only adrenal cortical hyperplasia but also hyperpigmentation of the skin due
to increased melanotropins. Cortisol has a negative feedback on the pituitary and hypothalamus.

II. MAJOR PATHOLOGIC CONDITIONS

A. CORTICAL HYPERPLASIA - This is generally the result of pituitary hypersecretion of ACTH, but
may also occur in cases of ectopic production of ACTH. Hyperplasia is a bilateral process and the
adrenals often show multiple hyperplastic nodules in the cortex.
B. ADENOMA - These are relatively common but most are nonfunctional. Grossly, they appear as
expanding, yellow-orange nodules of varying size usually containing lipid-laden cells resembling
the cells of the zona fasciculata admixed with a few cells resembling the zona reticularis. Small
well-differentiated lesions may be difficult to distinguish from a simple focus of nodular hyper-
plasia while the larger adenomas may show hemorrhage, calcification, or cystic degeneration and
be difficult to distinguish from carcinomas.
C. CARCINOMA - Although rare, these tumors are highly malignant with a 5-year survival rate of only
about 15-20%. Despite the fact that most are functional, they are usually large and infiltrative when
first discovered, although some may be difficult to distinguish from a large adenoma. They have
a propensity to invade veins and lymphatics and can disseminate widely.

III. HYPERADRENALISM

A. EXCESS GLUCOCORTICOIDS (CUSHING'S SYNDROME) - This syndrome typically presents in middle

age females and, in its fully developed form, is characterized by moon facies, buffalo hump, truncal
obesity, abdominal stria, hirsutism, menstrual disorders, emotional lability, easy bruisability,
susceptibility to infection, impaired glucose tolerance, muscle weakness, osteoporosis, etc. The
diagnosis of Cushing's syndrome requires the demonstration of excess cortisol and the lack of
suppression of cortisol secretion by dexamethasone, a potent glucocorticoid which suppresses
ACTH.

1. PRIMARY HYPERCORTISOLISM - This is associated with a low serum ACTH and is due
to either a cortisol-secreting cortical neoplasm (in which case, the contralateral adrenal

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 gland will usually be atrophic) or, occasionally, bilateral nodular hyperplasia (apparently
the result of factors other than ACTH stimulation).
2. SECONDARY HYPERCORTISOLISM - This is associated with high serum ACTH and is due
to an ACTH-producing pituitary adenoma (Cushing's disease). It may also result from
ectopic production of ACTH. This generally leads to bilateral diffuse or nodular adrenal
cortical hyperplasia in which the zona reticularis (and to a lesser extent the zona
fasciculata) is expanded.
3. IA TROG ENIC - Chronic exogenous corticosteroid use may produce the clinical
manifestations of Cushing's syndrome but treatment usually is discontinued, if possible,
before deleterious side effects occur. Administration of exogenous steroids, however, is
the most common cause of adrenal cortical atrophy (mostly of the zona fasciculata and
zona reticularis) due to suppression of pituitary ACTH.

B. EXCESS ANDROGENS (ADRENOGENITAL SYNDROMES)

1. INHERITED (AUTOSOMAL RECESSIVE) DISORDERS - These disorders affect the activity of

various enzymes in the steroidogenesis pathway resulting in congenital adrenal
hyperplasia. The metabolic defects all block the production of cortisol thereby eliminating
the negative feedback on the pituitary, increasing the serum ACTH, and leading to bilateral
diffuse or nodular hyperplasia. Clinical features include:

a. Virilizing - Partial 21 hydroxylase deficiency shunts the steroid pathway away

from cortisol production and toward androgen production. In females, this
presents as virilization of infants or, if less severe, as infertility problems after
puberty. In males, this produces precocious puberty.
b. Virilizing and salt losing - 21 hydroxylase deficiency shunts the steroid pathway
away from cortisol production and toward androgen production, but it also
interferes with aldosterone production leading to hyponatremia and hyperkalemia.
c. Virilizing and hypertensive - 11 hydroxylase deficiency shunts pathway away
from cortisol and toward androgens as well as causing buildup of an aldosterone
precursor which is a potent mineralocorticoid. This causes hypokalemia, hyper-
natremia, and hypertension.

2. ANDROGEN SECRETING NEOPLASM - Neoplasms that secrete androgens are more likely
to be carcinomas as opposed to adenomas.

C. EXCESS MINERALOCORTICOIDS - This will produce metabolic derangements characterized by

hypernatremia and hypertension, hypokalemia and hypokalemic alkalosis, and increased urine
potassium.

1. PRIMARY HYPERALDOSTERONISM (Conn's syndrome) - This is most frequently seen in

middle aged females and presents as moderate hypertension (due to the hypernatremia)
which may be associated with chronic fatigue and weakness (rarely paralysis) and cardiac
arrhythmias due to hypokalemia. Due to elevated aldosterone levels, the serum rellill
levels are depressed. The most common cause is an aldosterone-secreting cortical
adenoma; but occasionally idiopathic bilateral adrenal hyperplaSia (primarily a childhood
disorder) may be responsible.
2. SECONDARY HYPERALDOSTERONISM - This results from the persistent stimulation of renin
secretion (as the byproduct of renal ischemia, hypovolemia, or renin producing tumors)

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 and is therefore associated with increased levels ofrenin. Clinical signs and symptoms are
similar to primary hyperaldosteronism.

IV. HYPOADRENALISM

A. PRIMARY CHRONIC ADRENOCORTICAL INSUFFICIENCY (Addison's Disease) - This results from

any chronic destructive process that destroys more than 90% of cortical tissue. Clinically, there is
an insidious onset of weakness and fatigue, anorexia, weight loss, nausea and vomiting, hypo-
tension, and hyperpigmentation of skin. Eventually, serum Na+, CI" HC0 3-' and glucose levels fall
while serum K+ increases. Serum cortisol and urine cortisol (l7-hydroxycorticosteroids) are
decreased in primary adrenocortical failure but the lack of adrenal response to ACTH stimulation
must be demonstrated before the diagnosis can be made.

1. IDIOPATHIC ATROPHY - Probably autoimmune in origin, this may occur as an isolated

disease but not infrequently occurs in association with other autoimmune diseases as part
of a spontaneous or inherited clinical syndrome. A majority of these patients have auto-
antibodies to adrenal antigens. Grossly the glands are small with a thin, atrophic cortex
draped around a relatively normal appearing medulla. Microscopically, there are atrophic
and degenerated cortical cells, foci of fibrous scarring, and a variable lymphocytic
infiltrate.
2. DESTRUCTNE OR INFILTRATWE PROCESSES - This includes tuberculosis (once the leading
cause of Addison's disease but now responsible for less than 20%), metastatic tumors,
infection, trauma, hemorrhage, amyloid, etc. The glands are usually grossly enlarged but
microscopically show extensive cortical destruction.

B. SECONDARY ADRENOCORTICAL INSUFFICIENCY - This is the result of decreased ACTH secretion

from the pituitary from whatever cause. Since ACTH levels are low, these patients lack the
cutaneous hyperpigmentation and the other clinical features are usually less striking than those in
Addison's disease. Also, the zona glomerulosa is not affected so there will be little or no signs of
hypoaldosteronism. For the diagnosis to be conclusively established, the capacity of the adrenals
to respond to exogenous ACTH must be demonstrated.
C. ACUTE ADRENAL INSUFFICIENCY

1. ADDISONIAN CRISIS - This can develop in patients with Addison's disease who experience
sudden stress (trauma, infection, surgery, etc.). This may lead to hypotension, shock, and
vasular collapse.
2. IATROGENIC - This is caused by abrupt withdrawal of exogenous steroids in a patient
whose cortex has been suppressed by these drugs or inadequate steroid administration to
a patient with non-functioning adrenals.
3. HEMORRHAGE - This usually is the result of trauma (especially in newborns);
anticoagulant therapy; or bacteremia (Waterhouse-Friderichsen syndrome). In the latter,
patients develop fever and extensive total body hemorrhage manifested as petechia and
purpura on skin and mucus membranes. This is followed by circulatory collapse and death
unless appropriate intervention is available.

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 DIFFUSE ENDOCRINE SYSTEM

The observation that some endocrine tumors could secrete hormones other than their native hormone and that some
non-endocrine tumors could secrete hormones or hormone-like substances, led to the postulation of a diffuse
endocrine system arising from a common precursor. Indeed, a diffuse distribution of cells called "neuroendocrine"
or APUD (Amine £recursor Uptake and Decarboxylation) cells has been identified (particularly in the GI and
respiratOlY tracts) that have many physical similarities by EM (neurosecretory granules, etc). Originally felt to be
derived from cells that migrated from the neural crest to endocrine glands during embryogenesis, it is now felt that
some cells are somehow secondarily programmed by the neural crest and/or that non-endocrine tissues, undergoing
neoplastic transformation, may develop the capability to express polypeptide hormones either through gene
rearrangement or "derepression" of a preexisting gene. Tumors of the diffuse endocrine system often come to
clinical attention as the result of hyperplastic or neoplastic functional activity, but also may present simply as
unexplained mass lesions.

I. PARAFOLLICULAR "c" CELLS - These cells give rise to the thyroid medullary carcinomas [see
Thyroid Section].
II. GANGLION CELLS and PHEOCHROMOCYTES - These are the differentiated neural crest cells of
the adrenal medulla but also occur in other locations. Normally, the cells of the adrenal medulla produce
and store catecholamines (epinephrine and norepinephrine). Urinary metabolites of the catecholamines
include metanephrine, normetanephrine, vanillylmandelic acid (VMA), and homovanillic acid (HV A).
These cells may give rise to:

A. NEUROBLASTOMA - Derived from the ganglion cell line, this is one of the more common tumors
of childhood and, in general, is confined to the pediatric age range. Although they can occur in a
variety of locations, most arise in the adrenal medulla (50-80%) or the posterior mediastinum.
Usually, the tumors are bulky and soft with areas of hemorrhage and necrosis. They may also have
areas of calcification which may serve as a radiographic clue. Histologically, these are one of the
"blue tumors" of childhood consisting of small round cells with scant cytoplasm and
hyperchromatic nuclei which tend to grow in a largely disorganized manner. The classic histologic
feature is the presence of Homer-Wright rosettes although these are not always present. At the time
of diagnosis, the tumors of infancy are generally localized tumors but those occurring after the age
of two years have often metastasized widely with predilection for bone marrow and liver. In
infants, the tumor sometimes mature into a ganglioneuroblastoma or a ganglioneuroma, and on
rare occasions, spontaneous remissions have been reported in infants, even those who had
widespread metastases (excluding bone metastases). Generally, however, the prognosis for patients
older than 2 years is poor. Clinically, presenting symptoms are usually due to rapid tumor growth
or the effects of metastases (weight loss, abdominal mass, malaise). Although patients generally
are not hypertensive, most neuroblastomas secrete norepinephrine and the urinary metabolites will
be elevated.
B. PHEOCHROMOCYTOMA - Derived from pheochromocytes, these are more frequently seen in
middle aged adults. There is some suggestion that the tumors arise from a progressive sequence
of diffuse hyperplasia -> nodular hyperplasia -> neoplasia. Known as the" 10% tumor", 10% are
extra-adrenal (primarily located below the diaphragm in the periaortic ganglia or organ of
Zuckerkandl), 10% are bilateral, 10% are malignant (more likely with the extra-adrenal forms), and
10% are inherited as an isolated autosomal dominant disease or in association with other endocrine
neoplasms (multiple endocrine neoplasia syndromes - see below). Grossly, the tumors vary greatly
in size but are generally round and well demarcated from the surrounding adrenal tissue. As they
grow larger, they tend to develop areas of necrosis and hemorrhage. Microscopically, tumor cells

133
 may be highly pleomorphic but generally have an abundant cytoplasm containing granules of stored
catecholamines and are arranged in a trabecular or alveolar pattern with rich vascularity and thin
fibrous stroma. The histologic appearance, however, does not accurately predict behavior.
Clinically, these patients may present with sustained hypertension, sustained hypertension with
paroxysms of severe hypertension, or intermittent hypertension. Sudden release of catecholamines
(primarily norepinephrine) into the circulation may result from manipulation of the tumor, stress,
postural changes, etc., and result in paroxysms of hypertension, diaphoresis, anxiety, nausea and
vomiting, abdominal pain, tremors or, more ominously, MI or CV A. Urinary catecholamines,
metanephrine, and VMA are elevated.

III. PARAGANGLION CELLS - These are similar to the pheochromocytes but are scattered throughout the
body associated with the autonomic nervous system. Paragangliomas are rare tumors but, like
pheochromocytomas, have the capacity to secrete catecholarnines. Those derived from the parasympathetic
chemoreceptor system (carotid body tumors, glomus jugulare tumors, aortic body tumors, etc.) tend to
be nonfunctional tumors. Those derived from the abdominal aorticosympathetic paraganglia (retro-
peritoneal paragangliomas or extraadrenal pheochromocytomas) are more likely to be functional tumors.
Generally, they are benign but some may recur locally and, rarely, a few may metastasize widely.
IV. MERKEL CELLS - These are present in the basal layer of the epidermis and can be the origin of a rare
skin carcinoma predominantly of the head and upper extremities in elderly patients. Microscopically, these
show features of small cell endocrine neoplasms, and electron micrographs demonstrate neurosecretory
granules. Elaboration of endocrine substances, however, is not generally seen. These tumors may
disseminate widely and prove fatal in 15-20% of cases.
V. ENTEROCHROMAFFIN CELLS - These give rise to carcinoid tumors (argenta..ffinomas). Occurring
most frequently in the GI tract (appendix, small bowel, rectum), these potentially malignant tumors may
be found anywhere "neuroendocrine" cells are encountered (bronchi, esophagus, biliary tract, pancreas,
ovaries, and urinary tract). They tend to be small mucosal lesions that occasionally are multiple. On cut
section, they have a yellow or gray, firm appearance and are composed of nests, strands, or sheets of small
monotonous cuboidal cells which penetrate the submucosa and tend to invade the deeper tissues. They may
be asymptomatic or produce symptoms related to local invasion, obstruction (from desmoplastic tissue
response to the neoplasm), or elaboration of secretory products. The metastatic potential seems to be
related to the site of origin, the depth of penetration of the tumor, and its size (> 2cm). A majority of extra-
appendiceal carcinoids are associated with metastases to regional lymph nodes or to the liver at the time
of diagnosis. In patients who have metastatic liver involvement from intestinal carcinoids or who have
extra-intestinal carcinoids, a symptom complex known as carcinoid syndrome may occasionally occur. This
is characterized by vasomotor disturbances (transient flushing and cyanosis of the skin), intestinal hyper-
mobility (diarrhea, cramps, nausea, vomiting), bronchoconstriction (cough, dyspnea, wheezing), cardiac
involvement (endocardial fibrosis and valvular deformity of the right side of heart) and hepatomegaly (from
hepatic metastases). These symptoms are probably mediated by tumor secretion of serotonin (5-
hydroxytryptamine), histamines, and kinins. Increased levels of 5-hydroxyindolacetic acid (5-HIAA), a
metabolic product of serotonin, may also be found in the serum and urine. 5-year survival in appendiceal
carcinoids approaches 100%, rectal carcinoids 85% and gastric, small bowel, and colonic carcinoids 50%.
In patients who have the carcinoid syndrome, however, the disease tends to be progressive with an
ultimately fatal outcome.
VI. PANCREATIC ISLET CELLS - Normal islets consist of ex cells (glucagon secretors), p cells (insulin
secretors), 0 cells (somatostatin secretors), and PP (pancreatic polypeptide) cells (secrete polypeptides
whose functions are not well defined). Other non-hormone producing cells have been identified including
enterochromaffm cells from which pancreatic carcinoid tumors arise and D 1 cells which secrete vasoactive
intestinal peptide (VIP).

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A. DIABETES MELLITUS - This is probably the most common endocrine disease and affects as much
as 2% of the general population in the United States. The disorder results from a deficiency in
production of insulin and/or end organ unresponsiveness to insulin. The genetic code for insulin
(produced by the beta cells of the pancreatic islets) resides on short arm of chromosome 11. Insulin
is an anabolic hormone involved not only in carbohydrate metabolism but in protein and lipid
metabolism as well. Its primary role is to increase rate of glucose transport into fibroblasts, adipose
cells, and striated muscle, but it also functions to promote glycogen formation in the liver and
skeletal muscle, convert glucose to triglycerides, and promote nucleic acid and protein synthesis
(stimulating cell growth and differentiation). Although other compounds can stimulate insulin
release, hyperglycemia is the primary stimulus for the synthesis and release of insulin. Since, in
diabetes, there is interference with carbohydrate metabolism, attempts to supply an alternate form
of energy (metabolism of lipids and protein) produces a metabolic acidosis (ketoacidosis). Over
a period of time, hyperglycemia (a common feature of diabetes mellitus) can lead to non-enzymatic
glycosylation of various proteins (including collagen) leading in some cases to irreversible
structural or functional alterations of various tissues. Glycosuria produces an osmotic diuresis
leading to electrolyte imbalances and dehydration.

1. GESTA TlONAL DIABETES (GDM) - This refers to glucose intolerance that appears for the
first time during pregnancy, and occurs in 3-5% of all pregnancies. The major impact of
GDM is the increased morbidity and mortality for the offspring. These risks can be
reduced or eliminated by control of maternal hyperglycemia, which can usually be
accomplished with diet alone. Screening for GDM at 24 to 28 weeks gestation is
recommended for all pregnant women. A screening test for GDM is measurement of
venous plasma glucose one hour after 50 g oral glucose challenge. Women with a positive
screening test (plasma glucose> 140 mg/dL) should have an oral glucose tolerance test
(OGTT) to confirm the diagnosis ofGDM.
2. TYPE I (JUVENILE ONSET, INSULIN DEPENDENT) - This is seen in 15% of diabetics and is
the result of inadequate production of insulin. The mass and number of p cells in the
pancreatic islets are reduced. In chronic states there is severe atrophy of islets and virtual
absence of p cells. These individuals may have a genetic predisposition to developing both
cytotoxic T cells and autoantibodies to p cells which becomes expressed when triggered
by some environmental factor (viral?, chemical?).
3. TYPE II (ADULT ONSET, NON-INSULIN DEPENDENT) - This is, by far, the more common
form of diabetes mellitus. In these patients, although there may be a deficiency or delay in
insulin secretion from the beta cells, there is also an end-organ resistance to the effect of
insulin. There is a decrease in the number of cellular insulin receptor sites as well as
functional abnormalities in the receptor activities. This type of diabetes has a strong genetic
component, but it is not well understood. Often, these patients are obese (which hampers
insulin action even in non-diabetics) but do not need insulin injections. Microscopically,
the pancreatic islets are normal in number but show variable degrees of hyalinization (this
may also occur in non-diabetic patients and is not diagnostic). Fibrosis of the islets also
may occur.
4. COMPLICATIONS - For the most part, diabetic complications are due to structural changes
to the macro- and microvasculature and to metabolic disturbances.

a. Macrovascular cbanges - These complications are the result primarily of an

accelerated development of atherosclerosis and include myocardial infarcts (the
leading cause of death in Type II), cerebrovascular accidents, and peripheral
vascular ischemic disease.

135
b. Microvascular changes - These contribute to the frequently associated
nephropathy, opthalmopathy, and neuropathy.

(1) Nephropathy (the leading cause of death in Type I) - This is usually

heralded clinically by proteinuria and followed by azotemia leading to
renal failure within five years. Major histologic changes include
arteriolosclerosis of afferent and efferent arterioles; glomerulosclerosis
(although not the most frequent pattern, nodular glomerulosclerosis, or
Kimmelstiel-Wilson disease, is virtually diagnostic of diabetes);
pyelonephritis; and necrotizing papillitis.
(2) Ophthalmopathy - Diabetic retinopathy is one of the more common
causes of blindness in the United States. The retina is supplied by a
network of interlacing vessels whose arterioles develop hyaline thickening
and whose capillaries develop basement membrane thickening and
increased permeability. Degeneration of vascular pericytes contribute to
the formation of micro aneurysms which may rupture or leak serum to
produce the retinal exudates and hemorrhage seen clinically. Basement
membrane thickening and increased vascular permeability reduces blood
flow and stimulates proliferation of new, but poorly formed, vessels
between the vitreous and the inner tissue layer of the retina (retinitis
prol~rerans). Leakage of serum and hemorrhages from these poorly
formed vessels ultimately result in fibrosis which tends to pull the retina
from the underlying anchoring choroid causing retinal detachment.
Cataracts and glaucoma are also more frequently seen in diabetics.
(3) Neuropathy - Damage to Schwann cells and axons by unknown
mechanisms (vascular ischemia or metabolic abnormalities may playa
role) produce a variable presentation (unilateral vs. bilateral, peripheral vs.
cranial vs. autonomic, transient vs. permanent, etc.) but most frequently
produces motor and sensory deficits of the lower extremities. A common
manifestation is the neuropathic ulcer occurring along the pressure points
of the sole of the foot.

c. Ketoacidosis - This is most likely to occur in Type I diabetes and is basically a

defect in lipid metabolism. With a deficiency of insulin, there is mobilization of
adipose tissue resulting in increased free fatty acids. Glucagon (which is in excess)
increases hepatic oxidation of the fatty acids to produce ketone bodies. Amino
acid uptake by muscle is inhibited and protein catabolism occurs giving a negative
nitrogen balance. Increased ketogenic amino acids in the serum compounds the
problem. Since cellular uptake of glucose is inhibited, as glucose levels rise water
and electrolytes are drawn out of the cell and excreted in the urine causing
dehydration and contributing to the developing metabolic acidosis. The patients
may lapse into unconsciousness and have a "fruity" odor to the breath and labored
Kussmaul breathing.
d. Miscellaneous - Other complications include increased risk of infection, poor
wound healing and necrobiosis lipoidica (atrophy and ulceration of the skin of the
lower legs).

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 B. PANCREATIC ISLET CELL TUMORS - Islet cell tumors may be solitary or multiple, functional or
non-functional, benign or malignant.

1. INSULINOMA (p cell tumor) - This is the most common islet cell tumor. The majority of
insulinomas (70%) are solitary adenomas. Although they can reach a very large size, they
rarely exceed 5-6 cm in diameter and may even be grossly unnoticeable. Round, firm,
encapsulated nodules are composed of nests and cords of normal appearing p cells. 10%
prove to be malignant tumors but, in general, islet cell tumors should not be considered
malignant until there is evidence of metastases. Although most insulinomas secrete insulin,
only about 20% ever become clinically apparent. Although fewer in number, the malignant
tumors tend to be more hormonally active. Symptoms, when they occur, are related to
hypoglycemic episodes that are temporally related to periods of high glucose utilization
(fasting, exercise). This may cause stupor and loss of consciousness and can be aborted
by administration of glucose.
2. GASTRINOMA - Although a gastrin producing cell has not been identified in the normal
pancreas, certain tumors of pancreatic islet-cell origin have been shown to secrete gastrin
and appear similar to the gastrin-secreting cells of the intestine and stomach which can
also, but less frequently, form gastrin-secreting tumors (predominantly duodenal). These
tumors are associated with gastric acid hypersecretion from hyperplastic gastric parietal
cells responding to the increased gastrin stimulation. The hypersecretion of gastric acid
results in intractable peptic ulceration of duodenum, stomach, and jejunum
(Zollinger-Ellison syndrome). In addition, these patients develop fluid and electrolyte
disturbance secondary to diarrhea and malabsorption. Slightly over 50% of the gastrinomas
are malignant with most showing metastases at the time of diagnosis. The remainder are
benign adenomas that may be associated with other endocrine tumors.

MUL TIPLE ENDOCRINE NEOPLASIA SYNDROMES

I. MEN I (Wermer syndrome) - This consists of hyperplasia or neoplasia of the pituitary, parathyroid, and
pancreatic islet cells and is frequently associated with the Zollinger-Ellison syndrome. Less often, the
thyroid and adrenal cortex may also be involved.
II. MEN II

A. MEN IIa (Sipple syndrome) - This consists of pheochromocytoma, thyroid medullary carcinoma,
and occasionally parathyroid adenoma or hyperplasia.
B. MEN lIb (sometimes classified as MEN III) - This is the same as MEN lIa but without parathyroid
disease and with the addition of multiple mucocutaneous neuromas. It tends to run a somewhat
more aggressive course.

III. CLINICAL PRESENTATION - These syndromes are inherited in an autosomal dominant pattern.
Clinical signs and symptoms are variable but may include hypertension (pheochromocytoma), ulcers
(gastrinoma), Cushing's syndrome (adrenal cortical hyperplasia/adenoma), hypercalcemia (parathyroid
hyperplasia/adenoma), hypoglycemia (insulinoma), or mass effects (medullary carcinoma).

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 BREAST

I. REVIEW OF NORMAL

A. ANATOMIC STRUCTURE - At about six weeks gestation, bilateral thickening of the epidermis forms
ridges (milk lines) running between the upper and lower limb buds along ventral surface of body.
These ridges progressively atrophy except for the superior portions which give rise to nipples. At
birth, rudimentary branching ducts have developed from the basal epithelium of the nipple.
Prepubertal ductal development progresses slowly, and at puberty, essentially ceases in the male.
Female breasts however, in response to increasing sex hormone levels, undergo proliferation of
the fibrous interductal stroma (giving bulk), and rapid ductal growth and branching ultimately
developing rudimentary gland buds emanating from small terminal ductules. This yields 15-20
separate wedge shaped lobes each of which drain to the nipple by a lact(ferous (collecting) duct.
The nipple and outer portion oflactiferous ducts are lined by stratified squamous epithelium which,
as ducts get smaller, changes to a pseudostratified columnar epithelium (segmental ducts), then
a double layered cuboidal epithelium (subsegmental ducts), and finally a flattened cuboidal
epithelium encircled by a layer of myoepithelial cells (terminal ducts and ductules). The terminal
ductules and the gland buds (terminal duct-lobular unit) are embedded in a loose myxomatous
stroma (peri ductal and intralobular connective tissue) and individual lobules are separated by a
more dense fibrous (interlobular) stroma. This epithelial-stromal parenchyma is embedded within
variable amounts of adipose tissue. Fibrous stromal condensations (Cooper's ligaments) suspend
and anchor the breast to the deep fascia of the thoracic wall. Not uncommonly, breast parenchyma
may extend past .the anterior axillary line and into the axilla but is of no significance except that
benign mass lesions may be mistaken for tumor metastases to axillary lymph nodes.
B. PHYSIOLOGIC CHANGES - Under estrogen influence, the epithelium of the terminal ductules and
gland buds proliferate. Increased progesterone levels during the latter part of menstrual cycle
stimulate intralobular stromal growth and edema (clinically resulting in swollen tender breasts).
With the rapid decline in estrogen and progesterone levels at the time of menses, these changes
regress. The breast, however, does not develop complete physiologic or anatomic maturation until
onset of pregnancy. Under the influence of placental hormones, numerous secretory glands branch
out from gland buds so that with increased gestational age, the breast lobules becomes packed with
secretory glands which are lined by a single layer of cuboidal cells and obscure the stromal
component of the breast parenchyma. During the 3rd trimester, increasing prolactin levels initiate
secretory activity and immediately following birth, milk secretion begins. After lactation the glands
regress and atrophy, but the breast does not completely revert back to the pre-parous state. At
menopause, there is further ductular and glandular atrophy which may result in the appearance of
small cysts (cystic atrophy) and replacement of the fibrous stroma by adipose tissue.

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II. DEVELOPMENTAL DISORDERS - Failure of the embryologic milk line to regress may lead to
supernumerary nipples (polythelia) or breasts (polymastia) which, in addition to cosmetic concerns, are
also subject to diseases of breast. Congenital inversion of the nipple may simulate, and must be
distinguished from, the nipple retraction sometimes seen in association with breast malignancies.
III. HYPERTROPHY (Since most of these changes include a hormonally driven increase in the number of
epithelial cells, hyperplasia might be a more accurate term.)

A. NEONATAL - During gestation, maternal honnones stimulate proliferation of ductal epithelium and
periductal connective tissue and, on occasion, there may be abortive secretory activity. These
changes quickly regress after birth due to withdrawal of hormonal support.
B. PREPUBERTAL - Usually bilateral, this suggests excess estrogen activity (ovarian or adrenal disease,
pituitary tumors, etc). These changes usually regress with correction of the underlying problem and
lowering of hormone levels.
C. VIRGINAL - Although of obscure etiology, this may be related to increased sensitivity of breast
tissue to honnonal stimulation. It may be unilateral or bilateral, generally does not regress, and may
require reduction mammoplasty.
D. GYNECOMASTIA - Hypertrophy of the male breast is usually due to excess estrogen levels (most
often due to hepatic cirrhosis, lung carcinoma, estrogen therapy, testicular tumors, aging, etc) or
high prolactin levels (pituitary tumors).

IV. INFLAMMATORY DISEASE

A. ACUTE MASTITIS - Although most commonly seen in women who are lactating, it may also be
secondary to various skin diseases involving the nipples. Cracks or fissures in the nipple provides
a portal of entry for bacteria - usually staph (which tends to cause localized inflammation and
abscess fonnation) and, less commonly, strep (which tends to cause diffuse, spreading cellulitis).
Usually unilateral, the breast is red, swollen, and painful. Tissue necrosis with resultant scar
formation may lead to nipple retraction or dimpling of the skin and later be mistaken for
carCInoma.
B. PLASMA CELL MASTITIS (mammary duct ectasia) - Uncommon and of obscure etiology, this may
be due to inspissated lipids causing chronic obstruction and ultimate rupture of major excretory
ducts. Most women with this disorder have borne children and many have had problems with
nursing. This usually occurs perimenopausally and is characterized clinically by an ill-defined area
of pain, tenderness, stringy induration, and occasional axillary lymphadenopathy. Dilated ducts
(single or multiple) contain cellular debris and lipid-laden macrophages, and show erosion of the
duct epithelium with marked periductal and stromal granulomatous inflammation comprised of
large numbers of plasma cells.
C. FAT NECROSIS - This is a localized, often granulomatous, inflammatory reaction to necrosis of fatty
tissue. Initially there are foamy, lipid-laden macro phages and a neutrophilic infiltrate but, with
resolution, a dense fibrous scar develops which may contain dystrophic calcifications or cause skin
dimpling or nipple retraction. Fat necrosis has little clinical significance except for its potential
confusion with cancer.
D. GALACTOCELE - This is a cystic dilatation of excretory ducts, often multiple, due to duct
obstruction during lactation. Acutely tender, these may develop into abscesses if they become
infected.

v. FIBROCYSTIC CHANGE - The most common "disorder" of the breast is the result of exaggeration and
distortion of nonnal cyclic alterations that occur during the menstrual cycle and most frequently becomes
symptomatic in mid to late reproductive life. Initial manifestations are uncommon before puberty or after

139
 menopause. Most likely related to relative hyperestrinism (reflected by overstimulation of terminal ductal
epithelium and stromal growth) and/or an abnormal end-organ response to hormones, there is a wide
variability in clinical manifestations, gross appearance, and histology.

A. FIBROSIS (increased stromal fibrous tissue without epithelial hyperplasia) - This is a common
denominator in most patients with fibrocystic disease but when occurring as an isolated lesion (an
infrequent occurrence), it often presents as a unilateral, upper outer quadrant, poorly defined,
rubbery, mobile mass which may be tender to palpation (especially prior to menses). Proliferation
of fibrous stroma compresses terminal ducts and glands with obliteration of periductal and
intralobular loose connective tissue. There is no predisposition to subsequent malignancies.
B. CYSTIC CHANGE - Stromal hypertrophy and progressive hyperplasia and dilatation of terminal
ducts without complete regression after menses results in a diffuse ill-defined increase in tissue
consistency punctuated by discrete nodules. Usually multifocal and often bilateral, these macrocysts
(>0.3 cm) may produce pain and tenderness (especially prior to menses). Solitary cysts, however,
may be clinically confused with cancer especially if micro calcifications develop in the wall.
Grossly, cysts may be brown or blue (blue dome cysts) depending on the fluid contained within.
Cysts are usually lined by flattened epithelium but apocrine metaplasia is not uncommon and is
almost always an indicator of benignity. The presence of cysts does not imply any increased risk
for the development of subsequent malignancy.
C. ADENOSIS - Intralobular fibrosis with proliferation of terminal ducts and gland buds results in a
firm, relatively well defined, possibly tender or painful, mass lesion that tends to manifest
unilaterally in the upper outer quadrant. Often, but not always, it is associated with other cystic
changes. Florid ductuIar proliferation may result in "back-to-back glands" (adenosis) and fibrosis
may compress ducts into apparent nests and ribbons of epithelial cells (sclerOSing adenosis) easily
confused with cancer. Adenosis, however, does not carry an increased risk for subsequent
development of malignancy.
D. EPITHELIAL HYPERPLASIA - Hyperplasia of the terminal duct and intralobular ductular epithelium
may cause increased thickness of the epithelium or produce papillary projections into the lumens
which may be focal or more generalized (ductal papillomatosis). In general, these changes do not
cause discrete mass lesions but are often associated with other fibrocystic changes that do. Micro-
calcifications may be present. The association between jibrocystic disease and breast cancer is
proportional to the degree ofepithelial hyperplasia and atypia. Mild hyperplasia (3-4 cells thick)
does not carry increased risk. Moderate or florid hyperplasia (> 4 cells thick) carries l.5-2 times
risk. Atypical hyperplasia carries 5 times the risk.

VI. BENIGN AND BORDERLINE NEOPLASIA

A. FIBROADENOMA - Possibly the result of focal hypersensitivity to estrogen, this is the most common
benign breast tumor. They tend to occur in young women under the age of 35 and typically
present as a solitary, well defined, discrete, rubbery, mobile 2-4 cm mass arising in the upper outer
quadrant. Histologically there may be a prominent glandular component (pericanalicular), a
prominent stromal pattern (intracanalicular), or a mixture of the two. Large (10-15 cm), bulky,
lobulated, giantfibroadenomas may deform the breast causing pressure necrosis and ulceration
of overlying skin.
B. PHYLLODES TUMOR (CYSTOSARCOMA PHYLLODES) - Although similar to fibroadenomas, these
tend to have a more cellular myxoid stroma (which unlike the fibroadenoma is monoclonal) and
which, in a minority of cases, may become malignant resulting in a sudden and rapid increase in
size. Histologic appearance, however, does not presage biologic behavior very well. Both benign
and malignant forms tend to recur after excision. Malignant cystosarcoma, however, tends to

140
 remain localized for prolonged periods and eventually metastasizes to distant sites in only 10-15%
of cases. In general, phyllodes tumors behave favorably if the tumor is < 5 cm and the patient <
20 years old.
e. INTRADUCTAL PAPILLOMA - Usually occurring in the lactiferous duct of middle aged to elderly
females, these are solitary papillary neoplasms. They may produce a watery or bloody nipple
discharge and a small subareolar mass. Rare cases may show malignant change (intraductal
papillary carcinoma) and become invasive but usually have little or no involvement of the axillary
lymph nodes, and the prognosis is generally good.
D. NIPPLE ADENOMA - Occurring most often in elderly women, these represent benign sweat gland
tumors (hidradenoma papill?ferum) that produce a mass immediately beneath nipple and may lead
to nipple ulceration.

VII. MALIGNANT NEOPLASIA - Second only to lung cancer as the leading cause of cancer deaths in
women, 8-11 % of all women will develop breast cancer. Breast cancer is rare before 25 years of age, but
the incidence increases with age to peak levels during the perimenopausal years. For those women in high
risk groups, however, the incidence continues to rise throughout life. Currently there is an overall 5-year
survival rate of approximately 75% with breast cancer.

A. ETIOLOGY

1. GENETIC - A family history of breast cancer (especially premenopausal cancer in mother

or sister) greatly increases an individual's risk. Family history of other types of cancer
(except for ovarian and endometrial carcinomas) does not appear to increase risk.
Aberrations of chromosome 17 ( mutations of the p53 suppressor gene and the recently
identified BRCA I gene in patients with inherited forms of breast cancer) are present in
over half of the patients with breast cancer.
2. HORMONAL - Breast cancer is more common in those patients whose breasts have not
achieved full anatomic maturity and physiologic function (i.e. prolonged lactation). This
includes nulliparous women, women who have not had children until late in life (after 35),
and women who have had children but were unable or unwilling to nurse. This suggests
a role of steroid hormone (estrogen) activity over a long reproductive life span as an etio-
logic factor. This is supported by an increased incidence of breast carcinoma in women
with early menarche (before 13) and/or delayed menopause (after 50); in post-menopausal
women with increased estrogen levels (due to tumor, ovarian cortical hyperplasia,
exogenous administration, obesity, etc); in those with a previous history of breast, ovarian,
or endometrial cancer; and even in men receiving estrogen therapy for prostatic cancer.
Continuous use of oral contraceptives over an extended period of time also increases the
incidence.
3. ENVIRONMENTAL - The incidence of breast carcinoma is higher in patients who have
received ionizing radiation, particularly during puberty. Other possibilities include viral
infection and geographic location. Some feel that high fat diets contribute to breast
carcinoma, although other studies have cast doubt on that theory.

B. SIGNS AND SYMPTOMS - In the m<yority of cases discovered by the patient, the presenting symptom
is an unexplained "lump" that was noticed during self-examination. These tend to be firm,
non-tender masses with ill-defined borders that may befixed to skin or deep muscle. A fibrous
desmoplastic response may cause dimpling of skin or deviation or retraction of nipple (not to be
confused with congenital inversion) and lymphatic involvement of the skin may result in edema and

141
 a "peau d'orange" appearance. With routine mammography and other imaging techniques,
however, more and more subclinical lesions are being identified, biopsied, and treated.
C. LOCATION - The most common location is the upper outer quadrant (45%) followed by the nipple
or subareolar area (20%), upper inner quadrant (15%), lower outer quadrant (10%), and lower
inner quadrant (10%).
D. CLASSIFICATION - Although they do not always have a glandular architecture, almost all malignant
tumors arise from the terminal duct-lobular unit and are therefore adenocarcinomas. 90% of these
are derived from the terminal ductal epithelium with an additional 7-8% arising from lobular
(glandular) epithelium.

1. CARCINOMAS ARISING FROM DUCTAL EPITHELIUM

a. Intraductal carcinoma-in-situ (nelS) - Generally occurring after menopause,

patients may present with a cloudy nipple discharge, but currently most cases are
identified by biopsy because of suspicious areas (microcalcifications, etc) identi-
fied on mammography. Arising from the terminal ducts, malignant epithelial cells
proliferate, in differing histologic patterns, within the confines of the ductal
basement membrane. The most common pattern is for tumor cells to completely
fill and distend the duct with central necrosis and dystrophic calcification. With
pressure, this necrotic pasty material can be expressed from the ducts and hence
the name comedocarcinoma, referring to the resemblance to necrotic material that
can be expressed from comedones (blackheads). In other instances, tumor cells
may bridge the lumen of the ducts to create evenly rounded "holes" (cribr~rorm
pattern) or they may exhibit a micropapillary pattern or a solid pattern. DCIS is
generally slow growing and if no penetration of the basement membrane is
identified (comedocarcinoma is the most likely to show microinvasion and is
associated with a higher risk of recurrence), the prognosis is generally good.
Without treatment approximately 30% of these patients will develop invasive car-
cinoma, and a small proportion may develop invasive carcinoma of the
contralateral breast.
b. Infiltrating ductal, NOS (scirrhous) - By far the most common form of breast
cancer (75%), this has a peak incidence in the perimenopausal age range and
presents as a hard, gritty, gray-white mass with irregular or indefinite borders.
Although there is microscopic variability, there is usually a reactive dense
hyalinized fibrous tissue stroma (desmoplasia) punctuated by nests and strands of
malignant cells which may infiltrate the skin or pectoral muscles to produce
fixation, skin dimpling, or retraction of the nipple. A majority have axillary lymph
node metastases at the time of diagnosis and the five year survival is only a little
better than 50%.
c. Medullary carcinoma - These uncommon tumors (5%) usually present as a deep-
seated, relatively large, circumscribed mass. The tumor appears soft and may
show areas of necrosis or hemorrhage. Microscopically, it is characterized by
sheets of large malignant cells, scanty stroma, and a prominent lymphocytic
infiltrate. The tumor tends to have a "pushing" rather than infiltrative margin, are
generally slow growing, slow to metastasize, and have a favorable prognosis for
five year survival.
d. Mucinous (colloid) carcinoma - Occurring in older women, these tumors are
also uncommon (3%) but are frequently large and bulky with a mucoid gelatinous
appearance. Microscopically, malignant cells may be floating in pools of mucin,

142
 form well-defined mucin producing glands, or form sheets of "signet ring" cells.
These tend to be slow growing, are slow to metastasize, and have a relatively good
prognosIs.
e. Paget's disease of the breast - Usually occurring in older women, this is
characterized by a long hiStOlY of burning, itching, or soreness of the nipple which
may produce fissuring, weeping, crust formation and, ultimately, ulceration.
These nipple changes are associated with an underlying carcinoma (usually of a
major excretol)' duct) which mayor may not be clinically evident. Microscopically
the nipple changes are characterized by the presence in the epidermis of large,
pale, vacuolated cells (Paget cells) which stain positively with PAS and mucin
stains. These represent intraepithelial metastases from the underlying carcinoma.
The prognosis depends on the extent of the underlying tumor.

2. CARCINOMAS ARISING FROM LOBULAR EPITHELIUM

a. Lobular carcinoma-in-situ (LeIS) - Arising from the terminal ramifications of

the intralobular terminal duct, this does not cause mass lesions and usually is
discovered in tissue biopsied for other reasons. The terminal ducts and acini
become distended by proliferation of malignant cells which have a monotonous,
deceptively benign appearance. It may be multifocal within the involved breast and
is bilateral in about 25%. There is some question as to whether this lesion itself
progresses to invasive carcinoma, but nevertheless it does imply a high risk of
developing subsequent carcinoma.
b. Infiltrating lobular carcinoma - Although much less common (5%) than their
ductal counterparts, these tumors have gross, microscopic, and prognostic
characteristics similar to infiltrating ductal carcinomas. The cells are slightly
smaller and tend to be arranged in a "singlefUe" pattern or oriented in concentric
rings around normal ducts (targetoid pattern). At one time, these were felt to have
a greater incidence of bilaterality than ductal carcinoma, but this may not be true.
Evidence suggests that ductal carcinoma is also associated with an increased risk
of contralateral malignancy, and several studies have shown approximately equal
incidence of bilaterality with both lobular and ductal carcinomas. Lobular
carcinoma does, however, show a somewhat greater incidence of axillaI)', GL
ovarian, peritoneal, and bone marrow metastases than infiltrating ductal carcinoma

3. "INFLAMMATORY" CARCINOMA - This is not a specific type of cancer but rather is a

clinical term used to describe any breast carcinoma which has widely infiltrated and
obstructed the subepidermal lymphatics and blood vessels resulting in the sudden onset of
heat, redness, and swelling mimicking an acute inflammation. This tends to occur in large
pendulous breasts of young women, especially during lactation when the breast contains
wide-open blood and lymphatic channels. As might be surmised, the prognosis is poor.

E. SPREAD - The principal route of metastasis is via lymphatics, especially the axillary lymph nodes
since the majority of lesions are found in the upper outer quadrant. However, there may also be
involvement of the internal mammary chain and supraclavicular nodes. Distant metastases are
found most frequently in the lung, bone (osteolytic), liver, adrenal, brain, and ovaries.

143
F. STAGING - Staging is based on tumor size and the presence or absence of axillary nodal and distant
metastases.

1. STAGE I -Tumor less than 2 cm., no palpable lymph nodes, no evidence of distant spread
(85% 5-year survival).
2. STAGE D - Axillary lymph node metastasis or tumor between 2 and 5 cm with no palpable
lymph nodes and no evidence of distant spread (66% 5-year survival).
3. STAGE III - Tumor greater than 5 cm, clinically palpable lymph nodes with fixation, no
evidence of distant spread (41 % survival).
4. STAGE IV - Distant metastases (10% 5-year survival).

G. MODES OF THERAPY

1. SURGERY - This may involve a modified radical mastectomy or simple "lumpectomy" with
removal of the axillary nodes.
2. HORMONAL MANIPULATION - If the tumor is estrogen receptor positive (ER+) about 50%
will respond to hormonal therapy (anti-estrogen drugs such as tamoxifen). If the tumor is
progesterone receptor positive (PgR+), about 75% will respond. If the tumor is estrogen
receptor negative (ER-), only about 15% will respond. In general, there is an increasing
probability ofER+ with increasing age of the patient.
3. RADIATION
4. CYTOTOXIC DRUGS

H. PROGNOSIS - In the absence of distant metastases, important indicators of prognosis include the
number of axillary lymph nodes involved and the tumor's size, histology, nuclear grade and
hormone receptor status. In addition, poor prognostic indicators include tumors with amplification
of the HER-2lneu oncogene, p53 positivity, DNA aneuploidy, and a high percentage of cells in the
S phase of the cell cycle. Other serum tumor markers may be useful in monitoring the effectiveness
of therapy, but have little value in diagnosis or in determining prognosis.

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 GENITAL TRACT

REVIEW OF NORMAL

I. GONADAL DEVELOPMENT - In both sexes, the gonads develop from bilateral genital ridges
comprised of specialized mesenchyme that is covered by the coelomic (germinal) epithelium. Soon after
the appearance of these genital ridges, germinal epithelium penetrates the underlying mesenchyme to
produce the primary sex cords which are invaded by the germ cells migrating from the yolk sac along the
root of the mesentery. In males, under the influence of the Y chromosome, the primary sex cords ultimately
differentiate into the seminiferous tubules (consisting of Sertoli cells derived from germinal epithelium and
spermatogonia derived from germ cells) and the rete testis. Leydig cells develop from the mesenchyme that
separates the seminiferous tubules. In females, the primary sex cords evolve into the rudimentary rete ovarii
while secondary sex cords develop from the cortex and ultimately form the primordial follicles. The
granulosa cells surrounding the follicles are derived from the secondary sex cords. The stromal cells
adjacent to the granulosa cells differentiate into the concentric perifollicular theca intern a and externa.
II. GENITAL TRACT DEVELOPMENT - At about six weeks gestation, invaginations of the germinal
epithelium covering the genital ridges form the paramesonephric (mUellerian) ducts which lie adjacent to
the previously existing mesonephric (wolffian) ducts. In males, under the influence of the developing testes,
the paramesonephric duct degenerates as the mesonephric duct develops into the epididymis, vas deferens,
and seminal vesicles. In the female, the paramesonephric duct develops to ultimately form the fallopian
tubes and, by fusing together in the midline, the uterus, cervix, and upper vagina. The lower 2/3 of the
vagina develops from the urogenital sinus which grows cephalad to fuse with the upper portion. During
this process, the mesonephric duct degenerates.
III. ENDOCRINE FUNCTION - In both sexes, germ cell development and sex hormone production are
under the influence of the pituitary gonadotropins, FSH and LH. FSH promotes testicular spermatogenesis
and ovarian follicle development. It also induces the secretion of inhibin which acts to decrease FSH
release. LH promotes androgen production. In the male, testosterone (the most potent androgen) is
produced by the Leydig cells with lesser amounts of androstenedione and dehydroepiandrosterone
(DHEA). In the female during the proliferative (pre-ovulatory) phase of the menstrual cycle, LH promotes
the production of androstenedione and testosterone by the theca interna cells of the developing follicle~
Also during the proliferative phase, the rising FSH levels stimulates the aromatization of testosterone to
estradiol (the most potent estrogen) and androstenedione to estrone (a weak estrogen) by the granulosa
cells of the follicle. Increasing estrogen levels have an inhibitory effect on FSH secretion but are responsible
for the LH surge at midcycle which induces rupture of the follicle and ovulation. During the secretory
(post-ovulatory) phase, LH promotes the production of progesterone (primarily 17-hydroxyprogesterone)
by the luteinized theca cells and lesser amounts of androgens. [Progesterone has weak mineralocorticoid
activity accounting for the edema and weight gain during secretory phase.] If the egg is fertilized, the

145
 syncytiotrophoblasts of the developing placenta produce beta HCG which maintains the progesterone
production of the corpus luteum until the placenta can produce its own progesterone. The placenta will also
produce estrogens in the form of estriol.

Androgens are also produced by the adrenal cortex and the ovarian hilar cells. The adrenals produce
primarily androstenedione and DHEA (both of which are 17 ketosteroids and can be measured in urine).
Most of the testosterone in females, however, is derived from ovarian conversion of androstenedione to
testosterone. Androstenedione can also be aromatized to estrone in the peripheral adipose tissue and
becomes an important source of estrogen in the post-menopausal female. Estrogen compounds are
metabolized in the liver and excreted in bile.

Estrogens and androgens are both bound to sex hormone binding globulin (SHBG), a transport protein
synthesized in the liver. SHBG has a greater affinity for testosterone so that with SHBG excess (such as
seen with hyperestrinism conditions), there is more binding of testosterone which exaggerates the effects
of the hyperestrinism. With SHBG deficiency (such as seen with obesity and hypothyroidism) there is more
unbound testosterone and a tendency toward virilization (hirsutism, etc.)

DEVELOPMENTAL DISORDERS

I. MUELLERIAN DUCT ANOMALIES - Embryologic fusion anomalies may result in unusual conditions
such as organ agenesis, abnormal septation, organ duplication, etc.
II. GARTNER'S DUCT CYST - These arise in women from remnants of the degenerted
mesonephric/wolffian duct. They appear in the anterolateral vaginal wall submucosa and may measure 1 -
2 cm in size.
III. IMPERFORATE HYMEN - This may not be recognized until puberty when patients complain of failure
to menstruate. Physical exam may reveal vagina, uterus, and fallopian tubes distended with retained blood
(hematocolpos, hematometria, and hematosalpinx).
IV. HVPOSPADIASIEPISPADIAS - In males, abnormal development of the urethral canal may result in the
urethral opening lying along the ventral (hypospadias) or the dorsal (epispadias) surface of the penile shaft.
This is often associated with other genitourinary malformations (cryptorchism, bladder exstrophy, etc).
Either may produce partial urinary obstruction predisposing to urinary tract infection.
V. PHIMOSIS - This refers to the inability to retract the foreskin over the glans penis because of an
abnormally small preputial opening. This may result from abnormal development or may be acquired by
inflammation of the glans and foreskin (balanoposthitis) with resultant adhesions to the foreskin. Phimosis
prevents adequate cleansing of the glans and predisposes to additional infection. Paraphimosis refers to
the inability to replace the foreskin after retraction and is usually due to constriction and swelling of the
glans.
VI. CR YPTORCHIDISM - This refers to the failure of the testis to descend into the scrotum from its
embryologic position in the coelomic cavity and is usually unilateral. Although there is early arrest of germ
cell production due to the higher ambient temperature, gross atrophy usually does not become apparent
until puberty. These patients have an increased risk of subsequent testicular cancer in both the cryptorchid
testis (regardless of surgical repositioning) and the contralateral "normal" testes.

146
 SEXUALLY TRANSMITTEDIINFECTIOUS DISEASES

I. VIRAL

A. HERPES (Herpes simplex IT virus) -lIDs virus causes painful red papules which develop into crops
of vesicles which then ulcerate. The ulcers heal in 10-20 days but may recur over a lifetime.
Histologically, there are intraepidermal vesicles formed by acantholysis due to balloon degeneration
of infected epidermal cells. Characteristic features on cytologic scrapings of the lesions include
large multinucleated giant cells and intranuclear eosinophilic inclusions. Clinically, the vesicles are
paingul, dysuria is frequent, and systemic symptoms of fever and malaise may be present.
B. CONDYLOMA ACUMINATA (Human papilloma virus) - These appear as either flat or verrucous
alterations of squamous epithelium (venereal warts). They are most frequently seen, but not limited
to, the cutaneous surfaces of the perineal/perianal/penile areas but may also affect the vagina,
cervix, and other mucosal surfaces. The verrucous condylomas show hyperkeratosis, parakeratosis,
acanthosis and koilocytosis of the epidermis. Flat condylomas may result from infection by a
different viral strain and do not have the verucoid appearance but do tend to have more cellular
atypia of the epidermis. They may be associated with subsequent dysplasia/neoplasia.
C. HEPATITIS B [see Hepatobiliary Section]
D. AIDS

II. BACTERIAL

A. GONORRHEA (N. gonorrhoea) - In women, the initial site of infection is frequently Bartholin's
glands, Skene's glands, or the endocervix. The organism tends to spread superficially along
mucosal surfaces and incites a heavy purulent exudative response. Acute inflammation of
Bartholin's gland may lead to occlusion of the duct and abscess formation (Bartholin's gland
abscess) which, with resolution of the suppurative exudate, becomes a Bartholin's duct cyst.
Whether the site of primary or secondary infection, the endocervix also exudes a purulent exudate.
Traversing the endometrial cavity (usually during or immediately following menses) to the fallopian
tube, gonorrhea is one of the leading causes of purulent salpingitis. If untreated, the fimbria
agglutinate and pus accumulates to form a pyosalpinx. With time, the pus is reabsorbed and
replaced by clear fluid to form a hydrosalpinx. In males, the organism infects periurethral glands
and generally presents as dysuria and a milky urethral discharge. From the urethra, it can spread
to prostate, seminal vesicles, etc.
B. BACTERIAL VAGINOSIS - This is caused principally by gardnerella vaginalis (hemophilus
gardnerella) in addition to mixed aerobic and anaerobic bacteria. It is the cause of most cases of
non-specific vaginitis and produces a thin, scanty, grey-white, malodorous discharge. The organism
does not penetrate the mucosa and does not incite much of an inflammatory response so that wet
mount shows clue cells (epithelial cells having a stippled-appearing cytoplasm due to bacterial
coating of the cell) with a meager inflammatory background.
C. CHANCROID (H. ducreyi) - lIDs causes genital ulcers ("soft chancre") and regional lymphadenitis.
The latter, if untreated, may progress to form an inguinal abscess (bubo). Histologically, the most
notable feature is lumenal occlusion and thrombosis of blood vessels beneath the ulcer due to rapid
endothelial cell proliferation. The organism can only rarely be shown in tissue with special stains
but smears of the lesion often demonstrate the short, gram-negative rods.

146a
 D. GRANULOMA INGUINALE (Calymmatobacterium granulomatis) - This occurs in perianal or genital
skin as a solitary lesion or a small group of ulcers filled with granulation tissue. The ulcers spread
by peripheral extension and can become quite large. The dermis contains a dense infiltrate of
macro phages and plasma cells and occasional neutrophilic abscesses. The most conspicuous
histologic finding is the presence of intracytoplasmic inclusion bodies (Donovan bodies) within
macrophages. Their demonstration is requisite for the diagnosis which may be accomplished by
special stains of tissue or smears of biopsy material.

III. CHLAMYDIA (C. trachomatis) - This is a common organism that infects the same tissues as gonococcus
but, in general, produces few clinical symptoms.

A. NON-SPECIFIC URETHRITIS, CERVICITIS, SALPINGITIS - This is a common chlamydial infection

most of which have few clinical symptoms and are often unrecognized. In females, chlamydia is
probably responsible for a majority of the cases of salpingitis resulting in infertility. In males, it may
produce a non-specific urethritis with mild dysuria and a mucoid discharge. The organism is hard
to culture but may be identified by monoclonal antibodies.
B. LYMPHOGRANULOMA VENEREUM - This is an uncommon disease caused by a different serotype
of C. trachomatis which produces papular and ulcerative skin lesions. Lymphatic involvement
results in fibrosis, scaring, and strictures of the anus and rectum.

IV. SYPHILIS (T. pallidum) - The spirochete penetrates small abrasions in the skin or mucous membranes
and after an incubation of 3 weeks causes a painless papule at the site of infection which soon ulcerates
(chancre) but will eventually heal spontaneously. Weeks to months later, during the stage of secondary
syphilis, systemic symptoms (headache, low-grade fever, lymphadenopathy, etc) develop and syphilitic
warts (condyloma lata) and rashes appear. This, too, heals spontaneously to possibly be followed by the
cardiovascular and neurologic effects of tertiary syphilis years later.
V. CANDIDA (C. albicans) - This is a common disorder in females, especially in diabetics and in conditions
of high progesterone states (pregnancy, BCP, etc.). Vaginal infections are characterized by itching/burning
and a white, curdy discharge. Diabetic vulvitis results from repeated candida infections and causes a
thickened, red, pruritic vulva. With KOH prep, budding yeast and pseudohyphae can be seen.
VI. TRICHOMONAS (T. vaginalis) - In females who are symptomatic (itching, dysuria, dyspareunia), the
vaginal mucosa has a bright red "strawberry" appearance with thick, frothy, yellow-green to grayish
discharge adherent to the mucosal surface. Wet mount may identifY the flagellated pear shaped protozoan.
In males, it is generally asymptomatic.

146b
 VULVANAGINA

I. INFLAMMATORY DISEASE - In the prepubertal and post-menopausal periods, the vulva and vagina
are prone to infection because of the warm, moist environment and the effects of hypoestrinism.
Hypoestrinism tends to decrease skin vascularity and results in atrophy and decreased cornification of the
epithelium, rendering the tissue more prone to trauma and infection. In elderly patients, this is called senile
atrophic vulvitis or vaginitis. A urethral caruncle is a painful polypoid nodule of granulation tissue
occurring at the urethral meatus 2° to epithelial atrophy, but it regresses rapidly with topical estrogen
treatment.
II. VULVAR DYSTROPHY - This disorder generally occurs in middle aged to elderly post-menopausal
women as white plaque-like lesions of the skin (leukoplakia) which are often multiple. There are two
histologic forms and, on occasion, both may be seen in the same lesion. It tends to develop in women with
anal-compulsive, rigid personalities and the primary symptom is itching. Scratching produces minor
lacerations and inflammation which causes more itching, etc. Difficult to manage clinically - must break
the scratch-itch cycle.

A. ATROPHIC DYSTROPHY (lichen sclerosis et atrophicus) - This is characterized by atrophic labia,

narrowed introitus, and smooth vulvar skin with small papules that coalesce into thin gray
parchment-like areas that are susceptible to trauma and infection. Histologically, there is epithelial
atrophy overlying a hypocellular, "collagenized" upper dermis and a band-like lymphocytic
infiltrate. It does not progress to cancer.
B. HYPERTROPHIC DYSTROPHY (with or without atypia) - Clinically similar to atrophic dystrophy,
microscopically there is hyperkeratosis and acanthosis with or without cellular atypia. Those lesions
which do have atypia have a low « 10%) malignant potential. This form may also be seen in
prepubertal females but usually regresses at the time of puberty.

III. VULVAR NEOPLASIA

A. GRANULAR CELL TUMOR - This tumor is probably derived from Schwann cells and is composed
oflarge cells with prominent granular cytoplasm. Most are small and almost all are benign, but they
may induce a pseudoepitheliomatous hyperplasia of the overlying skin that may histlogically closely
resemble squamous cell carcinoma. These tumors may also appear in other areas (vagina, breast,
tongue).
B. HIDRADENOMA PAPILLIFERUM - This is a benign tumor derived from apocrine sweat glands which
presents as a nodular mass usually on or between the labia. Histologically, there is a complicated
papillary architecture which may be mistaken for adenocarcinoma although close observation will
disclose a two cell layered epithelium (epithelial and myoepithelial).
C. BOWEN'S DISEASE (squamous cell carcinoma-in-situ) - This appears to be increasing in frequency
and arising at a younger age (mean age'" 40). It may present as raised, red, velvety lesions often
involving the labia but also has a tendency to be multicentric (especially with involvement of the
periclitoral and perianal skin). Histologically, condylomatous features may be present. HPV can
be identified in 80% of these lesions and HSV antigens in '" 50%. Only about 10% - 20% of
patients will progress to invasive carcinoma of the vulva (usually elderly or immunosuppressed)
but 25% are associated with CIS or invasive carcinoma of cervix and/or vagina.
D. SQUAMOUS CELL CARCINOMA (SCC) - Invasive SCC occurs primarily in post-menopausal women
but has shown an increasing frequency in younger populations (associated with preexisting HPV
infection). Clinically, SCC, in the early stages, looks like vulvar dystrophy with itching and local
discomfort the predominant symptoms. However, with time, they will become firm and indurated

147
 with possible central ulceration. They may be multicentric - both geographically and temporally.
Although most squamous carcinomas are histologically well differentiated, at the time of diagnosis
65% have metastasized to regional lymph nodes (inguinal, femoral, pelvic) and will later
metastasize to viscera. Lesions> 2 cm and with lymph node metastases have only a 25% 5-year
survival (25%). Smaller lesions treated with vulvectomy and pelvic lymphadenectomy have 60-
80% 5-year survival and, if there are no lymph node metastases, the 5-year survival approaches
90%. Verrucous carcinoma is a variant of squamous cell carcinoma in which the cells are
extremely well differentiated although the gross appearance is that of a large fungating tumor.
Typically this cancer will invade locally but will not metastasize.
E. EXTRAMAMMARY PAGET'S DISEASE - This presents as a red, crusted, well demarcated lesion
usually on labia majora in women who give a history of chronic pruritus and irritation. Vacuolated
tumor cells are present singly and in clusters within the epithelium and probably arise from adnexal
epithelium. They are PAS and mucicarmine positive and are usually confined to the epidermis and
skin appendages. Unlike Paget's disease of the breast, underlying adenocarcinoma is uncommon.
Intraepithelial neoplasia may persist for years with lateral spread but without invasion. Once
invasion occurs, however, the prognosis is poor.

IV. VAGINAL NEOPLASIA - The most frequently identified malignancy involving the vagina is metastatic.
Primary malignancies are uncommon and include:

A. SQUAMOUS CELL CARCINOMA (SCC) (1 % of genital cancer) - Most are well differentiated and
arise in the posterior fornix. They can invade the cervix and peri vaginal structures by direct
extension. The upper 1/3 of vagina drains to iliac nodes while the lower 2/3 drain to femoral,
inguinal, and pelvic nodes. SCC may come to clinical attention as the result of vaginal discharge
or spotting and is primarily seen in older women. Prognosis depends on clinical stage but ranges
from 20%-90% 5-year survivals.
B. ADENOCARCINOMA - Arising on the anterior wall (upper 113), clear cell carcinomas may occur
(.001 %) in young (15 - 27 yo) daughters of women treated with diethylstilbestrol (DES) during
pregnancy. It is preceded by vaginal adenosis (which occurs in 30-50% of DES exposed patients
and represents a persistence offetal histology where there is a delayed transformation of glandular
epithelium to squamous epithelium). Although often disappearing by the 4th decade, adenosis
appears as red areas contrasted against the normal pink mucosal background imparting a
"cobblestone" appearance. DES related tumors in general have a more favorable 5 year survival
rate than regular vaginal carcinomas.
C. SARCOMA BOTRYOIDES - This is a rare form of rhabdomyosarcoma that occurs in young girls, has
a polypoid grape-like appearance, invades locally, and metastasizes widely. Poor prognosis in
general.

PENIS

I. PREMALIGNANT AND MALIGNANT CONDITIONS

A. ERYTHROPLASIA OF QUEYRA T - This is essentially the same disorder as Bowen's disease of the
vulva and appears grossly as a raised, erythematous plaque usually on the glans. Microscopically,
there is severe epithelial dysplasialcarcinoma-in-situ and chronic inflammation. Without treatment,
a small number (5-10%) may progress to invasive squamous cell carcinoma.

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 B. BOWENOID PAPULOSIS -This also represents a squamous cell carcinoma-in-situ that clinically
presents as multiple (rather that solitary) lesions of the penis and tends to occur in a younger age
group. HPV -16 can be demonstrated in about 80%.
C. SQUAMOUS CELL CARCINOMA - This reaches a peak incidence in the fifth to seventh decade and
occurs more frequently in uncircumcised males. Chronic inflammation of the glans and foreskin
associated with poor hygiene and accumulation of smegma are predisposing conditions. Although
some studies show an association with HPV, it is much less convincing than the relationship
between HPV and SCC of the female genital tract. The tumors usually begin near the coronal
sulcus as a painless, white, plaque-like lesion which eventually ulcerates (or less commonly grows
in a fungating fashion). The tumors are usually well-differentiated and slow growing with only 20%
showing metastases to superficial inguinal nodes at the time of diagnosis. Prognosis depends on
the depth and extent of invasion and nodal involvement.
D. VERRUCOUS CARCINOMA - This is an uncommon condition (5% of penile cancers) representing
a well differentiated papillary squamous cell carcinoma that spreads horizontally and does not
appear to be associated with HPY. It is recurrent and locally invasive but does not metastasize until
late in its course.

CERVIX

I. REVIEW OF NORMAL

A. ANATOMY - The junction between the squamous epithelium of the exocervix and the columnar
mucin secreting epithelium of the endocervix (transition zone) migrates anatomically over time.
At birth, columnar epithelium is present on the exocervix but progressively recedes due to
replacement by squamous metaplasia In perimenopausal and postmenopausal women, the junction
may be high in the endocervical canal and may interfere with the accuracy of routine PAP
screening. Although occasionally gradual, the transition between cell types at the squamo-columnar
junction is usually abrupt and the mucus secreting endocervical "glands" are, in reality, clefts whose
epithelium is an extension of the surface epithelium.
B. HORMONAL RESPONSE - Estrogen produces maturation of the superficial squamous cells while
progesterone produces maturation of the intermediate squamous cells. Conditions of estrogen
excess (tumors, drugs, etc) will show a preponderance of superficial cells on Pap smears;
conditions of progesterone excess (pregnancy, etc) will show a preponderance of intermediate
cells; and absence of these hormones will result in a preponderance of parabasal cells. The
character of cervical mucus also changes with fluctuating hormone levels and can be used as a
diagnostic tool. If cervical mucus is air-dried on a glass slide, a crystalline or "ferning" pattern
indicates estrogen predominance while an amorphous appearance indicates progesterone
predominance. This can be used to differentiate between the two major causes of amenorrhea -
pregnancy (increased progesterone) and anovulation (increased estrogen).

II. INFLAMMATORY DISEASE

A. ACUTE - Although gonococcus is probably the most commonly identified agent causing acute
cervicitis, Chlamydia may be the more common etiologic agent, but it is less symptomatic and
more difficult to diagnose. Other organisms may also cause cervicitis particularly in post-abortion,
post-partum, or post-trauma states. Unlike gonococcus, most other organisms tend to spread via

149
 lymphatics (rather than over the mucosal surface) and therefore cause less purulent exudation and
discharge but may nevertheless lead to bacteremia, peritonitis, bowel adhesions, etc.
B. CHRONIC - Nonspecific lymphocytic infiltrates are present to some extent in virtually all adult
women. Grossly, chronic cervicitis appears as a reddened granular cervical mucosa. When severe,
lymphoid follicles may develop (follicular cervicitis). Stenosis and obstruction of the endocervical
"glands" may result in mucus retention and cystic dilatation (Nabothian cysts) which imparts a
pebbly appearance to the endocervical canal but has little clinical significance.

III. POLYPS

A. INFLAMMATORY - Occurring in '" 5% of women, cervical polyps arise in the 4th to 5th decade and
are usually solitary. They develop from the endocervical canal and produce soft sessile or
pedunculated lesions of varying size composed of a loose fibromyxomatous stroma containing
cystically dilated glands, thick-walled blood vessels, and varying degrees of inflammatory infiltrate.
With trauma, the surface epithelium erodes and easily bleeds so that they come to clinical attention
due to irregular spotting.
B. HYPERPLASTIC (microglandular hyperplasia, ''pill'' polyp) - These are usually seen in hyper-
progesterone conditions (pregnancy, BCP) and consist of tightly packed hyperplastic endocervical
glands. Clinically, they look similar to inflammatory polyps but potentially may be confused with
adenocarcinoma by microscopic appearance.

IV. CARCINOMA - The vast majority of cervical malignancies are squamous cell carcinomas (90%). The
frequency of cervical squamous dysplasia/neoplasia appears to be increasing, but the frequency of invasive
carcinoma and mortality due to cervical squamous cell carcinoma has decreased. Although much less
frequent, adenocarcinomas derived from endocervical epithelium tend to occur at a somewhat older age
and present at a more advanced stage with a correspondingly poorer prognosis. Adenosquamous carcinoma
combines elements of both, arises from the reserve cells of the endocervical epithelium, and also has a less
favorable prognosis.

A. ETIOLOGY - A recent study suggests that women who have used oral contraceptives have a
significantly greater risk of developing cervical carcinoma and that the risk increases in proportion
to the duration of usage. The bottom line risk factors, however, appear to be 1) early onset of
sexual activity, 2) increasing numbers of sexual partners, and 3) the promiscuity of those sexual
partners. With the exception of cigarette smoking, all other identified risk factors are probably
related to these three and suggests that a sexually transmissible agent may be involved. An
association between viral infections and cervical carcinoma has been noted which suggests four
possibilities: 1) viruses may simply have greater affinity for neoplastic cells; 2) viral infection
predisposes to cancer under appropriate environmental conditions; 3) viral infection precedes and
causes cancer; or 4) viruses and cancer may both be venereally transmitted but independent disease
processes. Suspected agents include:

1. HPV - The cellular changes characteristic of cells infected with HPV (koilocytosis) are seen
in dysplastic epithelium and HPV DNA has been found in both dysplastic and neoplastic
epithelial cells. Strains 16, 18, and 31 are felt to represent high risk strains in terms of
carcinogenic potential while strains 6 and 11 (those most typically associated with
condyloma acurninata) are felt to be lower risk strains.
2. HSV n - Statistically, women with genital herpes have a higher incidence of dysplasia and
carcinoma than the general population. Antibodies to HSV II antigens (specifically AG-4)
are higher in women with cervical dysplasia/neoplasia, and the AG-4 antigen can be

150
 demonstrated in neoplastic cells in 90% of cervical cancer biopsies compared to 10% of
non-cancer cervical biopsies. HSV II DNA sequences have been found in the DNA
structure of malignant cells and dysplasia has been induced in animals after inoculation
with HSV II. Although the herpes virus is primarily a cytopathic virus, it may be that HSV
II hastens the transforming properties of HPY.

B. PATHOGENESIS - Invasive carcinoma follows a long history of progressively worsening dysplastic

changes. Dysplasi~ therefore, must be considered a premalignant lesion. Dysplastic/neoplastic cells
are characterized by increased N/C ratio, greater nuclear pleomorphism, increased mitoses, and
loss of polarity. These changes first appear in the basal layer and, with increasing severity of
dysplasia, progressively involve a greater percentage of the epithelial thickness disrupting the
normal maturation sequence. Dysplasia/neoplasia (cervical intraepithelial neoplasia) virtually
always begins at the squamo-columnar junction and can be graded as mild dysplasia (CIN I),
moderate dysplasia (CIN II), severe dysplasia (CIN III), or carcinoma-in-situ (also CIN III). The
newer Bethesda classification utilizes two categories (low grade and high grade intraepithelial
neoplasia). Each grade may persist or progress to a more severe level. The more severe, the shorter
the time interval to the development of CIS. Whether or not dysplasia can spontaneously regress
has been subject of controversy, but at least it can be easily eradicated.
C. EVALUATION - Although dysplasia/neoplasia begins at the squamo-columnar junction, there are
no consistent grossly recognizable changes. Diagnostic evaluation, therefore, involves:

1. PAP SMEARS- Smears are 95% reliable (5% false negatives) assuming proper specimen
collection and competent evaluation.
2. SCHILLER TEST - The cervix is painted with a solution of iodine and potassium iodide.
Normal cells will stain brown due to their glycogen content. Abnormal cells (neoplastic
or inflammatory) lose cytoplasmic glycogen and therefore will not stain. Biopsy is directed
at the non-staining areas.
3. COLPOSCOPY - The colposcope is a lighted instrument which magnifies cervical mucosa
20x. Areas of abnormality of the epidermis (thickened white plaques) or vasculature
(punctuation, mosaicism) have been found to be associated with dysplasia/neoplasia, and
the biopsy is directed to these abnormal areas.

D. MORPHOLOGY - Grossly, invasive carcinomas appear infiltrative, ulcerative, or exophytic (most

common appearance), and there are three microscopic patterns of squamous cell carcinoma, large
cell nonkeratinizing (most frequent), large cell keratinizing, and small cell.
E. BEHA VIOR - Growth by local extension may involve the bladder, ureter, rectum, and vagina.
Metastases occur primarily via lymphatics to regional (paracervical, hypogastric, and external iliac)
and periaortic lymph nodes, then to liver, lung, bone, etc. Hematogenous spread is unusual.
F. PROGNOSIS - This is generally related to the clinical stage of the tumor with an overall 5 year
survival rate of approximately 60%. Chemotherapy is notoriously ineffective, and death frequently
results from uremia due to ureteral obstruction.
G. STAGING
Stage 0 Carcinoma-in-situ
Stage Ia Microinvasive and confined to cervix
Stage Ib Invasive and confined to cervix
Stage lIa Extends to upper vagina but not to parametrium
Stage lIb Involves parametrium
Stage III Extension to pelvic sidewall or involves lower vagina
Stage IV Beyond the pelvis or involvement of rectal or bladder mucosa

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 UTERUS
I. REVIEW OF NORMAL - Uterine pathology can be divided into those conditions that primarily affect
the endometrium (both endometrial glands and endometrial stroma) and those that affect myometrium.
The endometrium is responsive to the cyclic variations in hormones throughout the menstrual cycle which
is reflected in its histologic appearance. During the proliferative phase ofthe menstrual cycle (the first 14
days starting with the onset of menses), the endometrium responds primarily to the increasing serum
estrogen levels by proliferation of both the glands and stroma to increase endometrial thickness and
volume. The glands are lined by pseudostratified columnar epithelium and mitoses are apparent in both
the glands and the stroma Ovulation, produced by the LH surge in mid-cycle, initiates the secretory phase
of the menstrual cyle which is characterized by progesterone induced glandular secretions and predecidual
changes of the stroma in anticipation of the implantation of a fertilized ovum. If a fertilized ovum does not
implant, the declining progesterone and estrogen levels results in necrosis and sloughing of the
endometrium down to the basal layer, and the cycle begins anew.
II. DYSFUNCTIONAL UTERINE BLEEDING - This refers to abnormal uterine bleeding in the absence
of an organic lesion of endometrium or uterus.

A. ANOVULATORY CYCLE - Failure of ovulation results in prolonged estrogenic stimulation without

progesterone-induced secretory change. This may result in mild hyperplasia and generally occurs
just after menarche and just before menopause. The etiology is unknown in the majority of cases,
but endocrine dysfunction (thyroid, adrenal, pituitary), ovarian abnormalities (polycystic ovaries,
functional neoplasms), or metabolic abnormalities (obesity, malnutrition, chronic disease) can
result in failure to ovulate.
B. OVULATORY CYCLE

1. INADEQUATE LUTEAL PHASE - This results from low progesterone output by the corpus
luteum and is clinically manifested by infertility (endometrium is not adequately primed
for implantation) and either amenorrhea or increased bleeding.
2. IRREGULAR SHEDDING - This is possibly due to delayed involution of corpus luteum with
prolonged progesterone stimulation. Secretory endometrium may be admixed with
proliferative endometrium. Clinically manifested by profuse, regular menstrual bleeding
lasting 1-2 weeks.

III. INFLAMMA TORY DISEASE

A. ACUTE ENDOMETRITIS - Although the normal endometrium is generally resistant to acute infection,
when it occurs it is most commonly seen in post-abortion or post-partum states when there has
been retained fetal or placental parts. Microabscesses or neutrophilic destruction of endometrial
glands will be present. An accumulation of pus may develop within the endometrial cavity
(pyometra) especially ifthere is some obstruction of the endocervical canal.
B. CHRONIC ENDOMETRITIS - This may be seen in post-abortion/post-partum states or associated with
IUDs, but in 15% of cases they are without definable underlying cause. Clinically, patients may
present with pelvic pain, abnormal bleeding, and/or infertility. Histologically, it is characterized
by presence of plasma cells in the endometrial stroma.

IV. ADENOMYOSIS - This refers to the presence of endometrial tissue (glands and stroma) buried within
the myometrium and is felt to arise from abnormal downgrowth of basal endometrium into the
myometrium. Rarely are these foci responsive to cyclic hormonal change but when extensive they may

152
 cause myometrial hypertrophy and uterine enlargement. Clinically, adenomyosis may present as
menorrhagia, menstrual cramps, or dyspareunia.
V. ENDOMETRIOSIS - Estimated to occur in 20% of adult females (usually 3rd and 4th decade) and a
significant cause of infertility, endometriosis is characterized by the presence of benign, potentially
functional endometrial tissue (glands and stroma) outside of the uterus. The most common site of
involvement is the ovaries followed by uterine ligaments, rectovaginal septum, and pelvic peritoneum, but
it may occur anywhere (lungs, umbilicus, soft tissue, etc).

A. PATHOGENESIS - Although the mechanism of dissemination of the endometrial tissue is unknown,

theories include focal differentiation of the coelomic epithelium (remember this is the same
epithelium that forms the muelleri an duct) into endometrial tissue, regurgitation of endometrial
tissue through the fallopian tubes during menses, and lymphatic or hematogenous dissemination.
B. MORPHOLOGY - Grossly, the lesions appear as red-blue to yellow-brown nodules on or beneath
serosal surfaces. Bleeding induces fibrous adhesions with consequent problems of pelvic visceral
distortion. Large "chocolate" cysts may develop in the ovaries. The histologic diagnosis rests on
the identification of ectopic endometrial glands and stroma or hemosiderin associated with ectopic
placement of either glands or stroma.
C. CLINICAL PRESENTATION - Endometriosis most often presents due to pain and/or infertility, but
the presentation may depend on the site of involvement and the functional activity of the tissue.
Most often, the tissue is functional and bleeds cyclically. Patients may complain of dysmenorrhea
and pelvic pain from periuterine adhesions; pain on defecation due to rectal involvement; dysuria
from bladder involvement, etc.

VI. ENDOMETRIAL POLYPS - These may be solitary or multiple, are often pedunculated and of varying
size, and tend to occur postmenopausally. They may be composed of non-functional endometrium or, more
commonly, hyperplastic endometrium with cystically dilated glands, a cellular stroma, and thick walled
vessels. Many are asymptomatic but they may cause intermittent bleeding and a small proportion «3%)
may harbor adenocarcinoma.
VII. ENDOMETRIAL HYPERPLASIA - This represents an increased proliferation of both epithelial and
stromal elements with a concomitant increase in endometrial volume. Hyperplasia is seen primarily in the
post-menarchal or peri-menopausal age groups and is associated with prolonged or excessive estrogen
stimulation. Therefore, estrogen secreting tumors, increased adrenocortical function, Stein-Leventhal
syndrome, and exogenous estrogen administration may be associated with endometrial hyperplasia.
Clinically, hyperplasia causes irregular or excessive bleeding (i.e. metrorrhagia or menorrhagia) but the
majority of cases are self-limiting and spontaneously regress. If they do not, however, over a period of years
there is a definite risk of progression to endometrial adenocarcinoma related to the degree of hyperplasia.

A. CYSTIC (MILD) HYPERPLASIA - Cystically dilated glands of varying sizes are lined by mitotically
active columnar epithelium. There is increased stroma but scant stromal mitoses and a minimal risk
of subsequent carcinoma.
B. ADENOMATOUS (MODERATE) HYPERPLASIA - An irregularly thickened grayish endometrium
shows an increased number of irregularly shaped glands. There is a moderately increased risk for
development of subsequent carcinoma.
C. ADENOMATOUS HYPERPLASIA WITH ATYPIA (ATYPICAL HYPERPLASIA) - There is increased
mitoses and glandular crowding with cellular atypia ranging from mild to severe. This is associated
with a high risk of subsequent cancer.

VIII. ENDOMETRIAL GLANDULAR EPITHELIAL TUMORS - These are now the most common female
genital malignancies and appear to be increasing in frequency with 90% occurring after menopause.

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 Although there are exceptions, in general the developmellt of adellocarcilloma is related to prolollged
or excessive estrogell stimulatioll. Endometrial carcinomas have been experimentally induced in animals
with high dose estrogens. In humans, risk factors include obesity, diabetes, hypertension, and infertility. In
the peripheral adipose tissue of post-menopausal women, there is increased synthesis of estrogens from
adrenal and ovarian androgens. Carcinoma may also be associated with functional ovarian tumors, pre-
existing hyperplasia, and a history of breast cancer. The most common symptoms are irregular vaginal
bleeding and leukorrhea.

A. MORPHOLOGY - Carcinomas may be focal and polypoid or widespread and diffuse. Eventually the
endometrial cavity becomes filled with nodular and partially necrotic tumor. 60%-75% are
adenocarcinomas varying from well-differentiated (Grade I) to poorly differentiated (Grade III).
20%-30% contain foci of squamous differentiation. Although these used to be subclassified as
adenoacanthoma if the squamous component was benign and adenosquamous carcinoma if the
squamous component was malignant, current evidence suggests that the prognosis is better
predicted by the grade of the glandular component. A particularly aggressive tumor that should be
distinguished from "ordinary" adenocarcinoma is the uterine papillary serous carcinoms (UPSC)
which tends to spread widely over the peritoneal surfaces
B. NATURAL HISTORY - With time, tumor may extend into the myometrium and through the serosal
surface to involve adjacent structures. Lymphatic spread is to regional and periaortic lymph nodes,
and hematogenous spread is to lung, liver, bone, etc. The prognosis is dependent on depth of
myometrial invasion, degree of cellular differentiation, and type of tumor. Tumors in older women
tend to be less well-differentiated and more invasive than those in younger women.
C. STAGING

I - confined to corpus (80%) 95% 5 yr survival

II - involves corpus and cervix 30-50% 5 yr survival
III - outside uterus but within pelvis < 20% 5 yr survival
IV - bladder or rectal mucosal < 15% 5 yr survival
involvement or outside pelvis

IX. ENDOMETRIAL STROMAL TUMORS - These tumors are characterized by the presence, within the
myometrium, of endometrial stroma of varying cytologic atypia.

A. BENIGN STROMAL NODULES - These appear as expanding nodules of endometrial stroma buried
within the myometrium.
B. ENDOLYMPHATIC STROMAL MYOSIS - This represents a low-grade sarcoma in which endometrial
stromal tissue in the myometrium tends to invade lymphatics and blood vessels. 50% recur and
15% show distant metastases.
C. ENDOMETRIAL STROMAL SARCOMA - This usually arises high in the fundus, fills the endometrial
cavity, and grows into the myometrium with extensive vascular invasion. The cellular cytology
shows variable differentiation but mitoses are> 10/hpf. There is a 50% 5 yr survival.

X. MALIGNANT MIXED MUELLERIAN TUMORS - These tend to occur in elderly postmenopausal

patients and present with bleeding. Derived from muellerian mesoderm, the tumor consists of malignant
glandular and stromal components. The stromal component may be homologous (stromal sarcoma,
leiomyosarcoma) or heterologous (chondrosarcoma, rhabdomyosarcoma, etc). There is only a 25% 5 yr
survival.

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XI. MYOMETRIAL TUMORS

A. LEIOMYOMA - This is probably the most common neoplasm in women and affects up to 25%
during their reproductive life. They tend to be more common in Blacks and are usually first noticed
to arise in the 3rd to 4th decade, tending to decrease in size after menopause. Grossly these are
well circumscribed, grey-white, rubbery spheroids which have a whorled cut surface. They may
be pedunculated, submucosal, subserosal, or intramural and are often multiple and of varying size.
Some may undergo cystic degeneration, hyalinization, or calcification. Histologically, they are
composed of interlacing bundles of benign smooth muscle cells. Malignant transformation is
distinctly unusual « 0.1 %). When symptoms occur, they are usually related to the size of the
tumors (pressure on bladder or rectum, sensation of heaviness) to abnormal bleeding patterns
(particularly submucosal tumors), or to pain from degeneration, infarction, and hemorrhage.
B. LEIOMYOSARCOMA - Malignant smooth muscle tumors are uncommon. They may present as
fleshy masses invading into the uterine wall or as polypoid masses growing into the endometrial
cavity. They are felt to arise de novo rather than from a preexisting leiomyoma. They vary in
histologic appearance from low-grade (well-differentiated) to high-grade (poorly differentiated).
Criteria of malignancy may simply rest on number of mitoses/HPF and cytologic atypia. In the
uterus, smooth muscle tumors which have a mitotic rate of> 5 mitoses per 10 HPF should be
considered malignant. The overall 5 yr survival is 40-50%.

FALLOPIAN TUBES

Transport of ova and sperm is an active process aided by the ciliated epithelium of the tubal mucosa. Anything that
interferes with the tubal epithelium (inflammatory changes, etc.) or tubal mobility (peritubal adhesions, etc.) may
also interfere with fertility.

I. INFLAMMA TORY DISEASE

A. SALPINGITIS - Acute saplingitis is usually an extension of a pre-existing cervicitis or endometritis,

and gonorrhea and chlamydia are the most frequent etiologic agents. Unless recognized and
treated, the salpingitis may become chronic and result in infertility due to intratubal adhesions of
the plica. Microscopically, this produces follicle-like spaces (follicular salpingitis) that interfere
with tubal transport.
B. TUBD-OVARIAN ABSCESS - These usually result from microabscess formation in the cortex of the
ovary which secondarily involves the fimbria of the tube in the inflammatory process.

II. SALPINGITIS ISTHMICA NODOSA - This refers to nodular lesions that develop at the isthmus of the
tube. Histologically, the tube has a decreased lumenal size and increased thickness of the muscular wall
which contains gland-like spaces lined by tubal epithelium. The etiology is not known, but the process may
be similar to adenomyosis and may interfere with tubal transport of the fertilized egg to the endometrial
cavity.
III. CYSTS - Embryologic remnants of the muellerian and wolffian ducts are present in the mesosalpinx and
may become cystic (paratubal cysts, hydatids ofMorgagni). Most are small, clinically asymptomatic, and
do not interfere with fertility.
IV. ECTOPIC PREGNANCY - This occurs when the fertilized ovum implants in an area other than the
endometrium and is increasing in frequency. Most ectopic pregnancies involve the fallopian tube (90%),
but on rare occasions it may occur in the ovary or peritoneal cavity. Predisposing factors include those that

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 inhibit tubal transport of the ovum (chronic salpingitis, peritubal adhesions, large cysts, tumors, etc), but
in about half of the cases, no underlying pathology can be identified. Since the tubal mucosa has a limited
ability to undergo decidual change, the developing placental tissue is poorly anchored and hemorrhage
occurs at the implantation site creating a hematosalpinx. Ectopic pregnancy is the most common cause of
hematosalpinx. As the placenta grows, it burrows through the thin wall of the tube and may rupture the
tube causing life-threatening intraperitoneal hemorrhage. This usually occurs 2-6 weeks after pregnancy
ensues if the implantation is in the isthmic portion of the tube but may be as late as 12 weeks if the
implantation is in the ampullary portion. Clinically, at the time of rupture, there is abrupt onset of severe
abdominal pain, and the patient may go into shock. A negative pregnancy test is not sufficiently reliable to
rule out an ectopic pregnancy, but finding blood in the pouch of Douglas on culdocentesis may be helpful
in establishing the diagnosis.
v. NEOPLASIA - Malignant involvement of the tubes is most likely to represent metastatic disease. Primary
neoplasms are rare but adenocarcinomas and benign adenomatoid tumors (mesotheliomas) can occur.

OVARY

I. NON-NEOPLASTIC OVARIAN ENLARGEMENT - The clinical finding of an adnexal mass on pelvic

examination must be pursued. Non-neoplastic masses are generally caused by the development of cysts
within the ovary. They may be asymptomatic or present with abdominal pain and/or abnormal menstrual
cycles.

A. "GERMINAL" INCLUSION CYSTS - Common cysts (particularly in the premenopausal period), these
may be multiple and of varying size (although usually < 1 cm), and result from downgrowth and
entrapment of the surface epithelium into the ovarian cortex.
B. PHYSIOLOGIC OR FUNCTIONAL CYSTS - Several follicles develop during each menstrual cycle but
only one ruptures. The remainder regress and become atretic. The theca cells of the ruptured
follicle undergo hyperplasia and luteinization to produce a corpus luteum. Ultimately, the corpus
luteum becomes hyalinized to form a corpus albicans. Physiologic cysts arise from exaggerations
of these normal cyclic changes.

1. FOLLICLE CYSTS - These are extremely common and consist of one or more cysts
developing from follicles that are undergoing atresia. They vary in size, are lined by
granulosa cells or flattened atrophic cells and contain clear fluid. Usually they are of no
clinical significance although rarely they may continue to secrete estrogens with resulting
endometrial hyperplasia.
2. CORPUS LUTEUM CYST - This represents a cystic enlargement of a corpus luteum and
usually shows central hemorrhage. It too is usually of no significance, but if it ruptures
through the capsule, it may mimic an ectopic pregnancy. Persistent secretion of
progesterone may cause menstrual irregularities.
3. THECA LUTEIN CYSTS - These may develop after improper atresia of unruptured follicles
so that there is hyperplasia and persistence of luteinized theca cells stimulated by
conditions in which there are high circulating levels of gonadotropins (pregnancy,
hydatidiform moles, superfecundations, erythroblastosis fetalis, etc). Often this IS a
bilateral condition and, on occasion, these cysts may rupture to cause hemorrhage.

C. POLYCYSTIC OVARIES - One of the more common causes of infertility, the ovaries are bilaterally
enlarged with multiple cysts underlying a thick white collagenous capsule. The cysts are lined by

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 granulosa-theca cells which may be luteinized (and androgen secreting). Corpora lutea are absent.
Clinically, there are a variety of symptoms ranging from symptoms of hyperestrinism (abnormal
bleeding, hypermenorrhea) to symptoms of virilization (amenorrhea, hirsutism). The Stein-
Leventhal syndrome consists clinically of 2° amenorrhea, obesity, hirsutism, and infertility. The
etiology is not known but probably involves a dysfunction of the hypothalamic-pituitary-ovarian
axis so that abnormal secretion of gonadotropin releasing factor from the hypothalamus results in
pituitary gonadotropin release and continuous ovarian stimulation. LH stimulates production of
androstenedione and testosterone by the theca cells which is converted to estrogens (primarily
estrone) in the peripheral adipose tissue. The increased estrogens inhibit FSH release by the
pituitary and therefore follicles never develop normally. For unknown reasons, wedge resection
of the ovary will restore normal cycling in a majority of patients.
D. STROMAL HYPERPLASIA - Occasionally, particularly in postmenopausal women, proliferation of
ovarian stromal cells will result in nodular masses (primarily in the ovarian medulla) of both
ovaries that clinically present as ovarian enlargement. Many of the stromal cells are luteinized
(hyperthecosis) and produce androgens which may lead to virilization. Peripheral conversion of
androgens to estrone, however, may lead to hyperestrogen symptoms such as endometrial
hyperplasia and carcinoma.

II. NEOPLASTIC OVARIAN ENLARGEMENT - Most (80%) ovarian neoplasms are benign. Ovarian
carcinoma, however, is the third most frequent female genital tract malignancy, and although ranking
behind endometrial and cervical carcinomas in incidence, ovarian carcinoma results in greater mortality
(50%) than those two combined. This is primarily due to late presentation. Unless endocrinologically active,
they tend to be asymptomatic until the size of the tumor causes symptoms of abdominal pain and
distension, GI or urinary tract compression or invasion, or abdominal bleeding. Ovarian neoplasms tend
to be most prominent during reproductive years with the malignant forms tending to occur pre- or
perimenopausally. The risk of ovarian neoplasia appears to be increased in women with a family history
of ovarian tumors and women who have not borne children. Unlike breast or endometrial cancer, estrogen
does not appear to playa role.

A. TUMORS DERNED FROM SURFACE (GERMINAL) EPITHELIUM - These are the most common of
the ovarian neoplasms. The paramesonephric (Muellerian) duct which ultimately provides the
epithelial lining of the fallopian tube, uterus, and endocervix is embryologically derived from the
same coelomic epithelium that covers the surface of the ovary. This epithelium therefore has the
potential to differentiate into tubal epithelium (serous secreting, ciliated columnar), endometrial
epithelium (non-ciliated columnar) or endocervical epithelium (mucus-secreting, nonciliated
columnar), and ovarian neoplasms may mimic any of these cell types. As a group, the surface
epithelial tumors are most frequently seen in adults with the malignant forms tending to occur in
an older age bracket. They tend to grow relatively slowly causing low abdominal pain and
distension. GI and urinary symptoms may intervene. Because of their location, the malignant forms
are often not recognized until they have spread, many by diffuse peritoneal seeding which can
cause massive ascites. Even benign tumors, however, can torse, infarct, and behave similar to an
acute abdomen. CA 125 has been used as a serum marker for the presence of these tumors.

1. SEROUS TUMORS - These mimic the epithelium of the fallopian tube and overall are the
most common of the ovarian tumors.

a. Serous cystadenoma (50% of serous tumors) - Typically this benign lesion is a

unilocular cystic structure filled with clear fluid. The capsule is generally smooth
and glistening, but there may be a few papillary projections on the internal or

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 external surface of the cyst wall. The cyst is lined by tall ciliated and nonciliated
columnar epithelium without cellular atypia. As the size of the tumor increases,
it may become multilocular and the epithelial lining may become flattened against
the cyst wall. 20-30% are bilateral.
b. Serous cystadenocarcinoma (35% of serous tumors) - These make up about half
of all malignant ovarian tumors. The cyst wall shows papillary projections on both
sides and there are usually solid, nodular thickenings of the capsule. The histology
shows piling up and stratification of the epithelium to more than three cells in
thickness. Papillary structures, cellular cords, or solid cellular masses penetrate the
tumor capsule and invade surrounding ovarian stroma. 65-70% are bilateral.
Although psammoma bodies are commonly seen in (and are characteristic ot)
serous tumors, they do not necessarily imply benignity or malignancy. Depending
on the degree of cellular atypia, the tumors are graded I (well-differentiated) to III
(poorly differentiated), however the clinical stage appears to be of greater
prognostic significance than the histologic grade. 10 year survival is 10-20%.
c. Serous borderline tumor (15 % of serous tumors) - These tumors show the cyst
lining cells beginning to stratifY (2-3 layers) with the potential to form complex
papillary and glandular patterns. Although cellular atypia and mitoses are present,
the atypia is not as severe nor are the mitoses as frequent as is seen in carcinoma.
A cellular stroma separates the neoplastic glands and there is no evidence of
capsular or ovarian stromal invasion. 10 year survival is '" 75%.

2. MUCINOUS TUMORS - These tumors mimic the epithlium of the endocervical canal and are
most frequently seen in the 30-60 year age range.

a. Mucinous cystadenoma - This is about equal in incidence to the benign serous

tumors. Grossly, they also appear similar to serous tumor but have a greater
tendency to be unilateral, multiloculated, and large. They contain a mucinous,
gelatinous fluid. Histologically, the cyst is lined by a non-ciliated mucous secreting
epithelium. The mucin will stain variably with PAS, alcian blue, and mucicarmine.
As the tumor enlarges, and pressure within the cyst increases, the epithelium may
become flattened.
b. Mucinous cystadenocarcinoma - This is much less frequent than its serous
counterpart, but basically the same gross and histologic criteria apply for
diagnosis: piling up of the epithelium into more than 3 layers, complex papillary
and glandular formations creating a cribriform pattern or solid cellular
proliferations, and invasion of the ovarian stroma. The epithelial cells have
decreased amounts of cytoplasmic mucin. If peritoneal seeding occurs,
pseudortlyxoma peritoneii may result. 10 year survival is ",35% (60% if confined
to ovary).
c. Mucinous borderline tumor - These show piling up and stratification (2-3 layers)
of the epithelium with mild to moderate cellular atypia and occasional mitoses.
The epithelium forms papillary structures with secondary cyst formation. A true
cribriform pattern, however, is confined to the malignant lesions. 10 year survival
'" 68% (96% if confined to ovary).

3. ENDOMETRIOIDTUMORS - These tumors mimic endometrial glandular epithelium. Almost

all of these are malignant at inception and overall comprise 20-30% of ovarian epithelial
malignancies. 30-40% are bilateral. Histologically, these are more of a glandular neoplasm

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 than a papillary neoplasm and closely resemble endometrial carcinoma. Up to 30% of
patients will have a coexistent endometrial cancer. This tumor, however, is felt to arise de
novo rather than as a metastasis from the endometrium or a malignant transformation of
a focus of endometriosis. Foci of squamous differentiation within the tumor is a helpful
diagnostic sign. The overall 5 year survival is 40-50%. Clear cell carcinoma is a variant
of endometrioid carcinoma and appears similar to clear cell carcinoma of the
endometrium. If confined to the ovary there is a 5 year survival of 50%, but if not, survival
is less than 10%. Other endometrial-like tumors (mixed mesodermal tumors, endometrial
stromal sarcomas, etc) can also arise in the ovary but are rare.
4. BRENNER TUMORS - These are infrequent tumors having peak incidence in the 40-70 age
range. They are usually unilateral, small, solid, and benign. Up to 25% may also be
associated with another surface epithelial tumor of the ovary. Although the proportions
vary, generally there is a fibrous stroma punctuated by nests of epithelial cells resembling
the transitional epithelium that might be found lining the ureter or urinary bladder. They
may alternatively resemble squamous epithelium (prekeratin can be demonstrated in the
cell cytoplasm). Occasionally these cellular nests may have small cystic spaces in the center
and resemble mucinous glandular structures. The stromal component may also contain
lipid and appear luteinized and these have been reported in association with endometrial
hyperplasia and adenocarcinoma Borderline Brenner tumors resemble low-grade papillary
transitional cell carcinomas with cellular mitoses but no stromal invasion. Malignant
Brenner tumors resemble higher-grade transitional cell carcinomas.
5. SEROUS SURFACE PAPILLOMA, CYSTADENOFIBROMA, ETC. - These are primarily benign
stromal proliferations with a surface epithelial component (usually serous in nature).

B. TUMORS DERNED FROM SEX CORD/STROMA - These are derived from the specialized gonadal
mesenchyme and, as such, have the potential of endocrinologic function.

1. GRANULOSA-THECA CELL TUMORS - Although pure granulosa cell and pure theca cell
tumors occur, generally there is a mixture of the two to varying degrees. Although the
greatest incidence is in the post-menopausal years, they can occur during the reproductive
years but rarely appear before puberty. Usually unilateral, they vary in size and may be
solid and/or cystic. If endocrinologically active, they secrete estrogens and will have a
yellowish hue due to the presence of the lipid precursors to steroid hormones. There is a
large histologic variability with different architectural patterns (microfollicular [Call-Exner
bodies], macrofollicular, trabecular, solid, insular, etc.) but this has little prognostic value.
Theca cells are sometimes difficult to tell from fibrous stroma. It may also be very difficult
to differentiate benign from malignant, but they should be considered potentially malignant
even though they generally follow a relatively benign course. Those with greater proportion
of granulosa component are more frequently malignant while those with greater proportion
of theca component are more frequently functional. The functional tumors may cause
precocious puberty or, in adults, they may be associated with endometrial hyperplasia and
breast carcinoma. Without treatment 15-25% of patients will develop endometrial
carcinoma If the androstenedione production by these cells is not converted to estrogens,
these tumors may on occasion be virilizing. Clinically, there is a 5-25% recurrence rate
with an 88% 5 year survival.
2. FIBROMA - Most (90%) are unilateral, solid, round, firm, white masses 5-10 cm in size.
A thecal component may be present and estrogen secreting (fibrothecoma). For unknown
reasons, when the tumor grows larger than 6 cm in size, 40% of patients will develop
ascites and right-sided pleural effusion (Meig's syndrome).

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 3. SERTOLl-LEYDIG CELL TUMOR (arrhenoblastoma, androblastoma) - These may occur at
any age but have a peak incidence during adolescence and young adulthood. They usually
are unilateral, grey-white, solid masses with focal hemorrhage and necrosis. The tumors
contain sertoli cells, Leydig cells, and a primitive gonadal stroma. The histology varies
considerably but tends to recapitulate testicular development. Well differentiated,
intermediate (most common), and sarcomatoid forms are present. With the less well
differentiated tumors, the stroma becomes increasingly prominent and heterologous
elements (usually mucinous intestinal epithelium but also cartilage, skeletal muscle, etc)
may appear. On occasion these may have estrogenic activity, but the majority, if
fimctionally active, elaborate androgenic hormones causing defeminization (amenorrhea,
hair loss, breast atrophy) and virilization (hirsutism, male hair distribution, lowering of
voice, clitoral hypertrophy, muscular build, etc.). Most follow a benign course and early
surgical excision may reverse some of the endocrine effects.
4. HILUS (HlLAR) CELL TUMOR - These consist of large lipid laden cells felt to arise from
ovarian hilus cells, the counterpart of the testicular Leydig cells. Intracytoplasmic Reinke
crystallOids confirm the diagnosis. Appearing in postmenopausal women, they are usually
small, unilateral, virilizing, and benign. Increased urinary 17 ketosteroids are unresponsive
to cortisone suppression.
5. LIPID CELL TUMORS - These cells may resemble Leydig cells and/or adrenal cortical cells.
Although some feel that they may arise from adrenal rests, others feel that they simply
represent Leydig cell tumors devoid of Reinke crystalloids. They are usually small, benign,
and may be hormonally active (estrogen or androgen).
6. SERTOLI CELL TUMORS - These tumors are rare and tend to develop in young adults. The
majority are functional with 45% secreting estrogens and 20% secreting androgens. The
cells resemble the Sertoli cells that are present in the Sertoli-Leydig cell tumors.

C. TUMORSDERNED FROM GERM CELLS - Although most of these tumors are benign, the malignant
forms constitute the most common form of ovarian malignancy in children.

1. TERATOMA - These tumors all have a 46XX karyotype which implies parthenogenetic
origin from a single postmeiotic haploid germ cell.

a. Mature cystic teratoma (dermOid cyst) - These constitute 95% of germ cell
tumors. They most often arise in young adults, are unilateral, and usually less than
10 cm. These tumors are prone to torsion and infarction and clinically, patients
may present with abdominal pain, pelvic mass, irregular periods, etc. Grossly they
appear as a unilocular or multilocular cyst lined by squamous epithelium and
containing cheesy sebaceous debris, matted hair, cartilage, teeth, etc. Microscopic
elements are derived from all germ layers and may consist of mucus glands,
cartilage, respiratory or GI epithelium, skin and skin adnexa, brain, thyroid, etc.
Struma ovarii refers to a teratoma consisting predominantly of thyroid tissue. 10%
of patients are hyperthyroid and thyroid carcinomas may originate in this tissue.
b. Immature (malignant) teratoma - These are rare tumors which tend to arise in
a slightly younger age group (adolescents) than the mature teratomas. Almost
always unilateral, these are predominantly solid tumors (with areas of necrosis and
hemorrhage) which grow rapidly with local extension and metastases. Histology
shows immature elements in addition to mature elements. Often there is immature
neuroepithelium and unless the tumor is sampled carefully, it may be missed.

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 2. DYSGERMINOMA - This represents 2% of malignant ovarian tumors but over 50% of
malignant germ cell tumors. The majority arise in adolescence and early adulthood, and
are usually unilateral, solid, lobulated yellow-white to grey-pink fleshy masses. The size
varies but they are usually relatively large when first discovered. The malignant cell is
derived from primordial germ cells and recapitulate the undifferentiated embryologic
gonad. This is the ovarian counterpart to testicular seminoma. Sheets and cords of medium
sized cells with vesicular nuclei and clear or granular glycogen-rich cytoplasm are
separated by scant fibrous stroma infiltrated by mature lymphocytes and occasional
granulomas. Mitoses may be frequent. Although all are malignant, cellular atypia is
variable and only 30% are aggressive. Like seminoma, these are radiosensitive and the 5
year survival runs 70-90%.
3. ENDODERMAL SINUS (YOLK SAC) TUMOR - These arise in young women and children and
are derived from malignant germ cells showing extra-embryonic yolk sac differentiation
with histologic recapitulation of the endodermal sinus. Grossly, it is usually a large
unilateral, solid tumor with small cystic spaces and extensive necrosis and hemorrhage.
The most common microscopic pattern is reticular with small tubules lined by single
layered cuboidal to flattened epithelium arranged in a loose reticular stroma. Alternatively,
papillary projections having a central blood vessel and lined by immature epithelium
sometimes in hob-nail pattern may be present. Papillary structures may project into the
tubules (Schiller-Duval bodies). Hyaline droplets are scattered throughout the neoplasm
and the cells are rich in alpha fetoprotein and alpha I-antitrypsin. Rapid aggressive growth
and poor response to therapy originally characterized these tumors, however current
survival rates are greater than 50% even with advanced disease.
4. EMBRYONAL CARCINOMA - This is a rare tumor similar to the more common embryonal
carcinoma of the testis. They occur in children and adolescents, are unilateral, and are
usually large when first discovered. They may result in precocious puberty and menstrual
abnormalities. They secrete HCG from syncytiotrophoblastic giant cells and alpha
fetoprotein from the embryonal cells.
5. CHORIOCARCINOMA - This is often seen in combination with other germ cell tumors. Pure
choriocarcinomas, however, are almost always seen in younger patients and produce a
hemorrhagic unilateral mass composed of malignant syncytiotrophoblasts and
cytotrophoblasts. They produce high quantities of HCG. Unlike the placentally derived
choriocarcinoma, these metastasize hematogenously and have an extremely high fatality
rate.

D. METASTATIC TUMORS - These are relatively common (7%) with GI tract (Krukenberg tumor),
breast, and other pelvic organs as the usual primary sites.

TESTIS

I. INFLAMMATORY DISORDERS

A. INFECTIOUS ORCHITIS
B. GRANULOMATOUS ORCHITIS - This is probably an autoimmune disease that usually presents as a
painful mass in the testis. Histologically, there is granulomatous inflammation which must be
differentiated from infectious granulomas.

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II. NON-NEOPLASTIC ENLARGEMENT OF SCROTAL CONTENTS

A. HYDROCELE - This refers to an accumulation of serous fluid within the tunica vaginalis secondary
to trauma, infection, systemic edema, etc.
B. HEMATOCELE - This refers to an accumulation of blood within the tunica vaginalis secondary to
trauma or hemorrhagic diathesis.
C. CHYLOCELE - This refers to an accumulation of lymphatic fluid within the tunica vaginalis due to
lymphatic obstruction by tumor, parasites, etc.
D. SPERMATOCELE - This refers to a cystic dilatation of epididymal ducts containing semen.
E. TORSION - This refers to a twisting of the spermatic cord (usually due to trauma) which may induce
infarction, hemorrhage, and testicular enlargement.

III. NEOPLASTIC ENLARGEMENT OF SCROTAL CONTENTS - Like their ovarian counterparts,

testicular neoplasms can arise from the surface epithelium (tunica vaginalis), sex cord/stromal tissue, or
germ cells. Unlike the ovaries, however, the vast majority of testicular neoplasms take origin from the germ
cell. Testicular neoplasms are increasing in frequency, have a peak incidence in young adults (15-30 years),
and generally cause painless enlargement of the testis. In the 15-34 year age group, testicular tumors are
the most common neoplasm of males and account for 14% of all cancer deaths. Predisposing factors
include cryptorchidism, genetic factors, and testicular dysgenesis.

A. GERM CELL TUMORS (95% of testicular neoplasms)

1. SEMINOMA - This is the most common testicular tumor and is the male counterpart of the
ovarian dysgerminoma. It is most prevalent in the 4th-5th decade. They are bulky, firm,
lobulated, tan-yellow tumors without necrosis or hemorrhage. They first spread to
common iliac and para-aortic lymph nodes but are very radiosensitive and, in general, have
an excellent prognosis. Three morphologic variants are recognized:

a. Classic seminoma (85%) - This consists of uniform cells with round nuclei, clear
cytoplasm, and distinct cytoplasmic borders. There is a variable amount of fibrous
stroma with a prominent lymphocytic infiltrate, and occasional granuloma
formation.
b. Anaplastic seminoma (5-10%) - This shows greater cellular pleomorphism and
increased numbers of mitoses. Although controversial, it may be associated with
a more aggressive clinical course.
c. Spermatocytic seminoma (4-6%) - This shows cellular pleomorphism and
features of spermatocytic maturation. The lymphocytic component of the classic
seminoma is absent. Typically affecting elderly males, these are slow growing
tumors that do not metastasize and have an excellent prognosis.

2. EMBRYONAL CARCINOMA (15%) - This has a peak incidence in the third decade and is
often a small infiltrative mass lesion consisting of large pleomorphic cells with a variable
architectural pattem and often exhibiting necrosis and hemorrhage. Up to 90% may contain
HCG and AFP. It does not respond well to radiation but if found early, prognosis is
relatively good.
3. TERATOMAS (5%) - These are tumors which contain a mixture of tissue derived from the
three embryologic germ cell layers. The mature teratoma tends to occur in younger
individuals and contains benign differentiated tissue (neural, muscle, cartilage, thyroid

162
 tissue and squamous, bronchial, and GI epithelium). The immature teratomas are
composed of incompletely differentiated elements, and although the tissue elements may
only appear immature rather than cytologically malignant, these tend to behave clinically
in a malignant fashion. Malignant teratomas contain cytologically malignant tissue.
4. ENDODERMAL SINUS (YOLK SAC) TUMOR (1 %) - Although not a common tumor, it is the
most frequently seen testicular tumor in babies and young children and consists of
undifferentiated cells with a variable architectural pattern (microcystic, glandular, alveolar,
and papillary formations with characteristic Schiller-Duval bodies and intra- and
extracytoplasmic hyaline inclusions. Like its ovarian counterpart, the tumor is rich in alpha
fetoprotein and a-I-antitrypsin. Iffound early, and with current methods of treatment, the
prognosis is generally good.
5. CHORIOCARCINOMA (1 %) - This tumor is uncommon in its pure form. It is usually small,
necrotic, and hemorrhagic consisting of both cytotrophoblasts and syncytiotrophoblasts.
Like the ovarian choriocarcinomas, HCG is produced by the syncytiotrophoblasts and is
a clinically useful marker. The tumor spreads quickly and widely via the bloodstream and
the initial clinical complaints may be due to metastases. The tumor is highly aggressive,
and the prognosis is generally poor.
6. MIXED TUMORS (40%) - These contain a mixture of two or more "pure" germ cell tumors,
most commonly a mixture of teratoma and emb'Yonal carcinoma (teratocarcinoma). Most
will contain HCG or AFP. The prognosis is dependent on the more aggressive element.

B. SEX CORD/STROMAL TUMORS - In general, these are benign tumors but, as in the ovary, they may
be endocrinologically active.

1. LEYDIG CELL TUMOR (2%) - This can occur at any age and may secrete androgens or
estrogens creating feminization or precocious masculinization in boys. The only clinical
effect in adult males would be gynecomastia in estrogen secreting tumors. They are
bilateral in up to 10% of cases and microscopically may show Reinke crystalloids.
2. SERTOLI CELL TUMORS - These are rare tumors which may also secrete androgens or
estrogens and may contain cells resembling ovarian granulosa cells. Most are benign.

C. SURFACE EPITHELIAL TUMORS - Unlike the ovary, these tumors are rare in the testis and consist
primarily of the testicular mesothelioma (adenomatoid tumors).
D. STAGING OF MALIGNANT TUMORS

Stage 1- Tumor confined to testis (with or without involvement of testicular adnexa

or scrotum).
Stage II - Metastases to retroperitoneal lymph nodes below the diaphragm.
Stage III - Extranodal infradiaphragmatic metastases or any metastases above the
diaphragm.

PROSTATE

I. INFLAMMA TORY DISEASE - This may be asymptomatic or associated with low back pain or
symptoms of urina'Y tract infection.

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 A. ACUTE PROSTATITIS - Focal or diffuse acute suppurative inflammation in the prostatic parenchyma
leads to a swollen acutely tender gland. It most frequently is an extension from other genitourinary
bacterial infections but may arise as complications of trauma (catheterization, transurethral
resection, etc).
B. CHRONIC PROSTATITIS - This has a more insidious onset and is characterized by infiltrates of
lymphocytes, plasma cells, and macrophages. When bacterial in origin, it is frequently a source
of recurrent urinary tract infections. More commonly, however, no bacteria can be cultured.
C. GRANULOMATOUS PROSTATITIS - This is a non-specific granulomatous inflammatory reaction to
prostatic secretions that are exposed to the stroma following acute or chronic prostatitis. Infectious
etiologies (TB, etc), however, must be ruled out when granulomas are encountered.

II. BENIGN PROSTATIC HYPERTROPHY (BPH) - This is actually a misnomer since the lesion primarily
represents a nodular hyperplasia of the gland. It is a common disorder which usually begins in the fifth
decade and which increases in frequency with increasing age (95% of men over age 70). Only 5-10% of
patients, however, will require surgical treatment. Although the etiology is unclear, there is an apparent
relative imbalance between androgens and estrogens with the increasing estrogen levels seen with
advancing age somehow sensitizing the prostatic tissue to the effects of testosterone since BPH will only
occur in the presence of intact testes. The periurethral tissue is the most susceptible and leads to a spongy
nodular enlargement of the median and lateral lobes which may cause symptoms related to partial urinary
obstruction or retention of urine and predispose to urinary tract infections. There does Ilot appear to be
allY causal relatiollship to the subsequellt developmellt o/prostatic callcer. Microscopically, there is
epithelial hyperplasia causing papillary budding and infolding of epithelium into the lumen of cystically
dilated glands, inspissated prostatic secretions, focal squamous metaplasia, and fibromuscular hypertrophy.
III. PROSTA TIC CARCINOMA - This is probably the most common malignancy in males, but ranks behind
lung and colon cancer in terms of mortality. Unusual before the age of 50, it increases in frequency with
advancing age so that prostatic cancer occurs in up to 70% of men by the age of 80. Many of these cancers,
however, are small, biologically indolent, and identified incidentally on microscopic examination of the
prostate for other reasons (Stage A carcinoma). Again, the etiology is unclear but it appears that genetic,
environmental, and hormonal factors are involved. The tumor originates in the "peripheral" zone of the
gland. It frequently involves the posterior lobe and may be palpated as a hard irregular nodularity on rectal
examination (Stage B carcinoma). Microscopically almost all are adenocarcinomas and most of these are
well-differentiated with few mitoses and little pleomorphism. "Back-to-back" glandular crowding without
intervening stroma, a single layer epithelium, and capsular, vascular, or perineural "lymphatic" invasion are
all indicators of malignancy. The Gleason grading system is the most widely used and assigns a tumor grade
based on the degree of glandular differentiation and the growth pattern of the tumor in relation to the
stroma. The major symptom is urinary obstruction, but this usually does not occur until late in the course
of the disease so that the majority of patients present with extension of the tumor through the prostatic
capsule (Stage C) or metastases (Stage D). Lymphatic spread is to regional lymph nodes and hematogenous
spread is generally to bone (where the tumor produces osteoblastic lesions). Death is usually due to
disseminated disease or obstructive nephropathy. Prostate spec~fic antigen (PSA) is a protease that is
excreted exclusively by prostate epithelial cells and can be measured in the serum. Although it can be
elevated in men with either benign (BPHIprostatitis) or malignant disease ofthe prostate, it may be of value
in screening for malignant disease in those patients at increased risk.

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 PLACENTAL DISORDERS

I. REVIEW OF NORMAL - Histologically, first trimester villi are large and hydropic. They are bordered
by two layers of trophoblast: an outer syncytiotrophoblast and an inner cytotrophoblast. The vessels
contain erythroblasts and nucleated red blood cells, but persistence of these beyond 10 weeks gestation is
abnormal. In the latter part of the first trimester, Hofbauer cells become increasingly numerous; these cells
function in nutrient transport and, probably, in host defense. Second trimester villi become about half the
size of a first trimester terminal villus. The trophoblastic border progressively condenses. Its double-
layered appearance becomes lost as the inner cells become less and less apparent. These inner Langhans
cytotrophoblastic cells never completely disappear but, rather, are obscured by syncytiotrophoblast. Third
trimester villi progressively halve their size again. Early in the third trimester the Hofbauer cells become
less conspicuous as their villous boundary develops syncytial knots. Development of knotting becomes
recognizable in the latter half of the third trimester. Irrespective of the histologic plane of sampling, no
more than four or five vascular channels are ever present in a normal third trimester terminal villus.
Grossly, although there is a variability in the size and weight of "normal" placentas, term placentas
(trimmed of their membranes) in excess of 600 grams are abnormal. This may be due to diabetes, any kind
offetal immunohemolytic anemi~ chronic intrauterine infection, fetal heart failure or maternal anemia; but
most often, the cause is idiopathic.
II. VASCULAR DISORDERS

A. TOXEMIA OF PREGNANCY

1. PRE-ECLAMPSIA - This consists of a clinical triad of edema, hypertension, and proteinuria

which usually develops during the third trimester of pregnancy and may clinically present
as headaches, blurred vision, and abdominal cramps. Placental prostaglandins protect
pregnant women against an increased vascular sensitivity to angiotensin. If this protection
is lost, the increased sensitivity leads to vasoconstriction, hypertension, and vascular
damage. Preeclamptic toxemia is evidenced by shrinkage of villi and by placental
infarction.
2. ECLAMPSIA - This refers to the development of convulsions in addition to the findings of
pre-eclampsia and is usually associated with DIC. Immunologic damage to uterine vessels
causes placental ischemia leading to the release of thromboplastic substances which initiate
DIe.

B. INFARCTS - Many placentas show an occasional infarct. There are times when infarcts are
associated with severe fatal and neonatal compromise and other times when infarction of up to
one-third of the placenta is free of complication. 40% of small-for-gestational age newborns have
placentas with severe infarction and chronic ischemic change.

III. INFLAMMATORY DISORDERS - Acute inflammatory cells which infiltrate throughout the membranes
and placental surface (chorioamnionitis) are a consequence of ascending infection, even if it be that the
specific etiology is not proven by routine culture techniques. Causative organisms include chlamydia,
mycoplasma and anaerobes, in additional to the more popularly recognized organisms such as group B
beta-hemolytic streptococcus and E. coli. Spontaneous abortion between 20-28 weeks gestation is almost
always associated with chorioarnnionitis, and some initially normal neonates, who have severe
chorioamnionitis, later succumb to sepsis. It has become clear in the past few years that congenital
infections traditionally regarded as "transplacental" (e.g. cytomegalovirus, herpes simplex virus and rubella
virus) may also have as their origin the ascent of an agent from an infected cervix. Group B hemolytic

165
 Streptococcus is now the commonest cause of perinatal bacterial sepsis. The organism can be isolated from
cervical cultures of anywhere from 5 to 30% of asymptomatic pregnant women, and also from their sexual
partners. There are two neonatal clinical presentations: an acute septicemic form occurs in the first few
hours or days of life, typically with features of pneumonia; a delayed meningitic manifestation presents
anywhere from the 2nd to the 12th week of life. E. coli accounts for about 75% of gram negative perinatal
infections while Staphylococci, listeria monocytogenes, and other organisms may, on occasion, cause
pneumonia, meningitis and sepsis. The main causes of chronic congenital infections can be conveniently
listed as Toxoplasmosis, Rubella virus, Cytomegalovirus, Herpes simplex virus and Syphilis. These
diseases, conveniently called "TORCH(S)", have similar overt and/or inapparent clinicopathologic features:
fetal growth retardation, hepatosplenomegaly, (hepatitis and extramedullary hematopoiesis), skin petechiae
and/or purpuric lesions (EMH), encephalitis, cataracts, chorioretinitis, microcephaly, encephalomalacia,
cerebral calcifications, disseminated intravascular coagulation, and cardiac and hearing defects.
IV. GESTATIONAL TROPHOBLASTIC NEOPLASMS - This group of tumors include a spectrum of
neoplastic diseases of trophoblastic tissue which range from benign (hydatidiform mole) to overtly
malignant (choriocarcinoma).

A. COMPLETE HYDATIDIFORM MOLE - This occurs in approximately 1:2000 pregnancies and tends
to have a higher incidence in older women (40-50 yrs). It is felt to arise from loss or inactivation
of matemal chromosomes in the fertilized egg. The embryo dies at an early stage, but the placenta
continues with abnormal growth. Clinically these often present in the 4th to 5th month of pregnancy
with the passage of vesicular tissue from the vagina, and there may be a history of uterine bleeding
since early pregnancy. The uterus is usually larger than would be expected for the gestational age
but no fetus is detectable. HCG levels are elevated and there may be bilateral ovarian enlargements
due to theca-lutein cysts. Grossly, a delicate bulky tumor consisting of grape-like cystic structures
fills the endometrial cavity. Microscopically, there is hydropic swelling of avascular villi with
variable degrees of trophoblastic hyperplasia and anaplasia. The major complication is the
potential for the development of choriocarcinoma.
B. INCOMPLETE (PARTIAL) MOLE - This refers to a mixture of normal and hydropic villi without
appreciable trophoblastic proliferation. A fetus with a triploid phenotype is generally present. There
is much less risk of subsequent development of choriocarcinoma as compared to a complete mole.
C. INVASIVE MOLE (chorioadenoma destruens) - Invasion into and/or through the myometrium by
molar villi and trophoblastic tissue can result in uterine perforation. This is clinically characterized
by bleeding associated with irregular uterine enlargement. The neoplasm may embolize to distant
sites (i.e. lungs) but the embolic lesions will usually spontaneously regress when the uterine lesion
is removed. The response to chemotherapy is usually good and can be monitored by HCG levels.
D. CHORIOCARCINOMA - This is a trophoblastic malignancy which may arise from either a preexisting
normal pregnancy (20%) or an abnormal pregnancy (50% of which are hydatidiform moles).
Clinically, it is characterized by irregular bleeding during otherwise apparently normal pregnancy
or continued bleeding after miscarriage. The tumor is usually soft and friable with areas of
hemorrhage and necrosis. It consists of neoplastic trophoblastic tissue containing both
cytotrophoblasts and syncytiotrophoblasts without the presence of chorionic villi. The tumor
spreads early and widely by lymphatic and hematogenous dissemination. Metastases are usually
present at the time of diagnosis and most commonly involve lungs, vagina, brain, liver, and kidney.
Metastatic lesions are occasionally found without evidence of a primary uterine lesion. As long as
viable syncytiotrophoblasts are present, there are markedly elevated levels ofHCG which can be
used to monitor the course of the disease. Chemotherapy with methotrexate and actinomycin has
been very effective with cures being possible. Unfortunately, choriocarcinomas arising outside of
the gestational setting do not show the same response or prognosis.

166
 URINARY TRACT

KIDNEY

I. REVIEW OF NORMAL

A. EMBRYOLOGY - The kidney arises from a succession of developmental changes that occur along
the nephrogenic cord which resides in the urogenital ridge on the dorsal wall of the coelomic
cavity. Running lengthwise through the nephrogenic mesenchyme is a tubular structure (pronephric
duct) connected at the caudal end to the cloaca. The development of the cephalad pronephros
occurs early and degenerates as the mesonephros is developing. The pronephric duct at this point
becomes the mesonephric (wo~ffian) duct. As the mesonephros is degenerating, the true kidney
is being developed from the most caudal portion of the nephrogenic cord, the metanephros. A
ureteric bud develops from the caudal end of the mesonephric duct and penetrates into the
metanephric mesenchyme. The stalk of the ureteric bud becomes the ureter while its expanded
cranial end becomes the renal pelvis. The pelvis divides successively to form the major and minor
calyces. Blind ended collecting tubules penetrate the nephrogenic mesenchyme and give off
approximately twelve generations of dichotomously branching arching ducts. The leading portions
of these ducts induce the development of adjacent metanephric vesicles which elongate rapidly to
form the distal convoluted tubule, the loops of Henle, the proximal convoluted tubule, and
Bowman's space. The distal convoluted tubule and the proximal portion of the collecting duct
eventually fuse. The nephron, therefore, develops from the metanephric mesenchyme while the
collecting system develops from the ureteric bud. As the fetus matures, the kidneys ascend cranially
from their initial pelvic location and derive their vascular supply from a succession of more
cranially located renal arteries.
B. ANATOMY - The renal cortex consists of glomeruli, proximal and distal convoluted tubules and
collecting ducts. It normally measures approximately 1.5 cm in thickness and includes the columns
of Bertin which extend between the medullary pyramids. The medulla consists of the renal
pyramids whose tips (papillae) protrude into the minor calyces. The pyramids contain the loops of
Henle and the collecting ducts. A glomerulus consists of endothelium; visceral and parietal
epithelial cells (which define Bowman's space); and the "supporting" mesangial cells and their
matrix. In addition, a glomerular basement membrane is interposed between the endothelium and
the foot processes of the visceral epithelial cells (podocytes). The glomerular filter consists of
fenestrated endothelial cells, the basement membrane, and the foot processes. Substances penetrate
or are excluded by this filter on the basis of size and charge.

167
II. CONGENITAL/DEVELOPMENTAL DISORDERS

A. RENAL AGENESIS - Bilateral agenesis is incompatible with life and is associated with pulmonary
hypoplasia., oligohydramnios, and Potter's facies (wide-set eyes, beaked nose, micrognathia, and
low-set ears). Unilateral agenesis is more common and seen most frequently in males. The
remaining kidney may become hypertrophied and there may be association with esophageal atresia
or congenital heart disease.
B. PELVIC KIDNEY - This results from the failure of kidney to ascend to its proper location. May be
identified as a pelvic mass but generally asymptomatic although somewhat more prone to infection
and ureteral obstruction.
C. HORSESHOE KIDNEY - This is a fusion of the kidneys into one organ which stretches across the
midline. The majority are fused at the lower pole. Again, they are usually asymptomatic but are
prone to infection and ureteral obstruction.
D. CYSTIC DISEASE

1. CHILDHOOD POLYCYSTIC KIDNEY (POTTER'S TYPE I) - This is an autosomal recessive

disease that is almost always bilateral and usually eventuates in death soon after birth. It
is characterized by dilated collecting ducts which gives a uniform spongy appearance to
the kidneys. Although the cortical nephrons are decreased in number, they are relatively
normal in appearance. It is also associated with cystic changes in intrahepatic bile ducts,
and those who survive childhood may later present with jaundice and signs of liver failure.
2. DYSPLASTIC KIDNEYS (POTTER'S TYPE II) - This results from failure of the ureteric bud
to induce nephron formation from the metanephric mesenchyme. Both the collecting ducts
and abnormal nephrons are decreased in number and the collecting ducts are dilated.
Bilateral involvement is probably more common but leads to death soon after birth. It may,
however, be unilateral and these are the patients who come to medical attention because
of an abdominal mass. The kidney may be large and polycystic or small. Microscopically,
there are abnormal collecting ducts surrounded by collars of undifferentiated mesenchyme.
The majority will show islands of cartilage formation.
3. ADULT POLYCYSTIC KIDNEY (POTTER'S TYPE ill) - This has an autosomal dominant
inheritance with high penetrance. It affects up to 1:500 individuals and is almost always
bilateral. It results from interference with nephron induction as in Type II but at a later
stage of development. There are, therefore, a variable number of normally formed and
functioning nephrons. These patients usually do not come to medical attention until the 3rd
or 4th decade of life. They may present with hematuria resulting from hemorrhage·into the
cysts, but will eventually develop chronic renal failure. This may also be associated with
benign hepatic cysts or saccular "berry" aneurysms of the cerebral vasculature.
4. MEDULLARY SPONGE KIDNEY - This is a disease of unknown etiology which is often
discovered incidentally during workup for some other problem. It consists of benign
dilatation of the collecting ducts in the medulla of the kidney which may predispose to
infection or stone formation.
5. UREMIC-MEDULLARY CYSTIC DISEASE - This is possibly an autosomal recessive disease
which causes renal failure in teenagers and young adults. Small medullary cysts (especially
at the corticomedullary junction) are associated with the development of cortical tubular
atrophy, interstitial fibrosis, chronic inflammation, and decreased numbers of glomeruli.
The initial symptoms may be related to loss of tubular function with loss of concentrating
ability (polyuria nocturia), sodium wasting, and tubular acidosis.

168
III. RENAL CALCULI - Calculi may arise when there is an excessive amOlmt of stone constituents (calcium,
oxalates, uric acid, cystine, etc) present in the urine and a favorable environment for the precipitation of
those constituents. Acid urine pH will facilitate precipitation of uric acids and cystine. Alkaline urine pH
will precipitate phosphates which may combine with magnesium and ammonium (converted from urea by
Proteus and other urea-splitting bacteria) to form large staghom calculi that may fill the calyces and pelvis.
The presence of bacteria and the stasis of urine are also predisposing factors. The majority of stones contain
calcium which may be mixed with oxalate, phosphate, or hydroxyapatite. Large stones tend to be
asymptomatic and but predispose to infection and may produce hematuria due to trauma to the urothelial
surfaces. Smaller stones are more likely to enter into and obstruct the ureter creating clinical symptoms of
colicky abdominal pain radiating from the flank to the groin.
IV. URINARY OBSTRUCTION - This can result from stones, BPH, congenital defects, tumors, functional
disorders, pregnancy, etc. and predisposes to infection and stone formation. Hydronephrosis refers to the
dilatation of the renal pelvis and calyces due to the obstruction to the outflow of urine and is associated
with progressive atrophy of the kidney. Depending on the site of obstruction, it may be unilateral or
bilateral. The renal changes become irreversible after about three weeks of complete obstruction or several
months of partial obstruction. If the obstruction is acute, there may be pain related to acute dilatation of
collecting ducts or stretching of the renal capsule. Gradual unilateral obstruction, either partial or complete,
may be asymptomatic and found only during evaluation of other problems. Bilateral partial obstruction may
first become manifest by loss of concentrating ability with resulting polyuria and nocturia. Hypertension
may ensue. Bilateral complete obstruction will obviously lead to anuria.
V. GLOMERULAR DISEASE - Injury to the glomerulus is often reflected by the presence of blood
(hematuria) or protein (proteinuria) in the urine implying that the filter which normally excludes these
substances is damaged.

A. MECHANISMS OF GLOMERULAR DAMAGE

1. LOSS OF GLOMERULAR BASEMENT MEMBRANE (GBM) POLYANIONS - This allows

increased filtration of anionic compounds such as albumin.
2. HYPERFILTRATION - A decreased number of functioning nephrons places an increased
dema.I)d on those that are functional. To maintain normal filtration, this demands an
increased glomerular filtration rate (GFR) resulting in increased glomerular blood flow and
increased capillary pressures. This leads to increased permeability to plasma proteins
which accumulate in urine or in the mesangium, the latter leading to mesangial
proliferation and sclerosis of the glomeruli. This reduces the number of functioning
glomeruli and a vicious cycle is initiated.
3. IMMUNOLOGIC

a. Native "fixed" antigens - Antigens on the GBM or associated with the podocytes
may induce antibody formation. The former would give a diffuse, linear staining
on immunofluorescence while the later would give a granular, subepithelial
staining on immunofluorescence.
b. Non-glomerular antigens - These may become attached to, and incorporated
within, the glomerular structure (i.e. DNA, lectins, cationic proteins bound to
anionic GBM, etc.) and be secondarily attacked by antibody. This would lead to
a granular appearance on immunofluorescence.
c. Circulating antigen-antibody complexes - These can become filtered and
trapped in the glomeruli, activate complement, and attract neutrophils and
monocytes which liberate digestive enzymes. When there is antibody excess,
however, the Ag-Ab complexes are usually large and are picked up by the RES.

169
 With small production of Ab, the Ag-Ab complexes usually are soluble and do not
become trapped, but with moderate Ab production, the insoluble complexes may
be filtered out. High cationic compounds tend to traverse the GBM and become
trapped in the subepithelial region, anionic compounds tend to be trapped in the
subendothelial region, and neutral compounds tend to get trapped in the
mesanglUm.

B. GLOMERULAR RESPONSE TO INJURY - Glomeruli respond to injury with cellular proliferation

(which can involve endothelial, epithelial, or mesangial cells), inflammatory response (manifested
primarily by neutrophils and monocyte/macro phages) , glomerular basement membrane thickening
(either true thickening or by the deposition of electron dense deposits), and/or hyalinization and
sclerosis (an 19am of plasma protein, basement membrane material, and mesangial matrix which
destroys glomerular architecture).
C. NEPHRITIC SYNDROME - This is a constellation of signs characterized acutely by hematuria, red
blood cell casts, azotemia, hypertension, and oliguria.

1. ACUTE PROLIFERATIVE (DIFFUSE PROLIFERATIVE, POST-INFECTIOUS)

GLOMERULONEPHRITIS - This disorder most frequently results from trapping of immune
complexes involving exogenous antigens, but less frequently may be due to endogenous
antigens. Although this does affect adults, it is seen most frequently in children 1-3 weeks
after a Group A p-hemolytic streptococcal infection. Children most frequently present with
malaise, fever, oliguria, hematuria, nausea, periorbital edema, and mild-moderate
hypertension. Red blood cell casts and mild protein « 1 gm) are present in the urine. In
adults, there may be abrupt onset of hypertension or edema. In the acute phase, there is
often elevated ASO titers, decreased C3, positive cryoglobulins, and elevated ESR. The
kidneys may be swollen and "flea-bitten". Microscopically, the glomeruli are hypercellular
(proliferation of mesangial, endothelial, and to a lesser extent, epithelial cells), have a
diffuse neutrophilic and monocytic infiltrate, and are bloodless. On immunofluorescence,
there is granular deposition ofIgG and C3 in the subepithelial region. In children, 95%
recover clinically within two months of onset and morphologically within three years
although a few may progress to chronic glomerulonephritis or rapidly progressive
glomerulonephritis. The prognosis in adults is controversial but probably a little poorer.
2. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) - This is a disease which
affects children and young adults. Light microscopy shows hypercellular glomeruli due to
endothelial and mesangial proliferation creating a centrilobular accentuation and a "tram-
track" appearance to the basement membrane due to mesangial interposition (mesangial
matrix and cellular cytoplasm being forced between the endothelial cells and the GBM. On
EM, electron dense deposits are found in subendothelial (Type I), intramembranous (Type
II, Dense Deposit Disease), or subendothelial and subepithelial (Type III) locations. Most
cases slowly progress to chronic renal failure but some patients may develop RPGN. There
is a high incidence of recurrence in transplants.
3. CRESCENTIC or RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN) - This is a clin-
icopathologic syndrome in which there is a rapid progression to renal failure in those
patients who show morphologic evidence of glomerular "crescent" formation (prolif-
erating parietal epithelial cells, monocyte-macrophages, and fibrin). They may have an
abrupt onset of oliguria and hematuria with lesser degrees of hypertension, edema, and
proteinuria. Crescent formation is always an indicator of severe underlying glomerular
disease and may be associated with:

170
 a. Immune Complex Disease (Post-infectious GN) - A few patients (more
commonly adult patients) with post-infectious GN develop persistent oliguria
leading to anuria.
b. Goodpasture's Disease (Anti-GBM) - This is seen most frequently in young
adult males who develop an anti-GBM antibody which may also cross reacts with
pulmonary alveolar BM. Pulmonary involvement may occur first and is usually
manifested by recurrent hemoptysis or pulmonary hemorrhage. In the kidney, there
is early focal and segmental then diffuse fibrinoid necrosis in the capillary tufts,
degeneration of the epithelial and endothelial cells with disruption of the GBM and
fibrin deposition. On immunofluorescence, there is linear IgG and C3 deposition
along the GBM.
c. Idiopathic Crescentic GN (no immune deposit disease) - This is generally a
diagnosis of exclusion and characterized by lack of immunofluorescence.

4. IgA NEPHROPATHY (Berger's Disease) - This is a form of focal glomerulonephritis charac-

terized by recurrent self-limiting episodes of hematuria in children or young adult males
often following an upper respiratory tract infection. Less frequently it may present as the
nephrotic syndrome. The histology varies from focal GN with segmental mesangial
proliferation to diffuse mesangioproliferative GN to RPGN but on immunofluorescence,
deposits ofIgA, properdin, and C3 are identified diffusely throughout the mesangium. It
may be a genetic abnormality with overproduction of IgA or excessive exposure to
antigens eliciting an IgA response. It is slowly progressive with 20% progressing to chronic
renal failure.

D. NEPHROTIC SYNDROME - This is a constellation of signs characterized by proteinuria (> 3.5

gm/day), hypoalbuminemia (reversed albumin:globulin ratio), hyperlipidemia (increased LDL
and/or VLDL), Iipiduria (free fat and oval fat bodies in urine), and edema (pitting edema most
marked in dependent and periorbital soft tissue due to hypoalbuminemia and salt and water
retention). Complications include infections (due to loss of immunoglobulins and complement) and
thrombosis (due to loss of anticoagulant factors).

1. MINIMAL CHANGE DISEASE (lipoid nephrosis) - This disorder represents the most
common cause of nephrotic syndrome in children but also accounts for 15-20% of adult
cases. The pathogenesis is uncertain but there is a selective proteinuria to low molecular
weight proteins. Light microscopy is normal and immunofluorescence shows no consistent
evidence of Ig, C', or electron dense deposits in the glomeruli. Electron microscopy,
however, reveals visceral epithelial distortion with cytoplasmic vacuolization, swelling and
retraction ("fusion") of foot processes, and flattening of the epithelial cells against the
capillary basement membrane. Response to corticosteroid therapy is dramatic but a
significant proportion of patients will have periodic relapses after steroid withdrawal. The
disease does not appear to progress to chronic renal disease.
2. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FOCAL SCLEROSIS) - Although this may
represent non-specific glomerular change, there is a group of patients that develop an
insidious onset of nephrotic syndrome but also have micro-hematuria, hypertension, non-
selective proteinuria, deposits ofIgM and C3 in sclerotic mesangium, a poor response to
steroids, and a high (50%) progression to chronic renal failure. The lesions begin in the
juxtarnedullary glomeruli and initially consist of focal and segmental collapse of capillary
structure with adhesions to Bowman's capsule. On EM, in addition to the changes of lipoid
nephrosis, there is focal loss of epithelial cells and thickening of the capillary basement

171
 membranes in the affected areas. Presumably, protein is able to enter the mesangium
where it initiates a mesangial reaction with sclerosis and the accumulation of a PAS
positive material (hyalinosis). With time, there is progression to global sclerosis. There is
a high incidence of recurrence (25-50%) in transplants.
3. MEMBRANOUSGLOMERULONEPHROPATHY - This is the most common cause of nephrotic
syndrome in adults. Grossly, the kidneys are large, swollen, and pale. With light
microscopy, there is normal glomerular cellularity but uniform diffuse thickening of the
capillary walls which, as demonstrated by EM, is due to irregular subepithelial deposits of
electron dense material (Stage I). Granular deposits of IgG and C' may be seen on
immunofluorescence. GBM material subsequently accumulates between deposits forming
"spikes" (Stage II) which eventually surround the deposits (Stage III) and incorporate them
into the GBM (Stage IV). Additionally, there is a loss of epithelial foot processes.
Although up to 15% may be associated with known antigens, the remainder are idiopathic
and presumably the result of chronic Ag-Ab reactions. Although some spontaneous
remissions occur, most progress to renal failure over a variable period of time.

VI. PYELONEPHRITIS (TUBULOINTERSTITIAL NEPHRITIS) - Most commonly infectious in origin, the

dominant organisms are gram negative bacteria (usually E. coli) from the patient's intestinal tract. The
normal kidney is resistent to blood borne infection, therefore the most common route of infection is
bacterial ascension from the urinary bladder.

A. ACUTE PYELONEPHRITIS - Acute disease is often associated with urinary obstruction,

instrumentation of the urinary tract, vesicoureteral reflux, pregnancy, prior renal disease, and
diabetes. Symptoms include acute onset of fever and malaise, costovertebral angle pain, dysuria,
frequency, and urgency. Histology reveals an interstitial suppurative inflammation and tubular
necrosis. Abscesses, which are often multiple, are most readily apparent in cortex. The acute
inflammatory cells rupture into tubules and travel to collecting ducts. Laboratory studies reveal
pyuria, WBC casts, and positive cultures with greater than 105 organisms. Complications may
include necrotizing papillitis, (usually bilateral), pyonephrosis, and perinephric abscess. Healing
leads to scarring with cortical depression and calyceal deformity. Appropriate antibiotic therapy
is needed to eradicate the causative organisms. The incidence of recurrence, however, is as high
as 33%.
B. CHRONIC PYELONEPHRITIS - This is a m<yOf cause of chronic renal failure. Although it may be the
result of chronic obstruction leading to recurrent infections, more commonly it is the result of
reflux nephropathy. Clinically, it may be characterized by repeated bouts of acute pyelonephritis
or it may be insidious, presenting as renal insufficiency and hypertension. Tubular damage leads
to polyuria and nocturia. Grossly, the kidneys are small with broad irregular cortical scars and
deformed blunted calyces. Microscopically, there is tubular atrophy and/or dilatation with protein
casts ("thyroidization"), interstitial fibrosis, and chronic inflammation. Periglomerular fibrosis and,
in the late stages, glomerular sclerosis may develop. On culture, bacteria mayor may not be
present.
C. DRUGS AND TOXINS - These can produce an interstitial nephritis either through immunologic
hypersensitivity or direct toxic damage to the tubules. Depending on the drug or toxin, this may
induce sudden damage with acute renal failure or cumulative damage over a longer period of time
leading to chronic renal failure.

VII. HYPERTENSION - Blood pressure is determined by cardiac output (influenced by blood volume) and
the peripheral resistance of arterioles. Peripheral resistance is regulated by vasoconstrictors (angiotensin
II, leukotrienes, thromboxane, catecholamines) and vasodilators (kinins and prostaglandins).

172
 A. RENAL CONTROL

1. SECRETION OF PRESSOR SUBSTANCES - Decreased pressure in afferent arterioles,

decreased sodium or chloride reaching macula densa, or direct sympathetic (B-adrenergic)
stimulation of juxtaglomerular (JG) cells cause release of renin. Renin acts on a circulating
liver-derived a globulin (angiotensinogen) to produce angiotensin I which is cleaved to
angiotensin II which in tum increases peripheral resistance. Renin also stimulates
aldosterone secretion from the adrenal cortex (zona glomerulosa) to retain sodium and
water which increases blood volume. There is a negative feedback on renin secretion by
1) decreased stimulation of stretch receptors of afferent arterioles due to increased blood
pressure; 2) increased blood volume which leads to increased GFR which leads to
decreased sodium reabsorption in the proximal tubule which leads to increased sodium
reaching macula densa; 3) increased blood pressure which decreases the sympathetic
stimulation of JG cells; and 4) direct suppression of JG cells by angiotensin II. Any
condition resulting in increased renin therefore produces increased blood pressure.
2. MAINTENANCE OF FLUID AND ELECTROLYTE BALANCE - Sodium is controlled by GFR
(decreased GFR causes less filtered Na+ and increased proximal tubular reabsorption),
aldosterone (increases Na+ reabsorption in distal tubule), and natriuretic factor (increased
volume causes Na+ loss by an unknown mechanism). Therefore mechanisms that leads to
increased Na+ and H20 retention promotes increased blood pressure.
3. RENALANTIINPERTENSIVES - These include prostaglandins, kallikrein-kinin, and neutral
lipid factor. Therefore, mechanisms which decrease secretion of antihypertensives
promotes increased blood pressure.

B. RENAL MANIFEST A TlONS

1. BENIGN (ESSENTIAL) HYPERTENSION - The kidneys show bilateral, fine cortical

granularity. Thickening and hyalinization of walls of arterioles and small arteries
(arteriolonephrosclerosis) is not the cause of increased blood pressure but once formed
may perpetuate or accelerate increased blood pressure. These vascular changes cause
ischemic damage leading to glomerular damage, tubular atrophy, and interstitial fibrosis.
Collagen is deposited inside Bowman's capsule. The larger arcuate and interlobular arteries
show reduplication of the elastic lamina and fibrosis of media.
2. MALIGNANT HYPERTENSION - This results from an accelerated progression of previously
"benign" hypertension. Fibrinoid necrosis of arterioles and "onion skinning" of interlobular
arteries lead to ischemia and infarction. Increased renin, angiotensin II, and aldosterone
are present in the serum. A vicious cycle is established where increased blood pressure
causes endothelial damage, leading to fibrin deposition in vessels, leading to renal
ischemia, leading to increased renin, angiotensin II, and aldosterone, leading to increased
blood pressure, leading to further endothelial damage. Clinically, there may be abrupt
onset of cardiovascular or CNS symptoms (headache, nausea and vomiting, visual
scotomas, etc). Unless treated, death by cardiovascular disease, stroke, or uremia generally
follows within a year.

VIII. ACUTE RENAL FAILURE (ARF) - Thix may be due to diffuse vascular disease (polyarteritis, malignant
hypertension, etc), severe glomerular disease (RPGN), acute interstitial disease (hypersensitivity to drugs),
massive pyelonephritis, cortical necrosis (DIC), urinary obstruction, or acute tubular necrosis.

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 A. ACUTE TUBULAR NECROSIS (ATN)

1. ISCHEMIA (hypotension, shock, decreased RBF) - This causes patchy epithelial necrosis
throughout the tubule (more prominent in proximal tubule) with damage to the basement
membrane and hyaline or granular cast formation in the distal tubule and collecting duct.
2. TOXINS (heavy metals, solvents, antibiotics, mushrooms, antifreeze etc.) - These generally
cause proximal tubular epithelial necrosis without rupture of the basement membrane and
sparing of the distal tubule.
3. CLINICAL COURSE - The clinical onset generally begins 24-36 hours after the initiating
insult. Oliguria and decreased GFR leads to fluid overload, uremia and electrolyte
retention. This may last up to 3 weeks. Oliguria arises from tubular fluid leaking into the
interstitium and tubular obstruction from interstitial edema or cast formation. Decreased
glomerular filtration is the result of decreased perfusion or prolonged vasoconstriction,
decreased glomerular capillary permeability, and tubular obstruction. Recovery is heralded
by a diuresis which may cause electrolyte loss. As tubular damage is repaired the diuresis
abates. In general, toxic ATN has a better progress because unless other organs are
damaged by the toxin, there is no severe underlying disease.

IX. CHRONIC RENAL FAILURE - When the GFR is 20-30% of normal, azotemia (increased BUN and
creatinine) will develop and is often associated with hypertension. When GFR is 15-20% of normal
azotemia is complicated by the symptoms of the uremic syndrome.

A. FLUID, ELECTROLYTE, AND ACID/BASE MANIFESTATIONS - Tubular damage impairs the ability
to concentrate urine leading to polyuria and nocturia. Decreased glomerular filtration will increase
N a+ and water retention leading to edema. Retention of H+ produces metabolic acidosis and
resultant Kussmaul breathing. Increased P0 4- and decreased Ca++ leads to increased PTH and
parathyroid hyperplasia Decreased serum Ca++ results from the inability of the kidney to synthesize
1,25 OH2 Vit. D. and leads to renal osteodystrophy.
B. CARDIOPULMONARY MANIFESTATIONS - Volume overload and salt retention may lead to
congestive heart failure. Hypervolemia may cause hypertension, and uremia may produce
pericarditis, pleuritis, and pneumonitis.
C. HEMATOLOGIC MANIFESTATIONS - Decreased production of erythropoietin, uremic hemolysis,
and GI bleeding contribute to the development of normochromic, normocytic anemia. Abnormal
platelet functioning leads to bleeding diatheses.
D. GASTROINTESTINAL MANIFESTATIONS - These include nausea and vomiting, GI bleeding.
E. DERMATOLOGICMANIFESTATIONS - These include itching, accumulation of urochrome pigment,
uremic frost.
F. NEUROLOGIC MANIFESTATIONS - These include myopathy, neuropathy, and encephalomyopathy
which may lead to coma.

X. NEOPLASMS

A. RENAL CORTICAL "ADENOMAS" - These are fairly common, asymptomatic benign lesions < 2 em
in size and yellow in color. The histologic architecture may be papillary, tubular, cystic, or solid.
B. RENAL CELL CARCINOMA (RCC) - The most frequent form of renal cancer in adults, RCC tends
to occur in mid to late life and has a male predominance. Patients may be asymptomatic until the
tumor reaches a size to cause space-occupying problems or it may present as hematuria with or
without a palpable mass. It may have endocrine-like effects and produce polycythemia

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 (erythropoietin), hypercalcemia (PTH), hypertension (renin), Cushing's (glucocorticoids), etc.
Grossly, the tumor is usually solitary, bulky, unilateral, yellow in color with foci of necrosis and
hemorrhage, and has a tendency to invade the renal vein. Microscopically, the architecture may be
papillary, tubular, solid, or trabecular. The characteristic cell is a clear cell with abundant clear
cytoplasm containing glycogen and lipid. Granular cells and spindle cells may also be present. The
clinical course is very unpredictable; the tumor can metastasize widely with the most common
locations being lung and bone.
e. ONCOCYTOMA - This is a relatively unusual tumor demonstrating a solid, mahogany-brown, well-
circumscribed gross appearance. It may attain a large size and be clinically difficult to differentiate
from RCC. The vast majority are low-grade and clinically behave in a benign fashion. The
oncocytes are composed of cells with abundant, acidophilic, granular cytoplasm (numerous
mitochondria) and small, round nuclei.
D. WILMS' TUMOR - This is one of the more common tumors of childhood. It may present with
abdominal pain, GI obstruction, hypertension, hematuria, or pulmonary metastases. Grossly, they
tend to be large unilateral (90%) masses and may extend across midline. The cut surface has a
variable appearance. Histologically, since the tumor is derived from nephrogenic mesoderm, it may
contain muscle, bone, cartilage, and fat with epithelial cells forming abortive tubules and primitive
glomeruli embedded in a spindle cell stroma. Striated muscle cells are the most commonly
identified mesenchymal components.
E. TRANSITIONAL CELL CARCINOMA (5-10% of adult renal cancer) - These tend to produce early
hematuria and are therefore often identified at an earlier stage. They may cause urinary obstruction
and hydronephrosis. They may be associated with concurrent transitional cell carcinomas elsewhere
within the urinary tract and the presence of multicentric lesions suggests this may be the effect of
a carcinogen in urine. The prognosis varies depending of the histologic grade of the tumor.

Xl RENAL MANIFESTATIONS OF SYSTEMIC DISEASE

A DIABETES MELLITUS - This is a major cause of nephrotic syndrome in the U.S. The renal
involvement is generally more severe in insulin dependent diabetes.

1. VASCULAR CHANGES - This includes hyaline arteriolosclerosis of both the afferent and
efferent arterioles.
2. GLOMERULAR CHANGES

a. Diffuse glomerulosclerosis - This is the most common glomerular lesion. There

is diffuse glomerular basement membrane thickening and mesangial cell
proliferation. Expansion of the mesangial matrix eventually crowds out the cells
of the glomerulus leaving a hyalinized, scarred, non-functional glomerulus.
b. Nodular glomerulosclerosis (Kimmelstiel-Wilson) - Although less common,
this is more suggestive of a diabetic etiology. "Hyalinized" mesangial nodules are
formed in the peripheral areas of the mesangium.
c. Capsular drop - This refers to a plasma protein coagulum which becomes
adherent to the parietal epithelium and is characteristic of diabetes.
d. Fibrin cap - This refers to a plasma protein coagulum between the glomerular
basement membrane and the epithelial cells. This, however, is a non-specific
change also associated with other glomerular diseases.

3. TUBULOINTERSTITIALCHANGES - These include acute or chronic pyelonephritis, papillary

necrosis (acute necrosis and sloughing of variable numbers of the renal papillae results in

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 colicky pam, hematuria, and acute renal failure. It may also be seen in non-diabetic patients
with renal infections, urinary obstruction, or analgesic abuse), thickening of tubular
basement membranes, and glycogen deposits in the tubular epithelial cells (Armanni-
Ebstein lesions).

B. SYSTEMIC LUPUS ERYTHEMATOSUS - The renal lesions of SLE are primarily confined to
glomerular changes resulting from the deposition of DNA-antiDNA complexes.

1. DIFFUSE PROLIFERATIVE GN (50%) - This presents as a nephritic syndrome with

hematuria and hypertension. Microscopically, there is diffuse glomerular hypercellularity,
focal necrosis, deposition of immunoglobulins and complement in capillary loops and
mesangium creating a "wire loop" appearance. By E.M., the deposits are characteristically
in a subendothelial location.
2. FOCAL PROLIFERATIVE GN (30%) - Clinically this presents as hematuria and proteinuria.
There is focal, segmental mesangial hypercellularity and thickening with focal necrosis.
3. MESANGIAL NEPHRITIS (10%) - This shows granular IgG and C3 in the mesangium and
a mild increase in mesangial cells and matrix. It presents as microscopic hematuria and
proteinuria.
4. DIFFUSE MEMBRANOUS (10%) - This presents as nephrotic syndrome or recurrent
proteinuria.

URINARY BLADDER
I. ACUTE CYSTITIS - This infection is almost always initially due to enteric organisms (E. coli, etc) and
are more frequent in females due to a shorter urethra and tendency for bacteria to colonize in the vagina
and distal urethra. Major predisposing factors include residual urine (congenital or acquired diverticulae,
benign prostatic hypertrophy), stasis of urine (low urine output, urinary retention), and mucosal trauma
(instrumentation, catheter, foreign bodies, etc). Grossly, the mucosa may appear hyperemic with exudates,
ulcerations, and/or hemorrhage. Microscopically, there is simply a hyperemia with an inflammatory
infiltrate. Clinically, it is manifested by frequency, dysuria, lower abdominal or pelvic pain.
II. CHRONIC CYSTITIS

A. MALAKOPLAKIA - This represents a chronic E. coli infection and is characterized by yellow

mucosal plaques comprised of foamy macro phages with a granular cytoplasm, giant cells, and
lymphocytes. The granules represent phagosomes stuffed with bacterial debris. Laminated
concretions (Michaelis-Gutmann bodies) are present both within and without macrophages.
B. CHRONIC INTERSTITIAL CYSTITIS (Runner's ulcer) - Typically occurring in middle aged women,
this is a cystitis of unknown etiology presenting with suprapubic pain, frequency, urgency, dysuria,
dyspareunia and malaise. The mucosa is edematous with petechial hemorrhages and focal mucosal
ulcerations. Pronounced chronic inflammation and fibrosis of the muscular wall of the bladder may
be present. Treatment is symptomatic and often ineffective leading to later development of
irritability, personality changes, and depression.
C. CYSTITIS CYSTICA - Mucosal epithelium becomes trapped beneath surface due to chronic
inflammation and forms cystic spaces. The epithelium may show mucous metaplasia (cystitis
glandularis).

III. CALCULI - These generally result from precipitation of urinary salts, especially phosphates in association
with magnesium and calcium. This is promoted by urea-splitting organisms which result in alkaline pH.

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IV. NEOPLASMS - Over 90% arise from urothelium in a sequence of hyperplasia (increased epithelial
thickness ~ 7 layer) -+ dysplasia (increased nuclear atypia., mitoses, cell immaturity) -+ carcinoma-in-situ
-+ carcinoma They tend to be multiple, both geographically and temporally. They often present as painless
hematuria.

A. PAPILLOMA - True benign papillomas are rare. They tend to arise on lateral walls or trigone and
usually single and polypoid in appearance with delicate papillary fronds.
B. TRANSITIONAL CELL CARCINOMA - More frequently seen in males, they tend to appear in middle
adulthood. Excretion and concentration of carcinogens in urine and/or chronic mucosal irritation
have been implicated as an etiology. Up to 70% are papillary, noninvasive low grade tumors.
Papillary lesions look alike grossly but histologically may range from "papilloma" (Grade I) to
Grade III. They are usually small (less than 0.5 cm), red, and possibly multicentric. As the
histologic grade worsens, the tumors tend to be flatter and more likely to become invasive. As
tumors recur, there tends to be greater cellular anaplasia.
C. SQUAMOUS CELL CARCINOMA - This is is less common than transitional cell carcinoma and usually
is an invasive, fungating, or ulcerative lesion that arises from preexisting squamous metaplasia.
D. ADENOCARCINOMA - This is relatively rare and arises from urachal remnants in the dome of the
bladder, metaplastic mucus secreting epithelium, or cystitis cystica.

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 HEAD AND NECK

TEETH AND ORAL CAVITY

I. REVIEW - Tooth formation results from the interaction of ectodermal (dental lamina, enamel organ) and
mesodermal (dental papilla, dental sac) constituents. Ameloblasts are derived from the enamel organ and
produce the tooth enamel while all other cell types involved in tooth production are of mesodermal origin.
Odontoblasts, derived from the mesenchyme of the dental papilla adjacent to the ameloblasts, produce
dentin (the dental "shock aborber") which surrounds the vital dental pulp. Dentin is covered by the
protective enamel over the crown of the tooth and by cementum (produced by cementoblasts) at the root
of the tooth. The tooth is anchored within its alveolar bone socket by the periodontal ligament which
originates from the mesenchyme of the dental sac and lies between the cementum and the bone.
II. CONGENITAL/DEVELOPMENTAL DISORDERS

A. ENAMEL HYPOPLASIA - This may be due to inherited factors (amelogenesis imperfecta), nutritional
deficiencies (rickets), excessive fluoride (snowcapped teeth or mottled enamel), childhood fevers
(chickenpox, measles), congenital syphilis (Hutchinson's incisors), hypocalcemia (parathyroid
disease, Vit.D deficiency) or other conditions that injure the ameloblasts during tooth development
or interfere with calcification of the enamel matrix. The crown of the tooth shows pitting of
variable severity, and tooth discoloration ranges from yellow to dark brown.
B. DENTINOGENESISIMPERFECfA - This is an autosomal dominant disorder in which the odontoblasts
produce a dentin matrix which does not calcifY normally. This produces a characteristic translucent
sheen to the teeth (Hereditary Opalescent Dentin) in addition to varying shades of discoloration.
The dentin tends to obliterate the pulp chambers and does not adhere normally to the overlying
enamel. The enamel chips off easily and the exposed dentin wears down readily to create stubby,
flattened teeth. This disorder has a close association with osteogenesis imperfecta.
C. FORDYCE GRANULES/SPOTS - These represent ectopic sebaceous glands which appear most
commonly on the buccal mucosa or inner lower lip as multiple, small, yellow-white nodules which
may be confluent. Although common, they are nonfunctional and asymptomatic.
D. MEDIAN RHOMBOID GLOSSITIS - Despite the name, this is not an inflammatory disorder. It is
characterized by a reddened, midline, rhomboid-shaped area on the dorsum of the tongue that is
devoid offiliform papillae. This area is felt to represent the failure of the tuberculum impar (tongue
side of thyroglossal duct) to degenerate before midline fusion of the lateral halves of the tongue.
It has no clinical significance although chronic candidiasis of the tongue may produce a similar
clinical appearance.
E. FISSURED TONGUE - This is a disorder characterized by deep clefts or fissures on the dorsum of
the tongue. It also has little clinical significance although food, candida, and bacteria may

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 accumulate in the depths of the grooves. Brushing of the tongue along with the teeth will prevent
possible infection.
F. GEOGRAPHIC TONGUE (MIGRATORY GLOSSITIS) - Of unknown etiology (inflammatory?
psychomatic?), this disorder is characterized by the appearance of irregular patches of
desquamation on the dorsum of the tongue (and occasionally buccal mucosa). The patches are
erythematous, devoid of filiform papillae (but not fungiform papilae), and outlined by a white
linear border. These areas heal fairly quickly but may reappear in a different location (hence the
term migratory). It generally is asymptomatic and requires no treatment.
G. HAIRY TONGUE - This condition usually develops after some type of alteration in the oral
environment (too much mouthwash, xerostomia, etc). For some reason, this induces
hyperkeratinization of the filiform papillae to produce hair-like filaments. These may become
colored (black hairy tongue) by microorganisms or exogenous pigment. Brushing of the tongue
may be helpful in removing the excess keratin and accumulated debris.
H. TORUS (pI. tori) - This represents a benign exostosis of the bone of the hard palate or mandible.
A relatively common lesion, they begin to appear in the late teenage years as a midline palatal
lesion and/or on the lingual side of the mandibular alveolar ridge (usually bilaterally). The may vary
in size and shape and are covered by an intact mucosa which is susceptible to trauma. They have
little clinical significance although they may interfere with the proper fitting of dentures.

III. ORAL CYSTS

A. DEVELOPMENTAL CYSTS - These are true cysts (epithelial lined cavities) that derive from abnormal
fusion of bones or from abnormal persistence of embryologic structures.

1. NASOPALATINE DUCT CYST - This common cyst originates from epithelial remnants of the
nasopalatine duct and is a midline lesion of the maxilla between the roots of the central
incisors. It may be lined by respiratory (cuboidal or pseudo stratified columnar) epithelium
and/or oral (stratified squamous cell) epithelium. They are usually asymptomatic and
discovered incidentally. On occasion, they may become infected and develop a fistula tract
to the mucosa of the hard palate (this is more likely in patients with dentures).
2. MEDIAN PALATAL CYST - This cyst arises in the midline of the hard palate from epithelial
rests trapped along the fusion line. Lined by squamous epithelium, they may reach a size
that requires surgical removal.
3. GLOBULOMAXILLARY CYST - This cyst develops in the lateral maxilla usually between the
roots of the lateral incisors and the canine teeth and should not be confused with an apical
periodontal cyst (see section on dental caries). These are lined by squamous epithelium and
are almost always asymptomatic.

B. ODONTOGENIC CYSTS - These are cysts that develop from epithelium associated with the
development of the teeth.

1. PRIMORDIAL CYST - This is a relatively uncommon cyst which develops from liquefaction
of the stellate reticulum of the enamel organ of either the deciduous tooth or the permanent
tooth. The cyst occupies the space where the tooth would have formed and is lined by
squamous epithelium. It has a predilection for the third molars but can occur anywhere.
Generally asymptomatic, it may expand, erode surrounding bone, and displace adjacent
teeth.
2. FOLLICULAR CYST (dentigerous cyst) - This cyst is more common than the primordial cyst
and develops from enamel epithelium after the crown of the tooth has formed. It is

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 therefore associated with the crown of a developed, but unerupted tooth (usually the
mandibular third molars). It is also lined by squamous epithelium and may expand with
resorption of bone and adjacent teeth. These cysts may be complicated by the
development of ameloblastoma or squamous cell carcinoma from the lining
epithelium.
3. ODONTOGENIC KERATOCYST - This is a generic name for odontogenic cysts that are lined
by a kertinizing squamous epithelium and may include a subset of primordial cysts and
follicular cysts. They can occur at any age, may be multiple, and the majority are located
in the mandible. As they enlarge, they erode the surrounding bone and often have a thin
wall. Depending on location and size, they may be difficult to remove surgically and are
especially noted for the high rate of recurrence.

IV. INFECTIOUS/INFLAMMATORY DISORDERS

A. DENTAL CARIES - Caries, perhaps the most common disease throughout the world, is basically due
to destruction of calcified tissue by acid-producing bacteria (multimicrobial) which colonize on the
tooth surface (dental plaque). These bacteria metabolize carbohydrate (usually unrefined sugar)
and produce acid that eats away at the enamel. Some individuals, based on heriditary factors, have
teeth that are more susceptible to caries than other individuals, but the elimination or control of
colonizing bacteria and their metabolic substrates exert a potent preventive effect. Saliva
production is an important defense mechanism since it helps buffer the bacterial acid production
and contains sIgA in addition to a variety of bacteriostatic factors. Xerostomia (drugs, radiation,
destruction of salivary gland, etc) greatly increases the incidence of caries. Fluoride, in appropriate
concentrations during tooth development, strengthens the enamel and mechanical brushing and
flossing is effective in removing accumulated dental plaque. In children, caries, often develop in
the pits and fissures since these are areas difficult to keep clean. Older people are also susceptible
to root surface decay as the gingiva recede and there is no enamel to protect the roots. Once the
bacteria reach the dentin, they spread laterally and invade through the dentin tubules on a broad
front to the dental pulp. Although transient pain may occur as the enamel is being eroded, the
characteristic pain begins when pulp becomes inflamed and there is increase edema and exudate
within the pulp chamber. From here, the infection may spread through the root canal to the
periapical tissues and form a periapical abscess on an acute basis and/or periapical granuloma on
a chronic basis. Either of these can produce bone destruction and may progress to a periodontal
(radicular) cyst, a form of odontogenic cyst, lined by stratified squamous epithelium.
Complications may include bacteremia., osteomyelitis with fistula formation to gingiva., palate, skin,
sinuses, etc. Ludwig's angina is a medical emergency that can result from dental caries (especially
mandibular molars) and refers to a painful board-like rigidity of the floor of the mouth and ensuing
airway obstruction caused by cellulitis of the anterior neck. Asphyxiation, sepsis, and meningitis
may develop.
B. PERIODONTAL DISEASE - This is the most common cause of tooth loss in adults over the age of 40
and is the result of a chronic inflamatory process initiated by the presence of dental plaque and
tartar (calculus) at the junction of the gingva and the tooth in the gingival sulcus. It is clinically
characterized by a receding gum line with reddened, inflammed gingiva. Chronic periodontitis
destroys the periodontal ligament with subsequent loosening and loss of teeth. Periodontal
abscesses may also develop.
C. ACUTE NECROTIZING ULCERATNE GINGNITIS (ANUG) - Also known as trenchmouth, this is a
painful, malodorous ulcerative disease of the interdental gingival papillae caused by the presence
of a fusiform bacillus in combination with a spirochete (Borelli a vincentii) in an individual who has
a decreased resistance to infection (immune suppression, poor oral hygiene, etc). The ulcers may

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 may coalesce to involve a large area of the gingiva and may even extend to the tonsillar pillars
(Vincent's angina).
D. CANDIDIASIS - Candida is a common contaminant of the oral cavity and in most cases causes no
problems. It may, however become at least superficially invasive when the oral microbial
environment is altered due to drugs (antibiotics, steroids), diabetes (poor vascularity and impaired
phagocytic activity), debilitation (old age, AIDS), or dentures. Candida colonies appear as soft
slightly elevated white patches adherent to the mucosal surface which can be scraped off leaving
behind a raw, bleeding surface. Alternatively, it may simply present as an erythmatous plaque
which does not bleed. Angular cheilitis is seen primarily in elderly individuals, many of whom
wear dentures. With age, the skin at the comers of the mouth becomes folded and is warm and
moist encouraging candida growth. A clinical mimic of oral candidiasis is oral hairy leukoplakia,
a disorder caused by EBV, HIV, and HPV This is usually seen on the lateral surface of tongue and
consists of hyperkeratosis and acanthosis. Although there may be secondary candida infection, it
is not causative. This lesion may herald the subsequent development of AIDS.
E. HERPES SIMPLEX - This is a common viral infection affecting a majority of the population. The
primary infection usually occurs in childhood but only I % of those infected develop clinical
symptoms. Herpetic gingivostomatitis is characterized by multiple, painful ulcers on both the fixed
(gingiva and hard palate) and non-fixed (buccal and soft palate) mucosa. There is also an
associated low grade fever, malaise, and lymphadenitis. The virus persists in the trigeminal ganglia
in a dormant state and can be reactivated by a number of stimuli (trauma, stress, infection,
menstruation, fever, etc). The secondary lesions (cold sores, fever blisters) are characterized by
painful intraepithelial vesicles which develop predominantly on the sun-exposed portion of the lip,
usually at the vermillion border. The vesicles then rupture and become crusted. Less commonly,
intraoral vesicles may develop but, unlike primary herpes, are found only on the fixed mucosa.
These also rupture quickly leaving behind shallow ulcerations. The histologic features are similar
to herpetic lesions elsewhere on the body. There is ballooning degeneration of epithelial cells and
eosinophilic intranuclear inclusions (Lipshutz bodies) may be present. Smears of the vesicular fluid
(Tzanck preparation) may also reveal characteristic multinucleated giant cells created by cell
fusion.
F. APHTHOUS STOMATITIS (CANKER SORES) - This common disorder produces recurrent, painful,
round, crateriform, necrotizing ulcerations outlined by an erythematous ring and covered by a grey
pseudomembrane composed of fibrinopurulent exudate. Unlike intraoral herpes, these ulcerations
occur on the non-fixed mucosa and do not have a preceding vesicular stage. They are somewhat
more common in children and adolescents and, like herpes, may be induced by physical or
emotional stress. There are many theories as to etiology, but many feel that this represents a
hypersensitivity reaction or localized autoimmune disorder. Two variations of aphthous stomatitis
include Periadenitis Mucosa Necrotica Recurrens (Sutton's disease, Major Aphthous) in which
there are large, painful, persistent cankers that develop around salivary glands and produce
scarring, and Behcet's Syndrome in which there is recurrent aphthous stomatitis associated with
genital ulcers and uveitis/conjunctivitis.

V. TRAUMA

A. IRRITATION FIBROMA - This is a sessile firm nodule that usually develops inside the lower lip or
on the tongue in response to chronic irritation. It represents a reactive lesion consisting primarily
of scar tissue.
B. PYOGENIC GRANULOMA - This is a hemispheric, red, soft vascular nodule which usually develops
in the interdental papillae and bleeds easily when traumatized. Traumatic in origin, it also is a
reactive lesion and consists primarily of granulation tissue. It is more common during pregnancy

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 (pregnancy tumor) since the changes in the hormonal status predispose to excessive granulation
tissue production. Two clinically similar lesions are the peripheral giant cell granuloma (epulis)
which contains giant cells and the peripheral odontogenic (ossifying) fibroma which contains bone
or cementum.

VI. ORAL MANIFESTATIONS OF DERMATOLOGIC DISEASE (FOR ADDITIONAL INFORMATION REFER TO

CHAPTER ON SKIN DISEASE. PAGE 224)

A. ERYTHEMA MULTIFORME - Mucosal involvement is seen in the more severe cases of erythema
multiforme which is a hypersensitivity reaction against number of agents (drugs, organisms,
vascular disseminated antigen, etc). It can occur at any age but often is seen in males during their
late teens-early twenties. Multiple, painful superficial ulcerations produce reddened and crusted
lips with sloughing of the oral mucosa. It is rapidly progressive and requires aggressive steroid
therapy. Extensive involvement of the mucosal surfaces including the GI tract is referred to as the
Stevens-Johnson syndrome.
B. BENIGN MUCOUS MEMBRANE PEMPHIGOID - This disorder may involve the eyes, mouth, and
genitals. Analogous to bullous pemphigoid, antibody formation against basement membrane
produces sub-basilar bullae. Characteristic linear deposits of IgG and C3 in lamina lucida of
basement membrane differentiates this disorder from pemphigus which has a honeycomb staining
within the epithelium. Like pemphigus, however, there will be a positive Nikolsky's sign (firm
stroke over the gingiva with a cotton swab will induce blistering and sloughing of the mucosa).
Seen most frequently in post-menopausal women, the bullae are somewhat more common on the
gingiva than on the buccal mucosa and are extremely painful. The bullae rupture leaving mucosal
ulcerations that may heal by scarring. The disorder is not fatal, but it is difficult to treat.
C. PEMPHIGUS VULGARIS - The clinical presentation is similar to benign mucous membrane
pemphigoid, but this can be a fatal disease. Blistering and ulceration may occur throughout the oral
mucosa although areas of preference tend to be the hard palate and buccal mucosa. Autoantibodies
to components of the epidermal intercellular spaces causes acantholysis and supra-basilar bullae
which rupture easily. Tzanck cells (clumps of degenerated epithelial cells lying within the vesicular
fluid) may be seen on cytologic preparations. Over half of the cases of pemphigus vulgaris begin
in the oral cavity and ultimately over 90% of cases will involve the oral cavity to some extent.
D. LICHEN PLANUS - A relatively uncommon disorder, the reticular form oflichen planus produces
asymptomatic lacy or net-like patterns of white striae on the mucosa (Wickham'S striae). The
lesions are often bilateral and the most common sites are the buccal mucosa, tongue, and gingiva.
Some individuals develop an ulcerative form of lichen planus which may be painful. The histologic
feature are the same as for the skin lesions i. e. hyperkeratosis~ acanthosis of the prickle cell layer;
saw-toothed rete ridges; a band-like dermal infiltrate oflymphocytes; and liquefactive degeneration
of the basal cell layer.
E. LEUKOPLAKIA - This is a clinical term to describe white plaque-like lesions of the oral mucosa.
It may represent simple hyperkeratosis in response to chronic irritation (ill-fitting dentures, etc),
epithelial atypia, or epithelial dysplasia. 6-7% will ultimately undergo malignant transformation.
It is therefore imperative to biopsy such lesions. Erythroplakia (red patches) or speckled
leukoplakia (red and white patches) are more likely to develop into malignancies.

VII. NEOPLASIA

A. ODONTOMA - This benign tumor can occur at any age and consists of both epithelial (enamel,
enamel matrix) and mesencymal (dentin, cementum, pulp, etc) components. These may be

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 arranged to actually produce a tooth-like structure (compound odontoma) or mixed together
(complex odontoma). They should be surgically removed to prevent damage to adjacent teeth.
B. AMELOBLASTOMA - This is a benign but locally aggressive tumor that histologically mimics the
epithelial-derived enamel organ with islands of stellate reticulum surrounded by a perpendicular
layer of ameloblasts. Most arise in the ramus of the mandible during early to mid-adulthood and
may be of sufficient size to produce facial deformity. They are treated by partial jaw resection.
C. ODONTOGENIC MYXOMA - This is also a locally aggressive but benign tumor and is derived from
the mesodermal component of the tooth-forming structures. It usually arises during early adulthood
and is usually associated with a missing or unerupted tooth. It has a soft gelatinous appearance and
is comprised of loosly arranged spindle cells in a myxomatous matrix. There is a high rate of
recurrence with simple excision and partial jaw resection may be needed.
D. PAPILLOMA - Papillomas are the oral counterpart to cutaneous verrucous vulgaris and present as
a pedunculated cauliflower-like growth that can occur throughout the oral cavity. Histologically
there is proliferation of squamous epithelium on a fibrovascular core. Although benign, on
occasion they may seed to other locations.
E. SOLAR CHEILITIS - Like actinic (solar) keratosis, this refers to actinic damage to the lip. This is
much more frequent on the lower lip than on the upper lip. Clinically, there is loss of the normal
demarcation between the skin and the vermillion border of the lip. There is also a loss of the
vertical striations and the redness of the lip. Persistent ulceration and crusting of the lip is a warning
sign of the development of squamous cell carcinoma.
F. INTRA-ORAL SQUAMOUS CELL CARCINOMA - High risk factors for the development of intra-oral
squamous cell carcinomas include smoking, alcohol abuse, and chronic physical (ill-fitting
dentures) or chemical irritation. Particularly susceptible areas include the floor of mouth, lateral
ventral surface of the tongue, anterior tonsillar pillar, and posterior border of soft palate. Squamous
cell carcinoma of the dorsum of the tongue is rare but has been associated with syphilis and AIDS.
These tumors tend to be endophytic with invasion of underlying tissue. However, a variant of
squamous cell carcinoma, verrucous carcinoma, is an exophytic spreading lesion that penetrates
the basement membrane only late in the disease and is typical of smokeless tobacco use.

SALIVARY GLANDS

I. INFECTIOUS / INFLAMMATORY DISORDERS - Both viruses and bacteria produce inflammatory

conditions of the salivary glands. These may be de novo infections or secondary to sialolithiasis (produced
by duct obstruction, dehydration, or drugs). 5j"ogren's syndrome is an autoimmune processes affecting the
salivary glands as well as the lacrimal glands. Chronic polyclonal lymphocytic/plasma cell infiltrates
ultimately produce atrophy and fibrosis of the glands leading to xerostomia and keratoconjunctivitis sicca.
II. MUCOCELE - These are hemispheric, blue, fluctuent nodules that usually arise inside the lower lip. They
are the result of injury/rupture of a minor salivary gland duct with the extravasation of mucus into the
surrounding tissue. It will not spontaneously disappear permanently unless surgically excised along with
the associated minor salivary gland. A ranula is a similar, but larger, lesion found on the floor of the mouth
and is usually due to obstruction of the submandibular or sublingual salivary gland ducts.
III. NEOPLASIA - 80% of the major salivary gland tumors arise in the parotid, and 80% of these are benign.
Most minor salivary gland tumors arise in the palate, and 50% are malignant. Salivary gland tumors usually
present as a painless enlargement of the gland. In parotid tumors, ultimate involvement of the facial nerve
may produce pain, paresthesia, or paralysis.

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A. PLEOMORPHIC ADENOMA (MIXED TUMOR) - The most common of the salivary gland tumors,
these are painless, slow-growing tumors (with a female predominance) that are most frequently
found in the superficial lobe of the parotid. They arise from myoepithelial cells and glandular
epithelial cells. These cells are imbedded in a myxoid/chondroid mesenchyma-like stroma that is
probably a secretory product of the myoepithelial cells. Although benign, an incomplete capsule
and irregular extensions of the tumor into surrounding tissue requires wide margins of excision or
recurrence will develop. The proximity to the facial nerve may be a surgical problem. Rarely,
malignant transformation may occur.
B. ADENOLYMPHOMA (Warthin's tumor, papillary cystadenoma lymphomatosum, "red, white, and
blue tumor") - This benign tumor arises in mid-adult life although in a somewhat younger age
group than pleomorphic adenoma and exhibits a male predominance. Almost all occur in the
parotid and may be bilateral or multifocal. Histologically, clefts and cystic spaces (white) are lined
by a markedly eosinophilic epithelium (red) which overlies a heavy lymphoid infiltrate (blue).
C. MUCOEPIDERMOID CARCINOMA - This is the most common malignant tumor of the salivary glands
and arises most frequently in the parotid as a painless, slow growing, poorly encapsulated mass
which contains a mixture of mucus-secreting cells and squamous cells. Tumors with a larger
proportion of squamous elements that are less well differentiated behave in a more aggressive
fashion.
D. ADENOID CYSTIC CARCINOMA (CYLINDROMA) - This is the most common of the minor salivary
gland tumors and usually arises in the palate of middle-aged females. It has a characteristic "cookie
cutter" or cribriform histologic architecture and likes to invade bone. It metastasizes by
hematogenous and perineural lymphatic invasion and tends to bypass regional lymph nodes. Distant
metastases may appear many years after the primary tumor is removed.

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 GASTROINTESTINAL TRACT

REVIEW OF NORMAL

Food is propelled from the oropharynx to the stomach by coordinated propulsive muscular contractions of the
esophagus where it is mixed and rendered semisolid (chyme) by the action of the gastric secretions. The gastric
secretions - consisting of soluble and insoluble mucus, hydrochloric acid (secreted by the parietal cells), and the
proteolytic enzyme pepsin (derived from chief cell pepsinogen secretion) - are stimulated by acetylcholine
(vagal stimulation), gastrin (produced in antral pyloric glands in response to local stimulating factors and vagal
stimulation), and histamine (acts on H2 receptors). The normal gastric mucosa is immune to the effects of
hydrochloric acid-pepsin digestion due to the presence of a protective mucosal "barrier" formed by tight
intercellular junctions between mucosal cells that prevents the back diffusion of H+. Additional protection may
be derived from a surface layer of insoluble mucus and the secretion of bicarbonate and prostaglandins. Chyme
is released at a relatively steady rate into the duodenum where it is acted on by bile, pancreatic enzymes, and
intestinal enzymes to yield the breakdown products of carbohydrates, lipids and protein which are then
absorbed across the small intestinal mucosa. The colon functions primarily to reabsorb water and electrolytes.

With the exception of the esophagus, the basic histologic structure of the GI tract consists of a surface mucosal
epithelium (with associated glands, crypts, etc) overlying a supportive lamina propria. The lamina propria is
separated from the submucosa by a thin muscularis mucosa, and the submucosa is separated from the serosa
and subserosal connective tissue by a thick muscularis propria. The esophagus does not have a true lamina
propria or muscularis mucosa.

ESOPHAGUS

I. STUCTURAL/FUNCTIONAL/OBSTRUCTIVE DISORDERS - These disorders are frequently

clinically manifested by dysphagia (difficulty in swallowing) if there is narrowing or obstruction of the
lumen or if there is interference with muscular peristalsis.

A. ESOPHAGEAL ATRESIA - This is the most common developmental abnormality to involve the
esophagus and, on occasion, may be associated with vertebral defects, cardiovascular mal-
formations, or other GI/GU abnormalities. Maternal polyhydramnios may be an early clue. The
atretic portion is usually located at or near the tracheal bifurcation resulting in a blind upper pouch
(which may have a hypertrophic wall) that is clinically manifested by excessive salivation and
regurgitation of food. The lower segment is frequently (80-90%) connected to the trachea or a
bronchus by a fistulous tract (tracheo-esophageal fistula). This may lead to a distended stomach

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 and can also produce coughing spasms related to reflux of gastric secretions. Less commonly, there
is a fistulous tract between the trachea and the upper segment which may result in paroxysmal
suffocation (by food obstructing the tracheobronchial tree) and aspiration pneumonia.
B. ESOPHAGEAL WEBS/RINGS - Esophageal webs are circumferential, redundant mucosal folds that
occur in the upper esophagus of middle aged or elderly women and may be associated with severe
iron deficiency anemia and atrophic glossitis (Plummer-Vinson syndrome). They may produce
dysphagia, and these patients have an increased risk of developing squamous cell carcinomas of
the esophagus. Esophageal rings occur in the lower esophagus at the squamocolumnar junction
(Schatzki's rings), are occasionally associated with hiatal hernias, and probably represent
hypertrophied smooth muscle and fibrous tissue. They generally become symptomatic in young
adults and cause intermittent dysphagia.
C. PROGRESSIVE SYSTEMIC SCLEROSIS - Scleroderma is the most common collagen vascular disease
to affect the esophagus. It is associated with loss of peristalsis in the distal 2/3 of the esophagus and
a relaxation of the gastroesophageal sphincter. The smooth muscle of the distal esophagus is
replaced by fibrous tissue and the neurons are atrophic. Chronic reflux of gastric secretions may
lead to significant scarring and stenosis of the distal esophagus.
D. ACHALASIA - This is a disorder of esophageal motility often first manifested in early adult life and
characterized by the failure of the gastroesophageal sphincter to relax. An associated loss of normal
peristalsis in the distal 2/3 of the esophagus leads to a functional obstruction, increased intraluminal
pressures, and progressive dilatation. Although the etiology is unknown, there is a lack of, or
reduction in, the number of ganglion cells in the myenteric Auerbach's plexus in the body of the
esophagus. There may also be a hypersensitivity of the gastroesophageal sphincter to humoral
constricting mediators. Proximal to the gastroesophageal sphincter, there may be compensatory
muscular hypertrophy although the wall may appear thinned from dilatation. Clinically, there will
be progressive dysphagia, eventual regurgitation of ingested food, and occasionally aspiration
pneumonia. There is a slightly increased incidence of developing esophageal carcinoma in the
dilated segment due to chronic irritation of the mucosal surface.
E. DIVERTICULA - These are abnormal outpouches of esophageal mucosa and submucosa through
weak areas in the muscle wall related to increased intraluminal pressures (pulSion diverticulum)
or eversions of all layers of the esophagus resulting from the healing of inflammatory processes
external to the esophagus (traction diverticulum). Traction diverticula usually occur at or below
the tracheal bifurcation and are usually associated with the tuberculous scarring of hilar lymph
nodes. The most common diverticulum (Zenker's diverticulum) is a pulsion diverticulum that
develops on the posterior wall of the esophagus proximal to the cricopharyngeal muscle and is
probably due to increased peristalsis needed to push food through an incompletely relaxed upper
esophageal sphincter. Symptoms are usually related to bad breath, the sensation of a "lump" in the
throat, and regurgitation and/or aspiration of undigested food. Other pulsion diverticula may
develop immediately proximal to the gastroesophageal sphincter (epiphrenic diverticula).
F. HIATAL HERNIA - This refers to a protrusion of a portion of the stomach above the diaphragm.
Most of these are asymptomatic but a minority «10%) of patients will develop reflux esophagitis
and "heartburn".

1. SLIDING HERNIA (80-90%) - Traction from a scarred or congenitally shortened esophagus

pulls the cardia of the stomach upward through the esophageal hiatus. The hernia may be
accentuated by swallowing.
2. PARAESOPHAGEAL (ROLLING) HERNIA - A defect in the esophageal hiatus allows a
portion of the stomach to protrude and lie alongside the esophagus to form an
intrathoracic sac which, although infrequent, may become strangled and infarcted. This
hernia may be accentuated by increased intraabdominal pressure.

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II. VASCULAR DISORDERS

A. ESOPHAGEAL VARICES - Portal hypertension, from any cause, diverts the normal portal venous
flow into the azygous system via the coronary (left gastric) veins and esophageal veins. This
produces tortuous distended veins beneath the esophageal mucosa or in the periesophageal tissue
which run parallel to the long axis. They are asymptomatic until rupture occurs with ensuing
hematemesis (frequently massive). Rupture may be idiopathic or the result of trauma (vomiting).
Mortality may approach 70% (these patients often have complicating disorders such as coagulation
defects, etc) and for those that survive, recurrent hemorrhage within two weeks is common.
B. MALLORY-WEISS SYNDROME - Linear, longitudinal lacerations of the mucosa and submucosa
occurring along the lesser curvature of the proximal gastric cardia or distal esophagus are most
commonly seen after bouts of severe or prolonged vomiting, but occasionally develop after other
"trauma" (coughing, resuscitation, instrumentation, etc.). Most frequently seen in, but not limited
to, chronic alcoholics, it may lead to fatal hematemesis but, in general, has a much better prognosis
than ruptured varices, and there is less of a tendency for recurrence.

III. INFLAMMATORY DISEASE - If symptomatic, esophagitis is generally manifested by dysphagia,

odynophagia (pain with swallowing), and occasionally a sufficient amount of bleeding to cause melena or
hematemesis. With increasing severity and chronicity, clinically significant fibrous strictures may develop.

A. REFLUX ESOPHAGITIS - Reflux of gastric secretions mayor may not be associated with hiatal
hemia. The extent of injwy depends on the severity and chronicity of reflux, acid-pepsin levels, and
the presence of bile salts, bile acids and pancreatic enzymes. Intraepithelial inflammatory infiltrates
(eosinophils and neutrophils), superficial epithelial necrosis with peptic ulceration, and submucosal
inflammation are present to varying degrees in the distal third of the esophagus. In response, the
epithlium of the distal esophagus may, in some cases, undergo metaplastic change to a columnar
epithelium resembling gastric and intestinal mucosa (Barrett'S esophagus). In some families, this
tendency to undergo metaplastic change is an inherited (autosomal dominant) trait. Overall,
approximately 10% of patients with Barrett's esophagus will subsequently develop invasive
adenocarcinoma, and should therefore be carefully followed with periodic esophagoscopy and
cytology or biopsy. Of those patients that develop severe dysplasia, 50% will subsequently develop
adenocarcinoma and prophylactic esophageal resection might be considered.
B. INFECTIOUS (BACTERIAL, FUNGAL, VIRAL) ESOPHAGITIS - Infections are more frequently seen
than in the past due to increased numbers of patients in immunocompromised states. Candida,
herpes simplex, and cytomegalovirus are common agents. Generally, these cause small elevated
lesions of the mucosal surface with central ulcerations that produce pain and may produce
significant bleeding.
C. CHRONIC ESOPHAGITIS - Although there are well defmed predisposing factors such as reflux,
uremia, alcohol abuse, smoking, etc, many cases are idiopathic. The mucosa may become atrophic
or dysplastic and submucosal fibrosis creates clinically significant strictures. The incidence of
squamous cell carcinoma is also increased.

IV. NEOPLASIA - In the U.S., esophageal carcinoma is a relatively uncommon malignancy (although
increasing in frequency) which tends to arise in men over the age of 50. With increasing obstruction, there
is a gradual onset of dysphagia leading to weight loss and malnutrition. Carcinomas may be complicated
by bleeding, infections (resulting in sepsis), erosion into the aorta (resulting in massive hematemesis), or
erosion into trachea (resulting in aspiration of food). The insidious onset leads to late diagnosis at a time
when direct extension to contiguous structures often makes resection impossible. In general, there is a 5-

187
 10% five year survival, but with cytologic screening and early diagnosis in high risk patients, survival can
be significantly improved.

A. SQUAMOUS CELL CARCINOMA - This is the most frequent cell type (75-85%), tends to arise in the
mid-esophagus (50%), and is more common in Blacks. Although the etiology is unknown,
predisposing factors include chronic alcohol and tobacco abuse and/or pre-existing structural or
functional abnormalities of the esophagus contributing to a chronic esophagitis. The development
of carcinoma is probably preceded by asymptomatic, slowly progressive mucosal dysplasia which
over the course of months to years becomes malignant, encircles the mucosa while penetrating into
the submucosa, and presents as either a polypoid fungating mass protruding into lumen (60%), a
necrotic ulcerative lesion that may erode through esophageal wall and into surrounding structures
(25%), or a diffuse infiltration into the wall causing rigidity and lumenal narrowing (15%). Initially,
the tumors tend to spread by direct extension to involve periesophageal soft tissue and adjacent
mediastinal structures and later may show metastases to liver, lung, and bone.
B. ADENOCARCINOMA - This cell type comprises 15-25% of esophageal malignancies, is more
common in Whites, and has a high male:female ratio. Since they arise from the submucosal
mucous glands or a preexisting Barrett's esophagus, they are more frequently seen in the distal
esophagus.

STOMACH

I. STUCTURALIFUNCTIONAL/OBSTRUCTIVE DISORDERS

A. PYLORIC STENOSIS - The developmental form of pyloric stenosis occurs in 1:300 - 1:900 newborn
babies with a 4: 1 male predominance (frequently the first born male) and may be an inherited
(autosomal recessive) trait. Hypertrophy of the circular muscle of the gastric pylorus (perhaps
secondary to muscular hypersensitivity and spasm) produces a stenosis that may be aggravated by
inflammation and edema. A small epigastric mass may be palpated in the newborn. Projectile
vomiting characteristically begins around the third or fourth week of life, however on rare
occasions, symptoms may not develop until adulthood. Acquired forms of pyloric stenosis
(postinflammatory scarring or neoplastic infiltration of the pylorus) may also lead to symptoms of
pyloric obstruction.
B. GASTRICDILATATION/RUPTURE - Dilatation may result from pyloric obstruction or small bowel
ileus and can cause tremendous dilatation and thinning of the gastric wall. Although uncommon,
gastric rupture is usually due to trauma to a previously distended stomach and is rapidly followed
by shock and death.

II. INFLAMMATORY DISEASE

A. GASTRITIS

1. ACUTE (EROSIVE) GASTRITIS - This is associated with a wide variety of predisposing

factors (aspirin, toxins, etc) which can alter mucosal blood flow, produce ischemia, or
interfere with the protective mucoid barrier that prevents acid digestion of the gastric
mucosa. Histologic changes vary from localized hyperemia, edema, and mild mixed
inflammatory infiltrates of the lamina propria (acute superficial gastritis) to focal
hemorrhage and superficial sloughing of mucosa (acute hemorrhagic gastritis) to a diffuse

188
 hemorrhage and erosion of the mucosa (acute hemorrhagic erosive gastritis). With
increasing severity, there is more evidence of bleeding and a heavier inflammatory infiltrate
and the initially asymptomatic lesions may produce symptoms of epigastric pain, nausea
and vomiting. With severe cases, massive hematemesis may occur.
2. ACUTE PEPTIC ULCERATION ("stress ulcer") - This is basically an exaggeration of acute
erosive gastritis to where the mucosal erosion penetrates the muscularis mucosa. They tend
to arise initially in the proximal stomach but, depending on the severity, multiple ulcers
may involve the entire gastric mucosa. Usually they are small, circular ulcers with a
reddish-brown base (due to acid digestion of RBC) rarely extending deeper than the
submucosa. They initially appear within 24 hours after severe trauma i.e., extensive bums
(Curling's ulcers), acute brain damage (Cushing's ulcers), severe medical illnesses,
surgery, or shock. They may also be associated with steroid therapy, aspirin abuse, and
smoking. The pathogenesis is uncertain but it may involve disturbances in vascular
perfusion of the mucosa, damage to the mucosal mucus barrier, and back diffusion of
gastric acid. Acid must be present for the ulcers to occur but usually acid concentration
is not increased above normal except in the case of Cushing's ulcers where brain damage
causes increased vagal activity with resultant acid hypersecretion. Generally, stress ulcers
are asymptomatic but may cause mild to moderate, and occasionally massive, bleeding.
They usually heal without sequelae once the "stress" has been removed and do not
progress to chronic peptic ulcers.
3. CHRONIC (NON EROSIVE) GASTRITIS - This entity is a continuum of similar morphologic
and histologic changes produced by a variety of causes. Histologic changes in chroniC
superficial gastritiS consist of mild localized or diffuse superficial lymphocytic and
plasmacytic infiltrates of lamina propria while chroniC atrophiC gastritiS is characterized
by heavier and deeper inflammatory infiltrates with thinning of the mucosa, atrophy of the
glands, and surface epithelial atypia. Gastric atrophy is characterized by flattening or loss
of normal rugal folds; lymphocytic, plasmacytic, and occasionally eosinophilic infiltrates;
marked glandular atrophy; and replacement of surface or pit epithelium by gastric goblet
cells and intestinal epithelium (intestinal metaplaSia) which frequently show atypical or
dysplastic changes. Clinically, chronic gastritis is often asymptomatic but may present with
vague abdominal pain, nausea, or vomiting. The major clinical significance, however, is
the association of other more serious disorders in patients with chronic gastritis.

a. Type A (fundal) e;astritis - This results from immunologic destruction of the

gastric parietal cells and is therefore most prominent in the fundus. These patients
produce antibodies directed against intrinsic factor, intrinsic factor-Vitamin B12
complexes, and gastric parietal cells. The destruction of parietal cells results in
hypo- or achlorhydria and secondarily a hypergastrinemia. In addition to B12
deficiency anemia, these patients are more prone to developing gastric cancers,
hence the term pernicious anemia.
b. Type B (antral) gastritis - This is more common than fundal gastritis and is
associated with concommitant Helicobacter pylori infections and bile (esp
lysolecithin) reflux. Although these patients have intact parietal celis, the gastrin
producing G cells of the antrum are destroyed. Disintegration and loss of apical
mucus, epithelial pits, and microerosions are morphologic characteristics of
Helicobacter. This disrupts the protective mucus layer so that chronic peptic ulcers
may develop. Although generally not to the extent seen in type A gastritis, surface
epithelial metaplasia and dysplasia may be present, and there is an increased
incidence of gastric carcinoma in these patients.

189
 c. Type AB gastritis - This is probably the most common form of chronic gastritis
and combines features of both type A and type B. No specific etiology has been
elucidated, but it is felt to be due to envimomental causes. Both the antral and
ftmdic portions of the stomach are involved, and there is parietal cell destruction
although not as extensive as type A and not associated with antibody formation.
As with the other forms of chronic gastritis, surface epithelial changes (dysplasia
and metaplasia) increase the risk of subsequent neoplastic transformation.

B. CHRONIC PEPTIC ULCER DISEASE - Ulcers affect approximately 5-10% of general population. The
peak incidence is in mid-adult life and is uncommon before the age of 20 or in premenopausal
women. Resulting from acid-pepsin digestion of non-acid secreting mucosa, these are usually
solitary lesions occurring in the duodenum (most frequent) or stomach. Approximately 10% of
patients have both duodenal and gastric ulcers. They can, however, develop in Barrett's esophagus,
Meckel's diverticulum, and surgical gastroenteric anastomoses. The incidence of duodenal ulcers
is slowly declining while the incidence of gastric ulcers has remained steady.

1. DUODENAL ULCER - The mechanism of ulceration probably relates more to the delivery
of increased acid-pepsin secretion to the duodenum rather than altered mucosal resistance
although both mechanisms may playa role and pathogenetic mechanisms may vary from
individual to individual. Generally, in duodenal ulcer patients the mean acid secretion is
higher than that found in normal patients or those with gastric ulcers. The total parietal cell
mass of the gastric mucosa may be increased and roughly correlates with degree of acid
secretion. Parietal cells may be more sensitive to gastrin stimulation or gastrin secretion
may be abnormally prolonged due to impaired feedback inhibition by increased acid or
secretin levels. Rapid emptying of gastric contents into duodenum or impaired duodenal
secretion of protective prostaglandins (PGE 2) or bicarbonate may also occur. Duodenal
ulcers are increased in frequency in patients with a genetic predisposition (type 0 blood,
non-secretors of blood group antigens into body fluids, MEN I), those who smoke and/or
drink, and those who have concurrent COPD, hepatic cirrhosis, rheumatoid arthritis, or
hyperparathyroidism.
2. GASTRIC ULCER - The mechanism of ulceration probably relates more to a function of
altered mucosal resistance than to increased acid secretion. Most gastric ulcer patients have
preexisting or concurrent chronic gastritis and are normal or hyposecretors of acid-pepsin.
The mechanisms may be related to antroduodenal reflux of bile acid, pancreatic secretions,
and lysolecithin; deranged mucosal blood flow; decreased prostaglandin E production; .t!.
QY!Qri. infection; or other impairment of the mucosal barrier. There is an increased
incidence in patients who have type A blood, who smoke and/or drink, abuse aspirin, or
have COPD. There is less evidence of a genetic predisposition than with duodenal ulcer
patients.
3. ULCER MORPHOLOGY - Most (80-90%) are solitary. If duodenal and gastric ulcers are
both present (10% of patients), duodenal is the first to appear. Duodenal ulcers most often
occur on the anterior wall of the first portion of duodenum while gastric ulcers are usually
found in the antrum with slightly greater predilection for the lesser curvature. Ulcers are
usually under 2.0 cm diameter but may be greater than 4.0 cm diameter with the gastric
ulcers tending to be the larger. The crater appears punched-out with a straight wall
perpendicular to the base of the ulcer which usually lies within the submucosa or
muscularis propria. The crater base is usually grossly free of exudate and, over time,
scarring creates mucosal folds that radiate outward from the central crater. Mucosal

190
 surfaces along the margin of gastric ulcers are generally not indurated but do show
underlying chronic gastritis and may undergo intestinal metaplasia.
4. CLINICAL PRESENTATION - Patients may be asymptomatic. Alternatively, duodenal ulcers
may present with intermittent burning epigastric or substernal pain that classically begins
within a few hours after eating and is relieved by antacids, milk, or food which tends to
neutralize the excess acid. In patients with gastric ulcers, however, food may be irritating
and induce vomiting which is more likely to lead to anorexia and weight loss. Referred
pain may be present in thorax, back, or upper abdomen. Complications include bleeding
(30% of patients, 25% of deaths), perforation (5% of patients, 65% of deaths), or pyloric
obstruction due to scarring. Malignant transformation is rare in gastric ulcers and virtually
nonexistent in duodenal ulcers.

III. HYPERTROPHIC GASTROPATHY (MENETRIER'S DISEASE) - This is an uncommon disorder

which most frequently affiicts middle-aged men and usually presents with post-prandial pain, anemia, and
hypoproteinemia due to loss oflarge amounts of protein from the gastric mucosa. Grossly, the rugae in the
body of the stomach (the antrum is spared) are markedly thickened due to elongation and tortuosity of the
crypts and cystic dilation of the glands (which sometimes extend through the muscularis mucosa into the
submucosa). The disorder is generally recognized as a pre-malignant condition and should be followed with
periodic endoscopy.
IV. NEOPLASIA

A. GASTRIC CARCINOMA - In the U.S., the incidence has been declining. Occurring in mid to late
adulthood, these are most often found in the distal antral and pyloric regions, but there has been
an increasing frequency of proximal tumors. Predisposing conditions include benign neoplastic
polyps, chronic atrophic gastritis, and gastric atrophy. Common to all of these is epithelial
hyperplasia/dysplasia or intestinal metaplasia/dysplasia which may range from mild to severe.
Additionally, environmental and dietary factors (nitrites and nitrosarnines) probably also playa
significant role in the pathogenesis. All gastric carcinomas are adenocarcinomas and consist either
of cells reminiscent of intestinal columnar epithelium or gastric mucus producing cells (and
sometimes a mixture of the two). The former tend to produce expansile masses which consist of
nests and sheets of malignant cells tending to show glandular differentiation while the latter tend
to be less cohesive and diffusely infiltrating eliciting a striking desmoplastic stromal response or
sometimes producing abundant mucin ("signet-ring" carCinoma). Grossly, these tumors may grow
into the gastric lumen as fungating or polypoid masses, extend diffusely into the gastric wall
creating ill-defined mural thickening (linitis plastica), or create ulcerative lesions with indurated,
heaped up margins and a shaggy, necrotic base. If the tumors are identified early while still
confined to the mucosa and submucosa regardless of perigastric lymph node metastases (early
gastric cancer), gastric resection will markedly improve the prognosis. If not identified early, they
will eventually invade and penetrate the muscularis propria (advanced gastriC carCinoma), seed
the peritoneum, and metastasize to regional lymph nodes, liver, lungs, and other viscera.
Commonly, clinical symptoms are non-specific and include weight loss, abdominal pain, anorexia,
and vomiting. Occult blood loss may be demonstrated by "coffee-ground" vomitus or guaiac
positive stools. The initial symptoms may be due to the effects of metastases. The non-specific
nature of the presentation often delays the diagnosis until the disease is far advanced resulting in
only a 10% five-year survival rate. Prognostic indicators of poor outcome include advanced stage
of the disease and a proximal location.
B. GASTROINTESTINAL LYMPHOMA - Extranodal non-Hodgkin's lymphomas (most frequently diffuse
histiocytic type) occasionally arise in the G.I. tract, most often in the stomach and ileum and less
often in the colon and rectum. The gastric lymphomas may have an ulcerative, polypoid, or

191
 infiltrative appearance mimicing the gross appearance of gastric carcinomas, and some studies
have suggested a causal relationship to Helicobacter pylori infection. Intestinal lymphomas are
more likely to be infiltrative and multifocal. They may be associated with concurrent nodal or
visceral involvement and clinical manifestations depend on the size and location of the neoplasm.
M<lior prognostic indicators include the histologic grade and clinical stage. The five year survival
is often better than 50%.

SMALL BOWEL/COLON

I. STUCTURALlFUNCTIONALlOBSTRUCTIVE DISORDERS

A. SMALL BOWEL ATRESIA - The segmental failure (single or multiple) to develop a lumen may be
due to an intrauterine vascular insult. Atretic segments, represented only by a solid fibrous cord,
usually occur in the ileum and, because of the obstruction, are clinically manifested by early and
persistent vomiting of bile stained material.
B. IMPERFORA TE ANUS - This may simply be due to the failure of anal membranous septum to
perforate but, on the other hand, it may be associated with agenesis, atresia, or stenosis of the anal
canal. There may also be associated fistulas between the bowel and the female genital tract or the
male urinary tract.
C. HIRSCHPRUNG'SDISEASE (congenital megacolon) - This is an uncommon disorder with a strong
male predominance (9: 1) and may be associated with Down's syndrome or other congenital
anomalies. It is characterized by the failure of Meissner's (submucosal) and Auerbach's (myenteric)
plexuses to develop. This occurs at the anorectal junction and extends proximally to a variable
extent but is usually limited to the rectum and sigmoid. A lack of peristalsis creates a functional
obstruction and results in dilatation of the colon proximal to the aganglionic segment. Clinically,
these infants tend to be constipated from birth although there may be occasional passage of
diarrhetic liquid stool. As the colon dilates, there is abdominal distension and vomiting.
D. DIVERTICULA

1. SMALL BOWEL

a. Pulsion diverticula - These are uncommon, but when present, may be solitary or
multiple. They tend to occur along mesenteric border (where mesenteric vessels
and nerves enter the bowel wall) with protrusion of the mucosa and submucosa
through the muscularis propria. Rarely, this may result in bacterial overgrowth and
B12 deficiency, bleeding, or perforation.
b. Meckel's diverticulum - This developmental anomaly arises from persistence of
the proximal portion of the omphalomesenteric (vitelline) duct which
embryologically linked the midgut to the yolk sac. This occurs in 1-4% of the
general population with equal sex ratio although males are more likely to be
symptomatic. Variable in size, they are located along the antimesenteric border
of the ileum usually within 30 cm. of the ileocecal valve. Microscopically, about
50% contain heterotopic gastric mucosa and, therefore, may develop peptic
ulceration and bleeding (occasionally mimicking appendicitis) leading to iron
deficiency anemia. Scarring from repeated subclinical inflammation may lead to
obstruction. Rarely, they may perforate.

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 2. DIVERTICULAR DISEASE OF THE COLON - This is a disorder characterized by single or,
more commonly, multiple protrusions of colonic mucosa and submucosa through the
muscularis propria which becomes more prominent with increasing age. The etiology is
not clear, but it may be related to weakness of the bowel connective tissue either through
disease processes or by normal aging, increased intraluminal pressures created by
alteration of quantity and character of stool (low residue-low fiber diets), or a primary
intrinsic defect of colonic muscular coat. In the majority of patients, there is hypertrophy
of the circular and longitudinal muscular layers (prediverticular disease) with subsequent
herniation of the mucosa and submucosa through the colon wall (diverticulosis) at points
of weakness between the mesenteric and antimesenteric taenia where the vessels penetrate
the circular muscle. Most diverticula (95%) occur in the sigmoid colon, but they may
involve the entire length of the colon. Most patients with diverticular disease are
asymptomatic, but when symptoms occur, the onset is generally insidious with intermittent
or continuous lower abdominal discomfort, constipation, and distension. Progression of
the disease results in worsening constipation, abdominal cramps, and bleeding. A mass
may be palpable in the left lower quadrant. Secondary inflammation (diverticulitis) may
follow perforation or fecal impaction within a diverticulum and infrequently may result in
pericolic abscesses, peritonitis, or sinus/fistula tracts. Fever and leukocytosis are clinical
indicators of acute diverticulitis but may not be present in all cases. Chronic diverticulitis
may lead to fibrous thickening of the wall and decreased luminal diameter simulating colon
carCInoma.

E. ANNULAR PANCREAS - Although rare, abnormal embryologic development and rotation of the
ventral pancreatic bud may cause it to encircle the duodenum before fusion with the dorsal bud,
thereby leading to partial obstruction of the duodenum. Apancreatic rest refers to submucosal foci
(usually duodenal) of aberrant but normal pancreatic tissue which may elevate the mucosa and
grossly simulate a neoplastic process.
F. ABDOMINAL HERNIA - This is a serosa-lined protrusion of peritoneum occurring in areas of
weakness or defect in the abdominal wall (femoral or inguinal canals, umbilicus, previous surgical
sites, etc). Segments of bowel may enter these sacs and are particularly prone to do so during
periods of increased intra-abdominal pressure (defecation, lifting objects, etc.). If the venous
drainage of the bowel is compromised, ensuing venous stasis and edema traps the bowel within
the hernia sac (incarceration) and may ultimately result in ischemic necrosis (strangulation) and
possible perforation.
G. FIBROUS ADHESIONS - Peritonitis from any cause (bacterial, surgical, etc.) may result in the
development of fibrous adhesions between loops of bowel or between the bowel and abdominal
viscera or peritoneal wall. Since the small bowel is relatively mobile, portions may get trapped
between adhesions resulting in symptoms of obstruction, and the potential for incarceration and
strangulation exists.
H. INTUSSUSCEPTION - This occurs when a portion of bowel (intussusceptum) becomes telescoped
into a more distal portion (intUSSUSCipiens). This usually occurs in children and involves the
telescoping of the terminal ileum into the cecum. Hyperplasia of Peyer's patches is the most
frequent cause in children. In adults, however, it is often associated with polyps or tumors which
get caught up in peristaltic action. As the proximal portion is being propelled further distally by
peristalsis, its attached mesentery is being pulled along also and may lead to vascular compromise
and infarction. Clinically, intussusception is characterized by acute obstructive symptoms. In
children, the intussusception may be reduced by barium enema or gentle abdominal palpation, but
with adults, surgical intervention is usually indicated.

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 I. MALROTATION - This is the result of the cecum failing to descend to its normal position in the right
lower quadrant. It usually is of little significance but may confuse the diagnosis of acute
appendicitis since the appendix does not lie in its characteristic location.
1. MELANOSIS COLI - Associated with chronic anthracene laxative abuse, this is an asymptomatic
discoloration of the mucosal surface of the colon due to accumulation of brown-black pigment
within macro phages of the lamina propria. The pigment apparently results from apoptosis of the
colonic epithelial cells, which are then digested by the macrophages in the lamina propria, with
indigestible cell fragments becoming the pigment. The chemical nature of the pigment remains
unknown.

II. VASCULAR DISORDERS

A. ISCHEMIC BOWEL DISEASE

1. TRANSMURAL INFARCTION - Although arterial vasospasm or hypotension may result in

bowel infarcts, they are most often the result of arterial or venous obstruction. As with
other organ systems, the consequences of vascular compromise depends on the degree, the
rate at which it develops, the physical location in the vascular bed, the patency of other
collateral vessels, and the p02 of the blood. Interruption of arterial flow is responsible for
approximately 60% of transmural bowel infarcts although the numerous anastomoses
between branches of the celiac, superior mesenteric, and inferior mesenteric arteries
reduces the overall incidence. The colon is further protected by virtue of additional
vascular supply from the posterior abdominal wall (colon infarcts are most commonly due
to hypovolemialhypotension and are seen in the "watershed" areas of arterial supply i.e. the
splenic flexure and mid-rectum). Arterial obstructions are usually due to thrombus
formation on an atherosclerotic plaque, but may also be the result of emboli or intrinsic
vascular disease. Venous obstruction is usually due to thrombus formation secondary to
trauma (surgery), intraperitoneal infection, polycythemia, or external compression.
Vascular occlusion, either arterial or venous, will result in patchy or confluent
hemorrhagic infarction of the bowel which is first manifest by congestion and hemorrhage
of the mucosal, submucosal, and subserosal tissue. The borders of arterial infarcts are
usually distinct while those of venous infarcts tend to be blurred. Edematous thickening
of the bowel wall, sloughing of the mucosal surface, and inflammatory infiltrates follow.
Fibrinous or fibrinopurulent exudate appears on the serosal surfaces within 24 hours and,
without surgical intervention, secondary bacterial contamination, peritonitis, and
perforation can occur. Although the incidence of transmural infarction is relatively low,
it has an increasing frequency with age and is a surgical emergency. Clinically, patients
tend to be older males with thrombus formation in atherosclerotically compromised
mesenteric arteries who develop abrupt onset of severe abdominal pain with nausea,
vomiting, possible bloody diarrhea, and ensuing shock. Bowel sounds are decreased and,
with the onset of peritonitis, a rigid abdomen develops. Without intervention, sepsis,
shock, blood loss, or perforation will culminate in death within 48 hours. In some
instances, patients may have a previous history of intestinal angina - abdominal pains
resulting from transient postprandial ischemia due to stenotic mesenteric vessels.
2. ACUTE HEMORRHAGIC ENTEROPATHY - Multifocal areas of ischemic necrosis of the
mucosa and submucosa (mucosal infarction) and muscularis propria (mural infarction)
with sparing of the serosa is usually due to tissue hypoperfusion secondary to shock,
cardiac failure, infections, vasoconstrictive drugs, etc. Except for the sparing of the serosa

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 and subserosal tissue and the patchy multifocal nature, the gross and microscopic
appearance is similar to transmural infarctions. Clinically, patients present with abdominal
pain, cramping, and bloody diarrhea. The prognosis is generally better than that of
transmural infarcts, and patients can often be managed without surgical intervention.

B. VOLVULUS - This refers to a twisting of bowel on its mesenteric attachment resulting in

obstruction, vascular compromise, and infarction. This occurs most often in the small bowel due
to its mobility but may also occur at the sigmoid colon or cecum.
C. ANGIODYSPLASIA - This is an acquired dilatation (telangiectasia) of thin walled veins in the
superficial lamina propria of the cecum and, occasionally, ascending colon of older individuals.
The etiology is unclear but may be related to transient but repeated occlusion of submucosal veins
as they penetrate through the muscular wall of the bowel. Like esphageal varices, they are
asymptomatic until they rupture. Although hemorrhage is unlikely to be extensive, this may
represent a major cause of lower GI bleeding and anemia in the elderly population.
D. HEMORRHOIDS - These are extremely common, but except for gravid women, are unusual before
the age of 30. Persistently elevated venous pressure in the hemorrhoidal plexuses (chronic
constipation, pregnancy, portal hypertension, etc) causes variceal dilatation of veins beneath rectal
(internal hemorrhoids) and/or anal (external hemorrhoids) mucosa. When symptomatic, they
produce pain, itching, and rectal bleeding characterized by streaks of blood on the external surface
of the stool. Thrombosis, superficial ulceration, fissure formation, and hemorrhagic infarction are
possible complications.

III. MALABSORPTIVE DISORDERS - These consist of a variety of conditions which arise from altered
or abnormal absorption of ingested food and water and, in general, are clinically characterized by anemia,
muscle wasting and weight loss, abdominal distension, borborygmi, and abnormal stools (steatorrhea,
diarrhea, etc). Malabsorption may result from lack of adequate nutritional factors in the diet; defects in
gastric, hepatobiliary, or pancreatic function; alteration of the absorptive surface area of the bowel; defects
in transport of absorbable molecules across the bowel mucosal; or defects in transport of absorbed foods
into portal circulation. Most absorption occurs in the duodenum and jejunum except for vitamin B]2 and
bile salts which are absorbed in the ileum.

A. CELIAC DISEASE (gluten-sensitive enteropathy, non-tropical sprue) - This results from an

immunologic hypersensitivity to gliadin (a glycoprotein constituent of the protein gluten found in
wheat, oats, barley, and rye products) which induces, usually beginning in childhood, increased
levels ofIgA and IgM antibodies in the intestinal mucosa. Whether the antibodies are cytotoxic or
whether there is cell mediated destruction of the surface epithelial cells of the jejunum is not
certain. There is, however, accelerated sloughing of the jejunal epithelium (most severe in the
upper jejunum and decreasing distally) leading to severe atrophy of the jejunal villi (thereby
decreasing the absorptive surface area), increased depth of the intervillous crypts due to epithelial
hyperplasia (in an attempt to repopulate the surface epithelium), and increased chronic inflam-
matory cell infiltration of the lamina propria. Residual surface epithelial cells show cytologic
alterations including irregular nuclear positions and poor staining. Although patients may present
with an unexplained anemia, diarrhea is usually the presenting complaint. Elimination of wheat,
oats, barley, and rye products from the diet will restore normal physiologic function and, in most
cases, will restore normal histology of the jejunum although there is an increased incidence of
subsequent small bowel lymphomas and, to a lesser extent, adenocarcinomas.
B. TROPICAL SPRUE - This is most likely the sequelae of an as yet unclassified bacterial enteritis. Most
frequently seen in adolescents and young adults, it is clinically characterized by steatorrhea and
folate deficiency anemia. The histology varies from no mucosal abnormality to changes resembling

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 celiac disease but, unlike celiac disease, the histologic changes tend to involve the small bowel
uniformly or be more severe in the distal bowel. Fortunately, most patients can be cured by broad
spectrum antibiotic therapy and folic acid supplementation.
C. WHIPPLE'S DISEASE - This is a systemic disease involving small bowel, heart (fibrous pericarditis,
aortic valve vegetations), lung, liver, kidney, spleen, lymph nodes, skeletal muscles, and CNS.
Although the etiology is most likely infectious, no organisms have been consistently isolated. Using
molecular genetic techniques, however, a potential causative organism (Tropheryma whippelii)
related to actinomycetes has been described. EM reveals rod-shaped bacilli within lysosomes of
macrophages and along the brush border of (and occasionally within) epithelial cells, and the
disease can often be cured by antibiotic therapy. The characteristic feature is the presence of
macro phages filled with PAS positive, diastase-resistant granules (the bacilli-bearing lysosomes)
which are found most commonly in lamina propria of small bowel but which may also be seen in
lymph nodes, synovial tissue, etc. In the small bowel, villi become distended and blunted by the
accumulated macrophages which imparts a shaggy appearance to mucosal surface. Lymphatic
obstruction results in dilatation of lacteals and, if these rupture, lipogranulomas may form.
Occasionally fine lipid vacuoles can be seen within surface epithelial cells. Having a strong
predilection for males, the disorder usually presents in middle age as severe malabsorption
(steatorrhea, abdominal cramps, fever, and emaciation), but alternatively it may also present with
migratory polyarthralgia, CNS symptoms, lymphadenopathy, etc.
D. DISACCHARIDASE DEFICIENCY - This prevents ingested disaccharides from being broken down
into absorbable monosaccharides at the brush border of the intestinal epithelial cells. These
undigested disaccharides then draw water into the bowel which results in bloating, abdominal
cramps, and diarrhea In adults, an acquired lactase, sucrase, or maltase deficiency may be related
to other forms of bowel disease or appear spontaneously. When occuring as a congenital defect
(unusual), the deficient enzyme is usually lactase and, at first milk feeding, these infants develop
abdominal distension and explosive, watery, frothy diarrhea There is little, if any, histologic
changes of the mucosa and treatment is by dietary elimination of milk and milk byproducts.
E. ABETALIPOPROTEINEMIA - This is an autosomal recessive inborn error of metabolism manifested
in infancy by diarrhea, steatorrhea, and failure to thrive. These infants are unable to synthesize the
apoprotein B utilized in the lipoprotein coat of chylomicrons, VLDL, and LDL and are therefore
unable to transport lipids in the circulation. Triglycerides accumulate in mucosal cells and severe
hypolipidemia ensues. Acanthocytosis and neurologic deficits may also be associated.

IVi INFLAMMA TORY DISEASE

A. ACUTE APPENDICITIS - Like cholecystitis, acute appendicitis is probably initiated by local events
rather than primary bacterial infection. Obstruction of mucus drainage from the lumen by fecaliths,
lymphoid hyperplasia, fibrosis, tumor, etc. may lead to distension, vascular compromise, and
secondary bacterial invasion. As neutrophils emigrate from vessels, a fibrinopurulent exudate
appears on the serosal surface. Suppurative necrosis of the mucosa and muscularis further
compromises the vascular supply resulting in gangrenous necrosis and predisposing to frank
rupture. Appendicitis is clinically characterized by diffuse abdominal discomfort eventually
localizing to the right lower quadrant (McBurney's point) accompanied by nausea, vomiting,
anorexia, and diarrhea/constipation. As the inflammation involves the peritoneal wall, abdominal
guarding with rebound tenderness, fever, and leukocytosis develop. Without surgical intervention,
rupture, peritonitis, sepsis, abscess formation, or portal thrombosis may lead to death.
B. CROHN'S DISEASE (REGIONAL ENTERITIS) - This is a systemic inflammatory disease primarily
characterized by segmental, transmural, and granulomatous involvement of the small bowel and/or
colon, but which less commonly may involve any portion of the G.I. tract from the oral cavity to

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 the anus. Skin, skeletal muscle, joints, bone, etc. may also be involved. The incidence appears to
be increasing in frequency with only a slightly greater predilection for females. Peak incidence
occurs in the adolescent-young adult years. The etiology is unknown but various theories include
a genetic predisposition; an as yet unidentified infectious agent; an autoimmune disorder; and cell-
mediated immune deficiencies. Regional enteritis is also occasionally associated with other diseases
related to autoimmunity such as ankylosing spondylitis, erythema nodosum, autoimmune hemolytic
anemia, and sclerosing cholangitis.

1. MORPHOLOGY - The gross appearance is characterized by segmental involvement ("skip"

leSions) of the bowel. Affected areas are sharply demarcated from intervening normal
bowel. Most often small bowel and colon are both involved (50-60%), however, the small
bowel alone (30-35%) or the colon alone (granulomatous colitis - 20%) may be affected.
Classically, in involved areas there is transmural thickening and fibrosis of the bowel
wall with narrowing of the bowel lumen, linear serpentine ulceration of the mucosal
surface running along the long axis ofthe bowel (cobblestone mucosa), and encirclement
of the bowel by thickened, edematous, and fibrotic mesenteric fat (creeping fat).
Characteristic microscopic findings include non-specific chronic inflammation affecting
all layers of the bowel wall with non-caseating granuloma formation, and lymphoid
aggregates. Approximately 40% of cases, however, fail to reveal granulomatous
inflammation. There is marked thickening, chronic inflammation, and fibrosis of the
submucosa and subserosal areas with relative preservation of the muscularis propria. The
mucosa shows varying degrees of necrosis and ulceration, goblet cell hyperplasia, and over
time, dysplastic changes of the surface epithelium.
2. CLINICAL COURSE - The disease begins as intermittent bouts of fever, right-sided
abdominal pain, and diarrhea. As the disease progresses, the intervals between attacks
become shorter and the symptoms become more pronounced leading to nausea, vomiting,
anorexia, weight loss, slow blood loss, and electrolyte imbalance. Complications include
bowel obstruction secondary to fibrous strictures (especially oftenninal ileum), adhesions,
fistula formation, peritoneal abscess, hemorrhage, and malabsorption of protein, vitamin
B 12, folic acid, and iron. Patients with this disease have an increased risk of developing
adenocarcinoma of the colon or, less likely, small bowel. Recurrence rate after surgical
resection is high.

C. ULCERATIVE COLITIS - This is an acute and chronic inflammatory disease of unknown etiology
causing extensive ulceration of the mucosal surfaces of the colon and, infrequently, the terminal
ileum. With somewhat greater frequency, patients with ulcerative colitis develop extraintestinal
manifestations similar to those found in regional enteritis (arthritic, dermatologic, ocular,
hepatobiliary, vascular, etc). Theories on etiology are similar to regional enteritis and include the
possibility of an as yet unidentified infectious agent and/or an immunologic mechanism. Some
authors feel that ulcerative colitis and regional enteritis are simply different manifestations of the
same disease process and should be lumped under the tenn "inflammatory bowel disease". In cases
where histologic features of both disorders overlap, the term "indeterminate" colitis may be used.

1. MORPHOLOGY - Ulcerative colitis always begins in the rectum and spreads proximally
without "skip lesions" and, although infrequent, may spread into terminal ileum
("backwash ileitis'). Early lesions begin as small mucosal hemorrhages and crypt
abscesses. The abscesses may undermine surrounding mucosa and produce mucosal
sloughing and ulceration. With progression, the ulcers may extend to the muscularis
propria. On the rare occasion that the process extends through the muscularis, pericolic

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 abscesses may form. Residual islands of edematous, inflamed mucosa stand out in contrast
to the surrounding ulceration and are called inflammatory pseudopolyps. Moderate
fibrosis of the bowel wall with non-specific chronic inflammatory infiltrates may occur but
rarely to the extent seen in regional enteritis. The epithelium of the ulcer margins may
undergo metaplastic and dysplastic changes, and this may account for the high incidence
of malignant transformation seen with ulcerative colitis. Although fistula formation can
occur, it is less frequent than in regional enteritis and usually is confined to the perianal-
perirectal regions.
2. CLINICAL COURSE - Ulcerative colitis is a recurrent disease initially manifested most often
in young adulthood (20-40 years) as abdominal pain, cramps, and bloody diarrhea often
subsequent to emotional stress. Symptom free intervals may vary from months to years.
With recurrent attacks, weight loss, fever, and electrolyte disturbances may occur. During
acute attacks, patients may develop marked colonic distension (toxic megacolon) requiring
immediate surgical intervention. Malignant transformation is about five times more
common than in regional enteritis and risk is partially dependent on the duration of the
disease (the longer the disease is present, the greater the risk - usually 15-20 year intervals
between diagnosis and cancer), the age of onset (the younger the age of onset, the greater
the risk), the chronicity (the shorter the symptom free intervals, the greater the risk), and
the extent (the greater the involvement, the greater the risk). The cancer may be multifocal
(predominantly left colon) and is usually flat and infiltrating, often poorly differentiated,
and aggressive.

D. PSEUDOMEMBRANOUS COLITIS - This refers to the presence of a membrane-like inflammatory

exudate consisting of mucin, neutrophils, and fibrin, which is patchily distributed over the mucosal
surface of the colon or, to a lesser extent, small bowel. Underlying the membrane are
inflammatory infiltrates and varying degrees of mucosal necrosis. It occurs with various conditions
that allow the proliferation of Clostridium difficile. This may occur after the use of various
antibiotics (especially clindamycin and lincomycin) or subsequent to severe trauma or
medical/surgical illness. The bacterial exotoxins bind to the colonic epithelial cells causing
hypersecretion and inducing a suppurative inflammation with focal mucosal necrosis. This initially
occurs within the crypts and spews an inflammatory coagulum onto the surface of the bowel which
may coalesce into large patches forming a pseudomembrane. It is clinically characterized by either
profuse diarrhea developing during antibiotic therapy which generally will resolve within two
weeks after discontinuation of the drug or, altematively, copious bloody diarrhea which may
develop many days after antibiotic therapy has been completed and may rapidly lead to electrolyte
imbalance and possible death particularly in those patients who are already seriously ill.
Vancomycin is the drug of choice.

V. GASTROINTESTINAL POLYPS - Polyps may be defined as a mass lesion arising from the intestinal
mucosal epithelium that protrudes above the surface of the surrounding mucosa. They may occur anywhere
along the gastrointestinal tract but are most commonly found within the colon.

A. HAMARTOMATOUS POLYPS

1. JUVENILE RETENTION POLYP - As the name implies, most of these occur in childhood (4-
5 yr) but approximately 10% are found in adults. The rectum is most frequent site and
although typically solitary, they may be multiple. They may arise from developmentally
malformed or occluded crypts that gave rise to mucous retention cysts. Grossly they appear
as smooth, unfissured, pedunculated masses less than 2 cm. in size that contain mucus or

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 pus filled cysts. Microscopically, there are dilated, cystic spaces lined by normal colonic
epithelium within an expanded lamina propria containing a mild acute and chronic
inflammatory infiltrate. Malignant transformation is extremely rare.
2. PEUTZ-JEGHERS POLYP - Peutz-Jeghers syndrome is an autosomal dominant disease first
manifested in adolescence and young adulthood by polyposis of the entire G.I. tract (with
predilection for jejunum, ileum, and stomach) in association with melanin pigmentation
of the buccal mucosa, lips, and digits. The polyps consist of highly convoluted normal
mucosa overlying a branching core of smooth muscle. Atypia and mitoses are rare, but
infrequently these may be associated with G.I. malignancies as well as other visceral
neoplasms (pancreas, breast, ovary, and lung).

B. HYPERPLASTIC POLYPS - These are the most common type of polyp in adults and are most often
found in the rectosigmoid area although they may occur elsewhere. Thought to result from a loss
of normal growth restraint, there is cellular crowding, hyperchromatism and increased mitotic
activity in the proliferative zone at the base of the crypts but the nuclei retain their basal position
within the cell. There is lengthening of the crypts and as the cells migrate toward the surface, the
crypt lumen acquires a serrated or "saw-tooth" appearance. A similar proliferative stimulus acts
on fibroblasts to produce a thickened collagen layer beneath the surface epithelium. These changes
produce small « 0.5 cm.), pink-tan, sessile mucosal nodules that are most often multiple.
Clinically, they are asymptomatic, and malignant transformation is virtually nil.
C. NEOPLASTIC (ADENOMATOUS) POLYPS - These neoplasms may occur throughout the GI tract but
approximately half arise in the rectosigmoid area. They increase in incidence and frequency with
advancing age with most appearing after the age of 40 unless associated with one of the polyposis
syndromes. Normal growth restraints on the epithelial cells appears to be lost and the existing cells
do not mature as rapidly as normal cells. The proliferative zone within the crypts is expanded and
the production of new cells outstrips the sloughing of senescent cells creating the development of
a polypoid mass.

1. TUBULAR ADENOMA - This pattern makes up about two-thirds of the neoplastic polyps of
the colon but may also occur in the small bowel or stomach. They may be single or
multiple and typically appear as pedunculated polyps with a tan, spherical, irregularly
fissured head measuring up to 2 cm in diameter, occasionally larger. Within the head,
tubular spaces are lined by pseudostratified epithelium which has lost its normal
differentiation and shows varying degrees of cellular atypia and mitotic activity. Up to 25%
of a tubular adenoma may show a villous architecture. As the size of the polyp increases
(usually reflecting an increase in the villous component), the cellular atypia tends to
become more prominent and the elongated tortuous tubules become crowded "back-to-
back" to form a cribriform histologic pattern with little or no intervening stroma. This
generally signifies malignant transformation. However since the bowel mucosa does not
contain lymphatics, intraepithelial or intramucosal malignancy (carcinoma-in-situ) is of
little clinical significance until the malignant cells invade the muscularis mucosa where
they may be borne off to distant sites by the submucosal lymphatics. Malignant
transformation is most likely to occur in areas showing a villous architecture. Clinically,
these polyps are usually asymptomatic, but they may bleed secondary to trauma or become
infarcted secondary to torsion of the stalk.
2. VILLOUS ADENOMA - Although much less common than the tubular adenoma, these are
usually large (> 2 cm), solitary, firm, grey-tan, sessile lesions that occur most frequently
in the rectosigmoid area. Microscopically, more than 50% of the lesion reveals long,
slender, villous, "finger-like" projections having a fibrovascular core and lined by

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 pseudostratified epithelium with varying degrees of cellular atypia. By the time of
discovery, approximately 30-50% have undergone malignant transformation and, of these,
about half will have invaded through the muscularis mucosa. The larger the tumor, the
greater the chance of invasive carcinoma. These may also be asymptomatic but more often
produce rectal bleeding and/or copious mucoid diarrhea with resultant loss of protein,
fluid, and electrolytes (particularly potassium).
3. TUBULOVILLOUSADENOMA - About one fourth of the neoplastic polyps display a mixture
of tubular and villous architecture with the villous component ranging between 25-50%.
As with tubular adenomas, the malignant potential is proportional to degree of villous
component, therefore, the incidence of malignant transformation lies between that of the
tubular adenoma (which may contain up to 25% villous component) and the villous
adenoma (which contains more than 50% villous component).

D. POLYPOSIS SYNDROMES

1. FAMILIAL POLYPOSIS COLI - This autosomal dominant disease is characterized by the

appearance during the teenage years of thousands of neoplastic polyps (primarily tubular
adenomas) of the colon with rare involvement of the small bowel and stomach. Unless the
colon is resected, carcinoma invariably develops by the age of 40 years. The genetic defect
is a mutation of the APC (adenomatous polyposis coli) gene located on the long arm of
chromosome 5. A similar mutation is also found in many, but not all, cases of spontaneous
neoplastic polyp development.
2. GARDNER'SSYNDROME - This autosomal dominant disease is characterized by polyposis
involving the colon, small bowel, and stomach in association with benign lesions of the
skin (epidermoid cysts), soft tissue (fibroma, lipoma), and/or bone (osteomas). There is
inevitable development of colon carcinoma.
3. TURCOT'S SYNDROME - Thought to be autosomal recessive, this rare disease is char-
acterized by colonic polyposis in association with malignancies of the central nervous
system (medulloblastoma, glioblastoma, ependymoma) and a high risk of developing colon
cancer.

VI. NEOPLASIA

A. BENIGN LESIONS (leiomyoma, fibroma, lipoma, etc.) - These can occur anywhere throughout the
G.I. tract. Occasionally, they may become large enough to induce symptoms, but in general, are
small and asymptomatic. The possibility of malignancy must be ruled out, however, whenever a
mass lesion is identified.
B. SMALL BOWEL MALIGNANCIES - Carcinoid tumors and lymphoma, although relatively uncommon,
are the most frequent malignant neoplasms of the small bowel. Primary small bowel
adenocarcinomas are rare. When they occur, they usually arise in the ileum and produce a
constricting mass but rarely cause symptoms until late in the course of the disease. They spread to
involve regional lymph nodes, liver, lungs, and other viscera. Carcinomas that involve the ampulla
of Vater, however, may present early with signs and symptoms of obstructive jaundice.
C. COLORECTALMALIGNANCIES - Approximately 5% of the U.S. population will develop colorectal
carcinoma. There is an increasing incidence with age with the majority appearing after the age of
50. The vast majority are adenocarcinomas and are found (in decreasing order of frequency) in the
sigmoid colon, rectum, right colon, transverse colon, and descending colon although there is some
suggestion of a recent increase in right-sided cancers and decrease in sigmoid colon cancers.

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1. PATHOGENESIS - Both genetic and dietary factors have received scrutiny. A few families
have an autosomal dominant pedigree of colorectal carcinoma, but most cases appear
spontaneously. A high calorie diet rich in red meat and low in fiber increases the risk of
colorectal cancer. Animal fats increase bile acid secretion and concentration within the
bowel. This becomes converted to secondary bile acids and fatty acids by the action of
normal anaerobic bacterial flora. These may be directly toxic to the mucosa or potentiate
the action of various carcinogens. Increased fiber may bind to potential carcinogens and
also acts to increase the stool bulk thereby lowering the concentration of potential
carcinogens and speeding the transit time through the bowel. Like other malignancies,
colon cancer arises after multiple mutations of genetic material. In many cases of
colorectal carcinoma, there is activation of the ras oncogene and deletion of the p53
suppressor gene. There may also be a mutation of the APC gene among other mutations.
2. LEFT-SIDED CARCINOMAS - In general, these tumors begin as small plaques which tend
to remain superficial but over the course of 1-2 years completely encircles the lumen. The
tumor then begins to invade deeper into the wall of the colon and as it compromises the
blood supply, ulceration of the central portions occur. It may spread by direct extension
into surrounding fat or metastasize to regional lymph nodes. Vascular invasion results in
metastases to the liver, lung, bone marrow, brain, and other viscera. Clinically, these
tumors are often heralded by rectal bleeding but may produce obstructive symptoms
(constipation, decreased caliber of stools, etc) as well.
3. RIGHT-SIDED LESIONS - These tumors also begin as mucosal indurations but tend to
develop into a fungating mass lesion that protrudes into the lumen rather than an infiltrative
constricting lesion. They eventually may spread to the mesentery by direct extension or
metastasize to regional lymph nodes and other viscera. Due to chronic bleeding from the
tumor, patients often have occult blood in the stool and present with symptoms of anemia
(weakness, malaise, etc) and weight loss.
4. LABORATORY EVALUATION - The guaiac test for occult blood in the stool is an important
screening tool but is positive in only about half of the cases of colorectal carcinoma.
Elevated levels of carcinoembryonic antigen (CEA) in the serum is usually only seen in
advanced carcinoma and is not appropriate as a screening mechanism but may be valuable
in following the course of the disease and detecting the presence of metastases.
5. MODIFIED DUKES' CLASSIFICATION - Although poorly differentiated and signet ring cell
carcinomas tend to be more aggressive, the major prognostic indicators of a poor
prognosis are increased depth of invasion and metastasis to 4 or more lymph nodes. (A
TMN classification has also been proposed).

STAGE EXTENT 5-YR

B.URVIVAl

A Limited to mucosa or submucosa 95 %

Bl Extension into but not through the 80%

muscularis propria. Negative lymph nodes.

B2 Extension through wall. Negative 60%

lymph nodes.

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 Cl Limited to wall. Regional lymph node 50%
involvement.

C2 Extension through wall with regional 35 %

lymph node involvement.

D Distant metastases 25 %

D. APPENDICEAL MUCINOUS TUMORS

1. NON-NEOPLASTIC "MUCOCELE" - Local obstruction of the lumenal drainage of the

appendix or hyperplasia of the mucosa with excessive mucus production may lead to a
distended appendix due to retention of mucoid secretions.
2. APPENDECEAL MUCINOUS CYSTADENOCARCINOMA - This is a malignant neoplasm
characterized by the excessive production of mucin with resultant cystic dilatation of the
appendix. Histolgically, the tumor is often well differentiated and mimics the benign
mucocele, but clinically it is aggressive and will seed the peritoneal cavity and fill it with
abundant mucoid secretions (pseudomyxoma peritonei).
3. APPENDICEAL MUCINOUS CYSTADENOMA - This is the most frequent cause of a mucoid
filled cystically dilated appendix. Generally asymptomatic, it may rupture and spill mucoid
material into the peritoneal cavity. It does not, however, seed the cavity nor produce
pseudomyxoma peritonei.

E. GASTROINTESTINAL CARCINOID TUMORS - [See Endocrine System section]

F. GASTROINTESTINAL STROMAL TUMORS - These are spindle-cell neoplasms that may occur
anywhere along the length of the GI tract. The majority appear to arise from smooth muscle and
may behave in either a benign or malignant fashion.
G. TUMORS OF THE ANAL CANAL - These tumors often present with bleeding, pain, and the presence
of a mass in the anal canal. Predisposing factors are similar to those factors related to other
squamous neoplasms of the genital tract (chronic irritation, viral infections, etc). Although these
tumors may have variable microscopic patterns (squamous cell carcinoma, cloacogenic carcinoma,
mucoepidermoid carcinoma, etc), they tend to behave in a similar clinical fashion.

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 LIVER, BILIARY TRACT, AND EXOCRINE PANCREAS

LIVER

I. REVIEW OF NORMAL - The liver and gall bladder develop from a diverticulum which arises from the
ventral foregut. The liver weighs about 1400 to 1600 grams in the normal adult. It receives blood from the
hepatic arteI)' (a branch of the celiac arteI)') and the portal vein and is drained by the hepatic veins into the
inferior vena cava. There are four areas of anastomoses between the portal and systemic venous
circulations: the gastric and esophageal veins; para-umbilical veins; hemorrhoidal veins; and retroperitoneal
veins. Histologically, the classic hexagonal hepatic lobule is centered around the central vein with plates
or chords ofhepatocytes radiating out toward the portal tracts that contain the branches of the hepatic arteI)'
and portal vein and the bile ducts. The hepatocytes surrounding the portal tracts are termed the limiting
plate. Delicate reticulin fibers form the structural framework of the lobules. In contrast, the functional
hepatic acinus is centered around the portal tract (zone 1) and delimited by the central veins (zone 3).
Blood flows from the portal area, through the hepatic sinusoids and into the central vein. Therefore, the
least well perfused area of the liver is the centrilobular region (zone 3 of the acinus), and the best perfused
area is the periportal region (zone 1). Bile, on the other hand, flows in the opposite direction i. e. from the
centrilobular region to the portal tracts through the small bile canaliculi (formed between hepatocytes along
their non-sinusoidal surfaces), the intermediate ductules of Hering, and the interlobular bile ducts.
II. BILIRUBIN METABOLISM - A normal adult produces approximately 250-275 mg of bilirubin per day.
The majority (75%) is derived from the breakdown of red blood cells in the reticuloendothelial system
where the heme pigment is converted to biliverdin, then to bilirubin. Soluble in lipid but insoluble in blood
most, but not all, bilirubin formed outside the liver is tightly bound to albumin for transport to the liver and,
in this form, cannot be excreted in the urine or pass the blood brain barrier. If the amount of bilirubin
exceeds the capacity of albumin to bind it (> 20 mg/dl), the unconjugated (indirect) bilirubin may cross the
blood brain barrier where it tends to localize in the cerebral cortex and basal ganglia, causing kernicterus.
Kernicterus will usually result in brain damage and, if severe enough, can cause death. Bilirubin dissociates
from albumin at the liver cell membrane and enters the hepatocyte where, in the endoplasmic reticulum,
it is made water soluble by conjugation to glucuronic acid through the action of glucuronyl transferase.
When present in the blood, conjugated (direct) bilirubin is only loosely bound to albumin and may be
excreted in the urine. The hepatocyte excretes the conjugated bilirubin into the bile canaliculi by an
unknown rate-limiting mechanism. Lecithin, bile acids, bile salts, cholesterol, calcium, and other
electrolytes are added to the bile by active transport as it passes through the biliary system to the gallbladder
where it is concentrated. Upon appropriate stimulus, such as ingestion of a fatty meal, the ampulla of Vater
relaxes and the gallbladder contracts to discharge bile into the duodenum. The diglucuronide is split and
the bilirubin is converted by small bowel bacteria to urobilinogen. Some of the urobilinogen reabsorbed
into the portal circulation returns to the liver, comprising the enterohepatic circulation, and some passes

203
 into the general circulation to be later excreted by the kidneys. The urobilinogen left in the stool is
converted to urobilin which is partially responsible for the normal brown color of the stool.
III. JAUNDICE (ICTERUS) - This refers to a yellow-green discoloration of the skin and sclera produced by
accumulation of bilirubin in the tissues and body fluids. The normal serum bilirubin ranges from 0.1 to 1.0
mg/dl. Depending upon the discriminatory ability of the examiner,jaundice may become detectable at some
point between 1.8 and 3.0 mg/dl. The most frequent causes of jaundice in the United States are viral
hepatitis, cirrhosis, extrahepatic biliary obstruction and drug induced cholestasis. Mechanisms of bilirubin
accumulation include:

A. EXCESS PRODUCTION OF BILIRUBIN

1. HEMOLYTIC ANEMIA - This results in increased levels ofunconjugated bilirubin and mild
jaundice. Serum bilirubin levels, however, rarely exceed 5 mg/dl because the liver is
capable of conjugating and excreting most of this overload. If there is hepatic hypoxia or
intercurrent hepatic disease however, a more severe jaundice may result. Tightly bound
to albumin, unconjugated bilirubin cannot pass into the urine or pass the blood brain
barrier.
2. MASSIVE HEMORRHAGE OR HEMORRHAGIC INFARCTIONS -This may increase production
of bilirubin as the destroyed red cells are resorbed.

B. REDUCED HEPATIC CELL UPTAKE - The precise method for uptake of bilirubin into the liver cell
is poorly understood, although it is known that the unconjugated bilirubin separates from albumin
prior to being taken up. Inside the cell, bilirubin is picked up by acceptor proteins and ultimately
transported to the endoplasmic reticulum to be conjugated.

1. DRUGS -These may occasionally cause reactions which reduce uptake of bilirubin.
2. GILBERT'S SYNDROME - Thought to be transmitted as an autosomal dominant disease, this
is characterized by a mild, chronic elevation of unconjugated bilirubin, which is usually
detected only as an incidental lab finding (usually less than 3 mg/dl.) or when some
unrelated event transiently elevates bilirubin levels further to produce jaundice. Although
there is decreased glucuronyl transferase activity, the major defect appears to be in hepatic
uptake of bilirubin.

C. IMPAIRED CONJUGATION

1. PHYSIOLOGIC JAUNDICE OF THE NEWBORN -This is thought to be due to immaturity of

the hepatic conjugating system. Jaundice develops around the third to fifth day of life in
full-term infants and may be more pronounced and more prolonged in premature babies.
Jaundice in this case results from unconjugated bilirubin. Phototherapy can decrease serum
bilirubin concentration by breakdown of bilirubin to smaller, more polar, less toxic
derivatives which are excreted in bile or urine.
2. CRIGLER-NAJJAR SYNDROME

a. Type I - Probably transmitted as an autosomal recessive disorder, this is the more

severe form with levels ofunconjugated bilirubin ranging from 15-48 mg/dl. Due
to a defect in glucuronyl transferase activity, conjugation of bilirubin does not
occur and kernicterus invariably develops with affected individuals ultimately
dying of neurologic problems.

204
 b. Type II -This is transmitted as an autosomal dominant disorder, gives bilirubin
values of6-25 mg/dl with normal conjugated (direct) bilirubin concentrations, and
is usually not fatal. Type II may be more closely related to Gilbert's than to
Crigler-Najjar Type I.

D. IMPAIRED EXCRETION OF CONJUGATED BILIRUBIN - Interference with the excretion of conjugated

bilirubin may occur anywhere between the liver cell and the ampulla of Vater resulting in
cholestasis. Cholestasis, whether as the result of intrahepatic or extrahepatic obstruction, tends to
have similar clinical signs and symptoms and, to a large extent, similar morphologic alterations in
the liver as well. Because extrahepatic jaundice can be treated by surgical means and intrahepatic
jaundice is treated by medical management, it is clinically of importance to know whether jaundice
results from intrahepatic or extrahepatic causes.

1. INTRAHEPATIC CAUSES - In general, all forms of intrahepatic jaundice are associated with
increased levels of the transaminases and LOR, and also may result in decreased prothrom-
bin levels with consequent prolonged prothrombin times.

a. Hereditary disorders

(l) Dubin-Johnson syndrome - Although it may not become manifest until

adulthood, this is an autosomal recessive disorder that results in a
generally mild conjugated bilirubinemia, chronic or recurrent jaundice,
and accumulation of a peculiar dark pigment, possibly related to melanin,
in hepatocytes.
(2) Rotor syndrome -This is similar to the Dubin-Johnson syndrome but is
less common and lacks the hepatic pigmentation.

b. Drugs (estrogens, oral contraceptives, anabolic steroids, etc)

c. Hepatocellular injury -This may interfere with bilirubin uptake, conjugation,
and/or excretion.
d. Disruption of liver architecture (cirrhosis, hepatitis, etc) - may cause
intrahepatic cholestasis.

2. EXTRAHEPATIC CAUSES -These result from narrowing or obstruction of the biliary tract
or the ampulla of Vater. Gallstones lodged in the common duct or carcinoma affecting any
duct structures or the head of the pancreas are the most common causes of posthepatic
obstructive jaundice. Tumor metastasis to the porta hepatis lymph nodes may obstruct the
biliary tract, as can swelling of the head of the pancreas in acute pancreatitis.
3. MORPHOLOGY - In both intrahepatic obstruction and extrahepatic obstruction, the liver
may assume a green discoloration. Microscopically, bile plugs may be present in distended
canaliculi predominantly in the centrilobular areas and cytoplasmic bile pigment can be
seen in the Kupffer cells and hepatocytes. Alterations in the cytoplasmic organelles and the
accumulation of bile acids produce afeathery degeneration of the hepatocytes that are
surrounded by mononuclear cells. With extrahepatic obstruction or obstruction of the large
intrahepatic bile ducts, bile backs up into the intrahepatic ducts and induces proliferation
of the portal tract bile ducts which also become twisted and tortuous. Acute inflammatory
cells may be present in the portal areas indicating infection proximal to the obstruction.
Ultimately canaliculi may rupture to produce "bile lakes" containing dead or dying bile
stained hepatocytes.

205
 4. CLINICAL SIGNS AND SYMPTOMS - In obstructive jaundice there is an increase of
conjugated bilirubin in the serum, and the stools lose their normal color to become clay-
colored (acholic stools). Lack of bile in the gut also causes decreased absorption of fats
and fat soluble vitamins causing a temporary malabsorption syndrome to develop.
Bilirubinuria develops but urine urobilinogen levels decline. The accumulation of bile
acids in the blood causes pruritus. With chronic cholestasis, plasma cholesterol levels also
increase due to both increased hepatic synthesis and decreased excretion. The
hypercholesterolemia may be mainfested as xanthelasma beginning at the inner canthus
of the eyes and spreading laterally. Later tuberous xanthomas may develop on extensor
surfaces, in pressure areas, and in scars. Discoloration of the nails by bile pigment and
clubbing of the digits may also occur.
5. LABORATORY FINDINGS - Serum alkaline phosphatase levels, which tend to represent
damage to biliary epithelium, are markedly increased. Obstruction of bile outflow also
results in hepatocellular damage with elevation of the parenchymal enzymes (LDH and
transaminases) as well, although not to the extent seen with primary liver cell damage.

IV. DRUG INDUCED DISEASE - Many therapeutic drugs have been shown to have adverse effects on the
liver either through direct toxicity to the hepatic cells by the drug or one of its breakdown products,
secondary effects of the drug on hepatocytes, or the induction of hypersensitivity. While some drugs are
predictable in the type of injury that they produce, others do not produce the same pattern of injury in all
cases.

A. PATTERNS OF INJURY

I. CHOLESTASIS - This is produced by drugs that interfere with the excretion of conjugated
bilirubin and other organic anions from the hepatocytes. Microscopically, intracytoplasmic
bile pigment is present within swollen hepatocytes and Kupffer cells, and small bile plugs
are seen in the canaliculi, particularly in the centrilobular areas. Upon removal of the drug,
the changes promptly disappear.
2. CHOLESTASIS AND FOCAL NECROSIS - These are produced by a variety of drugs where,
in addition to cholestatic changes, there may be focal necrosis of the hepatocytes with a
scant mononuclear infiltrate. Adjacent portal triads may contain lymphocytes or
eosinophils. Most patients show no particular untoward effects when taking these drugs,
but some individuals become jaundiced. With discontinuation of the drug, such signs
usually clear rapidly.
3. NECROSIS - Certain drugs (halothane, isoniazid, etc) may produce either zonal or massive
necrosis of the liver. In some instances, a hypersensitivity to the drug develops so that the
hepatic damage occurs only on the second or third exposure to the drug whereas other
drugs appear to have a direct cytotoxic effect on hepatocytes. Histologically, changes from
focal necrosis to massive destruction of the entire liver may be found. This may be
followed by fibrosis/cirrhosis, etc.
4. NEOPLASIA - Some drugs (oral contraceptives, anabolic steroids) have been implicated in
the development of both benign and malignant neoplasias.

B. LABORATORY FINDINGS - In individuals with only cholestasis, alkaline phosphatase may be

elevated slightly without elevation oftransaminases (which generally indicate cellular damage). In
association with drugs that induce necrosis as well as cholestasis, both alkaline phosphatase and
transaminase levels may be elevated. In cases of massive hepatic necrosis, transaminase levels may

206
 reach as high as 10,000 units and then drop precipitously as if the liver had spilled all of its
enzymes in a single necrotic episode.

V. CIRCULATORY DISORDERS

A. CONGESTION - Since hepatocytes are highly sensitive to hypoxia, vascular stasis is an important
cause of hepatocellular injury.

1. ACUTE CONGESTION - This is characterized by an enlarged swollen liver engorged with

blood. The central veins of the lobules are dilated and grossly appear dark purple-red.
Severe, rapid congestion of the liver such as seen with severe right heart failure may cause
the sinusoids to rupture and produce a central hemorrhagic necrosis. The liver fraction
of LDH generally becomes elevated almost immediately and the transaminases may
become slightly elevated.
2. CHRONIC CONGESTION - This shows irregular dilatation of the sinusoids progressing
toward the periphery of the lobule sometimes appearing to fuse and produce congestive
bridges with dilated sinusoids in adjacent lobules. The congested central portions of the
lobule become depressed but stand out against the paler liver tissue to create a "nutmeg
liver". The long-standing pressure may cause atrophy or necrosis of the adjacent liver cells
and subsequent fibrosis of the necrotic areas may lead to cardiac sclerosis. The fibrous
scarring fans out irregularly from the central veins to produce a slightly shrunken liver with
a fine granular pigskin-like surface.

B. INFARCTION - The double blood supply to the liver makes hepatic infarction unusual.

1. ARTERIAL - Occlusion of the hepatic artery is most serious when it occurs distal to its last
major extrahepatic branch (gastroduodenal). Occlusion of intrahepatic arteries (from
emboli, aneurysms, polyarteritis nodosa, etc) may result in an infarct which is usually pale
but may be hemorrhagic.
2. VENOUS - Occlusion of a portal vein branch (termed Zahn's infarct), does not lead to a
true infarct but rather to a well demarcated purplish discoloration of the parenchyma
resulting from congestion of the sinusoids. Causes include regional infections, extension
of a thrombus from the portal vein, hypercoagulable states, or external compression.

C. HEPATIC VEIN THROMBOSIS

1. BUDD-CHIARI SYNDROME - This syndrome results from thrombosis of the major hepatic
veins or inferior vena cava It is usually the result of a hypercoagulable state (polycythemia
vera, pregnancy, oral contraceptives) or a primary carcinoma of the liver that grows into
the hepatic veins. Such blockage of outflow of blood results in sinusoidal congestion.
Sudden occlusion causes an acute painful enlargement of the liver. Severe, intractable
ascites develops and patients usually die in hepatic failure. If the obstruction develops
insidiously, liver enlargement is gradual and less painful, but ascites develops nonetheless.
As a consequence of the central congestion, central veins become thickened, sometimes
with atrophy of the adjacent hepatocytes and delicate fibrosis in the central regions of the
liver lobules much like the changes seen in cardiac sclerosis. In an effort to bypass the
obstruction, subcutaneous veins of the abdomen and thorax may become distended.

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 2. VENO-OCCLUSIVE DISEASE - This is a similar process but involves the small to medium
sized branches of the hepatic veins. Among other causes, it may be triggered by high dose
chemotherapy.

D. PORTAL VEIN THROMBOSIS - Extrahepatic obstruction is usually related to intravascular

thrombosis precipitated by infection, extension of thrombi from the splenic or mesenteric veins,
extrinsic compression by tumor, or direct invasion by tumor. Peritonitis, peritoneal abscess, or
abdominal surgery may be associated with formation of a small thrombus in a portal branch which
may propagate into the main vein. Within the liver, primary or metastatic cancer or a strategically
located abscess may cause portal obstruction. The liver is not enlarged or tender but portal
hypertension will occur and result in congestive splenomegaly, possible ascites, and circulatory
diversion through systemic venous anastomoses especially retroperitoneal and esophageal veins.
E. SYSTEMIC HYPOTENSION - This is reflected in the liver by necrosis of the poorly oxygenated
centrilobular regions.

VI. PORTAL HYPERTENSION - This is the result of impairment of venous flow through the portal system.
Most frequently, this is the result of Laennec's cirrhosis although the Budd-Chiari syndrome, veno-
occlusive disease and portal vein thrombosis/compression can also be causes. Obstruction of intrahepatic
veins results in a backup of blood causing increased pressure in the portal vein. Additionally, there are
intrahepatic shunts between the hepatic artery and the portal vein and, in cirrhosis, these anastomoses are
enlarged and may be a major contributor to the increased portal pressure. Portal hypertension produces a
number of changes but the primary ones are ascites, collateral venous channels and splenomegaly.

A. COLLATERAL VENOUS CHANNELS

1. GASTROESOPHAGEAL PLEXUS - This results in esophageal varices in about 67% of

patients with advanced cirrhosis. The principle cause of death in about half of the patients
with cirrhosis is bleeeding from ruptured esophageal varices.
2. HEMORRHOIDAL PLEXUS - This connects the superior mesenteric vein of the portal system
with the inferior mesenteric system. Severe hemorrhoids develop in up to half of the
patients with cirrhosis. This constitutes a significant source of discomfort in such patients,
though they do not normally cause significant hemorrhage.
3. PERIUMBILICAL - In patients in whom the fetal umbilical vein has not become totally
obliterated, the typical caput medusae may develop.
4. RETROPERITONEAL - These channels generally do not produce signs or symptoms or
result in significant hemorrhage.

B. CONGESTIVE SPLENOMEGALY - This may result in spleens weighing as much as 1000 gms.
Hypersplenism may develop, producing anemia, leukopenia, and thrombocytopenia and, especially
if combined with abnormalities of clotting factors, the patient may develop a hemorrhagic diathesis.
Peptic ulcer disease is more frequent in these patients than in the normal population.
C. ASCITES - This is the intraperitoneal accumulation of watery fluid. Glucose, sodium, and potassium
are essentially in equilibrium with the serum concentrations. In cirrhosis, increased sinusoidal
pressures drive the venous fluid across the discontinuous endothelial lining of the sinusoids and
into the hepatic lymphatics where it ultimately weeps in large quantities from the surface of the
liver into the peritoneal cavity. Sequestration of fluid in the peritoneal cavity reduces renal blood
flow which stimulates renin activity to retain sodium and water thereby entering into a viscious
cycle. Liters of ascitic fluid may accumulate and produce discomfort due to distension of the
abdomen. Drainage of such fluid produces considerable loss of protein and electrolytes. Removal

208
 of ascitic fluid is often followed by prompt reaccumulation since the rate of exchange of the
peritoneal fluid with the plasma is as high as 80% per hour. Red cells and neutrophils are normally
not present in ascitic fluid, although mesothelial cells and a few lymphocytes may be present
normally. The presence of red cells in ascites fluid should alert the physician to the possibility of
carcinomatosis of peritoneal surfaces. The presence of large numbers of neutrophils probably
indicates peritoneal irritation, most likely peritonitis.

VII. INFLAMMA TORY DISEASES

A. VIRALHEPATITIS - This may be caused by any number of viral agents under appropriate conditions.
In general usage, however, the term applies to a group of viruses that are specifically hepatotropic.

I. HEPATOTROPIC VIRUSES

a. Hepatitis A (HAV) - This is a single stranded RNA virus which is acquired by

ingestion of fecally contaminated water or food and which causes an acute self-
limited form of hepatitis. Often associated with childhood or rural epidemics,
outbreaks also occur when conditions are crowded (military installations) or
sanitary conditions are poor (mental institutions, developing countries). The
incubation period for type A hepatitis is two to six weeks and this is the period of
peak infectivity since the virus is shed in the feces during this time. A short period
of viremia occurs just before the onset of clinical symptoms but transfer of the
virus via blood is rare. By the time clinical symptoms appear, however, the virus
is no longer being shed. The disease tends to be less severe in children (95% of
childhood cases recover completely and less than I % progress to acute fulminant
hepatitis.) Unlike the other types of hepatotropic viruses, HA V is not known to
have a carrier state or to progress to chronic hepatitis. Serum antibodies to HA V
are initially of the IgM type followed by the longer lasting IgG type.
b. Hepatitis B (HBV) - This consists of a double shelled 42 nm particle (Dane
particle) having an inner 28 nm core particle containing DNA polymerase and
double stranded circular DNA. The Dane particle is probably the infectious virion
and is transmitted primarily by the parenteral route - usually through blood
products or contamination of needles by infected blood. The core is thought to
proliferate in the nucleus of the liver cell, with the surface double-shelled material
added in the cytoplasm. Hepatitis B virus has also been identified in stool, urine,
saliva, sweat, semen, and menstrual blood and may be transmitted by aerosols or
by sexual contact. The incubation period for hepatitis B is six weeks to six months
and the resulting disease may range in clinical severity from asymptomatic to
fulminant. Three major antigens are associated with HBV - an outer coat antigen,
HBsAg (hepatitis B surface antigen - also known as "Australia antigen"); and two
antigens associated with the viral core, HBcAg (core antigen) and HBeAg. 5 - 10%
of HBV patients become asymptomatic carriers of the virus.
c. Hepatitis C (Non-A, Non-B hepatitis; NANBV) - This is a single stranded,
positive sense RNA virus. Most cases arise as the result of transfusion of
contaminated blood, and there is a greater predilection to develop chronic disease
(50%) than with HBV. Other cases, however, may be spread by the fecal-oral
route and are more prone to produce fulminant acute disease than HAV. Recently
developed (1990) screening kits to test for antibody against the protein C-1 00-3
have allowed testing of blood supplies and hopefully the incidence of NANB

209
 hepatitis will decline. A newer (1992) multiple antigen test is now available which
may double the identification ofHCV positive blood.
d. Hepatitis D (HDV) -lbis is an RNA virus which relies on the HBV outer coat in
order to replicate and is therefore dependent on a coexistent HBV infection, either
in an active or carrier form. In patients with active HBV infection, coinfection with
HDV tends to worsen the acute course but chronic disease is unusual. HDV
infection ofHBV carriers, however, is likely to induce chronic progressive hepatic
damage. The virus is probably transmitted much in the same manner as HBY.
e. Hepatitis E (HEV) - This is a non-A, non-B, non-C virus that is spread by the
fecal-oral route, usually by fecally contaminated drinking water, with an incubation
period of 2-9 weeks. Currently, outbreaks have been limited to developing
countries and no endemic cases have been reported in the U.S.

2. ACUTE HEPATITIS - All of the hepatotropic viruses produce similar clinical and
morphologic changes. Although the incubation periods differ, biochemical evidence of
hepatic damage (elevated ALT, AST, LDH) and peak infective periods precede the
development of clinical symptoms.

a. Clinical expression - If symptoms develop, there is a prodromal period in which

the patients develop a flu-like syndrome with malaise, weakness, loss of appetite
and nausea. Tobacco and coffee frequently become distasteful. Clinical symptoms
may abate (esp. hepatitis A) without the development of increased bilirubin levels
(anicteric hepatitis) or they may worsen with the development of fever, chills,
headache, myalgias, vomiting, diarrhea, and jaundice. As the bilirubin (primarily
conjugated) levels rise, the prodromal symptoms begin to subside although the
urine may darken (bilirubinuria) due to the conjugated bilirubin. If the bile
canaliculi become obstructed by hepatic edema or inflammation, the stools will
become lighter in color and an intense pruritus may develop due to retention of
bile acids. The patient may complain of fullness in the right upper quadrant of the
abdomen, and on physical examination the liver is slightly enlarged and usually
tender, frequently with a blunted edge. 5-10% of patients with Hepatitis B and 40-
50% of patients with Hepatitis C will enter into a chronic "carrier" state. Fulminant
hepatic necrosis and death is even less common.
b. Morphologic expression - During the prodromal period, liver biopsies reveal
wide spread hepatocellular and Kupffer cell swelling and a sparse
lymphocytic/monocytic infiltrate in portal areas. Isolated liver cell necrosis,
sometimes called cell dropout, may be present but is difficult to detect at this
stage. Characteristic features include:

(1) Liver cell injury - Injured cells swell and the cytoplasm appears watery
and vacuolated (ballooning degeneration). Such changes are most evident
in the centrilobular regions.
(2) Hepatic necrosis - Individual necrotic cells may disappear leaving no
trace while others undergo a peculiar coagulation and appear as round
eosinophilic bodies (Councilman bodies). Occasionally hepatocellular
necrosis is more extensive reaching from one lobule to another and
forming so-called bridging necrosis. In extremely severe cases, massive
necrosis of the liver may occur.
(3) Reticuloendothelial hypertrophy/hyperplasia

210
 (4) Portal infiltration - Macrophages and lymphocytes can be found in the
portal areas as well as in areas of focal liver cell necrosis.
(5) Regeneration of liver cells - During recovery, evidence of regeneration
ofhepatocytes (binucleate cells, increased mitoses) is present.
(6) Intrahepatic cholestasis - This is variably present with small droplets of
bile pigment seen in hepatocytes and Kupffer cells and inspissated bile
within the canaliculi.
(7) Lobular disarray - All of the preceding changes alter the normal
architecture of the hepatic lobule which may later interfere with normal
hepatic function.

3. CHRONIC HEPATITIS - This may be defined as any hepatitis which persists for more than
six months. Although most often the result ofhepatotropic viruses (excepting HA V), there
are a variety of other causes.

a. Chronic persistent hepatitis - This develops in less than 10% of cases of acute
hepatitis B but in a somewhat greater incidence in cases of Hepatitis C. Vague
recurrent symptoms of malaise, weakness, loss of appetite, right upper quadrant
discomfort and occasionally mild jaundice are present in about half of these
patients. The others remain asymptomatic. Transaminase levels may be slightly
increased to about 2-3 times normal, and bilirubin levels usually are less than 5
mg/dl. On liver biopsy, there is nonspecific portal mononuclear cell inflammation,
sometimes follicular, with preservation of the limiting plates. Intralobular necrosis
and inflammation are mild or absent. Most patients recover but a few convert to
chronic active hepatitis.
b. Chronic active hepatitis - This is characterized by progressive liver destruction.
About 90% of these cases are viral in origin, but the incidence of drug induced
chronic active hepatitis appears to be increasing. About 60-70% of all patients
with chronic active hepatitis belong to the group referred to as cryptogenic (now
felt to mostly represent previous Hepatitis C infection). Clinically, these patients
do not appear particularly ill when they first present. They have poorly defined
complaints of weakness, fatigue, and loss of appetite as is seen in acute hepatitis.
Jaundice usually is not present until late in the course when the disease is fairly
severe, but itching is common. Liver histology reveals mononuclear inflammation
(lymphocytes, macrophages, and plasma cells) spilling out of the portal areas with
piecemeal necrosis (destruction of the limiting plates) and bridging necrosis.
Kupffer cells are prominent and there may be periportal fibrosis and abnormal bile
duct proliferation. Macronodular cirrhosis then develops.

CA VEA T: Since there may be overlap between the two, many laboratories have
abandoned the terms chronic persistent hepatitis and chronic active hepatitis in favor of the
diagnosis of "chronic hepatitis" accompanied by an indication of the severity of the
inflammatory response and, if possible, a statement as to the likely etiology.

B. BACTERIAL DISEASE

1. CHOLANGITIS - This is characterized by purulent bacterial infection in the intrahepatic bile

ducts. The process generally begins in the extrahepatic biliary system as a complication of
obstruction of the common bile duct by gallstones or, less commonly, by carcinoma of the

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 head of the pancreas or some portion of the biliary tract. The infection, usually due to
enteric organisms, then spreads into the intrahepatic biliary tree (ascending cholangitis).
Pus can be expelled from the bile ducts and there is inflammatory infiltrate in surrounding
portal connective tissue. Clinically, cholangitis causes a high fever and a large tender liver.
Signs and symptoms are similar to those of acute cholecystitis. Severe cholangitis may lead
to formation of abscesses in the liver.
2. LIVER ABSCESS - Pyogenic bacteria may seed the liver via the bile ducts, portal vein,
hepatic artery, lymphatics, or by direct spread from adjacent infections. The causative
organism may be E. coli or other intestinal organisms, streptococcus or staphylococcus,
septic emboli or bacteria from bacterial endocarditis or other bacteremias. Abscesses in
these cases are usually small and widely distributed throughout the liver. Less commonly,
perforations of the gastrointestinal tract or other intraperitoneal infections, sometimes
following surgery, may give rise to subdiaphragmatic or subhepatic abscesses, which then
involve the liver. These present particular clinical problems because a patient who
improved following surgery then begins to follow a course of deterioration. Large
abscesses such as these must be drained for proper treatment.

C. SPIROCHETAL DISEASES

1. WElL'S DISEASE - This is characterized by jaundice in a patient with systemic leptospirosis.

There is a diffuse interstitial hepatic inflammation with swelling of Kupffer cells and
hepatocytes, scattered unicellular necrosis and widespread mitotic and regenerative
activity. Spirochetes can be found in interstitial tissue and sinusoids only with special silver
impregnation stains and after a long search.
2. RELAPSING FEVER - This is caused by the spirochete Borrelia recurrentis. This disease can
be spread either by the louse or by soft shelled ticks and is endemic to a slight degree along
coastal areas of the United States and in the state of Oklahoma. Changes are similar to
those seen in Weil's Disease.

D. PARASITIC DISEASE

1. AMOEBA - Amoebic hepatic abscesses are a serious complication of amoebic dysentery.

The parasites apparently traverse the portal vein to reach the liver (and possibly brain) and
cause a chronic fever of unknown origin. E. histolytica secretes proteolytic enzymes that
lyses hepatic tissue to create an abscess. Such abscesses may spread through the
diaphragm into the lungs or rupture into the peritoneal cavity. Typically a disease of young
adult males, there may be point tenderness over the abscess. Characteristically on gross
examination, the abscess contains a creamy brown exudate referred to as "anchovy paste".
2. ECHINOCOCCUS GRANULOSA - This small tapeworm produces hydatid cysts in its
intermediate host. The liver is a frequent site of such cysts though they may also be found
in muscle or in the brain or other tissues. The liver may contain one or several cysts which
may vary in size from small to large enough to replace an entire lobe. The large cysts are
mother cysts which contain multiple small thin walled daughter cysts, each one capable of
developing in a definitive host into a separate adult tapeworm. The mother cyst wall is
composed of laminated layers of chitinous material as is each daughter cyst, and each may
reveal scolices or hooklets of the Echinococcus organism. If one of these cysts is ruptured
at surgery, the fluid containing the daughter cysts may be spread throughout the peritoneal
cavity where each daughter cyst may develop into a mother cyst, widely spreading the
disease.

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 3. SCHISTOSOME (Bilharziasis) - The mansoni andjaponicum species may involve the liver
when the schistosome eggs pass to the liver by way of the portal vein, where they lodge in
portal spaces and sometimes in sinusoids. These eggs initiate an inflammatory process
characterized by eosinophils and mononuclear cells and initiate a peripheral zone of
fibrous connective tissue. Such lesions are sometimes called pseudotubercles. When the
fibrotic process extends to smaller portal spaces, proliferation of bile ducts and formation
of pseudolobules result in development of cirrhosis.
4. LIVER FLUKES - Fasciola hepatica, Clonorchis sinensis, and Opisthorchis felinus are
associated with liver disease. These organisms are relatively large parasites which primarily
affect bile ducts producing an exudate in the immediate vicinity. This exudate contains
eosinophils, lymphocytes and plasma cells. Fibrosis of portal spaces occurs with severe
epithelial hyperplasia of bile ducts, eventually resembling adenomas. This process rarely
progresses to cirrhosis.
5. LEISHMANIA (Kala azar) - This produces a large tense liver which is pale yellow on cut
section as a result of fatty metamorphosis, or sometimes red because of hyperemia.
Leishmanial organisms are present in the Kupffer cells and in cases of heavy infection may
involve hepatocytes and histiocytes in the portal areas. Fatty degeneration of periportal
hepatocytes occurs, and enlarged Kupffer cells usually contain hemosiderin. A sparse
portal exudate of lymphocytes and large mononuclear cells may also be present.

VIII. CIRRHOSIS - This is a very important clinical disorder because of its prevalence, its disruption of hepatic
architecture, and its consequent interference with liver function, but there is no universal classification of
cirrhosis on either morphologic or etiologic grounds. Cirrhosis is characterized by hepatic necrosis,
regeneration, fibrosis, and architectural distortion. Regeneration probably occurs from preserved hepatic
cells of the limiting plate in the portal areas. When hepatic necrosis occurs without collapse of the
underlying reticular framework of the liver, the remaining liver cells are able to regenerate the entire lobule
with its normal architecture. If the total lobule and its reticulin framework are destroyed, adjacent liver cells
may proliferate producing nodules of hepatic cells which lack normal canalicular and sinusoidal
relationships. Such cells can function in the normal metabolic activities of the liver but cannot normally
excrete bile. The patterns of scarring (micronodular vs. macronodular) are not specific but may give a clue
as to the underlying etiologic event.

A. LAENNEC'S (ALCOHOLIC) CIRRHOSIS - This is the most common form of cirrhosis in the United
States accounting for 30 - 60% of all cases.

1. PATHOGENESIS - The majority (about 90%) of patients who develop Laennec's cirrhosis
have a history of chronic alcoholism. Ingestion of ethanol results in increased transport of
fat from the periphery of the body to the liver, reduced fatty acid oxidation in the liver, and
increased synthesis oftriglycerides. It appears also that mobilization oflipids as lipoprotein
is impaired. This results in rapid fatty change of the hepatocytes. In the early stage the liver
is enlarged, smooth, yellow and obviously fatty, weighing up to as much as 4 to 6 kg. On
cut section, the tissue is soft and greasy with a bulging surface. Hepatic cells may be
swollen with some bile stasis apparent in the bile canaliculi and in hepatocytes. Frequently,
pink hyaline material (known as alcoholic hyaline or Mallory bodies) is present within the
cytoplasm of scattered liver cells many of which are necrotic and surrounded by
neutrophils. Exaggeration of this process leads to "alcoholic hepatitis". Active fibroblastic
proliferation produces progressive fibrosis within the lobule. Gradually, the liver decreases
in size and demonstrates a finely nodular pattern (micronodular cirrhosis) with yellow

213
 orange color. It may weigh less than 1200 gms and have a fibrotic consistency. As the liver
shrinks, fat tends to disappear and the liver becomes progressively darker brown.
2. CLINICAL COURSE - Cirrhosis may develop gradually over a period of several decades.
Eventually non-specific symptoms of weight loss, anorexia, nausea, vomiting and vague
gastrointestinal complaints occur. Sometimes the first evidence of liver disease is the
development of jaundice. Ascites, splenomegaly, and gastrointestinal bleeding from
esophageal varices or gastritis may also be presenting symptoms. Death usually occurs as
a result of hepatic failure, infection, gastrointestinal hemorrhage, or rarely, the
development of hepatic carcinoma.

B. POSTNECROTIC CIRRHOSIS - This comprises between 10 and 30% of the total cases of cirrhosis
that are reported.

1. PATHOGENESIS - Generally, postnecrotic cirrhosis follows an episode of viral hepatitis or

drug or chemical toxicity which resulted in a marked degree of acute hepatocellular
necrosis. Grossly, the liver may be small and misshapen frequently weighing less than 1000
grams. Large, irregular and variably sized regenerative nodules (macronodular cirrhosis)
are interspersed among depressed scars of varied width. Microscopically, there is irregular
coarse scarring with only occasional scattered bile ducts and blood vessels in the scars.
Occasional areas of persistent normal liver parenchyma may be present between scars, but
most areas consist of regeneration of liver cells in large disorganized masses. Prominent
bile stasis is usually present in regenerative nodules.
2. CLINICAL COURSE - When symptoms occur, they are usually the result of liver failure or
portal hypertension. Some patients with this form of cirrhosis develop hepatocellular
carcinoma and it is this type of cirrhosis with which hepatocellular carcinoma is most
frequently associated.

C. BILIARY CIRRHOSIS

1. PRIMARY BILIARY CIRRHOSIS - This is a poorly understood entity that is associated with
considerable humoral and cell mediated immunologic disturbances, elevated serum
cholesterol levels, and skin xanthomas. Antimitochondrial antibodies are found in 85 to
95% of patients with primary biliary cirrhosis, but in less than 1% of patients with
mechanical obstruction of the main bile ducts. Some patients also have other autoimmune
disorders.

a. Morphology - Grossly, the liver is large and green. In earlier stages it appears
smooth, but with progression it becomes coarsely nodular. The gallbladder and
extrahepatic bile ducts are normal. Frequently there are enlarged, hyperplastic bile-
stained lymph nodes in the porta hepatis and along the common bile duct. The
spleen is generally enlarged as a result of portal hypertension. Microscopically, in
the earlier stages, septal and larger interlobular bile ducts are damaged and
surrounded by a dense infiltrate of lymphocytes, histiocytes (or epithelioid cells),
plasma cells, and occasionally eosinophils. IgM has been detected in the tissue
adjoining damaged bile ducts and may indicate that the bile duct damage is a result
of antigen-antibody reactions. Lymphoid aggregates with or without germinal
centers may be found and poorly defined granulomas are often present but the
limiting plate remains intact. As the disease progresses, there is ductular prolif-
eration, fibrosis, and acute and chronic inflammation with granulomas becoming

214
 less frequent. Later the inflammation subsides and relatively acellular fibrous septa
extend from portal tracts into and around lobules. Regenerative nodules develop
and cholestasis may become severe.
b. C1inical- 90% of the patients who develop biliary cirrhosis are women between
the ages of 40 and 60. The disease starts most frequently as pruritus without
jaundice. Jaundice may develop, however, within 6 to 24 months of the onset of
itching. Patients usually feel well and have a good appetite in spite of the jaundice.
Abdominal pain is rare. The liver is usually enlarged and firm, and the spleen
palpable. In the late stages of the disease, patients often complain of backache and
pain over the ribs, sometimes involving pathological fracture. Duodenal ulcers and
hemorrhage are common. Portal hypertension, with bleeding esophageal varices
is frequent, but usually a late development. Laboratory findings include marked
elevation of the alkaline phosphatase, and serum IgM may be very high.

2. SECONDARY BILIARY CIRRHOSIS - This usually is due to mechanical obstruction of the

biliary outflow tract, usually by gallstones or carcinoma of the head of the pancreas,
ampulla of Vater, or extrahepatic bile ducts. Biliary atresia or stricture of the extrahepatic
bile ducts may lead to a similar picture. If tumor or gallstones are present as the cause of
mechanical obstruction, ascending cholangitis may add to the damage. The morphology
and clinical manifestations are those of extrahepatic biliary obstruction.

D. PIGMENTARY CIRRHOSIS - This occurs in individuals who are unable to process iron by the normal
metabolic pathways (hemochromatosis) and those who have excessive iron intake (hemosiderosis).
The excess iron is stored in the liver and other parts of the body. Consequently, the liver assumes
a deeper brown color and grossly appears similar to a moderately advanced stage of Laennec's
cirrhosis. Microscopically, brownish pigment granules are found within the cytoplasm of liver cells,
Kupffer cells, bile duct epithelium, and within fibrous connective tissue. Individuals with
hemochromatosis are apt to develop diabetes mellitus with pigmentation of the pancreas as welL
They also develop dark skin due to pigment deposition. The skin pigment is not iron, but rather
melanin, possibly resulting from failure of a feedback mechanism to shut off pituitary MSH
production. Most patients with pigmentary cirrhosis develop hepatic failure or portal hypertension.
Individuals with pigmentary cirrhosis as well as those with post necrotic cirrhosis have a much
higher incidence than the normal population of primary hepatocarcinoma.
E. WILSON'S DISEASE (hepatolenticular degeneration) - This is an inborn error of copper metabolism
which is inherited as an autosomal recessive trait. Symptoms usually appear in the second or third
decade of life. There is inadequate synthesis of the plasma copper-binding protein ceruloplasmin.
Copper, after absorption from the diet, is normally transported complexed to this protein. In
patients with Wilson's disease, inadequate levels of ceruloplasmin permit copper to be transported
loosely complexed with albumin from which it is readily dissociated to be deposited in the liver,
basal ganglia of the brain, the cerebral cortex, kidney, and the cornea. Wherever copper is
deposited, damage to tissues occurs. Copper deposits in the eye are found in Descemet's membrane
at the limbus of the cornea, producing characteristic Kayser-Fleischer rings pathognomonic of
Wilson's disease. The disease often presents in an adolescent child described as having bird-like
facies, whose behavior becomes erratic and bizarre. Early in the course of Wilson's disease,
hepatocellular necrosis accompanied by formation of hyaline acidophilic inclusions (Mallory
bodies) similar to those present in alcohol abuse are described. Scarring follows this stage of
necrosis, producing delicate trabeculae or broad massive areas of collapse suggesting post necrotic
cirrhosis. Laboratory tests show low serum copper levels, low serum ceruloplasmin levels and
increased excretion of copper in the urine. Patients in whom the diagnosis is made early can be

215
 successfully treated with chelating agents, such as penicillamine, to control accumulation of excess
amounts of copper and prevent subsequent brain and liver damage.

IX MASS LESIONS

A. HEPATIC CYSTS - These may be inherited (polycystic liver disease which is often associated with
polycystic kidney disease, Caroli's disease) or acquired (simple cysts).
B. NODULAR HYPERPLASIA - Although relatively uncommon, this tends to occur in women (oral
contraceptives have been implicated) and appears as tan nodules which have a central scar showing
a heavy lymphocytic infiltrate and multiple bile ducts. They mayor may not be bile stained.
C. NEOPLASIA

1. HEMANGIOMA - Cavernous hemangiomas are the most common of the benign tumors
which may be found in the liver. They arise from blood vessels, may be single or multiple,
are usually subcapsular, and generally are small (less than 1 cm in diameter) although they
may grow larger. It is debatable as to whether they should be considered neoplasms or
hamartomas. Usually, they are darker than surrounding tissue and are spongy.
Histologically, some show large endothelial lined vascular spaces filled with red cells while
others may have become sclerosed by fibrous replacement. Generally, they are of no
clinical importance. An unusual pattern known as peliosis hepatis consists of diffuse
angiomatoid lesions throughout the liver.
2. HEMANGIOENDOTHELIOMA - This is a well-encapsulated, benign but potentially malignant
tumor that usually is found in infant girls and may present as jaundice and hepatomegaly.
It sometimes is associated with hemangiomas elsewhere. Congestive heart failure may
occur because of arterio-venous shunts that form the tumor. Histologically, an orderly
proliferation of the small blood vessels, occasionally with an aggressive pattern of darker
pleomorphic endothelial cells, is seen.
3. ANGIOSARCOMA - This consists of pleomorphic endothelial cells with large
hyperchromatic nuclei, giant cells in frequent mitosis and irregular vascular channels. The
cells may appear spindle shaped, and cirrhosis is present in 20 to 40% of the cases. These
have also been linked to vinyl chloride and thorotrast exposure.
4. BILE DUCT ADENOMA - These are usually small encapsulated, spherical, yellow white
nodules ranging up to 1 cm in diameter. Microscopically, multiple small acini lined by
epithelium similar to that present in small bile ducts is seen and are surrounded by fibrous
stroma. Unlike liver adenomas, these are more frequent in males.
5. CHOLANGIOCARCINOMA - This arises from bile duct epithelium to form acini or papillary
structures lined by mucous secreting cells. Abundant fibrosis creates a sclerotic pattern
which may simulate a metastatic adenocarcinoma. Multicentric cholangiocarcinoma is
extremely difficult to differentiate from metastatic adenocarcinoma and requires careful
examination of the patient for possible other sites of origin. In contrast to hepatocellular
carcinoma, it is not associated with cirrhosis, alpha-fetoprotein is not elevated, and it does
not produce bile although bile may be detected in the tumor mass when it has been
produced by liver cells which cannot drain adequately into the external biliary tract. It
tends to metastasize earlier and more widely than hepatocellular carcinoma. Patients with
thorotrast exposure, hemochromatosis, polycystic disease, or liver flukes have an increased
incidence of cholangiocarcinoma.
6. HEPATOBLASTOMA - This is almost always seen before age two and consists of epithelial,
mesenchymal, or mixed components. Fetal and embryonal type hepatocytes may be seen
with primitive spindle cells, osteoid tissue, cartilaginous tissue and muscle cell elements.

216
 7. LIVER ADENOMA - This tends to arise in young women and may also be associated with
oral contraceptives. They appear as yellow-tan masses, unless stained green by bile, that
may range up to 25 cm in diameter. Microscopically, they are composed of well -
differentiated liver cells with sinusoids and plates but lack normal lobular structure or bile
ducts. When subcapsular, they may hemorrhage into the peritoneum especially during
pregnancy.
8. HEPATOCELLULAR CARCINOMA (HEPATOMA) - Worldwide, the incidence of this disease
varies considerably depending upon geographic location. The disease is rampant in parts
of Asia and Africa where Hepatitis B is prevalent and there are a large number of carriers.
Portions of the viral genome have been demonstrated in the DNA of malignant cells.
HBsAg and a number of chemicals (vinyl chloride, thorotrast, aflatoxin, etc) have been
implicated in human hepatocarcinogenesis. In the U.S., about 80% of hepatocellular
carcinomas arise in cirrhotic livers and about 2% of all cases of cirrhosis are complicated
by hepatocellular carcinoma. The clinical presentation of patients with hepatocellular
carcinoma includes hepatomegaly, abdominal pain, and abdominal mass. About 15% of
the patients are jaundiced and 10% are febrile. Hepatocellular carcinoma should be
suspected in cirrhotic patients who suddenly develop enlarged liver, ascites, deteriorating
hepatic state and arterial murmur heard over the liver, or unusual hormone signs. Patients
with hepatocellular carcinoma may develop polycythemia due to increased erythropoietin
levels, hypercalcemia due to increased levels of parathyroid hormone-like substances,
hyperlipemia or hypoglycemia. Alpha fetoprotein may be increased (60-75%) but this is
not specific for hepatocellular carcinoma. The tumor progressively enlarges and, in the
later stages, metastatsizes primarily to the lung. Most patients die within six months of
diagnosis from liver failure, bleeding, or inanition. Grossly, hepatocellular carcinoma may
appear as a solitary massive tumor that virtually replaces one lobe of the liver, as multiple
nodules scattered throughout the liver with an appearance similar to that of metastatic
disease, or as a diffuse infiltrative lesion difficult to distinguish from underlying cirrhosis.
When multiple nodules are present it is difficult to decide whether these are the result of
spread of a single primary focus or multicentric origin. The tumor may be yellow-white
or various shades of green. Bile pigmentation is frequent in hepatocellular carcinoma
because there is no functional drainage through bile ducts. These tumors have a propensity
to invade hepatic veins and may cause Budd-Chiari syndrome. Occasionally, they even
extend directly from the hepatic vein into the right side of the heart through the vena cava.
Microscopically, the cells resemble hepatocytes but may have increased cytoplasmic
basophilia. In well differentiated tumors, cells tend to form cords, sometimes separated by
sinusoids, or pseudoacinar/microacinar structures and may elaborate bile. Mallory bodies
are occasionally seen. Others, however, are composed of anaplastic giant cells with
abundant cytoplasm and multiple nuclei, frequently in mitosis. Usually, very little fibrous
stroma is present in hepatocarcinoma.
9. METASTATIC - The malignancy most frequently encountered in the liver is metastatic from
a distant site. Many arise in the gastrointestinal tract, particularly in the colon, and spread
through the portal veins into the liver. Other tumors which frequently metastasize to the
liver include pancreas, lung, breast, and kidney. The liver may be involved by
lymphomatous or leukemic infiltration as well.

X. REYEIS SYNDROME - This disorder of undetermined etiology consists of fatty liver associated with
encephalopathy. It may affect children up to age 15 years, but is most common between ages 1 and 3. In
the typical case, the child appears to be recovering from an upper respiratory infection when vomiting
suddenly occurs. Within 24 hours, irritability, restlessness, lethargy, convulsions, and coma intervene. The

217
 course is rapid and the fatality rate very high. No focal neurologic signs are present, nor does meningismus
occur. Rapid respiration is common. About half the time, mild to moderate enlargement of the liver is
detected. Jaundice is often absent or mild. Serwn bilirubin is usually normal. Transaminases are increased;
prothrombin time is prolonged and blood ammonia levels nonnally are increased; however, ammonia levels
do not correlate well with the status of the patient. Spinal fluid glutamine levels have the best direct
correlation with the course of this disease. Some of these patients become hypoglycemic. Spinal fluid exam
reveals normal cell count, sterile culture, normal protein, and if the blood glucose is low the spinal fluid
glucose will be proportionately low. Liver biopsy may be useful in diagnosing this disease and reveals
diffuse small lipid deposits in all hepatocytes (microvesicular steatosis) without significant necrosis or
inflammation. Mortality runs from 20 to 50% in these cases. Treatment is primarily supportive with
correction of electrolyte imbalance and metabolic acidosis. Cerebral edema is present and must be
controlled by use of glycerol and mannitol. Many cases of Reye's syndrome have followed influenza
epidemics, but other cases have followed various viral infections.
XI. HEPA TIC FAILURE - This may occur as a result of a single episode of massive destruction, or a patient
who has had chronic liver problems with minimal marginal reserve function may be thrown into hepatic
failure by stress from sudden blood loss or infection. Although hepatic failure may arise as a complication
of many diseases, viral hepatitis and cirrhosis are frequent causes and in both of these disorders the liver
is diffusely involved, in one with disturbance of cellular function, and in the other with disruption of the
architectural pattern and presumed consequent disturbances of cellular function. Hepatic failure is
potentially reversible because of the remarkable regenerative capacity of the liver. If acute hepatic
destruction is present and the patient can be maintained during the immediate severe metabolic disorder
and electrolyte imbalance, the chances for recovery are very good. On the other hand, individuals who have
long-standing chronic liver disease are far less likely to recover. This group of patients is unlikely to change
lifestyles and habits which resulted in the liver damage. Recently, exchange transfusion or plasma
exchanges carried out on centrifugal cell processors have been found to reduce undetermined toxic
substances with remarkable improvement of patients with hepatic failure. By itself, jaundice is not
indicative of liver failure but is almost invariably present when failure occurs. Patients with liver failure
develop personality alterations, confusion, and mental obtundation ranging from mild lethargy to coma
(hepatic encephalopathy). Blood ammonia levels, although not directly correlated with the severity of
encephalopathy, tend to reflect the course of the patient during therapy. If the ammonia levels are
increasing the encephalopathy is likely to become worse, whereas if the ammonia levels begin to decrease
the likelihood of clearing of the sensorium is improved. Ammonia accumulates because of an inability to
fonn urea and, therefore, blood urea levels may also decrease. There is some increase of astrocytes in the
cerebral cortex, thalamus and several other nuclei of the brain, but no apparent change in ganglion cells.
A characteristic flapping tremor of outstretched hands referred to as "liver flap" (asterixis) occurs in
patients with liver failure. Patients in hepatic failure fail to metabolize estrogens, which accumulate and
result in hypogonadism, loss of libido, and gynecomastia in the male. Palmar erythema and spider
angiomas of the skin have been attributed to increased estrogens since both are known to occur during
pregnancy, but definite proof is not offered. Patients sometimes develop a pungent sweet-sour odor known
as fetor hepaticas and the urine is particularly pungent. Renal insufficiency or failure may be present
(hepatorenal syndrome), the precise pathophysiology of which is obscure and under debate. In spite of
renal functional insufficiency there often is no evidence of morphological changes in the kidneys. Patients
in hepatic failure do not synthesize albumin, globulins, and prothrombin properly, with a consequent
increase in amino acid levels in the blood as well as the expected problems associated with deficiencies of
these proteins. Inability to store glycogen may result in hypoglycemia.

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 GALLBLADDER AND BILIARY TRACT

I. CONGENITAL - Anomalies of the gallbladder range from complete agenesis to total reduplication to
aberrant locations (imbedded within the hepatic parenchyma or "floating" unattached to the liver).
Angulation or kinking of the gallbladder fundus can cause an expanded bulbous tip known as a phrygian
cap. Generally, these anomalies are rare and, for the most part, not clinically important. Anomalies of the
bile ducts, however, may be life threatening and include localized or diffuse biliary agenesis or atresia.
Agenesis and severe atresia are incompatible with life unless transplant or surgical correction is possible.
II. CHOLELITHIASIS - In the United States, between 10 and 20% of the adult population have gallstones.
Although genetic predisposition probably plays a role, gallstones are more frequently seen in women,
increase in incidence with age, and are related to obesity and high caloric diets. Gallstones generally form
in the gallbladder from three primary constituents: cholesterol (the most common constituent), calcium
bilirubinate, and calcium carbonate. The prevalence of stones can be related to excess amounts of
unconjugated bilirubin or cholesterol secreted into the bile by the liver, or disturbances in bile acid and bile
salt metabolism.

A. PATHOGENESIS - Cholesterol, insoluble in water, is maintained in solution in the form of a micelle

containing a central core of cholesterol, surrounded by hydrophilic bile salts and lecithin. When the
amount of cholesterol exceeds the capacity of the bile salts and lecithin to maintain it in solution
(cholesterol excess or bile salt/lecithin deficiency) and when factors are present that will promote
precipitation of cholesterol crystals, gallstones begin to grow by accretion.

1. CHOLESTEROL STONES - In a "pure" form, these comprise approximately 10% of all

gallstones. They occur singly or multiply, vary from small to 5 or 6 cm. in size, and are
radiolucent. Smaller stones are usually spherical and translucent with an obvious crystalline
appearance. As they enlarge, they develop a smooth egg-shell surface, which reveals a
radial crystalline structure on cut section.
2. CALCIUM BILIRUBINATE STONES - These are less common than cholesterol stones and are
encountered in diseases in which excessive production of bilirubin is a principle feature
(hemolytic anemi~ pernicious anemia, malaria, and chemical toxicity to red cells). These
usually are radiolucent, jet black stones measuring up to 1 cm in size. These almost never
occur singly.
3. CALCIUM CARBONATE STONES - These are rare, but are radio-opaque. Because calcium
is not usually present in bile in high concentration, the source of the salts making up these
calculi is poorly understood.
4. MIXED AND COMBINED STONES - These account for about 80% of all biliary calculi in
surgically removed gallbladders. Mixed stones are those having varying proportions of all
three of the stone forming constituents of bile. Combined stones refer to those in which
either the central core or external layers are pure and the remainder is a mixture of
constituents. Mixed stones are usually multiple whereas combined stones are sometimes
solitary. Stones may have a multifaceted exterior or may have a mulberry shape and
appearance.

B. COMPLICATIONS - Although most gallstones are asymptomatic, about 25% of patients will develop
one or more of the following complications:

1. OBSTRUCTION OF CYSTIC OR COMMON BILE DUCT - This is usually due to smaller stones
which become impacted within the ducts to cause partial or total obstruction. Nausea,

219
 vomiting, and severe pain (biliary colic) results from spastic episodic contraction of the
gallbladder musculature in an effort to expel the obstructive stone. If the stone remains in
the cystic duct, mucoid distension (hydrops) of the gallbladder may result but the patient
will not be jaundiced. If the stone lodges in the common bile duct or the ampulla of Vater,
however, jaundice usually results.
2. CHOLECYSTITIS [see below]
3. GALLSTONE ILEUS - Rarely, gallstones may erode the wall of the gallbladder and adherent
intestinal loops to create cholecystointestinal fistulas. Such stones may pass unnoticed
through the stools, but very large stones may obstruct the GI tract, particularly at the
ileocecal region.
4. CANCER [see below]

III. INFLAMMA TION

A ACUTE CHOLECYSTITIS - This may constitute a surgical emergency and usually starts as acute right
upper quadrant pain referred to the right shoulder. Fever, nausea, vomiting, white count elevation,
and rigid abdominal wall are usually present with severe cramping pain. A mild degree of jaundice
is present about 25% of the time.

1. PATHOGENESIS - Obstruction of biliary outflow from the gallbladder, whether partial or

complete, creates conditions for progressive concentration of bile and chemical irritation
of the gallbladder walL Secondary bacterial infection is often present The inflammatory
response to the bacteria and chemical injury may further compromise the blood supply
creating additional insult to the mucosa (gangrenous cholecystitis). In a large majority of
cases, stones can be found impacted at the neck of the gallbladder or within the cystic duct
Occasionally, however, especially in seriously ill (major trauma, sepsis, bums, etc),
debilitated, or elderly patients, no physical obstruction is identified (acalculous
cholecystitis). Unless diagnosed and treated early, this form of cholecystitis has a high
mortality rate.
2. PATHOLOGY - The gallbladder is usually enlarged and tense with a variegated color
ranging from red to green-black The serosa may be covered by a fibrinous exudate, and
the lumen is filled with blood, pus, bile, and often additional stones. In areas of mucosal
necrosis, ulcers may penetrate the wall, creating abscesses or causing generalized chemical
peritonitis. Other complications include ascending cholangitis and hepatic abscesses.
Histologically, edema, leukocytic infiltration, vascular congestion, and sometimes abscess
or gangrenous necrosis is seen. A prominence of eosinophils indicates a subacute
cholecystitis, and calcification of the wall may ultimately lead to aporcelain gallbladder.
Acute changes can also be seen superimposed on the changes of chronic cholecystitis.

B. CHRONIC CHOLECYSTITIS - is often characterized by intolerance to fatty foods, belching, and

postprandial epigastric distress, sometimes including nausea and vomiting. The differential
diagnosis includes peptic ulcer, hiatal hernia, appendicitis, myocardial infarction, renal stones and
pleurisy.

1. PATHOGENESIS - The exact evolution of chronic cholecystitis is obscure, as it is rarely

preceded by a well-defined episode of acute cholecystitis. Almost all, however, are
associated with cholelithiasis and are therefore most commonly seen in obese females.
2. PATHOLOGY - The most frequent finding is fibrous thickening and chronic inflammation
of the wall of the gallbladder although both may be minimal. If obstruction is present, the

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 gallbladder may be distended, but the mucosa is generally intact. Only about 30% of cases
have concomitant bacterial superinfection. Outpouching of the mucosa through the wall
(Rokitansky-Aschoffsinuses) are found in about 90% of chronically inflamed gallbladders
and should not be confused with carcinoma. Mucosal epithelium may get trapped in the
lamina propria by fibrous tissue and form small cystic spaces (cholecystitis glandularis).

IV. CHOLESTEROLOSIS - This is also commonly referred to as strawberry gallbladder, because lipid-
laden macrophages accumulate in the tips of the mucosal folds and resemble the pale yellow-gray seeds
that punctuate the surface of a strawberry. It may be found in up to 10% of the general autopsy population,
but rarely causes clinical symptoms. It is not thought to predispose to cholecystitis and is unrelated to blood
levels of cholesterol. Histologically, the mucosal folds are enlarged and distended into club shapes with
collections of round to polyhedral histiocytes. These histiocytes have foamy, reticulated fat laden
cytoplasm, and small, round, dark prominent nuclei. Rupture of these cells may induce an inflammatory
reaction of white cells, giant cells and fibroblasts (xanthogranuloma).
V. NEOPLASIA

A. BENIGN LESIONS - Although fibromas, myomas, neuromas, hemangiomas and carcinoids have
been described in gallbladder, they are rare and have little clinical significance. Papillomas and
adenomas of the gallbladder are both derived from the mucosal epithelium and usually are
relatively small. The papilloma grows as a pedunculated branching structure and the adenoma is
a flat sessile thickening. Neither are clinically significant except to differentiate them from
malignant growths.
B. CARCINOMA OF GALLBLADDER - This arises from the mucosal epithelium and, although relatively
rare, is the most common malignancy of the biliary system. Predominantly a disease of adulthood,
females are involved four times as often as males. Most are adenocarcinomas although a small
number are squamous cell carcinomas. "Metaplastic" adenocarcinomas are the more common and
are associated with gastric or intestinal metaplasia in the adjacent gallbladder mucosa. In the
majority of cases, cholelithiasis and chronic cholecystitis is also present. Although some carcinomas
are fungating lesions that expand into and fill the lumen while simultaneously burrowing into the
wall, the more common form is an infiltrating lesion that simply produces an indurated mucosal
plaque while infiltrating into the wall and surrounding tissue while eliciting an exuberant
desmoplastic response. Ulcerations and fistulas may develop and the tumor may grow into adjacent
viscera, including Ii ver, loops of bowel, or stomach. Metastatic sites also include perihilar lymph
nodes and lungs. Although most of these neoplasms develop within the fundus and neck of the
gallbladder, they are generally asymptomatic until they spread to the adjacent bile ducts. Symptoms
take the form ofloss of appetite, nausea and vomiting, and intolerance to fatty foods with frequent
belching. Jaundice occurs when the tumor has infiltrated major bile ducts or extended into the liver
bed to obstruct an intrahepatic bile duct, or when metastasis to porta hepatis nodes puts extrinsic
pressure on the bile duct. About half the time a palpable mass is present in the right upper quadrant
and about the same frequency, right upper quadrant pain or colic is present. Courvoisier's law
contends that when biliary obstruction is due to gallstones, the gallbladder is usually not distended,
but frequently will be fibrotic and shrunken because of chronic cholecystitis. If neoplastic
obstruction of the common duct is present, however, the gallbladder more often becomes enlarged
and the tip of it may be palpable by abdominal examination. Unfortunately, the "law" is wrong
about as often as it is right. Weakness and weight loss progress as the tumor enlarges. The
prognosis depends on the stage of the disease but the average life expectancy is about 1 year after
diagnosis is made, although rare five year survivals have been reported.
C. CARCINOMA OF THE BILE DUCTS AND AMPULLA OF VATER - Although less frequent, like
carcinomas of the gallbladder these malignancies occur during mid to late adulthood, but show a

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 slightly greater incidence in men. Again, most are adenocarcinoma and grow either as nodular,
fungating, or infiltrative lesions. The most frequent location is the ampulla of Vater and the lower
end of the common duct. Stones are identified in only about one third of these patients, but chronic
inflammation or irritation may play a role in pathogenesis. Ascaris and some of the biliary
trematodes (flukes) are associated with increased incidence of biliary carcinoma. Because of their
location, these tumors tend to cause obstructive lesions earlier in the course of the disease. Jaun-
dice is therefore a prominent feature of these tumors, but may remit if a part of the tumor becomes
necrotic, breaks off, and relieves the obstruction. Obstructive jaundice may cause pruritus, acholic
stools, bile stained urine, cholangitis and even biliary cirrhosis. Three major differential diagnostic
possibilities involving obstructive jaundice include common duct stone, carcinoma of the head of
the pancreas, and carcinoma of the extrahepatic bile ducts, including the papilla of Vater. In spite
of the early manifestations, a majority of these tumors have spread at least locally by the time of
diagnosis. The overall outlook of tumors of the biliary ducts is poor with five year survival of about
10%.

EXOCRINE PANCREAS

The exocrine function of the pancreas resides in the ductal and acinar tissue whose function is to manufacture
and secrete digestive enzymes that are used to breakdown food into small components capable of being
absorbed by the small bowel. The digestive enzymes are synthesized in an inactive form, stored in the zymogen
granules of the acinar cells, and, when stimulated by the duodenal hormone cholecystokinin, released into the
acinar lumen where trypsin becomes activated and, in turn, activates the other enzymes.

I. EMBRYOLOGIC DEVELOPMENT - The pancreas originates as dorsal and ventral diverticular buds
off of the caudal foregut (duodenum). As the ventral pancreas (which ultimately forms much of the head
of the pancreas) rotates to fuse with the dorsal pancreas (which forms most of the body and tail), the ventral
duct fuses with the distal portion of the dorsal duct to form the main pancreatic ductal system. In most
people, the duct ofWirsung (ventral duct) joins the common bile duct as it empties into the duodenum at
the ampulla of Vater. Occasionally, the proximal portion of the dorsal duct remains to form an accessory
duct (duct ofSantorini). Position anomalies of the pancreatic ductal system are not uncommon, but rarely
are clinically significant. If the ventral bud rotates improperly, an annular pancreas develops which may
predispose to duodenal obstruction, especially in children. Nodules of aberrant, but histologically normal,
pancreatic tissue (heterotopic or ectopic pancreas) is occasionally noted in the submucosal tissue of the
stomach or duodenum (and less frequently in other areas of the GI tract). Usually found during workup for
other problems, it has little or no clinical significance except that it must be differentiated from a true
neoplasm.
II. ACUTE PANCREATITIS - This results from diffuse enzymatic destruction of pancreatic tissue and, in
its severe form (acute hemorrhagic pancreatitis, acute pancreatiC necrosis), constitutes a medical
emergency. In a large number of patients, a specific etiology is never uncovered; however, it is particularly
common in alcoholics, and gallstones are present in 40-70% of the patients. Other less common causes
include trauma, sepsis, and hypercalcemia. The conditions leading to liberation of activated digestive
enzymes within the pancreatic tissue probably revolve around abnormal or inappropriate intracellular
activation of the enzymes, injury to the acinar cell, and/or pancreatic duct obstruction. Whatever the
mechanism, activated proteases, lipases, and amylases are liberated into the pancreatic tissue resulting in
enzymatic fat necrosis, hemorrhage, and autodigestion of the pancreas. Grossly the pancreas appears
swollen and hemorrhagic with chalky white precipitates (enzymaticfat necrosis) throughout the abdomen
(pancreatic stroma, peripancreatic tissue, mesenteric fat, and omentum). Histologically, there is proteolytic
destruction of pancreatic tissue, necrosis of blood vessels with associated hemorrhage, enzymatic fat

222
 necrosis, and acute inflammation. Clinically, most cases present in middle age with the sudden onset of
severe unrelenting pain which may radiate sharply into the back. Electrolyte disturbances, vascular collapse,
and shock may quickly intervene. Serum amylase levels rise within the first 24 hours and serum lipase
(more specific for a diagnosis of acute pancreatitis) follows suit 2-3 days later. Both enzymes can be found
in the urine. Deposition of calcium in the necrotic tissue contributes to a hypocalcemia which, if persistent,
is a poor prognostic sign. 20%-50% of these patients will die in the first week of their disease, and if they
survive, may develop pancreatic abscesses, pseudocysts, or duodenal obstruction.
III. CHRONIC (RELAPSING) PANCREATITIS - This probably results from recurrent episodes of mild
or subclinical acute pancreatitis that eventually leads to fibrosis of a large portion of the exocrine
parenchyma. Although the etiology is multifactorial (not all of which are known), it is most frequently seen
in middle-aged alcoholic males. With alcoholics, the pancreas is firm in consistency with both calculi and
multiple foci of smaller calcifications. Acini are atrophic, fibrous tissue is markedly increased, and chronic
inflammation surrounds dilated cructs containing inspissated protein secretions. For the most part, however,
the islets survive intact until late in the course of the disease. Repeated attacks of mild to moderate
abdominal pain is typical but some patients may be totally asymptomatic until sufficient pancreatic tissue
is destroyed to produce symptoms of pancreatic insufficiency. During the initial attacks, there may be mild
fever and jaundice with slight elevations of serum amylase and alkaline phosphatase, but as the disease
progresses weight loss, hypoalbuminemia, steatorrhea, and diabetes ensue.
IV. PSEUDOCYST - As a sequela of acute/chronic pancreatitis or abdominal trauma, pseudocysts present
as a solitary, unilocular, and occasionally massive collection of fluid and necrotic debris that produces
abdominal pain and predisposes to intraperitoneal hemorrhage or peritonitis. The absence of an epithelial
lining distinguishes these from the less common true pancreatic cysts.
V. NEOPLASMS

A. CYSTADENOMA - This is an uncommon neoplasm arising from the ductal epithelium in middle-
aged females and is usually solitary and multilocular with a tendency to occur more frequently In
the tail. Both serous and mucinous types occur. The malignant counterpart, cystadenocarcinoma,
has a similar gross appearance but is histologically invasive. The serous forms are less common
but carry a better prognosis than mucinous forms.
B. ADENOCARCINOMA - Typically a tumor of mid to late life, these arise from exocrine ductal
epithelium (only 1% from acinar cells) and are increasing in frequency. Both environmental and
genetic factors have been implicated in the development of these tumors. Although some are
diffusely spread throughout the pancreas, the majority (60%) arise in the head of the pancreas
followed by the body (20%) and tail (10%). Tumors of the body and tail of the pancreas tend to
be hard, irregular masses that have infiltrated widely throughout the pancreas and contiguous
structures and have distant metastases. Because of a long interval of silent growth, anorexia, weight
loss, abdominal and/or back pain, or symptoms of metastatic disease are often the presenting
symptoms. This late onset of symptoms delays diagnosis and portends a poor prognosis. Tumors
of the head of the pancreas are more often small with infiltrative margins that invade the duodenum
or biliary structures. Patients often present with painless jaundice due to impingement upon biliary
tract structures. Early symptoms aid in early diagnosis and prognosis is correspondingly improved,
but the overall 5-year survival for pancreatic carcinoma is less than 5%.

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 SKIN

ECZEMA AND ACUTE NON-INFECTIOUS INFLAMMATORY DERMATOSES

I. ECZEMA - This is a cutaneous inflammatory reaction pattern with a well-defmed morphology

(spongiotic dennatitis) but diverse etiology. Eczema is synonymous with "dennatitis" in ordinary usage
and comprises over half of all dennatologic disease. Inciting agents include internal allergens, external
allergens, irritants, trauma, and certain microorganisms. Some patients with hay fever and asthma also
display chronic eczema associated with their genetically-detennined atopic state. In the acute stage, the
epidennal changes (spongiosis and spongiotic vesicles) are superimposed on a background of dermal
inflammation (lymphocytic) and edema. This is clinically expressed as pruritic erythematous patches with
epidennal vesiculation and oozing (depending on anatomic site and etiology). This is the stage that is most
likely to become secondarily infected. With subacute lesions, there is less erythema, the oozing subsides,
and a crust and fine scale (hyperkeratosis and parakeratosis) develop. Without intervention and with
continued rubbing, the chronic phase evolves into a wrinkled, leathery induration (lichen simplex
chronicus) Lichenification reflects reactive epidennal acanthosis and hyperkeratosis and may be hypo- or
hyperpigmented.

A. ATOPIC DERMATITIS - In "atopies", there is an inherited tendency to develop allergies to common

ingested or inhaled antigens. This may be manifested by asthma, hay fever, allergic rhinitis or
conjunctivitis, migraine headaches, or urticaria. However, no convincing evidence exists that the
dermatitic skin changes are due to an antigen-antibody reaction. These patients tend to have a low
itch threshold and most of the objective changes are produced by rubbing and scratching. "Infantile
eczema" is the earliest manifestation of atopic dermatitis. Erythematous, finely papular, and oozing
patches are predominant on the cheeks, but may extend over the entire face, extensor aspects of
forearms and legs and elsewhere on the body. In the most severe cases, the infants have extensive
areas of cutaneous disease and scratch frantically, even in their sleep. During childhood, there is
less tendency for the lesions to ooze. The lesions consist mainly of excoriated papules or lichenified
patches on the extensor aspects of extremities or on popliteal and antecubital spaces. In adults, the
lesions are also predominant in popliteal, antecubital, and wrist regions but, in addition, occur in
the periorbital and neck regions. Primary lesions are rarely vesicular except when palmar or
plantar in location. Flareups tend to occur seasonally and with emotional tension. Other
characteristic features found in some, but not all, patients include the presence of multiple,
circulating, reagin-type (IgE) antibodies to common environmental antigens, demonstrable by
intradermal tests. Elevated serum IgE levels are usual. An exaggerated cutaneous vasoconstrictor
tendency is manifested by sallow appearance of non-dermatitic skin. Other stigmata include
Dennie's pleat (extra fold under lower eyelid), hyperlinear palms, dry skin (xerosis) and keratosis

224
 pilaris. Complications include secondary bacterial (streptococcal and/or staphylococcal) and viral
(herpes) infections which, on occasion, can lead to overwhelming, fatal sepsis. The goal of
treatment is to reduce itching and scratching since the lesions are induced by scratching. Patients
should avoid extemal irritants (rough or woolen clothing, strong soaps, excessive bathing, etc) and
avoid extreme heat and humidity. Oral antihistamines (for itching) and topical corticosteroid
therapy (for inflammation) are helpful. Systemic corticosteroid therapy is rarely necessary.
B. CONT ACT DERMATITIS - This is the result of contact with external irritants or allergens. The
number of potential substances is legion. The severity ranges from faint transient erythema to
massive bullae on a swollen erythematous base. Itching is generally severe. The initial reaction
occurs in the exposed region and a sharp demarcation is present between affected and normal skin.
Complications include secondary bacterial infection and generalized exfoliative dermatitis.

1. PRIMARY IRRITANT CONTACT DERMATITIS - This constitutes approximately 90% of all

contact dermatitis. Primary external irritants (strong alkalis, acids, bleaches, oxidizers, sol-
vents, etc) will induce a reaction in any individual if applied in sufficient concentration.
Since no antigen-antibody reaction is involved, prior exposure to the agent is not a
conditioning factor.
2. ALLERGIC CONTACT DERMATITIS - This constitutes approximately 10% of all contact
dermatitis (90% of which is poison ivy). The responsible antigens are diverse but all have
the essential characteristic of being able to penetrate the skin barrier for immunologic
processing by the Langerhans cells and provoking a delayed hypersensitivity. Sensitization
is acquired as a result of repeated exposure, and the incubation period between exposure
and development of sensitivity varies from one week to many years. Allergic contact
dermatitis is usually patterned. Often the pattern suggests a cause and may make the
diagnosis readily apparent. The fact that a patient has been exposed to a given allergen for
years does not exclude it as a possible cause of dermatitis.

C. NUMMULAR DERMATITIS - This usually presents as one or several discrete "coin-shaped" patches
predominantly on the legs and arms. It is probably a variant of atopic dermatitis in most instances
and results from persistent rubbing of the skin.
D. STASIS DERMATITIS - This is the result of chronic venous insufficiency and usually involves the
lower legs (often above the medial malleolus). Depending on the severity, there is varying degrees
edema, purpura, and hemosiderotic staining of the skin. Ulcerations may also develop.

II. URTICARIA - This may be acute or chronic. It is an eruption of hives (wheals), which are erythematous,
edematous, sharply circumscribed pruritic plaques that have a predelection for pressure points.
Dermatographism may also be demonstrated. Acute urticaria manifests wheals that last less than 24 hours
but typically recur episodically. They are often allergic in etiology (Type I IgE mediated hypersensitivity)
and result from the action of locally released histamine and other vasoactive substances on the post-
capillary venules. Others may be due to trauma, drugs, etc. Chronic urticaria manifests wheals that last
longer than 24 hours, and tend to appear continually, often for months. They are usually not allergic in
etiology, but their pathogenesis is unknown. Urticaria seldom requires a biopsy for diagnosis, and the
histologic findings (edema with sparse perivenular accumulation oflymphocytes and neutrophils followed
by interstitial infiltration of eosinophils) are not diagnostic.
III. ACNE - Acne vulgariS affects essentially all adolescents. The onset is generally earlier in females, but the
severity is greater in males. Acne begins with the hyperplasia of sebaceous follicles at puberty due to rising
levels of testosterone. Sebum production increases, and the normal sebaceous microbial flora (especially
Propionibacterium acnes) proliferate and produce lipases that release fatty acids from the sebum. At the
same time, there is hyperkeratinization and occlusion of the neck of those sebaceous follicles that are not

225
 associated with a hair. This produces the primary lesion of acne - the comedo. Depending on the level of
obstruction of the follicle, a comedo may be "open" (high obstruction holds the follicle orifice open and
produces the "blackhead) or "closed" (lower obstruction allows the orifice to close and results in the
"whitehead"). The closed comedo is more significant in that as sebum continues to be produced, the follicle
may rupture with an ensuing inflammatory reaction and formation of pustules, red papules, nodules, and
cysts. These last lesions commonly coalesce ("acne conglobata") and leave disfiguring scars. The severity
of acne is in part familial and in part dependent on how rapidly androgen levels rise. The characteristic
course of acne is one of exacerbation and remissions, sometimes related to the previous mentioned factors
but frequently without apparent explanation. Therapies include topical bacteriostatic (most commonly
benzyl peroxide) and keratolytic lotions and soaps (salicylic acid, resorcinol and sulfur are common
ingredients). Systemic treatment with antibiotics or isotretinoin may also be initiated. Other acneiform
lesions that clinically resemble acne in some respects include:

A. ROSACEA - This occurs in an older age group and may resemble acne except that comedos do not
develop. The central face is prominently involved, and exhibits patulous sebaceous orifices,
pustules, nodules, erythema and telangiectasia. In men, it may eventuate into rhinophyma (the
"W.C. Field nose") due to reactive connective tissue formation.
B. PERIORAL PAPULAR DERMATITIS - This is seen mainly in women, and usually follows the
prolonged use of potent topical corticosteroids or oil-containing cosmetics (cold creams, etc) on
areas of the face. The lesions are erythematous papules.
C. CHLORACNE - This occurs with heavy exposure to certain chlorinated hydrocarbons. Open
comedos usually predominate, and the distribution of lesions is highly characteristic.

IV. ERYTHEMA MULTIFORME - This is a common cutaneous vascular reaction to any of several possible
sensitizing substances, most often medications and infections (especially Herpes Simplex virus). It is
thought to be immune-complex mediated, with a reaction cascade starting in a superficial dermal vessel,
and then expanding peripherally. The cutaneous reaction goes through sequential phases of erythema,
edema, hemorrhage, and epidermal necrosis, resulting in a concentric pattern ("target" or "iris" lesion).
Microscopically, there is a heavy lymphohistocytic perivascular infiltrate, and endothelial swelling.
Peripherally, the lymphocytes are seen invading the epidermis causing vesiculation and keratinocyte
necrosis. Centrally, the process is more advanced with exocytosis of lymphocytes into the epidermis around
areas ofkeratinocyte necrosis (zonal necrosis). With elimination of the cause, this process resolves in 3-4
weeks and mild cases require no treatment. However, severe cases, with extensive mucosal and cutaneous
lesions, may cause profound illness requiring systemic corticosteroid therapy.
V. ERYTHEMA NODOSUM - This is a deep dermal and subcutaneous vascular inflammatory reaction
pattern, manifesting clinically as tender red nodules, usually on the legs, and more frequently seen in
women. It may be idiopathic, or induced by certain drugs (oral contraceptives, etc) or infections (TB,
coccidioidomycosis, leprosy, etc), and it may be recurrent and episodic. The histology reveals septal
panniculitis and perivascular inflammation, without vascular necrosis.
VI. ERYTHEMA INDURA TUM - This has a similar clinical picture to erythema nodosum but generally is
not related to underlying disease. The inflammation is throughout the subcutaneous fat (lobular
panniculitis) and is associated with a vasculitis and caseous necrosis.
VII. VASCULITIS - Although the term literally means inflammation of vessels, in dermatopathology it is
defined by inflammation and necrosis. The etiology is often a hypersensitivity reaction (e.g., immune
complex reaction) leading to neutrophil infiltration and fibrinoid necrosis. Lymphocytic vasculitis may be
infectious (e.g. rickettsiae) or autoimmune (e.g. lupus erythematosus). Clinically one sees purpura which
is palpable, i.e., papular or nodular, except for very mild forms of vasculitis such as Schamberg's disease.

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 INFECTIOUS INFLAMMATORY DISORDERS

Microorganisms may cause a primary disease or complicate other skin diseases. Microorganisms isolated from
skin lesions may be pathologic but often are only normal residents, colonizers (organisms growing on, but not
contributing to the disease process), saprophytes, or transients and contaminants of no significance. Since
serum is an excellent culture medium, microorganisms can invariably be cultured from any dermatosis in which
the cutaneous barrier is not intact. Their presence does not, however, imply etiologic significance and does not
suggest they are complicating the dermatitis. Perhaps of more value than culture is a smear and gram stain. The
finding of bacteria within leukocytes on gram stain is an aid to diagnosis of primary infection, since colonizing
organisms do not ordinarily elicit a host response.

I. BACTERIAL

A. FOLLICULITIS - This is a staphylococcal infection of a hair follicle. Superficial folliculitis manifests

as pinhead sized pustules on an erythematous background centered around hair follicles. A deep
folliculitis (furuncle or boil) produces a palpable dermal nodule. A carbuncle refers to a deep
seated abscess with multiple openings to the cutaneous surface.
B. IMPETIGO - This is caused by Group A 13-hemolytic streptococci or, in the case of neonates and
infants, coagulase-positive staphylococci. The initial lesions are subcorneal bullae which rupture
to leave a heavy, yellowish (honey-colored) crust of dried serum. Histologically, the sub corneal
blisters are filled with neutrophils. Occasional acantholytic cells may be seen in base of bullae and
the underlying epidermis shows spongiosis. The disease is contagious by direct contact so that
exposed skin (face and hands) is typically involved. Direct systemic complications are uncommon
except in debilitated patients but streptococcal impetigo may precede the appearance of post-
infectious glomerulonephritis. Ecthyma is similar to impetigo but extends below the epidermis.
Removal of the overlying crust reveals an ulcer.
C. CELLULITIS - This is a cutaneous inflammation most commonly caused by Group A streptococcus.
It is characterized by diffuse and rapidly spreading erythema and swelling with a sharply defined
indurated border. Red streaks of lymphangitis often extend toward lymph nodes. It is often
accompanied by fever, headache, and leukocytosis and in some people has a tendency to recur.
Erysipelas refers to a more superficial cellulitis whose borders are somewhat less well defined than
in deep cellulitis.

II. VIRAL

A. HERPES SIMPLEX - Although the primary, or initial, infection may result in an acute febrile illness
with vesicular eruptions, it is usually subclinical or undiagnosed. Immunity to herpes simplex is
feeble and the virus resides in a quiescent state in neural ganglia until it becomes reactivated by
some stimulus. The most common inducing factor is sunlight but heat, fever, systemic infection,
and anxiety can also induce reactivation. Recurrent herpes simplex is, therefore, the more common
form of the disease. Clinically, herpes simplex is characterized early by grouped vesicles on an
erythematous base. The vesicles often progress into pustules and/or become confluent. Mild
trauma may result in an erosion. There are two common herpes simplex types: type I commonly
occurs above the waist and is responsible for most cases of "fever blister"; Type II commonly is
associated with sexually transmitted ano-genital disease. Treatment is symptomatic but, when
indicated, systemic acyclovir may be used.

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 1. NEONATAL HERPES SIMPLEX - 1bis can be acquired at birth in infants whose mothers have
no immunity. Visceral involvement and death is the usual consequence.
2. ECZEMA HERPETICUM - 1bis is disseminated herpes simplex in an individual who has
atopic eczematous dermatitis. The lesions develop predominantly in areas affected by the
dermatitis. Thus the danger is greatest in persons with wide-spread eczema. These
individuals should avoid exposure to herpes simplex.

B. VARICELLA-ZOSTER - Both varicella and zoster are caused by the same herpesvirus, the varicella-
zoster virus. The histopathologic changes in both are similar to those of herpes simplex lesions.

1. VARICELLA (CHICKEN POX) - This results from exposure of a nonimmune person to the
virus. Almost all are children. A generalized cutaneous eruption follows exposure by about
2 weeks. Lesions begin as small papules which become vesicular and then crust. These
tend to develop over several days so that lesions of variable age are often present together
at the height of involvement. Occasionally some lesions may become pustular and lead to
scarnng.
2. ZOSTER (SHINGLES) - This occurs in partially immune patients that have been previously
exposed to the virus. It is caused by reactivation oflatent virus harbored in cranial and/or
spinal sensory ganglia that then spreads along sensory nerves to the skin. Most cases occur
in adults and are usually self-limiting. The cutaneous eruption follows the development of
neuritic pain and typically consists of exquisitely painful, grouped papules on an
erythematous base which rapidly become vesicular. They are distributed along a sensory
nerve (or nerves) dermatome and usually stop abruptly at the midline. In order of
frequency, the thoracic, cervical, trigeminal, and lumbosacral nerves are most commonly
involved. Temporary or permanent paresthesias may occur. Post-herpetic neuralgia pain
may develop and vary in intensity from annoying to excruciating. Attacks are of more
frequent, more severe, and more widespread when the immunological response is impaired
(lymphomas, Hodgkins disease, AIDS, etc).

C. HUMAN PAPILLOMA VIRUS (HPV) -1bis virus produces various kinds of "warts" (verruca vulgaris.
plantar warts, condyloma acuminata, etc) depending on the strain of the virus. Approximately 56
strains have been identified to date. Strains 1-4 give rise to common warts while strains 6. II. 16.
and 18 are associated with sexually transmitted diseases as well as various carcinomas (especially
strain 16 and cervical carcinoma). Warts have varying degrees of epithelial atypia (koilocytosis,
etc), acanthosis, parakeratosis, and hyperkeratosis with downward growth of the lateral rete ridges.
HPV has also been implicated in the development of various neoplasias (Bowen's disease,
verrucous carcinoma, laryngeal carcinoma, cervical carcinoma, etc). There is no uniformly
successful treatment for warts. Since the average wart regresses without therapy and without
scarring within 2-3 years, methods producing mutilation or scarring are generally unjustified. 10-
20% podophyllin in tincture of benzoin is efficacious in the treatment of genital warts, but severe
local and systemic reactives can occur if large warts are treated at one time.
D. RETROVIRUS (reverse transcriptase containing RNA viruses) - Formerly associated only with
various animal tumors, have been shown to play an important role in human disease and neoplasia.
HTLV (Human T celllymphotrophic virus) types I and II are causal of several rare lymphomas in
man. They are related to monkey and bovine leukemia viruses. The related HIV viruses (Human
Immunodeficiency Viruses) types I and II produce the disease AIDS and the AIDS associated
disorders. These viruses are commonly found in and probably originate from central and west
Africa and are productive of human and primate disease. In Western society, the HIV viruses are
primarily transmitted sexually and produce irreversible immunosuppression leading to death from

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 opportunistic infections and various malignancies, especially lymphomas and Kaposi's sarcoma.
They presently represent a great threat not unlike that of syphilis in the sixteenth century since there
is no available effective vaccine against or treatment for infection with HIV viruses.
E. POXVIRUS (MOLLUSCUM CONTAGIOSUM) - Variable numbers of small, flesh-colored, dome-
shaped, umbilicated, pruritic papules erupt on the skin and mucous membranes, primarily of
children. Although they will spontaneously disappear with time, since they are infective, most are
treated by curretage to remove the virus. Histologically, there is acanthosis, and numerous
epidermal cells (with the exception of basal cells) are filled with large, basophilic intracytoplasmic
inclusion bodies known as molluscum bodies. Little inflammatory infiltrate is present in the dermis
except around lesions that are undergoing spontaneous involution.

III. FUNGAL

A. DERMATOPHYTOSES - This term refers to a group of superficial fungal infections (trichophyton

sp., rnicrosporum sp., etc) that are confined to the stratum corneum and that do not invade living
tissue, presumably due to a serum antifungal factor. The diseases differ in respect to location on
the body, age of involvement, etc, but generally produce irregular annular lesions with irregular
interior clearing and peripheral scale (containing the fungal hyphae). The diagnosis of
dermatophyte infection can be made by microscopic examination of a KOH preparation of the
peripheral scales. Hyphae appear as doubly refractile, branching filaments.

1. TINEA CAPITIS - This is a patchy, scaly alopecia, often with broken off hairs and is usually
found in anthropophilic tinea infections. Zoophilic or geophilic fungi often cause a baggy
purulent impetiginous mass (kerion). A greenish fluorescence on Wood's (black) light
examination may be of value in screening children during epidemics.
2. TINEA CORPORIS - This is usually manifested as an annular scaly, patch, but it may be
pustular or granulomatous.
3. TINEA CRURIS (jock itch) - This involves the groin and the upper, inner thighs. It should
be differentiated from Candida albicans infection which results in more inflammation and
satellite pustules.
4. TINEA PEDIS - This involves the intertriginous area of the toes. Acute episodes result in tiny
vesicles which may become chronic with scaling hyperkeratotic lesions.
5. TINEA UNGUIUM - This involves the nails and is characterized by thick, crumbly and
distorted nails.
6. TINEA VERSICOLOR - This is a distinct superficial fungus infection of the skin and, unlike
the above, does not respond to griseofulvin. Tinea versicolor is characterized by
hypo pigmented or hyperpigmented scaly patches or sheets, usually on the trunk. Scrapings
show both hyphae and spores ("spaghetti and meatballs").

B. CANDIDA - This is relatively common especially in diabetics and pregnant females. Pruritic
erythematous patches develop primarily in intertriginous or other moist areas and are frequently
accompanied by smaller satellite papules.

IV. SYPHILITIC - This can be classified on the basis of length of infection and type of skin response. The
chancre of primary syphilis is a relatively painless, ulcerated, indurated nodule typically on the genitalia,
lips, fingers, etc. It involutes spontaneously in 2 to 6 weeks. Secondary syphilis may mimic many other skin
ailments. Histologically, it represents an interface dermatitis with a perivascular plasma cell infiltrate
frequently present. Protean manifestations include macules, papules, pustules and alopecia. Scaly reddish
brown papules of the palms and soles are very suggestive of secondary syphilis. These develop one to three

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 months after contact. Tertiary syphilis produces gummatous lesions which may not develop for several
years after acquiring the infection.

PAPULOSQUAMOUS DISEASES

These disorders seem to be reactions to various external "triggers" and are characterized by well circumscribed
"scaly" lesions.

I. PSORIASIS - This is a common (2-6% of population), genetically predetermined (dominant gene with
incomplete penetrance), accelerated epidermal turnover in response to various stimuli. Normal epidermal
turnover requires 28 days but in psoriasis the turnover takes only 3 to 4 days. Because of this rapid
turnover, keratinization is incomplete and extensive parakeratosis results.

A. CLINICAL APPEARANCE - The parakeratosis is manifest as dry, well demarcated, occasionally

annular, salmon-colored plaques that are covered by distinctive silvery micaceous scales. Scraping
away the scales reveals pinpoint areas of bleeding (Auspitz phenomenon). Individual papules are
frequently not evident because they rapidly become confluent and form large thick white plaques
that typically involve the scalp, elbows, lower back, buttocks, and knees. Genitalia may also be
involved. Localized psoriasis may occur in areas of trauma (Koebner's phenomenon). One form
(sebopsoriasis) tends to involve oily skin areas (scalp, face, and central chest). Involvement of the
nails produces a characteristic orange discoloration immediately proximal to the detachment of the
nail, and the presence of "thimble-like" pitting of the nails is virtually pathognomonic. Joint changes
closely resembling rheumatoid arthritis may also be present.
B. HISTOLOGIC APPEARANCE - Features include regular elongation of the rete ridges with blunting
of the lowermost portion (club-shaped acanthosis) and concomitant elongation of the dermal
papillae with papillary edema; thinning of the stratum malpighii overlying the elongated papillae
(which may contain a small spongiform pustule); thinning or absence of the stratum granulosum;
and marked parakeratosis (which may contain Munro microabscesses). On occasion the pustules
become grossly apparent and lead to a pustular psoriasis.
c. CLINICAL COURSE AND TREATMENT - The initial onset of psoriasis is usually in late childhood.
The clinical course tends to be chronic with exacerbations and remissions. The severity ranges
from one or two scattered scalp lesions to generalized exfoliative involvement. Treatment
procedures which decrease the mitotic rate are beneficial. Topical steroids, tar, and anthralin
creams and ointments are useful. Sun or ultraviolet light exposure is beneficial and the lesions often
improve in the summer months because of increased ultraviolet light. For extensive psoriasis,
PUV A therapy (oral psoralen photosensitization with UV A therapy) is utilized. Very severe disease
may be treated with methotrexate or etretinate systemically.

II. PITYRIASIS ROSEA - This is a common, self-limiting (three to six weeks), generally asymptomatic
disease of young adults that tends to occur during the spring and summer. The sudden eruption and limited
duration suggest a viral (retroviral?) etiology, and some patients may have a prodrome of upper respiratory
infection.

A. CLINICAL APPEARANCE - The initial lesion is generally a single, almost perfectly oval ring with
peripherally attached "cigarette paper" like scales and is often misdiagnosed as "ringworm". This
"herald lesion" is followed by the appearance over the next few days of similar but smaller lesions
over the trunk and proximal extremities. The long axis of the lesions tend to run with the lines of

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 cleavage of the skin and form the typical "christmas tree" pattern on the back (running parallel to
the ribs). An inverse form may develop primarily in intertriginous areas. Extensive eruptions may
be mistaken clinically for secondary syphilis, but they spare the palms and soles. With resolution,
there may be residual hyperpigmentation of the skin which will gradually disappear over time.
B. HISTOLOGIC APPEARANCE - This looks like an "interface dermatitis" with a mononuclear cell
infiltrate in the upper dermis, exocytosis, spongiosis with occasional spongiotic vesicles, mild
acanthosis and focal parakeratosis.
C. TREATMENT - This is unnecessary in the majority of cases, but in severe cases, steroid creams or
systemic steroids may be used.

III. LICHEN PLANUS - This is less common and represents a cutaneous reaction pattern to a variety of
stimuli.

A. CLINICAL APPEARANCE - It presents with multiple small, violaceous, pruritic papules which tend
to coalesce into larger angular plaques which may have fine white linear or lace-like scale
(Wickham's stria). The lesions tend to show symmetrical involvement of the wrists, forearms, and
elbows and, like psoriasis, may also appear in areas of trauma (Koebner's phenomenon). The
lesions may also be generalized and will, like secondary syphilis, involve the palms and soles.
Unlike the other papulosquamous disorders, the oral mucosa is frequently involved.
B. HISTOLOGIC APPEARANCE - It includes hyperkeratosis; degeneration and necrosis of basal cells
(which may produce colloid (Civatte) bodies in the papillary dermis; irregular "sawtooth"
acanthosis; and a dense band-like dermal infiltrate that extends to the dermal-epidermal junction
and is sharply demarcated at the lower margin.

IV. PITYRIASIS RUBRA PILARIS - This is an uncommon disorder which begins as small papules around
follicles characterized by parakeratosis at the follicular edge. Unlike most other disorders, areas of sparing
have a convex border. Hard thickened palms and soles are also a distinctive feature.
V. SEBORRHEIC DERMATITIS - This is an inflammatory (erythematous), papulosquamous (scaly),
moderatly pruritic eruption usually located in areas of high sebaceous activity. It does not occur before
puberty except in early infancy when sebaceous activity is stimulated by transplacental maternal androgens.
It reaches its peak from 18-40 years of age, is extremely common, and usually is worse in winter. It ranges
in severity from mild dandruff to an eruption characterized by marginated (although not as well defined
as psoriasis), erythematous, greasy, scaly, plaques and patches located in the scalp, eyebrows, nasofacial
creases, ears (canals and posterior folds), and in axillary, inframammary, umbilical, inguinal, and gluteal
folds. Like psoriasis, the scale is the result of increased turnover of epidermal cells (5-7 days), and the
inflammation may be a reaction to the presence of scale. Simple dandruff is no diagnostic problem, but
erythematous lesions of the central face can be confused with lupus erythematosus. Intertriginous and scalp
lesions may resemble psoriasis. All forms can be confused with eczema. Treatment is usually with 1%
hydrocortisone creams and lotions, tar, shampoos, zinc and salicylic acid.
VI. OTHER "SCALY" DISORDERS - Other disorders that need to be included in the differential diagnosis
of papulosquamous lesions include chronic eczematous disorders, the dermatophytoses, lupus
erythematosus, and drug eruptions.

VESICULOBULLOUS DISORDERS

Bullous (blistering) diseases are classified in several ways based on biopsy of the lesion. The proper location
of a biopsy is intact skin adjacent to the blister. The initial categorization is by histologic localization of the level

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of the blisters (subepidermal, intraepidermal, etc). Additional studies (direct and indirect immunofluorescence,
electron microscopy, genetic evaluation) may also be needed. At a submicroscopic level, the epidermal/dermal
junction is very complex and many of the vesiculobullous diseases have in vivo fixed antibodies to various elements
that make up the junction.

I. EPIDERMOLYSIS BULLOSA (EB) - This comprises a group of at least 17 bullous diseases which are
also known as "mechanobullous diseases" since the lesions are elicited by mechanical trauma. Most are
inherited, either autosomal dominant or autosomal recessive, with the autosomal recessive forms being
more severe, appearing in infancy, and proving fatal. The pathogenesis is related to inherited structural
weaknesses in various components of the epidermal basal cell layer or dermal-epidermal junction area. The
diagnosis is determined primarily by identifYing the structural defect by electron microscopy. Genetic
counselling is especially important.
II. DERMA TITIS HERPETIFORMIS (DH) - This is a relatively common idiopathic disease that appears
in late childhood through early to mid-adulthood. It is associated with a mild or asymptomatic gluten
sensitive enteropathy and the formation ofIgA antibodies that react with anchoring fibrils in the uppermost
dermis. The lesions which are located on the extensor surfaces of the extremities, shoulders, and gluteal
region tend to be intensely pruritic and arise in a grouped or clustered ("herpetiform") configuration, but
the disease is /lot related to herpes viruses. Most patients have HLA-B8 histocompatibility antigens. The
histologic characteristics are subepidermal blister formation, infiltration of eosinophils beneath the blister,
and papillary dermis neutrophilic abscesses lateral to the blister site (lateral papillitis). Lesions suitable for
biopsy, i.e. unexcoriated papules, may be hard to find. Fortunately, however, the diagnosis can be
confinned by direct immunofluorescence demonstrating a granular pattern ofIgA autoantibodies in normal
skin which is accentuated at the tips of the dermal papillae. The disease is incurable but controllable with
drugs (dapsone, sulfapyridine).
III. LINEAR IgA DISEASE - This is a rare bullous disease which is similar to dermatitis herpetiformis
microscopically but which does not respond well to drugs. A childhood form ("chronic bullous disease
of childhood"), and an adult form exist. Clinically, the lesions are distributed somewhat differently
(tendency to aggregate around the genitalia) than in DH and the patients do not have the associated gluten-
sensitive enteropathy and HLA-B8 antigen. The direct immunofluorescence, however, is the best way of
distinguishing from DH since the IgA autoantibody pattern is linear rather than granular.
IV. PEMPHIGUS - This is a bullous disease which occurs in two basic forms: pemphigus vulgaris/vegetans
and pemphigus foliaceous/erythematosus. Young to middle age adults are primarily affected, and there
appears to be ill-defined genetic influences. It is difficult to control even with high doses of steroids, and
it is sometimes fatal. Autoantibodies to certain components of the epidermal intercellular spaces cause
acantholysis at characteristic levels of the epidermis, resulting in blister formation. The blisters are fragile
and rupture easily, therefore appearing as crusted erosions. The mouth is usually affected first, followed
by skin lesions that vary in severity. The histologic hallmark of the pemphigus group is acantholysis: high
epidermal in p. foliaceous/erythematosus forms "comflake-like" scaly lesions, and low epidermal
(suprabasilar) in p. vulgaris/vegetans to form blisters. In both forms, then, the basal layer remains attached
to the basement membrane. IgG autoantibodies and C3 can be seen in the intercellular spaces by direct
immunofluorescence, and this causes the loss of cohesion between cells. By indirect immunofluorescence,
the autoantibodies can also be demonstrated in the serum, and the levels in the serum tend to parallel the
severity of the disease.
V. BULLOUS PEMPHIGOID (BP) - This is the commonest of the bullous diseases. Although clinically
somewhat similar to pemphigus, it occurs mainly in the elderly. The bullae are generally large, tense, and
widely distributed including the axillae, inguina, and flexor surfaces of the forearms. They may cause
considerable debility in the elderly patient. The mucous membranes are more frequently, but not always,
spared. A localized form (mucous membrane pemphigoid) does affect the mucous membranes. The
histologic characteristics are subepidermal bulla formation, eosinophil infiltration in and below the bulla,

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 and spontaneous re-epithelization of the bulla floor. These findings, however, are non-diagnostic, and direct
immunofluorescence is usually necessary. A linear subepidermal pattern (in the lamina lucida) of IgG and
C3 deposition is characteristic. The antigens apparently originate in the epidermal cytoplasm. Steroids may
be required to control the disorder. Since there is no damage to the lamina densa and underlying connective
tissue, there is no scarring as these heal.
VI. HERPES GESTATIONIS (PEMPHIGUS GESTATIONIS) - This is a rare bullouslinflammatory
disease of pregnancy. Although the cause is unknown, it is not related to herpes virus infection and
histologically resembles bullous pemphigoid. Linear deposits of C3 and, in most cases, IgG auto anti bodies
can be demonstrated in the lamina lucida of the epidermal basement membrane zone of unaffected skin.
In the third trimester of pregnancy, pruritic lesions appear, typically on the trunk, and tend to persist until
after delivery. The disease often recurs in subsequent pregnancies, and although controversial, many feel
that there is an increase in infanct mortality.
VII. PORPHYRIA CUTANEA TARDA (PCT) - This is the commonest of the porphyrias. It is related to
hepatic deficiency of uroporphyrinogen decarboxylase, which may be inherited. The clinical manifestations
are usually precipitated by exposure to hepatotoxic substances, such as ethanol, estrogens, iron, and certain
chlorinated hydrocarbons. There is a broad range of cutaneous manifestations, most notably
photosensitivity, with blisters and fragility. Chronic changes include hyperpigmentation, hypertrichosis, and
sclerodermoid lesions of sun-exposed skin. The mechanisms of these changes are poorly understood.
Histologically, there is subepidermal blister formation with scant inflammatory infiltrate, homogenization
of collagen around capillaries, and prominent dermal papillae. Direct immunofluorescence is of little
additional value. The important diagnostic test is the demonstration of increased urinary excretion of
uroporphyrins and coproporphyrins.

NON-NEOPLASTIC DISORDERS OF SKIN APPENDAGES

I. HAIR - Hair is located on all skin except palms and soles, and its length, caliber, and growth pattern vary
with age, sex, and location on body. With the possible exceptions of nose and ear hairs, the significance
of hair is entirely cosmetic. Human hair has an asynchronous growth cycle with 90-95% of the hair in the
growing (anagen) phase and 5-10% in the resting/shedding (telogen) phase. Common disorders include:

A. ALOPECIAAREATA - This is a sudden loss of hair in one or more patches. The scalp itself remains
normal in appearance. Anagen hairs become dystrophic and fall out. The etiology is unknown.
Regrowth is usual except in extensive cases.
B. TELOG EN EFFLUVIUM - This is a marked increase in the number of resting and shedding hairs.
There is a temporary diffuse alopecia following systemic stress, e.g., sudden hair loss 3-4 months
after childbirth, surgery, or serious illness.
C. MALE PATTERN BALDNESS - The universal "M" shaped alopecia of adolescence is followed by an
androgen-dependent alopecia in genetically susceptible individuals. Frontal and/or supra-occipital
loss of normal (terminal) hairs is replaced by fine, short (v ell us) hairs.
D. HIRSUTISM - Abnormal excessive hairiness may be on a hormonal (usually androgenic) or
hereditary basis.

II. APOCRINE GLANDS - Located in the axillae, perianal and genital areas, and areolae of breasts, these
are large coiled glands that empty via a duct, usually into the hair follicle near the skin surface. They are
poorly developed in children but enlarge at puberty due to sex hormones. Secretions can be provoked by
emotional stimuli, probably via circulating adrenalin or adrenergic sympathetic nerve supply of the duct.
The secretory product is a milky fluid which is odorless when it reaches skin surface but, after bacterial

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 decomposition. it takes on the typical odor. Therefore, reduction of skin bacteria reduces odor. Effective
deodorants contain antibacterial agents. There are no drugs available at present that effectively inhibit
apocrine secretion.
III. ECCRINE GLANDS - These are small coiled glands with secretory and ductal portions that exit at the
skin surface independent of the pilosebaceous unit. They are located over the entire skin but are much more
concentrated on palms, soles, forehead, axilla. They function as an evaporative cooling mechanism. The
activity of the gland is controlled by two major stimuli: thermal (general body surface) and emotional
(palms, soles, forehead, axilla). Disorders include:

A HYPERHIDROSIS (excess sweating) - This occurs most commonly in the axillary and palmar areas
and is provoked by emotional stimuli.
B. MILIARIA (heat rash) - This results from an obstruction of the duct as is associated with increased
sweating in hot humid conditions. Other factors involved are skin bacteria and maceration at the
duct orifice. Lesions appear as tiny clear vesicles when the obstruction is in the stratum corneum
(miliaria crystallina); red papules when the obstruction is intraepidermal (miliaria rubra); and skin
colored papules when the obstruction is intradermal (miliaria profunda). Only miliaria rubra is
pruritic.
C. ANHIDROSIS - This is an impairment or absence ofsweating and may be generalized or localized.
Causes include congenital ectodermal defects, neuropathies, certain drug or heavy metal
poisonings, scleroderma, atrophic or scarring diseases of skin, etc.

IV. SEBACEOUS GLANDS - These are distributed over the entire skin except for palms and soles. They are
largest and most numerous on the central face, chest and scalp. The exact function is uncertain.
Presumably, they aid in retaining moisture in the skin and keeping the skin lubricated and pliable. The
sebaceous gland is holocrine; its secretion, sebum, is formed by the disintegration of the glandular cells.
The gland is a lobulated collection of clear fat laden cells with a duct emptying into the neck of the hair
follicle or through the surface epidermis. The cells are formed at the periphery and as they move to the
center and through the duct, they disintegrate and become sebum. They are stimulated primarily by the
direct action of androgens on the gland. Estrogens inhibit growth by reciprocal inhibition of androgens. The
activity is directly proportional to the size of the gland and rate of turnover of the cells.
V. NAILS - The nail plate is formed in the matrix which underlies the proximal nail fold. It grows distally
with the nail bed and remains attached to it. Although the potential for variation in appearance is limited
(nail loss, thickening, cross ridging, change in color, onycholysis, subungual keratinization, pitting and
various distortions), nail changes are seen in many diseases. Chronic paronychia, psoriasis (pits), eczema
(ridging), fungus (thickening), trauma (distortion) and developmental defects will account for 90% of all
nail problems.

DRUG ERUPTIONS

A drug eruption is a cutaneous reaction to a systemically administered drug or to one of its metabolic
degradation products. Reactions may be very serious and/or fatal. The mechanisms of most drug reactions is
unknown. Some are by interference with metabolic pathways, and some (penicillin, sulfonamide, etc) are
"allergic" and involve an antigen-antibody reaction. Eruptions may be produced by a small quantity of a drug
which may have been taken without incident for many years previously. Eruptions may also be caused by
disparate drugs if they have a common metabolic end product which is a hapten serving as an antigenic
determinant. Eruptions are exceedingly diverse in morphology and may mimic almost any known skin disorder.
A given drug may cause a different type reaction in different persons or different drugs may cause the same

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skin reaction in a given patient. Common reaction patterns include: scarlatiniform, morbilliform, vesicular, bullous,
urticarial, erythema multiforme, fixed (lesions occur in exactly the same site on subsequent reexposure to the
offending drug), acneiform, lupus erythematosus-like, eczematous, photosensitivity, etc. There may be an
associated fever, malaise, anemia, or leukopenia. If the offending drug is continued, worsening of the eruption may
result in generalized exfoliative dermatitis.

CONNECTIVE TISSUE (AUTOIMMUNE) DISORDERS

I. LUPUS ERYTHEMATOSUS (LE) - There are two major forms of lupus erythematosus: nonsystemic
and systemic. In the former only the skin is involved, while in the latter, there is systemic involvement with
significant patient morbidity and mortality. As with many connective tissue diseases, however, the
cutaneous changes may be the initial presentation of the disease.

A. CHRONIC CUTANEOUS (DISCOID) LE - This is essentially confined to the skin and subcutaneous
tissues, although various circulating antinuclear antibodies are commonly present in low titers.
Large, discrete, erythematous "discoid" patches with surface scaling and follicular plugging appear
typically on the face and scalp. The lesions of so-called disseminated discoid LE occur
predominately on the upper trunk and arms and facial lesions mayor may not be present.
Microscopically, the lesions show epithelial atrophy with destruction of cells in the basal layer and
the lesions may be hypopigmented due to the loss of melanocytes. There is hyperkeratosis,
orthokeratosis, and follicular plugging; dermal edema with homogenization of the upper dermal
collagen; and patchy lymphocytic infiltrate localized about cutaneous appendages.
Immunofluorescence may demonstration fixed autoantibodies at the dermal-epidermal junction.
Scarring and atrophy are common sequelae.
B. SUBACUTE CUTANEOUS LE - This is mainly cutaneous but may also exhibit relatively mild systemic
manifestations such as arthralgia or Raynaud's phenomenon. Frequently seen in sun-exposed areas,
the cutaneous lesions are more numerous and disseminated than in chronic cutaneous LE and are
typically urticarial, annular, or psoriasiform. Oral mucous membranes are often involved. Unlike
chronic cutaneous LE, scarring and/or atrophy is not characteristic. Most patients have anti-Ro
(SSA) and anti-La (SSB) circulating antibodies but are ANA negative by the commonly used
screening tests. These antibodies can cross the placenta children born of these women may have
lesions oflupus (neonatal LE) which resolve as the antibodies dissipate after birth. About half of
these neonates, however, demonstrate a congenital heart block.
C. SYSTEMIC LE (SLE) - Although this represents a systemic disease, the cutaneous lesions may be
the first to appear, and the severity of cutaneous involvement often parallels the severity of visceral
involvement. The initial cutaneous lesions in SLE are often nonspecific, but in well developed
lesions the changes are similar to discoid LE with epithelial atrophy and degeneration of the basal
layer that obscures the dermal/epidermal junction. The cutaneous lesions are most prominent in
areas of sun exposure and are often confluent and widely disseminated. The facial "butterfly"
erythema (corresponding to the areas of greatest sun exposure) is characteristic. Ultraviolet light
alters the nuclear DNA in the basal cell layer and antibodies to the altered DNA are developed.
Laboratory tests are used to confirm or rule-out a diagnosis of SLE. Besides the findings associated
with involvement of other organs, tests such as the fluorescent anti-nuclear antibody (ANA) are
positive in up to 90% of untreated SLE patients. More specific is the anti-dsDNA antibody test;
its demonstration carrying a grave prognosis because of the high association with renal disease.
Another test of substantial value is the so-called lupus band test which may demonstrate, by direct

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 immunofluorescence, granular deposition of immunoglobulins (lgA, IgM or IgG) and/or
complement (C3) at the dermal-epidermal junction of involved and uninvolved sun-exposed skin.

II. SCLERODERMA - This represents a group of diseases manifested by proliferation of collagen with
eventual replacement and sclerosis of subcutaneous tissue.

A. LOCALIZED CUTANEOUS SCLERODERMA (MORPHEA) - This is usually limited to the skin and
subcutaneous tissue. In the most common form, there are round to oval indurated but smooth-
surfaced plaques that are ivory in color and that have a violaceous border ("lilac ring"). Early
histologic changes include thickening of the reticular dermis and a moderately severe dermal
lymphocytic infiltrate. Older lesions are more sclerotic and inflammatory cells are largely absent.
The epidermis is atrophic and the reticular dermis is thickened and dense. Dermal appendages are
often atrophic in involved areas. There is no systemic involvement, although many patients have
circulating anti-single stranded-DNA antibodies. The significance of these antibodies is unknown.
B. SYSTEMIC SCLERODERMA - This involves the fibroblast production and deposition of excessive
amounts of collagen in many organs, including the skin and subcutaneous tissue. Initially
erythematous and edematous, the skin becomes progressively sclerotic with a "salt and pepper" loss
of pigmentation and eventually is replaced by hard, smooth ivory colored areas which are immobile
upon the underlying tissue. One form (acrosclerosis), which has a good prognosis, begins with
Raynaud's phenomenon and tends to involve distal extremities most prominently. A worse form
(progressive systemic sclerosis) begins centrally and progresses more rapidly. The facies become
taut, beak-like and expressionless. The hands become indurated and claw-like. Calcification of
affected areas is common in long standing cases. On occasion, it may be fatal due to the
involvement ofintemal organs (particularly the esophagus, GI tract, heart, lungs, and kidneys). The
CREST syndrome is calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly,
and telangiectasia. Certain circulating antibodies are characteristic: the Sel-70 antibody In
progressive systemic sclerosis, and the anti-centromere antibody in CREST syndrome.

III. DERMATOMYOSITIS - As the name implies, both skin and skeletal muscle are involved. In children,
dusky lilac discoloration of the upper eyelids ("heliotrope rash") is characteristic. Although proximal
muscular weakness of the extremities may be present, abdominal pain and gastrointestinal hemorrhage may
dominate the clinical picture. Soft tissue calcifications may appear late in the disease. Adult
dermatomyositis, on the other hand, is different than the childhood form in that it lacks the associated
abdominal pain, GI bleeding, and muscular calcifications seen in childhood disease. In addition, there is
an association with malignant neoplasia developing months or years after the appearance of the skin lesions.
Besides the heliotrope rash on the eyelids commonly associated with childhood dermatomyositis, other
areas of cutaneous involvement include the chest, knees, elbows, knuckles and distal phalanges. These
lesions often resemble those ofSLE both clinically and histopathologically. Erythematous, scaly Gottron's
papules occuring on the dorsum of the hand, however, are specific for this disease.
IV. MIXED CONNECTIVE TISSUE DISEASE (MCTD) - As the name implies, this has clinical features
ofSLE, progressive systemic sclerosis, and polymyositis but no anti-dsDNA antibody. There is little renal
involvement, and the disorder responds fairly well to steroid therapy.

EPITHELIAL TUMORS AND TUMOR-LIKE CONDITIONS

Most tumors of the epidermis are related to sun damage and, therefore, tend to appear on sun-exposed portions
of the skin. There appear to be two forms of sun damage related to the subsequent development of epithelial

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tumors: those related to chronic sun exposure which increase the risk of squamous cell and basal cell carcinomas;
and those related to severe blistering sunburns in childhood which increase the incidence of nevi and malignant
melanomas.

1. EPITHELIAL CYSTS - These are relatively common lesions presenting as slow-growing subcutaneous
nodules. They are usually unimportant although secondary bacterial infection may cause abscess formation
and ruptured cysts will induce a painful, florid foreign body granulomatous response.

A. EPIDERMOID (SEBACEOUS, EPITHELIAL INCLUSION) CYSTS - These are derived from and lined
by normal squamous epithelium which continues to desquamate keratin into the cystic cavity. They
occur principally on the face, neck, and back and grossly contain rancid, cheesy keratinaceous
debris.
B. PILAR (TRICHILEMMAL) CYSTS - These are derived from the epithelium of the pilar units and
therefore do not histologically demonstrate the normal layers of the superficial epithelium.
Commonly called a "wen", most appear on the scalp and some may undergo partial calcification.

II. PSEUDOCARCINOMA TOUS (PSEUDO EPITHELIOMA TOUS) HYPERPLASIA - This is a

reactive epithelial hyperplasia associated with certain infectious agents that cause chronic inflammation,
chronic inflammation of noninfectious etiology, and the margins of chronic ulcers. Additionally, granular
cell tumors located in the dermis (or tongue) may induce pseudocarcinomatous hyperplasia in the overlying
epidermis. Downward proliferation of the hyperplastic epidermis into the dermis along with cytologic
atypia suggests a squamous cell carcinoma both clinically and histologically. The differentiation from true
cancer may at times be difficult.
III. SEBORRHEIC KERATOSIS - Appearing only after middle age, this lesion is the most frequent tumor
of the skin in adults and, in many instances, is a sun-related lesion appearing in areas that were sunburned
(face, trunk, and occasionally extremities) during childhood. There is also a familial tendency indicating
genetic predisposition. Often multiple, these tumors are located almost entirely above the surface of the
surrounding normal skin, giving rise to a "stuck on" appearance which helps to distinguish them from other
lesions. The surface is usually flat but may be irregular or even verrucous and have a "greasy" feel. They
are usually a light brown, but may be the color of normal skin or almost black, depending upon the level
ofmelanocytic activity. Pigmented seborrheic keratoses may be confused with nevi or melanoma. There
are several variant forms (verrucous, acanthotic, reticular, stucco, etc), but the important clinical features
in common are that they are well demarcated from surrounding skin and are benign. Histologic features
are hyperplasia of the basal epithelium (basaloid acanthOSiS) and hyperkeratosis (forming horn
pseudocysts). They usually don't come to clinical attention unless they are cosmetically displeasing or until
one becomes irritated or "activated". When this occurs, the lesion becomes pruritic, loses its normal color,
and grows rapidly. Irritated lesions have more of a squamous appearance (rather than a basaloid
appearance) histologically. There is marked spongiosis of the epithelium with inflammatory infiltrate of the
dermis and these may be misdiagnosed as squamous cell carcinoma.
IV. KERA TOACANTHOMA - This is a rapidly evolving but benign, firm, nodular lesion with a central
keratin-filled crater that may simulate squamous cell carcinoma. They tend to occur on the sun-exposed
areas (digits and upper lip). Most will regress spontaneously within a few weeks leaving a scar, but a few
may reach large size. Histologically, it is an invaginated acanthotic lesion with central hyperkeratosis and
a ground glass appearance of the epithelial cytoplasm (superkeratinized). The microscopic appearance may
be identical to a squamous cell carcinoma, and the diagnosis rests on clinical history. There is a
suggestion of viral etiology since approximately 10% have been associated with HPV.
V. ACTINIC (SOLAR) KERATOSIS - This is related to chronic sun damage and usually presents as
multiple keratoses occurring on sun-exposed skin, most notably the face and hands. They are most common
in fair-complected individuals who sunburn readily but tan poorly. The ultraviolet radiation damage to the

237
 basal cells begets abnormal squamous cells. Characteristically, a gritty scale overlies an erythematous
macule or papule. Histologic changes include solar degeneration of the upper dermis, dysplasia of the
epidermis (notably in the lower 1/3), and hyperkeratosis (which may on occasion form cutaneous horns).
Occasionally, there may be epithelial atrophy. These lesions may progress to invasive squamous cell
carcinoma (12%), particularly when they involve the ear, lip, or dorsum of the hand.
VI. BOWEN'S DISEASE (SQUAMOUS CELL CARCINOMA-IN-SITU) - This can occur on both
exposed (sun related damage) and non-exposed (HPV or arsenic related damage) areas of skin. The lesion
initially appears as a solitary etythematous patch with an irregular but well-defined border that often clinic-
ally appears more inflammatory than neoplastic, which may delay the diagnosis. The patch, however,
progressively increases in size. Microscopic exam shows a total loss of maturational sequence in the
epithelium and trans epidermal nuclear atypism with dyskeratosis. Conversion to invasive squamous cell
carcinoma is unusual, but once it occurs, there is a likelihood of regional or distant metastasis especially
when the tumor involves the lip, ear, or cheek.
VII. SQUAMOUS CELL CARCINOMA - Although this tumor may arise from non-solar chronic skin
damage, it usually arises from areas of actinic keratosis, especially on the lip and ear, and is therefore
related primarily to sun exposure. They begin as indurated keratoses that with time become nodular and
tend to ulcerate with a keratotic or crusted granular surface. The margins are usually solid and indurated.
Histologically, the tumor consists of irregular masses, cords, and nests of neoplastic squamous cells that
invade the underlying dermis. Keratin "pearl" formation is seen in tumors with higher degrees of
differentiation. In general, cutaneous squamous cell carcinomas arising from actinic damage have a much
lower metastatic potential than those arising from mucous membranes (cervix, bronchus, etc) except for
those that arise from bum scars (Marjolin ulcer) and chronic leg ulcers.
VIII. BASAL CELL CARCINOMA (BCC) - This is the most common malignant tumor of the skin, is also
related to chronic solar radiation damage, and occurs on sun-exposed areas of the skin. There also appears
to be a genetic component to the development of these lesions. They appear most commonly at the root
of the nose and along the scalp line where they usually present as a solitary, slightly translucent or "pearly"
nodule with a depressed center and superficial telangiectases. Infiltrative BCC however may resemble scar
on gross exam. Histologically, they consist of islands ofbasaloid cells with peripheral palisading that invade
into, but tend to show slight separation or "clefting" from, the underlying dermis. The neoplastic cells also
tend to form their own stroma which is different from collagen. There are many clinical variants
(superficial, nodulo-ulcerative, pigmented, sclerosing) which may, on occasion, be confused with other
benign and malignant dermatologic conditions. There is an inherited condition, the basal cell nevus
syndrome, in which patients deveop hundreds of basal cell carcinomas. Although BCC rarely metastasizes,
its infiltrative nature makes definition of the surgical boundaries difficult, and recurrences are common.
IX. ADNEXAL TUMORS - These are derived from apocrine glands, eccrine glands, sebaceous glands, and
pilar units. They are genetically predetermined, most are benign, and they have similar clinical appearances.
Although a solitary lesion could clinically be mistaken for a basal cell carcinoma, these are generally
multiple tumors occurring principally around the central face, forehead, and base of nose in younger
patients who have a strong family history of similar lesions.

DERMAL TUMORS AND TUMOR-LIKE CONDITIONS

Structural components of the dermis (fibroblasts, blood vessels, peripheral nerve, smooth muscle) and cellular
migrants through the dermis (mast cells, histiocytes, lymphocytes, etc) may all give rise to dermal tumors, some
of which are peculiar to the skin and others which are similar to tumors of soft tissue elsewhere in the body.

238
I. DERMATOFIBROMA (benign fibrous histioc.-ytoma) - This is a common benign tumor derived from
dermal histiocytes/fibroblasts that can arise at any age but mostly in young to middle aged adults. They
occur most frequently on the lower extremities of females as a firm, slow-growing nodule which, because
of variable coloration, may occasionally mimic melanoma clinically. Histologically, the tumor is relatively
well demarcated remaining separated from the overlying epidermis (which frequently shows a basaloid
hyperplasia that may simulate basal cell carcinoma) but occasionally extending into the underlying
subcutaneous tissue. There also tends to be trapping of mature collagen by new collagen at the periphery
of the lesion. The lesion may contain fibroblasts, capillaries and histiocytes in varying proportions.
Histologic variants include those with a storiform pattern of spindle cells, bands and bundles of round-oval
cells that dissect through the collagen, those with prominent vascular proliferation, and those with large
"monster" cells.
II. DERMA TOFIBROSARCOMAPROTUBERANS - This is a locally aggressive, slow growing form of
malignantfibrous histiocytoma which tends to occur on the trunk and proximal extremities of young to
middle aged adults (more frequently males). It usually begins as an indurated plaque that develops multiple
nodules. Histologically, the tumor is composed of crowded spindle cells arranged in a storiform pattern
which has a broad expanding border. There is often atrophy and ulceration of the overlying epidermis and
the subcutaneous tissue is frequently involved. There is a high rate of recurrence after resection.
III. CAPILLARY HEMANGIOMA

A. CHERRY OR RUBY HEMANGIOMA (senile angioma) - This is a small cherry-colored hemangioma

that occurs commonly in middle age and beyond, mostly on the trunk and scalp.
B. STRAWBERRY HEMANGIOMA - This usually appears shortly after birth as superficial, soft, elevated,
strawberry-colored vascular tumor which may grow relatively rapidly and appear cosmetically
disfiguring. Over 90%, however, regress spontaneously and disappear by mid-childhood. It consists
of endothelial hyperplasia and localized proliferation of capillaries with small lumens.
C. PORTWINE STAIN - This is a more diffuse proliferation of capillaries within the dermis although
some feel that they simply represent weakening and dilatation of the dermal blood vessels. These
usually appear after birth, most frequently on the face and scalp. They do not regress and, on
occasion, may be associated with other clinical syndromes (5'turge-Weber, etc).

IV. CAVERNOUS HEMANGIOMA - This is a vascular tumor caused by the proliferation of larger vascular
elements (primarily veins). They are soft, bulky, deep seated, dark blue tumors which also appear in
infancy. These also have a tendency for spontaneous regression so that excision may not be necessary.
V. PYOGENIC GRANULOMA (lobular capillary hemangioma) - This is basically a reactive granulation
tissue process in response to trauma or localized infection. There is proliferation of capillaries in an
edematous stroma with mixed inflammatory infiltrates and an epidermal "collarette" around the base of the
lesion. The overlying epidermis is often ulcerated.
VI. MASTOCYTOSIS - This refers to a group of diseases characterized by mast cell proliferation. The
cutaneous form is urticaria pigmentosa and generally occurs in children as multiple brown papules or
plaques which, when rubbed, develop edema and erythema (Darier's sign). A similar reaction will occur
when non-Iesional skin is stroked (dermatographism). This results from the degranulation of the
accumulated mast cells. Systemic symptoms may involve palpitations, flushing, diarrhea, pruritus, etc.
VII. XANTHOMAS - These are cutaneous accumulations of lipid-laden macrophages often admixed with
multinucleated giant cells and a variable degree of inflammatory cells. Xanthogranulomas are clinically
similar to dermatofibroma except for a yellower color. They are seen primarily in children and usually
spontaneously regress. Eruptive xanthomas appear on the buttocks and posterior thighs and fluctuate with
serum triglyceride levels; tuberous xanthomas occur on the elbows, knees, fingers and buttocks; tendinous
xanthomas appear over the achilles tendon and extensor tendons of the fingers; plane (flat) xanthomas
occur in the palmar creases; and xanthelasma appears on and around the eyelids. The xanthomas are

239
 frequently related to familial hyperlipidemias and/or lymphoproliferative disorders. In familial hypercholest-
erolemia, tuberous and tendinous xanthomas are common. In the hyperlipemia of diabetes, papular eruptive
xanthoma is common. In hypercholesterolemia of biliary cirrhosis, plane xanthomas are common. About
1/3 of patients with xanthelasma have hypercholesterolemia. Some xanthomas (histiocytosis X), however,
are not associated with abnormalities of circulating lipids.

MELANOCYTIC TUMORS AND TUMOR-LIKE CONDITIONS

There appear to be three major factors (sun bum, genetic predisposition, and hormonal status) in the development
of pigmented lesions, only one of which (sun exposure) is under behavioral control. The function of the epidermal
melanocytes is to protect the basal cells and young keratinocytes from ultraviolet radiation by capping them with
melanin. Acute sunbum produces individual degenerating and necrotic keratinocytes ("sunburn cells") at all levels
of the epidermis. Chronic sun exposure is reflected more by pigmentary changes and basophilic degeneration of
the upper dermis (solar degeneration). Atrophic, wrinkled, easily bruised skin is more a reflection of chronic sun
damage than of age.

I. EPHELIS (freckle) - This is a small circumscribed pigmented macule which occurs mainly in fair skinned
persons and tends to darken in summer and fade in winter. Often multiple, they result from increased
melanocyte activity at the dermal-epidermal junction rather than an increase in the number of melanocytes.
II. LENTIGO ("liver spot") - This is a pigmented macule or patch occurring in the middle-aged and elderly,
and pigmentation does not vary with the season. These result from increased numbers and activity of
melanocytes within elongated rete ridges.
III. PIGMENTED NEVI - At birth, almost all individuals (99%) are devoid of pigmented nevi. They appear
and increase in number in relation to increased sun exposure and acute sunburn so that by the age of 10,
approximately 66% of individuals have developed pigmented nevi. By the age of 80, however, most
pigmented nevi have spontaneously disappeared. Nevi consist of nevus cells which resemble melanocytes
except that they occur in clusters and they do not have the dendritic processes of normal melanocytes. The
life cycle of a nevus begins with nests of nevus cells proliferating at the dermal-epidermal junction
(junctional nevus). These usually appear in childhood and in pregnant women (melanocytes have estrogen
and progesterone receptors), are flat, may be irregular in color, and may have an irregular border. The
nevus cells then grow into the underlying dermis to produce a more homogeneously colored, elevated,
dome-shaped compound nevus. With time, junctional activity disappears leaving behind a softer, fleshier
intradermal nevus which eventually disappears. All growth occurs from cellular activity at the dermal-
epidermal junction.

A. CONGENITAL PIGMENTED NEVUS - This can be defined as a nevus appearing within two weeks of
birth or a nevus greater than 5 cm. in diameter. They may occur on non-sun exposed skin and are
usually solitary. Although they vary in size, the risk of malignant melanoma is increased only in
those larger that 20 cm in size. The histology may vary, but nevus cells tend to be located in the
mid to deep dermis (with a nevus free zone in the upper dermis) and in the subcutaneous fat
suggesting that these lesions may arise from arrested migration of melanocytes to the epidermis.
B. BLUE NEVUS - This is a well circumscribed, firm nodule of uniform blue-grey color (due to the
presence of pigmented nevus cells in the deep dermis) that should not be mistaken for malignant
melanoma.
C. DYSPLASTIC NEVUS - Clinically, these nevi tend to be large (0.5-1.5 cm) with an irregular border
and irregular pigmentation. They often arise in non-sun exposed skin. Histologically, the nests of
nevus cells are not distinct, merge from one rete ridge to the next, and are irregular in size and

240
 shape. There is cytologic atypia and an eosinophilic alteration of the collagen at the dermal-
epidermal junction. The dysplastic nevus syndrome is a familial disorder in which these nevi
appear in large numbers (>40) on both exposed and non-exposed skin. Unlike persons with a
solitary dysplatic nevus, these patients are at high risk for developing malignant melanoma.
D. SPITZ NEVUS - Originally confused with melanoma, this is a special type of compound nevus.
Clinically these are red, yellow or brown nodules that do not appear malignant and occur mostly
in children. Although certain features of malignancy are present, the lesion is benign and the
diagnosis can usually be made histologically.

IV. MALIGNANT MELANOMA - Associated with a history of severe acute sunburn during childhood, these
tumors rarely appear before puberty. All melanomas originate at the dermal-epidermal junction and are
comprised of loose nests of large abnormal melanocytes which have irregular nuclear outlines often
enclosing a large eosinophilic nucleolus. The tumor may then grow laterally along the dermal-epidermal
junction (radial growth) and/or invade into the deeper dermis (vertical growth). Worrisome clinical features
include asymmetry with irregular borders, variegated coloration (tan, black, red, blue, brown), large
diameter, elevation from surrounding skin, and a family history. The prognosis for all melanomas is related
to the depth of invasion (the deeper the invasion, the poorer the prognosis). Those that penetrate less than
1. 7 mm into the dermis have an excellent prognosis. It is therefore extremely important to recognize these
lesions early in their evolution.

A LENTIGO MALIGNA MELANOMA (5%) - This lesion arises from a preexisting lentigo maligna
(Hutchinson'S freckle) which is a slowly enlarging unevenly pigmented macular lesion with
irregular borders that usually occurs on the face of elderly persons. About 30% of lentigo malignas
undergo malignant transformation. These melanomas spread laterally through the lower epidermis
and upper dermis and only late in its course develops vertical growth into the deeper dermis. The
onset of malignancy is heralded by increasing irregularity of pigment and the development of
nodularity. This type of melanoma has an exceedingly low rate of metastasis.
B. SUPERFICIAL SPREADING MELANOMA (70%) - This is the more common form of melanoma and
clinically appears similar to a dysplastic nevus. It usually develops on the trunk. Arcuate borders
and variegated color, with shades of pink, are typicaL It has a long radial growth phase but also
grows upward to give the epidermis a "buckshot" appearance histologically. After six months to
two years, it too will develop a downward growth.
C. NODULAR MELANOMA (15%) - This has, from its inception, downward growth as well as radial
growth. The histologic appearance of the malignant cells is variable (round cells, spindle cells, etc)
but loss of cohesion is a common feature. Clinically, this produces a nodular lesion which may
ulcerate. Widespread metastases occur fairly early, and the prognosis is correspondingly grim.
D. ACRAL LENTIGINOUS MELANOMA (10%) - This arises on the hands and feet around the nails or
on the palms and soles. These also have a long radial growth phase but ultimately develop
downward growth somewhat earlier than the lentigo maligna melanomas. Diagnosis may be
delayed because the pigmented nature of the lesion may be obscured by the thick stratum corneum
in these locations.

LYMPHOMAS AND PSEUDOLYMPHOMAS

I. T-CELL LYMPHOMAS - These tend to be epidermotropic with infiltrative involvement of the epidermis
and upper dermis.

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 A. MYCOSIS FUNGOIDES - This is the second most common lymphoma (next to Hodgkin's
lymphoma). The clinical presentation varies but early lesions may present as eczematoid patches
that do not respond to topical treatment. These may progress to slightly indurated, well-
circumscribed, purplish-blue plaques and ultimately fimgating nodules. Early in the disease, lesions
resemble an interface dermatitis with edema of the lower epidermis and hydropic degeneration of
the basal layer. The diagnostic feature, however, is the presence of an upper dermal infiltrate of
atypical monomorphous T -lymphocytes that invade the epidermis to lie in epidermal "lacunae"
(Pautrier's microabscess). These cells (mycosis cells) have characteristic hyperchromatic,
pleomorphic, and convoluted (cerebriform) nuclei. Later in the disease process, there is diffuse
infiltration into the epidermis with necrosis and ulceration. An annular form can resemble
dermatophytosis while others may resemble urticaria or erythema multiforme. An erythrodermic
variant with generalized cutaneous involvement is associated with the presence of mycosis cells
in the circulating blood (Sezary syndrome). The lesions are often asymptomatic and since they can
be mistaken for other skin disorders, they tend to be diagnosed at a later stage. Early, antecedent
lesions to full-blown mycosis fungoides include:

1. INTERFACE PARAPSORIASIS This produces, on non-exposed surfaces, vague

-
hyperpigmented and/or scaly patches which resemble chronic eczematous conditions.
Histologically, these show an interface dermatitis with hydropic change at the
dermal/epidermal junction but no atypical lymphocytes or microabscesses.
2. ACTINIC RETICULOID - This presents as chronic erythema of sun-exposed surfaces and
resembles sun damage.

B. HTLV-l LYMPHOMA (ADULT T-CELL LYMPHOMA) - This may appear as spontaneous skin tumors,
but microscopically the infiltrate is more dense and more pleomorphic than in mycosis fungoides.
Patients also tend to have high calcium levels.

II. B-CELL LYMPHOMAS - These are not epidermotropic but tend to be more angiocentric. They involve
the full thickness of the skin rather than the epidermis and upper dermis. They consist of monomorphic
cells which appear normal but distort easily.
III. PSEUDOLYMPHOMAS - These are lesions that are histologically malignant but clinically benign in their
behavior.

A. LYMPHOMATOID PAPULOSIS - This consists of large pox-like lesions that histologically closely
resembles malignant lymphoma.
B. PITYRIASIS LICHENOIDES - This produces necrotic pox-like lesions that may clinically resemble
severe pityriasis rosea. Unlike pityriasis rosea, however, chronic lesions may last for months. This
is probably due to a retrovirus infection.

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 BONE AND JOINT

BONE

I. CONGENITAL/DEVELOPMENTAL DISEASE

A. OSTEOGENESISIMPERFECfA ("brittle bone disease") - This consists of a group of disorders which

have in common an inherited disorder which interferes with the synthesis of Type I collagen.
Patients develop recurrent bone fractures, hearing impairment or deafuess (due to fracture of
middle ear ossicles), and lax joints resulting in joint dislocation. It is also associated with blue
sclerae, sunken chest (pes cavus), kyphoscoliosis, and blue-yellow abnormally formed teeth
(dentinogensis imperfecta).
B. ACHONDROPLASIA (classic "dwarfism") - This is an autosomal dominant inherited disease in which
there is impaired proliferation of cartilage in the bony epiphyses which results in decreased growth
of long bones. The trunk is of normal size, but the head is enlarged and the extremities are
shortened.
C. OSTEOPETROSIS ("marble bone disease'~ - This is a group of rare inherited diseases characterized
by osteoclast dysfunction. In general, there is diffuse sclerosis of the bone with obliteration of the
marrow cavity, bone deformity. Surprisingly the bone is fragile and easily broken.

II. INFECTIOUS / INFLAMMATORY DISEASE

A. ACUTE OSTEOMYELITIS - This is most frequently seen in children secondary to transient

bacteremia with Staphylococcus aureus. A suppurative inflammatory response is accompanied by
intense edema resulting in ischemic necrosis of bone (sequestrum).
B. TUBERCULOUS OSTEOMYELITIS - This occurs in about 1% of patients with TB and may not be
noted until extensive bone destruction has occurred. Involvement of the spine is known as Pott's
disease.

III. METABOLIC BONE DISEASE

A. OSTEOPOROSIS (osteopenia) - This refers to an absolute decrease in bone mass below the level
necessary to maintain sufficient body support.

1. PRIMARY OSTEOPOROSIS - This is the most common type of metabolic bone disease but
the exact etiology is unknown. The incidence increases with age, and it is predominately
a disease of post-menopausal females resulting in fractures, usually of the femoral neck.

243
 2. SECONDARY OSTEOPOROSIS - This is usually due to malnutrition, endocrinopathies, or
prolonged immobilization.

B. RICKETS and OSTEOMALACIA - These are both caused by vitamin D deficiency which, in tum, may
be caused by dietary inadequacy, lack of exposure to sunshine, intestinal malabsorption, or chronic
renal disease. Bone changes are characterized primarily by inadequate mineralization of bone
matrix. Although the density of the bone is decreased, there is no initial decrease in bone mass.
Rickets occurs in children and is characterized clinically by pigeon-breast deformity, rachitic rosary
at costochondral junctions, lumbar lordosis, and bowed legs. Osteomalacia is the adult counterpart
and changes similar to those seen in rickets may occur but more common manifestations are
deformities of weight-bearing bones and incomplete pathologic fractures.

IV. NEOPLASIA

A. BONE-FORMING (OSTEOBLASTIC) TUMORS

1. OSTEOMA - This is a benign tumor usually found in the skull and composed of dense
normal bone.
2. OSTEOID OSTEOMA - This is a benign but painful tumor of young adults which usually
arise in the femur and tibia.
3. OSTEOGENIC SARCOMA (osteosarcoma) - This is a malignant neoplasm usually affecting
young people ages 10 to 25. The femur, tibia and humerus are common sites with about
75% occurring around the knee. Pain is usually an early feature and is accompanied by
rapidly increasing bone mass. Metastasis to lungs are frequently found at the time of
diagnosis.

B. CARTILAGE-FORMING (CHONDROGENIC) TUMORS

1. EXOSTOSIS - This is a benign neoplasm which protrudes from metaphyseal surface of long
bones (usually the lower femur or upper tibia). As an isolated lesion it has little
significance, but an inherited condition known as "hereditary multiple cartilaginous
exostosis" is associated with numerous exostoses that possess a definite potential for
malignant transformation.
2. ENCHONDROMA - This is a benign tumor that occurs deep within cancellous bone
(particularly small bones of hands and feet) of young adults. It may be erosive and cause
pain, swelling or pathologic fractures.
3. CHONDROSARCOMA - This is a malignant tumor which usually involves the pelvic bones,
vertebrae, and ribs. It occurs at an older age than osteosarcomas but the growth is much
slower and prognosis much better than osteosarcoma.

C. EWING'S SARCOMA - This is a rare but extremely malignant tumor of childhood that arises within
the bone marrow cavity. The cell of origin is uncertain. Early, widespread metastasis is common
and prognosis is generally poor.
D. METASTATIC CANCER - Bone is a common site of disseminated cancer. Common primary cancers
which tend to involve bone include breast carcinoma, lung carcinoma, prostatic carcinoma, renal
carcinoma, multiple myeloma, and malignant lymphoma.

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 JOINTS AND RELATED STRUCTURES

I. INFECTIVE (PYOGENIC) ARTHRITIS - This usually represents hematogenous dissemination from

a distant focus of infection. It is usually monoarticular and involves one of the larger joints (hip, knee,
ankle, shoulder, elbow, wrist). Clinical manifestations include redness, swelling, pain and tenderness of the
involved joint. If not effectively treated, it may become chronic and destructive.
II. OSTEOARTHRITIS (degenerative joint disease) - This is the most common disease of joints and is a
degenerative rather than an inflammatory disorder. Primary osteoarthritis is associated with aging while
secondary osteoarthritis may occur in young persons who have sustained injury through trauma or
infections to the joint. The common pathologic change is degeneration of articular cartilage. The joints most
commonly affected are the weight-bearing joints and the distal interphalangeal joints. Clinically, there is
slowly progressive joint stiffuess. Spur formation in distal interphalangeal joints of fingers produces nodular
swellings called "Heberden IS nodes" which are more common in females. Involvement of spine may cause
compression of nerve roots with radicular pain, spasms, and atrophy of skeletal muscle. Bony spurs may
project from the margins of the joint space limiting motion and causing pain. Bone spurs or fragments of
articular cartilage may break off to form free intra-articular foreign bodies (''joint mice").
III. RHEUMA TOlD ARTHRITIS - This is an idiopathic, chronic, systemic inflammatory disease which
may affect skin, skeletal muscle, bone, eyes, heart, blood vessels, lungs and other organs. It represents an
autoimmune disorder. The classic feature is a progressively deforming arthritis which usually affects
multiple joints. Classic rheumatoid arthritis begins with fatigue, malaise and low-grade fever before onset
ofjoint symptoms which, when it develops, is most apparent in the morning upon waking. The joints (most
frequently the proximal interphalangeal and metacarpophalangeal joints) are usually symmetrically affected
and may be enlarged, painful, and reddened. As the disease progresses and becomes chronic, there is
progressive joint deformity leading to permanent and disabling ankylosis. The hands may assume a "claw-
like" appearance with characteristic ulnar deviation. Early, the joints show an acute but nonspecific
inflammation. With progression, there is replacement of the synovial lining by a highly vascularized,
polypoid mass of inflammatory tissue (pannus formation). Advanced lesions show erosion of the entire
articular surface with obliteration of the joint space followed by fibrous adhesions or bony ankylosis
between opposing joint surfaces. A rheumatoid factor (RF) is found in nearly all patients with classic
disease. RF is an anti-IgG antibody which reacts with IgG to form immune complexes.
IV. GOUTY ARTHRITIS - This may appear in anyone with elevated blood uric acid levels. Gouty arthritis
is characterized by transient but recurrent attacks of acute arthritis due to precipitation of monosodium
urate crystals in the synovial spaces which may accumulate to form tophi. Most cases of gout are due to
a genetic disorder of metabolism and are seen predominately in adult males. Secondary gout may be due
to renal disease or excessive turnover of cells as may be seen with malignancies.

245
 NEUROMUSCULAR SYSTEM

CELLULAR COMPONENTS AND REACTION TO INJURY

I. NEURONS - Theses are the functional units of the nervous system and populate both the central nervous
system (CNS) and the peripheral nervous system (PNS). They consist of a cell body, afferent dendritic
processes, and the efferent axon which in most instances is surrounded by a myelin sheath. ill the CNS,
myelin is formed by the oligodendroglia, and in the PNS, the myelin is formed by Schwann cells. Neuronal
reaction to injury may include:

A. CENTRAL CHROMATOLYSIS - This is a reversible reaction resulting from axonal damage. The cell
body becomes swollen and rounded with dissolution of the central Nissl bodies and peripheral
displacement of the nucleus. The closer the axonal damage to the cell body, the more rapid and
severe the central chromatolysis.
B. SIMPLE CHROMATOLYSIS - This is a reversible reaction that involves dissolution of all Nissl
substance. The nucleus retains central location but ghost cells or shadow cells result.
C. ACUTE ISCHEMIC NECROSIS - This is an irreversible reaction resulting from hypoxic damage. The
cell body becomes swollen with an eosinophilic alteration of cytoplasm (red neuron), the nucleolus
is lost, and the nucleus becomes pyknotic. The neuron will eventually dissolve and drop out. The
morphologic changes first appear 5-6 hours after the hypoxic insult and the hippocampal, Purkinje,
and cortical neurons are most susceptible (see section on anoxic/hypoxic encephalopathy).
D. WALLERIAN DEGENERATION - This is the pathologic change in nerve fibers occurring distal to the
site of a focal destructive lesion of the axon. The initial axonal changes are the accumulation of
organelles in the proximal and distal axonal stumps with subsequent fragmentation of the distal
axoplasm. Schwann cell changes consist of initial retraction of paranodal myelin with subsequent
fragmentation of myelin sheaths. Schwann cells proliferate and regeneration may occur by
axoplasmic sprouting from the proximal axonal stump. If regeneration fails, Schwann cells atrophy
and are replaced by fibrous tissue. Regenerated axons may be remyelinated.
E. AXONAL DYSTROPHY (dying-back neuropathy or axonal degeneration) - This is a more gradual
process thought to occur in a variety of nerve diseases (such as inherited, toxic, metabolic diseases,
etc.). There may be selective involvement of certain fiber populations and certain organelles. The
distal or even terminal parts of axon are affected more severely, and it may be accompanied by
secondary segmental demyelination.
F. AXONAL ATROPHY - This is a term used to describe changes encountered in chronic, progressive
neuropathies, many of which are hereditary. It may simply represent a more chronic form of axonal
dystrophy.

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 G. SEGMENTAL DEMYELINATION - This is produced by disorders primarily damaging Schwann cells
and/or myelin sheaths. The demyelination is segmental with myelin degeneration tending to involve
individual myelin intemodes with relative preservation of axonal integrity. Involved Schwann cells
may survive myelin degeneration or adjacent, less involved Schwann cells may proliferate. Neurons
of the PNS may remyelinate but those of the CNS will not. Remyelinated internodes are abnormally
short (intercalated segments) and have abnormally thin myelin.
H. SECONDARY SEGMENTAL DEMYELINATION - Disorders formerly considered as "classic" examples
of segmental demyelination have now been found to be accompanied by significant axonal
alterations. It may be preceded or accompanied by axonal dystrophy or atrophy. The integrity of
the myelin sheath is dependent on the integrity of the axon but the reverse is not necessarily true.
I. "ONION BULBS" - These are concentric lamellae of Schwann cell processes around a nerve fiber.
It is a non-specific response to repeated episodes of segmental demyelination and remyelination.
J. BANDS OF BUNGNER - These represent stacks of Schwann cell processes within a common
basement membrane and reflect complete degeneration ofaxons.

II. ASTROCYTES - These cells are of neuroectodermal origin and are found in two major forms.
Protoplasmic astrocytes are found primarily in the gray matter and have numerous thick branching
processes. Fibrillary astrocytes have fewer thinner processes, show less branching, and contain glial fibrils
that are not present in protoplasmic astrocytes. All astrocytes have processes which abut on blood vessels
(vascular footplate) to form a perivascular glial membrane. This vaso-astral network acts as an interstitial
framework for the CNS. Astrocytic reaction to injury includes:

A. ASTROCYTOSIS (cellular gliosis) - Four to five days after injury, astrocytes undergo hyperplasia and
hypertrophy developing an eosinophilic cytoplasm with eccentric nuclei (gemistocyte).
Protoplasmic astrocytes develop glial fibers to become fibrillary astrocytes. The astrocytes act as
scar tissue by replacing damaged tissue with fibrillary processes. Eventually the cells are crowded
out leaving a fibrillary gliosis or glial scar.
B. CLASMATODENDROSIS - Fragmentation and loss of cell processes with disintegration of the cell
body occurs with severe injury and represents death of astrocytes.
C. ALZHEIMER TYPE II ASTROCYTES - This is a specific reaction of protoplasmic astrocytes seen in
liver disease. Enlarged, pale nuclei are present in an otherwise normal cytoplasm.
D. CORPORAAMYLACEA (brain sand) - These are basophilic laminated structures which form in the
terminal processes of astrocytes. They are seen with advancing age and are found predominately
around vessels and in subpial and subependymal areas.
E. ROSENTHAL FIBERS - These are elongated, dense, tapering bodies associated with long standing
gliosis.

III. OLIGODENDROGLIA - Of neuroectodermal origin, these are small, dark cells with relatively few, short,
thin processes. They are most numerous in the white matter where they line up in an interfascicular
arrangement and form myelin sheaths around nerve fibers early in fetal life. They are necessary to maintain
the integrity of existing myelin but, unlike Schwann cells, will not replace destroyed myelin. They are also
present in gray matter where they serve (along with microglia) as satellite cells to neurons. Their reaction
to injury basically involves cellular swelling with the formation of a perinuclear halo.
IV. EPENDYMA - Also of neuroectodermal origin, these are specialized ciliated glial cells which line the
ventricular cavities and central canal of spinal cord. Cilia arise from intracytoplasmic structures called
blepharoplasts. Irritation of the ventricular cavity may result in local proliferation of the sub ependymal glial
tissue which may protrude into the lumen (ependymal granulation) to cause granular ependymitis. This
usually is not significant unless it obstructs the CSF pathway (aqueductal or foraminal gliosis).

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V. MICROGLIA - Of mesodermal origin, these are small elongated cells with numerous processes which
function as CNS reticuloendothelial cells. In the gray matter they also serve, along with oligodendroglia
as satellite cells to neurons. Within a few days after CNS injury, microglia increase in number. The cell
body becomes bulkier as the cytoplasmic processes are drawn back into the cell. They become mobile with
phagocytic properties and become known as compound granule or gitter cells. They act as macrophages
and phagocytize myelin and tissue debris, migrate to and accumulate around blood vessels, and are
eventually bome off in the circulation. Injury to cortical neurons may evoke a focal increase in satellite cells
(satellitosis). If the neuron dies, microglial cells phagocytize the necrotic neuron in the process of
neuronophagia.

MALFORMATIONS OF THE CENTRAL NERVOUS SYSTEM

Central nervous system malformations are, by far, the most frequent cause of mental retardation (61 %). Other
mechanisms include destructive processes (25%), metabolic and degenerative disorders (5%), and neoplastic
disease (2%). Malformations may be due to genetic causes (25%) where the etiology is heterogeneous
(chromosomal or major gene defects playa role only in rare cases); early prenatal abnormality (18%); prenatal
infection (8%); perinatal damage (17%); or postnatal infection (6%).

I. DEFINITIONS

A. FIELD DEFECT - A morphogenetic field is a region or part of an embryo which responds as a

coordinated unit to embryonic interaction and results in complex or multiple anatomic structures.
Most malformations are field defects.
B. MALFORMATION - This is a morphologic defect of an organ, part of an organ, or a larger region
of the body resulting from an intrinsically abnormal developmental process.
C. DISRUPTION - This is a morphologic defect resulting from interference with normal development.
D. DEFORMATION - This is an abnormal form or shape caused by mechanical forces.
E. DYSPLASIA - This refers to abnormal organization of cells into tissues.

II. NEURAL TUBE ANOMALIES (DYSRAPHIC DISORDERS) - These constitute the most common
group of fatal malformations in some parts of the world. Risk factors include geography, month of
conception, epidemic trends, matemal age, birth order, socioeconomic group, maternal diet, drug exposure,
and maternal illnesses such as diabetes. Major anomalies include:

A. ANENCEPHALY - This is a lethal anomaly. Commonly associated with polyhydramnios, the defect
may involve all or a portion of the spine as craniorachischisis. The pituitary is often abnormal.
Associated malformations include cleft lip and palate, cyclopia, syndactyly, and renal and cardiac
anomalies. Inheritance is multifactorial with a recurrence risk of3-5%.
B. MENINGOCELE - This is a herniation of dura and arachnoid through a vertebral defect. Spina
b~fida or spinal dysraphism refer to midline defects of the osseous spine.
C. MENINGOMYELOCELE - This is a herniation of both meninges and spinal cord through a large
vertebral defect. Hydrocephalus is common in the form of the Arnold-Chiari malformation.
D. ARNOLD-CHIARI MALFORMATION - This is the brain malformation of meningomyelocele. Four
types were originally described; only type I (cerebellar tonsillar herniation in the adult) and type
II are of significance now. Type II is the Amold-Chiari malformation as now defined. It has two
major components: 1) an elongated unrolled vermis displaced downward through the foramen

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 magnum and 2) an elongated medulla kinked and extending downward through the foramen
magnum. Other numerous anomalies may exist, e.g. small posterior fossa.

III. TRISOMY 21 SYNDROME (DOWN'S SYNDROME) - This is the most common cause of mental
retardation (MR) in the u.s. Down's syndrome occurs in 1/600-2000 live births and accounts for 15% of
institutionalized patients. 95% result from nondisjunction and is maternal age-related.

A. CLINICAL FEATURES - These include hypotonia, poor Moro reflex, hyperextensibility of joints,
loose skin of posterior neck, flat facial profile, upslanting palpebral fissures, short ears, dysplastic
pelvis, clinodactyly of the fifth finger, and simian creases. Four or more of these features occur in
all cases; 6 or more in 90%.
B. ASSOCIATED ANOMALIES - These include cardiovascular (atrioventricularis communis, VSD,
PDA, ASD, and aberrant subclavian artery); gastrointestinal (TE fistula, pyloric stenosis, duodenal
atresia, annular pancreas, Hirschsprung's disease, imperforate anus; and neuromuscular (growth
delay, microcephaly, and Alzheimer's disease in older patients).

IV. HYDROCEPHALY AND HYDROCEPHALUS - Hydrocephaly is the preferred term for the condition
in general and is defined as an abnormal accumulation offluid in the cranium associated with enlargement
of the cranium, prominence of the forehead, thinning of the bones of the cranial vault, enlargement of
sutures and fontanels, and craniofacial disproportion. Hydrocephalus describes the head of the affected
individual.

A. OBSTRETRICHYDROCEPHALY - This develops in utero and is present in 2.5/1000 live births. 10%
are associated with polyhydramnios and approximately one third of the infants have a breech
presentation. 69% are stillborn and an additional 27% die in the neonatal period. Only 3% ever
leave the hospital. Although the procedure of intrauterine shunting has improved the statistics
somewhat, the overall prognosis remains poor.
B. INFANTILE AND CHILDHOOD HYDROCEPHALY - These children are born without difficulty, and
hydrocephalus is then detected sometime after birth, up to age 20 years. In early infancy, 81 % are
associated with myelomeningocele. Later, 7% develop perinatal hemorrhage or meningitis, 3% are
associated with other neurologic disorders, 0.3% with tumor, and 9% are uncomplicated.
C. GENE DETERMINED HYDROCEPHALY - 2% of hydrocephaly is sex-linked recessive in inheritance.
The chromosomal abnormality is uncommon. The type of pathology varies: 44% aqueductal
stenosis, 40% communicating hydrocephalus, 13% Dandy-Walker syndrome, 7% other.
D. DANDY-WALKER MALFORMATION - This includes hydrocephalus, a cyst-like enlargement of the
fourth ventricle and enlargement of the posterior fossa with elevated transverse sinuses and
tentorium. In some, there is a lack of patency of the foraminal outlets. There is poor outlook for
developing normal IQ. The empiric recurrence rate is 1-5%.

V. ANOMALIES OF ABNORMAL MIGRATION OF NEURONS

A. LISSENCEPHALY - This includes a smooth brain (pachygyria) with a 4-layered cortex. It can result
from many conditions including chromosomal abnormalities.
B. POLYMICROGYRIA - This includes an increased number of gyri, some of which will be small and
separated by shallow sulci; often 4 layers of cortex. The pathogenesis may be a disturbance of cell
migration in terms of spatial arrangement and timing, or a postmigratory selective destruction of
specific layers. There may be "polymicrogyria of the cerebellum", hyperconvoluted dentate
nucleus, and hypoplastic corticospinal tract.

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VI. HYDRANENCEPHALY - This is a severe brain anomaly characterized by absence of cerebral
hemispheres in the presence of intact meninges and a normal skull. There is prenatal destruction of the
brain, probably on an ischemic basis. In most cases the etiology is unknown, but in the past it has been
associated with toxoplasmosis, fungal infection, viruses and maternal trauma.
VII. HOLOPROSENCEPHAL Y - This is a complex malformation with impairment of midline cleavage of
the embryonic forebrain associated with various gradations of facial dysmorphic features. It occurs in
1116,000 live births, with a 3:1 female predominance. The etiology is heterogeneous: numerous
chromosomal anomalies are associated (commonly trisomy 13). It has also been reported as autosomal
recessive, rare autosomal dominant, and occasionally as sex-linked recessive (Kallmann's syndrome). The
degree of retardation is dependent upon severity of the brain anomaly. There are also many associated
malformations.
VIII. ENCEPHALOCELE - This is a herniation of cerebral tissue: common sites include occipital region,
parietal, frontal and basal.

A. OCCIPITAL ENCEPHALOCELES (75% of encephaloceles) - These have an incidence of 112000-5000

live births with female preponderance. The size of the bony defect and amount of cerebral tissue
involved is variable. They may be asymptomatic or present as hydrocephalus, with ocular palsies,
blindness, etc. 44% are retarded. Associated malformations are common, e.g., syndactyly, lung
anomalies, omphalocele, endocrine abnormalities.
B. PARIETAL ENCEPHALOCELES (l 0-14%) - These involve the interparietal midline and associated
malformations include absent corpus callosum and Dandy-Walker malformation. 50% show mild
to severe retardation.
C. ANTERIOR SINCIPITAL AND BASAL ENCEPHALOCELES (uncommon) - occur in 1135,000 live births.
Sincipital encephaloceles are visible while basal encephaloceles are not visible. Symptoms include
hypertelorism, exophthalmus, 6th nerve palsy, syndactyly, and optic nerve anomalies in the basal
forms.

IX. PORENCEPHALY - This is a collective term for cavities within the cerebral hemispheres. Many cases
are detected in adults as incidental findings. The presence of retardation is associated with the presence of
other brain anomalies. The etiology is commonly unknown. Symptoms include spasticity, seizures and
major neurologic deficits such as retardation. Associated malformations include microcephaly, agenesis
of olfactory lobes, congenital cataracts, bifid uvula, and malformed ears.
X. AGENESIS OF THE CORPUS CALLOSUM - This is an absence or partial absence of the corpus
callosum. The etiology is unknown: some are familial, some are rarely recessive or sex-linked inheritance.
It may be found in syndromes associated with chromosomal abnormalities. Many are diagnosed in
childhood because of life threatening associated cerebral anomalies. Associated anomalies include
anencephaly, holoprosencephaly, microcephaly, cleft lip and palate.

NONSPECIFIC CNS REACTION TO INJURY

I. INCREASED INTRACRANIAL PRESSURE (CSF pressure> 200 mm H2 0) - This occurs when CNS
volume exceeds physical capacity for expansion. This may be the result of local or generalized mass effect
resulting from tumor, abscess, edema, etc. It may be clinically manifested as intermittent headache, mental
slowness, confusion, and papilledema. Complications include:

A. LATERAL HERNIATION - This is reflected as either hippocampal (uncal) herniation (hippocampal

gyrus forced under tentorium cerebelli), contralateral cerebral peduncle laceration caused by edge

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 of tentorium (Kernohan's notch), and cingulate (subfalcial) herniation (cingulate gyrus forced
under falx cerebri).
B. OUTWARD HERNIATION - Transcalvarial herniation is where the brain herniates through a calvarial
defect - usually traumatically induced.
C. DOWNWARD HERNIATION - This involves tonsillar and medullary herniation through the foramen
magnum.
D. INFARCTION - This results from herniations which compress and occlude vessels. Most frequently
there is compression of the posterior cerebral artery against the tentorium cerebelli and the anterior
cerebral artery against the falx cerebri.
E. SECONDARY BRAIN STEM HEMORRHAGE - This may be associated with rapidly expending
supratentorial lesions.

II. CEREBRAL EDEMA - Edema may be local or generalized and cause increased intracranial pressure with
its resultant complications. It can be classified as cytotoxic (fluid accumulation within cells usually
secondary to metabolic disturbance), vasogenic (extracellular fluid accumulation due to damaged capillary
endothelial cells), or interstitial (fluid accumulation in periventricular white matter secondary to increased
passage of CSF across ventricular walls).
III. HYDROCEPHALY - This refers to increased CSF volume causing ventricular distention. CSF is
produced by choroid plexus and reabsorbed primarily by the arachnoid villi granulations. Increased CSF
volume may be result of overproduction of CSF, inability of arachnoid villi to transfer CSF to venous
drainage, or blockage of CSF pathways. A non-communicating (obstructive) hydrocephalus results if
blockage occurs within the brain and a communicating hydrocephalus if blockage occurs in subarachnoid
space. Ifhydrocephalus occurs before cranial sutures close, there is resultant enlargement of head. After
cranial sutures are closed, acute hydrocephalus will cause symptoms related to increased intracranial
pressure and is often associated with trauma, infections, subarachnoid hemorrhage or tumors. Slowly
progressive hydrocephalus, however, may not show elevated CSF pressures (normal pressure
hydrocephalus) and may be clinically manifested by progressive dementia, gait disturbances, and
incontinence. As ventricles dilate, the ependyma becomes flattened and disrupted and interstitial edema
may ensue with injury to surrounding white matter. Hydrocephalus ex vacuo refers to compensatory
ventricular dilation secondary to brain atrophy.

TRAUMATIC INJURY

With even a minor blow to the head, pressure waves are transmitted through the brain parenchyma and may cause
submicroscopic splits in individual axons. If the head is put into motion by the force of the impact, the skull
accelerates and decelerates faster than the brain resulting in impact lesions on the parenchyma and stretching and
injUty to the vessels which traverse the space between the brain and skull on both the ipsilateral and contralateral
surfaces. The ipsilateral lesion resulting at the primary impact site is the "coup" lesion while the contralateral lesion,
which is often larger, is the "contrecoup" lesion.

I. CONCUSSION - This is a clinical diagnosis characterized by transient loss of consciousness with

retrograde and anterograde amnesia. There is little, if any, damage to the CNS and no residual sequelae.
II. EPIDURAL HEMATOMA - This refers to bleeding between the skull and dura mater. It appears as dark
red gelatinous blood clot which adheres to the dura. Although atypically it may be of venous origin, most
frequently epidural hematomas result from tearing of the middle meningeal artery and are located over
the temporal areas. Clinical course is characterized by transient loss of consciousness with a subsequent

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 lucid interval followed, within 24 hours, by coma and signs of increased intracranial pressure. Unless
surgically drained, they tend to expand rapidly in volume with ensuing brain herniation and death.
III. SUBDURAL HEMATOMA - This refers to a collection of blood in the potential space between the dura
and leptomeninges. These usually result from rupture of bridging veins that cross this space and are most
often located over the convexities (15% bilateral). They are usually associated with blunt trauma without
an overlying skull fracture.

A. ACUTE - These are usually associated with underlying parenchymal damage and become clinically
manifested by fluctuating levels of consciousness within a few days after the trauma. The CSF may
be clear, bloody or xanthochromic depending on associated injuries.
B. CHRONIC - These become clinically apparent weeks or months after often otherwise insignificant
head trauma and are manifested by slowly developing confusion and inattention which may lead
to coma. As organization occurs around the periphery, both a visceral and parietal (usually thicker)
membrane develop. Unless drained, the hematoma may slowly expand resulting in herniation
and/or brain stem hemorrhage. The CSF is usually xanthochromic with increased protein content.

IV. CONTUSION - This refers to superficial areas of hemorrhagic necrosis of the cortex resulting from
crushing ofCNS tissue by blunt force. It is most often seen on the inferior surface of the frontal lobes, the
anterior tip of the temporal lobes, and the occipital poles. Initial foci of hemorrhagic necrosis are replaced
by glial scar to form irregular yellowish-brown depressed areas. These may act as foci of seizure activity
(particularly temporal lobes).
V. SUBARACHNOID HEMORRHAGE - Trauma is most common cause of subarachnoid hemorrhage and
results from rupture of corti co meningeal vessels. There is usually an associated contusion.

VASCULAR DISEASE

I. HYPOXIC ENCEPHALOPATHY - This can be produced by any process that reduces effective
oxygenation of the brain. To ensure adequate oxygenation, the cerebral circulation is regulated by various
metabolic and reflex homeostatic mechanisms to maintain adequate perfusion in the face of systemic
hypotension. Pre-existing vascular disease (atherosclerotic, hypertensive, etc.) or profound hypotension,
however, may overcome these mechanisms. Neurologic change depends on the extent and duration of
hypoxia and the length of survival after the insult. The first changes are seen 6-12 hours after the insult in
the hippocampal neurons and cerebellar purkinje cells which develop acute ischemic necrosis. Cortical
neurons may be haphazardly affected, but with extensive anoxia, laminar necrosis of the cortex may result.
II. INFARCTION - This results from loss of blood supply. Symptoms relating to cerebral infarcts depend
on the location and size of the infarct.

A. ETIOLOGY

1. VASCULAR THROMBOSIS - Thrombus formation within a vessel is usually associated with

underlying, pre-existing damage to the vessel wall (atherosclerosis, vasculitis, etc) and
tends to occur within the larger vessels (internal carotid, vertebral, basilar) of older
individuals. Infarcts due to thrombosis are often heralded by transient ischemic attacks
(TIA) and tend to produce ischemic infarcts.
2. EMBOLI - Most emboli arise from thrombi within the left heart or carotid arteries, from
atheromatous material at the carotid bifurcation, or from vegetations attached to the mitral
or aortic valves. Emboli tend to be multiple and involve smaller vessels (middle cerebral,

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 etc). Infarcts due to emboli are usually characterized by the sudden onset of neurologic
deficit and tend to produce hemorrhagic infarcts due to dissolution of embolus and
reperfusion of the infarcted necrotic tissue.

B. LOCATION

1. MIDDLE CEREBRAL ARTERY DISTRIBUTION - This is the most common and usually due
to carotid thrombosis or thrombosis/-embolus of middle cerebral artery.
2. LACUNAR INFARCTS - These are small infarcts in the deep white matter due to occlusion
of the deep penetrating arteries and are often seen in association with hypertension.
3. BORDER ZONE INFARCTS - These are hypotensive infarcts occurring in regions between
major vessel distribution patterns.

C. GROSS APPEARANCE - Slight discoloration of the parenchyma appears within 6-12 hours followed
by disintegration of tissue and surrounding edema occurring between 2-3 days. Later, there is
liquefaction, cyst formation, and glial reaction around the periphery.
D. MICROSCOPIC APPEARANCE - Ischemic neuronal necrosis with myelin disintegration and loss of
astrocytes and oligodendroglia develops within 6-12 hours. After about two days, there is a mild-
moderate acute inflammatory infiltrate which is soon replaced by proliferating macro phages which
reach a peak at about two weeks. Glial fibrosis then ensues.

III. HEMORRHAGE (NON-TRAUMATIC) - Hemorrhages greater than 3.0 cm. diameter within the
cerebral hemispheres or greater than 1.5 cm. diameter within the brain stem and cerebellum are considered
massive hemorrhages. Although less common than infarcts, hemorrhages account for more deaths. With
cerebral hemorrhage, opening pressure ofthe CSF is usually increased. Bloody fluid is present in 75% but
it may be xanthochromic (10%) or clear (15%). Protein usually is increased and glucose is normal. In
subarachnoid hemorrhage, the opening pressure is elevated. Fluid is bloody in first 24 hours and then turns
xanthochromic. Protein is increased but less than with cerebral hemorrhage. Glucose is normal.

A. HYPERTENSIVE HEMORRHAGE - This is the most common cause of non-traumatic hemorrhage

(25%) and occurs most frequently in the basal ganglia. The exact mechanism is not known, but
theories include primary rupture of vessels whose walls have been previously damaged by chronic
hypertension, hemorrhage into lacunar infarcts, and rupture of hypertensive microaneurysms
(Charcot-Bouchard aneurysms). Unlike infarcts, hemorrhages are not confined to an arterial
distribution, and they tend to compress and disrupt the parenchyma rather than destroy it. The
surrounding tissue and ventricles are distorted and the hemorrhage may rupture into the ventricular
system or, less often, the subarachnoid space. Herniation may occur secondary to the expanding
mass and the associated cerebral edema. If the patient survives, resolution may occur with
surprisingly little parenchymal destruction.
B. ANEURYSMS - These account for about 15% of non-traumatic hemorrhages.

1. SACCULAR ("BERRY") ANEURYSMS - These are the most common and are present in
5-6% of the general population. Although some feel these arise from a congenital defect
in the internal elastic membrane, others feel they are developmental in origin. Most occur
in the middle cerebral artery and its branches although those of the anterior circulation
(anterior cerebral and anterior communicating) are more prone to rupture and cause
clinical symptoms. They arise at the bifurcation of vessels and are multiple in 25% of
cases. Complications (in order of clinical significance) include:

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 a. Rupture - Hemorrhage into the parenchyma, ventricles, and subarachnoid space
is the most lethal complication and occurs in about half of the ruptures while
subarachnoid hemorrhage alone occurs in 25%.
b. Infarction - Vascular spasms may occur resulting in parenchymal necrosis and are
most often seen in association with anterior cerebral aneurysms.
c. Mass effects - Large aneurysms (which are less prone to rupture due to laminated
mural thrombus within the aneurysm) may uncommonly cause space-occupying
problems (compression of third ventricle and hydrocephalus).

2. INFLAMMATORY (MYCOTIC) ANEURYSMS - These usually are seen in small, peripheral

vessels due to septic emboli where organisms invade vessel wall with subsequent dilatation
and bleeding.
3. ATHEROSCLEROTIC ANEURYSMS - These produce a fusiform dilatation usually involving
vertebral or basilar artery but occasionally involving internal carotid. They usually do not
rupture but may thrombose or, due to size, cause cranial nerve dysfunction.

IV. VASCULAR MALFORMATION - These are relatively common (5% of general population) and are the
result of incomplete and/or abnormal resolution of embryonic vasculature.

A. ARTERIOVENOUS MALFORMATIONS (12%) - These consist of a tangled admixture of veins,

arteries, and arterialized veins which are separated by gliotic parenchyma. They are usually located
in the cerebral hemispheres and may "grow" by incorporating adjacent vessels. They are the type
of malformation most likely to cause seizures, "steal" (diverting blood from arterial to venous side
resulting in poor perfusion of the intervening and surrounding parenchyma), and intracerebral
hemorrhage from rupture.
B. VENOUS MALFORMATIONS (67%) - These are the most common malformation but are usually
asymptomatic. They consist of loose aggregates of venous channels.
C. CAVERNOUS ANGIOMA (7%) - This is a compact aggregate of sinusoidal channels without
intervening parenchyma. They are often located at the surface of the brain and may act as
epileptogenic foci.
D. TELANGIECTASIS (11 %) - These are small aggregates of capillaries usually found at the base of the
pons and are usually asymptomatic.
E. VARICES (3%) - This refers to any abnormally dilated vein within the neural parenchyma and is
generally asymptomatic.

INFECTIOUS DISEASE

I. BACTERIAL

A. LEPTOMENINGITIS - This is most commonly caused by E. coli (neonates), H. influenza (infants and
young children), N. meningitidis (older children, adolescents, young adults), and Strep.
pneumoniae (adults, young children). Grossly, the meninges become congested and clouded.
Purulent exudates may be observed and microscopic exam shows acute inflammatory infiltrate.
CSF shows increased pressure, increased neutrophils, increased protein, and decreased glucose.
Common symptoms include agitation, irritability, headache, photophobia, stiff neck, and positive
Kernig's sign. Complications consist of adhesions which can constrict cranial nerves, obliterate the
subarachnoid space around the brainstem, or obstruct the foramina of Luschka and Magendie

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 resulting in hydrocephalus. Other complications include the development of an arteritis or phlebitis
which may cause obstructive thrombus formation leading to small cerebral infarcts,
intraparenchymal abscesses, and death.
B. INTRAPARENCHYMALABSCESS - Most abscesses have no definable source. Others will be related
to sinus infection, ear infection, mastoiditis, direct implantation, or hematogenous spread. When
an organism can be cultured, anaerobic strep is often found. Septic emboli often cause multiple
abscesses. Aggregation ofneutrophils and central liquefactive necrosis is associated with extensive
cerebral edema. Fibroblasts and astrocytes attempt to wall off the necrotic area and, as dead tissue
is removed, an abscess cavity evolves. Symptoms are related to the edema, increased intracranial
pressure, and area of involvement. Without surgical drainage, abscesses tend to expand in size and
act as mass lesions. Rupture into ventricular cavities is usually fatal.

II. VIRAL - Viral meningitis and encephalitis are uncommon but important complications of systemic viral
disease and AIDS. Portals of entry are primarily from hematogenous spread (blood-brain barrier does not
inhibit passage of viruses) and from spread along peripheral nerves. CNS damage may occur by direct
destruction of tissue without inflammatory or immunologic response (slow viruses); cell lysis resulting from
immunologic reaction against virus infected cells (SSPE); immune complexes deposited in walls of vessels;
and autoimmune reactions to myelin. Histologic changes characteristic of viral disease include perivascular
mononuclear infiltrates (lymphocyte, plasma cell, macrophage); intranuclear or intracytoplasmic inclusions
- Cowdry A bodies (eosinophilic intranuclear inclusions with a hyaline or granular appearance often
surrounded by a halo) or Cowdry B bodies (small round indistinct inclusions which are less suggestive of
viral disease); glial nodules; and neuronophagia. The CSF shows increased mononuclear cells, normal
glucose, and normal or slightly increased protein. Many viruses are site-specific and clinical symptoms
depend on their virulence and the site affected. Diagnosis usually rests on serologic proof.

A. ENTEROVIRUS - As a group, these are the most common cause of viral meningitis. They are spread
from person to person and are usually seen in late summer or fall.

1. POLIOMYELITIS - This is heralded by nonspecific upper respiratory symptoms, GI

symptoms, and fever which may progress to headache and stiff neck. Most cases resolve
without sequelae but some may progress to involve the large motor neurons in the spinal
cord and brainstem with resultant lower motor neuron paralysis.
2. COXSACKIE B - This may cause meningoencephalitis and myocarditis especially in the
newborn period. It characteristically involves the inferior olivary nucleus.

B. ARBOVIRUSES - These are transmitted by mosquito and tick vectors. The causative agents of
Eastern eqUine encephalitis and Western eqUine encephalitis, the majority of cases are subclinical.
C. HERPES VIRUS

1. HERPES SIMPLEX TYPE I - The initial infection is usually childhood gingivostomatitis. The
virus is harbored in the trigeminal ganglia and may cause recurrent "cold sores".
Encephalitis is uncommon but when it occurs, it is heralded by a "flu-like" syndrome which
progresses to olfactory and gustatory hallucination, focal neurological signs, bizarre
behavior, seizures, obtundation and coma. It characteristically involves the inferior surface
of the frontal lobes and medial surfaces of the temporal lobes. Areas of hemorrhagic
necrosis, edema, perivascular infiltrates, and Cowdry type A inclusions are seen micro-
scopically. The virus cannot be isolated from blood or CSF.
2. HERPES SIMPLEX TYPE n - Venereally transmitted, the virus is harbored in sacral ganglia,
and uncommonly produces encephalitis in adults. Newborns, however, can be infected

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 during passage through the birth canal or, less often, in utero to produce a systemic
infection. Characteristic cutaneous vesicles may be present and about half will develop
CNS involvement. Cowdry Type A inclusions are present. The virus can be recovered
from blood and CSF.
3. HERPES ZOSTER - This virus is harbored in dorsal root ganglia, produces "shingles", and
rarely results in disseminated disease.
4. CYTOMEGALOVIRUS - Transplacental infection of the fetus causes a systemic disease
resulting in microcephaly, periventricular mineralization, hepatosplenomegaly, purpura,
pneumonitis, chorioretinitis, and G.I. lesions. Microscopically, it is characterized by large
cells with prominent nuclear inclusions and granular cytoplasm.

D. HUMAN IMMUNODEFICIENCY VIRUS (HIV-I) - Most patients will develop at some point a
peripheral neuropathy related to focal demyelination of peripheral nerves. The virus may also,
independent of its immunosuppressive effects, produce an aseptic meningitis similar to other forms
of viral meningitis and/or a dementive encephalitis characterized by the presence of virally infected
multinucleated giant cells in the white matter.
E. MUMPS VIRUS - This is the virus most likely to affect CNS but is usually only mild and transient
with headache and stiff neck.
F. RABIES - The incubation period is 1-3 months and the onset is characterized by fever, malaise, and
headache which progresses to profound CNS sensitivity (pain, convulsions, photophobia), coma,
and death. The brain shows edema and congestion with widespread neuronal degeneration
particularly within basal ganglia, midbrain, and floor of 4th ventricle. When seen (70% of cases),
multiple eosinophilic intracytoplasmic inclusions (Negri bodies) are diagnostic. Immunofluorescent
techniques are now used for diagnosis.
G. RUBELLA - Transplacental infection during the first trimester causes a reduction in cell growth and
division. Many fetuses are stillborn or aborted, but those born alive may show cardiovascular and
pulmonary defects, blindness, deafuess, mental retardation, and low birth weight.
H. RUBEOLA - Although rare, measles infection at an early age, may later lead to a progressive, fatal,
immune-mediated encephalitis called subacute sclerosing panencephalitis (SSPE). It is more
common in young males and heralded by intellectual deterioration, personality change, and gait
disturbances culminating in death within months to years. It probably represents antibody or cell
mediated reaction against virus infected cells. There is increased IgG in the CSF.
I. CREUTZFELDT-JACOBDISEASE - This is a slow-virus infection with an incubation period of many
years. The onset occurs in middle-aged to older adults and is manifested by personality changes
and disturbances in coordination followed by progressive severe dementia. It is characterized by
spong{form encephalopathy (vacuolization of neurons and glial processes) of the cortex and, to
a lesser extent, the basal ganglia.
l PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) - This is a slow virus infection of
oligodendroglia that causes death of the cells and foci of related demyelination. Intranuclear
inclusions can be identified. This occurs in immunosuppressed or immunocompromised patients
and the clinical manifestations vary greatly but are progressive.

III. TUBERCULOSIS - At one time this was most common cause of meningitis in children, but now is seen
primarily in adults and secondary to hematogenous spread from a pulmonary focus. It tends to localize at
the base of the brain where abundant shaggy, necrotic yellowish exudate accumulates. It may cause
compression of cranial nerves or brain stem, hydrocephalus from obliteration of subarachnoid space, or
ischemic necrosis secondary to obliterative vasculitis. It always results in death if untreated, and there is
a 30% mortality if treated.

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IV. SYPHILIS - Neurosyphilis occurs in about 30% of untreated cases. The spirochete enters the CNS
hematogenously during the secondary stage and becomes quiescent.

A. MENINGOVASCULAR - The meninges are infiltrated by perivascular plasma cells and lymphocytes.
Scarring may cause nerve compression or hydrocephalus. Vascular involvement (obliterative
vasculitis) may result in parenchymal infarction and present as "stroke". Congenital syphilis
produces meningovascular symptoms at, or soon after, birth.
B. PARENCHYMAL

1. GENERAL PARESIS OF THE INSANE - This results from cerebral involvement and produces
psychotic dementias with onset about 15 years after initial infection. Spirochetes are
abundant in the gray matter (particularly prefrontal and temporal lobes). There is a diffuse
cortical atrophy with neuronal loss, hyperplastic microglia (rod cells) and perivascular
infiltrates.
2. TABES DORSALIS - This results from involvement of the spinal cord with onset 10-25 years
after primary infection. Spirochetes are absent but there is degeneration of the large
diameter fibers of the posterior columns of spinal cord (pain, vibratory, position) resulting
in ataxia, urinary retention, and pupils reactive to accommodation but not to light (Argyll-
Robertson pupil).

V. FUNGAL

A. CRYPTOCOCCUS - This is the most common fungal infection of CNS and has an insidious onset
with headache or behavioral changes. The organisms give a "soap-bubble" appearance to the brain
and do not elicit much inflammatory reaction.
B. MUCORMYCOSIS - This is a commensal organism in the nasal turbinates which when pathogenic,
enters cavernous sinus via ophthalmic veins, enters the internal carotid artery, and is disseminated
to the brain where it obstructs vessels and produces parenchymal infarction. It is seen
predominantly in diabetics with ketoacidosis or immunocompromised patients.
C. OTHER - Candida, coccidiomycosis, blastomycosis, histoplasmosis, aspergillosis, etc may involve
CNS in disseminated disease.

VI. TOXOPLASMA - This is a parasitic protozoan that can cross the placental barrier between mother and
fetus. Maternal infection can cause extensive areas of necrosis of the developing fetal brain. These lesions
also appear in patients with AIDS.

DEMENTIAS AND DEGENERATIVE DISEASES

Dementia refers to impairment of orientation, memory, intellect, and judgement with associated alterations in mood
and behavior.

I. ALZHEIMER'S DISEASE - Most of these cases occur sporadically but a few familial cases (autosomal
dominant pattern) have been identified. There is evidence that the pathogenesis involves abnormalities of
chromosome 21. Clinically, there is an insidious onset of behavioral changes (anxiety, depression,
insomnia, visual hallucinations, paranoia), recent memory loss, and progressive intellectual impairment
leading to eventual inability to comprehend, communicate, or care for oneself. Death is often secondary
to respiratory infections. Grossly, the meninges are thickened, gyri atrophic with corresponding widening

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 of sulci, and dilatation of ventricles due to the cortical atrophy (hydrocephalus ex vacuo). Characteristic
histologic changes include increased numbers of senile plaques (consisting of granular or filamentous
argyrophilic material arranged around a central amyloid core), neurofibrillary tangles (neuronal
intracytoplasmic masses of fibrillary argyrophilic structures), granulovacuolar degeneration
(intracytoplasmic vacuoles of hippocampal pyramidal cells which contain an argyrophilic granule), and
amyloid angiopathy (abnormal amyloid deposition in subarachnoid and penetrating cortical vessels).
II. PICK'S DISEASE - This is clinically indistinguishable from Alzheimer's disease but occurs more
frequently in females. The cortical atrophy occurs primarily in frontal and temporal lobes except for sparing
of the posterior 2/3 of the first temporal gyrus. There is gliosis of subcortical white matter (lobar sclerosis)
and occasional involvement of the anterior portions of the caudate and putamen. Characteristic
intracytoplasmic spherical inclusions (Pick bodies) may be seen in cortical and basal ganglia neurons.
III. HUNTINGTON'S CHOREA - This is an autosomal dominant inherited disease with an onset in the 4th
decade. The initial manifestations are usually choreiform movements and facial grimaces which are
followed by personality changes, emotional disturbances, and dementia. Grossly, there is marked atrophy
of the head of the caudate and putamen with corresponding ventricular enlargement. Microscopically, there
is loss of small neurons of the caudate and putamen with marked astrocytosis.
IV. PARKINSON'S DISEASE (paralysis agitans) - This is a relatively common disease whose onset in the
5th and 6th decades is heralded by resting "pill-rolling" tremors and bradykinesia. It progresses to rigidity
and postural changes, poor balance, shuffling gate, festination, and a mask-like facies. Less than half will
actually develop dementia. Histologically, there is degeneration and loss of the neuromelanin containing
cells especially within the substantia nigra but also in the loci cerulei and dorsal motor nucleus of the vagus,
accompanied byastrocytosis. Characteristic, but not pathognomonic, single or multiple round, eosinophilic
laminated intracytoplasmic inclusions (Lewy bodies) may be seen in remaining pigmented neurons.
V. AMYOTROPIDC LATERAL SCLEROSIS (ALS) - This is a relatively uncommon degenerative disease
which appears in the 6th decade and is characterized by gradual progressive motor weakness leading to
respiratory failure. Sensory function and mental function remain intact. Basically, there is degeneration of
upper motor neurons in the spinal cord and brain stem. Damage to the corticospinal tracts and
degeneration of anterior hom cells result in denervation atrophy of muscle groups. Other "motor-neuron
diseases" such as Werdnig-Hoffinan ("floppy infant") may be related.
VI. SPINOCEREBELLAR ATAXIAS - This refers to a group of inherited degenerative diseases
characterized clinically by a progressive disturbance of equilibrium and movement resulting from primary
neuronal atrophy. These include Friedreich IS ataxia and Olivopontocerebellar ataxia.

DEMYELINA TING DISEASE

I. MUL TIPLE SCLEROSIS - This is the most common of the demyelinating diseases. The etiology is
unknown but may be autoimmune reaction against oligodendroglia (CSF IgG is increased in approximately
2/3 of patients). The onset is frequently in young adulthood and the clinical signs and symptoms are highly
variable. Patients may show episodic exacerbations and remissions and may progress to blindness,
incontinence, ataxia, and paraplegia. Intelligence is usually not impaired. In the brain, there are multiple
irregular gray sclerotic plaques involving both the white and gray matter. In the cerebral hemispheres, these
are most prominent in the periventricular white matter, but are also almost always present in brain stem,
spinal cord, and optic nerves. Early, active lesions show perivenous demyelination and perivascular
mononuclear infiltrat~s. Oligodendroglia are markedly reduced in number or absent. These areas may
coalesce to form larger areas of demyelination with inflammatory reaction along their borders. Older
plaques show less mononuclear infiltrate but there is astrocytosis with proliferation of glial processes
imparting a firmer consistency to the plaque.

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II. GUILLAIN-BARRE DISEASE - This is an autoimmune disorder causing progressive, but usually self-
limiting, ascending motor paralysis which may affect both spinal and cranial nerves. It is often preceded
by a respiratory or gastrointestinal viral illness, and is characterized histologically by segmental
demyelination and perivascular mononuclear inflammatory cell infiltrates. Serum antibodies to peripheral
nerve myelin are present in the acute stages.
III. CHARCOT-MARIE-TOOTH DISEASE - This is an autosomal dominant disorder leading to weakness
and atrophy of the foot and leg muscles. There are two forms: the hypertrophic form which has an onset
in 2nd to 4th decade with palpably enlarged nerves in 25% of patients, loss of larger myelinated fibers,
axonal atrophy with secondary segmental demyelination, and prominent "onion bulbs"; and the neuronal
form which has a late onset, few enlarged nerves, and few or no "onion bulbs" although some
demyelination and axonal atrophy does occur.
IV. DEJERINE-SOTTAS' DISEASE - This is an autosomal recessive disorder with very early onset. The
peripheral nerves are strikingly enlarged, gelatinous, and contain numerous, very prominent "onion bulbs".

NUTRITIONAL AND TOXIC DISEASE

I. ALCOHOLIC ENCEPHALOPATHY - Morphologic changes are often the result of trauma or

complicating hypoxia, liver disease, or nutritional deficiencies.

A. WERNICKE'S ENCEPHALOPATHY - This is the result of thiamine deficiency and manifested as

ataxia, nystagmus, and extra-ocular palsies. Morphologic changes (proliferation and swelling of
small vessel endothelial cells and reactive gliosis) are found in mammillary bodies, wall of third
ventricle, floor of fourth ventricle, and periaqueductal gray matter.
B. KORSAKOFF SYNDROME - This is often seen in association with Wernicke's encephalopathy and
is characterized by profound memory impairment.
C. CEREBELLAR DEGENERATION - Degeneration ofpurkinje cells predominately in anterior superior
portion of vermis produces ataxic symptoms.
D. CENTRAL PONTINE MYELINOLYSIS - This is a demyelinating lesion in the center of pons. Usually,
there are no associated clinical symptoms.
E. ALCOHOLIC NEUROPATHY - Segmental demyelination and axonal degeneration of peripheral
nerves (especially lower extremities) lead to weakness, pain, and paresthesias.

II. B12 DEFICIENCY - Demyelination and gliosis of the posterior and lateral columns of the spinal cord leads
to weakness and paresthesias which, if untreated, may progress to ataxic paraplegia.
III. METHANOL POISONING - Methanol is metabolized to formaldehyde and formic acid resulting in a
profound metabolic acidosis. Low doses cause blindness secondary to retinal degeneration. Higher doses
result, if the patient survives, in bilateral often symmetric necrosis of putamen.

METABOLIC DISEASES

1. STORAGE DISEASES - These are genetic (usually autosomal recessive) diseases resulting from various
enzyme deficiencies which interrupt normal metabolic pathways and cause accumulation of precursor
substances in eNS and systemic organs.

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 A. SPHINGOLIPIDOSES

1. TAY-SACHS - 'This results from a hexosaminidase A deficiency with accumulation of GM2

- ganglioside. Infants are normal at birth but within the first year develop progressive
motor and mental retardation leading to blindness and vegetative state. Macular
degeneration produces a characteristic "cherry-red spot" in fundi.
2. GAUCHER'S DISEASE - This is a beta glucosidase deficiency with accumulation of
glucocerebroside. Mental retardation, hepatosplenomegaly, and yellow-brown cutaneous
pigmentation are associated. Gaucher cells are present in RE system. The infantile form
involves the CNS and appears earlier than the adult form which has little or no CNS
involvement.
3. NIEMANN-PICK DISEASE - This is a sphingomyelinase deficiency with accumulation of
sphingomyelin. Mental retardation, hepatosplenomegaly, olive-brown cutaneous
pigmentation are associated.

B. MUCOPOLYSACCHARIDOSES - There are approximately eight closely related variants including

Hurler's syndrome.
C. GLYCOGEN STORAGE DISEASES - Threre are approximately six variants including Pompe's disease
(Type II glycogenosis).

II. LEUKODYSTROPHIES - Inherited (usually autosomal recessive) biochemical abnormalities in the

development and maintenance of myelin include metachromatic leukodystrophy (cerebroside sulfatase
deficiency) and Krabbe's disease (galactoside beta galactosidase deficiency).
III. WILSON'S DISEASE (hepatolenticular degeneration) - This is an autosomal recessive disorder of
copper metabolism. There is increased copper absorption from GI tract and decreased copper excretion
in bile. A defect in the production of the copper binding transport protein, ceruloplasmin, results in
deposition of copper in tissue. About 1/3 show onset in childhood with liver failure. The remainder usually
have onset in early adult life. Characteristic, virtually pathognomonic, brownish-green discoloration occurs
around limbus of comea (Kayser-Fleischer ring). Laboratory data shows decreased serum ceruloplasmin
(a-2 globulin), decreased serum copper, increased hepatic copper, increased urinary copper excretion, and
abnormal liver function tests.

NEOPLASTIC DISEASE

Although the overall incidence of CNS neoplasms tend to increase with age, they represent the second most
common group of tumors in childhood. About 70% of primary childhood intracranial tumors develop in the
posterior fossa while about 70% of primary adult intracranial tumors are supratentorial.

I. PA THOGENESIS OF SYMPTOMS - There are no specific signs or symptoms of neoplastic disease.

Clinical manifestations depend on both local and general effects of the tumor.

A. LOCAL EFFECTS - These result from infiltration, invasion, and destruction of normal CNS tissue;
direct pressure on nerve structures causing degeneration; interference with local circulation due
to direct pressure on capillaries and small arteries and veins; and edema (which is most marked in
the region of the tumor). The edema may be sufficient to interfere with the function of nervous
tissue, adding to the clinical symptoms that are directly attributable to the tumor itself.

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 B. GENERAL EFFECTS - The rigidity of the cranium allows no room for expansion. The increased
pressure created by an expanding mass and the associated edema. therefore. is transmitted
throughout the brain and ventricular system and is an important cause of symptoms. Tumor growth
within or near the ventricular system causes direct obstruction of ventricular system with marked
hydrocephalus, but even when the tumor lies distant from the ventricles, the ventricular system may
ultimately be displaced and distorted sufficiently to cause obstructive hydrocephalus. Midline
structures are similarly displaced and distorted. Papilledema results from passage of CSF under
increased pressure along the arachnoidal sheath of the optic nerve to the optic disc and
engorgement of vessels due to compression of the central retinal vein. The mechanism of the
occasional acute focal symptoms caused by brain tumors is either hemorrhage within the tumor
or acute herniation. The commonest cause of death is herniation (from pressure created by
the tumor and surrounding edema) of medial temporal lobe structures at the tentorium or
cerebellar tonsils at the foramen magnum with resultant brainstem compression.

II. TUMORS OF INTRINSIC CNS CELLS

A. GLIAL CELL ORIGIN - These constitute about 50% of all brain tumors. With the exception of
cerebellar astrocytoma of childhood, all gliomas are basically infiltrative and malignant,
rendering them incurable. Ordinarily, they do not metastasize but occasionally spread throughout
subarachnoid space, causing multiple foci of growth in the leptomeninges. Most often CSF protein
is elevated without pleocytosis, but tumors growing in or near the ventricular system, especially
if necrotic, may cause some degree of CSF pleocytosis.

1. ASTROCYTOMA - This is the most important of the gliomas. It is an infiltrative tumor of

astrocytes that is most commonly located in the cerebral hemispheres of adults and the
brainstem and cerebellum of children.

a. Low grade/well differentiated astrocytoma (Grade I) - These tumors arise in

the white matter with a peak incidence in the 3rd and 4th decades. Symptom-
atology may include seizures, increased pressure, motor deficits, and mental
changes. Grossly, these are solid (although there may be foci of cystic
degeneration), grey masses with ill-defined boundaries which expand and distort
the brain parenchyma. Microscopically there is an increase in cellularity with an
unordered, uneven distribution and infiltrative margins. When infiltrating the grey
matter, there tends to be clustering around neurons (satellitosis). The cells have
a generous eosinophilic cytoplasm which gives off multiple processes to form a
fibrillary background. An occasional variant, the gemistocytic astrocytoma, is
composed largely of neoplastic astrocytes with aoundant eosinophilic glassy
cytoplasm that resembles reactive gemistocytes. The differential diagnosis lies
primarily with reactive gliosis and other forms of gliomas. The well differentiated
lesions have a slow growth rate but may undergo more malignant degeneration
(particularly the gemistocytic variant). Average post-operative survival is 3-10
years.
b. Intermediate grade/anaplastic astrocytoma (Grade II, III) - These have the
same distribution pattern as the well differentiated tumors but have a peak
incidence in the 5th decade. Many may be simply dedifferentiation of a preexisting
well differentiated tumor. Grossly, they may be somewhat more firm than the well
differentiated tumors. Microscopically, there is increased cellularity with greater

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 pleomorphism, increased mitoses, and endothelial proliferation, but no tumor
necrosis. Average post-operative survival is 2 years.
c. High grade/glioblastoma multiforme (Grade N) - Unfortunately, this highly
malignant neoplasm is the most common of the gliomas (50-60%). The peak
incidence is in the 5th to 6th decade. They usually arise in the frontal or temporal
lobes but may be more deeply seated within the basal ganglia or thalamus.
Symptomatology is the same as other astrocytomas but with more rapid
progression and deterioration. Grossly, they may appear deceptively discrete but
there is extensive infiltration of surrounding white and grey matter. Cystic
degeneration, necrosis, and hemorrhage impart a variegated coloration.
Microscopically, diagnostic features include necrosis (often marginated by
pseudopalisading of neoplastic cells) and vascular and endothelial proliferation.
Untreated, the average survival is 14 weeks. With radiation, survival may be
extended up to 10-11 months.
d. Cerebellar astrocytoma (spongioblastoma) - These tumors predominate in
childhood (Ist or 2nd decade) and arise in the cerebellar hemispheres or vermis.
Symptoms include cerebellar dysfunction and the effects of increased pressure.
They grossly appear as discrete lesions often with cystic degeneration. Prognosis
is good with long survivals (and some cures) even following partial resection.
e. Brain stem glioma - The peak incidence occurs in childhood. Most originate in
the pons and cause diffuse enlargement often at the expense of the 4th ventricle.
The tumors are unresectable and length of survival depends on degree of
differentiation.

2. OLIGODENDROGLIOMA (5% of gliomas) - These are primarily tumors of middle-aged

adults. They are very slow growing and often there is a history of a chronic seizure
disorder which may be progressively more refractory to anti-epileptic therapy. Grossly, the
lesions arise in the white matter (most commonly temporal lobes) and are relatively
discrete, soft, grey-pink masses. Microscopically, they consist of patternless sheets of
monotonous small round cells with round to oval nuclei, delicate chromatin, and
perinuclear halos. Vascular patterns may be prominent. Calcification is common (40%).
Most are well differentiated but there is a variable spectrum of anaplasia characterized by
increased cellularity, increased N/C ratio, increased pleomorphism, increased mitoses, etc.
These are usually unresectable and prognosis depends on the degree of differentiation and
aggressiveness of the tumor.
3. EPENDYMOMA (6% of intracranial gliomas but 65% of intraspinal gliomas) - These may
occur anywhere in the ventricular system but tend to occur most frequently in 3rd and 4th
ventricle with a peak incidence in the 1st and 2nd decade (20% of childhood intracranial
tumors). Symptoms due to obstructive effects are reflected by hydrocephalus or increased
pressure. Fourth ventricle lesions tend to grow into the ventricle while supratentorial
lesions have greater tendency to expand into the parenchyma but, compared to other
gliomas, usually have a sharper demarcation from the surrounding brain. Ependymal cells
are derived from neuroglia but also have epithelial properties and ependymomas may
reflect both glial and epithelial traits. Glial traits (most common form) shows unpatterned
proliferation of cells which tend to form vascular pseudorosettes (clear zones around
vessels composed of radiating cytoplasmic processes). Epithelial traits are reflected by
ependymal rosettes (columnar cells radially oriented around clear central lumina). The
presence of blepharoplasts are pathognomonic but usually found only in better
differentiated tumors which contain ependymal rosettes. Prognosis depends on location,

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 surgical accessibility, and degree of differentiation. They tend to recur locally and may
seed the subarachnoid space. Survival averages 5-6 years.

B. NERVE CELL ORIGIN (primitive neuroectodermal tumor; PNET)

1. MEDULLOBLASTOMA - This is almost exclusively a tumor of the vermis of the cerebellum

in childhood, comprising 20% of brain tumors in children, and is thought to arise from the
external granular cell layer of the cerebellum. Histology shows sheets of cells with
hyperchromatic nuclei and scant cytoplasm with little evidence of differentiation. The
tumor grows rapidly and often metastasizes throughout the neuraxis. Although moderately
sensitive to radiotherapy, most cases are ultimately fatal within 3-4 years.
2. NEUROBLASTOMA - This is a malignant tumor of childhood that arises from cells of the
sympathetic ganglia, or ganglion cells in adrenal medulla (see endocrine section).

C. PINEAL GLAND ORIGIN - These are rare tumors that may obstruct ventricular system by pressure
on midbrain producing blockage of the aqueduct. Compression of the midbrain tectum causes
signs of disturbed ocular motility.

1. PINEOCYTOMA/PINEOBLASTOMA - These are extremely rare tumors arising from the

intrinsic neuronal elements of the pineal and are really tumors of neuronal elements similar
to the medulloblastoma.
2. GERM CELL TUMORS - Similar to those arising in the ovary or testes, the most common
is dysgerminoma differentiation (similar to seminoma of testes) but there may be
choriocarcinoma, embryonal carcinoma, teratoma, teratocarcinoma, or yolk sac tumor
differentiation as well. The treatment and response is similar to that for the same
histological tumor arising in testes or ovary.

III. TUMORS OF COVERING STRUCTURES AND BLOOD VESSELS

A. MENINGIOMA - This is a relatively common tumor constituting 15% of all adult CNS tumors, is
more common in females than males, and is usually benign. It arises from arachnoidal cells of the
leptomeninges, not the dura, although they are usually tightly bound to the dura. Although they may
occur anywhere along the meninges, favored sites include the parasagittal regions and lateral
cerebral convexities. Occasionally, they may grow in a diffuse manner (en plaque) along the
meninges - particularly those that occur along the sphenoid wings. They affect the brain by
compression, which may be marked because slow growth allows large size before significant
symptoms (headache, seizures, visual disturbance) develop. They may cause hyperostosis of the
overlying skull, and occasionally will erode the skull. Although these tumors have a heterogeneous
appearance microscopically (psammoma bodies may be present), subclassification has disputed
prognostic significance. Rare tumors may show cortical invasion, increased cellularity, and
increased mitoses which indicate a more aggressive behavior. The prognosis depends primarily on
accessibility to surgical removal.
B. NEURILEMOMA (SCHWANNOMA) - This is an encapsulated peripheral nerve tumor, arising from
nerve sheath, presumably from the Schwann cell. The commonest intracranial site is cranial nerve
VIII ("acoustic neurilemoma"). Peripheral involvement more often affects sensory branches.
Histologic patterns include the Antoni A (interlacing bundles of spindle cells with tendency toward
nuclear palisading) and Antoni B (loose arrangement of stellate cells within a myxoid background).
These tumors grow slowly, compressing the nerve of origin. Acoustic nerve tumor ultimately

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 compresses the adjacent brainstem, cerebellum and other nearby cranial nerves, producing the
cerebellopontine angle syndrome. Rarely, they may undergo malignant transformation.
C. NEUROFIBROMA - This is an unencapsulated peripheral nerve tumor presumably derived from
perineural cells. In contrast to the neurilemoma which can be shelled off the nerve, the tumor cells
of the neurofibroma grow between and trap and compress the individual axons. Multiple
neurofibromas are characteristic of neurofibromatosis (von Recklinghausen's disease), a
dominantly inherited neurocutaneous syndrome. Areas of skin hyperpigmentation (cafe au lait
spots) are typical. Other associated nervous system tumors include acoustic neurilemomas (often
bilateral), meningiomas (often multiple), optic gliomas, and multiple cranial nerve and spinal root
neurofibromas.
D. HEMANGIOBLASTOMA (LINDAU'S TUMOR) - This is a tumor arising from capillary endothelium
and usually located in the cerebellum. It grows slowly and is usually cystic. They may occur as
isolated neoplasms or in association with the familial Von Hipple-Lindau syndrome (retinal
hemangioblastoma, visceral cysts, renal cell carcinoma, pheochromocytoma). Symptoms result
from obstruction of CSF leading to headache, vomiting, papilledema. Grossly, they appear as
discrete masses or as a small red-yellow nodule on the wall of a cyst which contains yellow-brown
fluid. There is a varied microscopic appearance but basically they are composed of vascular and
stromal cells. Although tonsillar herniation is a potentially fatal consequence, the prognosis is
generally good.

IV. TUMORS OF CELL RESTS

A. CRANIOPHARYNGIOMA - This arises from epithelial cell rests derived from Rathke's pouch. It
grows slowly, may be cystic, and contains areas of calcification, fibrous connective tissue, and
epithelium resembling squamous epithelium. It compresses hypothalamic structures, 3rd ventricle,
optic chiasm and pituitary.
B. COLLOID CYST OF 3RD VENTRICLE - This is an epithelial-lined cyst on the roof of the 3rd
ventricle and filled with a colloid substance secreted by the lining cells. It is not a true neoplasm,
but has been thought to be a remnant of a structure present during early embryonic development.
Although it expands very slowly, it may obstruct the foramina of Monro, causing hydrocephalus.
with such obstruction resulting in sudden death.
C. EPIDERMOID/DERMOID - These are commonly called cholesteatomas and are slow growing. They
arise from epithelial rests in the arachnoid and are composed of various structures of skin, forming
the wall of a cyst. They usually are located in the midline, such as suprasellar region, but may be
in the cerebellopontine angle or within tables of skull. Microscopically there is an squamous lined
cyst containing cholesterol crystals and other degenerative material. Dermoid implies the additional
presence of structures of dermal appendages (such as sweat or sebaceous glands and hair).
D. CHORDOMA - This arises from remnants of the notochord in the clivus. It also occurs at caudal end
of vertebral column. Slow-growing, it produces damage by brainstem and cranial nerve
compresSIOn.

V. TUMORS OF METASTATIC ORIGIN - These are very important, constituting from 20% to 50% of
all brain tumors. Symptoms (headache, seizures, motor deficits, mental changes, etc.) are the result of local
expansion and surrounding edema. The tumors primarily originate in the lung and breast and, to a lesser
extent, the GI and GU tracts. Most metastatic lesions appear in the cortex at the grey-white junction and
may be single or multiple. They tend to occur most frequently in the distribution of the middle cerebral
artery. Metastatic lesions invade the brain, rather than infiltrate, and therefore produce a well-defined
margin usually surrounded by a zone of marked edema. Often necrosis is extensive. Surgical removal and
cure is only rarely possible.

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 SKELETAL MUSCLE

I. MUSCULAR DYSTROPHIES - These are genetically determined myopathies in which progressive

atrophy and/or degeneration of muscle fibers is the hallmark.

A. DUCHENNE MUSCULAR DYSTROPHY - This is the most common form, is X-linked recessive (males
are affected, females are carriers), and is characterized by the absence of dystrophin, a normal
muscle protein that appears to stabilize the muscle fiber membrane. Although there are markedly
elevated "muscle enzymes" (CK and aldolase) and abnormal biopsies from birth, clinical weakness
is usually not apparent until age 3 or 4. The muscular weakness is progressive and most patients
are can no longer walk by age 10. Death usually occurs by age 20 from pneumonia or cardiac
involvement. In the early stages, although there is patchy necrosis and regeneration of muscle, the
involved muscles appear hypertrophied due to replacement by fibrofatty tissue, so-called
"pseudohypertrophy". In the late stages, little identifiable muscle tissue is observable.
B. BECKER MUSCULAR DYSTROPHY - This is also X-linked recessive and may be a milder form of
Duchenne's. It has a later onset and may not be noticed until after the age of25. It tends to have
a chronic course, and many patients live a normal lifespan.
C. FACIOSCAPULOHUMERAL DYSTROPHY - This is autosomal dominant and usually becomes
manifest during adolescence as progressive weakness of face, shoulder girdle and upper arms.
D. LIMB-GIRDLE DYSTROPHY - This is autosomal recessive and causes slowly progressive weakness
of the proximal muscle groups of the shoulder and pelvic girdles.
E. MYOTONIC DYSTROPHY - This is autosomal dominant and has two forms: a congenital form in
which there is extreme weakness from birth with death occurring in the neonatal period, and an
adult form in which the presenting complaint is usually distal muscular weakness and atrophy plus
myotonia (tonic muscular spasms persisting after cessation of stimulation). Patients may have
subnormal or borderline intelligence, and males may display frontal balding. Weakness and atrophy
are slowly progressive and may result in severe incapacitation in late life.

II. MYASTHENIA GRAVIS - This is a relapsing, remitting autoimmune disease in which weakness and
extreme muscular fatigue are characteristic. Autoantibodies against acetylcholine receptors on the post-
synaptic membranes of the neuromuscular junction are present in the serum of the majority of patients.
Mores commonly seen in females, it may appear at any age but the peak age of onset is about 20. Almost
all of the patients have abnormal thymus glands, either a thymoma or thymic hyperplasia. The disorder is
progressive but the prognosis is highly variable. Thymectomy and possibly plasmapheresis may be of
benefit.

265
 SELF ASSESSMENT EXAM A

DIRECTIONS (Items I-57): Each of the numbered items or incomplete statements in this section is followed by answers or by
completions of the statement. Select the ONE lettered answer or completion that is BEST.

I. A 40 year old woman who complains of a low-grade 6. Diverticulosis of the colon:

fever, malaise, and stiffness in her joints each morning
most likely has which of the following diseases: A. Increases in incidence with age.
B. Is a necessary precursor to the development of
A. Gout. hemorrhoids.
B. Metastatic carcinoma. C. Is complicated by diverticulitis in over half of the
C. Osteoarthritis. cases.
D. Rheumatoid arthritis. D. Is inherited as an autosomal dominant trait.
E. Villonodular synovitis. E. Predisposes to carcinoma of the colon.

2. The MOST common type of thyroid carcinoma is: 7. Which of the following features is most characteristic
of a neoplasm:
A. Anaplastic.
B. Follicular. A. Autonomous growth.
C Hw·thle cell. B. Increased vascularity.
D. Medullary. C. Large size.
E. Papillary. D. Necrosis.
E. Rapid growth.
3. Reticulocytosis would be a feature of:
8. A 24 year old female presents to the emergency room
A. Aplastic anemia. with a three day history offever, malaise, and dysuria.
B. Autoimmune hemolytic anemia. Physical examination reveals costo-vertebral angle
C. Megaloblastic anemia. tenderness. BUN and creatinine levels are normal.UA
D. Sideroblastic anemia. shows a few red blood cells, white blood cell casts, and
bacteria. The most likely diagnosis would be:
4. Huntington's chorea is characterized by:
A. Acute pyelonephritis.
A. Atrophy of the caudate nucleus. B. Chronic pyelonephritis.
B. Degeneration of upper motor neurons. C. Goodpasture's syndrome.
C. Demyelination of posterior spinocerebellar tract. D. Necrotizing papillitis.
D. Depigmentation of substantia nigra.
E. Necrosis ofPurkinje cells. 9. Inadequate mineralization of bone matrix IS
characteristic of:
5. A 62 year old insulin dependant diabetic with a past
history of myocardial infarction suddenly develops A. Achondroplasia.
acute abdominal pain and bloody diarrhea followed by B. Hypoparathyroidism.
ileus and abdominal rigidity. Exploratory laparotomy C. Osteogenesis imperfecta.
would most like reveal which of the following: D. Osteoporosis.
E. Rickets.
A. Bleeding duodenal peptic ulcer.
B. Encroachment of mesenteric fat over the serosal 10. A localized, destructive lesion of the posterior pituitary
surfaces of the bowel. would most likely affect which of the following serum
C. Thrombosis of the portal vein. values:
D. Thrombotic occlusion of proximal supenor
mesenteric artery. A. Calcium.
B. Creatinine.
C. Glucose.
D. Potassium.
E. Sodium.

266
I I. Renal failure is characteristically associated with: 17. Osteogenic sarcoma is known to be a complication of:

A. Acute myelogenous leukemia. A. Bone trauma.

B. Chronic lymphatic leukemia B. Osteitis deformans (paget's disease).
C. Hodgkin's disease. C. Osteoarthritis.
D. Multiple myeloma. D. Osteogenesis imperfecta.
E. Nodular lymphoma. E. Multiple myeloma.

12. The most distinctive structural defect in pulmonary 18. Which of the following tumors is most likely to be
emphysema is: associated with essential hypertension:

A. Cellular infiltration of the walls of small airways. A. Adrenal adenoma.

B. Dilatation and thickening of bronchial walls. B. Parathyroid adenoma.
C. Enlargement of air spaces and loss of alveolar C. Pheochromocytoma.
septa. D. Pituitary adenoma.
D. Increase in total mass oflung tissue. E. Thyroid adenoma.
E. Loss of alveolar epithelium.
19. Which of the following IS characteristic of acute
13. Which heart valve is most commonly affected 111 lymphocytic leukemia:
rheumatic heart disease:
A. Cytoplasmic auer rods.
A. Aortic valve. B. Hepatosplenomegaly.
B. Mitral valve. C. High incidence in children.
C. Pulmonary valve. D. Lymphadenopathy.
D. Tricuspid valve. E. Philadelphia chromosome.

14. Of the following, the most life-tlu-eatening 20. A decrease in suIi'actant activity is the underlying
complication of ulcerative colitis would be: problem in patients with:

A. Enterocutaneous fistulas. A. Alpha-I-antitrypsin deficiency.

B. Hemorrhage. B. Asbestosis.
C. Peritoneal adhesions. C. Asthma.
D. Stenosis of ileo-cecal valve. D. Bronchiectasis.
E. Toxic megacolon. E. Respiratory distress of the newbom.

15. Which of the following IS a benign neoplasm of 21. A myocardial infarct which is grossly detectable,
epithelial origin: yellow to gray in color, and microscopically contains
necrotic debris and macrophages but little evidence of
A. Astrocytoma. granulation tissue is probably:
B. Chondroma.
C. Lipoma. A. I hour old.
D. Melanoma. B. 12 hours old.
E. Papilloma. C. I day old.
D. I week old.
16. The phenomenon of wound contraction may be: E. I month old.

A. Advantageous in that it reduces the amount of scar 22. Of the following, hepatocellular carcinoma is most
tissue needed. often associated with:
B. Deleterious in that slows down the healing
process. A. Biliary atresia.
C. Both. B. Chronic pancreatitis.
D. Neither. C. Gallstones.
D. Hepatic cirrhosis.

267
23. A tibroadenoma of the breast is an example of: 29. The organism most frequently responsible for acute
bacterial endocarditis is:
A. Anaplasia.
B. Dysplasia. A. Beta hemolytic streptococcus.
C. Hyperplasia. B. Diplococci pneumoniae.
D. Metaplasia. C. Hemophilus influenzae.
E. Neoplasia. D. Staphylococcus aureus.
E. Streptococcus viridans.
24. The tensile strength of a healing wound appears to be
primarily a function of: 30. The typical outcome of hepatitis A is:

A. Collagen deposition. A. Chronic active hepatitis.

B. Dystrophic calcification. B. Chronic persistent hepatitis.
C. Exuberant granulation tissue. C. Hepatic cirrhosis.
D. Inflammatory infiltrate. D. Massive hepatic necrosis.
E. Vascular proliferation. E. Resolution.

25. A 22-year-old woman presents with a discrete 3 1. Which of the following terms would best describe the
upper/outer quadrant breast mass. The most likely presence of squamous epithelium lining the renal
diagnosis is: pelvis:

A. Fat necrosis. A. Desmoplasia.

B. Fibroadenoma. B. Dysplasia.
C. Fibrocystic change. C. Ectopia.
D. Intiltrating ductal carcinoma. D. Hyperplasia.
E. Intraductal papilloma. E. Metaplasia.

26. The MOST COMMON cause of hematosalpinx is: 32. Quantitatively, which of the following serum proteins
is present in the greatest concentration in a healthy
A. Ectopic tubal pregnancy. individual:
B. Endometriosis.
C. Gonorrheal salpingitis. A. Albumin.
D. Ruptured luteal cyst. B. Beta lipoproteins.
c. Gammaglobulins.
27. Which of the following non-Hodgkin's lymphomas has D. Haptoglobin.
the best prognosis:
33. Radiation is most likely to induce cell injury because of
A. Follicular small cleaved cell (nodular poorly its effects on the:
differentiated) .
B. Large cell immunoblastic (diffuse histiocytic). A. Cell membrane.
C. Lymphoblastic. B. DNA.
D. Small non-cleaved cell (diffuse undifferentiated). C. Endoplasmic reticulum.
D. Lysosomes.
28. In which of the following would an interstitial E. Mitochondria.
inflammatory infiltrate be most striking:
34. Metastatic, mucin-producing, signet-ring cancer cells
A. Bronchopneumonia. in the ovary most frequently come from:
B. Fungal pneumonia.
C. Lobar pneumonia. A. Astrocytoma.
D. Viral pneumonia. B. Endometrial carcinoma.
C. Gastrointestinal carcinoma.
D. Histiocytic lymphoma.
E. Malignant melanoma.

268
35. The primary vascular mechanism for the edema in 41. Which of the following statements conceming Crolm's
acute inflammation is considered to be: disease is TRUE:

A. Increased arterial flow. A. Always begins III the rectal area and extends
B. Increased arterial pressure. proximally.
C. Increased vascular permeability. B. Invariably associated with non-caseating
D. Lymphatic obstruction. granulomatous inflammation of the submucosal
E. Venous congestion. tissue.
C. May produce symptoms of partial bowel
36. Pleural mesotheliomas are most closely associated obstruction due to stenosis and/or strictures of the
ith: bowel lumen.
D. Patients are at high risk of developing colonic
A. Anthracosis. carcllloma.
B. Asbestosis.
C Berylliosis. 42. The most characteristic cell of the acute inflanmlatory
D. Silicosis. response is the:
E. Smoking.
A. Chant cell.
37. Which of the following IS most characteristic of B. Lymphocyte.
polyarteritis nodosa: C Monocyte.
D. Plasma cell.
A. Cutaneous rash. E. Polymorphonuclear leukocyte.
B. Hypothyroidism.
C. Jaundice. 43. During a pre-employment physical exam, a 35 year old
D. Necrotizing arteritis. female was found to have a peripherally located "coin
E. Urticaria. lesion" on chest X-ray. This would most likely
represent alan:
38. The development of edema would be expected when
there is: A. Abscess.
B. Carcinoma.
A. Decreased intravascular hydrostatic pressure. C. Granuloma.
B. Increased oncotic pressure of blood. D. Hamartoma.
C. Both. E. Infarct.
D. Neither.
44. The most accurate predictor of melanoma behavior is:
39. Infarcts ofthe brain which occur in the boundary zone
between major arterial supplies are usually the result A. Anatomic location.
of: B. Degree of inflaI11ll1atory reaction.
C. Lesion thickness.
A. Atherosclerosis. D. Number of mitoses per square centimeter.
B. Emboli. E. Presence or absence of ulceration.
C Hypotension.
D. Thrombosis. 45. Hypovolemic shock would be most likely to develop in
patients with:
40. Generation offree radicals is the major mechanism of
cell injury in: A. Bee stings
B. Cardiac failure.
A. Ischemia. C. Extensive bums.
B. Oxygen toxicity. D. Head trauma.
C. Both. E. Septicemia.
D. Neither.

269
46. In the central nervous system, myelin fonnation and 52. Infarcts tend to be hemorrhagic when they occur in the:
maintenance is a function of:
A. Heal1.
A. Astrocytes. B. Intestine.
B Axons. C. Kidney.
C. Microglia. D. Pancreas.
D. Neuron. E. Spleen.
E. Oligodendroglia.
53. In an axonal reaction, degeneration and disintegration
47. Of the following, dystrophic calcification would be of the myelin sheath and axon cylinder is called:
most closely associated with:
A. Axonal dystrophy.
A. Hyperphosphatemia. B Central chromatolysis.
B Necrotic tissue. C. Clasmatodendrosis.
C. Osteoporosis. D. Gliosis.
D. Parathyroid hyperplasia. E. Wallerian degeneration.
E. Renal calcium excretion.
54. Light microscopic exmnination of a pulmonary infarct
4R. Adenocarcinoma of the esophagus would most likely would reveal:
arise in the:
A. Caseous necrosis.
A. Distal esophagus. B Coagulation necrosis.
B Mid esophagus. C. Enzymatic fat necrosis.
C. Proximal esophagus. D. Gangrenous necrosis.
D. Equal distribution between all three of the above. E. Liquefaction necrosis.

49. A granulomatous inflammatory response is diagnostic 55. In contrast to carcinoma of the right colon, carcinoma
of: of the left colon tends to:

A. Alcoholism. A. Be annular and obstruct the colon earlier.

B. Bacterial disease. B. Be clinically silent or asymptomatic.
C. Fungal disease. C. Cause anemia and anorexia.
D. Tuberculosis. D. Produce steatorrhea.
E. None of the above.

50. The most common renal malignancy 111 childhood 56. Distant metastasis in prostatic carcinoma MOST
would be: COMMONL Y involves:

A. Neuroblastoma. A. Adrenal.
B Renal cell carcinoma. B. Bone.
C. Transitional cell carcinoma. C. Brain.
D. Wilms'tumor. D. Liver.
E. Lung.
51. The characteristic cutaneous immune deposits 111
systemic lupus erythematosus are seen in the: 57. Intennittent severe flank pain which radiates to the
groin would be the dominant symptom of:
A. Dennal blood vessels.
B. Dennal papillae. A. Acute pyelonephritis.
C. Epidennal basement membrane zone. B. Papillary necrosis.
D. Epidennal intercellular spaces. C. Renal infarct.
D. Ureter obstructed by calculus.

270
DIRECTIONS (Items 58-70): Each of the mnnbered items or incomplete statements in this section is negatively phrased as indicated
by a capitalized word such as NOT, LEAST, or EXCEPT. Select the ONE lettered answer or completion that is BEST in each case.

58. Factors predisposing to the development of breast 63. Morphologic features of viral hepatitis include each of
cancer m women include each of the following the following EXCEPT:
EXCEPT:
A Ballooning degeneration ofhepatocytes.
A Fibrocystic change of the breast. B. Focal necrosis ofhepatocytes.
B. Increasing age. C. Hypertrophy and hyperplasia of Kupffer cells.
e. Maternal history of breast cancer. D. Microabscesses.
D. Multiparity. E. Periportal inflammation.
E. Previous mastectomy for cancer.
64. Predisposing factors for thrombosis include all of the
59. Each of the following is a feature of Tetralogy of F allot following EXCEPT:
EXCEPT:
A Anemia.
A Atrial septal defect. B. Atherosclerosis.
B. Pulmonary stenosis. C. High serum protein levels.
C. Right ventricular hypertrophy. D. Thrombocytosis.
D. Ventricular septal defect. E. Venous obstruction.

60. A patient with Addison's disease is likely to exhibit all 65. After activation, each of the following chemical
of the following EXCEPT: mediators of inflammation often proceeds in a cascade
EXCEPT:
A Adrenal atrophy.
B. Central obesity. A Arachidonic acid.
C. Hyperpigmentation of skin. B. Complement.
D. Hypotension. C. Fibrinopeptides.
D. Kinin.
61. Characteristic features of polycystic ovary disease E. Neutral proteases.
include each of the following EXCEPT:
66. Complications of cystitis include each of the following
A Amenorrhea. EXCEPT:
B. Bilateral ovarian enlargement.
C. Hirsutism. A Acute pyelonephritis.
D. Obesity. B. Cystitis cystica.
E. Ovarian "chocolate" cysts. C. Formation of bladder stones.
D. Transitional cell carcinoma.
62. Each of the following statements concerning squamous
cell carcinoma of the uterine cervix is true EXCEPT: 67. Which one of the following is LEAST likely to
regenerate:
A It begins at the cervical/endocervical
squamo-columnar junction. A Axons.
B. It is associated with human papilloma virus B. Bone.
infection. C. Cardiac muscle.
e. It is usually preceded by dysplastic epithelial D. Hepatocytes.
changes. E. Renal tubular epithelium.
D. It shows early, widespread metastases.

271
68. Which of the following has the LEAST influence on
slowing hemorrhage from venules:

A. Blood coagulation.
B. Direct pressure on bleeding site.
C. Formation of platelet plugs.
D Vasoconstriction.

69. Which of the following is LEAST likely to be seen in

the renal biopsy of an individual who has had
non-insulin dependent diabetes mellitus for 15 years:

A. Diffuse glomerular sclerosis.

B. Hyaline mieriolosclerosis.
C. Nodular mesangial sclerosis.
D. Thickening of the glomerular capillary basement
membranes.

70. The benefits of inflammation include each of the

following EXCEPT:

A. Laying foundation for hypersensitivity.

B. Localization or walling off of site of dmnage.
C. Preparation of area for repair.
D. Removal of dead cells and debris.

272
 SELF ASSESSMENT EXAM B

DIRECTIONS (Items I-56): Each of the numbered items or incomplete statements in this section is followed by answers or by
completions of the statement. Select the ONE lettered answer or completion that is BEST.

I. Which of the following may show clinical symptoms 6. Most of the human papilloma viIuses (HPV) associated
related to low cardiac output: with human malignant tumors are strains related to:

A. Dilated cardiomyopathy. A. Epidermodysplasia.

B. Hypertrophic cardiomyopathy. B. Flat warts.
e Both. C. Immunosuppression.
D. Neither. D. Sexual transmission.

2. Which of the following disorders would be most likely 7. Massive pulmonary thromboemboli cause sudden
to present with hematemesis: death because of:

A. Achalasia. A. Acute cor pulmonale with arrhythmias.

B. Hiatal hernia. B. Acute pulmonary infarction.
e Mallory-Weiss syndrome. C. Asphyxia.
D. Plummer-Vinson syndrome. D. Cerebral anoxia.
E. Zenker's diverticulum. E. Massive hemoptysis.

3. Metastatic spread of a prostatic adenocarcinoma would 8. The greatest enlargement of the spleen is usually found
be most likely to occur through the: in which of the following diseases:

A. Arterial system. A. Acute granulocytic leukemia.

B. Lymphatic system. B. Acute lymphocytic leukemia.
e Peritoneal cavity. e Chronic granulocytic leukemia.
D. Venous system. D. Hodgkin's disease.
E. Multiple myeloma.
4. On radiologic exam, small scarred kidneys which show
blunting of the pyramids would be most consistent 9. Elevated serum levels of which of the following is
with: NOT associated with the development of clinically
significant atherosclerosis:
A. Chronic pyelonephritis.
B. Membranoproliferative glomerulonephritis. A. Alpha lipoproteins.
e Renal cell carcinoma. B. Beta lipoproteins.
D. Renal infarction. C. Low density lipoproteins
D. Pre-beta lipoproteins.
5. Of the following, the most common tumor that involves
bone is: 10. Hirschsprung's disease is characterized by absence of
ganglion cells in the:
A. Chondrosarcoma.
B. Giant-cell tumor. A. Adrenal medulla.
e Metastatic tumor from an extraosseous site. B. Body of the stomach.
D. Multiple myeloma. e Distal esophagus.
E. Osteogenic sarcoma. D. Rectum.
E. Ureters.

273
II. In most instances, metaplasia is the result of: 17. In which of the following clinical settings might you
expect acute cor pulmonale to most likely arise:
A. Chronic irritation.
B. Developmental defect. A. A patient with a two year history of stable
C. Immunologic reaction. angma.
D. Somatic mutation. B. A patient with an 85 pack-year smoking history
E. Viral infection. and chronic bronchitis.
C. A patient with kyphoscoliosis due to childhood
12. The buildup of excessive amounts of collagen during polio.
wound healing is called: D. An overweight patient in bed recovering from
surgery for cervicalcancer.
A. Contraction.
B. Exuberant granulation. 18. Early diagnosis of pancreatic cancer is most likely if
C. Keloid. the tumor:
D. Organization.
E. Proud flesh. A. Has metastasized to the brain.
B. Has metastasized to the liver.
13. The primary cartilage change in osteoarthritis IS C. Is located in the head of the pancreas.
characterized by: D. Is located in the tail of the pancreas.

A. Degeneration. 19. A malignant neoplasm of connective tissue origin is

B. Dysplasia. alan:
C. Hyperplasia.
D. Inflammation. A. Adenoma.
E. Regeneration. B. Carcinoma.
C. Hamartoma.
14. Secondary hyperparathyroidism will characteristically D. Sarcoma.
show: E. Teratoma.

A. Elevated serum calcium. 20. As a scar matures, it becomes:

B. Elevated serum PTH.
C. Both. A. Less vascular.
D. Neither. B. More cellular.
C. Both.
15. Massive splenomegaly would be most likely to D. Neither.
accompany which of the following:
21. Which of the following alterations that can be seen in
A. Acute lymphoblastic leukemia. fibrocystic change of the breast is most associated with
B. Chronic myelogenous leukemia. an increased risk of the development of carcinoma:
C. Multiple myeloma.
D. Hodgkin's disease. A. Apocrine metaplasia.
E. Sickle cell aneInia. B. Cystic ductal dilation.
C. Epithelial hyperplasia.
16. The lung cancer which most commonly produces and D. Stromal fibrosis.
secretes hormone-like substances is:
22. Which of the following tumors would be most likely
A. Adenocarcinoma. associated with abdominal stria, easy bruising, and
B. Large cell undifferentiated carcinoma. osteoporosis are associated with:
C. Small cell undifferentiated carcinoma.
D. Squamous cell carcinoma. A. Adrenal adenoma.
B. Craniopharyngioma.
C. Parathyroid adenoma.
D. Pheochromocytoma.
E. Thyroid adenoma.

274
23. Reed-Sternberg cells are characteristic of which of the 29. Of the following, the cell that is most likely to be
following diseases: damaged by ionizing radiation is:

A. Cat scratch disease. A. Fibroblast.

B. Chronic lymphocytic leukemia. B. Hepatocyte.
C. Histiocytosis X. C. Intestinal mucosal cell.
D. Hodgkin's disease. D. Neuron.
E. Thymoma E. Pancreatic islet cell.

24. The MOST frequent cause of symptomatic pulmonary 30. Which of the following is a masculinizing tumor of the
edema is: ovary:

A. Anaphylaxis. A. Dysgerminoma.
B. Infection. B. Granulosa cell tumor.
C. Left heart failure. C. Krukenberg tumor.
D. Shock. D. Mucinous cystadenoma.
E. Sertoli-Leydig cell tumor.
25. The MOST common cause of sudden death from
myocardial infarction is: 31. Factor VIII deficiency is associated with prolonged:

A. Angina pectoris. A. Bleeding time.

B. Arrhythmia. B. Clotting time.
C. Cardiac tamponade. C. Both.
D. Cardiogenic shock. D. Neither.
E. Ventricular aneurysm.
32. Which of the following is associated with an increased
26. Total functional regeneration of acutely injured liver is incidence of cancer:
dependent upon the degree of injury to:
A. Anthracosis.
A. Bile ducts. B. Asbestosis.
B. Central veins. C. Berylliosis.
C. Hepatocytes. D. Siderosis.
D. Portal veins. E. Silicosis.
E. Reticular framework.
33. An elderly male presents with a 3-month history of
27. A teratoma is most likely to arise in which of the severe throbbing pain and tenderness over the temple
following locations: The most likely diagnosis is:

A. Breast. A. Giant cell arteritis.

B. Kidney. B. Raynaud's disease.
C. Lung. C Rheumatoid arteritis.
D. Ovary. D. Syphilitic arteritis.
E. Prostate. E. Thromboangiitis obliterans.

28. Liver cells are an example of: 34. The pathogenic factor which appears to be responsible
for the majority of instances of cholelithiasis is:
A. Alternate cells.
B. Labile cells. A. Acute cholecystitis.
C. Permanent cells. B. Autoantibodies to bile.
D. Stable cells. C. Hemolysis.
D. High fat diet.
E. Supersaturation of bile with cholesterol

275
35. Traumatic skull fracture with tearing of the middle 41. Pooling of blood in capillary beds and venules due to
meningeal artery results in: impaired blood flow is known as:

A. Epidural hemorrhage. A. Congestion.

B. Hemorrhage in the base of the pons. B. Hyperemia.
C. Hemorrhage in the external capsule. C. Hypovolemia.
D. Subarachnoid hemorrhage. D. Shock.
E. Subdural hemorrhage. E. Vasoconstriction.

36. Which of the following features characterizes 42. Which of the following intracranial neoplasms has the
irreversible cell injury: highest incidence in adults:

A. Cellular swelling. A. Ependymoma.

B. Cytoplasmic granulation. B. Ganglioglioma.
C. Mitochondrial swelling. C. Glioblastoma multiforme.
D. Nuclear pyknosis. D. Neuroblastoma.
E. Polysome disaggregation. E. Oligodendroglioma.

37. Which of the following is embryologically related to

the paramesonephric duct: 43. In hypoxic cell injury, cellular swelling occurs because
of:
A. Gartner's duct.
B. Mesonephric duct. A. Active reabsorption of interstitial water.
C Mullerian duct. B. Osmotic influx of water due to increased cellular
D. Vitelline duct. glycogen.
E. Wolffian duct. C. Both.
D. Neither.
38. Fluid exudation and neutrophil emigration in acute
inflammation occur predominantly from: 44. Which of the following would favor a diagnosis of
ulcerative gastric carcinoma over a diagnosis of gastric
A. Arteries. peptic ulcer:
B. Arterioles.
C. Capillaries. A. Clean ulcer base.
D. Venules. B. Indurated ulcer margins.
E. Veins. C. Mucosal folds radiating from ulcer.
D. All of the above.
39. The most frequently identified neoplasm in the lung is:
45. The first blood cells to aggregate at the site of injury
A. Adenocarcinoma. usually are:
B. Bronchioloalveolar carcinoma.
C. Squamous carcinoma. A. Lymphocytes.
D. Undifferentiated carcinoma. B. Macrophages.
E. Metastatic carcinoma. C. Plasma cells.
D. Polymorphonuclear leukocytes
40. Tobacco smoking is closely associated with the
development of: 46. Necrosis of the renal papillae is MOST commonly seen
in patients with which of the following diseases:
A. Buerger's disease.
B. Giant cell arteritis. A. Chronic glomerulonephritis.
C. Polyarteritis nodosa. B. Chronic pyelonephritis.
D. Raynaud's disease. C. Diabetes mellitus.
E. Wegener's granulomatosis. D. Lupus erythematosus.

276
47. Mycosis fungoides is a lymphoma of which cell type: 52. The MOST malignant of testicular tumors is the:

A. B-celL A. Choriocarcinoma.
B. Langerhans celL B. Embryonal carcinoma.
C. Merckle celL C. Gonadal stromal tumor.
D. Null celL D. Seminoma.
E. T-celL
53. The disease most likely to cause nephrotic syndrome in
48. The most frequent site of venous thrombosis is the: a child is:

A. Brain. A. Focal sclerosis.

B. Kidney. B. Lipoid nephrosis.
C. Leg. C. Membranous glomerulonephritis.
D. Liver. D. Membranoproliferative glomerulonephritis.
E. Lung.
54. Most of the human papilloma viruses (HPV) associated
49. In the brain, which of the following cells are most with human malignant tumors are strains related to:
sensitive to anoxic damage:
A. Epidermodysplasia.
A. Astrocytes. B. Flat warts.
B. Ependyma. C. Immunosuppression.
C. Oligodendroglia. D. Sexual transmission.
D. Microglia.
E. Neurons. 55. Massive pUlmonary thromboemboli cause sudden
death because of:
50. Coagulation necrosis:
A. Acute cor pulmonale with arrhythmias.
A. Grossly appears soft with ill-defined borders. B. Acute pulmonary infarction.
B. Is characteristic of granulomatous inflammation. C. Asphyxia.
C. Is often associated with ischemia. D. Cerebral anoxia.
D. Results from lysosomal digestion of tissue. E. Massive hemoptysis.

51. Which of the following lesions of the colon and rectum 56. Of the following, the cerebrospinal fluid tinding most
is MOST common: consistent with acute bacterial meningitis is:

A. Juvenile adenoma. A. Increased glucose.

B. Pseudopolyp. B. Increased lymphocyte count.
C. Tubular adenoma. C. Increased protein.
D. Villous adenoma. D. Xanthochromia

DlRECTIONS (Items 57-70): Each of the numbered items or incomplete statements in this section is negatively phrased as indicated
by a capitalized word such as NOT, LEAST, or EXCEPT. Select the ONE lettered answer or completion that is BEST in each case.

57. Osteomalacia is associated with each of the following 58. Manifestations of right-sided heart failure might
EXCEPT: include all of the following EXCEPT:

A. Chronic renal insufficiency. A. Ascites.

B. Immobilization. B. Hepatic congestion.
C. Malabsorption states. C. Pulmonary edema.
D. Rickets. D. Splenomegaly.
E. Vitamin D deficiency.

277
59. Each of the following neoplasms are associated with 65. Each of the following could be considered an
the multiple endocrine neoplasia (MEN) syndromes obstructive disease EXCEPT:
EXCEPT:
A. Bronchial asthma.
A. Islet cell adenoma. B. Chronic bronchitis.
B. Medullary thyroid carcinoma. C. Mucoviscidosis.
C. Neuroblastoma. D. Pulmonary emphysema.
D. Pheochromocytoma. E. Pulmonary fibrosis.
E. Pituitary adenoma.
66. Each of the following cell types are capable of
60. Each of the following is characteristic of carcinoma of regeneration EXCEPT:
the vulva EXCEPT:
A. Astrocyte.
A. Affects post-menopausal age group. B. Cardiac muscle.
B. May be preceded by leukoplakia. C. Fibroblast.
C. Majority are derived from subcutaneous sweat D. Hepatocyte.
glands. E. Keratinocyte.
D. Regional node metastases often present at time of
diagnosis. 67. Which of the following clinical features is LEAST
likely to indicate a malignancy of the breast:
61. Causes of infertility include each of the following
EXCEPT: A. Alterations of breast contour.
B. Edema of the skin.
A. Cervical dysplasia. C. Nipple inversion.
B. Chronic salpingitis. D. Skin dimpling.
C. Endometriosis. E. Tenderness to palpation.
D. Leiomyomas.
E. Polycystic ovary disease. 68. Which of the following microscopic [mdings is LEAST
suggestive of Alzheimer's disease:
62. Common complications of alcoholic cirrhosis of the
liver include all of the following EXCEPT: A. Granulovacuolar degeneration.
B. Increased neuronal lipofuscin pigmentation.
A. Ascites. C. Neurofibrillary tangles.
B. Bleeding abnormalities. D. Senile plaques.
C. Cholelithiasis.
D. Enlarged spleen. 69. Which of the following disorders would bt: LEAST
E. Jaundice. likely to present as gross hematuria in a 46 yt:ar old
male:
63. Primary biliary cirrhosis is typically associated with
each of the following EXCEPT: A. Adult polycystic disease.
B. Carcinoma of the urinary bladder.
A. Alcohol abuse. C. Renal calculi.
B. Hyperlipidemia. D. Renal cell carcinoma.
C. Jaundice. E. Wilms' tumor.
D. Middle-aged women.
E. Pruritus. 70. Each of the following is a typical feature of breast
carcinoma as it grows and spreads EXCEPT:
64. All of the following cell types are found in acute and/or
chronic inflammatory reactions EXCEPT: A. Bone pain.
B. Enlargement of axillary lymph nodes.
A. Lymphocytes. C. Lung metastases.
B. Macrophages. D. Hormone production.
C. Megakaryocytes. E. Retraction of the nipple.
D. Plasma cells.
E. Polymorphonuclear leukocytes.

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 ANSWER KEY- EXAM A

I. D 1I. D 2I. D 3I. E 4I. e 5I. e 6I. E

2. E 12. e 22. D 32. A 42. E 52. B 62. D
3. B 13 . B 23. E 33. B 43. e 53. E 63. D
4. A 14. E 24. A 34. e 44. e 54. B 64. A
5. D 15. E 25. B 35. e 45. e 55. A 65. E
6. A 16. A 26. A 36. B 46. E 56. B 66. D
7. A 17. B 27. A 37. D 47. B 57. D 67. e
8. A 18. e 28. D 38. D 48. A 58. D 68. D
9. D 19. e 29. D 39. e 49. E 59. A 69. e
10. E 20. E 30. E 40. B 50. D 60. B 70. A

ANSWER KEY - EXAM B

I. e 11. A 2I. e 3I. B 4I. A 5I. e 6I. A

2. e 12. e 22. A 32. B 42. e 52. A 62. e
3. B 13 . A 23. D 33. A 43. D 53. B 63. A
4. A 14. B 24. e 34. E 44. B 54. D 64. e
5. e 15. B 25. B 35. A 45. D 55. A 65. E
6. D 16. e 26. E 36. D 46. e 56. e 66. B
7. A 17. D 27. D 37. e 47. E 57. B 67. E
8. e 18. e 28. D 38. D 48. e 58. e 68. B
9. A 19. D 29. e 39. E 49. E 59. e 69. E
10. D 20. A 30. E 40. A 50. A 60. e 70. D

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