Gynecologic Pathology [2 ed.]

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Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 GYNECOLOGIC PATHOLOGY, SECOND EDITION Copyright © 2021 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-35909-2

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Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous edition copyrighted 2009. ISBN: 978-0-323-35909-2

  

Content Strategist: Michael Houston Content Development Specialist: Angie Breckon Publishing Services Manager: Deepthi Unni Senior Project Manager: Manchu Mohan Design Direction: Amy Buxton    Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

Preface

All disciplines in the field of surgical pathology are constantly evolving, and female genital tract pathology is no exception. The last decade has brought remarkable progress in terms of our understanding of gynecologic disease and the role of tissue-based morphologic and molecular testing in its diagnosis. This second edition of Gynecologic Pathology, a volume in the Foundations in Diagnostic Pathology series, incorporates these advances using a schematic and simplified layout. In keeping with the highly successful format of the series, information is presented in both paragraph and bullet-point forms, and complemented by more than 1150 high-quality photographs. Each topic contains relevant clinical aspects including management and prognostic factors. The pathology information is organized in a systematic fashion: in addition to the key macroscopic and histopathologic features, emphasis is given to the role of ancillary testing (histochemistry, immunohistochemistry, and/ or molecular diagnostics). As a major element, the section of differential diagnosis discusses pitfalls and distinguishing characteristics helpful in the diagnostic work-up. The information contained in this volume aims to be practical and applicable to most practice settings. We also incorporate emerging evidence and practice recommendations that, while still in the process of being validated and implemented, are likely to become

standard of care in the future. Prime examples of this are the molecular-based classification of endometrial carcinoma and the role of molecular testing in the classification of uterine sarcomas. This book is the product of the scholarly work of experts in the fields of gynecologic pathology, dermatopathology, and cytopathology. Each author has not only extensive knowledge in their areas of practice, but also great passion for education. Their expertise and dedication is reflected in the high quality and educational value of the chapters. As editors, we were honored and educated by their contributions, for which we are deeply grateful. New to this second edition is the expansion to 21 chapters (from 17 in the first edition), including two new chapters on non-neoplastic lesions of the cervix and cytology in the practice of gynecologic pathology. We also cover the role of immunohistochemistry and molecular testing throughout the text and in a chapter fully devoted to this topic. We hope that the reader, whether a student or an experienced pathologist, finds in this reference a simple yet comprehensive tool to navigate through the practice of gynecologic pathology. Marisa R. Nucci, MD and Carlos Parra-Herran, MD, FASCP

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Other books in this series  Busam: Dermatopathology, 2e 978-0-323-26191-3

 Folpe and Inwards: Bone and Soft Tissue Pathology 978-0-4430-6688-7

 Hsi: Hematopathology, 3e 978-0-323-47913-4

 Iacobuzio-Donahue and Montgomery: Gastrointestinal and Liver Pathology, 2e 978-1-437-70925-4

 Marchesvsky, Abdul-Karim, and Balzer: Intraoperative Consultation 978-1-4557-4823-5

 O’ Malley, Pinder, and Mulligan: Breast Pathology, 2e 978-1-4377-1757-0

 Prayson: Neuropathology, 2e 978-1-4377-0949-0

 Procop and Pritt: Pathology of Infectious Diseases 978-1-4377-0762-5

 Thompson: Head and Neck, 3e 978-0-323-47916-5

 Zhou and Magi-Galluzzi: Genitourinary Pathology, 2e 978-0-3231-8827-2

 Zander: Pulmonary Pathology, 2e 978-0-323-39308-9

Acknowledgements

The editors thank each of the authors of this second edition for their invaluable work, patience, and collegiality throughout the entire process of bringing this book to completion. We also want to acknowledge the following authors of the first edition of Gynecologic Pathology: • • • • • • • • • •

Timothy R. Quinn Sanjay Logani Maureen L. Harmon Kumarasen Cooper David W. Kindelberger Isabel Alvarado-Cabrero Michael T. Deavers Patricia Baker Russell Vang Brigitte M. Ronnett

A special note of gratitude goes to Dr. Esther Oliva, co-editor and author of the first edition, for her previous contributions which certainly added to the success of the first iteration of this book.

To our mentors, we extend our deepest gratitude for giving us foundations that allowed us to complete this work. Marisa R. Nucci wants to acknowledge Christopher Crum and Christopher Fletcher. Carlos Parra-Herran wants to acknowledge Drs. Martha Cabarcas, Lilia Sanchez, Rocio Lopez, C. Felipe Villamil, Monica Garcia-Buitrago, Christopher Crum, Bradley Quade, Theonia Boyd, Sharon Nofech-Mozes, and Wedad Hanna for their mentorship and guidance, and Dr. Marisa R Nucci for being a role model, colleague, and friend like no other. Lastly, we thank the editorial team at Elsevier, in particular Angie Breckon, Michael Houston and Manchu Mohan for their continuous support and professionalism. Marisa R. Nucci, MD and Carlos Parra-Herran, MD, FASCP

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To my family—my loving husband Branch, my two beautiful sons Julian and Cole, and our rambunctious but adorable cattle dog Rusty. Marisa R. Nucci, MD To my mom for her endless love, sacrifice, and insuperable example; to my dad, my brothers, and their families for being a continuous source of support and inspiration; and to Chris for being the best part of my day and the brightest part of my future, today and always. Carlos Parra-Herran, MD, FASCP

List of Contributors

Bojana Djordjevic, MD Staff Pathologist Anatomic Pathology Sunnybrook Health Sciences Centre Associate Professor Laboratory Medicine and Pathobiology University of Toronto Toronto, Ontario, Canada Oluwole Fadare, MD Professor of Pathology and Chief of Anatomic Pathology University of California San Diego La Jolla, California, United States C. Blake Gilks, MD Professor Pathology and Laboratory Medicine Vancouver General Hospital and University of British Columbia Vancouver, British Columbia, Canada Beth Harrison, MD Associate Pathologist Department of Pathology Brigham and Women’s Hospital Instructor Department of Pathology Harvard Medical School Boston, Massachusetts, United States Lynn N. Hoang, MD, FRCP(C) Gynecologic Subspecialist Pathologist Anatomical Pathology Vancouver General Hospital Vancouver, British Columbia, Canada Mary Kinloch, MD, FRCP(C) Gynecologic Pathologist Pathology and Laboratory Medicine Division of Anatomical Pathology University of Saskatchewan Saskatoon, Saskatchewan, Canada

Teri A. Longacre, MD Professor of Pathology Department of Pathology Stanford University School of Medicine Stanford, California, United States Xavier Matias-Guiu, MD, PhD Professor of Pathology Hospital Universitari Arnau de Vilanova (IRBLLEIDA), University of Lleida Hospital Universitari de Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain Anais Malpica, MD Professor Departments of Pathology and Gynecologic Oncology University of Texas MD Anderson Cancer Center Houston, Texas, United States Jelena Mirkovic, MD, PhD Staff Pathologist Anatomic Pathology Sunnybrook Health Sciences Centre Assistant Professor Laboratory Medicine and Pathobiology University of Toronto Toronto, Ontario, Canada W. Glenn McCluggage, FRCPath Professor of Gynecological Pathology Department of Pathology Royal Group of Hospitals Trust Belfast, Northern Ireland, United Kingdom Marisa R. Nucci, MD Professor of Pathology Harvard Medical School Director Division of Women’s and Perinatal Pathology Department of Pathology Brigham and Women’s Hospital Boston, Massachusetts, United States

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LIST OF CONTRIBUTORS

Kay J. Park, MD Associate Attending Pathologist Department of Pathology Memorial Sloan Kettering Cancer Center New York, United States

Christopher R. Shea, MD Eugene J. Van Scott Professor Chief, Section of Dermatology University of Chicago Chicago, Illinois, United States

Carlos Parra-Herran, MD, FASCP Associate Professor Department of Laboratory Medicine and Pathobiology University of Toronto Pathologist Department of Laboratory Medicine Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Ie-Ming Shih, MD, PhD Richard W. TeLinde Distinguished Professor Gynecology and Obstetrics Johns Hopkins University Director of Breast and Ovarian Cancer Program Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore, Maryland, United States

Victor G. Prieto, MD, PhD Professor and Chair Ferenc and Phyllis Gyorkey Chair for Research and Education in Pathology Department of Pathology University of Texas MD Anderson Cancer Center Houston, Texas, United States

Robert A. Soslow, MD Attending Pathologist Memorial Sloan Kettering Cancer Center Professor of Pathology and Laboratory Medicine Weill Cornell Medical College New York, United States

C. Matthew Quick, MD Associate Professor of Pathology Department of ­Pathology University of Arkansas for Medical ­Sciences Little Rock, Arkansas, United States

David C. Wilbur, MD Professor of Pathology Department of Pathology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, United States

Gynecologic Pathology Second EDITION A Volume in the Series Foundations in Diagnostic Pathology Editors

Marisa R. Nucci, MD

Professor of Pathology Harvard Medical School Director Division of Women’s and Perinatal Pathology Department of Pathology Brigham and Women’s Hospital Boston, Massachusetts, United States

Carlos Parra-Herran, MD, FASCP Associate Professor Department of Laboratory Medicine and Pathobiology University of Toronto Pathologist Department of Laboratory Medicine Sunnybrook Health Sciences Centre Toronto, Ontario, Canada

Series Editor

John R. Goldblum, MD, FCAP, FASCP, FACG Chairman, Department of Anatomic Pathology The Cleveland Clinic Foundation Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland, Ohio, United States Philadelphia, Pennsylvania, United States

1 Inflammatory Diseases of the Vulva nn Lynn N. Hoang and Mary Kinloch

nn INTRODUCTION Almost any inflammatory dermatological condition occurring on nongenital skin can afflict the vulva. Histopathologic diagnosis in the vulva, however, is often complicated by its unique anatomy (where there is increased occlusion, friction, and moisture, causing a variety of secondary changes), delayed seeking of medical attention due to patient embarrassment, and the use of self-treatment regimens which may not be readily divulged to the treating clinician. Moreover, vulvar dermatoses exhibit varying histologic features depending on the course of the disease and when the biopsy was taken. A patient may have endured multiple trials of recalcitrant treatments before a biopsy is eventually obtained. In the setting of vulvar inflammatory dermatoses, it must be emphasized that clinical information is of utmost importance to arrive at an accurate diagnosis. The initial histologic approach to any inflammatory disorder of the skin or mucosa requires knowledge of the precise anatomic location and an appreciation of the alterations in the regional mucocutaneous anatomy. The mons pubis and labia majora closely resemble skin from other anatomic regions of the body and are composed of a slightly rugose, keratinizing, stratified epithelium containing all of the cutaneous adnexal structures and a richly vascular dermis. Areas of compact stratum corneum, in addition to the conventional basket-weave stratum corneum, are a normal finding in the mons pubis/labia majora. The labia minora, in contrast, have a stratified, glycogen-rich squamous epithelium. Adnexal structures are absent. On each side, the mucocutaneous junction between the labium majus and labium minus (also known as Hart’s line) may exhibit a focal zone of parakeratosis and should not be mistaken for a pathologic abnormality. The subjacent dermis is highly vascular and contains erectile tissue. The next step in evaluating an inflammatory process is the identification at low power of the major tissue reaction pattern, followed by the pattern of inflammation. Detailed descriptions of this approach, championed initially in the teachings of Wallace Clark, have been further popularized and refined by Ackerman, Weedon, and LeBoit. The tissue reaction pattern is a distinctive group of

morphologic findings which allows the observer to place a biopsy within a specific group of cutaneous diseases. This rational framework was also adopted by the 2006 International Society for the Study of Vulvovaginal Disease (ISSVD) classification of vulvar dermatoses (Table 1.1). The pattern of inflammation refers to the distribution of the inflammatory infiltrate within the dermis and subcutis (Box 1.1). Once the major tissue reaction pattern and pattern of inflammation are identified, the pathologist can generate a working differential diagnosis (Table 1.1). In 2011, the ISSVD published a separate clinically oriented framework to classify vulvar dermatoses, allowing the clinician to generate a differential diagnosis based on macroscopic features (Table 1.2). This 2011 ISSVD framework serves as an adjunct tool to aid in diagnosis and was meant to supplement, not supplant, the 2006 classification scheme. The above approach can be applied to the most common inflammatory disorders of the vulva, which should allow the pathologist to categorize lesions and generate a rational differential diagnosis. This, in turn, will allow the clinician to develop a meaningful treatment plan.

nn SPONGIOTIC (ECZEMATOUS) REACTION PATTERN The terms “eczema” and “eczematous dermatidities” are clinical terms used to describe a variety of lesions that share similar clinical and histologic features (spongiotic dermatitis), but often are etiologically unrelated. Eczematous dermatitis can be due to intrinsic factors (atopic dermatitis and seborrheic dermatitis) or be triggered by extrinsic agents (irritant contact dermatitis [ICD]). All eczematous dermatidities demonstrate epidermal spongiosis during their evolution, clinically seen as crusted patches and plaques, papules and vesicles, and, at the far end of the spectrum, frank bullous lesions and, rarely, ulceration. The histologic changes of spongiotic dermatitis typically affect the epidermis and sometimes upper dermis, while the lower dermis, follicular infundibula, and acrosyringia are spared. The cardinal histologic feature of the spongiotic (eczematous) epidermal reaction pattern is spongiosis, seen histologically as an increase in 1

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TABLE 1.1 Adapted 2006 ISSVD Classification of Vulvar Dermatoses: Pathologic Subsets and Clinicopathologic Correlation a Pattern

Characteristic Morphologic Feature

Clinical Correlation

Spongiotic (Eczematous) Pattern

Epidermal edema

Atopic dermatitis Allergic dermatitis Irritant contact dermatitis

Acanthotic Pattern

Epidermal hyperplasia

Psoriasis Lichen simplex chronicus - Primary/idiopathic - Secondary (superimposed on lichen sclerosus, lichen planus, or other)

Lichenoid Pattern

Band-like lymphocytic infiltrate at dermal–epidermal junction with basal keratinocyte damage

Lichen sclerosus Lichen planus Erythema multiforme

Dermal Homogenization/ Sclerosis Pattern

Dermal sclerosis

Lichen sclerosus

Vesiculobullous Pattern

Subepidermal or intraepidermal blister formation

Pemphigoid, cicatricial type Linear IgA disease

Acantholytic Pattern

Clefting of epithelial cells due to breakage of intercellular junctions

Hailey-Hailey disease Darier disease Papular genitocrural acantholysis

Granulomatous Pattern

Granulomas

Crohn disease Melkersson-Rosenthal syndrome Tuberculosis

Vasculopathic Pattern

Vascular injury

Aphthous ulcers (Non-sexually related acute genital ulcers, aka Lipschutz ulcer) Behcet disease Plasma cell vulvitis

ISSVD, International Society for the Study of Vulvovaginal Disease. aThe ISSVD excludes vulvar infections.

BOX 1.1

TABLE 1.2

Patterns of Inflammation

2011 ISSVD Classification of Vulvar Dermatological Disorders

Superficial perivascular inflammation Superficial and deep perivascular inflammation Folliculitis and perifolliculitis Panniculitis

Skin-colored lesions Red lesions: patches and plaques Red lesions: papules and nodules White lesions

the intercellular space between keratinocytes, due to the accumulation of edema fluid within the epidermis. As the vulvar skin is often confined by clothing, secondary changes such as crusting are also frequently found. If the severity of the response increases, there is widening of the intercellular space, eventuating in desmosomal rupture, followed by formation of vesicles within the epidermis. These vesicles may contain fluid, lymphocytes, Langerhans cells, and acantholytic or ruptured keratinocytes. Due to the laxity of the vulvar skin, vesicle formation is generally less common than in other parts of the body. In very severe cases, erosions and ulceration may occur. Chronic lesions can become progressively lichenified and

Dark-colored (brown, blue, gray, or black) lesions Blisters Erosions and ulcers Edema (diffuse genital swelling) ISSVD, International Society for the Study of Vulvovaginal Disease.

evolve into lesions that resemble lichen simplex chronicus (LSC). At this stage, changes related to the inciting event will likely have dissipated. Although absolute histologic distinction between the various categories of spongiotic dermatitis is not possible, there are some features that may be utilized to favor a

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FIG. 1.1 Atopic dermatitis. Psoriasiform epidermal hyperplasia is associated with parakeratosis and spongiotic microvesicles. There is also lymphocyte exocytosis and a perivascular lymphohistiocytic infiltrate.

more specific clinical-pathologic correlate. In many cases, arrival at the correct diagnosis is contingent on the clinical history. The most important differential considerations in genital skin will be discussed.

nn ATOPIC DERMATITIS CLINICAL FEATURES Atopic dermatitis is a chronic, pruritic process which occurs in individuals (more often men) with a personal or family history of atopic diathesis (including asthma, allergic rhinitis, allergic conjunctivitis). The disease usually first manifests during childhood as an erythematous papulovesicular rash involving the flexural and extensor surfaces of the extremities. The lesions evolve towards scaly lichenified patches and plaques over time. The vulva is infrequently involved.

epidermal hyperplasia with parakeratosis (Fig. 1.1), and a decrease in the extent of spongiosis. Chronic lesions display more marked psoriasiform epidermal hyperplasia and lichenification with very mild to absent spongiosis. Further lichenification produces prominent hyperkeratosis with “vertical streaking” of collagen in the papillary dermis, leading ultimately to LSC.

DIFFERENTIAL DIAGNOSIS The distinction between atopic dermatitis, allergic contact dermatitis (ACD), and ICD (drug, ingestant, scabetic infestation, others) is difficult without clinicopathologic correlation. Direct immunofluorescence can be performed if there is a vesiculobullous lesion associated with eosinophils, to rule out pemphigus vegetans or bullous pemphigoid. Chronic lesions can resemble psoriasis histologically. Unlike the regular pattern of epidermal hyperplasia found in psoriasis, the rete ridges in advanced stages of a chronic eczematous dermatitis are generally irregular in both length and width.

MICROSCOPIC FEATURES Atopic dermatitis features the classic histologic changes of spongiotic dermatoses. In acute lesions, there is intercellular, and to some extent, intracellular edema of the lower epidermis with epidermal and perivascular infiltration by lymphocytes. Perivascular eosinophils are rare. Subacute lesions exhibit increasing psoriasiform

PROGNOSIS AND TREATMENT Most cases of atopic dermatitis resolve spontaneously by the age of 30. Treatment is aimed towards hydration of the skin, minimizing triggering factors and symptoms, and decreasing inflammation. The latter is usually achieved

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with topical steroids. Nonsteroidal immunosuppressive agents such as tacrolimus are also considered as they have fewer disadvantages compared with chronic steroid use.

TABLE 1.3 Potential Causes of Allergic Contact and Irritant Contact Dermatitis in the Vulva.

ATOPIC DERMATITIS—FACT SHEET

Endogenous

Urine, feces, sperm

Definition n Chronic pruritic dermatitis in individuals with personal or family history of atopic diathesis (atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis)

Exogenous

Detergents, soaps/shampoos, perfume/deodorants, fabrics/wools, textile dyes, sanitary napkins, antiseptics/disinfectants, spermicides, latex, nickel, cosmetic fillers (silicone, hyaluronic acid)

Drugs

Antibiotics/Neosporin, corticosteroids, anesthetics (benzocaine in Vagisil), imiquimod, podophyllin

Incidence n Common n ∼20% of infants and young children symptomatic, 90% before age 5 Morbidity n Predisposition to infection due to compromised cutaneous barrier Gender and Race n Increased risk in males n Increased risk in people of African or Asian descent Clinical Features n Erythematous papulovesicular rash in flexural and extensor surfaces of arms and legs n Sometimes vulvar involvement, particularly in children n Scaly lichenified patches and plaques n Secondary infection may occur Prognosis and Treatment n Generally spontaneous remission throughout childhood n Few cases persist over age 30 n Treatment includes hydration of skin, minimizing trigger factors, relief of pruritus, and decreasing inflammation n Topical steroids and nonsteroidal immune modulators

ATOPIC DERMATITIS—PATHOLOGIC FEATURES Microscopic Findings Acute Lesion n Intercellular edema of lower epidermis n Exocytosis of lymphocytes n Perivascular lymphohistiocytic infiltrate with occasional eosinophils and rarely neutrophils n  Epidermis of normal thickness with normal basket-weave stratum corneum n Can have edema of papillary dermis Subacute Lesion n Psoriasiform epidermal hyperplasia with parakeratosis n Serum crust can form, made of proteinaceous debris, neutrophils, and parakeratotic cells n Variable lymphocyte exocytosis Chronic Lesion n Marked psoriasiform epidermal hyperplasia n Compact hyperkeratosis, hypergranulosis, and less parakeratosis n Mild to absent spongiosis and lymphocyte exocytosis n Can resemble lichen simplex chronicus Differential Diagnosis n Contact dermatitis n Spongiotic hypersensitivity reaction n Pemphigus vegetans or bullous pemphigoid

nn ALLERGIC CONTACT DERMATITIS ACD is a type IV hypersensitivity reaction initiated by contact with an allergen to which an individual has been previously exposed and sensitized. Lesions typically develop within 12–48 hours following exposure to the allergen. Numerous chemical, biological, and physical agents can elicit this reaction pattern (Table 1.3). Exposure to the offending agent may be related to the patient’s occupation or daily hygiene routines. Topical medications, fragrances, and preservatives are the most common causes of ACD. Patch testing with an allergist can be helpful to identify the offending agent.

CLINICAL FEATURES ACD is more frequent in females and in white persons. Common findings include a pruritic papulovesicular eruption, discretely patterned crusted plaques, or, occasionally, bizarre-appearing patterns, depending on the extent of contact with the agent.

MICROSCOPIC FEATURES In acute episodes, the spongiosis is limited to the lower epithelium, and the stratum corneum remains uninvolved. With persistent allergen exposure, there is formation of coalescing vesicles at various levels of the epidermis, imparting a “Swiss-cheese” appearance (Fig. 1.2). Intraepithelial inflammatory cells are usually lymphocytes (rarely eosinophils). Chronic forms feature progression from a spongiotic to a lichenoid pattern like in atopic dermatitis.

DIFFERENTIAL DIAGNOSIS See atopic dermatitis section.

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FIG. 1.2 Allergic contact dermatitis. Spongiosis leads to the formation of microvesicles within the epithelium imparting a “Swiss-cheese” appearance. There is associated lymphocyte exocytosis. The stratum corneum remains unchanged, in keeping with the acute nature of the insult.

PROGNOSIS AND TREATMENT Removal of, or protection from the offending agent is paramount. Without it, the disease will persist, leading to longer and more severe episodes, and to complications such as infection. In addition, treatment includes shortterm topical corticosteroid therapy to reduce inflammation, and emollients to allow the reestablishment of the barrier function of the skin. ALLERGIC CONTACT DERMATITIS—FACT SHEET Definition n  Type IV hypersensitivity reaction initiated by contact with allergen to which an individual has been previously sensitized

ALLERGIC CONTACT DERMATITIS—PATHOLOGIC FEATURES Microscopic Findings n Spongiotic microvesicles within various levels of epidermis (“Swisscheese” appearance) n  Exocytosis of lymphocytes and eosinophils (eosinophilic spongiosis) n Unchanged stratum corneum in acute reaction n  Epidermal hyperplasia and diminution of spongiosis if persistent allergen Differential Diagnosis n Atopic dermatitis n Eczematous hypersensitivity reaction n Pemphigus vegetans or bullous pemphigoid

Incidence n Common (4%–7% of all dermatologic consultations) Morbidity n  R elapse and chronicity from reexposure to offending antigen, particularly occupational exposure n May impact individual occupational choices Gender and Race n Approximately twice as common in females as in males n More frequent in whites than in other racial groups Clinical Features n Pruritic papulovesicular eruption n Circumscribed crusted plaques n Occasionally bizarre-appearing patterns Prognosis and Treatment n Excellent prognosis if removal or protection from offending agent n Emollients and short-term topical steroid therapy

nn IRRITANT CONTACT DERMATITIS In contrast to ACD, ICD is caused by the direct effect of an irritant compound on an epithelial surface, and therefore occurs rapidly (minutes to hours) after exposure to the agent, not requiring prior sensitization. Offending agents can be similar to that seen with ACD (Table 1.3).

CLINICAL FEATURES Females are more frequently affected than males, with no particular genetic predisposition. A large range of clinical appearances may be seen, including erythema, eczematous

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GYNECOLOGIC PATHOLOGY

changes, vesiculobullous lesions, and epidermal necrosis. Lesions tend to be confined to the areas of contact with the offending agent, thus often sparing the genitocrural folds.

MICROSCOPIC FEATURES In contrast to ACD, the agent responsible for ICD produces direct injury to the epidermis. The degree and

FIG. 1.3 Irritant contact dermatitis. Direct injury to the epidermis manifests acutely with necrosis and epithelial denudation. Adjacent remaining epithelium shows spongiosis and infiltration by neutrophils, which also infiltrate the superficial dermis along with lymphocytes and macrophages.

FIG. 1.4 Irritant contact dermatitis. This example has only mild spongiosis with accumulation of Langerhans cells within the spaces. The superficial dermis is edematous.

severity of the epidermal injury varies based on the nature, potency, and concentration of the irritant. Histologically, common changes include ballooning degeneration of the surface keratinocytes with subsequent necrosis and surrounding epidermal spongiosis. Neutrophil infiltration is seen in areas of epidermal necrosis (Fig. 1.3). The underlying superficial dermis contains perivascular inflammation composed of lymphocytes, macrophages and, frequently, neutrophils. Interstitial edema and vasodilatation are also present (Fig. 1.4).

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CHAPTER 1  Inflammatory Diseases of the Vulva

DIFFERENTIAL DIAGNOSIS See atopic dermatitis section.

PROGNOSIS AND TREATMENT Removal of, or protection from, the offending agent is paramount to prevent recurrences. Management aims to restore the skin’s barrier function. Topical applications containing ceramides may be particularly helpful. Corticosteroids and immune modulators are in general not recommended. IRRITANT CONTACT DERMATITIS—FACT SHEET Definition n Dermatitis initiated by direct effect of an irritant compound on epithelial surface Incidence n Common Morbidity n Significant long-term sequelae possible if chronic exposure Gender, Race, and Age Distribution n  More common in women than men, secondary to environmental rather than genetic factors n No age or racial predilection Clinical Features n  Wide range of clinical appearances, including erythema, eczematous changes, vesiculobullous lesions, and epidermal necrosis n  Lesions often well-demarcated (confined to areas of contact with offending agent and sparing genitocrural folds) Prognosis and Treatment n  Excellent prognosis if removal of, or protection from, offending agent n Emollients reestablish cutaneous barrier function n Topical steroids and immune modulators not helpful

IRRITANT CONTACT DERMATITIS—PATHOLOGIC FEATURES Microscopic Findings n Ballooning degeneration and necrosis of surface keratinocytes n Neutrophil exocytosis in areas of epidermal necrosis n Interstitial edema and vasodilatation n  Chronic cases can form pseudoverrucous papules, nodules, and dermal fibrosis Differential Diagnosis n Allergic contact dermatitis (ACD) n Eczematous hypersensitivity reaction n Pemphigus vegetans or bullous pemphigoid

nn SEBORRHEIC DERMATITIS CLINICAL FEATURES Seborrheic dermatitis is a common eczematous dermatitis occurring in areas of the skin that have the greatest number of sebaceous glands (scalp, face, chest, upper back, axillae, and anogenital skin). Not surprisingly, men are more commonly affected than women. Most patients present during the fourth to fifth decade; however, an infantile form (in babies during first three months) has been described. The affected vulvar skin, more commonly the genitocrural folds, is erythematous with scaling “bran-like” papules and plaques with a “greasy yellow” appearance. Immunosuppressed patients, especially those with human immunodeficiency virus (HIV) infection, have a higher prevalence of this disease. The pathogenesis is unknown; however, Malassezia species (Pityrosporum) has been implicated as an etiologic factor; in many patients, flares of the disease correlate with proliferation of Malassezia spp. and respond to antifungal agents. It is thought that the yeast triggers an immunologic response affecting the hair-bearing epidermis.

MICROSCOPIC FEATURES In its acute form, seborrheic dermatitis features mild spongiosis with a parakeratotic scale crust containing scattered neutrophils (Fig. 1.5). The papillary dermis is mildly edematous with a mixed perivascular inflammatory infiltrate (composed of lymphocytes, histiocytes and, rarely, neutrophils) involving the superficial plexus. As lesions progress, psoriasiform hyperplasia appears and becomes extensive with parafollicular accentuation of the parakeratotic scale (“shoulder parakeratosis”) (Fig. 1.6). Neutrophils are commonly observed within the scale crust and within spongiotic foci. In chronic lesions, the psoriasiform hyperplasia is prominent and the parakeratotic scale crust may extend into the interfollicular epidermis.

DIFFERENTIAL DIAGNOSIS The presence of neutrophilic parakeratosis and psoriasiform epidermal hyperplasia raises consideration of psoriasis. Features in favor of seborrheic dermatitis are irregular elongation of the epidermal rete, accentuation of parakeratosis and scale crusts about the follicular ostia, and predilection of the follicular and epidermal spongiosis toward the upper layers of the epidermis. However, distinction can be difficult. Neutrophil-rich parakeratosis is also a feature observed in many impetiginized eczematous dermatitis. A tissue Gram stain is a helpful adjunct in excluding this possibility.

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FIG. 1.5 Seborrheic dermatitis. As in other spongiotic dermatoses, there is psoriasiform epidermal hyperplasia with spongiosis and a parakeratotic scale crust. A lymphohistiocytic infiltrate can be seen in the papillary dermis.

FIG. 1.6 Seborrheic dermatitis. Parakeratosis is characteristically accentuated around the opening of the hair follicles (“shoulder parakeratosis”). Also note the presence of neutrophils in the scale crust and areas of spongiosis.

GYNECOLOGIC PATHOLOGY

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PROGNOSIS AND TREATMENT Seborrheic dermatitis generally exhibits a mild chronic clinical course with little discomfort. Treatment is directed towards removal of the scales with keratolytics, followed by sparing use of topical corticosteroids. Topical antifungal agents (i.e., ketoconazole, ciclopirox) constitute an important adjunct in therapy and tend to reduce or eliminate the need for steroid therapy over time when used consistently. Resistance to therapy may be a sign of immunodeficiency, particularly HIV infection.

ACANTHOTIC EPIDERMAL REACTION PATTERN The acanthotic reaction pattern is defined by an increase in the number of keratinocytes in the epidermis, leading to overall thickening of the epidermis. “Psoriasiform hyperplasia” and historically “squamous cell hyperplasia,” are terms that have also been used to describe this reaction pattern.

nn PSORIASIS SEBORRHEIC DERMATITIS—FACT SHEET Definition n  Common eczematous dermatitis occurring on skin with greatest number of sebaceous glands Incidence n Common; approximately 5% prevalence Morbidity n Cosmetic Gender, Race, and Age Distribution n More common in men than women n No racial predisposition n Common in fourth to fifth decade n Self-limited infantile form in first 3 months of life Clinical Features n Erythematous skin, with papules and plaques with fissures causing “bran-like” scale and “greasy yellow” appearance n Most affect the genitocrural folds n  Extensive therapy-resistant seborrheic dermatitis may indicate underlying HIV infection Prognosis and Treatment n Mild clinical course with little discomfort other than cosmetic concerns n Removal of scale with keratolytics followed by sparing use of corticosteroids and antifungal agents

SEBORRHEIC DERMATITIS—PATHOLOGIC FEATURES Microscopic Findings Acute Lesion n Mild spongiosis with neutrophilic parakeratosis n  Papillary dermal edema and lymphohistiocytic perivascular infiltrate Advanced Lesion n  Substantial psoriasiform hyperplasia and “shoulder parakeratosis” (perifollicular accentuation of parakeratosis) Differential Diagnosis n Psoriasis n Impetiginized eczema

Psoriasis is the prototype of a group of dermatoses characterized by epidermal hyperplasia.

CLINICAL FEATURES Psoriasis is a chronic dermatitis characterized by a hyperproliferative epidermis. It is a common disorder, affecting 2%–4% of whites (less frequently other ethnicities). The disease usually manifests during early adulthood. Vulvar involvement can be a manifestation of the classic, generalized form or of the so-called inverse psoriasis which affects intertriginous areas. The most common clinical vulvar presentation is a pruritic, bilaterally symmetrical, erythematous, well-demarcated, nonscaly, macular eruption or plaque, as opposed to patches and plaques with a “silvery” scale typical of other anatomic regions. The anatomic distribution is wide, and most patients that present with a vulvar psoriasiform lesion will have evidence of lesions elsewhere on the body. These lesions tend to concentrate in areas of persistent trauma or friction (elbows, knees, sacrum, scalp, and intertriginous areas). Other triggers include drugs and infections. Superinfection by yeast, fungi, and bacteria is possible.

MICROSCOPIC FEATURES Psoriasis, like many other dermatoses, has a range of microscopic changes that evolve over time. Early lesions have a nonspecific spongiotic epidermal reaction pattern that includes superficial dermal vascular congestion, edema, and lymphocyte-rich perivascular inflammation. As lesions progress, a characteristic (“psoriasiform”) pattern of epithelial hyperplasia appears, characterized by regular acanthosis, elongation of the rete ridges, thinning of the suprapapillary plates, and loss of the granular cell layer (hypogranulosis) (Fig. 1.7). Other typical findings

10 include mounds of neutrophil-rich parakeratosis and increased basal mitotic activity. Confluence of neutrophilic aggregates within the parakeratosis is seen in mature lesions. Intraepidermal neutrophil collections located in the stratus corneum are termed “Munroe microabscesses,” whereas those in the spinous layer are called “spongiform pustules of Kogoj” (Fig. 1.8). The accompanying epidermal hyperplasia has a regular appearance, characteristically with intervening thinned suprapapillary plates and

FIG. 1.7 Psoriasis. This lesion exhibits evenly distributed (regular) acanthosis, patchy loss of the granular layer (hypogranulosis), and thinning of the suprapapillary plates.

FIG. 1.8 Psoriasis. This mature lesion shows confluent neutrophil-rich parakeratosis and hypogranulosis. Neutrophil collections are seen within the stratum corneum (“Munroe microabscesses”) and the stratus spinosum (“spongiform pustules of Kogoj”).

GYNECOLOGIC PATHOLOGY

subjacent dilated capillaries, frequently in immediate apposition to the overlying epidermis (Fig. 1.9).

DIFFERENTIAL DIAGNOSIS Late-stage lichen simplex chronicus can be distinguished from psoriasis by the presence of thicker suprapapillary

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CHAPTER 1  Inflammatory Diseases of the Vulva

plates, hypergranulosis, and thickened vertically oriented collagen bundles within the papillary dermis. Distinction of psoriasis from seborrheic dermatitis can be very difficult, particularly at early stages; the presence of spongiosis involving the rete ridges is not typical of psoriasis, and favors seborrheic dermatitis instead. Chronic candidiasis and dermatophytoses may feature neutrophil exocytosis and psoriasiform epidermal hyperplasia. Therefore, special stains should be routinely considered to exclude the presence of fungal elements.

PROGNOSIS AND TREATMENT Psoriasis is a chronic condition characterized by frequent relapses. Complications include psoriatic arthritis (seen in up to 30% of patients) and infections. Thus, long-term management is required, focusing on balancing the extent of disease involvement with the potential side-effects of therapy. Topical treatment, in the form of emollients, corticosteroids, tars, vitamin D analogs, and tacrolimus, is utilized for localized plaques. Systemic therapies for severe disease include methotrexate, retinoids, and cyclosporine. Phototherapy and photochemotherapy (psoralen with ultraviolet A) are also used.

PSORIASIS—FACT SHEET Definition n  Chronic dermatitis characterized by hyperproliferative epidermis and regular epidermal hyperplasia Incidence n 2%–4% prevalence rate in whites Morbidity n Significant cosmetic impact on quality of life n Psoriatic arthritis (5%–30%) Gender, Race, and Age Distribution n No gender predisposition n Low prevalence in Asians, Native Americans, and Africans n Earlier onset in females than males n Onset before age 40 in ∼75% of patients Clinical Features n Circumscribed, well-demarcated erythematous patches and plaques n  Wide anatomic distribution, but mostly in areas of persistent trauma or friction Prognosis and Treatment n Long-term management due to chronic course of disease n Topical therapies for localized disease n Systemic therapies for severe disease, including methotrexate, retinoids, cyclosporine, phototherapy, and photochemotherapy (psoralen with ultraviolet A)

FIG. 1.9 Psoriasis. There is vascular ectasia within the dermal papillae, often seen in immediate apposition to the thinned overlying epidermal plates.

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GYNECOLOGIC PATHOLOGY

PSORIASIS—PATHOLOGIC FEATURES

1° skin irritation 2° dermatoses

Microscopic Findings Early Lesion n Epidermal spongiosis n Papillary dermal vascular congestion and edema n Sparse perivascular dermatitis Advanced Lesion n Regular acanthosis with increased basal mitotic activity n Mounds of neutrophil-rich parakeratosis n Hypogranulosis Mature Lesion n  Marked regular psoriasiform epidermal hyperplasia with thinned suprapapillary plates n Confluent neutrophil-rich parakeratosis, “Munroe microabscesses,” and “spongiform pustules of Kogoj” n Papillary dermal vascular ectasia n Lymphocytic-rich perivascular dermatitis Differential Diagnosis n Lichen simplex chronicus n Seborrheic dermatitis n Dermatophytosis and candidiasis

nn LICHEN SIMPLEX CHRONICUS CLINICAL FEATURES LSC is a condition in which scaly plaques are formed in response to repetitive irritation of affected sites by rubbing or scratching. Women are more commonly affected, usually between the third and fifth decades of life. Anatomic sites of predilection include the perianal and genital regions, and the posterior neck, forearms, and pretibial areas. Within the vulvar region, LSC can present as a primary or secondary condition. Heat, sweat, and friction can be a primary cause of skin irritation that can ignite the itch/scratch cycle leading to the features of LSC (Fig. 1.10). Secondary causes can be numerous and are important for the pathologist to identify as the underlying cause of LSC, especially when premalignant or malignant in nature.

MICROSCOPIC FEATURES LSC is characterized by epidermal acanthosis (hyperplasia) with psoriasiform appearance. The epithelium shows broad compact orthokeratosis with hypergranulosis; parakeratosis is present, often with a patchy distribution (Fig. 1.11). Focal erosion or ulceration is common. The rete ridges are thick without suprapapillary plate thinning. A characteristic feature is the presence of thickened eosinophilic bundles of collagen

skin thickening

pruritis/scratching

FIG. 1.10 The itch/scratch cycle in lichen simplex chronicus.

arranged in vertical streaks within the papillary dermis (Fig. 1.12), although compared to the skin this feature is less developed in the mucocutaneous surfaces of the vulva and perineum.

DIFFERENTIAL DIAGNOSIS Superimposed changes of LSC can be observed in virtually all dermatoses, therefore careful evaluation to exclude a primary dermatosis is essential before rendering a diagnosis of idiopathic LSC; this particularly applies to instances in which primary treatment is unsuccessful. Superimposed LSC on high grade squamous intraepithelial lesion/vulvar intraepithelial neoplasia of usual type (HSIL/u-VIN), a human papillomavirus (HPV) associated premalignant skin lesion, is an important differential. Close examination of the lower epithelial layers is key: nuclear enlargement, hyperchromasia, loss of polarity, overlapping, and loss of maturation with mitoses above the basal membrane are features indicative of HSIL. Importantly, HSIL with superimposed LSC will show rather abrupt maturation of the dysplastic epithelium, which may lead to not only misinterpretation as idiopathic LSC but also as a lowgrade squamous intraepithelial lesion (LSIL/VIN1) or differentiated VIN. A VIN3 lesion with superimposed LSC can also resemble a VIN2 lesion, but this distinction may not carry clinical consequences. In equivocal cases, strong, nuclear, and cytoplasmic block staining of p16 immunohistochemistry will help point to a diagnosis of HSIL. Atypical verruciform lesions of the vulva also present with hyperkeratotic lesions that show irregular epidermal hyperplasia. Verruciform proliferations of the vulva, including the so-called verruciform LSC, are rare and still poorly understood. Importantly, some are regarded as neoplastic in nature. The most important is verrucous carcinoma, which is locally aggressive. Unlike LSC, verrucous carcinoma presents clinically as a large

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.11 Lichen simplex chronicus. There is marked irregular acanthosis with thick rete ridges of variable sizes, compact orthokeratosis, areas of hypergranulosis, and focal parakeratosis.

FIG. 1.12 Lichen simplex chronicus. Thick eosinophilic bundles of collagen are arranged in vertical streaks within the papillary dermis.

exophytic mass. Histologically, they show expansile invasion into the vulvar stroma in the form of bulbous nests with broad-fronts and smooth edges. While LSC, if tangentially sectioned, may give this appearance,

the depth and complexity of the growth of verrucous carcinoma are usually obvious and exceed that of tangential cutting. Other verruciform lesions that deserve distinction from LSC include entities historically known as vulvar acanthosis with altered differentiation (VAAD) and atypical verruciform hyperplasia, recently grouped into the term differentiated vulvar intraepithelial lesion (DEVIL). DEVIL presents clinically as plaques or areas of exophytic cauliflower-like growth, corresponding histologically to epithelial acanthosis with verruciform growth lacking cytologic atypia (see Chapter 2). The finding of frequent PIK3CA mutations and absence of TP53 mutations, added to the observation of DEVIL-type lesions preceding or accompanying verrucous carcinoma, has led to consideration of this constellation of atypical verruciform proliferations as a third category of squamous preinvasive neoplasia. It is important to note that verrucous carcinoma and DEVIL have bland cytomorphology throughout, and their distinction from LSC must be based on the severity and distribution of the epithelial proliferation. The distinction between DEVIL-type lesions and LSC can be quite difficult. In fact, the term “verruciform LSC” has been used to describe LSC lesions with prominent exophytic growth, and these lesions have been found to harbor PIK3CA mutations linking them to DEVIL. From the diagnostic perspective, it is important to suspect DEVIL if the lesion is exophytic and produces verruciform growth, and if it persists despite treatment or recurs over time. Complete excision and close monitoring may be prudent in this scenario.

14

PROGNOSIS AND TREATMENT Identification and treatment of any underlying process, and cessation of the traumatic stimulus, are imperative in the treatment of this condition, something that may be quite difficult in the long-term. Emollients, topical steroids, and simple barrier occlusion may help break the itch–scratch cycle. Behavioral modification and psychological/psychiatric intervention can be beneficial, particularly if no underlying etiologic factor is identified and medical management is not effective. LICHEN SIMPLEX CHRONICUS—FACT SHEET Definition n  Condition in which skin becomes thickened with scaly plaques in response to repetitive rubbing and/or scratching of affected sites n Can be primary (idiopathic) or secondary to an underlying dermatosis that causes itching Incidence n Common Morbidity n Cosmetic n Superinfection if abraded and ulcerated lesions Gender, Race, and Age Distribution n More common in women than men n No racial predilection n Peak incidence between 30 and 50 years Clinical Features n Hyperpigmented scaly plaques at sites of repetitive rubbing n Perianal and genital regions, posterior neck, forearms, and pretibial areas most common Prognosis and Treatment n Cessation of the itch–scratch cycle n Emollients, topical steroids, and barrier occlusion n  Behavior modification and psychopharmacologic agents in select patients

LICHEN SIMPLEX CHRONICUS—PATHOLOGIC FEATURES Microscopic Findings n Compact orthokeratosis and focal parakeratosis n  Hypergranulosis with subjacent irregular psoriasiform epidermal hyperplasia n Thick eosinophilic bundles of collagen in “vertical streaks” in papillary dermis n Variable perivascular inflammation n  Signs of dermatitis, lichen sclerosus, or other dermatoses may be present Differential Diagnosis n High-grade squamous intraepithelial lesion n Verrucous carcinoma n Atypical verruciform lesions (DEVIL)

GYNECOLOGIC PATHOLOGY

nn LICHENOID REACTION PATTERN This tissue reaction pattern is characterized by basal keratinocyte damage via T-cell-mediated cytotoxic damage or induction of apoptosis. By convention, the damaged keratinocytes are termed dyskeratotic cells, “Civatte bodies” if they are confined to the epidermis, and “colloid bodies” when they descend into the papillary dermis. In addition to basal keratinocyte damage, vacuolar change may also be present, sometimes more prominent than cell death in certain dermatoses. Vacuolar change consists of intercellular keratinocyte vacuole formation and edema with separation from the basement membrane zone. The distribution of the inflammatory infiltrate is an important characteristic. The infiltrate may appose the basal layer or obscure the dermoepidermal junction (DEJ). The density and composition of the infiltrate also vary according to the specific disorder. The presence and quantity of displacement of melanin into the dermis (“pigment incontinence”) should also be noted. Lastly, the phase of the lichenoid epidermal reaction pattern is important, as it can point towards a specific histopathologic diagnosis. For instance, in acute cytotoxic reactions the epidermis is minimally affected, as in the early lesions of erythema multiforme (EM) (erythema multiforme-like epidermal reaction pattern). In more chronic lesions, such as those found in lichen planus (LP), the epidermis shows signs of reaction such as premature terminal differentiation (lichen planus-like epidermal reaction pattern). Over time, there may be supervening epidermal hyperplasia, which may be regular (psoriasiform epidermal reaction pattern) as in secondary syphilis, or irregular, as observed in discoid lupus erythematosus. The final or end-stage epidermal reaction pattern is found in those dermatoses featuring epidermal atrophy (lichen sclerosus [LS]). Integration of all these findings with the clinical picture will allow the pathologist to make a specific histopathologic diagnosis in most cases.

nn LICHEN PLANUS CLINICAL FEATURES Lichen planus (LP) is a T-cell mediated inflammatory dermatosis that affects keratinized and nonkeratinized epithelium. While idiopathic in nature, LP is sometimes associated with other disorders such as ulcerative colitis, hepatitis B/C, immunodeficiency, cirrhosis, and peptic ulcer disease. Several clinical variants exist, but there are three most important to the vulva: classic (papulosquamous), hypertrophic, and erosive, each with its own unique clinical and histologic features (Table 1.4). Erosive lesions are a more common presentation at anogenital sites; they appear clinically as ulcerated and

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CHAPTER 1  Inflammatory Diseases of the Vulva

TABLE 1.4 Clinicopathologic Characteristics of Lichen Planus Patterns in the Vulva. Pattern

Classic (Papulosquamous)

Hypertrophic

Erosive

Location

Keratinized skin

Keratinized skin

Nonkeratinized skin Can include vaginal involvement

Clinical Features

Violaceous-pink flat-topped papule

Raised hyperkeratotic red papules and plaques

Well-demarcated Glazed erythema Hyperkeratotic border Reticulate lacy lesions

Histopathology

Lichenoid infiltrate at epidermal– dermal junction “Wedge-shaped” hypergranulosis Dyskeratotic and vacuolar changes at basilar layer

Lichenoid infiltrate Acanthosis Parakeratosis Hypergranulosis Hyperkeratosis Pseudoepitheliomatous hyperplasia

Lichenoid infiltrate Superimposed erosive ulcer

Differential Diagnosis

Lichenoid drug eruption Early lichen sclerosus Lichen simplex chronicus

Squamous cell carcinoma

Bullous disorders Differentiated vulvar intraepithelial neoplasia (dVIN)

Treatment/ Prognosis

Self-limiting

Self-limiting

Ultra-potent steroids Chronic, poor response to therapy

dVIN, Differentiated vulvar intraepithelial neoplasia

friable patches in the mucosa. Other types of LP clinically appear as reticulate lacy lesions. When chronic, erosive lesions may evolve to scarring.

MICROSCOPIC FEATURES Evolved lesions of classic (papulosquamous) LP feature a band-like infiltrate composed of lymphocytes with an admixture of macrophages, which adhere to the basal aspect of the epidermis (Fig. 1.13). The associated basal cell damage is seen as abrupt maturation (“squamatization”) of basal keratinocytes, dyskeratotic cells throughout the epidermis (Fig.1.14), and eosinophilic colloid bodies in the papillary dermis. The infiltrate does not obscure the interface and does not extend into the suprabasilar epidermis. Plasma cells may be prominent in mucosal epithelium or at mucocutaneous interfaces. Other hallmarks of LP include irregular acanthosis, hyperkeratosis, “wedge-shaped” hypergranulosis (adjacent to acrosyringia or acrotrichia), and clefts which appear at the dermoepidermal junction (“Max–Joseph” spaces). Importantly, parakeratosis is not a feature of LP and its presence should suggest other disorders. As chronicity ensues, dermal fibrosis becomes apparent and the epidermis becomes progressively flattened and thinned. Hypertrophic LP features the same lichenoid infiltrate with accompanying hypergranulosis and acanthosis. The latter can sometimes be quite exuberant, producing the so-called “pseudoepitheliomatous hyperplasia,” which can be mistaken for a premalignant or malignant process. Erosive LP, as the term implies, exhibits

a superficial ulcerative surface with a lichenoid stromal infiltrate. If present, the edge of the lesion will show changes of classic LP (Fig. 1.15).

ANCILLARY STUDIES Immunofluorescence shows irregular fibrin deposits in the DEJ. IgM deposits around necrotic keratinocytes are common and, when prominent, are helpful to confirm the diagnosis of LP. IgG, C3, and IgA deposits can also be present.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of LP in the vulva depends on the variant of LP . Classic/papulosquamous LP features a band-like infiltrate and attention should be drawn to the epidermal reaction pattern and composition of the infiltrate because, although uncommon in flexural or mucosal sites, lichenoid drug eruptions may be histologically indistinguishable from LP. Helpful clues in favor of lichenoid drug eruption are: presence of eosinophils within the infiltrate, involvement of the deep vascular plexus, and the presence of parakeratosis. Early lesions of LS are virtually indistinguishable from LP, and a descriptive diagnosis of “lichenoid dermatosis” followed by a differential may be prudent. The diagnosis of LS can, nonetheless, be raised if signs of chronicity are identified (effacement and flattening of the rete pegs,

16

GYNECOLOGIC PATHOLOGY

FIG. 1.13 Lichen planus. A band-like (“lichenoid”) infiltrate is present at the dermoepidermal interface. The overlying epidermis is acanthotic with hyperkeratosis and hypergranulosis.

FIG. 1.14 Lichen planus. The lichenoid inflammation results in basal cell damage seen as squamatization of basal keratinocytes and dyskeratotic cells. Necrotic keratinocytes appear as eosinophilic hyaline ovoid bodies in the epidermis adjacent to the dermoepidermal junction (“Civatte bodies”, arrows) or within the dermis (“colloid bodies”). Sharply angulated (“saw-tooth”) rete ridges are also appreciated.

homogenization of the papillary dermis). If the infiltrate is rich in plasma cells, plasma cell (zoon) vulvitis may be considered; however, in this disorder the epithelium displays atrophy and hypogranulosis, unlike LP. Hypertrophic LP may raise the differential diagnosis of a neoplastic proliferation such as a squamous cell carcinoma due to their overlying pseudoepitheliomatous hyperplasia and lichenoid-type host response. The

presence of epithelial atypia and irregular inward growth should raise the possibility of malignancy. Long-standing lesions may overlap morphologically with LSC; the presence of basal cell damage, particularly at the base of the rete ridges, is indicative of LP. Lichenoid keratosis or LP-like keratosis is a solitary lesion that is essentially a T-cell-mediated regression of a variety of benign “keratoses” including warts, seborrheic keratosis, and lentigines.

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.15 Erosive lichen planus. This pattern, quite common in the vulva, is characterized by denudation of the epithelium and dense lichenoid lymphocyte-predominant dermal inflammation. Adjacent intact epithelium shows dyskeratotic cells.

These may be present alongside the inflammatory infiltrate and be a helpful histologic clue to the diagnosis. As a pitfall, the inflammation associated with regression of pigmented lesions (including melanoma) and atypical keratinocytic proliferations (including squamous cell carcinoma in situ and basal cell carcinoma) may have a striking lichenoid appearance. Any lichenoid infiltrate containing numerous melanophages should be treated with caution, and additional level sections and immunohistochemical stains for melanocytic markers may be useful in evaluating a clinically ambiguous lesion. Likewise, the presence of large epithelioid cells or keratin plugs should prompt consideration for epithelial markers to exclude epithelial neoplasia. Erosive LP requires distinction from other ulcerative lesions, particularly aphthous ulcers and infections (fungi, syphilis, herpes). In addition to correlating with the clinical history, it is very important to examine the edge of the eroded area to identify classic LP changes, or microorganisms or viral cytopathic changes in the epithelium. A dense plasma cell infiltrate should raise the possibility of syphilis. A neutrophilic perivascular infiltrate is more in keeping with aphthous ulcers.

PROGNOSIS AND TREATMENT Most cases of LP have a self-limiting course; indeed, over two-thirds of patients experience spontaneous remission in the 12–18 months following diagnosis. Treatment is largely symptomatic and consists of immunosuppressive agents, either topical or intralesional steroids (for local to regionally confined lesions), or systemic corticosteroids, retinoids, and cyclosporine (for cases with widespread involvement).

LICHEN PLANUS—FACT SHEET Definition n Idiopathic T-cell mediated skin disorder n Prototype of the lichenoid-type reaction Incidence n 1% worldwide n In vulva: erosive subtype>papulosquamous>hypertrophic Morbidity n Occasional vulvar scarring as consequence of erosive subtype Gender, Race, and Age Distribution n Female predominance n No racial predisposition n Rare in childhood; typically 30–60-year range n No difference in age distribution between variants Clinical Features n  Predilection for wrists, ankles, and genitalia, but may be widespread, including mucous membranes, nails, and hair n Erosive Well-demarcated glazed erythema Hyperkeratotic border Reticular lacy lesions n Hypertrophic: Raised hyperkeratotic plaque n Classic (papulosquamous): Violaceous papules n Pruritic or asymptomatic n Associated with ulcerative colitis, hepatitis B/C, immunodeficiency disorders, cirrhosis, and peptic ulcer disease Prognosis and Treatment n Generally self-limited disorder (12–18 months) n Topical or intralesional steroids for regionally confined lesions n Systemic steroids, retinoids, or cyclosporine for widespread involvement

18 LICHEN PLANUS— PATHOLOGIC FEATURES Microscopic Findings n Prototypical lichenoid tissue reaction pattern n  Band-like lymphohistiocytic infiltrate at dermoepidermal junction accompanied by basal keratinocyte damage n Infiltrate does not obscure dermoepidermal junction or extend into epidermis n Other epidermal changes include hyperkeratosis, “wedge-shaped” hypergranulosis, and clefting at dermoepidermal junction (“Max-Joseph” spaces) n Erosive LP: ulcer surrounded by mucosa with classic LP changes Ancillary Studies n  Immunofluorescence: clumps of fibrinogen at epithelial base and IgM deposits around necrotic keratinocytes Differential Diagnosis n Lichenoid drug eruption n Lichen sclerosus n Fixed drug eruption n Plasma cell vulvitis n Aphthous ulcer n Infectious ulcer

nn ERYTHEMA MULTIFORME Erythema Multiforme (EM) consists of a clinical spectrum of disorders which affect the skin and may at times involve the mucous membranes. It is secondary to exposure to drugs (nonsteroidal anti-inflammatory drugs [NSAIDs], antibiotics, oral contraceptives) and infections (particularly herpes simplex virus [HSV] and mycoplasma).

CLINICAL FEATURES EM typically presents as urticarial papules or papulovesicles often assuming a classical “targetoid” morphology, favoring acral rather than axial locations (EM minor). In some cases, there is additional involvement of one or more mucous membranes with epidermal detachment affecting 90% in dVIN and 63% in LS) and p53. Regarding the latter, strong basal p53 staining with positive cells in upper epithelial layers counts as abnormal; up to 80% of LS cases show this pattern of expression, particularly long-standing cases. Ki-67 is also frequently increased.

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.20 Early lichen sclerosus. There is a dense band-like lymphocytic infiltrate and focal papillary dermal fibrosis (arrows). In this example, epidermal acanthosis is not prominent.

DIFFERENTIAL DIAGNOSIS In its early phases, LS is highly similar to lichen planus morphologically. Indeed, in many cases the distinction is not possible, and a descriptive diagnosis (e.g., lichenoid dermatosis) followed by a list of differential is prudent. Nonetheless, the presence of pointed rete pegs, basal layer squamatization, wedge-shaped hypergranulosis, and preservation of the superficial elastic tissue are all in keeping with LP over LS. Acute-phase LS can also resemble lichen simplex chronicus (LSC); moreover, LSC changes are often superimposed to LS if leading to persistent rubbing. Identification of LS in this context is possible only if signs of chronicity are present. In some cases of morphea, there is homogenization of the papillary dermis similar to that observed in late-stage LS. However, morphea is also characterized by preservation of the superficial elastic tissue and formation of thick collagen bundles in the reticular dermis, unlike LS. Late-stage radiation dermatitis often exhibits great overlap with late-stage LS; thus, the clinical history is important in this differential. The presence of atypical endothelial cells and fibroblasts, perivascular fibrin deposition, and an admixture of elastotic and sclerotic collagenized stromal changes are more in keeping with late-stage radiation dermatitis. Differentiated vulvar intraepithelial neoplasia (dVIN) is a preinvasive squamous lesion with a high risk of progression to invasive squamous cell carcinoma. It arises in a background of a chronic inflammatory dermatosis, typically LS and/or

LSC. Indeed, the chronic inflammatory nature of these conditions predisposes the epithelium to DNA damage (frequently via TP53 abnormalities) and progression to malignancy. Initial and follow-up biopsies in a patient with LS should be carefully examined for the presence of architectural and cytologic features of dVIN (basal and parabasal nuclear enlargement and atypia, individual dyskeratotic cells, acantholysis, elongation and fusion of rete pegs). Immunohistochemistry has a limited value in this differential, as LS usually overlaps with dVIN (see previously in the text). However, a normal (wild type) staining at the base will favor LS, whereas complete absence of p53 staining (null phenotype) should strongly suggest the diagnosis of dVIN.

PROGNOSIS AND TREATMENT The course of LS is chronic with frequent relapses and only partial regression with treatment. Control of symptomatic lesions with conservative use of topical corticosteroids may be useful. Calcineurin inhibitors are an alternative for maintenance therapy. LS is a recognized risk factor for non-HPV related dysplasia, namely dVIN and vulvar squamous cell carcinoma, occurring approximately in 4% of patients as a long-term complication. If dVIN or carcinoma are highly suspected or confirmed, surgery is the mainstay of primary treatment. Surgery may also be required to prevent or treat stricture.

24

GYNECOLOGIC PATHOLOGY

A

FIG. 1.21 Advanced lichen sclerosus. Marked papillary dermal sclerosis with homogenization and vascular “drop-out” are present. The homogenized dermis may show pallor (A) or a more uniform eosinophilic “hyaline-like” appearance (B). Notice the flattening of the dermoepidermal interface due to loss of rete ridges. There is some residual lichenoid inflammation, which usually subsides as the lesion ages.

B

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CHAPTER 1  Inflammatory Diseases of the Vulva

LICHEN SCLEROSUS—FACT SHEET Definition n Fibrosing dermatitis with predilection for anogenital skin in women Incidence n 14.6 per 100,000 woman-years n More common in gynecologic than dermatologic practices Morbidity n Vanishing of labia majora and urethral stenosis may occur in longstanding lesions n  Secondary differentiated vulvar intraepithelial neoplasia (dVIN) and squamous cell carcinoma (∼4%) Gender, Race, and Age Distribution n Female predominance (10:1) n More common in whites n Bimodal distribution: prepubescent and perimenopausal (fifth decade) Clinical Features n “Figure-of-eight” distribution and “porcelain-white” plaques with wrinkled surface and follicular plugging Prognosis and Treatment n Chronic waxing and waning clinical course n  Topical steroids and calcineurin inhibitors for local control, but uncommon complete resolution n Regular observation for development of dysplasia n Surgery if severe introital stenosis or complicated by dVIN or squamous cell carcinoma

response of the donor cells to mismatch of minor histocompatibility antigens in the host. GVHD is relatively common: it complicates ∼3% of bone marrow transplantations, thus clinical history of a prior stem cell transplant should prompt consideration for the diagnosis of GVHD. It has also been documented in 15% of peripheral blood transfusions. Genital involvement of GVHD usually presents within the chronic phase (>100 days from transplantation). Extragenital involvement of skin, oral cavity, liver, gastrointestinal tract, and eyes is common but sometimes vulvar involvement is the only manifestation of chronic GVHD. Of importance, primary ovarian failure is another manifestation of GVHD and a subtle one, sometimes interpreted as a consequence of chemotherapy (as many patients with GVHD have a previous hematologic malignancy).

CLINICAL FEATURES In early forms, GVHD manifests with vaginal dryness, pain or burning sensation, and dyspareunia. Long-standing lesions progress to introital stenosis or complete vaginal closure. The severity of symptoms can range from mild discomfort and erythema, moderate desquamation and erosions, to severe fibrosis, vaginal stenosis, and occlusion.

MICROSCOPIC FEATURES LICHEN SCLEROSUS—PATHOLOGIC FEATURES Microscopic Findings n Early lesion Psoriasiform epidermal hyperplasia with band-like lymphohistiocytic infiltrate, papillary dermal fibrosis, and hyperkeratosis n Mature lesion Papillary dermal homogenization, pallor, and vascular drop-out with epidermal atrophy Ancillary Studies n Frequent expression of CK17, p53 overexpression, and high Ki-67 Differential Diagnosis n Early lesions Lichen planus Lichen simplex chronicus n Mature lesions Chronic radiation dermatitis Localized scleroderma (Morphea) Differentiated vulvar intraepithelial neoplasia

nn GRAFT VERSUS HOST DISEASE Graft versus host disease (GVHD) is a systemic complication due to allo-hematopoietic stem cell transplant (allo-HSCT), characterized by a T-cell mediated immune

The microscopic features depend on the clinical lesion biopsied. An earlier lesion will show the prototypical histopathologic features of a lichenoid infiltrate with hypergranulosis and irregular acanthosis. Dyskeratotic cells in the epidermis adjacent to lymphocytes are features unique to GVHD (Fig. 1.22). Lesions with a protracted course may still show a lichenoid infiltrate but may also have more fibrosis in the dermis. The inflammatory infiltrate is composed of CD4 and CD8 T-cells, with a predominance of cytotoxic (CD8-positive) cells.

DIFFERENTIAL DIAGNOSIS The histomorphology of early lesions of GVHD can be identical to lichen planus. Both dermatoses demonstrate a lichenoid infiltrate with hypergranulosis and irregular acanthosis. Moreover, hypergranulosis in GVHD can have a “wedge-shaped” distribution further mimicking LP. Lesions of GVHD that have a prolonged presentation can appear similar to lichen sclerosus, exhibiting dermal fibrosis. A lichenoid infiltrate may still persist.

26

GYNECOLOGIC PATHOLOGY

FIG. 1.22 Graft versus host disease. There is liquefaction degeneration (vacuolar alteration) of the basal keratinocyte layer and dyskeratotic keratinocytes (arrows), which sometimes are found adjacent to lymphocytes (“satellite cell necrosis”).

PROGNOSIS AND TREATMENT The prompt recognition of the disorder and treatment with potent glucocorticosteroids can help ameliorate the severity of the disease and prevent complications such as ovarian failure. Long-term surveillance is recommended to monitor ovarian function and detect recurrences early. GRAFT VERSUS HOST DISEASE—FACT SHEET Definition n Systemic T-cell mediated immune disorder following allo-hematopoietic stem cell transplant Incidence n 3% of bone marrow recipients n 15% of peripheral blood recipients n Increasing as allo-HSCT rate increases Morbidity n Dependent on severity and time to treatment n Introital stenosis or complete vaginal closure

GRAFT VERSUS HOST DISEASE—PATHOLOGIC FEATURES Microscopic Findings n Lichenoid inflammation n Hypergranulosis n Irregular acanthosis n Dyskeratotic cells surrounded by lymphocytes Immunohistochemical Features n Mix of CD4+ and CD8+ cells with predominately CD8+ cells in the dermis Differential Diagnosis n Lichen planus n Lichen sclerosus

ACANTHOLYTIC REACTION PATTERN

Gender, Race, and Age Distribution n No age or race predilection

Acantholytic disorders are due to disruptions in the intercellular adhesions tethering keratinocytes together which results in clefting between keratinocytes and rounding of keratinocytes (“acantholytic cells”) within the epidermis.

Clinical Features n Dryness, burning, pain, dyspareunia n Lichen planus-like features, lichen sclerosus-like features

nn PAPULAR GENITOCRURAL ACANTHOLYSIS

Prognosis and Treatment n Rapid treatment with high-dose steroids n Long-term gynecologic follow up required

Papular genitocrural acantholysis is also known as papular acantholytic dyskeratosis of the vulvocrural area and acantholytic dermatosis of the genitocrural/perineal region.

27

CHAPTER 1  Inflammatory Diseases of the Vulva

As its name implies, it is a sporadic acantholytic skin disorder affecting specifically the genital skin, which distinguishes this disorder from systemic acantholytic disorders (Darier disease and Hailey-Hailey disease). Some believe that papular genitocrural acantholysis is a localized form of Darier disease.

“grains” (elongated cells with abundant keratohyaline granules and scant cytoplasm) are seen in the stratum corneum. There is usually minimal to no inflammation. Direct immunofluorescence studies are negative.

DIFFERENTIAL DIAGNOSIS CLINICAL FEATURES This localized disorder affects predominantly young adults. It presents as isolated lesions or groups of domeshaped, flesh colored papules measuring up to 1 cm in the vulva and perianal area. On occasion, lesions can extend onto the perineum and thigh. A variety of clinical appearances, including vesicles, bullae, patches, and plaques can also be seen. Some patients complain of pruritus and burning, but the majority are asymptomatic. By definition, there is no family history of Darier disease or Hailey-Hailey disease and there are no lesions elsewhere on the body.

MICROSCOPIC FEATURES In addition to acantholysis, the lesions exhibit hyperkeratosis, hypergranulosis, and acanthosis (Fig. 1.23). “Corps ronds” (double contoured keratinocytes with pyknotic nuclei surrounded by a clear halo and eosinophilic cytoplasm) are seen in the granular layer, and

Darier disease and Hailey-Hailey disease are both characterized by acantholysis and can have very similar histologic features. Lesions occurring outside the genitocrural area and occurring in the setting of a family history point to Darier and Hailey-Hailey disease. Eutectic mixture of local anesthetics (EMLA) treatment can also elicit an acantholytic reaction indistinguishable from papular genitocrural acantholysis; documentation of exposure to EMLA is therefore important to exclude this scenario. Warty dyskeratoma may enter in the differential; this is a benign solitary dome-shaped lesion characterized by an invaginated center showing acantholysis and dyskeratosis; the dermal papillae, lined by only basal epithelium, project into the invagination resembling villi; follicular structures are often seen in association with the lesion.

PROGNOSIS AND TREATMENT The lesions tend to be chronic with variable treatment success using steroids, retinoids, electrocautery,

FIG. 1.23 Papular genitocrural acantholysis. This lesion exhibits hyperkeratosis, acanthosis, and marked acantholysis, where the keratinocytes appear rounded and “falling apart”. Left inset shows “corps ronds,” which are double contoured keratinocytes with pyknotic nuclei surrounded by a clear halo and eosinophilic cytoplasm. Right inset shows “grains” which are elongated acantholytic cells within the stratus corneum.

28

GYNECOLOGIC PATHOLOGY

and cryosurgery. Complications are very rare and include superimposed infection and LSC. Given that most patients are asymptomatic, reassurance and follow-up to monitor for complications may be ­sufficient.

PAPULAR GENITOCRURAL ACANTHOLYSIS—FACT SHEET Definition n Sporadic acantholytic disorder limited to the genital skin n May represent limited form of Darier disease Incidence n Rare Morbidity n

Majority are asymptomatic and without long-term s­ equelae

Gender, Race, and Age Distribution n Affects young and middle-aged women n In men, can affect penis and scrotum Clinical Features n Solitary or group flesh-colored or white papules n Lesion may coalesce to form plaques Prognosis and Treatment n Steroids, topical retinoids, cryotherapy, and laser therapy have variable success n Reassurance may suffice, as most lesions are asymptomatic

PAPULAR GENITOCRURAL ACANTHOLYSIS— PATHOLOGIC FEATURES Microscopic Features n Acantholysis with dyskeratotic cells (“corps ronds” and “grains”) n Acanthosis, hyperkeratosis, and hypergranulosis n Direct immunofluorescence negative Differential Diagnosis n Hailey-Hailey disease n Darier disease n Eutectic mixture of local anesthetics (EMLA) n Warty dyskeratoma

GRANULOMATOUS REACTION PATTERN Granulomatous inflammation is a distinctive chronic inflammatory response triggered by a wide variety of etiologies, including infectious, autoimmune, foreign body, and neoplastic. Granulomas are round masses made of a conglomerate of activated histiocytes (epithelioid or rounded, with abundant granular cytoplasm). Multinucleated giant cells are often present.

nn HIDRADENITIS SUPPURATIVA Hidradenitis suppurativa is a recurrent chronic inflammatory disease due to chronic follicular occlusion and subsequent rupture, causing secondary abscesses, sinuses, and scarring. It has a predilection for sites rich in apocrine or mammary-like glands, such as the axilla and groin. Hidradenitis suppurativa is considered part of the follicular occlusion tetrad, alongside acne conglobata, dissecting cellulitis of the scalp, and pilonidal sinus.

CLINICAL FEATURES Hydradenitis suppurativa is relatively common, affecting 1%–4% of the adult population, mostly young adults in the second and third decades of life. The disorder is rare in postmenopausal women, suggesting that sex hormones play a predisposing role. Other risk factors include inflammatory bowel disease, Dowling-Degos disease, smoking, and obesity. It is typified by recurrent abscesses, draining sinuses and scarring of the pubic, perineal, perianal, axillary, mammary, inframammary, and inguinal regions. Early lesions present as tender deep-seated nodules or “blind boils”. “Twin” or “double-barreled” comedones (dilated hair follicles filled with dark crusty debris), separated by 1–2 mm, are considered pathognomonic. The hair follicles subsequently rupture, resulting in abscesses, draining sinus tracts, bridging scars (hypertrophic fibrotic bands that criss-cross), and contractures. Secondary infection may ensue.

MICROSCOPIC FEATURES Early lesions show dilated keratin-filled hair follicles with surrounding inflammation. The mixed inflammatory infiltrate can extend into the subcutis. Granulomatous or foreign body giant cell reaction is often seen due to the abundant keratinous debris (Fig. 1.24). Later lesions show sinus tracts with reepithelialized surfaces connecting to the overlying skin, adjacent granulation tissue, and abscess formation (Fig. 1.25). Dense scarring can result in the loss of skin appendages. Secondary inflammation of the apocrine and eccrine glands occurs in up to half of cases (Fig. 1.26).

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes furunculosis or other infections of the skin, Crohn Disease, pilonidal sinus, and pyoderma gangrenosum. The diagnosis of hidradenitis suppurativa is largely based on clinical findings. Lack of response to antibiotic therapy is also a diagnostic clue.

29

CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.24 Hidradenitis suppurativa, early lesion. There is a markedly dilated keratin-filled hair follicle with adjacent chronic granulomatous inflammation (arrows).

FIG. 1.25 Hidradenitis suppurativa, late lesion. A deep sinus tract has developed with adjacent chronic granulomatous inflammation (arrows) and partial reepithelialization.

PROGNOSIS AND TREATMENT Secondary infection can occur at any point during the course of the lesions. If extensive and long-standing, the process leads to lymphatic obstruction and lymphedema and significant deformity (sometimes leading to significant psychosocial sequelae). Moreover, patients with hydradenitis suppurative are five times more

likely to develop vulvar squamous cell carcinoma, likely due to persistent chronic inflammation and epithelial injury. Treatment is aimed at controlling infection and suppressing inflammation. Medical treatment includes analgesics, antibiotics, anti-inflammatories, immune modulators, anti-androgens, and retinoids. Surgical treatment may be performed to treat recalcitrant sinus tracts (unroofing), incise and drain abscesses, or excise the affected skin.

30

GYNECOLOGIC PATHOLOGY

FIG. 1.26 Hidradenitis suppurativa. Secondary inflammation of the eccrine sweat glands is a frequent finding.

HIDRADENITIS SUPPURATIVA—FACT SHEET Definition n  Recurrent inflammatory disease of axilla and groin due to chronic follicular occlusion Incidence n Estimated 1%–4% prevalence Morbidity n Secondary infection n Lymphedema may result from obstructed lymphatic drainage n Deformity of skin can lead to social isolation and depression n Five times increased risk of developing squamous cell carcinoma Gender, Race, and Age Distribution n Second to third decades of life n More common in women n  Risk factors include inflammatory bowel disease, Dowling-Degos disease, smoking, obesity, and hormones (fades after menopause) Clinical Features n  Affects skin rich in apocrine and mammary-like glands (pubic, perineal, perianal, axillary, mammary, inframammary, and inguinal skin) n Recurrent deep seated painful and red nodules “blind boils” n “Twin” or “double-barreled” comedones n  Abscesses, draining sinuses, contractures, bridging scars, and secondary infection Prognosis and Treatment n Chronic relapsing condition n  Treatment may be medical (analgesics, antibiotics, antiinflammatories, immune modulators, anti-androgens, retinoids) or ­surgical

HIDRADENITIS SUPPURATIVA—PATHOLOGIC FEATURES Microscopic Features n Dilated keratin-filled hair follicles with folliculitis and perifolliculitis n Granulomatous or foreign body giant cell reaction to keratinous debris n Sinus tracts with re-epithelialized surfaces connecting to overlying skin n  Granulation tissue and mixed inflammatory reaction can extend into subcutis n Abscesses and secondary infection n Scarring with loss of skin appendages n Secondary inflammation of apocrine and eccrine glands Differential Diagnosis n Furunculosis or other skin infections n Crohn disease n Pilonidal sinus n P yoderma gangrenosum

nn CROHN DISEASE Crohn disease is an idiopathic chronic inflammatory disease of the gastrointestinal tract. It is characterized by transmural inflammation of the alimentary canal, anywhere from the oral cavity to the perianal area. Approximately 10% of patients will suffer from cutaneous lesions, and in up to 25% of affected women, vulvar involvement is the initial presenting symptom.

CLINICAL FEATURES In the North American population, Crohn disease has a prevalence of 0.3%. Women of white, Eastern European,

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.27 Crohn disease. There is superficial and deep chronic granulomatous inflammation. The granulomas (inset) are typically noncaseating.

and Ashkenazi Jewish descent are more likely to be affected. Patients typically present in their second to third decades of life with gastrointestinal symptoms, such as abdominal pain, severe diarrhea, blood stools, and weight loss. There can be a multitude of extraintestinal manifestations, including arthropathy (sacroiliitis, ankylosing spondylitis), uveitis, primary sclerosing cholangitis, renal stones, thromboembolism, and cutaneous lesions (erythema nodosum, pyoderma gangrenosum, and EM). In women, vulvar involvement can range from swelling, pain, and erythema to more severe, knife-like ulcers, fissures, abscesses, sinuses, and anocutaneous fistulas. Vulvar involvement by Crohn disease is divided into two main etiologies, either direct extension from the gastrointestinal tract (which includes involvement by fistulas), or noncontinuous lesions which are referred to as “metastatic” Crohn disease. Metastatic Crohn disease accounts for 90% of cases with vulvar involvement.

MICROSCOPIC FEATURES In the vulva, there can be superficial and deep noncaseating (or sarcoid-like) granulomas, associated with a mixed inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils (Fig. 1.27). Granulomas, however, are only present in 40% of vulvar Crohn disease, and thus their presence is not an entirely sensitive feature. Neutrophilic abscesses, related to abscesses, fissures, and sinuses, are a more consistent, albeit nonspecific, feature.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for granulomatous inflammation of the vulva is wide, and the diagnosis of vulvar Crohn disease relies heavily on the clinical picture. A myriad of infectious (mycobacteria, syphilis, lymphogranuloma venereum, granuloma inguinale) and noninfectious (hidradenitis suppurativa, sarcoidosis, foreign material/cosmetic fillers) entities are in the differential diagnosis. In the setting of a vulvar granulomatous reaction, special stains for microorganisms (GMS and PAS stain for fungi, Gram stain for bacteria, AFB stain for mycobacteria) should be performed routinely. A positive result is highly specific, but false negative results are frequent, and the clinical context is again paramount to sort the differential diagnosis. Cosmetic filler related granulomatous inflammation can be due to direct vulvar injection of hyaluronic acid or silicone for cosmetic reasons or the treatment of vulvar atrophy. Knowledge of filler use is key in the diagnosis. Furthermore, silicone material can be appreciated within the granulomas, engulfed by giant cells. Rare cases of cosmetic fillers migrating from the breast and buttock to the vulva have also been reported.

PROGNOSIS AND TREATMENT Crohn disease is characterized by intermittent exacerbations and periods of remission. Up to 80% of patients will require hospitalization at some point during their disease course. Long-term sequelae include fistulas, abscesses, bowel obstruction, and, in rare cases, toxic megacolon,

32 bowel infarction, and sepsis. Patients with Crohn disease have a higher risk of developing colon cancer. Treatment is aimed at controlling exacerbations and maintaining remissions, usually through a combination of antibiotics, anti-inflammatory agents (aminosalicylate), steroids, and biologics (anti–tumor necrosis factor [TNF] t­ herapy). CROHN DISEASE—FACT SHEET Definition n  Chronic idiopathic granulomatous inflammatory disease of gastrointestinal tract Incidence n Affects 3/1000 persons in North America Morbidity n Chronic relapsing disease n  Complications include fistulas, abscesses, bowel obstruction, toxic megacolon, bowel infarction, and sepsis Gender, Race, and Age Distribution n Presents in second to third decade of life n No gender predilection n  More commonly affects persons of Eastern European and Ashkenazi Jewish descent Clinical Features n Gastrointestinal symptoms predominant; extraintestinal manifestations mainly affect joints, eyes, gallbladder, and skin n Vulvar swelling, pain, erythema, linear ulcerations, fissures (typically along creases), abscesses and fistulas n Vulvar involvement as presenting sign in 25% of cases n  Other cutaneous manifestations include erythema nodosum, erythema multiforme, and pyoderma gangrenosum Prognosis and Treatment n Chronic relapsing disease n  Treated with combination of antibiotics, antiinflammatory agents, steroids, and biologic agents (i.e., infliximab)

CROHN DISEASE—PATHOLOGIC FEATURES Microscopic Features n Superficial and deep dermal noncaseating (sarcoid-like) granulomas n  Mixed inflammatory cell infiltrate with lymphocytes, plasma cells, eosinophils n Neutrophilic abscesses and fistulas Differential Diagnosis n  Infectious (mycobacterial, tertiary phase of syphilis, lymphogranuloma venereum, granuloma inguinale) n Sarcoidosis n Hidradenitis suppurativa n P yoderma gangrenosum n Cosmetic fillers (hyaluronic acid, silicone)

nn VASCULOPATHIC REACTION PATTERN The vasculopathic pattern is characterized by histologic evidence of blood vessel damage, usually occurring in

GYNECOLOGIC PATHOLOGY

the setting of widespread dermal inflammation. As a consequence of the disrupted oxygen and nutrient flow, lesions tend to erode or ulcerate.

nn APHTHOUS AND LIPSCHUTZ ULCER Aphthous ulcers are painful shallow ulcers which affect the oral and genital mucosa. They are nonsexually acquired and affect prepubertal girls and young women. This disorder is common, and up to 20% of girls and adolescents are affected, with higher prevalence in women of Middle Eastern, Mediterranean, and South Asian descent. The exact etiology remains elusive but is thought to be related to immune dysregulation. Lesions typically are precipitated by a stress event, such as a viral infection (i.e., Epstein Barr virus). There also appears to be an association with stress, hormonal factors, vitamin deficiency, and family history. Ultimately, aphthous ulcers can only be diagnosed after excluding other causes of genital ulceration. Lipschutz ulcer is considered a special variant of an aphthous ulcer, which is associated with fever and systemic symptoms. This disorder is also known as ulcus vulvae acutum.

CLINICAL FEATURES Aphthous ulcers are shallow ulcers, 1–2 mm in depth, with well-circumscribed borders and an edematous and erythematous rim. They preferentially occur in the labia minora. Oral lesions are also frequently found simultaneously. The central ulcer bears yellow fibropurulent exudate or eschar. Aphthosis can be divided into simple and complex. Simple aphthosis is characterized by orogenital ulcers that occur several times a year separated by disease-free intervals and lesions which heal within 7–14 days without scarring. In contrast, complex aphthosis is persistent and chronic, where there is the continuous presence of three or more ulcers. The lesions in complex aphthosis are more painful, more numerous, and take longer to resolve (4–6 weeks). The Lipschutz ulcer is usually located on the midportion of the labia minora and has a mirrored symmetrical lesion on the opposite labia known as the “kissing pattern.”

MICROSCOPIC FEATURES The diagnosis of aphthous ulcers is usually made clinically and thus biopsy is seldom taken. Histologic findings include a superficial ulcer with perivascular neutrophilic infiltrate at the base. In older lesions, the inflammation becomes mixed with lymphocytes and plasma cells. A dense superficial neutrophilic infiltrate surrounds the capillaries (leukocytoclastic vasculitis) (Fig. 1.28).

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.28 Aphthous ulcer. This ulcer is well-demarcated or “punched-out” and shallow. Superficial neutrophilic infiltrates surround the capillaries.

DIFFERENTIAL DIAGNOSIS The ulcers in HSV infection can look similar and it is important to search for evidence of HSV cytopathic effect and perform immunoperoxidase stains when necessary. In erosive lichen planus, evidence of lichenoid inflammation and wedge hypergranulosis at the edges of the ulcer is helpful. Unlike aphthous ulcers, Behcet disease involves uveal mucosae and has a predominant lymphocytic vasculitis. In erythema multiforme, history of a triggering factor is often known, and histologically there is full-thickness epithelial detachment (which may be better observed at the edge of the lesion, if ulcerated). Although rare, mucosal and skin ulceration can occur as a complication of methotrexate, an antimetabolite used in the management of a variety of cutaneous (e.g., psoriasis) and neoplastic processes. Histologically, methotrexate-related ulcers are characterized by hyperkeratosis, vacuolar change at the dermoepidermal junction, and apoptotic keratinocytes. Importantly, the perivascular infiltrate is lymphocytic, not neutrophilic. It is important to identify this lesion, as it often precedes the onset of methotrexate-induced pancytopenia.

PROGNOSIS AND TREATMENT Most aphthous ulcers are self-limited and do not recur. Recurrences, when present, decrease in frequency with age. The management goals are to provide symptomatic relief and wound care. NSAIDs and analgesics can be

provided. In severe cases, patients will need hospitalization with placement of a urinary catheter to help with pain control.

APHTHOUS AND LIPSCHUTZ ULCER—FACT SHEET Definition n  Aphthous ulcer: nonsexually related shallow painful ulcers of the oral and genital mucosa n  Lipschutz ulcer: form of aphthosis associated with fever and systemic illness Incidence n Common, estimated to occur in one out of five young individuals Morbidity n Painful ulcers can cause significant morbidity n Severe cases require bladder catheterization to help control pain n Generally self-limited Gender, Race, and Age Distribution n Prepubertal girls and young women n  More common in persons of Middle Eastern, Mediterranean, and South Asian descent Clinical Features n Inner aspect of labia minora n Ulcers with regular 1–2 mm depth, well-defined borders, and peri­ lesional edema and erythema n Typically occurs after precipitating trigger (e.g., viral infection or stress) Prognosis and Treatment n Typically self-limited and resolves within 7–14 days n Frequency of recurrence diminishes with age n Treatment for symptomatic relief and preventing secondary infection

34 APHTHOUS AND LIPSCHUTZ ULCER—PATHOLOGIC FEATURES Microscopic Features n Early lesions: superficial ulcer and perivascular neutrophilic inflammation at base n Late lesions: dense neutrophilic and lymphoplasmacytic infiltration, superficial ulceration with fibrinopurulent debris, leukocytoclastic vasculitis Differential Diagnosis n Herpes simplex virus infection n Behcet disease n Erosive lichen planus n Erythema multiforme n Methotrexate-associated ulcers

nn BEHCET DISEASE Unlike aphthous ulcers which are self-limited and localized, Behcet disease is a chronic relapsing multisystem inflammatory disorder due to systemic vasculitis of unknown etiology. It is uncommon in North America (1/1,000,000 people) but is significantly more prevalent in Asiatic and Mediterranean countries (e.g., Turkey has a prevalence of 370/100,000 people). The classic triad of Behcet disease includes oral ulcers, genital ulcers, and ocular lesions (uveitis). Genital ulceration occurs in more than half of patients. The systemic vasculitis, however, can affect vessels of all sizes and locations, and in rare cases patients suffer from cardiopulmonary, urogenital, gastrointestinal, and central nervous system complications.

CLINICAL FEATURES Behcet disease manifests during early adulthood (second to fourth decades). It is characterized by deep seated and exquisitely painful ulcers in the vulvar and femoroinguinal regions. The ulcers are well-demarcated with central necrotic yellow areas and edematous edges. They may be solitary or occur in crops. The ulcers will heal within 2–4 weeks, but frequently with scarring. Acneiform papules and pustular lesions with abscess formation can also occur. Other cutaneous manifestations include furuncles, pyoderma gangrenosum, erythema nodosum, and superficial thrombophlebitis. The ulcers of Behcet disease can also affect the upper respiratory tract, such as the pharynx and larynx, leading to significant discomfort. Other clinical manifestations can include loss of vision, aseptic meningitis, meningoencephalitis,

GYNECOLOGIC PATHOLOGY

pyramidal/cerebellar dysfunction, myelopathy, synovitis, thrombosis, aneurysm formation, and gastrointestinal bleeds. For a diagnosis of Behcet disease, the International Study Group requires that oral ulcers recur at least three times in a 12-month period and at least two of the four criteria: (1) recurrent genital ulceration, (2) anterior or posterior uveitis, (2) cutaneous lesions, or (4) positive pathergy test (formation of a pustule or red papule on the forearm 24–48 hours after local skin injury, i.e., being pricked with a small sterile needle).

MICROSCOPIC FEATURES The microscopic features are rather nonspecific and the diagnosis of Behcet disease relies on the clinical evaluation. Histology will show epidermal necrosis, dense neutrophilic dermal infiltrate admixed with histiocytes and lymphocytes, and necrotizing vasculitis of vessels of all calibers. Ulceration is deep and often involves not only skin but also underlying subcutaneous tissue (Fig. 1.29). The vasculitis tends to be lymphocytepredominant. Thrombi and suppurative folliculitis may also be present.

DIFFERENTIAL DIAGNOSIS Behcet disease is typified by lymphocytic vasculitis. In contrast, HSV infection and aphthous ulcers are characterized by leukocytoclastic vasculitis. The differential diagnoses considered for aphthous ulcers can also be considered in the setting of Behcet disease. Fortunately, the typical clinical presentation with multi­ site involvement is classic and makes the diagnosis straightforward.

PROGNOSIS AND TREATMENT Behcet disease has a relapsing and remitting course. The first 5 years tend to be the most severe, followed by less intense and less frequent episodes. In general, the earlier the onset of disease the more severe the course. The greatest morbidity and mortality stems from ocular, neurologic and large vessel involvement, leading to blindness and life-threatening hemorrhages. Indeed, Behcet disease accounts for up to 25% of blindness cases in India, Iran, and Japan. Treatment involves primarily steroids and immunomodulator therapy.

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.29 Behcet disease. In contrast to aphthous ulcer, this ulcer is deep-seated, extending into subcutaneous adipose tissue. This patient presented with multiple ulcers involving the tongue, buccal mucosa, gingiva, and vulva (measuring up to 1.5 cm in size) and bilateral periorbital swelling with conjunctivitis, clinical features in keeping with Behcet disease.

BEHCET DISEASE—FACT SHEET

BEHCET DISEASE—PATHOLOGIC FEATURES

Definition n Multisystem inflammatory disorder due to systemic vasculitis

Microscopic Features n Generally nonspecific n Epidermal necrosis and fibropurulent debris n  Dense dermal infiltrate comprising of neutrophils, histiocytes, and lymphocytes n Ulceration and inflammation extends to deep dermis and subcutaneous tissue n Necrotizing vasculitis which is lymphocyte predominant n More than two-thirds of patients will have deep-seated scars

Incidence n 1/1,000,000 in North America Morbidity n Uveitis in up to two-thirds of patients; leading cause of blindness in Asiatic countries n Large vessel involvement in one-third and can lead to thrombosis, hemorrhage, and aneurysm formation n  Delay in diagnosis and lack of diagnostic tests contribute significantly to morbidity Gender, Race, and Age Distribution n  Equal gender predilection, although severity of symptoms greater in men n Young adults 20–40 years of age n More common in regions along ancient silk road (Asia to the Mediterranean) Clinical Features n Classic triad of oral ulcers, genital ulcers, and uveitis n  Deep seated well-circumscribed ulcers in vulvar and femoroinguinal regions n  Other cutaneous lesions include acneiform papules, pustules, furuncles, pyoderma gangrenosum, erythema nodosum, and superficial thrombophlebitis n Systemic symptoms can affect any organ system Prognosis and Treatment n Most severe symptoms occur within first 5 years of disease onset n Patients with an early age of onset follow a more aggressive course

Differential Diagnosis n Aphthous ulcer n Herpes Simplex infection n Erosile lichen planus n Erythema multiforme n Methotrexate-associated ulcers

nn PLASMA CELL VULVITIS (ZOON VULVITIS) CLINICAL FEATURES This is an uncommon, benign condition which was originally described in the glans penis of older men but has a counterpart in women under a variety of terms (Zoon vulvitis, vulvitis circumscripta plasmacellularis, plasmacytosis mucosae). Most patients are adult, in reproductive age or postmenopausal (age range 26–70 years). Lesions on the vulva are usually asymptomatic, composed of solitary or multiple, sharply defined, red-brown,

36 shiny patches which frequently exhibit a speckled and hemorrhagic surface. Ulceration commonly supervenes.

MICROSCOPIC FEATURES Zoon vulvitis shows a dense plasma cell-rich and bandlike infiltrate, noticeable at scanning magnification, involving the papillary and upper reticular dermis. The infiltrate may contain a mixture of other inflammatory cells including lymphocytes, histiocytes, mast cells, and rare neutrophils or eosinophils (Fig. 1.30). The overlying epidermis is usually atrophic with loss of the stratum granulosum and stratum corneum, and spongiosis. The superficial keratinocytes often take on a “diamond” or “lozenge”-shaped configuration within the spongiotic foci (Fig. 1.31). Extravasated red blood cells and hemosiderin deposits are frequently found in the superficial dermis.

GYNECOLOGIC PATHOLOGY

hyperplasia and involve the deep vascular plexus. Immunohistochemical staining for spirochetes or Warthin-Starry stain may be needed to confirm the diagnosis. Occasionally, lichenoid drug eruptions may have a plasma cell-rich infiltrate, although the clinical appearance is much different. Resolving lesions of HSV infections may feature a plasma cell-rich infiltrate. Interestingly, herpesvirus antigen has been detected in occasional cases of plasma cell vulvitis; therefore, if clinical suspicion for HSV infection exists, additional level sections may be useful in excluding this latter possibility. The mixed inflammation of LP may contain plasma cells to a certain extent but usually not extensively. Lastly, a dense plasma cellrich infiltrate may raise concern for plasma cell dyscrasia. This term is used to group disorders characterized by clonal expansion of plasma cells, including monoclonal gammopathy of undetermined origin, plasma cell (multiple) myeloma, and plasmacytoma. Cutaneous and mucosal involvement is almost invariably seen in the context of systemic, advanced-stage disease, which facilitates the diagnosis.

DIFFERENTIAL DIAGNOSIS Clinically, the discrete, sometimes erosive, lesions mimic squamous cell carcinoma or erosive lichen planus and can cause concern for the clinician. Given an appropriate clinical history combined with the morphologic description, the differential diagnosis is narrow. Histologically, plasma cell vulvitis may mimic secondary syphilis. Syphilitic lesions are accompanied by psoriasiform epidermal

FIG. 1.30 Plasma cell vulvitis. A plasma cell-rich band-like infiltrate is present in the superficial and upper reticular dermis. The overlying epidermis shows hypogranulosis.

PROGNOSIS AND TREATMENT Improvement of symptoms can reliably be attained with a variety of different topical steroids. However, the clinical signs of the lesions may persist despite symptomatic relief. Refractory, circumscribed lesions have been rarely treated by excision.

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.31 Plasma cell vulvitis. The keratinocytes exhibit a “lozenge” or “diamond”-shaped configuration.

PLASMA CELL VULVITIS—FACT SHEET

PLASMA CELL VULVITIS—PATHOLOGIC FEATURES

Definition n Plasma cell-rich inflammatory lesion of unknown origin

Microscopic Findings n  Dense plasma cell-rich band-like infiltrate in papillary and upper reticular dermis n Spongiotic epidermis with absent stratum granulosum and stratum corneum n “Lozenge”-shaped configuration of superficial keratinocytes n Vascular proliferation in superficial submucosa with red cell extravasation and/or hemosiderin

Incidence n Rare Morbidity n  Chronic erosive and ulcerative vulvitis, even after symptomatic relief Gender, Race, and Age Distribution n Much more common in men n Wide age-range; more common in adults n No racial predilection

Differential Diagnosis n Squamous cell carcinoma (clinically and grossly) n Syphilis n Lichenoid drug eruption (uncommon) n Resolving herpesvirus infection n Erosive lichen planus n Plasma cell dyscrasia

Clinical Features n Solitary or multiple, sharply defined red-brown patches with speckled and hemorrhagic surface n Frequent ulceration n Burning, pruritus and dyspareunia

INFECTIONS

Prognosis and Treatment n Chronic condition n Symptomatic relief with topical steroids n Excision for unresponsive, circumscribed lesions

Infections of the vulvar skin can be primary or secondary (due to contiguous spread from adjacent sites or systemic infection). A variety of bacterial, viral, fungal, and parasitic organisms can be culprits, depending on geographic location and the patient’s underlying

38 immune status. This section covers the most common infections affecting the vulvar skin. The pathologic spectrum of HPV infection in the vulva is covered in Chapter 2.

nn SYPHILIS Syphilis is an infectious disease caused by Treponema pallidum which is a Gram negative, slender spiral spirochete, 6–16 μm in length with a “left-handed” helix orientation. Most cases are sexually transmitted; a less frequent route of infection is from mother to newborn after vaginal delivery. Following the introduction of antimicrobial therapy, the incidence of this disease decreased continuously over the following decades. Unfortunately, nowadays syphilis is undergoing resurgence, particularly among drug users, and in individuals who participate in highrisk sexual behavior. Men are more commonly infected than women. It is estimated that 10 in 100,000 suffer from the infection in the United States. Syphilis is closely associated with other sexually transmitted diseases, importantly HIV infection. Indeed, the genital ulceration caused by syphilis likely provides a portal of entry for HIV and other infectious agents.

CLINICAL FEATURES Syphilis infection is divided into four main stages: primary, secondary, latent, and tertiary. The primary or initial lesion is a chancre, which appears on the labium 20–30 days following direct exposure. The lesion characteristically appears as a painless, indurated, “punched-out” shallow ulcer with raised edges. The chancre is usually solitary and resolves without scarring in 1–4 weeks, unless the patient is immunocompromised. Lymphadenopathy occurs 3–4 days after the chancre appears; the nodes are nontender, rubbery, and mobile. Vascular invasion by the spirochete, leading to systemic spread, causes secondary syphilis, which manifests 6 weeks to 6 months after the primary infection. Constitutional symptoms and a generalized rash occur. The rash is typically distributed on the trunk, genital region, flexor surfaces of the limbs and the hands, and soles of the hands and feet. The morphologic appearance is broad, and may be maculopapular, annular, psoriasiform, pustular, lichenoid, and/or ulcerative. Occasionally, secondary syphilis presents as discrete papular verrucous-like lesions known as “condyloma lata,” which are elevated, flat-topped, fleshy, and redbrown to gray papules. Latent syphilis refers to the period of time between healing of the clinical lesions and appearance of late

GYNECOLOGIC PATHOLOGY

lesions. In the latent phase, patients are asymptomatic. In tertiary syphilis, the cutaneous manifestations evolve into nodular, gummatous, and ulceronodular lesions (Lues maligna). Tertiary syphilis can cause life-threatening neurologic (neurosyphilis) and cardiovascular (syphilitic aortitis) complications. Serological testing for syphilis includes nontreponemal (antibodies to cardiolipin [rapid plasma reagin] or Venereal Disease Research Laboratory, [VDRL]) and treponemal (T. pallidum hemagglutination assay or T. pallidum particle agglutination) assays.

MICROSCOPIC FEATURES Early primary lesions are often nonspecific, exhibiting plasma cell-rich perivascular dermatitis without significant epidermal alterations. Plasma cells are considered a hallmark for syphilis. As lesions evolve, there is psoriasiform epidermal hyperplasia, with a band-like infiltrate composed of plasma cells, lymphocytes, and macrophages at the DEJ, often accompanied by a deep perivascular infiltrate (Figs. 1.32 and 1.33). Endothelial swelling and proliferation can cause luminal occlusion and lead to ulceration. The lesions of secondary syphilis are highly variable, but psoriasiform and lichenoid are the two most common reaction patterns. Again, there is superficial and deep perivascular inflammation which can also affect the skin appendages. In condyloma lata, there is prominent acanthosis and intraepidermal microabscesses. In spirochete-rich lesions, neutrophilic spongiform pustules similar to those found in psoriasis may be present in the epidermis. Neutrophil-rich crusts may also surmount such lesions. Lesions of tertiary syphilis are marked by granulomatous inflammation but smaller numbers of microorganisms. Nodular tertiary syphilis shows granulomas with focal necrosis limited to the dermis. Gummatous tertiary syphilis, in contrast, exhibits necrotizing granulomas with dermal and subcutaneous involvement. In severe cases of syphilitic infection, thrombotic endarteritis obliterans can cause ischemia and infarction (Lues maligna).

ANCILLARY STUDIES Traditionally, silver stains (Warthin–Starry, Steiner, Levaditi) are used to demonstrate the organisms, but suffer from low sensitivity. They are being increasingly replaced by direct immunofluorescence, indirect immunofluorescence, and immunohistochemistry (Fig. 1.32). Polymerase chain reaction (PCR) detecting the TP47 gene of the organism can also be used on formalin-fixed tissue.

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.32 Secondary syphilis. Acanthotic epidermis is associated with a prominent band-like inflammatory infiltrate. The inset highlights the presence of spirochete microorganisms using immunohistochemistry.

FIG. 1.33 Secondary syphilis. The inflammation is mixed and comprised of lymphocytes, plasma cells, and histiocytes. Notice the mildly prominent (“swollen”) vascular endothelium.

DIFFERENTIAL DIAGNOSIS The presence of psoriasiform epidermal hyperplasia accompanied by plasma cell-rich lichenoid infiltrate

is strongly supportive of a diagnosis of syphilis. Some long-standing lichenoid hypersensitivity eruptions (drug, herpesvirus, Borrelia infection) may contain plasma cells; however, the clinical setting is quite different, and significant epidermal hyperplasia is generally absent.

40 Likewise, plasma cell vulvitis exhibits an atrophic epidermis with spongiosis, and in long-standing lesions hemosiderin is present. Lastly, correlation with the patient’s serology is helpful if diagnostic uncertainty remains.

PROGNOSIS AND TREATMENT Thankfully, syphilis remains exquisitely sensitive to penicillin therapy. When treated early, the prognosis is excellent. Following clinical cure, the patient is monitored for reversion to seronegativity. If left untreated, tertiary syphilis produces widespread manifestations in the skin, bone, central nervous system, heart, and great vessels.

SYPHILIS—FACT SHEET Definition n  Sexually transmitted infection caused by spirochete Treponema pallidum Incidence n 10/100,000 overall rate of infection (United States) Morbidity n Disfiguring nodules or progressively destructive ulcers may occur in late mucocutaneous lesions n  Neurosyphilis may lead to paralysis, numbness, blindness, and ­dementia n Syphilitic aortitis may lead to aortic aneurysm formation Gender, Race, and Age Distribution n Most common between 20 and 30 years n More common in men, particularly in men who have sex with men Clinical Features n Primary syphilis n Initial lesion (chancre): indurated, “punched-out,” painless ulcer, 20–30 days postexposure n Painless lymphadenopathy n Secondary syphilis n Lesions with broad morphology (pustules, macules, or hyperkeratotic lesions) weeks to months following primary infection n Includes Condyloma Lata (elevated flat-topped, red-brown to gray papules on mucosal surfaces of the labia) n Tertiary syphilis n Cutaneous nodular/gummatous syphilis, neurosyphilis, tabes  dorsalis, and cardiovascular syphilis n Lues maligna: severe ulceration and pseudolymphomatous lesions n  Serological testing includes nontreponemal (antibodies to cardiolipin [rapid plasma reagin] or Venereal Disease Research Laboratory, [VDRL]) and treponemal (T. pallidum hemagglutination assay or T. pallidum particle agglutination) assays Prognosis and Treatment n Excellent prognosis if early treatment with penicillin G n  If untreated, tertiary syphilis is associated with skin, bone, central nervous system, heart, and great vessel abnormalities n Immunocompromised individuals may require additional treatment

GYNECOLOGIC PATHOLOGY

SYPHILIS—PATHOLOGIC FEATURES Microscopic Features Primary syphilis n Slender spiral spirochetes, 6–16 μm in length n Mixed mononuclear inflammatory cell infiltrate, particularly plasma cells n Superficial and deep perivascular inflammation n Endothelial swelling and proliferation, luminal occlusion, and ulceration Secondary syphilis n  Highly variable histology but tends to be of two patterns: psoriasiform or lichenoid n Psoriasiform epidermal hyperplasia more common n  Lichenoid band-like infiltrate with plasma cells, vacuolar changes, dyskeratotic keratinocytes n Inflammation involves deep vascular plexus and skin appendages n  Condyloma lata: more prominent acanthosis and intraepidermal microabscesses n Pustular syphilis contains folliculocentric neutrophilic inflammation Tertiary syphilis n  Nodular tertiary syphilis: granulomas with focal necrosis limited to dermis n  Gummatous tertiary syphilis: necrotizing granulomas, dermal and subcutaneous perivascular plasmacytic inflammation, endarteritis obliterans n Lesser numbers of spirochetes at this stage n  Lues maligna: thrombotic endarteritis obliterans accentuated at dermal-subcutaneous junction, ischemia and infarction, dense plasmacytic and histiocytic infiltrate Differential Diagnosis n  Any mononuclear inflammatory response involving mucosal or paramucosal sites as syphilis is a great “mimicker” both clinically and morphologically

nn HERPES SIMPLEX VIRUS Genital herpes is the most common cause of genital ulceration worldwide. Herpes simplex virus (HSV) types 1 and 2 are double-stranded enveloped DNA viruses; they are ubiquitous and lead to primary, latent, and recurrent infections of the genital skin and orolabial region. The worldwide prevalence of HSV1 and HSV2 was 3700 and 420 million in 2012. Moreover, the seroprevalence for HSV1 and HSV2 in the US is estimated at 54% and 16%, respectively. HSV2 has historically been the most common cause of genital herpes, but an increasing prevalence of HSV1-induced genital ulcers has been observed in the last decade. The virus replicates at the site of inoculation, then travels via retrograde axonal flow to the dorsal root ganglia where the virus can stay dormant. Reactivation occurs either spontaneously or during times of stress (fever, ultraviolet radiation, immunosuppression).

CLINICAL FEATURES While HSV1 has equal distribution between genders, HSV2 is slightly more common in women (female:male

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CHAPTER 1  Inflammatory Diseases of the Vulva

FIG. 1.34 Herpes simplex virus (HSV) infection. In this well-developed lesion, there is an intraepidermal vesicle with keratinocytes exhibiting the classic “3 Ms”—multinucleation (arrows), nuclear molding, and nuclear margination of the chromatin due to “ground glass” inclusions. The inset shows the corresponding immunohistochemical stain for HSV.

ratio of 5:3). HSV1 is typical of pediatric patients (extremities Morbidity and Mortality n Low risk of (often late) recurrence Gender and Age Distribution n M>F n Wide range (mean 54 years) Clinical Features n Most asymptomatic n Slow growing painless mass/swelling Prognosis and Treatment n Local excision n Benign neoplasm with low risk of recurrence

nn PREPUBERTAL VULVAR FIBROMA CLINICAL FEATURES Prepubertal vulvar fibroma typically occurs in young girls (range 4–12 years) as a gradual vulvar swelling; it is typically unilateral, painless, and most commonly involves the labium majus.

PATHOLOGIC FEATURES GROSS FINDINGS

Prepubertal vulvar fibroma is typically an ill-defined subcutaneous mass usually measuring < 5 cm (range 2–8 cm). MICROSCOPIC FINDINGS

This lesion is poorly marginated and shows no clear interface with surrounding soft tissue or overlying epithelium, if present. It is characteristically hypocellular and composed of a patternless proliferation of bland spindle cells with oval to round nuclei and pale amphophilic cytoplasm. At the periphery the proliferation permeates surrounding fibroadipose tissue and grows around adnexal structures and nerves (Fig. 4.7). The

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FIG. 4.7 Prepubertal vulvar fibroma. Poorly marginated, hypocellular, patternless proliferation of bland spindle cells. Note the permeation into the adjacent adipose tissue (lower right).

cells are set within a variably myxoid, edematous or collagenous matrix and small- to medium-sized blood vessels, some with thickened walls, may be seen. Mitotic activity is uncommon and nuclear pleomorphism is absent.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

The spindle cells are typically positive for ER, PR, and CD34 but negative for smooth muscle actin, desmin, and S-100.

DIFFERENTIAL DIAGNOSIS Prepubertal vulvar fibroma shares some features with deep (aggressive) angiomyxoma as both are a hypocellular infiltrative process, however, the latter occurs in an older age group, is more homogenously myxoid, and contains evenly distributed medium- to largesized vessels with thickened walls. Moreover, the presence of myoid bundles and lack of CD34 staining help in this distinction. The distinction from cellular angiofibroma and angiomyofibroblastoma are discussed earlier.

PROGNOSIS AND THERAPY Prepubertal vulvar fibroma is benign but has the potential to recur when incompletely excised. There is debate as to whether these lesions represent neoplasms or an exaggerated physiologic response of the vulvar mesenchyme to hormonal surges around puberty. Conservative expectant management is an option. PREPUBERTAL VULVAR FIBROMA—FACT SHEET Definition n  Benign proliferation of vulvar mesenchyme in young girls, which may be either neoplastic or an exaggerated response to hormonal changes around puberty Incidence and Location n Uncommon n Labium majus most common Morbidity and Mortality n Benign process Gender and Age Distribution n Young girls Clinical Features n Gradual, unilateral painless swelling Prognosis and Treatment n May recur if incompletely excised n Observation may be an option (as regression may occur)

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PREPUBERTAL VULVAR FIBROMA—PATHOLOGIC FEATURES Gross Findings n Ill-defined mass, usually 5cm, (2) ≥5 mitoses in 10 HPFs, (3) infiltrative margins, and (4) moderate to severe nuclear atypia. The presence of three or more of these features also warrants a diagnosis of leiomyosarcoma (Fig. 4.12). The diagnosis of leiomyoma should only be made in the absence of any of the features described above. In lesions with one or two worrisome features, categorization as smooth muscle tumor of uncertain malignant potential (STUMP) should be considered.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Tumor cells are typically positive for smooth-muscle markers such as smooth-muscle actin, desmin, and h-caldesmon. They are also frequently positive for ER and PR. Keratin, EMA, and S-100 are typically negative.

FIG. 4.11 Leiomyoma. Benign-appearing smooth muscle cells show a lacy growth pattern secondary to the abundant myxohyaline matrix associated with the tumor.

FIG. 4.12 Leiomyosarcoma. Pleomorphic and mitotically active spindle cell population; notice the smooth muscle characteristics including fascicular architecture and elongated nuclei with blunted ends.

DIFFERENTIAL DIAGNOSIS Like leiomyoma, cellular angiofibroma and mammary-type myofibroblastoma have a fascicular growth of spindle-shaped cells. Cellular angiofibroma may show

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brisk mitotic activity and, if confused with a smooth-muscle tumor, it may be misdiagnosed as a leiomyosarcoma. In contrast to smooth-muscle tumors, blood vessels are more prominent; the tumor cells have scant cytoplasm and lack the blunt-shaped nuclei seen in leiomyomas, and desmin is negative in most cases. Mammary-type myofibroblastoma displays a haphazard spindle cell orientation and thick collagen bands, which helps in the distinction from a smooth muscle tumor. Immunohistochemistry for RB1 may help in difficult situations, as there is loss of this marker in myofibroblastoma and cellular angiofibroma. Leiomyosarcomas, particularly in the vagina, need to be distinguished from spindle squamous cell carcinoma, which can also feature fascicular growth and aberrant smooth muscle marker expression. Spindle squamous cell carcinoma typically has more obvious epithelial areas and expresses cytokeratins; p16 will be of limited value as it can be overexpressed in leiomyosarcoma, however human papilloma virus (HPV) detection studies may be used (confirming squamous cell carcinoma if positive).

PROGNOSIS AND THERAPY Vulvar leiomyomas are benign tumors and local excision with clear margins is the treatment of choice. Wide margins are required in the surgical management of vulvovaginal leiomyosarcoma and STUMP, as the potential for local recurrence and metastases is higher. VULVOVAGINAL SMOOTH MUSCLE TUMORS—FACT SHEET Definition n  Neoplasm composed of smooth-muscle cells, classified as benign (majority), malignant, and of uncertain malignant potential (STUMP) Incidence and Location n Infrequent Morbidity and Mortality n If large or malignant can be disfiguring Gender and Age Distribution n Wide age range but most common in fourth and fifth decades Clinical Features n  Typically painless slow-growing mass (leiomyoma) or rapidly enlarging tumor (leiomyosarcoma) n Often thought to represent a cyst Prognosis and Treatment n  Leiomyoma has excellent prognosis; treated with complete local excision n Leiomyosarcoma and STUMP requires excision with wide (>1 cm) margins; local recurrence and metastases are treated with chemotherapy and radiation

VULVOVAGINAL SMOOTH MUSCLE TUMORS— PATHOLOGIC FEATURES Gross Findings n Leiomyomas are well circumscribed with bulging cut section, white/ tan whorled appearance and rubbery consistency n  Leiomyosarcoma has an irregular border and fleshy, heterogeneous cut surface with hemorrhage and necrosis Microscopic Findings n  Intersecting fascicles of spindle-shaped cells with moderate amount of eosinophilic cytoplasm and blunt-ended nuclei n Variable amounts of myxohyaline matrix imparting a “lacy” growth pattern n Epithelioid morphology may be prominent n Diagnosis of malignancy relies on the presence of two or three of uterine smooth muscle criteria (moderate to severe nuclear atypia, >10 mitoses/10 high power fields [HPFs], tumor cell necrosis) or three or more of site-specific criteria: 1. >5 cm 2. Infiltrative margin 3. Moderate to severe cytologic atypia 4. >5 mitoses/10 high power fields (HPFs) n  Diagnosis of leiomyoma requires absence of all the features outlined above n  In tumors with one to two site specific features, or with necrosis only, smooth muscle tumor of uncertain malignant potential (STUMP) should be considered Immunohistochemical Features n Desmin, smooth-muscle actin, h-caldesmon typically positive Differential Diagnosis n Cellular angiofibroma n Mammary-type myofibroblastoma n Spindle squamous cell carcinoma

nn RHABDOMYOMA This uncommon, benign tumor with skeletal muscle differentiation is most frequently seen in the vagina, although it can also occur in the cervix and vulva.

CLINICAL FEATURES Patients range in age from 25 to 54 years and symptoms are typically related to the presence of a mass, including vaginal bleeding and pain.

PATHOLOGIC FEATURES GROSS FINDINGS

Rhabdomyoma is frequently polypoid, measuring up to 3 cm with a white to gray elastic cut surface.

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A

B FIG. 4.13 Rhabdomyoma. (A) Elongated and eosinophilic rhabdomyoblasts are seen in a background of loose connective tissue. (Courtesy Dr. Elvio G. Silva.) (B) Rhabdomyoblasts show prominent cross-striations. (Courtesy Dr. Elvio G. Silva.)

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MICROSCOPIC FINDINGS

The tumor lacks a capsule and well-defined border, although clear destructive infiltration is not seen either. It is composed of spindle and ovoid-shaped muscle cells with abundant eosinophilic cytoplasm containing cross-striations, haphazardly oriented in a loose connective tissue background (Fig. 4.13A). There is no accentuation of the cellularity towards the surface. The cells have regular vesicular centrally located nuclei with conspicuous nucleoli but without any cytologic atypia or mitotic activity (Fig. 4.13B).

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

RHABDOMYOMA—PATHOLOGIC FEATURES Gross Findings n Polypoid shape, up to 3 cm Microscopic Findings n Non-encapsulated, poorly demarcated (noninfiltrative) borders n  Spindled and ovoid-shaped cells with eosinophilic cytoplasm and visible striations n Haphazard orientation (with no subepithelial condensation) n Loose connective matrix Immunohistochemical Features n SMA, Desmin, myogenin, Myo-D1 Differential Diagnosis n Rhabdomyosarcoma n Fibroepithelial stromal polyp

The neoplastic cells are positive for muscle specific actin, desmin, myogenin, and myo-D1.

nn EMBRYONAL RHABDOMYOSARCOMA DIFFERENTIAL DIAGNOSIS This neoplasm can be histologically differentiated from rhabdomyosarcoma botryoides as it lacks a cambium layer (primitive small cells that condense beneath surface epithelium), and cytologic atypia and mitoses. In addition, embryonal rhabdomyosarcoma occurs most often at a younger age, grows rapidly, and is associated with an infiltrative growth. Another important differential is fibroepithelial stromal polyp, which can be densely cellular. Unlike rhabdomyoma, definitive skeletal muscle differentiation is not observed.

PROGNOSIS AND TREATMENT Rhabdomyoma is treated with local excision. It may very rarely recur years after excision. RHABDOMYOMA—FACT SHEET Definition n Benign tumor composed of mesenchymal cells with skeletal muscle differentiation Incidence and Location n Very uncommon Age Distribution n 25 to 54 years Clinical Features n Mass, bleeding, or pain Prognosis and Treatment n Indolent; surgical excision curative

In the female genital tract, this tumor most commonly occurs in the vagina and represents the most common primary sarcoma at this site. When the tumor forms a polypoid mass and histologically there is a distinct subepithelial cambium layer, it is designated as “sarcoma botryoides.”

CLINICAL FEATURES This tumor most commonly occurs in children, usually under 5 years of age; however, it can rarely be seen in postmenopausal women. Patients present with vaginal bleeding and/or a mass that may protrude from the introitus.

PATHOLOGIC FEATURES GROSS FINDINGS

This tumor frequently arises in the anterior vaginal wall, typically as multiple soft polypoid nodules, often having a grape-like configuration (Fig. 4.14). MICROSCOPIC FINDINGS

Embryonal rhabdomyosarcoma, botryoides type, is characterized at low-power magnification by a cambium layer, which is defined as a subepithelial layer of condensed small hyperchromatic cells separated from an intact epithelium by a zone of loose connective tissue (Fig. 4.15A). The tumor has alternating hypo- and hypercellular areas, the former being typically edematous and/or myxoid. The neoplastic cells range from

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GYNECOLOGIC PATHOLOGY

FIG. 4.14 Embryonal rhabdomyosarcoma. A polypoid growth imparts a “grape-like” appea­rance.

small and primitive in appearance with scanty cytoplasm, to cells with definitive rhabdomyoblastic differentiation and cross-striations. Mitotic activity is brisk and easy to identify in areas containing less-differentiated cells. Small islands of fetal-type cartilage may be present, similar to its cervical counterpart.

PROGNOSIS AND TREATMENT The overall survival of patients with vaginal rhabdomyosarcoma is currently excellent (90% or higher). Treatment includes tumor resection and chemotherapy. Brachytherapy may be added. Recurrences usually occur within the first 5 years after diagnosis.

ANCILLARY STUDIES EMBRYONAL RHABDOMYOSARCOMA—FACT SHEET

IMMUNOHISTOCHEMISTRY

Myogenin and myo-D1 are the most helpful immunohistochemical stains to establish the diagnosis as they have high sensitivity and specificity. Desmin, muscle specific actin, and myoglobin are also often positive in decreasing frequency (Fig. 4.15B). By electron microscopy, cytoplasmic thin and thick fibrils and Z-bands are seen.

DIFFERENTIAL DIAGNOSIS Fibroepithelial stromal polyp with atypical stromal cells and rhabdomyoma are the main considerations in the differential diagnosis. However, both lack a “cambium layer” and primitive small cells. Fibroepithelial stromal polyp also lacks cells with cross-striations while rhabdomyoma is less cellular and composed of mature rhabdomyoblasts with a bland cytomorphology.

Definition n Malignant tumor showing skeletal muscle differentiation n “Sarcoma botryoides” if polypoid (“grape-like”) and cambium layer is present Incidence and Location n Most common vaginal tumor in children n Most common vaginal sarcoma n Usually anterior vaginal wall Age Distribution n Most patients children 90% n Recurrences usually within 5 years after diagnosis n Surgery + chemotherapy +/− brachytherapy

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A

FIG. 4.15

B

Embryonal rhabdomyosarcoma, botryoides type. A dense subepithelial “cambium layer” composed of primitive small cells is present (A). The tumor cells are desmin positive (B).

108 EMBRYONAL RHABDOMYOSARCOMA - PATHOLOGIC FEATURES Gross Findings n Soft, polypoid nodules with a grape-like configuration n +/− hemorrhage and necrosis Microscopic Findings n  Cambium layer: Subepithelial layer of condensed small blue cells (rhabdomyoblasts) separated from an intact epithelium by a zone of loose stroma n  Alternating hypo- and hypercellular areas, the former typically edematous/myxoid n  Cells ranging from small and primitive to those showing rhabdomyoblastic differentiation (cross-striations) n Brisk mitotic activity, especially in less differentiated cells n Fetal-type cartilage may be seen Immunohistochemical Features n Myogenin and myo-D1 positive (high sensitivity and specificity) n Desmin>muscle specific actin>myoglobin positive Differential Diagnosis n Fibroepithelial stromal polyp n Rhabdomyoma

nn SOLITARY FIBROUS TUMOR CLINICAL FEATURES This is an uncommon tumor with a wide anatomic distribution; in the female genital tract, the vulva is the

FIG. 4.16 Solitary fibrous tumor. This lesion typically presents as a well-circumscribed mass with a yellow-tan cut surface and a vaguely lobulated appearance. Malignant tumors, such as this one, show areas of hemorrhage and necrosis.

GYNECOLOGIC PATHOLOGY

most common site. It occurs over a wide age range from the third to the eighth decade with a mean age of 48 years at presentation. Patients typically present with a slowly enlarging mass.

PATHOLOGIC FEATURES GROSS FINDINGS

The tumors are typically well circumscribed and may have a lobulated appearance and firm, homogeneous, yellow-tan cut surface (Fig. 4.16). They range in size from 1 to 25 (mean 7.5) cm. Malignant tumors may show foci of hemorrhage and/or necrosis. MICROSCOPIC FINDINGS

Histologically they have a similar appearance to solitary fibrous tumors described at other sites (Figs. 4.17 and 4.18). Tumors typically show variation in cellularity with a “patternless” proliferation of bland spindle cells. Characteristically, there is a prominent hemangiopericytoma-like vascular pattern often with perivascular hyalinization. Similar to extragenital tumors, diffuse stromal hyalinization, areas of dense keloid-like collagen, myxoid stroma, cytologic atypia, necrosis, and an adipocytic component are features that may be seen (Fig. 4.18A). The mitotic rate is variable.

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ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

The spindle cells are typically positive for CD34 and STAT6 (nuclear stain) (Fig. 4.18B) although rare cases may be negative for the latter. CD99 is also usually positive and RB1 expression is retained. Tumor cells are typically S-100, actin, desmin, and keratin negative. MOLECULAR ALTERATIONS

The vast majority of solitary fibrous tumors are characterized by NAB2-STAT6 fusion which correlates with nuclear STAT6 immunohistochemical positivity.

is negative for CD34 and STAT6. As both have alternating zones of cellularity, angiomyofibroblastoma may be considered in the differential diagnosis of solitary fibrous tumor; however, the latter also has a different vascular pattern, being composed of numerous capillary sized vessels; it is also negative for CD34 and STAT6. The adipocytic variant of solitary fibrous tumor may raise the possibility of an atypical lipomatous tumor or dedifferentiated liposarcoma. It is important to keep in mind that both of these tumors can be positive for STAT6 as the gene is located on 12q13, which is the region amplified in liposarcoma; however, solitary fibrous tumor is negative for CDK4 and MDM2.

PROGNOSIS AND THERAPY DIFFERENTIAL DIAGNOSIS Solitary fibrous tumors with myxoid change may cause concern for deep (aggressive) angiomyxoma; however, the latter shows infiltrative margins, is uniformly hypocellular and has a different vascular pattern containing medium- to large-sized vessels that have thickened walls which are different from the branching hemangiopericytoma-like vessels of solitary fibrous tumor. In addition, deep angiomyxoma

Predicting malignant behavior in solitary fibrous tumor is challenging. Most have a benign clinical course, but a significant subset (∼10%–20%) recur or metastasize. Most clinically aggressive tumors are histologically malignant (with atypia, mitoses, necrosis); however, the morphology may not always predict behavior. The most reliable features associated with high risk for malignant behavior include age >55 years, size >15 cm, and mitotic rate >4/10 HPFs.

FIG. 4.17 Solitary fibrous tumor. There is a variation in cellularity and an evident hemangiopericytoma-like vascular pattern with dilated “staghorn” vessels (A).

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A

FIG. 4.18 Solitary fibrous tumor. Some lesions have an adipocytic component and foci of prominent stromal hyalinization (A). Most solitary fibrous tumors display strong a diffuse STAT6 nuclear staining (B).

B

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CHAPTER 4  Mesenchymal Lesions of the Vulva and Vagina

SOLITARY FIBROUS TUMOR—FACT SHEET Definition n  Mesenchymal neoplasm composed of a variably cellular “patternless” growth of spindle cells with a prominent hemangiopericytoma-like vascular pattern Incidence and Location n Uncommon n Vulva most common site in female genital tract Morbidity and Mortality n Majority have benign clinical course n ∼10%–20% recur or metastasize Gender and Age Distribution n Wide age range (mean 48 years) Clinical Features n Slowly enlarging mass Prognosis and Treatment n Features associated with aggressive behavior: Age >55 years Size >15 cm Mitotic rate >4/10 HPFs

SOLITARY FIBROUS TUMOR—PATHOLOGIC FEATURES Gross Findings n Well circumscribed n Firm, homogeneous yellow-tan cut surface n Mean 7.5 cm Microscopic Findings n Variation in cellularity n “Patternless” proliferation of spindle cells n Prominent hemangiopericytoma-like vasculature n  Other features: dense keloidal collagen, myxoid stroma, cytologic atypia, necrosis, adipocytic component Immunohistochemical Features n CD34 and STAT6 (nuclear) positive n R B1 retained expression n S-100, actin, desmin, keratin negative Differential Diagnosis n Deep (aggressive) angiomyxoma n Angiomyofibroblastoma n Atypical lipomatous tumor/well-differentiated liposarcoma

nn EPITHELIOID SARCOMA (DISTAL AND PROXIMAL TYPES) CLINICAL FEATURES Epithelioid sarcoma is a malignant tumor of uncertain histogenesis of which two histologic types are recognized:

distal (conventional) and proximal. Both tumors are uncommon with the distal-type occurring more commonly than the proximal-type. Distal-type epithelioid sarcoma has a predilection for the extremities, particularly the wrist, and has a peak age of presentation in the second to fourth decade; this type rarely involves the genital area. Proximal-type epithelioid sarcoma also arises in the deep soft tissue of proximal extremities but has a predilection for the pelvis and genital area with a peak age of presentation that is slightly older (third to fifth decade). Patients with epithelioid sarcoma typically present with a slowly growing plaque or nodule, which is frequently painful and/or ulcerated. The most common location in the vulva is the labium majus followed by labium minus, clitoris, and Bartholin gland region; the latter location of the tumor may clinically mimic a Bartholin gland cyst.

PATHOLOGIC FEATURES GROSS FINDINGS

Epithelioid sarcoma typically is located in subcutaneous or deep soft tissue and appears as a single or multinodular, firm and fleshy, white to tan mass that may show foci of hemorrhage and necrosis (Fig. 4.19). Most subcutaneous tumors measure labium minus Morbidity and Mortality n Distal type: 33% die of disease n Proximal type: 45%–50% die of disease Gender and Age Distribution n Distal type: peak second to fourth decade n Proximal type: peak third to fifth decade Clinical Features n Slowly growing plaque or nodule n Frequently painful and/or ulcerated Prognosis and Treatment n Distal type: local recurrence (77%) n Proximal type: local recurrence (55%) n Surgical excision with wide margins

EPITHELIOID SARCOMA—PATHOLOGIC FEATURES Gross Findings n Single or multinodular firm, fleshy mass n White to tan cut surface n Hemorrhage and necrosis may be seen Microscopic Findings n Distal (conventional) type: “Garland”-like growth pattern around necrobiosis or hyalinization Epithelioid and spindle cells with eosinophilic or “glassy” cytoplasm Round to oval nuclei with distinct nucleoli Rhabdoid morphology occasionally seen

n

Proximal-type: Sheet-like or multinodular growth Large epithelioid cells with abundant cytoplasm Nuclei with vesicular chromatin and prominent nucleoli Rhabdoid morphology common

Immunohistochemical Features n Loss of SMARCB1 (INI1) expression in vast majority n Keratin and EMA positive; CD34 positive (∼50%) n CD31, ERG, actin, p63, claudin 4 negative Differential Diagnosis n Poorly differentiated squamous cell carcinoma n Myoepithelial carcinoma n Malignant melanoma n Malignant rhabdoid tumor

nn OTHER MESENCHYMAL NEOPLASMS There are a number of mesenchymal tumors/lesions which are more common at other sites but may occur in the vulvovaginal region; these include granular cell tumor, nodular fasciitis, dermatofibrosarcoma protuberans, Ewing sarcoma, synovial sarcoma, and liposarcoma. Up to 15% of granular cell tumors occur in the vulva, most commonly the labium majus although any site can be affected. They occur over a wide age range but most commonly affect women in their sixth decade, who typically present with a slowly growing painless mass; if symptomatic, pruritis and pain are most common. Granular cell tumors may be familial and they have a predilection to occur in African Americans. Grossly they appear as a well-defined, white and firm subcutaneous nodule that typically measures 20% clue cells (i.e., squamous cells with numerous adherent coccobacilli) and an altered background vaginal flora with numerous cocci, bacteria of different shapes, and few, if any, lactobacilli. This abnormal vaginal flora can also be seen on Gram stain. Clue cells can also be detected on Papanicolaou smears (Fig. 5.1). Fluorescence in situ hybridization shows a characteristic dense biofilm in confluent or patchy layers covering at least 50% of the vaginal epithelial surface in vaginal biopsies. These biofilms are polymicrobial and dominated by Gardnerella vaginalis.

PROGNOSIS AND THERAPY Bacterial vaginosis is treated with a 7-day course of oral metronidazole, a 5-day course of vaginal metronidazole gel, or a 7-day course of vaginal clindamycin cream. This infection is associated with an increased risk of upper genital tract infections and sexually transmitted diseases, and adverse pregnancy outcomes including increased risk for preterm birth and late miscarriage.

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FIG. 5.1 Bacterial vaginosis. Clue cells are present in a vaginal Papanicolaou smear.

BACTERIAL VAGINOSIS—FACT SHEET

BACTERIAL VAGINOSIS—PATHOLOGIC FEATURES

Definition n Clinical diagnosis requiring at least three of the following features: n Vaginal pH>4.5 n Thin, watery, noninflammatory discharge n Wet mount showing >20% clue cells n Positive “amine” odor test

Microscopic Findings n No specific histopathologic changes n Clue cells (i.e., squamous cells with numerous adherent coccobacilli) on wet mount or Papanicolaou smear n Altered vaginal flora with numerous cocci, bacteria of different shapes, and few, if any, lactobacilli on wet mount or Gram stain n Biofilm covering the vaginal epithelium by fluorescence in situ hybridization

Incidence n Most common cause of vaginitis Clinical Features n Thin, watery, nonpurulent discharge Prognosis and Treatment n 7 days of oral metronidazole, 5 days of vaginal metronidazole gel, or 7 days of vaginal clindamycin cream Morbidity n Increased risk of upper genital tract infections or sexually transmitted diseases, and adverse pregnancy outcomes

nn CANDIDA INFECTION This represents the second most frequent cause of acute vaginitis after bacterial vaginosis. The term “vulvovaginal candidiasis” is frequently used as the vulva is commonly affected and causes most of the patient’s symptoms. The majority (85% to 90%) are caused by Candida albicans but the number of cases caused by non–Candida albicans species is increasing, especially

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FIG. 5.2 Candida infection. Hyphal forms are seen on a Papanicolaou smear.

Candida glabrata. In asymptomatic patients, prevalence has been reported in up to 10%. Therefore, identification of vulvovaginal Candida is not necessarily indicative of vaginitis.

CLINICAL FEATURES Symptoms include vulvovaginal pruritus, soreness, irritation, dyspareunia, and a white, thick, nonmalodorous vaginal discharge. There is vaginal erythema and edema, and sometimes excoriation or fissure formation of the vulva. Host risk factors include pregnancy, diabetes mellitus, immunosuppression, systemic antibiotics, glucocorticoid use, and genetic predisposition. Behavioral risk factors include use of oral contraceptives, intrauterine device, hygiene and clothing habits, and sexual preferences.

PATHOLOGIC FEATURES GROSS FINDINGS

The vaginal mucosa frequently appears erythematous.

MICROSCOPIC FINDINGS AND ANCILLARY STUDIES

Hyphae or spores are visible on a potassium hydroxide wet mount or Papanicolaou smear (Fig. 5.2). Tissue sections show marked acute inflammation, reactive changes in the squamous epithelium, and fungal forms within the superficial layers of the squamous epithelium or within the detached squamous cells. A vaginal culture is useful if a wet mount is negative. Although polymerase chain reaction (PCR) to detect Candida genus is more sensitive than culture, it is not necessary in routine practice.

PROGNOSIS AND THERAPY Uncomplicated vaginal candidiasis (defined as three or fewer episodes per year) with mild to moderate symptoms, caused by C. albicans, and occurring in an immunocompetent host, is treated with a single dose of oral fluconazole or other topical antifungal agents. If complicated (i.e., pregnant patients, immunocompromised or debilitated patients or those who have uncontrolled diabetes, severe symptoms, infections by species other than C. albicans, or four or more episodes in 1 year), treatment may involve stronger and more prolonged antifungal regimens.

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CANDIDA VAGINITIS—FACT SHEET Incidence n Second most common cause of acute vulvovaginitis Clinical Features n White, thick, nonmalodorous vaginal discharge n Pruritus, soreness, irritation, and dyspareunia Prognosis and Treatment n Single dose oral fluconazole or topical antifungal agents, if uncomplicated n Tailored treatment, if complicated (immunosuppressed patients)

CANDIDA VAGINITIS—PATHOLOGIC FEATURES Gross Findings n Mucosal erythema Microscopic Findings n Marked acute inflammation and reactive changes of squamous epithelium Ancillary studies n Hyphae or spores identified in surface epithelium or within detached squamous cells in potassium hydroxide wet mount or Papanicolaou smear n Vaginal culture (if wet mount negative)

nn TRICHOMONAS VAGINALIS This intracellular parasite is the most common nonviral sexually transmitted infection worldwide. Prevalence rates vary greatly and depend on the affected population’s risk factors. In the United States, the highest prevalence of this infection is in African American women (rates of 13–51%). Other risk factors include older age, intravenous drug use, incarceration, multiple sexual partners, and bacterial vaginosis.

CLINICAL FEATURES Eighty-five per cent of women with T. vaginalis infection are asymptomatic. The remaining 15% present with yellow-green, malodorous vaginal discharge, pruritus, vulvar irritation, dysuria, and/or abdominal pain. On colposcopic examination, the vaginal mucosa is erythematous with variable punctate hemorrhages. If the cervix is involved, the term “strawberry cervix” has been applied.

PATHOLOGIC FEATURES MICROSCOPIC FINDINGS AND ANCILLARY STUDIES

On biopsy, the vaginal squamous epithelium is usually spongiotic with numerous neutrophils that can form intraepithelial abscesses; the organism is not usually seen. The diagnosis is made by identifying pear-shaped cyanophilic organisms, 10–20 μm in diameter, showing polar flagellae associated with numerous neutrophils in a saline preparation (sensitivity ranging from 50% to 70%; specificity approaches 100%). Trichomonas can also be detected on a Papanicolaou smear (∼70% sensitivity), where they are also pearshaped and show a “lancet”-shaped axostyle (microtubular structure that runs across the longer axis of the microorganism), an eccentrically placed nucleus and red cytoplasmic granules (Fig. 5.3). Diagnosis by nucleic acid probe techniques are highly (95%–100%) sensitive and specific, but expensive and not easily accessible.

T. VAGINALIS—FACT SHEET Clinical Features n Most common nonviral sexually transmitted infection n Patients typically asymptomatic (85%) n Yellow-green, malodorous vaginal discharge, pruritus, dysuria, vulvar irritation, and abdominal pain, if symptomatic Treatment n Oral nitroimidazole or tinidazole n Treatment of patient’s partner

T. VAGINALIS—PATHOLOGIC FEATURES Gross Findings n Mucosal erythema +/- variable punctate hemorrhage Microscopic Findings n Spongiotic squamous epithelium with numerous neutrophils that may form intraepithelial abscesses but without visualization of organism on biopsy material Ancillary studies n  Trichomonas appear as pear-shaped organisms on saline preparation or Papanicolaou smear

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FIG. 5.3 Trichomonas vaginalis infection. An organism showing an eccentric nucleus and fine cytoplasmic granules is seen (arrow) on a Papanicolaou smear.

nn GROUP A STREPTOCOCCUS (STREPTOCOCCUS PYOGENES) Infection by this organism is uncommon. Risk factors include a household or personal history of dermal or respiratory infection by Group A Streptococcus (GAS). It typically affects prepubertal girls but can also be seen in adult women, mostly in association with lactational and menopausal vaginal atrophy. GAS vulvovaginitis is a common cause of vaginal and/or perineal pain in contrast to most other types of vaginitis. In addition, patients have dyspareunia, burning sensation, or pruritis. Vaginal discharge is often copious and may be watery, yellow or purulent but is typically non-malodorous. Physical examination reveals marked erythema, edema, and tenderness of the vagina, vulva, and perineum that may be accompanied by excoriations secondary to scratching. Wet mount and Gram stain of vaginal smears typically show abundant leukocytes, gram positive cocci in singlets, duplets, or chains, and a lack of lactobacilli. GAS overgrowth on culture is required to confirm the diagnosis. Treatment includes penicillin or topical clindamycin. In cases of marked vaginal atrophy, topical estrogen may be necessary to prevent recurrences.

nn GROUP B STREPTOCOCCUS This Gram-positive bacterium is present in the digestive and vaginal tracts of 25% of the female population. Patients with symptoms and a positive culture should

be treated with antibiotics. In asymptomatic patients, vaginal group B Streptococcus does not require treatment except during pregnancy. As group B Streptococcus represents the leading cause of early-onset neonatal sepsis in the United States, universal screening, using both vaginal and rectal swabs, is recommended for pregnant women at 35 to 37 weeks’ gestation. Identification of group B Streptococcus in these samples, by routine cultures or using sensitive nucleic acid amplification tests, will prompt therapy which includes penicillin G, cefazolin, clindamycin, or vancomycin depending on allergies and antibiotic resistance.

nn ACTINOMYCES These are Gram-positive, non-acid-fast, anaerobic bacteria that are part of the normal flora of the oral cavity and rectum, but can also be occasionally found in the female genital tract. Vaginal colonization and secondary overgrowth may occur in the presence of a foreign body (e.g., permanent suture material or synthetic mesh to correct genital prolapse). In the upper genital tract, infection is typically associated with an intrauterine device. Their detection in asymptomatic individuals without a foreign body does not appear to require treatment. Symptoms related to Actinomyces infection include malodorous vaginal discharge, vaginal bleeding, or abdominopelvic pain due to abscess formation. Microscopically, these bacteria are seen as blue delicate filamentous organisms

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typically radiating from a central core in a background of neutrophils. A positive Grocott-Gomori methenamine silver nitrate (GMS) stain and gram stain is used to distinguish actinomycotic from noninfectious pseudoactinomycotic radiate granules; the latter typically also have thicker filaments. Treatment is warranted in symptomatic cases and involves removal of the foreign body and use of penicillin.

nn TOXIC SHOCK SYNDROME (TSS) This acute disease is characterized by hypotension and multisystemic involvement (including two or more of the following: renal impairment, coagulopathy, hepatic or central nervous system dysfunction, acute respiratory distress syndrome, gastrointestinal symptoms—such as vomiting or diarrhea, or muscular involvement—as severe myalgia or creatinine phosphokinase level at least twice the upper limit of normal) with or without erythematous macular rash that may desquamate. TSS may be associated with tampon use in which secondary vaginal ulcerations or erosions serve as an entry point for the organism. Withdrawal of highly absorbent tampons and polyacrylate rayon-containing products from the market partially explains the decrease in TSS; however, tampon use is still a risk factor. It may also occur postpartum, after a medical or missed abortion, C-section, surgical procedure, or carbon dioxide laser treatment, or skin, bone, or respiratory infections. Tampon-associated TSS is caused by Staphylococcus aureus, whereas S. aureus, Streptococcus pyogenes (group A Streptococci), Clostridium sordellii, or Clostridium perfringens may be implicated in other settings. In infections secondary to S. aureus the diagnosis is primarily clinical as blood cultures are positive in only approximately 5% of the cases. In contrast, in infections due to GAS, blood cultures are typically positive. Microscopically, mucosal hyperemia and/or ulceration can be noted. A Gram stain can demonstrate Gram-positive cocci (staphylococcal or group A streptococcal infections) or Gram-positive bacilli (clostridial infection). In clostridial infections, besides anaerobic culture, immunohistochemical studies using commercial polyclonal anti-Clostridium spp. antibody or PCR targeting a Clostridium specific gene have been used in formalin fixed tissue. Treatment includes clindamycin with or without penicillin and intravenous immunoglobulin G therapy.

nn PARASITIC VAGINITIS Parasitic infections are rare in the United States, being more common in countries where the infection is endemic. Vaginal amebiasis is caused by Entamoeba

histolytica; patients usually present with bloody vaginal discharge and ulcerated and friable lesions. Microscopically, ulcerated squamous epithelium is associated with fibrinopurulent exudate containing trophozoites measuring 15–60 μm in diameter that stain with periodic acidSchiff (PAS). Trophozoites can also be identified on wet smears from vaginal discharge. Metronidazole is the treatment of choice. Infection by Schistosoma mansoni and Schistosoma haematobium commonly results in vaginal discharge, pruritus, and dyspareunia. Clinical examination may show polyps, ulcers, or “sandy patches” of the mucosa. The latter are visible by colposcopy. Microscopically, viable or nonviable eggs are usually seen in the submucosa, associated with a prominent inflammatory response (including eosinophils) that ultimately results in marked fibrosis (Fig. 5.4). Praziquantel is the treatment of choice. Eggs and worms of Enterobius vermicularis have also been found in the vagina, where they elicit a granulomatous reaction associated with central necrosis (Fig. 5.5). Finally, eggs of Trichuris trichiura can be seen in the vagina as contamination in cases of intestinal infestation.

nn TUBERCULOSIS Vaginal involvement by tuberculosis is usually secondary to spread from pulmonary or renal disease with rare cases exclusively confined to the lower female genital tract. It tends to affect women of reproductive age, although it can also occur in postmenopausal women or in association with immunosuppression. Grossly, it may be seen as nodules or ulcers. Microscopically, it shows caseating granulomas containing acid-fast positive bacilli. Antituberculosis quadruple regimen is standard for this infection.

nn VIRAL INFECTIONS Genital infection by herpes simplex virus (HSV) often involves the vagina. The most common causative agent is herpes simplex virus type 2 (HSV-2) and, less frequently, herpes simplex virus type 1 (HSV-1). “Classic” outbreaks begin with a prodrome lasting 2–24 hours that includes regional pain or a burning sensation. In addition, patients may have fever, headache, malaise, lymphadenopathy, and anorexia. Subsequently, papules, vesicles, and erosions/ulcers appear over hours to days and can last from 2–6 weeks. The vesicles are usually asymptomatic, whereas the ulcers are very painful. Some patients can have intermittent bleeding and vaginal discharge. Recurrent HSV episodes are usually milder than the initial episode, typically with fewer lesions, and viral shedding occurs at a lower concentration and with

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FIG. 5.4 Schistosomiasis. Viable and nonviable eggs are surrounded by fibrosis in the vaginal submucosa.

FIG. 5.5 Enterobiasis. Multiple eggs of Enterobius vermicularis are associated with necrosis and acute inflammation. (Courtesy Dr. R.C. Neafie.)

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FIG. 5.6 Herpes simplex virus infection Infected squamous cells show multinucleation, nuclei with groundglass chromatin with peripheral margination and intranuclear inclusions.

shorter duration. Microscopically, there is prominent intracellular ballooning and reticular degeneration of the keratinocytes leading to intraepidermal vesicles, which may rupture and secondarily form ulcers. Acantholytic keratinocytes show nuclear molding, “ground-glass” or marginated chromatin, and sometimes multinucleation. Large eosinophilic nuclear inclusions surrounded by a pale halo (Cowdy A bodies) are less frequently seen (Fig. 5.6). The characteristic viral cytopathic changes are more commonly identified at the edge of the ulcer. The diagnosis is based on histologic findings or cytology preparation of the scraping of the base and edges of a fresh ulcer (by Tzanck preparation, Diff-Quik, Papanicolaou or thin-prep, Wright). Immunohistochemistry (HSV1 and HSV2), in situ hybridization, or PCR for HSV can be used to confirm the diagnosis (Fig. 5.7). Acyclovir and related compounds such as valacyclovir and famciclovir are used in the control of the outbreaks. Cytomegalovirus (CMV) infection causes vaginal, cervical and vulvar ulcers in immunocompromised patients, in particular those with human immunodeficiency virus (HIV). Ulcers, either single or multiple, may be confined to the lower genital tract or coexist with oroesophageal ulcers. They are painful, range in size from 1 to 6 cm, are often deep, and occasionally progress to form fistulas. Infected epithelial and/or endothelial cells are typically enlarged and contain intranuclear and intracytoplasmic inclusions. Peripheral clearing of the chromatin imparts an “owl’s eye” appearance. Confirmation of CMV infection by immunohistochemistry can be performed. Patients tend to respond to topical or systemic steroids.

VIRAL INFECTIONS—FACT SHEET Clinical Features n HSV type 2>type 1 n Pain or burning sensation, vaginal discharge, or intermittent vaginal bleeding n Fever, malaise, lymphadenopathy, and anorexia may be seen n CMV-associated ulcers are painful Prognosis and Treatment n Acyclovir and related compounds if herpes n Topical or systemic steroids for ulcers in AIDS patients if CMV

VIRAL INFECTIONS—PATHOLOGIC FEATURES Gross Findings n Herpes virus infection: papules, vesicles and erosions/ulcers n CMV infection: ulcers in immunocompromised patients Microscopic and Ancillary Findings n HSV: Prominent intracellular ballooning and reticular degeneration of keratinocytes with intraepidermal vesicles n Nuclear molding, “ground-glass” chromatin +/- multinucleation n Large eosinophilic nuclear inclusions surrounded by pale halo (Cowdry A bodies) Confirmation by immunohistochemistry (HSV and HSV2) and PCR n CMV: Enlarged epithelial and/or endothelial cells Intranuclear (“owl-eye”) and intracytoplasmic inclusions Confirmation by immunohistochemistry

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FIG. 5.7 Herpes simplex virus infection. In situ hybridization highlights the infected cells.

nn EMPHYSEMATOUS VAGINITIS This is a rare, benign, self-limited disease of unknown cause that typically involves the vagina, although occasionally can also affect the ectocervix.

CLINICAL FEATURES Patients range in age from 17 to 77 years. Symptoms, when present, include vaginal discharge or bleeding, pressure, pruritus, and a “popping” sound with intercourse or physical examination due to rupture of the gas-filled cysts.

PATHOLOGIC FEATURES

MICROSCOPIC FINDINGS

The hallmark of emphysematous vaginitis is the presence of variably sized pseudocystic spaces within the lamina propria. The walls are composed of fibroconnective tissue that may or may not contain multinucleated giant cells (Fig. 5.8). The pseudocysts are usually empty but may occasionally contain eosinophilic material. The overlying squamous epithelium is intact but may show acanthosis. On occasion, there is associated chronic inflammation.

PROGNOSIS AND THERAPY This benign lesion usually regresses spontaneously. However, superimposed infection (usually trichomoniasis or G. vaginalis) requires treatment.

GROSS FINDINGS

The lesions, which range in size from a few millimeters to 2 cm, usually involve, but are not limited to, the upper two-thirds of the vagina. They are often evenly distributed but may form clusters. Individual lesions are tense, smooth, and discrete, although as they aggregate, the vaginal mucosa acquires a pebbled or granular appearance.

nn DESQUAMATIVE INFLAMMATORY VAGINITIS This is an uncommon form of chronic purulent vaginitis that may be immune-mediated.

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FIG. 5.8 Emphysematous vaginitis. Several irregular pseudocystic spaces (lacking an epithelial lining) are surrounded by marked chronic inflammation. (Courtesy Dr. Michael Stamatakos.)

CLINICAL FEATURES It typically affects white women over a wide age range, with a peak in the perimenopause. Patients are typically symptomatic and have long standing complaints (usually >1 year before diagnosis) including purulent vaginal discharge, vulvovaginal burning sensation, dyspareunia, malodor, and vulvar pruritus. The vaginal pH is typically elevated (>4.5).

PATHOLOGIC FEATURES

ANCILLARY STUDIES Wet mount shows an increase in polymorphonuclear (PMN) leukocytes, defined as the ratio of PMN to epithelial cells >1:1 in at least 4 high power fields (HPFs), numerous parabasal cells, and naked nuclei. Absence of lactobacilli and outgrowth of Gram-positive cocci, visualized on Gram stain, is seen in up to 92% of patients.

DIFFERENTIAL DIAGNOSIS

GROSS FINDINGS

There is mucosal erythema and ecchymoses; the latter can also involve the vulva and cervix. Occasionally, erythematous papules with a pale center can be seen. MICROSCOPIC FINDINGS

The squamous epithelium, which may be thinned or ulcerated, and submucosa are associated with a dense acute and chronic inflammatory infiltrate.

Infectious vaginitis may show some overlapping features with desquamative inflammatory vaginitis. The presence of specific microorganisms will establish the correct diagnosis. In the presence of Gram-positive cocci, cultures will be necessary to exclude specific infections such as Streptococcus group B and Staphylococcus. The diagnosis of desquamative inflammatory vaginitis is, therefore, one of exclusion.

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PROGNOSIS AND THERAPY Treatment with topical clindamycin or steroids is effective, although ∼30% of patients may relapse. Therefore, maintenance treatment is required. DESQUAMATIVE INFLAMMATORY VAGINITIS—FACT SHEET Definition n Uncommon form of chronic purulent vaginitis Clinical Features n Wide age range, but more common in perimenopause n Purulent vaginal discharge or malodor n Vulvovaginal burning sensation, pruritus, dyspareunia n Elevated vaginal pH (>4.5) Prognosis and Treatment n Topical clindamycin or corticosteroids, daily for 2–4 weeks, followed by maintenance therapy as needed n Relapse rate ∼30%

DESQUAMATIVE INFLAMMATORY VAGINITIS— PATHOLOGIC FEATURES Gross Findings n Erythema and ecchymoses n Erythematous papules with a pale center Microscopic Findings n Dense acute and chronic inflammation involving squamous epithelium and submucosa Ancillary Studies n Increased number of acute inflammatory cells, numerous parabasal cells, and naked nuclei on wet mount (ratio of PMN to epithelial cells >1:1 in at least 4 HPFs) n Abnormal vaginal flora (absence of lactobacilli) Differential Diagnosis n Infectious vaginitis

nn LIGNEOUS VAGINITIS This is a rare disease in which patients develop mucosal lesions not only in the lower genital tract (vagina and cervix) but also conjunctiva, oral cavity, respiratory tract, middle ear, and intestine. It is caused by type I plasminogen deficiency, a form of inherited hypoplasminogenemia characterized by low levels of active and immunoreactive plasminogen which has been associated with a variety of homozygous

GYNECOLOGIC PATHOLOGY

or compound heterozygous mutations of the plasminogen gene. Such mutations most likely produce a rapid degradation of plasminogen—a key component of the fibrinolytic system. Decreased active plasminogen levels produce accumulation of fibrin at sites of repetitive mucosal trauma with the formation of subepithelial masses, which lead to further mucosal ulceration, initiating a cycle of mucosal damage and fibrin deposition.

CLINICAL FEATURES Patients typically range in age from 1 to 65 years and present with dysmenorrhea, vaginal discharge, and postcoital bleeding, as well as gingival disease or conjunctivitis. Patients may also be infertile if the upper genital tract is involved. Physical examination reveals “pseudomembranes,” plaques, ulcers, or exophytic lesions in one or more mucosal sites, and vaginal stenosis.

PATHOLOGIC FEATURES MICROSCOPIC FINDINGS

There is alternating denuded and hyperplastic patches of squamous epithelium with subepithelial accumulation of fibrin seen as amorphous eosinophilic amyloid or hyaline-like material (Fig. 5.9). It may be accompanied by granulation tissue near areas of ulceration. The fibrin deposits stain with PAS but not with Congo-red. Immunofluorescence studies demonstrate the presence of fibrinogen.

DIFFERENTIAL DIAGNOSIS Ligneous vaginitis should be distinguished from radiation-induced changes, amyloid deposition, and scar. Radiation induced changes are typically associated with hyalinization rather than fibrin deposition. Radiation also involves vessel walls, which appear obliterated and hyalinized. Amyloidosis typically involves vessel walls; Congo-red positivity (apple green birefringent) will confirm amyloidosis. Usually, scars have a variable amount of fibroblasts and inflammatory cells and well-defined collagen bundles, which are birefringent; furthermore, the alternating mucosal changes of ligneous vaginitis are not seen in scar formation.

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FIG. 5.9 Ligneous vaginitis. Compact deposits of fibrin are seen as amorphous eosinophilic amyloid-like material admixed with inflammation. (Courtesy Dr. Elvio G. Silva.)

PROGNOSIS AND THERAPY Prognosis is related to extent and severity of disease, particularly if there is extragenital involvement. This condition may be successfully treated with topical heparin-like preparations or plasminogen. Treatment with oral contraceptives or intravenous lys-plasminogen may also be beneficial by increasing serum plasminogen levels.

LIGNEOUS VAGINITIS—FACT SHEET Clinical Features n Age range 1–65 years n Dysmenorrhea, infertility, vaginal discharge, postcoital bleeding n Frequently associated with gingival disease or conjunctivitis Prognosis and Treatment n Prognosis related to extent and severity of disease, particularly in women with extragenital involvement n Topical treatment with heparin-like preparations or plasminogen n Oral contraceptives or intravenous lys-plasminogen may be used to increase endogenous plasminogen levels

LIGNEOUS VAGINITIS—PATHOLOGIC FEATURES Gross Findings n “Pseudomembranes,” plaques, ulcers, vaginal stenosis, or exophytic lesions Microscopic Findings n Alternating areas of denuded and hyperplastic squamous epithelium n Subepithelial fibrin deposition (amorphous eosinophilic amyloid-like material) Ancillary studies n Fibrin deposits are PAS, (+), Fibrinogen immunofluorescence (+), Congo-red (-) Differential Diagnosis n Radiation induced changes n Amyloidosis n Scar

nn MALAKOPLAKIA This rare chronic inflammatory disease appears to be caused by an acquired defect in macrophage function that results in an impaired histiocytic response to common pathogens. Escherichia coli has been the most

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FIG. 5.10 Malakoplakia. Michaelis–Gutmann bodies (arrow) are seen within the cytoplasm of histiocytes.

commonly isolated organism; however, a wide variety of bacteria and mycobacteria also have been identified. The vagina is the most frequently involved gynecologic site.

CLINICAL FEATURES Patients range in age from 29 to 84 years, but they are more commonly postmenopausal. Symptoms include bleeding, malodorous vaginal discharge, or pain. On physical examination, lesions form soft yellow nodules or plaques, typically 10 cm. The cysts are lined by cuboidal or low columnar nonmucinous epithelium (Fig. 5.21) that may be surrounded by smooth muscle. In contrast to the epithelium seen in Müllerian cysts, the epithelium is devoid of cytoplasmic mucicarmine or PAS-positive material. The differential diagnosis includes urethral diverticulum, which is typically lined by transitional or squamous epithelium.

CYSTS OF THE VAGINA—FACT SHEET Definition n Epithelial lined cysts of varying origin Incidence and Location n 1 in 200 women, but may be underestimated n Müllerian cyst most common; typically anterolateral wall n Epidermal inclusion cyst at site of prior surgical procedure n Gartner duct cyst typically lateral walls Age Distribution n Third and fourth decades most common Clinical Features n Usually asymptomatic n Mild vaginal discomfort, pressure or fullness, swelling or mass, dyspareunia, and urinary symptoms n Urinary system abnormalities may be associated with Gartner duct cyst or in epidermal inclusion cyst in neonates Prognosis and Treatment n Benign n Excision, if symptomatic

CHAPTER 5  Nonneoplastic Diseases of the Vagina

FIG. 5.19 Müllerian cyst. A cyst is lined by columnar mucin-producing epithelium (inset). (Courtesy Dr. Michael Stamatakos.)

FIG. 5.20 Epithelial inclusion cyst. The cyst is lined by mature multilayered squamous epithelium.

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144 CYSTS OF THE VAGINA—PATHOLOGIC FEATURES Gross Findings n Müllerian cysts:1.4–8 cm n Epidermal inclusion cysts: up to 4 cm; may contain “cheese-like” material n Gartner duct cysts: 0.1–4 cm Microscopic Findings n Müllerian cyst: endocervical columnar to cuboidal epithelium, less commonly endometrioid or tubal epithelium n Epidermal inclusion cyst: squamous epithelium associated with keratin debris n Gartner duct cyst: cuboidal or low-columnar nonmucinous epithelium +/- surrounding smooth muscle Differential Diagnosis n Endometriosis (vs. Müllerian cyst) n Urethral diverticulum (vs. Gartner duct cyst)

GYNECOLOGIC PATHOLOGY

“genitourinary syndrome of menopause” has been proposed as a substitute for “vulvovaginal atrophy” in menopausal patients as the former is a more generic label that more adequately describes urinary and genital symptoms.

CLINICAL FEATURES While atrophy is seen in most postmenopausal women, not all of them will be symptomatic. Symptoms include vaginal dryness and irritation, pruritus, dyspareunia, and postcoital bleeding.

PATHOLOGIC FEATURES GROSS FINDINGS

nn ATROPHY Vaginal atrophy occurs in hypoestrogenic states such as: (1) menopause (natural or postoophorectomy), (2) gonadotropin-releasing hormone (GnRH) agonist therapy for endometriosis or leiomyomas, (3) hypothalamic amenorrhea caused by excessive exercise, disordered eating or postpartum, (5) postpelvic radiation therapy, and (6) secondary to hormonal therapy for breast cancer (i.e., tamoxifen or aromatase inhibitors use). The term

FIG. 5.21 Gartner’s duct cyst. The cyst has an irregular outline and is lined by a single layer of cuboidal cells. Notice the fascicles of smooth muscle surrounding the cyst.

There is frequent loss of rugal folds and a pale, dry appearance of the mucosa that may be associated with petechiae. MICROSCOPIC FINDINGS

There is loss or variable reduction of superficial and intermediate squamous cells, usually resulting in an epithelium with 7–10 layers (Fig. 5.22A); however, the squamous epithelium may have a normal thickness. Cytoplasmic glycogen is often absent, resulting

CHAPTER 5  Nonneoplastic Diseases of the Vagina

A

B FIG. 5.22 Vaginal atrophy. The squamous epithelium appears flattened with decreased to absent intracytoplasmic glycogen (A). Ki-67 immunostain demonstrates rare positivity in the basal layer (B).

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146 in increased nuclear to cytoplasmic ratio. However, no cytologic atypia or mitotic activity is seen. In transitional cell metaplasia, considered to be a variant of atrophy, the epithelium is >10 cells thick and shows oval or elongated nuclei with frequent grooves, typically oriented vertically in the deeper layers, and horizontally with a streaming pattern superficially (with the main cell axis parallel to the basement membrane). The very superficial cells may resemble umbrella cells (Fig. 5.23). Mitotic figures are absent or rare. In addition, stromal sclerosis, which is likely reparative, can be seen. Elastic stain will demonstrate a marked increase in elastic fibers (Figs. 5.24 A,B).

GYNECOLOGIC PATHOLOGY

intraepithelial lesion, as it shows high nuclear to cytoplasmic ratios and lack of cell maturation. Absence of nuclear pleomorphism or mitoses in the upper layers, Ki-67 immunopositivity limited to scattered basal/ parabasal cells (Fig. 5.22B), and lack of p16 overexpression are in keeping with the diagnosis of atrophy. If there is stromal sclerosis, the differential diagnosis includes: (1) amyloidosis, which is Congo-red positive with apple green birefringence under polarized light, usually associated with generalized disease, (2) ligneous vaginitis, which typically occurs in premenopausal women with abundant deposition of fibrin, (3) lichen sclerosus extending into the vagina, which is characterized by a decrease, rather than increase, of elastic fibers.

ANCILLARY STUDIES An elevated vaginal pH level (>5.0) is often found. Increased numbers of parabasal cells are the norm in either wet preparation or Papanicolaou smear.

DIFFERENTIAL DIAGNOSIS Atrophy, including transitional cell metaplasia, may be confused with a vaginal high-grade squamous

FIG. 5.23 Transitional cell metaplasia. The thickened epithelium is composed of cells with oval to elongated nuclei. The main axis of the superficial cells tends to be oriented in parallel to the basement membrane.

PROGNOSIS AND THERAPY This benign condition is typically treated with vaginal moisturizers or lubricants, low-dose topical estrogen, transdermal and oral hormone therapy including ospemifene—a selective estrogen-receptor modulator. In breast cancer patients, the use of vaginal pH balanced gel and lidocaine appears to be a viable therapeutic option over the use of estrogen-based products.

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A

FIG. 5.24

B

Stromal sclerosis in atrophy, hyalinization of the stroma, hematoxylin and eosin stain (A) and increased elastin fibers, elastin stain (B).

148 VAGINAL ATROPHY—FACT SHEET Clinical Features n More often in postmenopausal women n Dryness, pruritus, dyspareunia, and postcoital bleeding n May be asymptomatic Treatment n Vaginal lubricants and moisturizers, low-dose topical estrogen, transdermal or oral hormone therapy

VAGINAL ATROPHY—PATHOLOGIC FEATURES Gross Findings n Loss of rugal folds n Pale and dry mucosa n Petechiae may be present Microscopic Findings n Reduced or normal-thickness squamous epithelium n Loss or variable reduction of superficial and intermediate squamous cells n Lack of glycogenation of squamous epithelium n Transitional cell metaplasia (variant of atrophy) n Epithelial thickness >10 cells n Nuclei oriented vertically in the deeper layers, and horizontally in the surface n Oval or spindle nuclei with frequent nuclear grooves n Increased nuclear/cytoplasmic ratio n Absent or minimal cytologic atypia and/or mitoses n Stromal sclerosis with an increased number of elastic fibers Differential Diagnosis n High-grade squamous intraepithelial lesion n Amyloidosis, ligneous vaginitis, and lichen sclerosus (if prominent sclerosis)

nn ECTOPIC DECIDUAL REACTION (DECIDUOSIS) Ectopic decidual reaction is not an infrequent finding in the vagina during pregnancy and can be detected from the sixth week of gestation to term. Rarely, it may mimic carcinoma as it can cause vaginal bleeding or form a mass. This lesion can be detected any time during pregnancy, undergoes spontaneous regression after parturition, and requires no specific treatment. Microscopically, it is characterized by polygonal or spindle-shaped cells with ample pale cytoplasm and nuclei that can display inconspicuous nucleoli. Ectopic decidual reaction may be mistaken for carcinoma due to its epithelioid and

GYNECOLOGIC PATHOLOGY

sometimes signet ring cell-like morphology. Awareness of the clinical setting, its uniform cytologic appearance, and lack of mitoses aids in its distinction. In difficult cases a negative keratin immunostain will facilitate the diagnosis. ECTOPIC DECIDUAL REACTION (DECIDUOSIS)—FACT SHEET Clinical Features n Detected from the sixth week of gestation to term n Very rarely vaginal bleeding or mass Prognosis and Treatment n Spontaneous regression after parturition

ECTOPIC DECIDUAL REACTION (DECIDUOSIS)— PATHOLOGIC FEATURES Microscopic Findings n Polygonal cells with abundant pale cytoplasm and round nuclei with or without inconspicuous nucleoli n No mitotic activity Differential Diagnosis n Carcinoma

nn RADIOTHERAPY-ASSOCIATED CHANGES Radiation therapy may cause atrophy, erosion, ulceration, necrosis, and secondary stenosis of the vagina. Microscopically, the squamous epithelium is thin and the cells display cytoplasmic vacuolization, nuclear enlargement (but with preserved nuclear to cytoplasmic ratio), multinucleation, and rare to absent mitoses (Fig. 5.25). Vascular changes include ectasia, vascular wall hyalinization, hyperplastic endothelial cells, thrombosis, and obliteration. Stromal inflammation and hyalinization with scattered enlarged and hyperchromatic fibroblast nuclei can be seen. The main differential diagnostic considerations are (1) vaginal high-grade squamous intraepithelial lesion, which in contrast to radiation changes is characterized by an increased nuclear to cytoplasmic ratio, nuclei with coarse chromatin, and conspicuous mitotic activity, (2) poorly differentiated carcinoma, which displays frank stromal destruction and higher degrees of cellularity and atypia than those seen with radiation, and (3) sarcoma, which will present as a rapidly growing mass with destructive growth in the vagina.

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FIG. 5.25 Radiation changes. The squamous epithelium shows nuclear enlargement and intercellular edema. Reactive fibroblasts with enlarged and hyperchromatic nuclei are admixed with chronic inflammation and ectatic vessels.

SUGGESTED READING RADIOTHERAPY-ASSOCIATED CHANGES—PATHOLOGIC FEATURES Gross Findings n Thin, friable erythematous mucosa +/− ulceration Microscopic Findings n Thinned squamous epithelium n Cytoplasmic vacuolization of squamous cells with enlarged nuclei, but preserved nuclear/cytoplasmic ratio n Rare mitoses n Vascular changes (ectatic vessels, hyalinization of vascular walls, hyperplastic endothelial cells, thrombosis, and vascular obliteration) n Stromal changes (fibroblasts with plump hyperchromatic nuclei, hyalinization, ≥ inflammatory infiltrate) Differential Diagnosis n High-grade vaginal intraepithelial neoplasia (versus radiation-induced mucosal changes) n Poorly differentiated carcinoma and sarcoma (versus radiation-induced stromal atypia)

Congenital Anomalies Alur, S., Nicandri, K., & Bhagavath, B. (2015). Longitudinal vaginal septa with associated uterine anomalies: a case series. Female Pelvic Medicine & Reconstructive Surgery, 21, 23–26. Dietrich, J. E., Millar, D. M., & Quint, E. H. (2014). Non-obstructive reproductive tract anomalies. Journal of Pediatric and Adolescent Gynecology, 27, 386–395. Dietrich, J. E., Millar, D. M., & Quint, E. H. (2014). Obstructive reproductive tract anomalies. Journal of Pediatric and Adolescent Gynecology, 27, 396–402. Ghadian, A., & Heidari, F. (2013). Is hymenotomy enough for treatment of imperforated hymen? Nephr Urol Mon, 5(5), 1012. Nagai, K., Murakami, Y., Nagatani, K., et al. (2012). Life-threatening acute renal failure due to imperforate hymen in an infant. Pediatrics International, 54(2), 280–282. Patnaik, S. S., Brazile, B., Dandolu, V., et al. (2015). Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a historical perspective. Gene, 555, 33–40. Sak, M. E., Evsen, M. S., Soydinc, H. E., Sak, S., & Yalinkaya, A. (2013). Imperforate hymen with elevated serum CA 125 and CA 19-9 levels. Journal of Reproductive Medicine, 58(1–2), 47–50. Ural, U. M., Tekin, Y. B., Sahin, F. K., Erdivanli, B., & Kazdal, H. (2015). Chronic abdominal pain in a patient with Escobar syndrome. Gynecologic and Obstetric Investigation, 79(1), 69–72. Watrowski, R., Jager, C., Gerber, M., et al. (2014). Hymenal anomalies in twins—review of the literature and case report. European Journal of Pediatrics, 173(11), 1407–1412.

150 Infectious and inflammatory lesions Anderson, B. L. (2014). Puerperal group A streptococcal infection: beyond Semmelweis. Obstetrics & Gynecology, 123(4), 874–882. Anderson, J., Clark, R. A., Watts, D. H., et al. (1996). Idiopathic genital ulcers in women infected with human immunodeficiency virus. Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology, 13, 343–347. Beauman, J. G. (2005). Genital herpes: a review. American Family Physician, 72, 1527–1534. Bowen, L. W., Sand, P. K., & Ostergard, D. R. (1986). Toxic shock syndrome following carbon dioxide laser treatment of genital tract condyloma acuminatum. American Journal of Obstetrics and Gynecology, 154(1), 145–146. Buppasiri, P., Temtanakitpaisan, T., & Somboonporn, W. (2010). Tuberculosis at vulva and vagina. Journal of the Medical Association of Thailand, 93(5), 613–615. Cagno, C. K., Pettit, J. M., & Weiss, B. D. (2012). Prevention of perinatal group B streptococcal disease: updated CDC guideline. American Family Physician, 86(1), 59–65. Chen, K. T., & Hendricks, E. J. (1985). Malakoplakia of the female genital tract. Obstetrics & Gynecology, 65, 84S–87S. Ciavattini, A., & Clemente, N. (2015). Female genital tract chronic graft-versus-host disease: review of the literature. Anticancer Research, 35, 13–18. Cohen, A. L., Bhatnagar, J., Reagan, S., et al. (2007). Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstetrics & Gynecology, 110(5), 1027–1033. de Mundi Zamorano, A., del Alamo, C. M., de Blas, L. L., et al. (1978). Egg of Trichuris trichiura in a vaginal smear. Acta Cytologica, 22, 119–120. Dixit, S., Fischer, G., & Wittekind, C. (2013). Recurrent menstrual toxic shock syndrome despite discontinuation of tampon use: is menstrual toxic shock syndrome really caused by tampons? Australasian Journal of Dermatology, 54(4), 283–286. Edwards, L. (2010). Dermatologic causes of vaginitis: a clinical review. Dermatol Clin, 28, 727–735. Eleuterio, E. J., Giraldo, P. C., Cavalcante, D. I. M., et al. (2008). Actinomyces-like organisms from a vaginal granuloma following intravaginal slingplasty with polypropylene mesh. International Journal of Gynaecology & Obstetrics, 102(2), 172–173. Feldmeier, H., Daccal, R. C., Martins, M. J., et al. (1998). Genital manifestations of Schistosomiasis mansoni in women: important but neglected. Memorias do Instituto Oswaldo Cruz, 93(1), 127– 133. Fishman, A., Ortega, E., Girtanner, R. E., et al. (1993). Malacoplakia of the vagina presenting as a pelvic mass. Gynecologic Oncology, 49, 380–382. Fox, H. (1985). The pathology of tampon usage and of the toxic shock syndrome. Postgraduate Medical Journal, 61(1), 31–33. Friedmann, W., Schäfer, A., Kretschmer, R., et al. (1991). Disseminated cytomegalovirus infection of the female genital tract. Gynecologic and Obstetric Investigation, 31, 56–57. Furtado, S. P., Junior, J. E., Rodrigues, D. C., et al. (2010). Cervicovaginal tuberculosis in a postmenopausal woman. International Journal of Gynaecology & Obstetrics, 110(1), 70–71. Goncalves, B., Ferreira, C., Alves, C. T., et al. (2016). Vulvovaginal candidiasis: epidemiology, microbiology and risk factors. Critical Reviews in Microbiology, 42, 905927. Kavala, M., Demir, F. T., Zindanci, I., et al. (2015). Genital involvement in pemphigus vulgaris (PV): correlation with clinical and cervicovaginal Pap smear findings. Journal of the American Academy of Dermatology, 73(4), 655–659. Kenyon, C. R., & Osbak, K. (2014). Recent progress in understanding the epidemiology of bacterial vaginosis. Current Opinion in Obstetrics and Gynecology, 26(6), 448–454. Kissinger, P. (2015). Trichomonas vaginalis: a review of epidemiologic, clinical and treatment issues. BMC Infectious Diseases, 15(1), 307. Kjetland, E. F., Leutscher, P. D., & Ndhlovu, P. D. (2012). A review of female genital schistosomiasis. Trends in Parasitology, 28(2), 58–65. Kogulan, P. K., Smith, M., Seidman, J., et al. (2001). Malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: case report and discussion of malakoplakia-associated bacteria. International Journal of Gynecological Pathology, 20, 403–406.

GYNECOLOGIC PATHOLOGY Lima-Silva, J., Vieira-Baptista, P., Cavaco-Gomes, J., Maia, T., & Beires, J. (2015). Emphysematous vaginitis. Journal of Lower Genital Tract Disease, 19(2), 43–44. Lotan, T. L., Tefs, K., Schuster, V., et al. (2007). Inherited plasminogen deficiency presenting as ligneous vaginitis: a case report with molecular correlation and review of the literature. Human Pathology, 38(10), 1569–1575. Low, D. E. (2013). Toxic shock syndrome: Major advances in pathogenesis, but not treatment. Critical Care Clinics, 29(3), 651–675. Martin Lopez, J. E. (2015). Candidiasis (vulvovaginal). BMJ Clinical Evidence, 3, 1–23. Meites, E., Zane, S., Gould, C., & Investigators, C. (2010). Fatal Clostridium sordellii infections after medical abortions. New England Journal of Medicine, 363(14), 1382–1383. Mendoza, C. F., Valladares, V., Ballesteros, A., et al. (2008). Ulceras vaginales en enfermedad de Behçet. Ginecología y Obstetricia de México, 76, 178–181. Moore-Maxwell, C. A., & Robboy, S. J. (2004). Mucinous adenocarcinoma arising in rectovaginal fistulas associated with Crohn’s disease. Gynecologic Oncology, 93, 266–268. Nemati, E., Taheri, S., Nourbala, M. H., et al. (2009). Vaginal tuberculosis in an elderly kidney transplant recipient. Saudi Journal of Kidney Diseases and Transplantation, 20(3), 465–467. Nopdonrattakoon, L. (1996). Amoebiasis of the female genital tract: a case report. Journal of Obstetrics and Gynaecology Research, 22, 235–238. Panagiotopoulou, N., Wong, C. S. M., & Winter-Roach, B. (2010). Vulvovaginal syndrome. Journal of Obstetrics & Gynaecology, 30(3), 226–230. Reichman, O., & Sobel, J. (2014). Desquamative inflammatory vaginitis. Best Practice & Research Clinical Obstetrics & Gynaecology, 28(7), 1042–1050. Selva-Nayagam, P., Fischer, G., & Hamman, I. (2015). Rituximab causing deep ulcerative suppurative vaginitis/pyoderma gangrenosum. Current Infectious Disease Reports, 17, 23. Shalaby, T., Anandappa, S., Pocock, N. J., et al. (2014). Lesson of the month 2: toxic shock syndrome. Clinical Medicine, 14(3), 316–318. Sides, C., Trinidad, M. C., Heitlinger, L., & Anasti, J. (2013). Crohn disease and the gynecologic patient. Obstetrical and Gynecological Survey, 68(1), 51–61. Sinniah, B., Leopairut, J., Neafie, R. C., et al. (1991). Enterobiasis: A histopathological study of 259 patients. Annals of Tropical Medicine and Parasitology, 85, 625–635. Swidsinski, A., Verstraelen, H., Loening-Baucke, V., et al. (2013). Presence of a polymicrobial endometrial biofilm in patients with bacterial vaginosis. PLoS One, 8(1), 53997. Tremlett, W., Michie, C., Kenol, B., et al. (2014). Recurrent menstrual toxic shock syndrome with and without tampons in an adolescent. The Pediatric Infectious Disease Journal, 33(7), 783–785. Van Schalkwk, J., Yidn, M. H., et al. (2015). Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. Journal of Obstetrics and Gynaecology Canada, 37(3), 266–276. Verstraelen, H. 1, Verhelst, R., Vaneechoutte, M., & Temmerman, M. (2011). Group A streptococcal vaginitis: an unrecognized cause of vaginal symptoms in adult women. Archives of Gynecology and Obstetrics, 284(1), 95–98. Wai, C. Y., Nihira, M. A., Drewes, P. G., et al. (2005). Actinomyces associated with persistent vaginal granulation tissue. Infectious Diseases in Obstetrics and Gynecology, 13, 53–55. Zane, S., & Guarner, J. (2011). Gynecologic clostridial toxic shock in women of reproductive age. Current Infectious Disease Reports, 13(6), 561–570. Zendel, K., & Edwards, L. (2013). Lichen sclerosus with vaginal involvement. Report of 2 cases and review of the literature. JAMA Dermatol, 149, 1199–1202. Pseudoneoplastic and Miscellaneous Lesions Castellvi Vives, J., Garcia Jimenez, A., Centeno Mediavilla, C., et al. (1997). Ectopic vaginal decidualization. An unusual finding that presents problems of differential diagnosis with carcinoma. European Journal of Gynaecological Oncology, 18(3), 183–184. Fadare, O. (2011). Vaginal stromal sclerosis: a distinctive stromal change associated with vaginal atrophy. International Journal of Gynecological Pathology, 30(3), 295–300.

CHAPTER 5  Nonneoplastic Diseases of the Vagina Goodman, A., Zukerberg, L. R., Nikrui, N., et al. (1991). Vaginal adenosis and clear cell carcinoma after 5-fluorouracil treatment for condylomas. Cancer, 68, 1628–1632. Guillou, L., Gloor, E., De Grandi, P., et al. (1989). Post-operative pseudosarcoma of the vagina. A case report. Pathology, Research & Practice, 185, 245–248. Heller, D. S. (2012). Vaginal cysts: a pathology review. Journal of Lower Genital Tract Disease, 16(2), 140–144. Hwang, J. H., Oh, M. J., Lee, N. W., et al. (2009). Multiple vaginal Müllerian cysts: a case report and review of literature. Archives of Gynecology and Obstetrics, 280(1), 137–139. Kazakov, D. V., Stewart, C. J., Kacerovska, D., et al. (2010). Prostatic-type tissue in the lower female genital tract: A morphologic spectrum, including vaginal tubulosquamous polyp, adenomyomatous hyperplasia of paraurethral Skene glands (female prostate), and ectopic lesion in the vulva. The American Journal of Surgical Pathology, 34(7), 950–955. Kelly, P., McBride, H. A., Kennedy, K., et al. (2011). Misplaced Skene’s glands: glandular elements in the lower female genital tract that are variably immunoreactive with prostate markers and that encompass vaginal tubulosquamous polyp and cervical ectopic prostatic tissue. International Journal of Gynecological Pathology, 30(6), 605–612. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause, 20(9), (2013), 888–902. Mazeron, J. J., & Gerbaulet, A. (1997). Late effects of ionizing radiations on the vulva, vagina and uterus. Cancer Radiotherapie, 1, 781–789. Mazzarello, S., Hutton, B., Ibrahim, M. F., et al. (2015). Management of urogenital atrophy in breast cancer patients: a systematic review of available evidence from randomized trials. Breast Cancer Research and Treatment, 152(1), 1–8. McCluggage, W. G., & Young, R. H. (2007). Tubulo-squamous polyp: a report of ten cases of a distinctive hitherto uncharacterized vaginal polyp. The American Journal of Surgical Pathology, 31(7), 1013–1019. McCluggage, W. G. (2009). Recent developments in vulvovaginal pathology. Histopathology, 54(2), 156–173.

151 Oliva, E., Gonzalez, L., Dionigi, A., et al. (2004). Mixed tumors of the vagina: an immunohistochemical study of 13 cases with emphasis on the cell of origin and potential aid in differential diagnosis. Modern Pathology, 17(10), 1243–1250. Parker, R. L., Dadmanesh, F., Young, R. H., et al. (2004). Polypoid endometriosis: a clinicopathologic analysis of 24 cases and a review of the literature. The American Journal of Surgical Pathology, 28, 285–297. Portman, D. J., & Gass, M. L. and Vulvovaginal Atrophy Terminology Consensus Conference Panel (2014). Genitourinary syndrome of menopause: New terminology for vulvovaginal atrophy from the International Society for the study of Women’s Sexual Health and the North American Menopause Society. The Journal of Sexual Medicine, 11(12), 2865–2872. Proppe, K. H., Scully, R. E., & Rosai, J. (1984). Postoperative spindle cell nodules of genitourinary tract resembling sarcomas. A report of eight cases. The American Journal of Surgical Pathology, 8, 101– 108. Robboy, S. J., Noller, K. L., O’Brien, P., et al. (1984). Increased incidence of cervical and vaginal dysplasia in 3980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project. Journal of the American Medical Association, 252, 2979–2983. Shah, C., Pizer, E., Veljovich, D. S., et al. (2006). Clear cell adenocarcinoma of the vagina in a patient with vaginal endometriosis. Gynecologic Oncology, 103, 1130–1132. Shield, P. W. (1995). Chronic radiation effects: a correlative study of smears and biopsies from the cervix and vagina. Diagnostic Cytopathology, 13, 107–119. Toz, E., Sanci, M., Cumurcu, S., et al. (2015). Müllerian cyst of the vagina masquerading as a cystocele. Case Reports in Obstetrics and Gynecology, 2015, 376834. Weir, M. M., Bell, D. A., & Young, R. H. (1997). Transitional cell metaplasia of the uterine cervix and vagina: an underrecognized lesion that may be confused with high-grade dysplasia. A report of 59 cases. The American Journal of Surgical Pathology, 21, 510–517. Young, R. H., & Clement, P. B. (1989). Pseudoneoplastic lesions of the lower female genital tract. Pathology Annual, 24, 189–226.

6 Neoplastic Lesions of the Vagina nn Anais Malpica

Primary neoplasms of the vagina, whether benign or malignant, are rare. Primary carcinomas are the most common malignant tumors and account for approximately 2% of all gynecologic malignancies. Among vaginal carcinomas, in situ and invasive squamous carcinomas are most frequent. As a general rule, when evaluating a malignant tumor involving the vagina, it is essential to exclude a metastatic origin. This chapter covers the most frequent primary neoplastic lesions of the vagina. Regarding mesenchymal lesions, most entities are covered in Chapter 4 (including smooth muscle tumors).

BENIGN NEOPLASMS nn MÜLLERIAN PAPILLOMA This is an uncommon papillary lesion lined by Müllerian-type epithelium that typically involves the vagina or uterine cervix.

CLINICAL FEATURES Müllerian papilloma typically occurs in girls less than 10 years of age, although it has been reported occasionally in adults. Patients usually present with vaginal bleeding or a mass, which on gynecologic examination may appear as “grape-like cluster.” The lesion is most common in the posterior vagina, followed by anterior and lateral walls. Rarely, it may be intramural.

PATHOLOGIC FEATURES GROSS FINDINGS

This lesion is typically well-circumscribed, papillary, or polypoid and measures up to 5 cm.

MICROSCOPIC FINDINGS

Müllerian papilloma is characterized by papillary fronds lined by columnar or cuboidal epithelium (Fig. 6.1). The fibrovascular core is usually thin but can appear edematous or myxoid. The lining epithelial cells are cuboidal to columnar and have eosinophilic cytoplasm, uniform bland nuclei, and absent or rare mitotic figures. The epithelial lining can form solid nests with scattered glandular lumina containing eosinophilic periodic acid–Schiff (PAS) positive and diastase-resistant globules. Hyaline globules can be seen. Rarely, heavily pigmented melanocytes may be observed within the epithelium.

ANCILLARY STUDIES The epithelial cells are positive for EMA, CEA, and CAM 5.2, and focally positive for CA125.

DIFFERENTIAL DIAGNOSIS Fibroepithelial polyp, condyloma acuminatum, embryonal rhabdomyosarcoma, and clear cell adenocarcinoma may enter into the differential diagnosis as they all are characterized by papillary to polypoid growth. Fibroepithelial polyp and condyloma acuminatum typically have blunt papillae and are lined by mature squamous as opposed to cuboidal to columnar epithelium. Fibroepithelial stromal polyps show a prominent vascular core and scattered stellate and multinucleate stromal cells in the subepithelial stroma. Exophytic condyloma exhibits koilocytes, at least focally. Embryonal rhabdomyosarcoma characteristically shows condensation of primitive rhabdomyoblasts underneath the surface epithelium (so-called cambium layer) in addition to spindled or strap-shaped cells with brightly eosinophilic cytoplasm within a loose myxoid stroma; these neoplastic cells are positive for skeletal muscle markers, including Myo-D1 and myogenin, antibodies 153

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FIG. 6.1 Müllerian papilloma. Papillary fronds are lined by bland cuboidal epithelium.

directed against skeletal muscle-specific nuclear transcription factors. Clear cell carcinoma occurs in an older age population, usually displays haphazard infiltration into the vaginal wall, and shows distinctive tubulocystic and solid growth patterns. Unlike papilloma, nuclear atypia in clear cell carcinoma is significant, comprised of enlarged hyperchromatic nuclei protruding towards the lumen (“hobnail” appearance).

CLINICAL FEATURES Patients range in age from 20 to 80 (mean 40) years at presentation. Most cases are detected incidentally during routine pelvic examination as a submucosal mass, typically located in the posterior wall close to the hymenal ring.

PATHOLOGIC FEATURES PROGNOSIS AND TREATMENT Müllerian papilloma is treated with local excision. It may recur, and rarely progress to a borderline-type neoplasm (i.e., cytologic atypia and conspicuous mitotic activity). Clear cell carcinoma arising in a Müllerian papilloma has been reported.

nn SPINDLE CELL EPITHELIOMA (MIXED TUMOR OF THE VAGINA) This uncommon tumor is characterized by a predominance of stromal-type cells with a minor component of glandular and/or squamous elements. Although this tumor has ultrastructural evidence of myoepithelial derivation, phenotypically it lacks true mixed/dual myoepithelial differentiation as seen in other anatomical sites. Therefore, the designation of “spindle cell epithelioma” is preferred.

GROSS FINDINGS

The tumor ranges in size from 1 to 9 cm. It is well-circumscribed and on cut section appears gray to white with a rubbery or soft gelatinous consistency. MICROSCOPIC FINDINGS

The tumors are well circumscribed and nonencapsulated with a smooth expansile margin (Fig. 6.2). They are typically superficially located, separated from the epithelium by scant connective tissue. The cellular stromal component, which is typically predominant, shows cells with scant cytoplasm and bland nuclei that range from oval or round to spindle. They can grow in sheets, fascicles, nests, or cords, or have a reticulate growth (Figs. 6.3 and 6.4). The background can appear myxomatous or hyalinized; hyaline globules may be seen and are secondary to condensation of stromal matrix. Mitotic figures are usually rare or absent. A minor epithelial component, either glandular

CHAPTER 6  Neoplastic Lesions of the Vagina

FIG. 6.2 Mixed tumor of the vagina (spindle cell epithelioma). A well-circumscribed tumor shows stromal-like and epithelial components (upper right).

FIG. 6.3 Mixed tumor of the vagina (spindle cell epithelioma). A reticular pattern of the stromal-like cells is associated with a myxoid background.

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FIG. 6.4 Mixed tumor of the vagina (spindle cell epithelioma). The stromal-like cells form irregular anastomosing cords.

FIG. 6.5 Mixed tumor of the vagina (spindle cell epithelioma). The epithelial component features irregularly shaped glands.

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or squamous, is generally present towards the periphery of the lesion (Fig. 6.5). The glands are lined by cuboidal or columnar epithelium; they can have areas of squamous metaplasia or contain PAS-positive, diastase-sensitive luminal material. In some cases, there are no glandular elements but only numerous squamous morules.

ANCILLARY FEATURES The epithelial and spindle cells are positive for keratin AE1/E3, WT-1, ER, PR, and CD10. The spindle cells can be variably positive for keratin 7 and EMA (and rarely keratin 20). These cells can also express smooth-muscle actin, desmin, and, less commonly, h-caldesmon. They are typically negative for S-100. By electron microscopy, the stromal-like cells lack myofibrils with dense bodies, pinocytotic vesicles, and basal lamina, features typically seen in myoepithelial cells.

DIFFERENTIAL DIAGNOSIS This lesion should be distinguished from squamous cell carcinoma, which can acquire a predominant spindle cell morphology (“spindle cell variant”). In carcinoma, the spindle cells show evident cytologic atypia and conspicuous mitoses; areas of squamous differentiation also appear atypical. In challenging cases, p16 overexpression by immunohistochemistry and demonstration of human papilloma virus (HPV) by molecular techniques will support the diagnosis of carcinoma. Since the spindle cell component usually predominates, the most common differential of spindle cell epithelioma is with mesenchymal lesions such as leiomyoma. Both share similar growth patterns (corded, nested, and fascicular), have a myxomatous background, and show extensive immunohistochemical overlap. In limited samples or when the epithelial component is not identified, heterogeneous staining for smooth muscle markers should raise the possibility of spindle cell epithelioma. Endometrial stromal neoplasms rarely involve the vagina but must be considered in the differential as, similarly to spindle cell epithelioma, they are cellular and are positive for CD10, ER, PR, and WT-1. However, EMA and smooth muscle markers are typically negative or weaker in endometrial stromal tumors than in spindle cell epithelioma.

PROGNOSIS AND TREATMENT Spindle cell epithelioma is a benign neoplasm that can recur locally months or years after the initial diagnosis. Treatment is mainly surgical for both initial and recurrent tumors.

SPINDLE CELL EPITHELIOMA (MIXED TUMOR OF THE VAGINA)—FACT SHEET Definition n  Benign tumor with predominance of stromal-type cells and minor component of glandular/squamous elements Incidence and Location n Uncommon n Usually lower posterior vaginal wall Age Distribution n 20–80 (mean 40) years Clinical Features n  Most frequently an incidental finding; rarely presents with vaginal bleeding Prognosis and Treatment n Surgical excision n Long-term follow up required, as late recurrences can occur

SPINDLE CELL EPITHELIOMA (MIXED TUMOR OF THE VAGINA)—PATHOLOGIC FEATURES Gross Findings n Well circumscribed n Gray or white with a gelatinous, soft, or rubbery consistency n 1 to 9 cm Microscopic Findings n Nonencapsulated, with well-demarcated expansile margin n Fascicular, nested, reticular, or corded growth of spindle cells; myxomatous background may be present n Minor epithelial component: glandular and/or glycogenated/metaplastic squamous component n Bland nuclei with rare or absent mitoses Immunohistochemical Features n Keratin AE1/E3, WT-1, ER, PR, and CD10 positive in epithelial and spindle cells n  Keratins 7 and 20, EMA, calretinin, and muscle markers variably positive in spindle cells n S-100 negative in spindle cells Differential Diagnosis n Spindle cell variant of squamous cell carcinoma n Leiomyoma n Endometrial stromal neoplasm

PREMALIGNANT AND MALIGNANT EPITHELIAL NEOPLASMS nn SQUAMOUS INTRAEPITHELIAL LESION (VAGINAL INTRAEPITHELIAL NEOPLASIA— VAIN) Squamous intraepithelial lesions of the vagina (VAIN) are rare, with an incidence of approximately 0.2–0.3 cases per

158 100,000 women in the United States. Associated risk factors include concurrent or prior cervical or vulvar squamous intraepithelial lesion, older age, low socioeconomic status, history of HPV infection (most commonly types 16 and 18) or sexually transmitted diseases, multiple sexual partners, smoking, immunosuppression, history of radiation therapy, and diethylstilbestrol (DES) exposure.

GYNECOLOGIC PATHOLOGY

in approximately 60% of cases. Usually, there is no grossly identifiable lesion; however, sometimes mucosal irregularities or color changes may be detected on examination. The most common colposcopic abnormality is acetowhite epithelium followed by punctation and, rarely, mosaicism. MICROSCOPIC FINDINGS

CLINICAL FEATURES Patients range in age from 16 to 84 (mean 47–53) years according to different series. Most patients are asymptomatic. The abnormality is frequently detected after colposcopic examination and biopsy for an abnormal Papanicolaou smear. Less commonly, a vaginal lesion is found during routine gynecologic examination, or patients present with symptoms such as recurrent vaginal discharge or vaginal bleeding. Not infrequently, squamous intraepithelial lesions of the vagina are discovered incidentally during the evaluation of a vulvar or cervical abnormality.

PATHOLOGIC FEATURES GROSS FINDINGS

Squamous intraepithelial lesions are more common in the upper third of the vagina and is multifocal

FIG. 6.6 Low-grade squamous intraepithelial lesion (vaginal intraepithelial neoplasia – VAIN I). Prominent koilocytosis is associated with minimal cytologic atypia of the basal layer.

Vaginal squamous intraepithelial lesions can be flat or exophytic. Depending on the degree and extent of the squamous atypia, they are classified as low-grade squamous intraepithelial lesion (VAIN1) and high-grade squamous intraepithelial lesion (VAIN2 and VAIN3) as per the lower anogenital squamous terminology (LAST). Low-grade squamous intraepithelial lesion (LSIL, VAIN1) encompasses epithelial changes including koilocytosis in the upper third of the epithelium (nuclear enlargement detectable at low power magnification, rigid and clear perinuclear halos of variable size, irregular nuclear contours, hyperchromatic nuclei, binucleation). There is retained maturation and organization of the lower third of the epithelium (Fig. 6.6). High-grade squamous intraepithelial lesions (HSIL) display progressive loss of maturation and cell organization involving the lower two-thirds and moderate to severe nuclear atypia (i.e., cell crowding, high nuclear-to-cytoplasmic ratio, significant variability in nuclear size, coarse chromatin, and frequent mitotic activity, including atypical mitoses). Changes involving the lower third or two-thirds, with preserved

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maturation of the upper third, have been categorized as VAIN2 (Fig. 6.7) whereas full-thickness atypia and loss of maturation is categorized as VAIN3 (Fig. 6.8); these are now categorized as HSIL. Koilocytosis may or may not be seen.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

p16 is the most robust immunomarker to distinguish HSIL (VAIN2 or 3) from their mimics (atrophy, and reparative epithelial changes among others). In HSIL, p16 is overexpressed (strong and diffuse nuclear and cytoplasmic staining of at least the lower third of the epithelium, namely “block staining”) (Fig. 6.9). In contrast, mimics including most low grade squamous intraepithelial lesions, show either a negative or nonspecific p16 staining (i.e., cytoplasmic-only or patchy nuclear staining) (Fig. 6.10). Of note, p16 may be strongly positive in low-grade lesions therefore this marker should not be used as the sole criterion in this distinction but rather the morphology should guide the diagnosis. Ki-67 and ProExc may sometimes be used as adjunctive diagnostic markers. In normal vaginal mucosa and LSIL, Ki-67 expression is confined to the parabasal epithelium,

whereas in HSIL it shows nuclear positivity in superficial layers.

DIFFERENTIAL DIAGNOSIS Distinction between LSIL and HSIL is usually straightforward if orientation and integrity of the specimen is maintained. Challenging issues include tangentially sectioned or partially denuded epithelium. Attention should be focused on the lower epithelial layers as in low-grade squamous intraepithelial lesions the organization and nuclear uniformity are retained. If p16 is applied, one should be aware that both HSIL and LSIL can be diffusely positive; however, if p16 is negative or only patchy positive, it excludes a high-grade lesion. The following issues in differential diagnoses apply more commonly to HSIL. In reactive inflammatory atypia, the epithelial cells may show increased nuclear/cytoplasmic ratio, nuclear hyperchromasia, and mitoses; however, the nuclei are evenly distributed and typically have dispersed chromatin and prominent nucleoli. Inflammatory cells are often interspersed between the epithelial cells, typically showing intercellular edema (spongiosis). Occasional binucleate cells and perinuclear halos (pseudokoilocytosis) may be seen but the nuclei do not show the enlargement

FIG. 6.7 High-grade squamous intraepithelial lesion (vaginal intraepithelial neoplasia – VAIN II). There is cellular crowding, nuclear enlargement and hyperchromasia involving the lower two-thirds of the epithelium but with superficial maturation.

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FIG. 6.8 High-grade squamous intraepithelial lesion (vaginal intraepithelial neoplasia – VAIN III). Severe cytologic atypia, mitotic activity, and loss of maturation are seen throughout the full thickness of the epithelium.

FIG. 6.9 High-grade squamous intraepithelial lesion. Strong and diffuse block positive p16.

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FIG. 6.10 Low-grade squamous intraepithelial lesion. Negative p16 staining.

(detectable at low power magnification), contour irregularity, and hyperchromasia diagnostic of koilocytosis. p16 may show patchy, but not “block” positivity within the squamous epithelium. Atrophy, including transitional cell metaplasia, is characterized by hypercellularity, lack of maturation, increased nuclear-to-cytoplasmic ratio, and dark evenly distributed chromatin. In contrast to HSIL, atrophy lacks significant nuclear pleomorphism, loss of organization, or mitotic activity. In addition, in transitional cell metaplasia, the nuclei in the upper third of the epithelium are perpendicularly oriented to the basal epithelium nuclei (so-called streaming pattern) and display frequent nuclear grooves. In radiation-induced atypia, the nuclei are enlarged but the nuclear-to-cytoplasmic ratio is low, the chromatin has a smudgy appearance (instead of the more clumped hyperchromasia of intraepithelial lesions) and the cytoplasm is often vacuolated, mitoses are absent or rare, and stroma and vessels appear hyalinized. Caution should be exercised before making a diagnosis of HSIL in a patient with a history of prior radiation. Vaginal micropapillomatosis (mucosal

excrescences) has a papillomatous appearance and thus may be misconstrued as low-grade dysplasia, but it has no evidence of koilocytosis.

PROGNOSIS AND TREATMENT Patients with LSIL can be followed every 6 months with Papanicolaou test and colposcopy as they have a low risk of progression to high-grade lesions. If persistent, treatment with carbon dioxide laser or topical agents, including 5-fluorouracil (5-FU), imiquimod or trichloroacetic acid is recommended. Patients with HSIL have an overall recurrence rate of ∼33% after appropriate treatment, which includes surgery and, if invasion is excluded, CO2 laser, or topical therapy such as 5-FU, imiquimod, or trichloroacetic acid. Moreover, concurrent or subsequent invasive squamous cell carcinoma has been reported in 10%–28% patients with vaginal HSIL; thus, close follow-up after excision is required.

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VAGINAL SQUAMOUS INTRAEPITHELIAL LESIONS (VAIN)—FACT SHEET

VAGINAL SQUAMOUS INTRAEPITHELIAL LESIONS (VAIN)—PATHOLOGIC FEATURES

Definition n  Squamous epithelium with variable degrees of atypia and loss of maturation, caused by HPV infection

Gross Findings n Often multifocal n  Commonly no gross lesion; less frequently, mucosal irregularities or color changes; acetowhite epithelium, punctation and mosaicism by colposcopy

Incidence and Location n Rare; 0.2–0.3 per 100,000 women in United States n Most common in upper third of vagina Morbidity and Mortality n 33% overall recurrence rate n 2%–5% risk of progression to invasive squamous carcinoma after appropriate treatment Age Distribution n 16–84 (mean 47–53) years Clinical Features n  Commonly asymptomatic and detected by abnormal cervicovaginal cytology n Vaginal bleeding or discharge (rare) n  Commonly associated with squamous intraepithelial lesions of cervix (65%) and vulva (10%) Prognosis and Treatment n Low-grade squamous intraepithelial lesion: Low risk of progression to malignancy Close observation (i.e., cytology and colposcopy every six months) Topical treatment if persistent n High-grade squamous intraepithelial lesion: Risk of concurrent invasive squamous cell carcinoma is 10%–28% Complete surgical excision

Microscopic Findings n Exophytic or flat n Low-grade squamous intraepithelial lesion (LSIL, VAIN1) Koilocytosis in upper layers Preserved maturation and polarity in lower epithelial layers, no significant atypia n High-grade squamous intraepithelial lesion (HSIL, VAIN2 or 3) Crowding, loss of organization and polarity and squamous maturation Significant cytologic atypia (high nuclear-to-cytoplasmic ratio, pleomorphism, coarse chromatin, mitoses) involving lower two-thirds (VAIN2) to full-thickness epithelium (VAIN3) Immunohistochemical Features n Negative or patchy p16 stain favors LSIL n p16 overexpression (strong “block” positivity, nuclear and cytoplasmic) favors HSIL n Ki-67 tends to show positive labelling in superficial epithelial layers in HSIL Differential Diagnosis n Reactive inflammatory atypia n Atrophy, including transitional cell metaplasia n Radiation atypia n Micropapillomatosis (vs. low grade squamous intraepithelial lesion)

CLINICAL FEATURES

nn SQUAMOUS CELL CARCINOMA This tumor represents 10 cm) and can be exophytic, plaque-like or ulcerative and may show deep infiltration of the vaginal wall.

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FIG. 6.11 Invasive well-differentiated squamous cell carcinoma. Nests of tumor cells with abundant eosinophilic cytoplasm show central keratinization.

MICROSCOPIC FINDINGS

The tumor is composed of malignant squamous cells that typically grow in sheets, nests, or cords and can be keratinizing or nonkeratinizing, the latter being more common. It can also be (arbitrarily) graded as well-differentiated (Fig. 6.11), moderately differentiated or poorly differentiated (Fig. 6.12). Morphologic variants include papillary (squamotransitional), warty, basaloid, verrucous, and spindle cell. Papillary (squamotransitional) carcinomas are usually macroscopically visible as a cauliflower/condylomatous mucosal lesion. They are composed of multiple branching papillae lined by highly dysplastic squamous epithelium with areas of transitional (urothelium-like) appearance (Fig. 6.13). In most cases, the tumor is predominantly or exclusively confined to the vaginal surface with little to no underlying stromal invasion, which poses difficulty at the time of biopsy diagnosis. Warty, basaloid, and verrucous variants are morphologically similar to their vulvar counterparts (see , Chapter 2). The spindle cell variant is composed of poorly differentiated neoplastic cells with a vaguely fascicular growth pattern recapitulating sarcoma; epithelioid areas are usually present, albeit focally (Fig. 6.14A).

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Diagnosis is usually achieved on morphologic grounds alone. HPV detection studies and p16 immunohistochemical overexpression are expected in carcinomas related to high-risk HPV infection; however, a minority will be negative. The spindle cell variant express cytokeratin, EMA, CK7, and p63, although frequently with a patchy distribution (Fig. 6.14 B,C).

DIFFERENTIAL DIAGNOSIS Tangential sectioning of a high grade squamous intraepithelial lesion may mimic stromal invasion. The pseudoinvasive nests in HSIL have a smooth and regular shape and retain a basaloid appearance in the outer aspect (lack of paradoxical maturation); there is no stromal response. Conversely invasive carcinoma in this location frequently elicits a prominent desmoplastic stromal response and has an irregular appearance and

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FIG. 6.12 Invasive poorly-differentiated squamous cell carcinoma. The tumor cells have scant eosinophilic cytoplasm, high-grade cytologic features, and lack keratinization.

A

FIG. 6.13 Papillary squamous cell carcinoma. Superficial tumor growth composed of frond-like papillae (A) lined by highly dysplastic squamous epithelium (B).

B

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A

B

FIG. 6.14

C

distribution throughout the stroma. Another scenario in which the distinction between a preinvasive (HSIL) and cancerous lesion is important is the setting of a papillary variant, particularly in small biopsies in which only the exophytic surface growth is represented. If the biopsy material shows dysplastic epithelium consistent with HSIL but with a papillary growth pattern, the diagnosis of “papillary squamous cell carcinoma” or “at least

Spindle cell squamous cell carcinoma. Malignant tumor with epithelioid (lower left) and spindle cell components, in areas showing fascicular growth (lower right) (A); tumor cells are strongly positive for low molecular weight keratin (B) and p63 (C).

HSIL with papillary growth” is advised, as invasion has not been excluded. Correlation with the clinical appearance is helpful in this scenario. Primary urothelial carcinoma can spread in a pagetoid fashion to the lower female reproductive tract and mimic a papillary squamous carcinoma of the vagina; the former is more distally located, is negative for HPV and typically shows CK7 and CK20 positivity, whereas the latter is more

166 commonly located in the proximal vagina, is HPV positive and expresses CK7 but not CK20. It is important to note that both urothelial and vaginal squamous cell malignancies can be diffusely positive for p16. Epithelioid trophoblastic tumor may simulate a squamous cell carcinoma because it is composed of cells with eosinophilic cytoplasm and is associated with an eosinophilic material; in addition, it is positive for keratins and p63. However, in contrast to the carcinoma, epithelioid trophoblastic tumor tends to be well circumscribed, shows a perivascular distribution of the tumor nests, and is positive for Cyclin E, inhibin, Mel-CAM, and HLA-G. In addition, epithelioid trophoblastic tumors are negative (or only focally positive) for p16. The spindle cell variant must be differentiated from a spindle cell epithelioma (discussed earlier in this chapter) and sarcoma (mostly leiomyosarcoma). Finding conventional areas of squamous cell malignancy with keratin pearl formation will help to establish the diagnosis of carcinoma. Of note, squamous epithelial markers (keratin, EMA, CK5/6, p63) are positive in spindled squamous cell carcinoma which is a helpful features, although they can be patchy. HPV studies can also be attempted (favoring squamous cell carcinoma if positive). The diagnosis of sarcoma should only be made once exhaustive examination fails to identify areas of squamous differentiation, and keratin and HPV studies are negative. Radiation-induced atypia of the squamous epithelium may also cause concern for invasive carcinoma especially when associated with epithelial hyperplasia where nests of squamous cells with irregular outlines are embedded in the superficial aspect of the mucosa. In this setting, squamous cells have low nuclear-to-cytoplasmic ratio, enlarged nuclei with smudgy chromatin and abundant vacuolated cytoplasm; the underlying stroma has dense fibrosis and hyalinization.

PROGNOSIS AND TREATMENT Tumor FIGO stage (Table 6.1) is the most powerful prognostic factor. One study by Eddy et al including 6 vaginal carcinomas with superficial invasion (defined as 4 cm, involvement of the mid or lower thirds of the vaginal canal and older age. More recently, patients with HPV-positive tumors have been reported to have a better prognosis than patients with HPV-negative tumors. Distant metastases are uncommon and when present mainly involve lung, liver, and bone. Standard treatment is radiotherapy, including brachytherapy and/or external-beam radiation. Surgical treatment may be indicated in selected patients, such as those with early-stage tumors or central recurrence following radiotherapy.

GYNECOLOGIC PATHOLOGY

nn ADENOCARCINOMA Primary adenocarcinomas of the vagina are uncommon (approximately 10% of all carcinomas at this site) with 1) intravascular foci in separate tissue sections or within the same section but widespread. Some authors recommend that LVI should be reported semiquantified as “focal” (one or two foci) or “substantial/extensive” (three or more). Lymphovascular space invasion is often seen along the infiltrative border of the tumor as cohesive clusters of tumor cells with smooth borders conforming to the shape of a lymphovascular space (Fig. 10.15A). There is often a

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A

B FIG. 10.12 Endometrial carcinoma with extension into adenomyosis. Areas of carcinoma have smooth, convex contours and the neoplasm does not haphazardly “entrap” smooth muscle (A). Residual normal glands or stroma can be appreciated (B).

change in the quality of the cytoplasm which may become either more eosinophilic or vacuolated, mimicking histiocytes. A lymphocytic infiltrate is often seen at the periphery of the involved vessel (Fig. 10.15B). Occasionally, endometrial carcinomas confined to the inner half of the myometrium are associated with tumor emboli in vessels in the outer half of the myometrium, or within vascular channels in the cervix, parametria, or adnexa. However, these findings should not result in upstaging the tumor.

Importantly, laparoscopic robot-assisted hysterectomies use an intrauterine manipulator which can dislodge tumor fragments and artificially introduce them into vascular spaces of the myometrium, adnexa, and cervix. Artifact is favored if intravascular tumor cells are disaggregated and associated with inflammatory debris, if they differ in shape and size from the harboring vessel, and appear “intact” (sometimes with gland lumen formation) (Fig. 10.16A). In the setting of artificial

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FIG. 10.13 Minimal deviation-type invasion by endometrial carcinoma. The tumor grows in a deceptively bland fashion being composed of glands with low grade cytology that do not elicit a stromal response, akin to minimal deviation adenocarcinoma of the cervix.

FIG. 10.14 Endometrial carcinoma with cervical stromal involvement. The most upper endocervical mucinous gland is considered the boundary between the cervix and the lower uterine segment (arrow). The absence of serosa in the outer aspect of the wall and the distal location, better seen at scanning view, is a supporting feature (inset).

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A

B FIG. 10.15 True lymphovascular space invasion by endometrial carcinoma. Notice the shape of the tumor cluster conforming to the shape of the vessel and eosinophilic cytoplasmic change (A), and the perivascular inflammatory infiltrate (B).

displacement, nontumoral endometrium sometimes can also be found inside vessels. LYMPH NODE INVOLVEMENT

The frequency of lymph node metastases in clinical stage I patients is related to the depth of myometrial invasion and the tumor grade. One-third of patients with metastatic pelvic lymph nodes also have positive

paraaortic lymph nodes. Prognosis of patients with metastatic tumor to pelvic lymph nodes is better than that of patients with positive paraaortic lymph nodes. Lymph node metastases in the context of gynecologic cancer are currently divided by size using the same criteria established for breast cancer: macrometastases (contiguous tumor deposit >2 mm), micrometastases (>0.2 but ≤2 mm, or >200 scattered individual tumor cells) and isolated tumor cells (ITCs, contiguous tumor

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FIG. 10.16 Artificial displacement of tumor into vascular spaces. This phenomenon is usually associated with disaggregated tumor fragments admixed with inflammatory debris.

deposit ≤0.2 mm or ≤200 scattered individual tumor cells). ITCs are usually detected by immunohistochemistry (performed in some institutions as part of sentinel lymph node protocols). A few studies have shown that patients with only ITCs or micrometastases in sentinel lymph nodes are associated with excellent disease-free survival comparable to patients without nodal disease. Conversely, patients with macrometastases have significantly worse recurrence-free survival. Although further evidence is required, it is recommended to routinely report the size of nodal metastatic disease and categorize them as macrometastasis, micrometastasis, or ITCs. Although there is not strong scientific evidence-based data, it is recommended to report the presence of extracapsular lymph node spread. POSITIVE PERITONEAL CYTOLOGY

Positive peritoneal cytology has been associated with high histologic grade, deep myometrial invasion, and extrauterine spread. This feature has been eliminated from the most recent FIGO staging. HISTOLOGIC TYPE AND GRADE

Histologic type has been recognized as an important prognostic factor in endometrial carcinoma (Box 10.3). Low-grade endometrioid and mucinous adenocarcinoma are associated with a favorable prognosis. In contrast, serous, clear cell, high-grade endometrioid,

BOX 10.3 Histological Classification of Endometrial Carcinoma (WHO, 2014) 1. Endometrioid carcinoma a. Squamous differentiation b. Villoglandular c. Secretory 2. Mucinous adenocarcinoma 3. Serous carcinoma 4. Clear cell carcinoma 5. Neuroendocrine tumors a. Low-grade neuroendocrine tumor (carcinoid) b. High-grade neuroendocrine carcinoma b.1. Small cell neuroendocrine carcinoma b.2. Large cell neuroendocrine carcinoma 6. Mixed adenocarcinoma 7. Undifferentiated and Dedifferentiated carcinoma WHO, World Health Organization

and undifferentiated carcinoma are associated with an unfavorable outcome, with overall 5-year survival rates ranging from 30% to 70%. The presence of signet-ring cells, trophoblastic or hepatoid differentiation is considered to impart a worse prognosis. Tumors confined to an endometrial polyp, including highgrade carcinomas such as serous or neuroendocrine carcinoma, may be associated with an overall good outcome. The grade of endometrial carcinomas has close correlation with the tumor type, as serous, clear cell,

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undifferentiated, and dedifferentiated carcinomas and carcinosarcoma are all, by definition, high-grade. Endometrioid and mucinous carcinomas, on the other hand, are divided into low- and high-grade categories. Separation of endometrial carcinomas according to grade has important diagnostic and prognostic implications. From the diagnostic point of view, low-grade endometrioid and mucinous carcinomas (FIGO grade 1 and 2) are usually straightforward and can be easily distinguished from other endometrial carcinoma types. Conversely, highgrade endometrioid carcinomas (FIGO grade 3) may show significant morphologic overlap with other highgrade types. Indeed, the interobserver reproducibility of histotype assignation in high-grade endometrial carcinoma is poor. Immunohistochemistry helps, but only to a certain degree. As a result, a subset of endometrial carcinomas requires categorization as “high-grade endometrial carcinoma with ambiguous features.” A molecular-based classification is an emerging and promising alternative to histologic type, particularly in the subset of high-grade tumors. MOLECULAR CLASSIFICATION

The Cancer Genome Atlas Research Network (TCGA) comprehensively characterized the genomic profile of endometrioid and serous carcinomas, and categorized them in four groups of tumors with different prognoses:   

1. Ultramutated carcinomas harboring mutations in the exonuclease domain of the DNA polymerase ɛ (POLE) gene. Most tumors in this category are endometrioid. Ultramutated carcinomas account for 6% of low-grade and 17% of high-grade endometrioid endometrial carcinomas. Despite their high-grade morphology, patients with these lesions had an exceptionally good prognosis with conventional therapy (which depended on grade, stage, and other parameters). 2. Hypermutated carcinomas with defective MMR protein function and microsatellite instability (MSI). They exhibit MLH1 promoter methylation and reduced MLH1 gene expression, or somatic or germline mutations in any of the MMR genes (MLH1, MSH2, MSH6, PMS2). These tumors are typically endometrioid. This group accounts for 29% of lowgrade and 54% of high-grade endometrioid endometrial carcinomas. They have an intermediate survival. 3. Carcinomas with low mutation rates and low frequency DNA copy-number abnormalities (copynumber low). Almost all (92%) of cancers in this group have somatically altered PI3K pathway. Conversely, they lack TP53 alterations. They comprise 60% of low-grade, 9% of high-grade endometrioid carcinomas, 2% of serous carcinomas, and 25% of

mixed histology carcinomas. They have an intermediate survival. 4. Carcinomas with low mutation rates and high frequency DNA copy-number abnormalities (copy-number high). These lesions are characterized by somatic TP53 mutations and consequent abnormal p53 expression. They account for >95% of serous carcinomas and 75% of mixed carcinomas. Carcinomas in this group are aggressive and have the worst survival outcomes.   

Although initially conceived in a cohort of endometrioid, serous, and mixed carcinomas, the TCGA classification has also been applied successfully to endometrial clear cell carcinoma. The incorporation of this molecular classification into routine practice is gaining momentum thanks to the validation of its prognostic value and the development of the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), which uses (mostly) routine tools as a surrogate of the genomic profile. In this algorithm, carcinoma is classified based on POLE mutational testing and immunohistochemistry for p53 and MMR proteins. Tumors with loss of expression of any MMR marker (MLH1, MSH2, MSH6 or PMS2) are classified as MMR-deficient (surrogate for the hypermutated group); tumors with pathogenic POLE mutations are assigned to the ultramutated group; and tumors with abnormal p53 expression (overexpression [strong nuclear staining in ≥80% of tumor cells] or complete absence of staining) are assigned to the copy-number high phenotype. Finally, tumors without MMR, p53 and POLE abnormalities are allocated to the copy-number low (p53 normal) group. Molecular classification seems to be particularly valuable in high-grade endometrioid carcinomas, since this is a highly heterogeneous group of tumors with variable prognosis. Regarding molecular classification, there are some unresolved issues. For example, POLE-mutated and some microsatellite unstable tumors show also strong p53 immunostaining and p53 mutation (“double positive”). These cases raise the differential diagnosis with serous-like/high copy-number endometrial carcinoma. p53 immunostaining is used to identify the serouslike or copy-number high group. However, correlation between p53 immunostaining and p53 mutation is not perfect. We envision that such categorization will become routine in the pathology work-up of endometrial carcinoma, at least as a complement to the standard prognostic pathologic variables. It remains to be determined whether POLE-mutated tumors can be managed conservatively with surgery and no systemic therapy, and the need to identify better tools to stratify patients in the intermediate categories (MMR-deficient and copy-number low).

358 In this regard, in the subset of low-grade early-stage endometrial carcinoma, mutations of CTNNB1 (beta-catenin) gene have been associated with worse survival. Nuclear expression of beta-catenin by immunohistochemistry has 100% specificity and 85% sensitivity in detecting CTNNB1 mutations. Nonetheless, and unlike mutational status, nuclear beta-catenin expression has not shown statistical association with patient outcome and further investigation is needed.

nn MANAGEMENT OF ENDOMETRIAL CARCINOMA Surgery (hysterectomy with bilateral salpingo-oophorectomy) is the mainstay of treatment of women with endometrial carcinoma. The surgical approach may include peritoneal cytologic sampling and abdominal exploration and biopsy of any suspicious lymph nodes or lesions. Omentectomy may be performed for serous carcinomas. Pelvic and paraaortic lymphadenectomy is appropriate when there is obvious involvement by tumor or known high-risk prognostic factors (highgrade, nonendometrioid morphology, deep myometrial invasion, or extension to the cervix or adnexa). The role of sentinel lymph node biopsy in endometrial carcinoma is still a matter of debate; however, it is practiced in many centers as a valid alternative to regional lymphadenectomy. The success of this technique depends on the surgeon’s experience and the adherence to an algorithm for sentinel node detection. Special processing protocols for sentinel lymph nodes, including “ultrastaging,” allow the identification of very small volume metastases (isolated tumor cells and micrometastases), the significance of which is still a matter of investigation. Low-grade and early stage (FIGO stage IA) patients can be placed on close surveillance, with surgical or radiation treatment of local (vaginal) recurrences, which is the most common complication. Adjuvant radiation therapy will be recommended in patients with highrisk prognostic indicators (high-grade, nonendometrioid morphology, deep myometrial invasion, or extension to the cervix or adnexa) and consists of vaginal vault brachytherapy or external beam radiotherapy. For women with disseminated disease, systemic therapy with progestational hormones or cytotoxic chemotherapy can be considered. A special consideration in the treatment of early stage and low-grade (FIGO grade 1 and selected FIGO grade 2 patients) endometrioid carcinoma is the alternative of primary hormonal therapy as a method to temporarily halt or slow tumor progression to achieve fertility goals. The risks of hormonal treatment in endometrial cancer include the possibility of an under-sampled high-grade endometrioid carcinoma or nonendometrioid

GYNECOLOGIC PATHOLOGY

carcinoma, advanced stage subclinically (10%–30% of cases are stages III–IV at presentation), and the potential for a subclinical synchronous ovarian carcinoma (seen in 5%–30% of premenopausal women). The diagnostic considerations presented in the section of AEH/EIN also apply to this setting: if possible, the original biopsy should be reviewed in conjunction with any follow-up material, and it is critical to know the time lapse since the diagnosis and the duration of the hormonal treatment. Depending on the diagnosis on follow-up sampling, the clinical outcome is classified as: (1) Resolution (benign endometrium, nonatypical hyperplasia), (2) Regression (AEH/EIN), (3) Persistence (endometrioid carcinoma FIGO grade 1), or (4) Progression (endometrioid carcinoma FIGO grade 2 or highgrade carcinoma).

nn LYNCH SYNDROME Lynch syndrome (known also as hereditary nonpolyposis colorectal cancer) is an autosomal dominant hereditary condition that predisposes patients to develop cancers in various organs including colon (most frequent), endometrium (second most frequent), ovary, and upper gastrointestinal tract among others. Women with Lynch syndrome have a risk of developing endometrial carcinoma ranging from 40%– 70%; importantly, endometrial neoplasia is often the first manifestation of the syndrome (“sentinel” event); thus, diagnosis of Lynch syndrome in the work-up of endometrial carcinoma can have important clinical implications for these patients, as they will be placed in close surveillance. Certain clinical and pathologic features have been associated with Lynch syndrome-related endometrial cancer including (Fig. 10.17A–C): (1) young women with a low body mass index, (2) localization within the lower uterine segment, (3) dense peritumoral and tumor infiltrating lymphocytes (>40/high power field), (4) intratumoral heterogeneity (e.g., dedifferentiated carcinoma), (5) endometrioid high-grade carcinomas in patients 40%). Only up to one-third of tumors have weak to moderate and focal WT1 expression although WT1 expression may be more strongly expressed in serous carcinomas confined to polyps. ER and PR typically are weakly positive. A subset of cases shows Her2Neu expression. Other markers that are often positive include IMP2, IMP3, and HMGA2. MOLECULAR ANALYSIS

At the molecular level, the pathogenesis of serous carcinoma is linked to alterations in TP53, loss of heterozygosity at numerous loci, and alterations in pathways involved in the regulation of cell division. Impaired TP53 function is related to accumulation of copy-number gains and losses, imparting a “copy-number high” profile as shown in the TCGA analysis of endometrial cancer.

DIFFERENTIAL DIAGNOSIS At low power, serous carcinoma with a predominant glandular architecture may be confused with low-grade (FIGO grade 1 or 2) endometrioid carcinoma. In the former, there is usually discordance between the architectural and cytologic features. Furthermore, the inner glandular contours have a “star-fish” shape due to cell stratification, loss of cell cohesion, and lack of nuclear polarity. Features that favor endometrioid carcinoma include a smooth luminal border, retained polarity, absence of pleomorphism, squamous, mucinous or secretory changes, and coexistence with AEH/EIN. In cases with equivocal atypia and architecture, immunohistochemistry is useful: strong and diffuse ER/PR, a normal p53, and negative or patchy p16 will support the diagnosis of low-grade endometrioid carcinoma; likewise, loss of expression of any MMR protein will also favor endometrioid carcinoma, as this finding is rare in serous carcinoma.

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A

B FIG. 10.30 Endometrial serous carcinoma. The low power architecture imparts a striking slit-like appearance (A). Irregularly shaped and variably sized papillae with stromal cores are lined by neoplastic cells with prominent pseudostratification and budding (B). A solid or pseudoglandular pattern is seen less commonly (C). The neoplastic cells are poorly cohesive and show high nuclear-to-cytoplasmic ratio and a high degree of pleomorphism (D); however, some tumors may show more uniform nuclear features. Notice the brisk mitotic rate and the striking slit-like architecture, which are characteristic features of this tumor (E). A “gaping gland” pattern of myometrial invasion is typically unassociated with stromal response (F).

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C

D FIG. 10.30, cont’d

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E

F FIG. 10.30, cont’d

CHAPTER 10  Endometrial Glandular Neoplasia

A

B FIG. 10.31 Endometrial serous carcinoma confined to the surface (formerly “serous intraepithelial carcinoma”). The preexisting glandular architecture is preserved; however, the lining cells are highly atypical, focally poorly cohesive, and even show papillary growth (A). Some may have a subtler cytologic appearance; however, high power demonstrates pseudostratified epithelium with loss of polarity and mitotic activity (B); p53 is strongly and diffusely positive (C).

385

386

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C FIG. 10.31, cont’d

The distinction of serous carcinoma from high-grade (FIGO grade 3) endometrioid carcinoma is even more challenging as both tumors are composed of high-grade neoplastic cells often with diffuse solid growth. The finding of slit-like spaces and the greater variability in nuclear pleomorphism favors serous carcinoma. In turn, lower-grade glandular areas, variant differentiation, normal p53 and abnormal MMR expression favor endometrioid carcinoma. This differential diagnosis may be particularly challenging in biopsy or curettage specimens, in which case a diagnosis of “high-grade endometrial carcinoma” can be rendered, with a comment including the differential diagnosis and deferring the histotype designation to the hysterectomy specimen. In most practices, this information suffices to determine the surgical approach. Upon evaluation of the hysterectomy specimen, some tumors will still defy classification as serous or high-grade endometrioid based on morphology and immunophenotype. These can be categorized as “high-grade carcinoma with ambiguous features.” Reporting the p53 and MMR status in these cases is important for prognostic and molecular classification purposes. Lastly, a pitfall to avoid when evaluating a high-grade endometrial carcinoma (endometrioid or serous) is to

pay attention to the accompanying stroma to exclude the possibility of a carcinosarcoma. Clear cell carcinoma is another important differential diagnosis, particularly in cases with prominent solid or papillary architecture. Serous carcinoma has large and irregular papillae, nuclear stratification, and cellular budding, unlike clear cell carcinoma which typically lacks complex papillary growth. Instead, papillae of clear cell carcinoma are bulbous and have a hyalinized core, and cell stratification in glands and papillae is not prominent; moreover, the nuclear atypia and hyperchromasia, while readily identifiable, are not as severe as in serous carcinoma. To help in this differential diagnosis, immunohistochemistry may be of value. Most serous carcinomas exhibit aberrant p53 expression while this is only seen in up to a third of clear cell carcinomas. Serous carcinomas are typically negative for Napsin-A and AMACR whereas the majority of clear cell carcinomas are positive for these markers (at least focally). In addition, loss of ARID1A is seen in approximately 40% of clear cell carcinomas of endometrium, while it is retained in serous carcinoma. ER and PR are not helpful, as variable (usually weak) expression can be seen in both tumors.

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In the context of a convincing serous carcinoma, the possibility of secondary endometrial involvement by a high-grade serous carcinoma of the tube, ovary, or peritoneum can be entertained. This applies to patients with an adnexal mass(es) and elevated CA-125. Nonetheless, it is more likely that the serous carcinoma is primary from the endometrium and spreads to the adnexa. WT1 may be useful in this scenario, as upper genital high-grade serous carcinoma is strongly and diffusely positive for this marker, and endometrial serous carcinoma is usually negative or only weakly positive.

nn ENDOMETRIAL CLEAR CELL CARCINOMA CLINICAL FEATURES Clear cell carcinoma is uncommon, representing 75% of the tumor) (Fig. 10.34C). E-cadherin staining is usually negative. Cyclin D1 is often strongly positive whereas ER and PR expression is typically low to absent. Focal expression of neuroendocrine markers may be seen. PAX8 is usually negative and p53 is often wild-type. About half of cases have loss of MLH1 and PMS2 expression. MOLECULAR ANALYSIS

Approximately half of undifferentiated/dedifferentiated carcinomas of the endometrium shows a hypermutated profile with loss of MMR protein expression; one-quarter of cases show low copy-number alterations (copy-number low). Much less commonly, they carry mutations in the exonuclease domain of POLE or show high copy-number alterations with abnormal p53 (copy-number high). These tumors also frequently show concurrent inactivating mutations involving BRG1 (SMARCA4), INI1, ARID1A and ARID1B.

DIFFERENTIAL DIAGNOSIS The main differential diagnosis of dedifferentiated carcinoma is with high-grade endometrioid carcinoma. In contrast to dedifferentiated carcinoma, the solid component of a high-grade endometrioid carcinoma typically shows cohesive cells arranged in conventional epithelial growths such as nests, trabeculae, or cords. A gland-forming component, if present, is intimately admixed with the solid areas, in contrast to the sharp demarcation between endometrioid and undifferentiated components of dedifferentiated carcinoma. Moreover, the solid component of a grade 3 endometrioid carcinoma displays strong and diffuse keratin and EMA (rather than patchy or weak), and is PAX8, ER, and PR positive. The biphasic architecture of a dedifferentiated carcinoma may raise the consideration of a carcinosarcoma; however, the former has a low-grade endometrioid component, and the undifferentiated component is typically monomorphic and lacks sarcomatous features as seen in carcinosarcoma. Furthermore, no heterologous components are seen. In addition, these tumors occur in a younger age population than those with carcinosarcoma. Neuroendocrine carcinoma may also be a consideration as they are often admixed with a low-grade endometrioid carcinoma, they can exhibit sheet-like growth, and are composed of cells with a high nuclear-to-cytoplasmic ratio. Helpful features favoring a small cell neuroendocrine carcinoma include the finding of salt and pepper chromatin, nuclear molding, and pseudorosette formation.

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A

B FIG. 10.33 Undifferentiated endometrial carcinoma. The tumor is entirely composed of cells arranged in loose aggregates (A); at high power, the lack of cohesion is evident by the slit-like separation in between cells. Notice the significant atypia of the nuclei, which are nonetheless relatively monotonous (B).

Of note, undifferentiated and dedifferentiated carcinomas may show expression of neuroendocrine markers and the diagnosis of small cell carcinoma should not be dependent solely on neuroendocrine marker positivity. The differential diagnosis of (pure) undifferentiated carcinoma includes a variety of small round cell tumors including, most commonly, lymphoma. The latter typically shows a population of small lymphocytes and positivity for lymphoid markers. Serous carcinoma is a potential consideration as it may show solid growth; however, tumor cells are cohesive at high-power magnification and display a greater degree of pleomorphism including markedly bizarre forms. Undifferentiated uterine sarcoma

is also a major consideration, importantly because both undifferentiated carcinoma and undifferentiated uterine sarcoma tend to be centered in the endometrium. While a minority of undifferentiated uterine sarcomas have monotonous cell morphology, most display high nuclear pleomorphism, easily identifiable at low power magnification, which is rather rare in undifferentiated carcinoma. Any pancytokeratin, EMA, CK8/18, or E-cadherin expression should suggest undifferentiated carcinoma; other markers are not useful as they are typically negative (PAX8, ER, PR). Recently, a novel subset of uterine sarcoma termed SMARCA4 deficient uterine sarcoma has been described. These tumors have significant

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morphologic overlap with undifferentiated carcinoma. High-grade endometrial stromal sarcoma may enter in the differential of undifferentiated carcinoma, as it is characterized by a population of large “round cells.” These are seen exclusively or admixed with a low-grade spindle cell population in a tumor with the typical growth pattern

of endometrial stromal sarcoma (uniformly distributed small vasculature, tongue-like myometrial and vascular infiltration). It is important to keep in mind that these lesions may display diffuse expression of cyclin D1, similar to undifferentiated carcinoma. BCOR immunohistochemistry may be of superior value in this differential.

A

B FIG. 10.34 Dedifferentiated endometrial carcinoma. Well-formed endometrioid-type glands (bottom) are juxtaposed to an undifferentiated component (A). The undifferentiated component shows a diffuse growth of monotonous noncohesive cells, which may appear solid on low power view, but are only loosely apposed and separated by thin slitlike spaces on high power magnification (B). Keratin expression is frequent but can be focal (C).

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C FIG. 10.34, cont’d

ENDOMETRIAL UNDIFFERENTIATED AND DEDIFFERENTIATED CARCINOMA—PATHOLOGIC FEATURES Gross Findings: Soft and friable exophytic mass Microscopic Findings: Undifferentiated carcinoma n Tumor cells arranged in sheets or poorly formed trabeculae n Monotonous population of noncohesive cells with high-grade features (high N:C ratio, nucleoli, frequent mitoses, necrosis) n Lack of cohesion Dedifferentiated carcinoma n  Biphasic tumor with two distinct tumor morphologies, one undifferentiated and one endometrioid (typically low-grade) Ancillary Studies Immunohistochemistry EMA positive, usually focal Cytokeratins (particularly CK8/18) usually focal E-cadherin usually negative PAX 8, ER and PR negative Abnormal MMR (MLH1/PMS2 loss) in ∼50% Differential Diagnosis: High-grade endometrioid carcinoma (FIGO grade 3) Carcinosarcoma Neuroendocrine carcinoma (small cell type) Lymphoma Serous carcinoma Undifferentiated uterine sarcoma High-grade endometrial stromal sarcoma

nn ENDOMETRIAL NEUROENDOCRINE CARCINOMA CLINICAL FEATURES Neuroendocrine tumors are a diverse group of neoplasms. They represent 10% of cells) is necessary to establish the diagnosis. Neuroendocrine carcinomas are also typically positive for pancytokeratin and CK18 with variable degree of staining that may have a dot-like perinuclear appearance. PAX8 may be positive, sometimes only focally. TTF1 is usually negative, but when positive is usually focal. MMR abnormalities are frequent (∼40%), mostly affecting MLH1/PMS2.

GYNECOLOGIC PATHOLOGY

DIFFERENTIAL DIAGNOSIS The main tumors in the differential diagnosis include small cell carcinoma of the cervix, undifferentiated/ dedifferentiated endometrial carcinoma, primitive neuroectodermal tumor (PNET), and lymphoma/leukemia. Cervical small cell carcinoma is typically centered in the cervix, often is associated with a squamous cell or adenocarcinomatous component and it is high-risk HPV-related. Undifferentiated/dedifferentiated carcinoma typically grows in sheets in contrast to the insular or trabecular growth seen in neuroendocrine carcinomas. Although the former may express neuroendocrine markers, it does it in a focal fashion (70 years), tumor size, myometrial invasion, and incomplete debulking. Recurrence rate is 55%, and the most frequent sites involved include the adnexa, omentum, and regional lymph nodes. The composition of the tumor metastases and recurrences usually reflects the predominant component in the original

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tumor. In general, the carcinomatous component is more frequently observed in the recurrence; less often it is the sarcoma or a mixture of both. Within the carcinomatous component, serous and clear cell types are associated with a higher incidence of metastases, deep myometrial invasion, lymphatic or vascular invasion, and cervical extension—all parameters indicative of aggressive behavior. Regarding the sarcomatous component, the presence of heterologous elements has been associated with worse outcome in some studies (particularly rhabdomyosarcoma). Radiation-induced tumors have more extensive disease at the time of diagnosis. Initial management includes total hysterectomy with bilateral salpingo-oophorectomy and staging procedures including regional lymphadenectomy, omentectomy, and peritoneal biopsies. Adjuvant chemotherapy is indicated in most patients, regardless of stage. Cisplatin-based chemotherapy has been shown to slow progression in patients with metastatic disease. Radiation therapy is also commonly used, although its role is less established. Radiotherapy may reduce the incidence of local and regional recurrences.

MÜLLERIAN CARCINOSARCOMA—PATHOLOGIC FEATURES Gross Findings n  Large, bulky polypoid masses, filling uterine cavity +/− prolapsing through endocervical canal n Fleshy cut surface n Frequent hemorrhage and necrosis with secondary cyst formation Microscopic Findings n  Admixture of high-grade carcinomatous and sarcomatous components n Carcinomatous component: Serous, high-grade endometrioid, clear cell most frequent Ambiguous morphology common Adjacent AEH/EIN occasionally n Sarcomatous component: Homologous or heterologous Endometrial stromal sarcoma, leiomyosarcoma, and undifferentiated uterine sarcoma most frequent homologous types Rhabdomyosarcoma and chondrosarcoma most frequent heterologous types n  Eosinophilic hyaline droplets common but not indicative of rhabdomyoblastic differentiation Ancillary studies

MÜLLERIAN CARCINOSARCOMA—FACT SHEET Definition n High-grade malignant tumor composed of malignant epithelial and mesenchymal elements; regarded as type of endometrial carcinoma with subsequent sarcomatous transformation Incidence n ∼5% of malignant tumors of the uterus Race and age distribution n Postmenopausal women (mean age 65 years) n ∼5% in patients ≤50 years Clinical Features n Postmenopausal bleeding n Enlarged uterus and/or pelvic pain n History of previous radiation in up to 37% of women (younger age at presentation) Prognosis and Treatment n 5-year survival rate from 5% to 35% for all stages (median survival ∼2 years for all stages) n 5-year survival rate from 40% to 60% for stage I–II tumors n Tumor extends outside the uterus (stages III–IV) at time of diagnosis in up to two-thirds n  Overall recurrence rate of 55%; ovaries, fallopian tubes, and omentum most common sites (mostly composed of carcinoma; sarcoma and carcinosarcoma less common) n Tumor stage most important prognostic factor n  Higher incidence of metastases if serous and clear cell components n Heterologous sarcomatous component may influence prognosis n  Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging are mainstay of treatment n  Cisplatin-based chemotherapy and radiation usually recommended; may slow progression

Immunohistochemistry n  Cytokeratin, EMA, CK8/18, and E-cadherin strongly and diffusely positive in carcinomatous component; lesser intensity (or negative) in sarcomatous component n Neuroendocrine markers (synaptophysin, neuron-specific enolase, and Leu-7) may be positive in epithelial component n Abnormal p53 and p16 frequent in both components Molecular analysis n  Monoclonality of both epithelial and mesenchymal components (identical patterns of X-chromosome inactivation, mutations of TP53 and KRAS, and loss of heterozygosity for identical alleles) Differential Diagnosis n Spindled low-grade endometrioid carcinoma n Hyalinized and corded low-grade endometrioid carcinoma n  Low-grade endometrioid carcinoma with extensive squamous morules n Low-grade endometrioid carcinoma with heterologous elements n High-grade endometrioid carcinoma n Serous, clear cell, undifferentiated, dedifferentiated carcinoma n Undifferentiated endometrial sarcoma n Leiomyosarcoma n Müllerian adenosarcoma

nn MESONEPHRIC-LIKE CARCINOMA Mesonephric carcinomas are observed in the cervix. Tumors with mesonephric morphology have also been reported involving the uterine corpus. Most of these likely arise from Mullerian uterine epithelium, and thus are best termed mesonephric-like carcinomas. It is possible, nonetheless, that a minority represent true mesonephric lesions arising from mesonephric remnants and/or

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mesonephric hyperplasia of the lower uterine segment. The latter can be considered in tumors seated in the outer uterine wall. Mesonephric-like carcinoma shows several patterns including tubuloglandular (resembling endometrioid carcinoma), papillary, retiform, solid, and spindle cell (resembling low-grade endometrial stromal sarcoma) patterns (Fig. 10.38A–D). They are characteristically negative for hormone receptors (a helpful feature in the differential from low-grade endometrial endometrioid carcinoma), and positive for GATA-3, calretinin, CD10,

and PAX8. These lesions show molecular overlap with endometrioid neoplasia (KRAS and PIK3CA mutations).

nn MIXED CARCINOMA Mixed adenocarcinomas are defined as tumors with two or more distinct endometrial carcinoma types, each representing at least 10% of the tumor volume. As mentioned

A

B FIG. 10.38 Mesonephric carcinoma of the uterus. The same tumor may display different growth patterns including endometrioid-like glands (A), tubulo-cystic (B), solid (C), and spindle cell or “sarcomatoid” (D).

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C

D FIG. 10.38, cont’d

previously, the exception to this rule is serous carcinoma, since any amount of tumor with serous morphology may influence the behavior and thus should be reported. The most common combinations are endometrioid and serous, endometrioid and clear cell, serous and clear cell, and endometrioid and neuroendocrine. The diagnosis of mixed carcinoma requires that all components are distinct by their geographic separation, contrasting architecture and cytomorphology, and dissimilar immunophenotype. Rigorous criteria are recommended to avoid diagnosis of mixed tumors in cases of serous carcinomas with focal glandular pattern, or cases of endometrioid carcinomas with papillary growth. The percentage of each component can be estimated and mentioned in the report. Carcinomas with

ambiguous features that preclude histotype classification should not be assigned to the category of mixed carcinomas. Importantly, recent evidence shows that the majority of these mixed carcinomas are clonally related and likely represent morphologic variation of a tumor with a common genotypic profile, rather than two independent tumors (or “collision” phenomenon).

nn SQUAMOUS CELL CARCINOMA This histologic subtype is exceedingly rare. It is purely composed of squamous epithelium with variable degrees

404 of differentiation and architecture, including papillary or spindled growth. Cytologic features depend on the degree of differentiation. To establish this diagnosis, no coexisting endometrial carcinoma should be present, there should be no continuity between the tumor and the cervix, and a history of a cervical squamous cell carcinoma should be excluded. The tumor may coexist with ichthyosis uteri and as it is not HPV-related, p16 is typically negative.

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Nucci, M. R., Crum, C. P., Prasad, C. J., & Mutter, G. L. (1999). Mucinous endometrial epithelial proliferations: a morphologic spectrum with diverse clinical significance. Modern Pathology, 12, 1137–1142. Ronnett, B. M. (2016). Endocervical adenocarcinoma: selected diagnostic challenges. Modern Pathology, 29(1), S12–S28. Soslow, R. A. (2013). High-grade endometrial carcinomas—strategies for typing. Histopathology, 62, 89–110. Soslow, R. A. (2016). Practical issues related to uterine pathology: staging, frozen section, artifacts, and lynch syndrome. Modern Pathology, 29(1), S59–S77. Soslow, R. A., Bissonnette, J. P., Wilton, A., et al. (2007). Clinicopathologic analysis of 187 high-grade endometrial carcinomas of different histologic subtypes: similar outcomes belie distinctive biologic differences. The American Journal of Surgical Pathology, 31(7), 979–987. Stewart, C. J., & Crook, M. L. (2015). PAX2 and cyclin D1 expression in the distinction between cervical microglandular hyperplasia and endometrial microglandular-like carcinoma: a comparison with p16, vimentin, and Ki67. International Journal of Gynecological Pathology, 34(1), 90–100. Talerman, A. (2002). Primary endodermal sinus tumor of the endometrium presenting as “recurrent” endometrial adenocarcinoma. Gynecologic Oncology, 84, 184. Wheeler, D. T., Bristow, R. E., & Kurman, R. J. (2007). Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins. The American Journal of Surgical Pathology, 31(7), 988–998. Xiong, J., He, M., Jackson, C., et al. (2013). Endometrial carcinomas with significant mucinous differentiation associated with higher frequency of k-ras mutations: a morphologic and molecular correlation study. International Journal of Gynecological Cancer, 23(7), 1231–1236. Yemelyanova, A., Gown, A. M., Wu, L. S., Holmes, B. J., Ronnett, B. M., & Vang, R. (2014). PAX8 expression in uterine adenocarcinomas and mesonephric proliferations. International Journal of Gynecological Pathology, 33(5), 492–499. Yemelyanova, A., Vang, R., Seidman, J. D., Gravitt, P. E., & Ronnett, B. M. (2009). Endocervical adenocarcinomas with prominent endometrial or endomyometrial involvement simulating primary endometrial carcinomas: utility of HPV DNA detection and immunohistochemical expression of p16 and hormone receptors to confirm the cervical origin of the corpus tumor. The American Journal of Surgical Pathology, 33(6), 914–924. Serous Carcinoma Euscher, E. D., Malpica, A., Deavers, M. T., & Silva, E. G. (2005). Differential expression of WT-1 in serous carcinomas in the peritoneum with or without associated serous carcinoma in endometrial polyps. The American Journal of Surgical Pathology, 29(8), 1074–1078. Gatius, S., & Matias-Guiu, X. (2016). Practical issues in the diagnosis of serous carcinoma of the endometrium. Modern Pathology, 29(1), S45–S58. Hendrickson, M. R., Ross, J., Eifel, P., Martinez, A., & Kempson, R. (1982). Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. The American Journal of Surgical Pathology, 6, 93–108. Jarboe, E. A., Miron, A., Carlson, J. W., et al. (2009). Coexisting intraepithelial serous carcinomas of the endometrium and fallopian tube: frequency and potential significance. International Journal of Gynecological Pathology, 28(4), 308–315. Kommoss, F., Faruqi, A., Gilks, C. B., et al. (2017). Uterine serous carcinomas frequently metastasize to the fallopian tube and can mimic serous tubal intraepithelial carcinoma. The American Journal of Surgical Pathology, 41(2), 161–170. Oliva, E., & Soslow, R. A. (2011). High-grade endometrial carcinomas. Surg Pathol Clin, 4(1), 199–241. Santacana, M., Maiques, O., Valls, J., et al. (2014). A 9-protein biomarker molecular signature for predicting histologic type in endometrial carcinoma by immunohistochemistry. Human Pathology, 45(12), 2394–2403. Sherman, M. E., Bitterman, P., Rosenshein, N. B., Delgado, G., & Kurman, R. J. (1992). Uterine serous carcinoma: a morphologically diverse neoplasm with unifying clinicopathologic features. The American Journal of Surgical Pathology, 16, 600–610.

406 Trinh, V. Q., Pelletier, M. P., Echelard, P., et al. (2019). Distinct Histologic, Immunohistochemical and Clinical Features Associated With Serous Endometrial Intraepithelial Carcinoma Involving Polyps. Int J Gynecol Pathol. 2019, Advanced Online Publication (PMID 30789501). Clear Cell Carcinoma DeLair, D. F., Burke, K. A., Selenica, P., et al. (2017). The genetic landscape of endometrial clear cell carcinomas. The Journal of Pathology, 243, 230–241. Fadare, O., Desouki, M. M., Gwin, K., et al. (2014). Frequent expression of napsin A in clear cell carcinoma of the endometrium: potential diagnostic utility. The American Journal of Surgical Pathology, 38(2), 189–196. Fadare, O., Parkash, V., Gwin, K., et al. (2013). Utility of α-methylacyl-coenzyme-A racemase (p504s) immunohistochemistry in distinguishing endometrial clear cell carcinomas from serous and endometrioid carcinomas. Human Pathology, 44(12), 2814–2821. Köbel, M., Tessier-Cloutier, B., Leo, J., et al. (2017 Jan 20). Frequent mismatch repair protein deficiency in mixed endometrioid and clear cell carcinoma of the endometrium. Int J Gynecol Pathol. 2017;36(6):555–561. Lim, D., Ip, P. P., Cheung, A. N., Kiyokawa, T., & Oliva, E. (2015). Immunohistochemical comparison of ovarian and uterine endometrioid carcinoma, endometrioid carcinoma with clear cell change, and clear cell carcinoma. The American Journal of Surgical Pathology, 39(8), 1061–1069. Undifferentiated and Dedifferentiated Carcinoma Altrabulsi, B., Malpica, A., Deavers, M. T., et al. (2005). Undifferentiated carcinoma of the endometrium. The American Journal of Surgical Pathology, 29(10), 1316–1321. Coatham, M., Li, X., Karnezis, A. N., et al. (2016). Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas. Modern Pathology, 29(12), 1586– 1593. Hoang, L. N., Lee, Y. S., Karnezis, A. N., et al. (2016). Immunophenotypic features of dedifferentiated endometrial carcinoma— insights from BRG1/INI1-deficient tumours. Histopathology, 69(4), 560–569. Ramalingam, P., Masand, R. P., Euscher, E. D., & Malpica, A. (2016). Undifferentiated carcinoma of the endometrium: an expanded immunohistochemical analysis including PAX-8 and basal-like carcinoma surrogate markers. International Journal of Gynecological Pathology, 35(5), 410–418. Rosa-Rosa, J. M., Leskelä, S., Cristóbal-Lana, E., et al. (2016). Molecular genetic heterogeneity in undifferentiated endometrial carcinomas. Modern Pathology, 29(11), 1390–1398. Shah, V. I., & McCluggage, W. G. (2015). Cyclin D1 does not distinguish YWHAE-NUTM2 high-grade endometrial stromal sarcoma from undifferentiated endometrial carcinoma. The American Journal of Surgical Pathology, 39(5), 722–724. Silva, E. G., Deavers, M. T., Bodurka, D. C., & Malpica, A. (2006). Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma? International Journal of Gynecological Pathology, 25(1), 52–58. Silva, E. G., Deavers, M. T., & Malpica, A. (2007). Undifferentiated carcinoma of the endometrium: a review. Pathology, 39(1), 134– 138. Review. Tafe, L. J., Garg, K., Chew, I., Tornos, C., & Soslow, R. A. (2010). Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Modern Pathology, 23(6), 781–789. Neuroendocrine Carcinoma Albores-Saavedra, J., Martinez-Benitez, B., & Luevano, E. (2008). Small cell carcinomas and large cell neuroendocrine carcinomas of the endometrium and cervix: polypoid tumors and those arising in polyps may have a favorable prognosis. International Journal of Gynecological Pathology, 27(3), 333–339.

GYNECOLOGIC PATHOLOGY Huntsman, D. G., Clement, P. B., Gilks, C. B., & Scully, R. E. (1994). Small-cell carcinoma of the endometrium. a clinicopathological study of sixteen cases. The American Journal of Surgical Pathology, 18(4), 364–375. Mulvany, N. J., & Allen, D. G. (2008). Combined large cell neuroendocrine and endometrioid carcinoma of the endometrium. International Journal of Gynecological Pathology, 27, 49–57. Pocrnich, C. E., Ramalingam, P., Euscher, E. D., & Malpica, A. (2016). Neuroendocrine carcinoma of the endometrium: a clinicopathologic study of 25 cases. The American Journal of Surgical Pathology, 40(5), 577–586. van Hoeven, K. H., Hudock, J. A., Woodruff, J. M., et al. (1995). Small cell neuroendocrine carcinoma of the endometrium. International Journal of Gynecological Pathology, 14, 21–29. Carcinosarcoma Abdulfatah, E., Lordello, L., Khurram, M., et al. (2018 Apr 3). Predictive histologic factors in carcinosarcomas of the uterus: a multiinstitutional study. International Journal of Gynecological Pathology ([Epub ahead of print] PMID: 29620586). Ablen, E. C., Smit, V. T., Wessels, J. W., de Deleeuw, W. J., Cornelisse, C. J., & Fleuren, G. J. (1997). Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed Müllerian tumours. The Journal of Pathology, 183, 424–431. Amant, F., Vloeberghs, V., Woestenborghs, H., Moerman, P., & Vergote, I. (2003). Transition of epithelial to mesenchymal differentiation during ovarian carcinosarcoma tumorigenesis. Gynecologic Oncology, 90, 372–377. Chiyoda, T., Tsuda, H., Tanaka, H., et al. (2012). Expression profiles of carcinosarcoma of the uterine corpus—are these similar to carcinoma or sarcoma? Genes Chromosomes Cancer, 51(3), 229–329. de Jong, R. A., Nijman, H. W., Wijbrandi, T. F., et al. (2011). Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component. Modern Pathology, 24(10), 1368–1379. Ferguson, S. E., Tornos, C., Hummer, A., Barakat, R. R., & Soslow, R. A. (2007). Prognostic features of surgical stage I uterine carcinosarcoma. The American Journal of Surgical Pathology, 31, 1653–1661. Inthasorn, P., Carter, J., Valmadre, S., et al. (2002). Analysis of clinicopathologic factors in malignant mixed Müllerian tumors of the uterine corpus. International Journal of Gynecological Cancer, 12, 348–353. Jin, Z., Ogata, S., Tamura, G., et al. (2003). Carcinosarcoma (malignant Müllerian mixed tumours) of the uterus and ovary: a genetic study with special references to histogensis. International Journal of Gynecological Pathology, 22, 368–373. McCluggage, W. G. (2002). Malignant biphasic uterine tumors: carcinosarcomas or metaplastic carcinomas? Journal of Clinical Pathology, 55, 321–325. Meis, J. M., & Lawrence, W. D. (1990). The immunohistochemical profile of malignant mixed Müllerian tumor. Overlap with endometrial adenocarcinoma. American Journal of Clinical Pathology, 94, 1–7. Menczer, J. (2015). Review of recommended treatment of uterine carcinosarcoma. Current Treatment Options in Oncology, 16(11), 53. Silverberg, S. G., Major, F. J., Blessing, J. A., et al. (1990). Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. International Journal of Gynecological Pathology, 9, 1–19. Singh, R. (2014). Review literature on uterine carcinosarcoma. Journal of Cancer Research and Therapeutics, 10(3), 461–468. Sreeman, J. J., & Hart, W. R. (1995). Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumours: further evidence for dominant role of the epithelial component and the conversion theory of histogensis. The American Journal of Surgical Pathology, 19, 666–674. Wada, H., Enomoto, T., Fujita, M., et al. (1997). Molecular evidence that most but not all carcinosarcomas of the uterus are combination tumors. Cancer Research, 57, 5379–5385.

11 Mesenchymal and Miscellaneous Lesions of the Uterus nn Carlos Parra-Herran

The spectrum of uterine lesions of mesenchymal and mixed mesenchymal-epithelial type has expanded in recent years, largely due to the cumulative experience reported in larger case series, as well as the identification of recurrent gene fusions and other molecular alterations. In routine practice, the approach to most mesenchymal neoplasms encountered in the uterus starts with a judicious morphologic approach, which in many cases suffices for the diagnosis. Smooth muscle tumors predominate, most of them being benign. The distinction of conventional and variant leiomyoma types from leiomyosarcoma is important but on occasion challenging, and some lesions remain in the category of unknown malignant potential. Endometrial stromal neoplasms follow in frequency; their distinction from other mesenchymal lesions may be difficult, and molecular testing is gaining momentum as a key ancillary tool in their diagnosis. These two major categories are covered in depth here, along with other mesenchymal lesions with significant occurrence in the uterus. An emphasis is given on the differential diagnosis of each entity. This chapter also covers neoplasms with mixed mesenchymal and epithelial components (except endometrial polyp, which is presented in Chapter 9); of these, the most important clinically is adenosarcoma. The chapter concludes with miscellaneous lesions of histopathologic diagnostic importance.

PURE MESENCHYMAL UTERINE NEOPLASMS

conditions harbor this tumor type. The frequency slowly increases with age: ∼20%–30% of women under 30 years have leiomyomas, compared to 40%–50% of women 40 years or older. Black women are more likely to be affected in whom they tend to be larger and more numerous. In spite of their high frequency, only a subset (∼25%) are symptomatic; large and submucosal lesions are more likely to produce symptoms. They are a common source of menorrhagia, dysmenorrhea, and infertility in reproductive-age women and postmenopausal bleeding, urinary incontinence, and prolapse in postmenopausal women. Large intramural and subserosal leiomyomas may present with pelvic pressure or bloating. Much less frequent clinical findings include secondary erythrocytosis, uterine rupture, uterine infection, and ascites (pseudo-Meigs syndrome). Clinically, large and bulky leiomyomas can be palpated on clinical pelvic and abdominal examination. On imaging, they are well-demarcated solid nodules. Although the primary imaging modality is transvaginal ultrasound, magnetic resonance imaging (MRI) offers higher specificity as it can better identify degenerative changes (hemorrhage, pseudocystic degeneration, ischemic-type change) and features concerning for malignancy (signal heterogeneity, tumor cell necrosis, irregular borders).

PATHOLOGIC FEATURES GROSS FINDINGS

SMOOTH MUSCLE NEOPLASMS nn LEIOMYOMA (CONVENTIONAL AND VARIANTS) CLINICAL FEATURES Leiomyoma is the most common neoplasm in women; approximately 70%–75% of resected uteri for benign

Leiomyomas range in size from 25 cm. When multiple, they are randomly distributed throughout the uterus. The conventional macroscopic appearance is of a well-demarcated, nonencapsulated spherical or ovoid mass situated in the uterine wall. Depending on its location, the lesion can bulge into the endometrium and be accompanied by mucosal ulceration and hemorrhage or toward the peritoneal cavity, where they may be pedunculated and attached to the wall by a thin stalk. In the latter scenario, the leiomyoma sometimes detaches, leaving 407

408

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FIG. 11.1 Conventional leiomyoma. Gross examination shows a well-defined mass with a uniform white to tan rubbery surface, in areas with a “whorled” appearance.

FIG. 11.2 Leiomyoma with red (“carneous”) degeneration, caused by prominent hemorrhage and congestion.

it free within the peritoneal cavity; subsequent adhesion to bowel or other abdominal or pelvic structures leads to the phenomenon of “parasitic leiomyoma.” Leiomyomas grow under the tension exerted by the uterine wall; so, upon sectioning, such tension is released and the cut surface of the tumor protrudes from the wall and the tumor shells out quite easily from the surrounding myometrium. The cut surface is usually rubbery, with a firmer consistency compared to the normal myometrium. It has a white-to-grey color and a vaguely trabeculated or whorled visual aspect (Fig. 11.1). A spectrum of degenerative changes can be seen in uterine leiomyomata. Ischemic infarction with superimposed hemorrhage has been associated with pregnancy and hormonal treatment; it is seen macroscopically as diffuse red soft tissue (carneous, “beefy” degeneration) (Fig. 11.2). Localized ischemic change and hemorrhage can also lead to pseudocystic degeneration and calcifications. Focal infarction can be soft yellow or densely firm (scar tissue), depending on the evolution of the necrotic area over time (Fig. 11.3). In the context of previous

arterial embolization, these focal ischemic changes can be seen in association with visible foreign material within uterine and parametrial vascular spaces. Leiomyoma variants have certain peculiar macroscopic characteristics. Highly cellular leiomyoma and epithelioid leiomyoma are soft rather than firm or rubbery (given their hypercellularity and lesser amount of extracellular matrix) (Fig. 11.4). Myxoid leiomyoma is also soft and often gelatinous (due to the abundance of myxoid stroma). Lipoleiomyoma has a heterogeneous cut surface with soft yellow areas (adipose tissue) admixed with firm rubbery areas (smooth muscle tissue) (Fig. 11.5). Dissecting leiomyoma has focal worm-like protrusions into the surrounding wall, sometimes into vascular spaces (namely, leiomyoma with intravascular intrusion). The term cotyledonoid leiomyoma applies when most of the tumor outline displays a worm-like or bulbous appearance resembling the cotyledons on the maternal surface of the placenta (Fig. 11.6). Diffuse leiomyomatosis is characterized by diffuse thickening of the myometrium by innumerable small (40 years, 20%–30% of ­women 25 cm), often multiple n Location: intramural, submucosal, or subserosal n Submucosal tumors often with surface ulceration and hemorrhage n  Subserosal pedunculated tumors can detach and adhere to other pelvic organs (parasitic leiomyoma) n  Sharp circumscription; tumor bulges from cut surface and easily shelled out n  Degenerative changes include edema, pseudocystic change, calcifi­ cation, hemorrhage Conventional leiomyoma n Rubbery/firm, white/gray, whorled cut surface Leiomyoma Variants n Highly cellular leiomyoma, epithelioid leiomyoma: soft, tan to yellow n Myxoid leiomyoma: soft gelatinous n Lipoleiomyoma: heterogeneous appearance with yellow soft areas n  Dissecting leiomyoma: worm-like processes into myometrium or uterine vessels (intravascular intrusion) n Cotyledonoid leiomyoma: bulging outline resembling placental surface n Diffuse leiomyomatosis: diffuse uterine wall enlargement containing small (≤1 cm) ill-defined nodularities Microscopic Findings n Well circumscribed Conventional Leiomyoma n Normocellular (similar nuclear density to normal myometrium) n Intersecting fascicles of spindle cells n Abundant eosinophilic cytoplasm n  Elongated “cigar-shaped” (tapered ends) nuclei if cut longitudinally, ovoid with perinuclear vacuole if cut transversally n ± Nuclear palisading n Prominent vasculature with many thick-walled blood vessels n Mild to absent cytologic atypia and low mitotic rate (10%) in conventional leiomyosarcoma, but not always in epithelioid and myxoid variants.

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A

FIG. 11.22

B MOLECULAR ANALYSIS

Unlike leiomyoma, which has absent or at most simple karyotypic aberrations, leiomyosarcoma is frequently aneuploid with a complex karyotype. The most frequent abnormalities include gain of 1q, 17p, and Xp and loss of heterozygosity of 10q (which involves the PTEN gene) and 13q (involving the RB1 gene). The most commonly mutated genes are TP53 (65%) and VIPR2 (92%). VIPR2 deletions have been associated with poor outcome. Alterations in ATRX and DAXX, which are involved in alternative lengthening of telomeres, have been described in ∼80% of uterine leiomyosarcomas. MED12 mutations are not frequent (∼10%) and differ from those found in leiomyomas (being more frequently truncating instead of hotspot).

Epithelioid leiomyosarcoma. The tumor is composed of polygonal cells with moderate nuclear enlargement and atypia, and readily identifiable mitoses (A). The lesion is large and has an irregular contour (inset). Keratin expression is not infrequent (B).

Recently, molecular grouping of uterine leiomyosarcoma by gene expression profiling results in two groups: one resembling normal smooth muscle (with overexpression of genes related to smooth muscle function, such as LMOD1, SLMAP, MYLK, and MYH11; associated with morphology in the lower end of the spectrum and good response to chemotherapy) and one with upregulation of epithelial to mesenchymal transition and other oncogenic pathways (including CDK6, MAPK13, and HOXA1 upregulation; associated with more overt pleomorphism, invasion and proliferation, and less response to chemotherapy). In addition, it has been shown that clinically malignant smooth muscle tumors have a high genomic index (calculated based on the amount of global copy number variations); in contrast, indolent tumors had a genomic index less than 10 (in keeping with the lack of copy number gains

CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

431

A

FIG. 11.23 Myxoid leiomyosarcoma. The tumor char­ acterized by irregular, often infiltrative borders (A and inset in B). A. Myxoid stroma must be a dominant feature, comprising at least 50% of the tumor volume; intense blue staining on Alcian blue stain confirms the presence of a myxoid matrix (inset). B. Atypia and mitoses are usually but not always present. Atypia is seen in the form of hyperchromasia and moderate pleomorphism; two mitoses can be appreciated (arrows).

B

and losses). These findings may open the door to the integration of molecular testing in the diagnosis and prognostic stratification of uterine smooth muscle tumors. Regarding myxoid leiomyosarcoma, the spectrum of molecular alterations is largely unknown. This tumor type is negative for ALK rearrangements. TP53 and CDK2N mutations have been reported in ∼50 cases. Molecular alterations of epithelioid leiomyosarcoma have not been yet described.

DIFFERENTIAL DIAGNOSIS When considering the diagnosis of leiomyosarcoma, distinction from leiomyoma variants is crucial. As discussed previously, these variants are characterized by the presence of one feature worrisome for malignancy (i.e., nuclear atypia, increased mitoses, myopermeative

infiltration, high cellularity, and epithelioid or myxoid morphology) but, importantly, lack all the other features diagnostic of leiomyosarcoma. The exception to this rule is geographic tumor cell necrosis, which even in isolation is a worrisome finding and is associated with tumor recurrence; thus, when encountered, additional sampling may be required to identify atypia and/or increased mitoses. In their absence, the diagnosis of uterine smooth muscle tumor of uncertain malignant potential (STUMP) is recommended. However, it is important to keep in mind that the interobserver reproducibility even among expert gynecologic pathologists in the distinction between coagulative and ischemic necrosis is at best fair; thus, caution is suggested in solely relying on necrosis as a criterion for malignancy. Other instances of diagnostic difficulty between leiomyoma and leiomyosarcoma will also default to the use of the term STUMP (see corresponding section further in this chapter). Ki67, p16, and p53 have been used in the distinction between benign and malignant

432 smooth muscle tumors. High Ki67 index, as well as abnormal p53 and p16 expression patterns, may be of value, although in the absence of unequivocal morphology of leiomyosarcoma their significance is unclear, and thus caution is advised. Leiomyosarcoma also requires distinction from other mesenchymal proliferations, including rhabdomyosarcoma (rare, characterized by highly atypical, pleomorphic cells with rhabdoid morphology, including densely eosinophilic round inclusions and cross-striations, and expression of myogenin and MyoD1), endometrial stromal sarcoma (with typical finger-like myometrial infiltration, a less prominent degree of nuclear atypia, and lack of thick-walled vessels within the tumor; negative smooth muscle markers and frequent positivity for specific recurrent gene rearrangements), and undifferentiated uterine sarcoma (highly pleomorphic population with lack of fascicular growth and smooth muscle morphology; negative smooth muscle markers). Carcinosarcoma is also an important consideration, as sometimes the carcinomatous component is minor and vastly outweighed by the sarcomatous component (which may have features of leiomyosarcoma). The identification of a high-grade carcinoma component with an evident “biphasic” separation from the sarcomatous proliferation will suffice to solve this differential, but it may require extensive sampling and correlation with previous biopsy material. Gastrointestinal stromal tumor may rarely involve the uterus (secondarily) but may pose great difficulty in its distinction from a smooth muscle neoplasm. C-KIT and DOG-1 are helpful if negative; however, staining for these markers has been reported in leiomyosarcoma, and molecular testing for C-KIT mutations may be necessary. A high index of suspicion is required, especially if the mass involves the intestine or has unclear anatomic origin on clinical and radiologic examination. Epithelioid leiomyosarcoma may require distinction from a poorly differentiated endometrial carcinoma, which most of the time has areas of glandular, papillary, and/or squamous differentiation. If immunohistochemistry is needed, it is important to note that epithelioid leiomyosarcomas are often positive for keratin and EMA, and a panel of smooth muscle markers need to be included. Perivascular epithelioid tumor (PEComa) greatly overlaps with leiomyosarcoma of the conventional and epithelioid types. The presence of clear or granular (instead of eosinophilic) cytoplasm and striking perivascular cell aggregation should raise this possibility. Expression of HMB45, Melan-A, microphthalmia transcription factor (MITF) and cathepsin-K is more in keeping with PEComa. Like with epithelioid leiomyoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor may mimic epithelioid leiomyosarcoma; however, these tumors are seen in younger, reproductive-age patients with a

GYNECOLOGIC PATHOLOGY

recent or remote history of pregnancy and are associated with mildly elevated HCG levels. Histologically, the presence of abundant fibrinoid deposition around cells and clusters of cells is characteristic. Immunohistochemistry for markers of intermediate trophoblast is often helpful (see Chapter 19). The differential diagnosis of myxoid leiomyosarcoma includes myxoid leiomyoma (discussed previously), inflammatory myofibroblastic tumor (IMT), and endometrial stromal sarcoma. IMT is often well circumscribed and lacks the infiltrative border typical of myxoid leiomyosarcoma, although it is important to keep in mind that it can show irregular and infiltrative edges. The neoplastic population often has a characteristic “tissue culture-like” appearance with fusiform plump cells dispersed individually rather than in fascicles and admixed with inflammation. Testing for ALK immunohistochemistry and ALK rearrangements by fluorescence in situ hybridization (FISH) or sequencing is helpful, and a positive result usually confirms the diagnosis of IMT. Of note, strong ALK positivity by immunohistochemistry highly correlates with ALK rearrangements. Importantly, a negative ALK does not necessarily exclude the diagnosis. In addition, some examples of IMT may show a false-negative result by FISH if the gene involved in the rearrangement is spatially close to the ALK gene. The recently described HG-ESS with BCOR genetic alterations has a predominant fibromyxoid appearance, high mitotic counts, necrosis and myometrial infiltration. Unlike myxoid leiomyosarcoma, these tumors are negative or only weakly positive for smooth muscle markers and strongly express CD10; they also may show strong diffuse staining for BCOR and cyclin D1, but not always. Fibromyxoid LG-ESS may enter in the differential; however, fibromyxoid change is usually focal and admixed with classic lowgrade endometrial stromal tumor morphology.

PROGNOSIS AND TREATMENT Leiomyosarcoma of the uterus is an aggressive neoplasm with an overall poor prognosis. The 5-year survival ranges from 15% to 65% and is stage dependent (being higher for tumors confined to the uterus). In addition to advanced stage, patient age >50 years, tumor size >5 cm, high mitotic count, vascular invasion, and incomplete surgical debulking have all been associated with worse patient outcome. High hormone receptor expression (particularly PR and AR) is associated with better prognosis. Up to 70% of patients with International Federation of Gynecology and Obstetrics (FIGO) stage I disease and almost all patients with stage II or greater will ultimately suffer local or distant recurrence, usually within the first 18 months. Distant tumor spread is hematogenous (much less likely through lymphatics), and the lung is the most common distant site involved, followed by liver and brain.

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

The prognosis of myxoid leiomyosarcoma, based on limited series, appears to be worse than conventional leiomyosarcoma. This variant is associated with frequent and rapid tumor recurrence and progression. The prognostic significance of epithelioid leiomyosarcoma is not fully elucidated, although late recurrences (more than 5–10 years after diagnosis) have been reported. The management of leiomyosarcoma is primarily surgical (total hysterectomy, bilateral salpingo-oophorectomy, and debulking of macroscopic disease). Since the diagnosis may not be confirmed or highly suspected preoperatively, intraoperative consultation may be requested. Nodal dissection and staging biopsy have no definitive role in leiomyosarcoma. Systemic treatment with chemotherapy and radiation can be considered in patients with recurrent of unresectable disease; unfortunately, the impact on survival is minimal, if any. Hormonal treatment with aromatase inhibitors is also an alternative. Targeted therapy with mTOR inhibitors may be of benefit in some cases.

nn SMOOTH MUSCLE TUMORS OF LOW OR UNCERTAIN MALIGNANT POTENTIAL (STUMP) The term smooth muscle tumor of unknown / uncertain malignant potential (STUMP), rather than a distinct diagnostic entity, encompasses a variety of uterine smooth muscle tumors in which current histopathologic criteria and ancillary tools do not permit categorization as benign or malignant. Every effort should be made to provide a more definitive diagnosis through proper sampling and careful microscopic examination.

CLINICAL FEATURES Age distribution is not significantly different from patients with leiomyosarcoma, with a mean age of 45–50 years (range 24–85 years). Most STUMPs clinically present as a pelvic mass presumed to be a fibroid on clinical and radiologic examination. In a minority, suspicious features like irregular contour, necrosis, or hemorrhage are recorded.

UTERINE LEIOMYOSARCOMA—FACT SHEET Definition n Malignant smooth muscle tumor of uterus Incidence n 1%–2% of all uterine malignancies n  Most frequent gynecologic tract sarcoma (>50% of all uterine ­sarcomas) Race and Age Distribution n  Mean age 60 years (perimenopausal and postmenopausal ­women) n Increased incidence among black women Clinical Features n Abnormal vaginal bleeding n Abdominal distention, pelvic pain or pressure n Constitutional symptoms n Occasionally hypercalcemia and eosinophilia n Rarely, prior history of radiation therapy or tamoxifen treatment Prognosis and Treatment n  5-year survival rate of 15%–65% depending on stage (better in stage I disease) n Stage is strongest prognosticator n  Other prognostic factors: age, tumor size, vascular invasion, completeness of debulking n Recurrence rate of ∼70% for stages I and II and almost 100% for stages III and IV (within 18 months) n Hematogenous spread to lung, liver over lymphatic spread n Myxoid leiomyosarcoma appears to have worse survival compared to conventional n Epithelioid leiomyosarcoma can have late recurrences (>10 years) n Treatment includes hysterectomy, bilateral salpingo-oophorectomy, and debulking n Systemic therapy if recurrent or advanced-stage disease; poor response n Hormonal therapy if progressing disease

PATHOLOGIC FEATURES GROSS FINDINGS

Tumors classified as STUMP vary in size. Most are grossly indistinguishable from a leiomyoma. MICROSCOPIC FINDINGS

As a diagnostic category, the definitions of STUMP vary among publications (and, likely, among practices). This diagnosis should be considered in the following scenarios: • S  ignificant cytologic atypia and mitotic activity approaching the threshold for malignancy (in the order of 8–9 mitoses/10 HPFs) in the absence of necrosis (Fig. 11.24). It is recommended to expand the search for mitotic figures to more than 50 HPFs and to perform extensive sampling (at least one section per centimeter of the tumor greatest dimension). The recurrence rate of published cases in this scenario is 11.2%. • Unequivocal coagulative tumor cell necrosis with no significant atypia and 15 mitoses/10 HPFs n Epithelioid tumor with significant atypia; equivocal epithelioid features n  Myxoid tumors with only one feature of the following: atypia, ≥2 mitoses/10 HPFs, or necro­sis; equivocal for myxoid change Molecular Analysis n M ED12 mutations are infrequent (11%). n Genomic index stratifies patients into prognostic groups (based on copy number variation burden) Differential Diagnosis n Leiomyoma n Leiomyosarcoma n Perivascular epithelioid cell tumor n Inflammatory myofibroblastic tumor

nn LEIOMYOMAS WITH UNUSUAL ANATOMIC DISTRIBUTION The phenomenon of uterine leiomyoma with extrauterine spread is exceedingly rare but well documented, which defies our current concepts of benign and malignant tumor behavior. The following categories have

PATHOLOGIC FEATURES GROSS FINDINGS

Intravenous leiomyomatosis is characterized by numerous well-defined nodules with firm consistency and whorled appearance filling dilated vascular channels. The nodularities often acquire the shape of the vessel and become elongated and tortuous (worm-like). A leiomyoma is not identified, or if present, is anatomically separate from the intravascular lesions. Benign metastasizing leiomyoma is usually a small (80% cases). The

A

B FIG. 11.27 Endometrial stromal nodule. The lesion is defined by its smooth, well-circumscribed borders; in this example, the tumor was confined to the endometrium (A). Minimal infiltration can be noted, less than 3 mm in size (B, lower aspect). The tumor harbors a uniformly distributed vasculature of small arteriole-sized vessels (C). The tumor cell population is monotonous and only mildly atypical, comprised of short spindled to ovoid cells with scant cytoplasm (C, D). Sex cord differentiation with a nested and trabecular pattern can be seen (D, left aspect).

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

C

D FIG. 11.27, cont’d

vasculature is distinctive and comprised of uniformly spaced, thin arteriole-sized vessels; thick or tortuously dilated vessels are absent, except at the tumor–myometrial interface occasionally. The stromal cells are surrounded by a scant collagenous matrix, which seldom becomes more prominent with hyalinized bands or ischemic-type change. Variant morphology is not uncommonly encountered and includes fibromyxoid, smooth muscle, skeletal muscle, sex cord stromal (Fig. 11.27D), and glandular differentiation (all covered in

detail in the “Low-Grade Endometrial Stromal Sarcoma” section).

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

The neoplastic spindle cell component shows strong and diffuse expression of hormone receptors (ER,

442 PR), CD10, WT1 and IFITM1. SMA is often positive. Desmin can be positive, sometimes in a diffuse distribution. Caldesmon is negative, except in areas of smooth muscle differentiation, which usually show positivity for all smooth muscle markers. Similarly, areas of sex cord differentiation may express SF1, calretinin, and inhibin. Keratin stains can show heterogeneous, nonspecific staining. Cyclin D1 and BCOR are expected to be negative, although these markers have not been tested in large numbers of ESNs. MOLECULAR ANALYSIS

Approximately 50%–65% of ESNs harbor a recurrent rearrangement of the JAZF1 and SUZ12 genes, resulting in a t(7:17)(p15:q21) fusion. This alteration is also the most frequent in LG-ESSs. Other fusions involving JAZF1, PHF1, and other genes, characteristic of LG-ESS, can also be found in ESN.

DIFFERENTIAL DIAGNOSIS Given its high cellularity, the most common differential of ESN is with cellular leiomyoma. Smooth muscle tumors usually bulge on gross examination and have a distinctive fascicular architecture on microscopic examination. Moreover, the presence of thick-walled vessels throughout the tumor and elongated nuclei with tapered ends argue against ESN and is more in favor of leiomyoma. Despite the significant overlap in terms of smooth muscle and endometrial stromal marker expression, diffuse and strong SMA, desmin and/or caldesmon staining is more in keeping with leiomyoma. It is important to keep in mind that lowgrade endometrial stromal tumors often have smooth muscle differentiation, which is usually minor but can exceed 30% of the tumor volume; thus, correlation of morphology with immunophenotype is essential. If the tumor exhibits significant sex cord stromal differentiation, uterine tumor resembling a sex-cord stromal tumor may be considered; however, by definition, this tumor entirely displays sex cord stromal morphology. ESN and LG-ESS have identical tumor morphology, and the distinction between the two requires microscopic evaluation of the tumor border. A smooth, noninvasive tumor outline is diagnostic of ESN. Appreciation of the border is usually not possible in biopsy, curettage, or fragmented excisional material. When encountered in such specimens, and in the absence of obvious myometrial infiltration or vascular invasion, the tumor should be diagnosed as

GYNECOLOGIC PATHOLOGY

low-grade endometrial stromal neoplasm followed by a comment. Consideration for definitive surgery (hysterectomy) can be advised. As previously mentioned, ESN can have minimal myometrial infiltration. Very few cases that slightly exceed these parameters have been described as endometrial stromal tumors with limited infiltration. They are characterized by four to six tongue-like projections measuring up to 9 mm in maximum length from the tumor outer contour. Although they appear to be indolent like ESN, the experience in the literature is scarce, and careful clinical monitoring should be advised. HG-ESS with YWHAE-NUTM2 fusion may be on the differential if the tumor has areas with round (rather than spindled) nuclei; however, the size of the nuclei in ESN is small (≤4× lymphocyte nucleus); furthermore, tumor cells are strongly positive for CD10, ER, and PR and negative for cyclin D1 and BCOR, unlike HG-ESS.

PROGNOSIS AND TREATMENT ESN is considered benign. Given the limitations of making this diagnosis in biopsy material, hysterectomy is performed in most cases and is curative. Endometrial stromal tumors with limited infiltration require in addition close surveillance.

ENDOMETRIAL STROMAL NODULE—FACT SHEET Definition n  Neoplasm with morphology resembling proliferative-phase endometrial stroma and absent to only minimal infiltration (fewer than three projections, 10 mitoses/10 HPFs), tumor cell necrosis, and moderate atypia compared to LG-ESS. BCOR and cyclin D1 are also frequently positive in this type of HG-ESS although not always. Molecular testing may provide a definitive answer in cases that cannot be classified based on morphology and immunophenotype. Rarely, LG-ESS may first manifest as an extrauterine mass, and biopsy of such lesion will be the first diagnostic specimen. The pathologic evaluation in this situation

448 will require a broader differential and may include solitary fibrous tumor (CD34 and STAT6 positive, ER negative) and gastrointestinal stromal tumor (C-KIT and DOG1 positive, the latter marker being more specific for the diagnosis).

PROGNOSIS AND TREATMENT Women with LG-ESS have an overall good prognosis, with a 5-year survival rate of ∼60%–80%. The clinical course is characterized by frequent, late (years to decades) and slow-growing tumor recurrences. Thus, long-term follow-up with imaging surveillance is indicated. Patients with stage I disease have a good prognosis (∼90% survival) but are still prone to recurrence (seen in 25%). Tumor relapse is more common in the pelvis, followed by abdomen, vagina, and lung. The management of LG-ESS is primarily surgical, with hysterectomy and salpingo-oophorectomy plus resection of any suspicious or obvious areas of extrauterine involvement (parametria, pelvic wall, lymph nodes). Depending on tumor stage, patients may undergo radiation therapy, which reduces the risk of local recurrence. Hormonal treatment (progestins, aromatase inhibitors) is usually reserved for patients with advanced stage or tumor relapse. Surgical resection of tumor recurrences is often performed, if ­feasible.

LOW-GRADE ENDOMETRIAL STROMAL SARCOMA—FACT SHEET Definition n  Neoplasm with morphology resembling proliferative-phase endometrial stroma and permeative infiltration into uterine wall ± lymphovascular invasion Incidence n 10%–15% of uterine sarcomas Age Distribution n 52 years (range 40–55 years) Clinical Features n Abnormal uterine bleeding or pelvic pain n Uterine enlargement and/or extrauterine spread on imaging Prognosis and Treatment n  5-year survival rate of approximately 60%–80% (stage dependent; >90% in stage I) n  Multiple slow-growing recurrences regardless of stage, occurring late (years to decades) n Common sites of recurrence: pelvis, abdomen, vagina, lung n  Primary treatment surgical (hysterectomy, bilateral salpingo-oophorectomy, and debulking of visible tumor) n Hormonal treatment if recurrent or advanced stage

GYNECOLOGIC PATHOLOGY

LOW-GRADE ENDOMETRIAL STROMAL SARCOMA— PATHOLOGIC FEATURES Gross Findings n  Dominant mass with irregular borders or less commonly diffuse uterine wall enlargement with trabeculation n Variable tumor size (from 15 cm) n Yellow, soft, and fleshy cut surface n  Worm-like tumorlets bulging from myometrium or uterine vessels Microscopic Findings n  Finger-like permeative infiltration of myometrium by variably shaped expansile nodules n Lymphovascular space invasion common n Tumor cell morphology and vasculature identical to ESN n Histiocytes and hyalinization may be present n Necrosis is uncommon n Morphologic variants: n Fibromyxoid: abundant myxoid to fibromatous matrix n Smooth muscle differentiation: fascicles, some with central collagen (starburst pattern) n Sex cord stromal differentiation: cords, trabeculae, tubules, retiform patterns n Glandular differentiation: endometrioid gland-like structures n Rarely: rhabdoid morphology, bizarre cells, osteoclast-like giant cells, adipocytes Immunohistochemical Features n ER and PR strongly and diffusely positive n CD10 and IFITM1 positive (both sensitive but lack specificity) n  SMA, desmin and calponin weak and focal (strong in areas of smooth muscle differentiation) n  SF1, calretinin, and inhibin may be positive (sex cord stromal differentiation) n Caldesmon, Cyclin D1 and BCOR typically negative n Ki67 proliferation index ≤5% Molecular Analysis n Recurrent gene rearrangements in ∼55% (ESN and LG-ESS) n JAZF1-SUZ12 most common in LG-ESS (33%–50% cases) n Other rearrangements: JAZF1-PHF1, EPC1-PHF1, MEAF6-PHF1, and MBTD1-Cxorf67 n  Negative molecular result does not preclude diagnosis of LG-ESS Differential Diagnosis n Endometrial polyp n Adenomyosis n Leiomyosarcoma n Intravenous leiomyomatosis n Leiomyoma with intravascular intrusion n Low-grade müllerian adenosarcoma n Uterine tumor resembling ovarian sex cord tumor n High-grade endometrial stromal sarcoma n Solitary fibrous tumor n Gastrointestinal stromal tumor

nn HIGH-GRADE ENDOMETRIAL STROMAL SARCOMA This category includes two recently described entities defined by their molecular alterations: the HG-ESS

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

A

B FIG. 11.32 High-grade endometrial stromal sarcoma with YWHAE-NUTM2 rearrangement, seen as a polypoid soft hemorrhagic mass (A). High-grade endometrial stromal sarcoma with ZC3H7B-BCOR rearrangement, seen as a soft yellow polypoid mass occupying the cavity and infiltrating the uterine wall (B).

with YWHAE-NUTM2A/B [t(10;17)(q22;p13)] rearrangements and HG-ESS with BCOR alterations, either ZC3H7B-BCOR [t(X;22)(p11;q13)] fusion or BCOR internal tandem duplications (ITDs).

CLINICAL FEATURES Women with YWHAE-NUTM2 HG-ESS have a wide range of age at presentation, with a mean age of 50 years (range 28-67 years). Patients with ZC3H7B-BCOR HG-ESS have similar age distribution (mean 54 years, range 28–71 years). Reported patients with BCOR ITDs are younger (mean 24 years). The most common presenting symptom is abnormal uterine bleeding (menorrhagia, perimenopausal or postmenopausal bleeding). Clinical and radiologic examination reveals a uterus enlarged by a predominant mass, often in association with extrauterine disease.

PATHOLOGIC FEATURES GROSS FINDINGS

YWHAE-NUTM2 HG-ESS ranges in size from 3 to 9 (median 7.5) cm. It is typically located in the uterine corpus, most often involving the mucosal surface and projecting into the endometrial cavity (Fig. 11.32A).

The cut surface of the tumor is soft and fleshy and often displays hemorrhage and/or necrosis. Infiltrative growth can be appreciable macroscopically. BCOR-altered HG-ESSs range from 1 to 12 (mean 9.7) cm. They are most commonly centered in the endometrium and appear as polypoid fleshy soft masses; pure intramural growth can also occur (Fig. 11.32B). MICROSCOPIC FINDINGS

On low-power examination, YWHAE-NUTM2 HG-ESS is similar to LG-ESS displaying high cellularity and geographic/finger-like infiltration of the uterine wall (Fig. 11.33A). Extensive coagulative tumor cell necrosis can be appreciated. The microscopic hallmark of YWHAENUTM2 HG-ESS is the presence of a round cell component, characterized by a relatively uniform population of cells that, compared to those of classic LG-ESS, have more abundant eosinophilic cytoplasm, larger nuclei (four to six times the size of a lymphocyte nucleus) with conspicuous nucleoli and a round shape (instead of spindled) (Fig. 11.33B,C). Mitoses in the high-grade areas are abundant (often >10/10 HPFs). The vasculature pattern is described as delicate and arborizing. In about 50% of cases, the round cell component comprises the entirety of the tumor; in the remaining cases, the round cell areas coexist with conventional or fibromyxoid LG-ESS areas (Fig. 11.33A). Most BCOR-altered HG-ESSs are predominantly based in the endometrium and submucosal

A

B

FIG. 11.33

C

High-grade endometrial stromal sarcoma with YWHAE-NUTM2 rearrangement. At low-power view, the tumor has a similar pattern of infiltration to low-grade endometrial stromal sarcoma (A); note the biphasic appearance between low-grade (upper right corner) and high-grade areas. At high-power view, a population with round cell morphology and larger nuclear size is identified, four to six times the size of a lymphocyte (B). Compare to a tumor area with conventional low-grade spindle cell morphology taken at the same magnification (C).

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

myometrium, with a pattern of infiltration similar to LG-ESS (Fig. 11.34A). The neoplastic cells are fusiform, have mild to moderate atypia and are distributed in a variably prominent myxoid stroma (Fig. 11.34B). Collagenous plaques are also often seen. Proliferative activity is prominent (usually >10 mitoses/10 HPFs). Tumor necrosis (more often ischemic type) and vascular invasion are common (59% and 64% of cases, respectively). Areas of LG-ESS morphology are not identified.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

The high-grade round cell component of YWHAENUTM2 HG-ESS has an immunophenotype that contrasts with LG-ESS: it is negative or weakly positive for CD10, ER, and PR and positive for cyclin D1 (usually strong staining in >70% of cells), C-KIT, and BCOR. The Ki67 proliferation index tends to be >5%.

A

B FIG. 11.34 High-grade endometrial stromal sarcoma with ZC3H7B-BCOR rearrangement. The tumor has a myopermeative pattern of infiltration similar to other endometrial stromal sarcomas. A myxoid component can be identified, which is sometimes prominent (A). The tumor is composed of elongated cells with mild to moderate nuclear atypia (B). BCOR, although not entirely specific, stains most high-grade endometrial stromal sarcomas with YWHAE-NUTM2 and BCOR alterations(C)..

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GYNECOLOGIC PATHOLOGY

C FIG. 11.34, cont’d

BCOR-altered HG-ESS expresses CD10, cyclin D1, and BCOR (usually diffuse, but can be focal and weak). Of note, BCOR expression by immunohistochemistry does not entirely correlate with BCOR genomic alterations, as it is also positive in YWHAE-NUTM2 HG-ESS (Fig. 11.34C). CD10 expression is strong in tumors with ZC3H7B-BCOR fusions but weak in tumors with BCOR ITDs. Conversely, they are negative or at most weakly and focally positive for SMA, desmin, and/or caldesmon. Hormone receptor expression is variable. MOLECULAR ANALYSIS

The diagnosis of HG-ESS can be confirmed by testing for the YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR fusion, and BCOR ITDs using FISH, RNA sequencing, and reverse transcription-polymerase chain reaction assays. It is yet unclear whether tumors with the previously described HG-ESS morphologies but negative testing for the corresponding genomic aberrations can be classified in these tumor categories. It is plausible that tumors with the described HG-ESS morphology and immunophenotype share the same biologic course even if the expected rearrangements are not found, which is the case in the LG-ESS and ESN categories. In this tumor type, expression of C-KIT by immunohistochemistry does not correlate with hotspot C-KIT mutations.

DIFFERENTIAL DIAGNOSIS Given their many histopathologic differences, the distinction between YWHAE-NUTM2 and BCOR-altered HG-ESS is usually straightforward and raises different differential diagnoses. For YWHAENUTM2 HG-ESS, an important entity in the differential is low grade endometrial stromal sarcoma (LG-ESS). In a tumor with endometrial stromal sarcoma architecture and conventional LG-ESS morphology, one should exclude the presence of a round cell component, which would be indicative of YWHAE-NUTM2 HG-ESS and should prompt immunohistochemical and/or molecular testing. Brisk mitotic counts and extensive necrosis are infrequent in LG-ESS, and their presence should prompt additional sampling and careful microscopic examination. Undifferentiated uterine sarcoma, particularly of the uniform type, may be a consideration since the round cell component of HG-ESS features a similar degree of nuclear enlargement and atypia with relative nuclear monotony. Unlike YWHAENUTM2 HG-ESS, undifferentiated uterine sarcomas lack the low-grade component and are usually positive for CD10. A similar differential, undifferentiated endometrial carcinoma requires exclusion through thorough sampling and immunohistochemistry: keratin and EMA expression occurs in ∼75%

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

undifferentiated carcinomas. Uterine epithelioid leiomyosarcoma is also part of the differential, as the round cell morphology of HG-ESS often displays an epithelioid appearance. Identifying areas of either conventional smooth muscle or LG-ESS differentiation is helpful. In addition, diffuse expression of smooth muscle markers and negative or weak cyclin D1 will favor leiomyosarcoma. Molecular testing may be warranted if the previous differential diagnoses cannot be convincingly excluded. BCOR-altered HG-ESSs characteristically contain myxoid areas, and the main diagnostic considerations are LG-ESS with fibromyxoid change, myxoid leiomyosarcoma, and IMT. Fibromyxoid LG-ESS displays the same infiltrative growth pattern as BCOR-altered HG-ESS; however, cytologic atypia is absent to mild, necrosis is less frequent, mitotic activity tends to be low, and tumor cells are strongly positive for hormone receptors and typically negative for cyclin D1 and BCOR. Myxoid leiomyosarcoma is consistently characterized by an infiltrative tumor edge, which can be myopermeative (ESS-like). Moreover, nuclear atypia and mitotic activity are often subtle or absent in myxoid leiomyosarcoma. Nonetheless, the nuclei are hyperchromatic, and cells tend to group in vague fascicles; in addition, they are positive for at least one smooth muscle marker (SMA, desmin, caldesmon). Inflammatory myofibroblastic tumor (IMT) usually has, in addition to myxoid zones, areas of bland fascicular growth that are not seen in BCOR-altered HG-ESS. Furthermore, the fasciitis-like appearance of the spindle cell population and the admixture of inflammatory infiltrates are highly suggestive of IMT. In difficult cases, molecular testing may be required,

and a positive result for BCOR alterations is diagnostic; a negative result should result in reassessment of the morphologic and immunohistochemical findings. Undifferentiated uterine sarcoma may be considered; however, these tumors are highly cellular, often pleomorphic, and lack the conspicuous myxoid appearance of BCOR-altered HG-ESS.

PROGNOSIS AND TREATMENT HG-ESSs are aggressive, with significantly higher prevalence of adverse events and outcome compared to LG-ESS but lower in comparison to undifferentiated uterine sarcoma. 83% of YWHAE-NUTM2 HG-ESS and 61% of ZC3H7B-BCOR HG-ESS have advanced FIGO stage (II or III) at presentation (compared to only ∼25% of women with LG-ESS). The 5-year survival of YWHAE-NUTM2 HG-ESS is ∼33%. Limited clinical follow-up data suggest that ZC3H7B-BCOR HG-ESSs are highly aggressive tumors with frequent local and distant recurrences, progressive disease despite chemotherapy and tumor-related deaths. Outcome data on sarcomas with BCOR ITDs are limited, but adverse events have also been reported. The primary treatment includes total hysterectomy, bilateral salpingo-oophorectomy and debulking of gross extrauterine disease, if possible. Adjuvant anthracycline-based chemotherapy and radiation appear to offer some effect in the management of YWHAE-NUTM2 HG-ESS. Hormonal therapy is likely to be of limited value in YWHAE-NUTM2 HG-ESS but may have a role in BCOR-altered HG-ESS.

HIGH-GRADE ENDOMETRIAL STROMAL SARCOMA—FACT SHEET Definition n Uterine sarcomas with more aggressive clinical course compared to LG-ESS and defining molecular alterations: n Y WHAE-NUTM2 HG-ESS: YWHAE-NUTM2A/B rearrangements n BCOR-altered HG-ESS: ZC3H7B-BCOR rearrangement or BCOR ITDs Incidence n Exceedingly rare Age Distribution n Wide range, typically in perimenopausal and postmenopausal (mean age 50–54 years)

Clinical Features n Abnormal uterine bleeding, pelvic mass n Extrauterine spread (advanced stage) frequent (60%–80% cases) Prognosis and Treatment n Both YWHAE-NUTM2 and BCOR-altered HG-ESSs are aggressive tumors n High risk of rapid recurrences and tumor progression n  Treatment primarily surgical (hysterectomy, salpingo-oophorectomy, debulking) n  Chemotherapy and radiation appear to be effective in YWHAENUTM2 HG-ESS

454

GYNECOLOGIC PATHOLOGY

HIGH-GRADE ENDOMETRIAL STROMAL SARCOMA—PATHOLOGIC FEATURES Gross Findings n  Irregular soft and fleshy mass, more often endometrial-based with submucosal myometrial extension n Tumor size: YWHAE-NUTM2 HG-ESS 3–9 cm (median 7.5 cm), BCOR-altered HG-ESS 1–12 cm (mean 9.7 cm) n Necrosis and hemorrhage are common Microscopic Findings n Permeative finger-like and destructive myometrial invasion n Y WHAE-NUTM2 HG-ESS: n “Round cell” component (either exclusive or admixed with conventional or fibromyxoid LG-ESS component) n Round cells are epithelioid, with eosinophilic cytoplasm and large nuclei (four to six times the size of lymphocyte nucleus); prominent nucleoli n Coagulative necrosis and brisk mitotic activity (>10 mitoses/10 HPFs) n BCOR-altered HG-ESS: n Prominent myxoid matrix, sometimes collagenous plaques n Fusiform spindle cells with elongated hyperchromatic nuclei and mild to moderate atypia n Brisk mitotic activity (>10/10 HPFs) Immunohistochemical Features n Y WHAE-NUTM2 HG-ESS: n High grade round cell component: BCOR, Cyclin D1 diffusely positive; CD10, ER, PR negative

MISCELLANEOUS MESENCHYMAL TUMORS

L ow grade spindle cell component: CD10, ER, PR positive; BCOR and Cyclin D1 variably positive n Weak to negative smooth muscle marker expression n Ki67 proliferation index >5% n BCOR-altered HG-ESS: n CD10 positive (strong in ZC3H7B-BCOR fusion HG-ESS, weak in BCOR ITD HG-ESS) n BCOR and cyclin D1 positive n Weak to negative smooth muscle marker expression n Variable ER, PR expression n

Molecular Analysis n Y WHAE-NUTM2 HG-ESS: YWHAE-NUTM2A/B rearrangements n BCOR-altered HG-ESS: ZC3H7B-BCOR rearrangement or BCOR ITDs Differential Diagnosis n Y WHAE-NUTM2 HG-ESS: n LG-ESS n Undifferentiated uterine sarcoma n Undifferentiated endometrial carcinoma n Epithelioid leiomyosarcoma n BCOR-altered HG-ESS: n Fibromyxoid LG-ESS n Myxoid leiomyosarcoma n IMT n Undifferentiated uterine sarcoma

PATHOLOGIC FEATURES GROSS FINDINGS

nn UNDIFFERENTIATED UTERINE SARCOMA This tumor category was formerly termed “undifferentiated endometrial sarcoma”; however, as the name implies, this lesion lacks definitive differentiation, and a precursor cell has not been identified. Moreover, not all tumors are predominantly located in the endometrium. Hence, the name “undifferentiated uterine sarcoma” is preferred. It has been hypothesized that these neoplasms represent dedifferentiation from other sarcomas (adenosarcoma, endometrial stromal sarcoma, leiomyosarcoma).

CLINICAL FEATURES Most patients with undifferentiated uterine sarcoma are postmenopausal (mean age 60 years), who present with postmenopausal bleeding and a rapidly enlarging mass on clinical examination and imaging.

The tumor is typically large (>10 cm), soft and fleshy, often with prominent hemorrhage and necrosis. Most lesions are polypoid and occupy the endometrial cavity, whereas a minority are predominantly or completely intramural. MICROSCOPIC FINDINGS

Microscopically, undifferentiated uterine sarcoma displays high cellularity and pleomorphism evident at scanning magnification (Fig. 11.35A). Neoplastic cells are arranged in diffuse sheets with no distinctive growth pattern. Cells have a high nuclear-to-cytoplasmic ratio, enlarged irregular nuclei with coarse chromatin, and prominent nucleoli (Fig. 11.35B). Mitotic activity is conspicuous (≥10 per 10 HPFs). It is common to find geographic tumor cell necrosis and infiltration into surrounding uterine tissue. By definition, the tumor lacks any morphologic evidence of mesenchymal-lineage differentiation (smooth muscle, endometrial stroma, or other). Undifferentiated uterine sarcoma has been

A

B

FIG. 11.35

C

Undifferentiated uterine sarcoma. Highly cellular tumor with evident nuclear atypia and no discernible differentiation at low power magnification (A). The tumor cells are are enlarged with irregularly shaped hyperchromatic nuclei and conspicuous nucleoli (B). Tumor cells can be positive for CD10 (C).

456 categorized as pleomorphic or uniform depending on the cell population. The morphology of “uniform” sarcomas overlaps with that of undifferentiated endometrial carcinoma (see Chapter 10). Rhabdoid features can be observed in this subset of tumors.

ANCILLARY STUDIES HISTOCHEMISTRY

Reticulin stain will highlight a reticulin network with pericellular distribution (surrounding individual cells). IMMUNOHISTOCHEMISTRY

Immunohistochemistry is important to exclude other diagnoses in the differential. Undifferentiated uterine sarcoma is negative for epithelial (keratins, EMA), smooth muscle (desmin, caldesmon, SMA), and skeletal muscle (myogenin, myoglobin) markers. CD10 is not infrequently positive and can be strong and diffuse (Fig. 11.35C). ER and PR can also be positive, usually focally and weakly. P53 expression can be abnormal. BRG1 (SMARCA4) loss has been reported. MOLECULAR ANALYSIS

Undifferentiated uterine sarcoma does not have specific translocations to date. It is characterized by a complex karyotype, as well as frequent TP53 mutations. Recurrent mutations in SMARCA4 mutations leading to loss of SMARCA4/BRG1 protein have been described in undifferentiated uterine sarcomas with uniform morphology, some of which have rhabdoid features. Interestingly, the same alteration has been reported in undifferentiated endometrial carcinoma and ovarian small cell carcinoma hypercalcemic type, suggesting that abnormalities in SMARCA4 may be a common (and potentially unifying) finding in gynecologic malignancies with absent or unclear lineage differentiation.

DIFFERENTIAL DIAGNOSIS Undifferentiated uterine sarcoma is a diagnosis of exclusion and can be made once extensive sampling and ancillary testing have ruled out other possibilities. Among these, dedifferentiated and undifferentiated endometrial carcinoma needs to be excluded, as therapy can be different and prognosis is better. Dedifferentiated carcinoma will have a distinct carcinoma component, typically low grade (endometrioid FIGO grade 1 or 2). Undifferentiated carcinoma, entirely composed of undifferentiated cells, is more

GYNECOLOGIC PATHOLOGY

problematic. First, these carcinomas have an atypical population that is monotonous and uniform in terms of nuclear size and shape; significant pleomorphism is not a typical feature of undifferentiated carcinoma and will thus be more in keeping with undifferentiated uterine sarcoma. The uniform variant of undifferentiated uterine sarcoma overlaps morphologically with undifferentiated carcinoma; however, vague nesting can be seen in the latter and is a helpful clue. Undifferentiated carcinoma usually has a nested pattern on reticulin stain (reticulin fibers surrounding groups of cells, which lack pericellular staining). Moreover, ∼70% of undifferentiated carcinomas show pan cytokeratin, low-molecular-weight keratin, and/or EMA expression, although this can be focal. Finally, undifferentiated carcinomas may show abnormal MMR expression. Of note, the molecular profile of undifferentiated carcinoma more closely overlaps with endometrial carcinoma. Leiomyosarcoma, high grade endometrial stromal sarcoma and rhabdomyosarcoma, when highly pleomorphic, can mimic undifferentiated uterine sarcoma. They, however, have areas with typical differentiated morphology. Expression of smooth or skeletal muscle markers will argue against undifferentiated sarcoma and will favor leiomyosarcoma or rhabdomyosarcoma, respectively. Müllerian adenosarcoma can have a high-grade mesenchymal component, which is distinguished from undifferentiated uterine sarcoma by the presence of mesenchymal differentiation (e.g., fascicular arrangement of spindle cells, collagenous or chondromyxoid extracellular matrix). Identification of the benign epithelial elements with the distinctive phyllodes-like growth is key in this differential; it may require extensive sampling if the lesion has sarcomatous overgrowth.

PROGNOSIS AND TREATMENT Undifferentiated uterine sarcoma is an aggressive tumor with rapid progression despite therapy; median survival is less than 2 years. Most patients (∼60%) present with extrauterine tumor spread, but even those at early stage have a poor prognosis. Recent studies, however, have found an independent association between a mitotic count of less than 25 mitoses/10 HPFs and better 5-year survival; one-third of patients survived beyond 5 years and tended to have mitotic counts of less than 25 mitoses/10 HPFs. Pleomorphic and uniform variants of undifferentiated uterine sarcoma have similarly aggressive clinical behavior; the distinction between the two may nonetheless help identify sarcomas with BRG1/SMARCA4 loss, which in other organs has been associated with germline SMARCA4 mutations.

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

UNDIFFERENTIATED UTERINE SARCOMA—FACT SHEET Definition n High-grade sarcoma with lack of specific mesenchymal-lineage differentiation Incidence n Rare Age Distribution n Postmenopausal women (mean age 60 years) Clinical Features n Postmenopausal bleeding n Rapidly enlarging mass Prognosis and Treatment n Poor prognosis n Overall survival usually ≤2 years, but >5 years in one-third n  Brisk mitotic count (>25 mitoses/HPF) correlates with worse survival. n Extrauterine spread frequent n Poor response to systemic therapy

nn UTERINE TUMORS RESEMBLING OVARIAN SEX CORD TUMORS Sex cord stromal differentiation can be observed in endometrial stromal neoplasms in variable amounts. Uterine tumors with exclusive sex-cord stromal morphology are now regarded as a separate entity, namely, uterine tumors resembling ovarian sex cord tumor (UTROSCT). Recent molecular discoveries support this separation; however, the cellular precursor of UTROSCT remains unknown.

CLINICAL FEATURES UTROSCT typically occurs in reproductive and postmenopausal women (third to sixth decades). Although some tumors are asymptomatic and incidental, others manifest with abnormal uterine bleeding or abdominal pain and are clinically interpreted as leiomyoma(s).

PATHOLOGIC FEATURES UNDIFFERENTIATED UTERINE SARCOMA— PATHOLOGIC FEATURES Gross Findings n Large (>10 cm), fleshy mass with heterogeneous cut surface n Polypoid (more frequent) or intramural Microscopic Findings n Hypercellular tumor with infiltrative borders n Diffuse sheet-like growth with no specific features n  High N:C ratio, irregular nuclear membranes, coarse chromatin, and nucleoli n  Tumor can be pleomorphic or uniform (relative monotony in nuclear size) n Absence of epithelial or mesenchymal differentiation Histochemical and Immunohistochemical Features n Pericellular reticulin network n  PAX8, epithelial (LMWK, pan keratin, EMA), smooth muscle (desmin, caldesmon, SMA), and skeletal muscle (myoglobin, myogenin) marker negative n CD10, ER, and PR can be positive Molecular Analysis n Complex karyotype n TP53 mutations frequent n SMARCA4 mutations in subset (uniform morphology) Differential Diagnosis n Undifferentiated and dedifferentiated carcinoma n Leiomyosarcoma n HG-ESS (YWHAE-NUTM2) n Rhabdomyosarcoma n High-grade adenosarcoma

GROSS FINDINGS

The lesion is well circumscribed and varies in size from 1 to >20 (median 6) cm. The cut surface is homogeneous, firm or soft (Fig. 11.36A). Necrosis is usually absent. MICROSCOPIC FINDINGS

Microscopically, UTROSCT is a cellular tumor with architecture mirroring ovarian sex-cord stromal neoplasms. The interface with the surrounding myometrium is usually smooth but can be infiltrative (Fig. 11.36B). Architectural patterns includes cords (plexiform pattern), trabeculae, nests, gland-like elements, tubules, and retiform growth (Fig. 11.36C). The cytomorphology is also reminiscent of ovarian sex-cord stromal tumors, as the cells can have an appearance similar to granulosa or Sertoli cell tumors; nuclear grooves are not uncommon but leydig-like cells are rare (Fig. 11.36D). Cytologic atypia, mitotic activity, and necrosis are rare; however, their presence should be reported as it may have clinical relevance (see Prognosis and Treatment).

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

UTROSCT is typically positive for inhibin, calretinin, CD99, WT1, ER, PR, and FOXL2 by immunohistochemistry; SF-1 and Melan A can also be positive. Of these, calretinin is the most consistent marker (95% sensitivity), and positivity for

458

GYNECOLOGIC PATHOLOGY

this plus at least one more other sex-cord stromal marker is considered highly specific for the diagnosis (Fig. 11.36E). In addition, the tumor is characteristically polyphenotypic and may be positive for SMA, desmin, caldesmon, cytokeratin, and EMA. HMB45 is typically negative. MOLECULAR ANALYSIS

Unlike endometrial stromal neoplasms (including those with sex-cord stromal differentiation), UTROSCT does not harbor JAZF1-SUZ12 fusion or PHF1

rearrangements. In addition, they lack FOLX2 and DICER1 mutations, characteristic of ovarian adult-type granulosa cell tumors and Sertoli–Leydig cell tumors, respectively. Conversely, recurrent fusions involving NCOA2 and NCOA3 (ESR1-NCOA3, ESR1-NCOA2, or GREB1-NCOA2) have been recently described in UTROSCT. NCOA2 and NCOA3 participate in steroid hormone expression, and genomic dysregulation of the nuclear receptor coactivator domain of NCOA2/3 has been proposed as a driving mechanism in the histogenesis of UTROSCT.

A

B FIG. 11.36 Uterine tumor resembling ovarian sex-cord stromal tumor. The lesion is grossly soft and tan (A). Focal infiltration can be observed (B). The tumor cell population is arranged in cords, nests, and trabeculae, mirroring the architecture seen in ovarian sex-cord stromal tumors (C). The cells are uniform with round to ovoid nuclei and scant cytoplasm (D). They are strongly positive for calretinin (E).

C

D

E FIG. 11.36, cont’d

460

DIFFERENTIAL DIAGNOSIS The presence of any areas with endometrial stromal morphology should raise the possibility of a low-grade endometrial stromal neoplasm with sex-cord stromal differentiation. These areas have the classic architecture, cytomorphology and vasculature of endometrial stromal neoplasia and are typically demarcated from the zones with sex-cord stromal differentiation. Testing for JAZF1 and PHF1 fusions can be considered in difficult cases. Endometrioid carcinoma may display minor areas of sex-cord differentiation; these tumors are predominantly endometrial (rather than intramural); the glandular component is predominant and often displays confirmatory endometrioid features (squamous, mucinous, or secretory differentiation). Perivascular epithelioid cell tumor (PEComa) and epithelioid smooth muscle tumor may show immunohistochemical overlap with UTROSCT, especially since the latter frequently expresses Melan-A and smooth muscle markers; nonetheless, both PEComa and leiomyoma are negative for calretinin, inhibin, SF1, WT1, and CD99, and PEComa is positive for HMB45, whereas UTROSCT is negative.

PROGNOSIS AND TREATMENT The clinical course of most patients with UTROSCT is indolent. However, extrauterine spread has been documented in 23.5% of patients, and fatality in 8.8% according to the largest case series published to date. Tumor cell necrosis and high mitotic count appear to correlate with adverse outcome. Given these relatively small but significant adverse events, UTROSCT is now considered a neoplasm of low malignant potential. Hysterectomy, followed by long-term follow-up, is recommended. Successful therapy with conservative excision has been reported in patients who desire fertility preservation. UTERINE TUMOR RESEMBLING OVARIAN SEX-CORD STROMAL TUMOR—FACT SHEET Definition n Tumors with predominant or exclusive morphology akin to ovarian sex-cord stromal neoplasms Incidence n Very rare Age Distribution n Adult women (third to sixth decades) Clinical Features n Often asymptomatic n Abnormal bleeding or pain; clinically interpreted as leiomyoma Prognosis and Treatment n Low malignant potential; good prognosis in most n Recurrence and extraovarian spread documented in subset (∼25%) n Necrosis and brisk mitotic activity more frequent in aggressive tumors n Therapy consists of hysterectomy and monitoring n Conservative excision can be considered

GYNECOLOGIC PATHOLOGY

UTERINE TUMOR RESEMBLING OVARIAN SEX-CORD STROMAL TUMOR—PATHOLOGIC FEATURES Gross Findings n Well circumscribed, variable size (median 6 cm) n Homogeneous yellow to tan cut surface Microscopic Findings n Well demarcated; irregular border with infiltration may occur n Cords trabeculae, nests, gland-like structures, tubules, and retiform growth reminiscent of sex-cord stromal tumors n Bland, uniform cells with scant to abundant eosinophilic cytoplasm Immunohistochemical Features n Calretinin (>95%), inhibin, CD99, WT1, FOXL2 positive n ER and PR positive n  Smooth muscle markers, Melan-A, CD10, and epithelial markers frequently positive n SF1 can be positive n H MB45 negative Differential Diagnosis n Endometrial stromal tumor (nodule or low-grade sarcoma) n Endometrial carcinoma with sex cord differentiation n Perivascular epithelioid cell tumor n Epithelioid smooth muscle tumor

nn PERIVASCULAR EPITHELIOID CELL TUMOR Perivascular epithelioid cell tumor (commonly known as PEComa) of the uterus is a rare but increasingly recognized lesion, and is part of a group of tumors that share a mixed myomelanocytic immunophenotype. This group includes clear cell “sugar” tumor of the lung and pancreas, angiomyolipoma, and the clear cell myelomelanocytic tumor of falciform ligament. PEComa occurs in many anatomic sites. By definition, these tumors have cells with abundant clear to eosinophilic granular cytoplasm with expression of melanocytic (HMB45, Melan-A) and smooth muscle markers (desmin, SMA, caldesmon).

CLINICAL FEATURES PEComas present over a wide range of age (25–75 years, more commonly in the fourth decade). Abnormal uterine bleeding, pelvic pain, and pressure are the most common symptoms. If detected clinically or radiologically, it is often mistaken as a smooth muscle tumor. PEComa can be associated with the tuberous sclerosis complex (TSC), a disorder linked to mutations in TSC1 or TSC2; in this setting, patients tend to be younger and present with multiple PEComas in gynecologic organs and pelvis (so-called PEComatosis).

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

PATHOLOGIC FEATURES GROSS FINDINGS

Some tumors will grossly resemble a leiomyoma, with well-circumscribed borders and a uniform rubbery cut surface; some, however, have overlapping features with leiomyosarcoma in that they can show indistinct and/or infiltrative borders; necrosis and hemorrhage may be present. Lesions may have indistinct or infiltrative edges. (Fig. 11.3A). Tumor size is variable; they are 5 cm on average, but some can be more than 30 cm. MICROSCOPIC FINDINGS

PEComas are characteristically composed of cells with abundant clear to eosinophilic granular cytoplasm (Fig. 11.37B,C). They are typically arranged in sheets, nests and/or vague fascicles. The intervening stroma is scant and contains a uniform network of capillaries and smallsized vessels, around which the tumor cells tend to cluster (Fig. 11.37C). This histologic pattern, defined by some as “epithelioid”, is consistently present in uterine PEComas. In addition, there is a “spindle cell” pattern, seen in ∼35% of tumors, comprised of elongated cells with less abundant cytoplasm and arranged in better formed fascicles resembling uterine smooth muscle. The neoplastic population is usually bland, lacking significant atypia and mitoses (Fig. 11.37C). However, worrisome features for malignancy may be observed and need to be assessed to determine malignant potential (see Prognosis and Therapy). Nuclear atypia may be low (minimal variation in nuclear size) (Fig. 11.37C), intermediate (twofold or less variation), or high (more than twofold variation) (Fig. 11.37D). Mitotic activity is reported as hot spot count per 50 HPFs. Invasion into the myometrium, if present, may be permeative (resembling endometrial stromal sarcoma) and/or destructive (Fig. 11.37E). Besides tumors with the classic features listed earlier, several variants of PEComa have been described: – P  EComatosis: Multiple PEComas involving the uterus as well as other pelvic structures. These are more common in patients affected by TSC. – Lymphangioleiomyomatosis (LAM)-like PEComa: Tumors resembling LAM seen in other anatomic locations; also seen more often in the setting of TSC. – Sclerosing PEComa: In this variant, the typical epithelioid cells are organized in cellular cords separated by a densely fibrotic and hyalinized matrix (Fig. 11.37F). – PEComa with TFE3 rearrangement: This variant is unrelated to TSC and is characterized instead by TFE3 gene fusions. They feature a predominant clear cell epithelioid component, with only minor spindle cell morphology. – PEComa with RAD51B rearrangement: Although morphologically indistinct from conventional PEComa, the presence of RAD51B fusion has been associated with aggressive tumor behavior.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Since the definition of PEComa incorporates immunohistochemistry, this tool is commonly applied in the diagnostic work-up. PEComas, by definition, co-express melanocytic and smooth muscle markers; however, the degree of expression can vary. HMB45 and cathepsin-K are the most sensitive melanocytic markers of uterine PEComa (positive in ∼100% tumors) whereas melan A is the most specific, but is only positive, sometimes only focally, in about half of tumors; (Fig. 11.37G). TFE3 translocation-associated PEComas are diffusely positive for TFE3, HMB45, and cathepsin K but lack (or are only focally) melan-A positive. In contrast to conventional PEComa not associated with this translocation, smooth muscle marker expression may be focal. MOLECULAR ANALYSIS

The genomic landscape of uterine PEComas is heterogeneous. The most common finding is the inactivation (mutation, deletion, copy number loss) of TSC2 followed by TSC1; importantly, inactivation leads to an abnormally activated mTOR pathway. As described earlier, recurrent TFE3 and RAD51B rearrangements characterize a subset of PEComas. Their diagnosis requires molecular techniques (e.g., in situ hybridization); in this regard, TFE3 immunohistochemistry is not specific and thus has limited value.

DIFFERENTIAL DIAGNOSIS PEComas need to be distinguished from epithelial neoplasms and other mesenchymal lesions with epithelioid morphology. Among the latter, epithelioid smooth muscle tumors can be diagnostically challenging, since PEComa can display smooth muscle–like areas and express smooth muscle markers by immunohistochemistry. Like other smooth muscle neoplasms, the epithelioid variant contains thick-walled vessels, which are not typical of PEComa. Moreover, epithelioid smooth muscle tumors are negative for melanocytic markers, particularly Melan-A (HMB45 is less specific and can be positive). PEComas with prominent cord-like appearance may resemble UTROSCT; absence of sex-cord stromal marker expression (WT1, calretinin, inhibin, SF1) will help exclude this diagnosis. HG-ESS with YWHAE-NUTM2 rearrangements has a characteristic round cell “epithelioid” component; nonetheless, neoplastic cells have little cytoplasm unlike the abundant clear to eosinophilic cytoplasmic profile of PEComa. An exceedingly rare tumor in the uterus, alveolar soft part sarcoma requires consideration as it greatly overlaps morphologically with PEComa. Moreover, alveolar soft part sarcoma is characterized by TFE3 gene fusions, which can also be seen in

A

B FIG. 11.37 Perivascular epithelioid cell tumor (PEComa). On gross examination, the tumor may be tan/white, rubbery, and bulge somewhat on cut surface resembling a leiomyoma; however, if malignant, it often shows irregular borders and areas of soft yellow discoloration consistent with necrosis (A). It is often composed of epithelioid and elongated cells with abundant cytoplasm, which ranges from eosinophilic granular (B) to clear (C). Notice the tumor cell aggregation around vessels (C). The tumor may display worrisome histologic features such as cytologic atypia in the form of nuclear enlargement and irregularity or (D) and infiltrative borders (E). Sclerosing PEComa is characterized by a prominent collagenous matrix separating tumor cell clusters (F). HMB45 is usually positive but can be patchy (G).

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C

D FIG. 11.37, cont’d

a subset of PEComas. However, in addition to the classic ASPSCR1-TFE3 fusion, alveolar soft part sarcoma will be negative for smooth muscle and melanocytic markers (although focal HMB45 staining has been reported). Endometrial carcinoma, if predominantly or purely solid and poorly differentiated, can resemble PEComa; however, most cases will show a cohesive pattern and architecture indicative of an epithelial process (glands,

papillae, tight cell clusters), as well as absence of melanocytic and smooth muscle marker staining. Primary or metastatic malignant melanoma is an important consideration, particularly if the tumor is highly pleomorphic or shows pigment deposition. Melanoma is usually positive for S100 and SOX10 (only ∼10% PEComas are positive for S100) and negative for desmin, SMA, and caldesmon.

E

F

G FIG. 11.37, cont’d

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TABLE 11.1 Classification systems for uterine PEComa Schoolmeester et al (Am J Surg Pathol 2014)

Bennett et al (Am J Surg Pathol 2018)

Revised Folpe criteria (J Clin Pathol 2015)

Benign

No worrisome features (size ≥5 cm, severe atypia, necrosis, vascular invasion, mitoses ≥1/50 HPFs)

Fewer than three features (size ≥5 cm, severe atypia, necrosis, vascular invasion, mitoses ≥1/50 HPFs)

One or fewer feature (invasive edge, size ≤5 to 30 cm) n Well-demarcated or infiltrative border n Rubbery or soft cut surface; may show hemorrhage and necrosis Microscopic Findings n Sheets or nests of epithelioid cells and/or fascicles of spindle cells n Scant intervening collagenous stroma n  Capillary and small-caliber vessels with characteristic perivascular tumor cell condensation n  Epithelioid morphology: polygonal cells with prominent clear to eosinophilic granular cytoplasm n Round nuclei with low (no variation in size), intermediate (twofold or less variation), or high (more than twofold variation) atypia n Fascicular growth (smooth muscle like) can be seen n Morphologic variants: sclerosing, LAM like Immunohistochemical Features n H MB-45, Melan-A, and MITF variably positive n Cathepsin-K positive (∼100%) n SMA, desmin, and caldesmon variably positive n Cytokeratin, inhibin, and S-100 negative

Definition n Tumor composed of cells with “perivascular epithelioid cell morphology” which co-express smooth muscle and melanocytic markers

Molecular Analysis n Inactivation of TSC2 and TSC1 (including patients with TSC) n Molecular variants: PEComa with TFE3 and RAD51B rearrangements

Incidence n Rare

Differential Diagnosis n Epithelioid smooth muscle tumors n HG-ESS n Alveolar soft part sarcoma n Endometrial carcinoma n Metastatic or primary melanoma

Age Distribution n Reproductive-age and postmenopausal women n Younger presentation in women with TSC

466

nn INFLAMMATORY MYOFIBROBLASTIC TUMOR Previously known as “inflammatory pseudotumor,” Inflammatory Myofibroblastic Tumor (IMT) is now considered a true neoplasm with a myofibroblastic phenotype. This tumor has been described in many anatomic locations in children and young adults. The uterus is the most frequent gynecologic site of origin. Its recognition has increased in recent years, and it is plausible that some are misdiagnosed as smooth muscle tumors, given the significant morphologic overlap between the two entities.

CLINICAL FEATURES This tumor is infrequent, with ∼60 cases reported. Uterine IMT affects women of all ages, although it is more common in adult women of reproductive age (fourth to fifth decades, mean age ∼45 years). Most lesions are clinically thought to represent a fibroid, manifesting with abnormal bleeding, pelvic pain, or pressure. Some lesions may be incidental.

PATHOLOGIC FEATURES GROSS FINDINGS

Most tumors form an intramural mass but they can sometimes be polypoid into the cavity. The border may be smooth or show an irregular edge. Cut section can be firm and rubbery (indistinguishable from a leiomyoma) or soft and fleshy or gelatinous (Fig. 11.38A). Most lesions are less than 10 cm in size (mean 5–7 cm) but have been reported to be as large as 20 cm. Hemorrhage and necrosis may be seen. MICROSCOPIC FINDINGS

IMTs more often have a well-demarcated border, but they may sometimes be poorly defined and infiltrative (Fig. 11.38B). It often displays a myxoid low-power appearance, composed of plump fusiform cells individually dispersed in a myxoid extracellular matrix in a pattern described as fasciitis like or tissue culture like (Fig. 11.38C,D). Tumor nuclei have an undulating to spindled contour, pointed ends, and open vesicular chromatin (Fig. 11.38D,E). This population is admixed with an inflammatory infiltrate of varying amounts that may be present within the tumor or along the tumor-myometrial border (Fig. 11.38D). Most tumors contain areas with less prominent myxoid appearance and spindle cells more densely packed in intersecting fascicles; these areas are described as smooth muscle-like (Fig. 11.38 E). A third morphologic pattern, which may be admixed with the others, is fibromatosis like, in which the matrix is collagenous and sclerotic and contains individual spindle cells with less conspicuous vesicular nuclei. Less

GYNECOLOGIC PATHOLOGY

commonly, the tumor cells may be epithelioid or ganglion cell like (Fig. 11.38F). Mitotic counts can be variable.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

ALK expression by immunohistochemistry is seen in approximately 50% of all IMTs. However, ALK positivity has been reported in the majority (>90%) of IMTs in the uterus, typically strong and diffuse, but on occasion focal (Fig. 11.38G). ALK-negative IMT in the uterus likely exists but is largely underrecognized because of the significant morphologic overlap with uterine smooth muscle tumors Smooth muscle markers can be positive (more often desmin and SMA than caldesmon), with stronger staining in dense fascicular areas of the tumor. ER and CD10 are frequently positive as well. Expression of p53 is normal (wild type) and p16 is usually patchy. ROS1 is negative. MOLECULAR ANALYSIS

Most IMTs of the uterus harbor recurrent rearrangements involving the ALK gene at 2p23; fusion partners include IGFBP5, THBS1, TIMP3, FN1, TPM3, DES, and SEC31. The fusion can be detected by FISH, although RNA sequencing has been recently proposed as a more sensitive method of detection. In addition, ETV6NTRK3 fusion has been rarely encountered. ROS1 fusions have not been reported in uterine tumors.

DIFFERENTIAL DIAGNOSIS The chief differential diagnostic consideration of uterine IMT is uterine smooth muscle tumors. If an IMT has a predominant dense fascicular appearance, misinterpretation as conventional leiomyoma is likely to occur. Although such distinction will be inconsequential in most cases, a minority of IMT has the potential to recur and behave aggressively; therefore, its identification is important. Fortunately, most tumors with adverse behavior are predominantly myxoid. In the setting of a uterine tumor with a predominant myxoid matrix, the diagnosis of IMT should be entertained and ALK immunohistochemistry performed. Myxoid leiomyoma and myxoid leiomyosarcoma are important differential diagnostic considerations, as one is benign and the second is an aggressive malignancy, different from the low malignant potential of IMT. Unlike IMT, myxoid smooth muscle tumors have a more diffuse fascicular architecture, and the myxoid stroma separates tumor cells into bundles and not individually. Moreover, tumor nuclei have blunted ends (cigar shape) and are more hyperchromatic. Smooth muscle markers are of

CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

A

B FIG. 11.38 Inflammatory myofibroblastic tumor. Soft and fleshy cut surface in this recurrent inflammatory myofibroblastic tumor in the omentum, which highly resembles the gross appearance of the uterine primary (A). The tumor has an indistinct infiltrative border (B). Fibromyxoid areas contain fusiform wavy cells dispersed individually (C), admixed with inflammatory cells (D). Fascicular areas blend with myxoid stroma and highly resemble smooth muscle (E). Less commonly, tumor may display epithelioid morphology (F). ALK expression can be demonstrated by immunohistochemistry (G).

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C

D FIG. 11.38, cont’d

CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

E

F FIG. 11.38, cont’d

469

470

GYNECOLOGIC PATHOLOGY

G FIG. 11.38, cont’d

limited value; however, caldesmon tends to be stronger and more diffusely expressed in smooth muscle tumors. ALK is a useful marker but has been reported positive in a minority of myxoid leiomyosarcomas. Thus, confirmation with molecular analysis for ALK is recommended in lesions difficult to classify. An abnormal p53 staining pattern or diffuse positivity for p16 should raise the possibility of leiomyosarcoma. Fibromyxoid LG-ESS and HG-ESS with BCOR alterations differ from IMT in their classic myopermeative growth, absence of ALK staining, and negative or very weak positivity for smooth muscle markers. Fibromyxoid LG-ESS will display, at least focally, the conventional endometrial stromal tumor cell morphology and vasculature. Molecular analysis including ALK, JAZF1, and BCOR genes can be useful.

PROGNOSIS AND TREATMENT In the uterus, IMT is currently viewed as a neoplasm with low malignant potential as local recurrence, metastatic spread and/or tumor-related death has occurred in ∼25% of cases reported. Several features have been correlated with adverse tumor behavior, including tumor cell necrosis, large tumor size (>7 cm), infiltrative borders, mitotic counts greater than 10 mitoses/10 HPFs, and moderate to severe atypia. Unlike uterine PEComa, a classification system of benign and malignant IMT based on these features does not exist. Nonetheless, the presence of any of these worrisome characteristics should be noted in the report. Primary treatment is hysterectomy. Conservative excision and close follow-up can be contemplated if fertility preservation is desired. Treatment with tyrosine kinase inhibitors (crizotinib) has been postulated as an alternative in patients with unresectable and/or recurrent disease.

INFLAMMATORY MYOFIBROBLASTIC TUMOR—FACT SHEET Definition n  Neoplasm with myofibroblastic phenotype, myxoid matrix and inflammation Incidence n Very rare in gynecologic tract (90%), typically strong n SMA and desmin frequently positive (in dense fascicular areas) n Caldesmon, CD10, and ER may be positive n Normal p53 and patchy p16 Cytogenetic Features n ALK rearrangements in most uterine tumors Differential Diagnosis n Conventional leiomyoma n Myxoid leiomyoma n Myxoid leiomyosarcoma n Fibromyxoid LG-ESS n HG-ESS with BCOR alterations

carcinosarcoma and high-grade adenosarcoma. Pure rhabdomyosarcoma of the genital tract is, on the other hand, exceedingly rare. The most common type is embryonal rhabdomyosarcoma, which typically occurs in the cervix of children and adolescents. Given its mucosal location and exophytic growth, embryonal rhabdomyosarcoma has also been termed “sarcoma botryoides.” The lesion usually manifests with abnormal uterine bleeding, discharge, or a mass protruding from the cervix. In adults, embryonal, pleomorphic, and alveolar types have been described; most patients are postmenopausal and present with vaginal bleeding. Most tumors show widespread extrauterine dissemination at the time of diagnosis.

PATHOLOGIC FEATURES GROSS FINDINGS

nn RHABDOMYOSARCOMA CLINICAL FEATURES Rhabdomyosarcomatous differentiation is a relatively common event in high-grade mixed tumors such as

Embryonal rhabdomyosarcoma involving the cervix and uterine cavity is characteristically a polypoid lobulated soft mass, 3–4 cm in average size (Fig. 11.39). Other types present as large heterogeneous intramural masses with necrosis and hemorrhage.

FIG. 11.39 Embryonal rhabdomyosarcoma (sarcoma botryoides). This polypoid lesion occupies the endocervical canal and protrudes through the cervical os.

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GYNECOLOGIC PATHOLOGY

MICROSCOPIC FINDINGS

The histomorphology of rhabdomyosarcoma is similar to that seen in other anatomic regions. Embryonal rhabdomyosarcoma is comprised of alternating areas of hyper- and hypocellularity, the latter typically myxoid and sometimes containing hyaline or fetal-type cartilage (Fig. 11.40A). Tumor cells are round to short spindled with scant cytoplasm (and high nuclear to cytoplasmic ratio), which imparts a “round blue cell” morphology. Globoid, brightly eosinophilic cytoplasmic processes with visible cross-striations may be noted and are pathognomonic (tadpole or strap-cells). If submucosal in location, the tumor forms a hypercellular band underneath the epithelium (cambium layer) (Fig. 11.40B).

A

FIG. 11.40 Embryonal rhabdomyosarcoma. The tumor is remarkable for having a myxoid stroma with hyaline cartilage formation (A). Submucosal tumors often show a characteristic condensation of neoplastic stroma directly beneath the surface epithelium. (B).

B

Alveolar rhabdomyosarcoma is composed of dyshesive small round cells with hyperchromatic nuclei organized around saccular spaces (alveoli) and separated by thin fibrous septa. Pleomorphic rhabdomyosarcoma is characterized by marked cellularity and cytologic atypia evident, in part, by the heterogeneity of the neoplastic population in terms of nuclear size and shape. Rhabdomyoblasts are readily identified. IMMUNOHISTOCHEMISTRY

Tumor cells are positive for desmin, myogenin, and MyoD1 and negative for ER and PR.

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MOLECULAR ANALYSIS

DICER1 inactivating mutations have been identified in embryonal rhabdomyosarcoma and are either germline (part of DICER1 syndrome) or somatic. Alveolar rhabdomyosarcomas are characterized by PAX3-FKHR or PAX7-FKHR gene fusions.

DIFFERENTIAL DIAGNOSIS It is important to sample the tumor thoroughly to exclude the possibility of carcinosarcoma and highgrade Müllerian adenosarcoma with rhabdomyosarcomatous differentiation. Rhabdomyosarcoma may undermine the normal cervical and endometrial mucosa and entrap epithelial elements, which can be misdiagnosed as adenosarcoma. Moreover, the cambium layer seen in embryonal rhabdomyosarcoma may resemble the periglandular condensation seen in adenosarcoma. The latter should only be diagnosed in the presence of an intimately admixed benign glandular population with the classic features of rigid cystic dilation and leaf-like processes. Leiomyosarcoma, when highly pleomorphic, may enter in the differential of pleomorphic rhabdomyosarcoma. Immunohistochemistry for smooth muscle and skeletal muscle markers will aid in their distinction. Fibroepithelial stromal polyp of the cervix can be quite cellular and contain atypical eosinophilic cells resembling rhabdomyoblasts, thus mimicking embryonal rhabdomyosarcoma. The absence of a cambium layer and the presence of bland stellate subepithelial stromal cells are helpful clues in the diagnosis of fibroepithelial polyp. Lymphoma and other tumors with round blue cell morphology should be entertained, including desmoplastic round cell tumor and round cell liposarcoma. These tumors are extraordinarily rare in the uterus; the presence of strap cells and expression of skeletal muscle markers will support the diagnosis of rhabdomyosarcoma.

PROGNOSIS AND TREATMENT Pediatric embryonal rhabdomyosarcoma has a good prognosis (80%–90% survival) with current treatment modalities, which include surgery and adjuvant chemotherapy. In the pediatric population, conservative excision with negative margins is often attempted first. Prognosis is slightly worse in adult patients with this tumor type, who are treated with hysterectomy and adjuvant chemotherapy. Conversely, the clinical outcome of pleomorphic and alveolar rhabdomyosarcomas is dismal, and no effective treatment options exist currently.

RHABDOMYOSARCOMA—FACT SHEET Definition n Malignant mesenchymal tumor with skeletal muscle phenotype n Three types: embryonal, alveolar, pleomorphic n  Sarcoma botryoides: embryonal rhabdomyosarcoma involving uterine mucosa (most often cervix) Incidence n Rare in uterus Age Distribution n  Embryonal rhabdomyosarcoma: children and adolescents (sarcoma botryoides), rarely adults n  Pleomorphic and alveolar rhabdomyosarcoma: postmenopausal women Clinical Features n Abnormal bleeding n Mass protruding through cervical os Prognosis and Treatment n Surgery (conservative complete excision in children, hysterectomy in adults) and adjuvant therapy n Embryonal rhabdomyosarcoma: good prognosis n Pleomorphic and alveolar rhabdomyosarcoma: dismal prognosis

MIXED MÜLLERIAN TUMORS OF THE UTERUS Tumors with mixed epithelial and mesenchymal components are frequent in the gynecologic tract. The underlying mechanisms that drive the harmonized growth of both components are largely unknown. However, there is evidence that in adenosarcoma and endometrial polyps, the mesenchymal proliferation is neoplastic whereas the epithelial component is not.

RHABDOMYOSARCOMA—PATHOLOGIC FEATURES Gross Findings n Sarcoma botryoides: exophytic, lobulated (“grape”-like), soft mass n Other types: large, heterogeneous fleshy intramural mass Microscopic Findings n Embryonal rhabdomyosarcoma: n Polypoid projections, if botryoid type n Hypercellular and hypocellular areas, latter with myxoid change n Submucosal condensation of primitive appearing small round blue cells (“cambium layer”), some with eosinophilic cytoplasmic projections that may show cross-striations (“strap” cells) n Fetal-type cartilage (~30%) n Alveolar rhabdomyosarcoma: n Small round blue cells arranged around empty saccular spaces ­(alveoli) n Pleomorphic rhabdomyosarcoma: n Numerous rhabdomyoblasts n Significant pleomorphism

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GYNECOLOGIC PATHOLOGY

Immunohistochemical Features n Desmin, myogenin, MyoD1 positive n Hormone receptor negative Molecular analysis n Embryonal rhabdomyosarcoma: DICER1 mutations n Alveolar rhabdomyosarcoma: PAX3-FKHR or PAX7-FKHR gene ­fusions Differential Diagnosis n Carcinosarcoma n High-grade adenosarcoma n Leiomyosarcoma n Fibroepithelial stromal polyp n Other round blue cell tumors

nn MÜLLERIAN ADENOSARCOMA Müllerian adenosarcoma is a mixed epithelial and mesenchymal neoplasm composed of a malignant mesenchymal component and an intimately admixed benign Müllerian glandular component.

FIG. 11.41 Müllerian adenosarcoma. Fleshy polypoid masses fill the endometrial cavity.

CLINICAL FEATURES This tumor represents 5%–10% of all uterine sarcomas. It is more often seen in perimenopausal and postmenopausal women (median age 58 years); however, it can be seen in all ages (range 13–89 years), and about 30% of affected patients are premenopausal. Common symptoms include abnormal uterine bleeding and pelvic pressure. In some patients, a history of prior uterine polyps is noted. Clinical examination may reveal an enlarged uterus or a polypoid lesion protruding through the cervix.

PATHOLOGIC FEATURES GROSS FINDINGS

The prototypic gross appearance of adenosarcoma is a polypoid exophytic mass based in the endometrium (>90%) or endocervix (∼10%). Invasion into the uterine wall, or predominant endophytic growth, can sometimes be appreciated. The cut surface is usually soft and tan, sometimes with bulbous protrusions, frond-like appearance and/or cysts (Fig. 11.41). The mean tumor size is 5 cm. Large size (≥10 cm) and presence of necrosis are more common in high-grade tumors. MICROSCOPIC FINDINGS

The hallmark of Müllerian adenosarcoma is its biphasic population, intimately admixed throughout the tumor in a distinct pattern (Fig. 11.42A). The epithelial component

is typically comprised cytologically bland cells with mild to at most moderate cytologic atypia and no architectural complexity. covering the surface and lining tubular and glandular structures. Epithelial metaplasia (squamous or mucinous) is often present. Secondary glandular neoplasia can arise in adenosarcoma and in this scenario, the glandular proliferation can be classified as endometrial intraepithelial neoplasia (EIN) or even low-grade endometrioid carcinoma (FIGO grade 1 or 2), otherwise identical to endometrial carcinoma arising in the endometrium. The mesenchymal component is prominent and displays high cellularity, particularly around the epithelial elements (described as periglandular condensation or “cuffing”) (Fig. 11.42B). The neoplastic stroma grows into the epithelial elements, narrowing their lumens and producing protrusions with a broad front, classically described as leaf-like architecture (Fig. 11.42C). The stromal proliferation may also surround cystic glands with “stiff” convex outlines (so-called “rigid” cysts) (Fig. 11.42D). The mitotic threshold of the stromal component for the diagnosis of adenosarcoma is somewhat controversial as a lower limit has not necessarily been agreed upon; however, most will have at least 2 per 10 high power fields. Stromal atypia varies as well; some tumors only show mild nuclear enlargement (Fig. 11.42E). The stroma away from zones of periglandular condensation tends to be less atypical, cellular and proliferative. Classification of adenosarcomas into clinically relevant groups is based on the nuclear grade and amount of stroma. Three categories have been proposed (Fig. 11.43A): – L ow-grade adenosarcomas (Fig. 11.43B), which comprise the majority. The sarcomatous compo-

CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

A

B FIG. 11.42 Müllerian adenosarcoma. The lesion is distinctively biphasic, composed of epithelial elements overlying a cellular stromal proliferation with welll developed leaf-like architecture (A, scanning magnification in inset). Characteristic features of adenosarcoma include: periglandular and subepithelial stromal condensation (B), broad-front stromal projections into the luminal spaces producing intraglandular polypoid projections and a leaf-like architecture (C), “rigid” cystic dilation (D), and stromal atypia and mitoses (E).

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C

D

E FIG. 11.42, cont’d

CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

A

B

C FIG. 11.43 Clinically relevant categories of adenosarcoma. Schematic classification of adenosarcoma based on nuclear grade separates tumors in clinically and pathologically distinct categories. The phenomenon of sarcomatous overgrowth is mostly seen in high-grade tumors, but not exclusively, and it must always be reported. AS, Adenosarcoma; HPFs, high-power microscopic fields; LG, low grade; SO, sarcomatous overgrowth. (Modified from Hodgson A et al, Am J Surg Pathol. 2017;41:1513–1522) (A). Low-grade adenosarcoma, with a monomorphic sarcomatous component (B). High-grade adenosarcoma, with classic growth but with a highly pleomorphic stromal cell component, discernible at low power view (C) and better appreciated at high power (D). Sarcomatous overgrowth, defined as pure stroma in >25% of the tumor; notice the complete absence of glands in this low power field (E, whole section in inset). Rhabdomyosarcomatous differentiation is common in high-grade adenosarcomas (F).

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GYNECOLOGIC PATHOLOGY

D

E

F FIG. 11.43, cont’d

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

nent is relatively monomorphic, and nuclear atypia is best seen only at high power magnification. Nuclear size variation is minimal and no more than two times the size of an endothelial cell nucleus. The stroma resembles LG-ESS. Variant differentiation has been described, including smooth muscle and sex-cord stromal differentiation. Most cases are FIGO stage I (confined to the uterus) and show no myometrial invasion or only superficial invasion. – High-grade adenosarcomas (Fig. 11.43C,D) are less frequent and only recently characterized. These tumors are often ≥10 cm in size. High-grade stromal morphology is defined as variation in nuclear size more than two times the size of an endothelial cell nucleus. This degree of atypia should be identified at low-power (scanning) view. Nuclei have irregular nuclear membranes, coarse chromatin, and prominent nucleoli. Heterologous differentiation, particularly rhabdomyosarcomatous, can be observed. High-grade adenosarcoma is usually associated with sarcomatous overgrowth. In some, the sarcoma is entirely high grade but in others is seen in conjunction with low-grade areas; the proportion of highgrade sarcoma ranges from 10% to 90%. –  Adenosarcomas with sarcomatous overgrowth (Fig. 11.43E) comprise approximately 10% of adenosarcomas. Sarcomatous overgrowth is defined as pure sarcoma representing ≥25% of the tumor volume. The areas of overgrowth are usually high grade and can be homologous or heterologous (Fig. 11.43F).

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Immunohistochemistry has a minor role in the diagnosis of adenosarcoma. The sarcomatous proliferation is positive for CD10, ER, and PR; these markers are more consistently positive in low-grade tumors. WT1 is also positive in adenosarcoma and has been reported to be stronger in areas of sarcomatous overgrowth. Low-grade adenosarcoma has a normal (wild type) p53 staining, whereas high-grade adenosarcoma often shows abnormal expression (overexpression or complete absence). MOLECULAR ANALYSIS

The mesenchymal component of Müllerian adenosarcoma harbors somatic gene alterations that are absent in the epithelial component, which supports the concept that these lesions are primarily sarcomas. TP53 mutations are rare and always seen in the context of high-grade adenosarcoma

and/or sarcomatous overgrowth. Other alterations described in adenosarcomas with sarcomatous overgrowth include complex karyotype, global chromosomal instability and chromothripsis, high copy number variation index, MYBL1 amplification, and ATRX mutations.

DIFFERENTIAL DIAGNOSIS The distinction between low-grade adenosarcoma and endometrial or endocervical polyp is clinically relevant. Benign polyps are characterized by a fibrotic stroma, bland and hypocellular relative to the normal endometrium. Some endometrial and endocervical polyps display some of the features seen in adenosarcoma, which represents a challenge. It has been demonstrated that polyps that focally have up to three of the diagnostic features and the features are not well-developed (leaf-like architecture, periglandular stromal condensation, or ≥2 mitoses/10 HPFs) behave in a benign fashion, even those that were diagnosed in biopsy/curettage and followed conservatively. Conversely, bona fide adenosarcomas have well developed leaf-like architecture and subepithelial stromal condensation. The term “uterine polyp with unusual features” has been suggested for polyps with equivocal features as described; in practice, this term can be used followed by a comment advising follow-up and sampling of any subsequent endometrial lesions. Atypical polypoid adenomyoma (APA) can be considered in the differential; nevertheless, the stromal component of these lesions has a bland smooth muscle phenotype, and the glands display greater degrees of density and proliferation than those seen in adenosarcoma. Adenosarcoma may require distinction from carcinosarcoma, especially if an endometrioid adenocarcinoma arises within the adenosarcoma or near it. The epithelial component of carcinosarcoma is malignant and high grade; conversely, carcinoma arising in adenosarcoma is low grade and usually only focally present, and tumor areas away from it have benign glandular elements. Low-grade endometrial stromal sarcoma may show a minor endometrioid glandular component, which can resemble the biphasic appearance of low-grade adenosarcoma. The typical architectural features of adenosarcoma are, however, lacking. Similarly, high-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma may entrap normal endometrial glands and therefore display focal “biphasic” morphology. This occurrence can be distinguished from high-grade adenosarcoma by its focality within the tumor and by the absence of periglandular condensation and leaf-like architecture. Adenosarcomas with rhabdomyosarcomatous differentiation may be confused with uterine rhabdomyosarcoma; however, thorough sampling will show the typical biphasic pattern of adenosarcoma.

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PROGNOSIS AND TREATMENT The overall survival of this lesion, once resected, is 80%–90%. From a biologic perspective, adenosarcomas can be divided into low-risk (low-grade adenosarcoma) and high-risk (high-grade and/or with sarcomatous overgrowth) groups. Low-grade adenosarcomas have a low malignant potential. Recurrence and metastases, seen in 25% of cases, are strongly associated with myometrial invasion and vascular space invasion. For this reason, and since adenosarcoma arises in the endometrial surface in most cases, the pathologic staging of adenosarcoma differs from other uterine sarcomas as per the latest FIGO and TNM schemes, and stage I tumors are substratified based on the presence and depth of myometrial invasion and not by tumor size. High-grade adenosarcoma and adenosarcoma with sarcomatous overgrowth have aggressive clinical behavior with frequent extrauterine spread at the time of diagnosis as well as rapid abdominopelvic recurrence (∼70%). Adenosarcomas with sarcomatous overgrowth are more frequently myo-invasive (60% vs. 25% in adenosarcomas without overgrowth). There is close association between high-grade morphology and sarcomatous overgrowth, but these features can occur independently: high-grade features can be seen in the absence of overgrowth, and sarcomatous overgrowth can occur in an otherwise low-grade adenosarcoma (30% of cases). Thus, these high-risk features need to be consistently assessed and reported. The primary treatment of adenosarcoma is complete excision with hysterectomy and bilateral salpingo-oophorectomy, followed by long-term surveillance. Pelvic radiation and systemic chemotherapy are usually administered to patients with recurrent or advanced stage disease.

GYNECOLOGIC PATHOLOGY

MÜLLERIAN ADENOSARCOMA—PATHOLOGIC FEATURES Gross Findings n Location: endometrium (most common), cervix (9%), or myometrium (4%) n Mean size 5 cm; high-grade lesions usually >10 cm n Exophytic soft mass n Solid or clefted (cauliflower-like) cut surface ± small cysts Microscopic Findings n Biphasic population with the following features throughout tumor: n Periglandular stromal condensation (“cuffing”) n Leaf-like architecture n Rigid cystic dilation n Stromal cytologic atypia (low or high grade) n ≥2 mitoses/10 HPFs n Benign glandular component n Endometrioid or endocervical epithelium n ± Epithelial metaplasia n ± Associated EIN or low-grade endometrioid carcinoma n Malignant mesenchymal component n Low grade: relatively monotonous stromal population (akin to LG-ESS); ± Sex cord or smooth muscle differentiation n High grade: significant pleomorphism (seen at low power), ­nuclear variation more than two times the endothelial nucleus size ± Heterologous elements (rhabdomyosarcoma most common) n Sarcomatous overgrowth: pure sarcoma representing ≥25% of the tumor n Myometrial invasion often superficial Immunohistochemical Features n CD10, ER, and PR positive (sarcomatous component) n W T1 positive (stronger in sarcomatous overgrowth) n Abnormal p53 (in high grade adenosarcoma) Molecular Analysis n TP53 mutations in high-grade tumors n  Sarcomatous overgrowth associated with global chromosomal instability, high copy number variation index, MYBL1 amplification, and ATRX mutations Differential Diagnosis n Endometrial/endocervical polyp n Atypical polypoid adenomyoma n Carcinosarcoma n LG-ESS n HG-ESS n Undifferentiated uterine sarcoma n Rhabdomyosarcoma

MÜLLERIAN ADENOSARCOMA—FACT SHEET Definition n Mixed Müllerian tumor with malignant mesenchymal and benign epithelial components Incidence n 5%–10% of all uterine sarcomas Age Distribution n More often in postmenopausal women (median age 58 years), but seen at all ages n 30% premenopausal

Clinical Features n Abnormal vaginal bleeding and/or pelvic pain n Enlarged uterus n ± History of recurring endometrial or endocervical polyps Prognosis and Treatment n Total abdominal hysterectomy and bilateral adnexectomy n 80%–90% overall survival rate n High-risk features associated with advanced stage, recurrences, and death n High-grade adenosarcoma n Sarcomatous overgrowth n Myometrial and vascular invasion

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

nn MÜLLERIAN ADENOMYOMA Adenomyomas are rare lesions that arise in the cervix or the uterine corpus; they contain endocervical and endometrial-type epithelium, respectively.

CLINICAL FEATURES Adenomyomas are typically encountered in reproductive-age women (range 22–60 years). They can be incidental or manifest with abnormal uterine bleeding or as a mass forming lesion protruding into the vagina, resembling a fibroid or mucosal polyp.

cigar-shaped nuclei, in keeping with smooth muscle. The myomatous stroma blends imperceptively with the surrounding myometrium, and the border may be difficult to appreciate (it will be best seen at scanning magnification). Polypoid adenomyomas are typically sessile and represent submucosal lesions projecting into the cavity; in these, the smooth muscle is distributed throughout the lesion. The glandular elements are lined by endocervical-type mucinous or endometrial type epithelium. They can be individually dispersed or form lobular aggregates. Some glands may be cystically dilated and contain simple papillae. In endometrial-type adenomyomas, the glands are usually surrounded by a rim of endometrial-type stroma. Both epithelial and mesenchymal elements are cytologically bland. Mitotic activity is sparse in the glands and endometrial-type stroma (if present) and absent in the myomatous component. Adenomyosis is seen in ∼30% of endometrial-type adenomyomas.

PATHOLOGIC FEATURES GROSS FINDINGS

These tumors are usually small (25% of the myometrial thickness. I pre­fer the latter approach (>25%) as it is more precise; the thickness of the uterine wall varies greatly among women and an absolute estimation can be inaccurate. Endomyometrial resections performed for refractory dysmenorrhea or abnormal bleeding usually contain myometrium. In addition, myometrial tissue may be present in an endometrial curettage. The pathologist should refrain from making the diagnosis of adenomyosis in these samples because the lack of orientation of the fragmented tissue precludes

GYNECOLOGIC PATHOLOGY

assessment of the endomyometrial junction. Of note, marked irregularity of the junction seen in these specimens has been associated with subsequent ablation failure and persistent symptoms leading to hysterectomy. In most cases, glands and stroma are present in all or most of the adenomyotic foci. In reproductive-age women, the physiologic changes in the endometrium corresponding to the menstrual cycle can also be observed in adenomyosis, although the changes are often attenuated or asynchronous. The diagnosis is more difficult when the foci are mostly or solely composed of stroma (“gland-poor adenomyosis”). This type of adenomyosis tends to be asymptomatic and focal in extent rather than diffuse. In addition, adenomyosis can be found within the blood vessel walls or inside lymphatic and vascular spaces (“intravascular adenomyomatosis”). The myometrium surrounding adenomyotic foci usually displays variable degrees of concentric hypertrophy.

DIFFERENTIAL DIAGNOSIS Adenomyosis and adenomyoma are related lesions with likely shared pathogenesis. The distinction between the two lies in the focality and nodular growth of the latter. The stromal component of adenomyosis can occasionally be very attenuated or even absent (“stroma-poor adenomyosis). In this scenario, the possibility

FIG. 11.49 Adenomyosis. Endometrial glands surrounded by endometrial stroma, haphazardly distributed throughout the myometrium.

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CHAPTER 11  Mesenchymal and Miscellaneous Lesions of the Uterus

of myo-invasive endometrial endometrioid carcinoma should be considered; generous sampling of the endometrium may be required to exclude the possibility of an endometrial glandular malignancy. Gland-poor and intravascular adenomyosis requires distinction from low-grade endometrial stromal sarcoma. The latter shows a haphazard infiltration of the myometrium highly resembling adenomyosis; however, it is comprised of expansile, finger-like projections with a very uniform small-caliber vasculature, and the concentric hypertrophy of the surrounding myometrium (typical of adenomyosis) will be absent. In difficult instances, molecular testing for endometrial stromal sarcoma-related translocations may be helpful.

PROGNOSIS AND TREATMENT If untreated, symptomatic adenomyosis is a chronic, potentially debilitating disease leading to chronic pain and anemia. Furthermore, it causes infertility and negatively affects assisted reproduction (e.g., in vitro fertilization) outcomes. It is also associated with obstetric complications such as preterm birth and premature rupture of membranes. Definitive treatment of adenomyosis requires hysterectomy. Medical management with analgesics and suppressive hormonal treatments (oral contraceptives, high-dose progestins, selective hormone receptor modulators, levonorgestrel-releasing intrauterine device, and aromatase inhibitors) can be used with variable symptomatic response and lesion regression on imaging.

ADENOMYOSIS—FACT SHEET Definition n  Presence of endometrial glands and/or stroma within myometrium (>25% of wall thickness) Incidence n Common (20%–35% hysterectomies) n  More common (up to ∼50%) if refractory menorrhagia and ablation failure Age Distribution n Premenopausal and perimenopausal women (20% 90% are spindle cell leiomyosarcomas; other variants have been reported. n Diagnosed using same criteria as uterine leiomyosarcoma Differential Diagnosis n Leiomyoma n Low-grade endometrioid stromal sarcoma n Gastrointestinal stromal tumor

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CHAPTER 12  Diseases of the Fallopian Tube and Broad Ligament

FIG. 12.38 Ependymoma of the broad ligament. These are comprised of cells with abundant eosinophilic cytoplasm oriented toward vascular structures.

nn EPENDYMOMA OF THE BROAD LIGAMENT CLINICAL FEATURES Ependymoma of the broad ligament is a very rare tumor that shows ependymal differentiation and which is broadly similar to comparable tumors in the central nervous system. The mean patient age is 38 years (range 13–48 years), and patients typically present with a pelvic mass or abdominopelvic pain.

PATHOLOGIC FEATURES GROSS FEATURES

Ependymomas are solid or multicystic, multilobulated tumors of varying sizes. They usually have a soft friable consistency, frequently with patchy hemorrhage and necrosis. MICROSCOPIC FEATURES

These tumors are similar in appearance to their counterparts in the central nervous system. They are composed

of papillae, closely packed tubules, and solid growth. The papillae and tubules are lined by flat to columnar ciliated cells with central to apical, round to elongated nuclei (Fig. 12.38). True perivascular rosettes, psammoma bodies, and small nodules of mature cartilage may be present. A subset shows distinct myxoid stroma (the so-called myxopapillary variant).

DIFFERENTIAL DIAGNOSIS These tumors can be confused with serous carcinomas because both may display papillary architecture and psammoma bodies and both may be immunoreactive for glial fibrillary acid protein. However, unlike HGSCs, ependymomas show true perivascular rosettes and are negative for CK7, PAX8, and WT1.

PROGNOSIS AND THERAPY Ependymomas have metastatic potential and long-term recurrences may occur. However, there is insufficient information to predict the behavior of an individual case.

540 EPENDYMOMA—FACT SHEET Definition n  Tumor showing ependymal differentiation, broadly similar to morphologically comparable tumors of central nervous system Incidence n Very rare Race and Age Distribution n Race distribution: unknown n Age distribution: 13–48 years Clinical Features n Presentation: pelvic mass or abdominopelvic pain Prognosis and Treatment n Unknown; may metastasize or show long-term recurrences n Primary treatment: no data

GYNECOLOGIC PATHOLOGY McComb, P. F., & Rowe, T. C. (1989). Salpingitis isthmica nodosa: evidence it is a progressive disease. Fertility and Sterility, 51, 542– 545. Punnonen, R., & Soderstrom, K. O. (1986). Inflammatory etiology of salpingitis isthmica nodosa: a clinical, histological and ultrastructural study. Acta Europaea Fertilitatis, 17, 199–203. Skibsted, L., Sperling, L., Hansen, U., et al. (1991). Salpingitis isthmica nodosa in female infertility and tubal diseases. Human Reproduction, 6, 828–831. Torsion Bernardus, R. E., Van der Slikke, J. W., Roex, A. J. M., et al. (1984). Torsion of the fallopian tube: some considerations on its etiology. Obstetrics & Gynecology, 64, 675. Chambers, J. T., Thiagarajah, S., & Kitchin, J. D., III. (1979). Torsion of the normal fallopian tube in pregnancy. Obstetrics & Gynecology, 54, 487–489. Gold, M. A., Schmidt, R. R., Parks, N., et al. (1997). Bilateral absence of the ovaries and distal fallopian tubes. A case report. Journal of Reproductive Medicine, 42, 375–377. Hibbard, L. T. (1985). Adnexal torsion. American Journal of Obstetrics and Gynecology, 152, 456–461. Tubal Pregnancy

EPENDYMOMA—PATHOLOGIC FEATURES Gross Findings n Solid, multicystic, and multilobulated n Soft, friable consistency Microscopic Findings n Papillae, closely packed tubules, and solid growth n Cells with abundant eosinophilic cytoplasm, cilia n True perivascular rosettes and psammoma bodies Differential Diagnosis n Serous carcinoma

SUGGESTED READING Metaplasias Wong, A. K., Seidman, J. D., Barbuto, D. A., et al. (2011). Mucinous metaplasia of the fallopian tube: a diagnostic pitfall mimicking metastasis. International Journal of Gynecological Pathology, 30(1), 36–40. Seidman, J. D. (1994). Mucinous lesions of the fallopian tube. A report of seven cases. The American Journal of Surgical Pathology, 18(12), 1205–1212. Rabban, J. T., Vohra, P., & Zaloudek, C. J. (2015). Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. The American Journal of Surgical Pathology, 39(1), 35–51. Salpingitis Isthmica Nodosa Bolaji, II, Oktaba, M., Mohee, K., et al. (2015). An odyssey through salpingitis isthmica nodosa. European Journal of Obstetrics & Gynecology and Reproductive Biology, 184, 73–79. Jenkins, C. S., Williams, S. R., & Schmidt, G. E. (1993). Salpingitis isthmica nodosa: a review of the literature, discussion of clinical significance, and consideration of patient management. Fertility and Sterility, 60, 599–607.

Bickell, N. A., Bodian, C., Anderson, R. M., et al. (2004). Time and the risk of ruptured tubal pregnancy. Obstetrics & Gynecology, 104, 789–794. Budowick, M., Johnson, T. R., Genadry, R., et al. (1980). The histopathology of the developing tubal ectopic pregnancy. Fertility and Sterility, 34, 169–171. Jacques, S. M., Qureshi, F., Ramirez, N. C., et al. (1997). Retained trophoblastic tissue in fallopian tubes: a consequence of unsuspected ectopic pregnancies. International Journal of Gynecological Pathology, 16, 219–224. Pauerstein, C. J., Croxatto, H. B., Eddy, C. A., et al. (1986). Anatomy and pathology of tubal pregnancy. Obstetrics & Gynecology, 67, 301–308. Tubal Endometriosis Donnez, J., Casanas-Roux, F., Ferin, J., et al. (1984). Tubal polyps, epithelial inclusions, and endometriosis after tubal sterilization. Fertility and Sterility, 41, 564–568. Kuzela, D. C., & Speers, W. C. (1985). Heterotopic endometrium of the fallopian tube. Fertility and Sterility, 44, 552–553. Stock, R. J. (1982). Postsalpingectomy endometriosis: a reassessment. Obstetrics & Gynecology, 60, 560–570. Florid Epithelial Hyperplasia Cheung, A. N., Young, R. H., & Scully, R. E. (1994). Pseudocarcinomatous hyperplasia of the fallopian tube associated with salpingitis. A report of 14 cases. The American Journal of Surgical Pathology, 18, 1125–1130. Limaiem, F., Chelly, I., Mekni, A., et al. (2010). Challenging diagnosis: florid epithelial hyperplasia versus adenocarcinoma of the fallopian tube. Pathology, 42(1), 99–101. Roboy, S. S., & Silva, E. G. (1989). Epithelial hyperplasia of the fallopian tube. Its association with serous borderline tumors of the ovary. International Journal of Gynecological Pathology, 8, 214– 220. Yanai-Inbar, I., & Silverberg, S. G. (2000). Mucosal epithelial proliferation of the fallopian tube: prevalence, clinical associations, and optimal strategy for histopathologic assessment. International Journal of Gynecological Pathology, 19(2), 139–144. Infectious Nongranulomatous Salpingitis Jaiyeoba, O., & Soper, D. E. (2011). A practical approach to the diagnosis of pelvic inflammatory disease. Infectious Diseases in Obstetrics and Gynecology, 2011, 753037.

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CHAPTER 12  Diseases of the Fallopian Tube and Broad Ligament Kiviat, N. B., Wølner-Hanssen, P., Eschenbach, D. A., et al. (1990). Endometrial histopathology in patients with culture-proved upper genital tract infection and laparoscopically diagnosed acute salpingitis. The American Journal of Surgical Pathology, 14(2), 167–175. Mardh, P. A. (2004). Tubal factor infertility with special regard to chlamydial salpingitis. Current Opinion in Infectious Diseases, 17, 49–52. Mitchell, C., & Prabhu, M. (2013). Pelvic inflammatory disease: current concepts in pathogenesis, diagnosis and treatment. Infect Dis Clin North Am, 27(4), 793–809. Paavonen, J., Teisala, K., Heinonen, P. K., et al. (1987 May). Microbiological and histopathological findings in acute pelvic inflammatory disease. British Journal of Obstetrics and Gynaecology, 94(5), 454–460. Soper, D. E., Brockwell, N. J., Dalton, H. P., et al. (1994). Observations concerning the microbial etiology of acute salpingitis. American Journal of Obstetrics and Gynecology, 170, 1008–1017.

Metaplastic Papillary Tumor

Granulomatous Salpingitis

Alvarado-Cabrero, I., Navani, S. S., Young, R. H., & Scully, R. E. (1997). Tumors of the fimbriated end of the fallopian tube: a clinicopathologic analysis of 20 cases, including nine carcinomas. International Journal of Gynecological Pathology, 16, 189–196. Choi, S. M., Choi, M. Y., Kang, W. D., Choi, H. S., & Kim, S. M. (2014). Serous borderline tumor of the fallopian tube. Obstet Gynecol Sci, 57(4), 334–337. Zheng, W., Wolf, S., Kramer, E. E., Cox, K. A., & Hoda, S. A. (1996). Borderline papillary serous tumour of the fallopian tube. The American Journal of Surgical Pathology, 20, 30–35.

Bahrami, S., Alatassi, H., Slone, S. P., et al. (2006). Tubal gestation and schistosomiasis: a case report. Journal of Reproductive Medicine, 51(7), 595–598. Goel, M. M., Budhwar, P., & Jain, A. (2012). Immunocytochemistry versus nucleic acid amplification in fine needle aspirates and tissues of extrapulmonary tuberculosis. Journal of Cytology, 29(3), 157–164. Nogales-Ortíz, F., Tarancon, II, & Nogales, F. F. (1979). The pathology of female genital tuberculosis. Obstetrics & Gynecology, 53, 422–428. Park, D. Y., Kim, J. Y., Choi, K. U., et al. (2003). Comparison of polymerase chain reaction with histopathologic features for diagnosis of tuberculosis in formalin-fixed, paraffin-embedded histologic specimens. Archives of Pathology & Laboratory Medicine, 127(3), 326–330. Actinomycotic Salpingitis Evans, D. T. (1993). Actinomyces israelii in the female genital tract: a review. Genitourinary Medicine, 69(1), 54–59. Goodman, H. M., Tuomala, R. E., & Leavitt, T., Jr. (1986). Actinomycotic pelvic inflammatory disease simulating malignancy. Journal of Reproductive Medicine, 31, 625–628. Munjal, K., Nandedkar, S., Subedar, V., et al. (2010). Tubo-ovarian actinomycosis mimicking as ovarian malignancy: report of three cases. Indian Journal of Pathology & Microbiology, 53(4), 870–871. Pusiol, T., Morichetti, D., Pedrazzani, C., & Ricci, F. (2011). Abdominal-pelvic actinomycosis mimicking malignant neoplasm. Infectious Diseases in Obstetrics and Gynecology, 2011, 747059. Yoonesi, M., Crickard, K., Cellini, I. S., et al. (1985). Association of actinomyces and intrauterine contraceptive devices. Journal of Reproductive Medicine, 30, 48–52. Adenomatoid Tumor Goode, B., Joseph, N. M., Stevers, M., et al. (2018). Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. Modern Pathology, 31, 660–673. Ragins, A. B., & Crane, R. D. (1948). Adenomatoid tumors of the fallopian tube. American Journal Of Pathology, 24, 933–945. Sangoi, A. R., McKenney, J. K., Schwartz, E. J., Rouse, R. V., & Longacre, T. A. (2009). Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases. Modern Pathology, 22, 1228–1235. Skinnider, B. F., & Young, R. H. (2004). Infarcted adenomatoid tumor: a report of five cases of a facet of a benign neoplasm that may cause diagnostic difficulty. The American Journal of Surgical Pathology, 28, 77–83. Srigley, J. R., & Colgan, T. J. (1988). Multifocal and diffuse adenomatoid tumor involving uterus and fallopian tube. Ultrastructural Pathology, 12, 351–355. Youngs, L. A., & Taylor, H. B. (1967). Adenomatoid tumors of the uterus and fallopian tube. American Journal of Clinical Pathology, 48, 537–545.

Jang, M. I., Sung, J. Y., Kim, J. Y., & Kim, H. S. (2017). Clinicopathological characteristics of metaplastic papillary tumor of the fallopian tube. Anticancer Research, 37, 3693–3701. Saffos, R. O., Rhatigan, R. M., & Scully, R. E. (1980). Metaplastic papillary tumor of the fallopian tube—a distinctive lesion of pregnancy. American Journal of Clinical Pathology, 74, 232–236. Adenofibroma Bossuyt, V., Medeiros, F., Drapkin, R., Folkins, A. K., Crum, C. P., & Nucci, M. R. (2008). Adenofibroma of the fimbria: a common entity that is indistinguishable from ovarian adenofibroma. International Journal of Gynecological Pathology, 27, 390–397. Serous Borderline Tumor of the Fallopian Tube

Endometrioid Carcinoma of the Fallopian Tube Alvarado-Cabrero, I., Stolnicu, S., Kiyokawa, T., Yamada, K., Nikaido, T., & Santiago-Payán, H. (2013). Carcinoma of the fallopian tube: results of a multi-institutional retrospective analysis of 127 patients with evaluation of staging and prognostic factors. Annals of Diagnostic Pathology, 17, 159–164. Culton, L. K., Deavers, M. T., Silva, E. G., Liu, J., & Malpica, A. (2006). Endometrioid carcinoma simultaneously involving the uterus and the fallopian tube: a clinicopathologic study of 13 cases. The American Journal of Surgical Pathology, 30, 844–849. Daya, D., Young, R. H., & Scully, R. E. (1992). Endometrioid carcinoma of the fallopian tube resembling an adnexal tumor of probable wolffian origin: a report of six cases. International Journal of Gynecological Pathology, 11, 122–130. Navani, S. S., Alvarado-Cabrero, I., Young, R. H., & Scully, R. E. (1996). Endometrioid carcinoma of the fallopian tube: a clinicopathologic analysis of 26 cases. Gynecologic Oncology, 63, 371–378. Rabczyński, J., & Ziółkowski, P. (1999). Primary endometrioid carcinoma of fallopian tube. Clinicomorphologic study. Pathology and Oncology Research, 5, 61–66. Carcinosarcoma of the Fallopian Tube DeQuerioz, A. C., & Roth, L. M. (1970). Malignant mixed müllerian tumor of the fallopian tube: report of a case. Obstetrics & Gynecology, 36, 554–557. Yokoyama, Y., Yokota, M., Futagami, M., & Mizunuma, H. (2012). Carcinosarcoma of the fallopian tube: report of four cases and review of literature. Asia-Pacific Journal of Clinical Oncology, 8(3), 303–311. Other Primary Tubal Carcinomas Alvarado-Cabrero, I., Stolnicu, S., Kiyokawa, T., Yamada, K., Nikaido, T., & Santiago-Payán, H. (2013). Carcinoma of the fallopian tube: results of a multi-institutional retrospective analysis of 127 patients with evaluation of staging and prognostic factors. Annals of Diagnostic Pathology, 17, 159–164. Alvarado-Cabrero, I., Young, R. H., Vamvakas, E. C., & Scully, R. E. (1999). Carcinoma of the fallopian tube: a clinicopathological study of 105 cases with observations on staging and prognostic factors. Gynecologic Oncology, 72, 367–379.

542 Grondin, K., Lidang, M., Boenelycke, M., et al. (2019). Neuroendocrine tumors of the fallopian tube: report of a case series and review of the literature [published online a head of print October 10, 2017]. International Journal of Gynecological Pathology, 38(1), 78–84. Kim, K. M., Cho, D. H., Chu, H. H., et al. (2015). Combined serous carcinoma and neuroendocrine carcinoma of the fallopian tube. Pathology, 47, 711–714. Liang, S. X., Brandler, T. C., Contreras, D., et al. (2015). A rare case of invasive mucinous adenocarcinoma of fallopian tube fimbria with metastasis to ipsilateral ovary, uterine serosa, myometrium and pelvis: case report and review of literature. Human Pathology: Case Reports, 2, 27–35. Magrill J, Karnezis AN, Tessier-Cloutier B, et al. Tubo-ovarian transitional cell carcinoma and high-grade serous carcinoma show subtly different immunohistochemistry profiles [published online ahead of print July 27, 2017]. International Journal of Gynecological Pathology. https://10.1097/PGP.0000000000000538. Malak, M., & Klam, S. (2015). Primary fallopian tube clear cell adenocarcinoma in pregnancy: case presentation and review of the literature. Case Rep Obstet Gynecol, 2015, 183243. Wheal, A., Jenkins, R., Mikami, Y., Das, N., & Hirschowitz, L. (2017). Primary mucinous carcinoma of the fallopian tube: case report and review of literature. International Journal of Gynecological Pathology, 36, 393–399. Metastatic Tumors to the Fallopian Tube Na, K., & Kim, H. S. (2017). Clinicopathological characteristics of fallopian tube metastases from primary endometrial, cervical, and nongynecological malignancies: a single institutional experience. Virchows Archiv, 471, 363–373. Rabban, J. T., Vohra, P., & Zaloudek, C. J. (2015). Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. The American Journal of Surgical Pathology, 39, 35–51. Sarcoma of the Fallopian Tube Xia, L. F., Ye, S., Shen, X. X., Tang, J., Yang, H. J., & Huang, Y. (2018). Primary leiomyosarcoma of the fallopian tube: three case reports and review of the literature. Taiwanese Journal of Obstetrics & Gynecology, 57, 456–461. You, D., Wang, Q., Jiang, W., et al. (2018). Primary leiomyosarcoma of the fallopian tube: a case report and literature review. Medicine (Baltimore), 97(17), e0536. Zagouri, F., Dimopoulos, M. A., Thomakos, N., Chrysikos, D., & Papadimitriou, C. A. (2011). Sarcomas of the fallopian tube: disentangling a rare entity. Onkologie, 34, 132–138. Cysts of the Broad Ligament and Paraovarian Region Genadry, R., Parmley, T., & Woodruff, J. D. (1977). The origin and clinical behavior of the parovarian tumor. American Journal of Obstetrics and Gynecology, 129, 873–880. Samaha, M., & Woodruff, J. D. (1985). Paratubal cysts: frequency, histogenesis, and associated clinical features. Obstetrics & Gynecology, 65, 691–694. Varras, M., Akrivis, C., Polyzos, D., Frakala, S., & Samara, C. (2003). A voluminous twisted paraovarian cyst in a 74-year-old patient: case report and review of the literature. Clinical & Experimental Obstetrics & Gynecology, 30, 253–256. Female Adnexal Tumor of Probable Wolffian Origin (FATWO) Devouassoux-Shisheboran, M., Silver, S. A., & Tavassoli, F. A. (1999). Wolffian adnexal tumor, so-called female adnexal tumor of probable wolffian origin (FATWO): immunohistochemical evidence in support of a wolffian origin. Human Pathology, 30, 856–863. Daya, D. (1994). Malignant female adnexal tumor of probable wolffian origin with review of the literature. Archives of Pathology & Laboratory Medicine, 118, 310–312.

GYNECOLOGIC PATHOLOGY Heatley, M. K. (2009). Is female adnexal tumour of probable wolffian origin a benign lesion? A systematic review of the English literature. Pathology, 41, 645–648. Heller, D. S., Kadire, B., & Cracchiolo, B. (2011). Malignant female adnexal tumor of probable wolffian origin: a case report. Journal of Reproductive Medicine, 56, 175–177. Kariminejad, M. H., & Scully, R. E. (1973). Female adnexal tumor of probable wolffian origin. A distinctive pathologic entity. Cancer, 31, 671–677. Mirkovic, J., Dong, F., Sholl, L. M., et al. (2019). Targeted genomic profiling of female adnexal tumors of probable wolffian origin (FATWO). International Journal of Gynecological Pathology, 38, 543–551. Papillary Cystadenoma of the Broad Ligament Aydin, H., Young, R. H., Ronnett, B. M., & Epstein, J. I. (2005). Clear cell papillary cystadenoma of the epididymis and mesosalpinx: immunohistochemical differentiation from metastatic clear cell renal cell carcinoma. The American Journal of Surgical Pathology, 29, 520–523. Brady, A., Nayar, A., Cross, P., et al. (2012). A detailed immunohistochemical analysis of 2 cases of papillary cystadenoma of the broad ligament: an extremely rare neoplasm characteristic of patients with von Hippel–Lindau disease. International Journal of Gynecological Pathology, 31, 133–140. Cox, R., Vang, R., & Epstein, J. I. (2014). Papillary cystadenoma of the epididymis and broad ligament: morphologic and immunohistochemical overlap with clear cell papillary renal cell carcinoma. The American Journal of Surgical Pathology, 38, 713–718. Nogales, F. F., Goyenaga, P., Preda, O., et al. (2012). An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type. Histopathology, 60, 748–757. Serous Borderline Tumor of the Broad Ligament Aslani, M., Ahn, G. H., & Scully, R. E. (1988). Serous papillary cystadenoma of borderline malignancy of broad ligament. A report of 25 cases. International Journal of Gynecological Pathology, 7, 131–138. Chandraratnam, E., & Leong, A. S. (1983). Papillary serous cystadenoma of borderline malignancy arising in a parovarian paramesonephric cyst. Light microscopic and ultrastructural observations. Histopathology, 7, 601–611. d’Ablaing, G., 3rd, Klatt, E. C., DiRocco, G., & Hibbard, L. T. (1983). Broad ligament serous tumor of low malignant potential. International Journal of Gynecological Pathology, 2, 93–99. Jensen, M. L., & Nielsen, M. N. (1989). Broad ligament mucinous and serous cystadenomas of borderline malignancy. Acta Obstetricia et Gynecologica Scandinavica, 68, 663–667. Loverro, G., Cormio, G., Renzulli, G., Lepera, A., Ricco, R., & Selvaggi, L. (1997). Serous papillary cystadenoma of borderline malignancy of the broad ligament. European Journal of Obstetrics & Gynecology and Reproductive Biology, 74, 211–213. Pather, S., Won, H., & Carter, P. J. (2011). A borderline serous broad ligament tumour complicating pregnancy. J Obstet Gynaecol, 31, 350–351. Carcinoma of the Broad Ligament Czernobilsky, B., & Lancet, M. (1972). Broad ligament adenocarcinoma of Müllerian origin. Obstetrics & Gynecology, 40, 238–242. Gardner, G. H., Greene, R. R., & Peckham, B. (1957). Tumors of the broad ligament. American Journal of Obstetrics and Gynecology, 73, 536–554; discussion, 554–555. Miyoshi, A., Miyatake, T., Hara, T., et al. (2016). Rare primary adenocarcinoma of the broad ligament: report of two cases and a literature review. International Journal of Surgical Pathology, 24, 436–442. Rojansky, N., Ophir, E., Sharony, A., Spira, H., & Suprun, A. (1985). Broad ligament adenocarcinoma: its origins and clinical behavior. A literature review and report of a case. Obstetrical and Gynecological Survey, 40, 665–671. 

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CHAPTER 12  Diseases of the Fallopian Tube and Broad Ligament Leiomyomas of the Broad Ligament Gowri, V., Sudheendra, R., Oumachigui, A., & Sankaran, V. (1992). Giant broad ligament leiomyoma. International Journal of Gynaecology & Obstetrics, 37, 207–210. Patel, V., Xing, D., Feely, M., Schoolmeester, J. K. (2019). Smooth muscle tumors of the visceral adnexal and uterine ligaments and adnexal connective tissue: a clinicopathologic study of 67 cases. International Journal of Gynecological Pathology. https://10.1097/ PGP.0000000000000578. Advanced Online Publication. PMID: 30702465. Sharma, P., Zaheer, S., Yadav, A. K., & Mandal, A. K. (2016). Massive broad ligament cellular leiomyoma with cystic change: a diagnostic dilemma. Journal of Clinical and Diagnostic Research, 10, ED01–ED02. Smith, C. C., Gold, M. A., Wile, G., & Fadare, O. (2012). Cotyledonoid dissecting leiomyoma of the uterus: a review of clinical, pathological, and radiological features. International Journal of Surgical Pathology, 20, 330–341. Leiomyosarcoma of the Broad Ligament Chaichian, S., Mehdizadehkashi, A., Tahermanesh, K., et al. (2016). Leiomyosarcoma of the broad ligament with fever presentation: a case report and review of literature. Iranian Red Crescent Medical Journal, 18, e33892. Murialdo, R., Usset, A., Guido, T., Carli, F., Boccardo, F., & Amoroso, D. (2005). Leiomyosarcoma of the broad ligament: a case report and review of literature. International Journal of Gynecological Cancer, 15, 1226–1229. Embryonic Rests and Other Miscellaneous Lesions of the Broad Ligament Adashi, E. Y., Rosenshein, N. B., Parmley, T. H., & Woodruff, J. D. (1980). Histogenesis of the broad ligament adrenal rest. International Journal of Gynaecology & Obstetrics, 18 102–110-4.

Nechi, S., Znaidi, N., Rammah, S., M’farej, M. K., & Zermani, R. (2013). Uterus-like mass of the broad ligament. International Journal of Gynaecology & Obstetrics, 123, 249–250. Samaha, M., & Woodruff, J. D. (1985). Paratubal cysts: frequency, histogenesis, and associated clinical features. Obstetrics & Gynecology, 65, 691–694. Whitehouse, H. B. (1926). Endometrioma between the layers of the broad ligament. Proceedings of the Royal Society of Medicine, 19 (Obstet Gynaecol Sect), 16. Zaarour, M. G., Atallah, D. M., Trak-Smayra, V. E., & Halaby, G. H. (2014). Bilateral ovary adrenal rest tumor in a congenital adrenal hyperplasia following adrenalectomy. Endocrine Practice, 20, e69–e74. Ependymoma of the Broad Ligament Bell, D. A., Woodruff, J. M., & Scully, R. E. (1984). Ependymoma of the broad ligament. A report of two cases. The American Journal of Surgical Pathology, 8, 203–209. Duggan, M. A., Hugh, J., Nation, J. G., Robertson, D. I., & Stuart, G. C. (1989). Ependymoma of the uterosacral ligament. Cancer, 64, 2565–2571. Idowu, M. O., Rosenblum, M. K., Wei, X. J., Edgar, M. A., & Soslow, R. A. (2008). Ependymomas of the central nervous system and adult extra-axial ependymomas are morphologically and immunohistochemically distinct—a comparative study with assessment of ovarian carcinomas for expression of glial fibrillary acidic protein. The American Journal of Surgical Pathology, 32, 710–718.

13 Nonneoplastic Lesions of the Ovary nn Teri A. Longacre and C. Blake Gilks

The ovary is a solid organ composed of (1) surface epithelium, an extension of the pelvic peritoneum; (2) the cortex, composed of cellular stroma, follicular units (comprised of a central oocyte surrounded by granulosa and theca cells), corpora lutea, and corpora albicantia; and (3) the medulla, composed of large vessels that merge in to the ovarian hilum, which is the point of attachment of the ovarian vessels (artery and vein) and the broad ligament. These compartments harbor elements that can be confused with benign and malignant epithelial lesions, including the following:    Endosalpingiosis: benign cortical glandular elements with tubal differentiation, including ciliated, nonciliated, and peg cells. When cystic, denominated Müllerian inclusion cysts (described later). Peritoneal inclusions: benign cortical elements lined by flat to low cuboidal bland epithelium. When cystic, denominated peritoneal inclusion cysts (described later). Rete ovarii: embryologic equivalent of the rete testis, seen in the hilar portion of the ovary as an area of compressed and irregularly shaped glandular structures with narrow lumens and low cuboidal bland    epithelium (Fig. 13.1). Nonneoplastic lesions of the ovary may be entirely asymptomatic incidental findings identified on gross or microscopic examination of the ovary, or they may be associated with a pelvic mass, pain, or manifestations of abnormal hormonal regulation. Many occur during the reproductive years and may be associated with infertility. They are an important category in neonates, children, and reproductive-aged women, and should always be considered in the differential diagnosis of cystic masses at this site.

nn CYSTS OF FOLLICULAR ORIGIN Solitary ovarian cysts of follicular origin occur at three different age peaks: neonates (rare after 6 months of age), around menarche (often associated

with endocrine manifestations) and in perimenopause but may occur anytime during reproductive age as a transient physiologic finding. In neonates, the cysts are thought to develop secondary to in utero stimulation by maternal hormones. Multiple follicular cysts associated with sclerosis of the superficial cortical stroma (sclerocystic ovaries) are usually indicative of chronic anovulation. Multiple follicular cysts secondary to excess of gonadotropins (hyperreactio luteinalis or ovarian hyperstimulation syndrome) are discussed later in this chapter, under the heading “Pregnancy-Associated Changes.” In contrast to follicular cysts, luteal cysts are much less frequent and typically occur in reproductive-age women as the normal corpus luteum undergoes hemorrhage and involution.

CLINICAL FEATURES Solitary follicular cysts are usually an incidental finding; when persistent, they may cause symptoms secondary to a pelvic mass and are typically excised to exclude malignancy. Acute abdominal pain secondary to torsion, with or without hemoperitoneum, may occur, particularly in neonates, although most follicular cysts that occur during the neonatal period regress within the first 6 months. Occasionally, follicular cysts may be associated with manifestations of excess estrogen production (isosexual pseudoprecocity in children or irregular menses related to disordered proliferative endometrium and/or endometrial hyperplasia in women of reproductive age). Postpubertal women with cystic fibrosis may have a predisposition to developing solitary follicular cysts. Multiple follicular cysts are part of the spectrum of abnormalities seen in polycystic ovary syndrome (PCOS), a common disorder characterized by hyperandrogenism of ovarian origin resulting in virilization, infertility, obesity, and insulin resistance (Stein–Leventhal syndrome). Only up to 10% of women with polycystic ovaries have clinical manifestations. A family history is common, but the genetic factors in this disease are poorly understood. 545

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FIG. 13.1 Rete ovarii. Microscopic focus of compressed glands lined by simple epithelium, located in the ovarian hilum.

The most common etiology is insulin resistance of peripheral tissue and/or an abnormality of the hypothalamic– pituitary–ovarian axis. The findings of multiple ovarian cysts associated with cortical sclerosis, although part of the spectrum of PCOS, is not specific and can be seen in other causes of chronic anovulation; therefore, clinical and biochemical assessment is required for this diagnosis. Solitary or multiple follicular cysts may also occur in association with McCune–Albright syndrome (polyostotic fibrous dysplasia, cutaneous melanin pigmentation, and endocrine organ hyperactivity) and in prepubertal patients with hypothyroidism. Cystic corpora lutea are a frequent finding in residual ovarian tissue in the setting of ovarian remnant syndrome. They may manifest as menstrual irregularities and rarely hematoperitoneum.

in diameter (but usually 3 cm.

Corpora lutea cysts have undulating contours and show prominent luteinization of granulosa and, to a lesser extent, theca interna cells (Fig. 13.7). In ovaries removed from patients with PCOS, there is prominent sclerosis of the superficial cortex, visible as a pale rim of heavily collagenized stroma underlying the surface epithelium, associated with multiple relatively uniformly sized and evenly spaced follicular cysts (Fig. 13.8). Usually, the theca interna is thicker than in a normal follicle and the theca cells often appear luteinized. The granulosa cell layer may be of variable thickness, but it is typically not luteinized. Evidence of prior ovulation (e.g., corpora albicantia or lutea) is sparse. It is also common to find increased numbers of hilar cells.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

The granulosa and theca cells are positive for inhibin, calretinin, and SF-1.

MOLECULAR ANALYSIS

Normal and cystic follicles do not harbor mutations in FOXL2.

DIFFERENTIAL DIAGNOSIS The chief differential diagnosis is with epithelial cysts, particularly when the lining is partially denuded. The most helpful features in establishing the diagnosis of a follicular cyst are the findings of surrounding theca cells, the stratification of round nuclei devoid of significant cytoplasm, and the lack of cilia. Cystic struma ovarii may also mimic a follicular cyst but will typically show small follicles, which may contain eosinophilic colloid within the wall. Immunohistochemistry can be used in difficult cases as epithelial cells are positive for epithelial membrane antigen and negative for inhibin; cystic struma is positive for TTF1 and thyroglobulin. Solitary follicular cysts must also be distinguished from unilocular cystic granulosa cell tumors, which are typically larger and have a thicker granulosa cell lining (average 10 cells

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A

B FIG. 13.3 Corpus luteum cyst. The cyst shows an orange-brown cut surface with central hemorrhage (A). An established corpus luteum cyst may show a yellow rim of variable thickness which delineates the wall (B).

CHAPTER 13  Nonneoplastic Lesions of the Ovary

FIG. 13.4 Polycystic ovary syndrome. The ovaries are enlarged bilaterally due to multiple follicle cysts and expanded stroma. Note normal-sized ovaries in the middle for comparison. (Courtesy Dr. Michael Hendrickson.)

FIG. 13.5 Follicular cyst. The cyst is lined by several layers of granulosa cells and luteinized theca cells.

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GYNECOLOGIC PATHOLOGY

B

FIG. 13.6 Follicular cyst. Torsion results in secondary infarction, fibrin deposition, and calcification (A). High-power scrutiny reveals ghost structures including primary follicles (B).

FIG. 13.7 Corpus luteum cyst. It is distinguished from a follicular cyst by its undulating contour and marked luteinization of the granulosa cells.

thick), which sometimes displays papillary or microfollicular patterns (the former with fibrous cores, the latter with Call-Exner bodies). An important pitfall to keep in mind is that cystic granulosa cell tumors can have luteinized theca cells at the periphery, although most

often the wall of the cyst is composed of fibrous tissue. Sampling of the adjacent parenchyma is important, as it may reveal more typical areas of granulosa cell tumor. In difficult cases, the presence of a FOXL2 mutation will be confirmatory of adult-type granulosa cell tumor.

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CYSTS OF FOLLICULAR ORIGIN—FACT SHEET Definition n  Physiologic (functional) follicle cyst or corpus luteum cyst measuring >3 cm (smaller lesions arbitrarily designated as “cystic follicles”) Incidence and Location n  Common, especially during neonatal ( storiform) rather than edematous background (Fig. 13.23A,B). Ovarian fibroma with marked edema and sclerosing stromal tumor typically form a discrete mass and do not have normal ovarian follicular structures within the tumor. Metastatic signet-ring cell carcinoma (Krukenberg tumor) is an important differential diagnostic consideration of massive ovarian edema, as both lesions appear solid and glistening macroscopically, and the malignant population of the former can be scant and easily missed on scanning magnification. The cut surface of metastatic carcinoma is often multinodular, and at high magnification signet-ring cells are identified, either individually or in clusters.

Clinical Features n Abdominal pain n  Virilization including hirsutism and, rarely, precocious pseudopuberty Prognosis and Treatment n Ovarian suspension and fixation n Excision if secondary torsion

MASSIVE OVARIAN EDEMA—PATHOLOGIC FEATURES Gross Findings n Enlarged ovary: 5.5–35 (mean 11.5) cm n Smooth surface and watery cut section Microscopic Findings n  Striking stromal edema separating ovarian stroma, in areas with pseudocyst formation n Spatially separated follicles and preexisting structures n Aggregates of luteinized cells (40%) in stroma n Recent hemorrhage frequent n Dilated vessels in ovarian hilum Differential Diagnosis n Ovarian fibromatosis n Fibroma with marked edema n Sclerosing stromal tumor n Metastatic signet-ring carcinoma (Krukenberg tumor)

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nn CORTICAL INCLUSION CYSTS Surface cortical inclusion cysts are thought to represent entrapment of epithelial elements within the ovarian cortex after disruption of the surface during ovulation. They are categorized as follows:    1. Peritoneal type: originate from the surface epithelium (an extension of the peritoneal surface) 2. Müllerian type: originate from entrapped Müllerian    elements, most likely from the distal fallopian tube

CLINICAL FEATURES

A

They most commonly are encountered in postmenopausal women but can also be seen in ovaries of children and women of reproductive age. They are typically asymptomatic.

PATHOLOGIC FEATURES GROSS FINDINGS

Although uncommonly visualized grossly, small cysts 3:1 variability)

Chromatin

Evenly distributed

Irregular distribution

Mitotic counta

≤12 mitotic figures/ 10 high power fields

>12 mitotic figures/ 10 high power fields

aMitotic

GROSS FINDINGS

figures are counted in the most active area.

though the tempo of disease progression is significantly more indolent when compared to low-grade and highgrade serous carcinoma.

nn BENIGN SEROUS TUMORS Benign serous tumors (cystadenoma, cystadenofibroma, adenofibroma, surface papilloma) comprise 50% of all serous ovarian neoplasms. They are almost always confined to the ovary.

CLINICAL FEATURES Benign serous tumors occur over a wide age range but are most common in the reproductive age group. They are often bilateral. Women may present with abdominal enlargement, pain or vaginal bleeding, but most patients with benign tumors are asymptomatic and the tumors are discovered incidentally during routine examination or evaluation of an unrelated condition.

Benign serous tumors are lined by epithelium that closely recapitulates the ciliated and secretory cells of the fallopian tube (Fig. 14.2). Varying amounts of fibromatous stroma (adenofibroma, cystadenofibroma) and cystic change (cystadenofibroma) are present. Serous surface papillomas are composed of small papillary growths lined by simple bland, serous-type epithelium growing on the surface of the ovary.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Benign serous tumors have an immunohistochemical profile that is similar to borderline and malignant serous tumors. Like many other ovarian epithelial tumors, they show a CK7-positive, CK20-negative phenotype. In addition, they express PAX8, WT1, ER, BerEP4, and CD15 (Leu-M1).

DIFFERENTIAL DIAGNOSIS Serous cystadenomas are (rather arbitrarily) distinguished from serous epithelial inclusion cysts on the basis of size (>1 cm). Distinction from rete cysts is made on the basis of location (rete cysts are hilar), presence of prominent cilia, and absence of a smooth muscle layer and hyperplastic hilar cells. An endometriotic cyst, especially in postmenopausal women, can closely mimic a serous cystadenoma. The presence of endometrial-type stroma, at least focally, helps in this distinction. If cystic, struma ovarii may resemble a serous cystadenoma, but the constituent cysts of struma contain colloid and are immunoreactive for thyroglobulin. The chief differential diagnosis is between benign and borderline serous tumors. Borderline tumors are characterized by epithelial proliferation in the form of stratification, hierarchical

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A

B FIG. 14.1 Benign serous tumors. Serous cystadenoma appears grossly as a thin-walled cyst with smooth and glistening external surface (A). Upon opening, the inner surface is smooth and devoid of excrescences (B).

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C

D FIG. 14.1, cont’d Serous cystadenofibroma has various amounts of fibrous stroma, seen grossly as solid nodular or thickened areas within the cyst (C). The fibromatous component sometimes forms excrescences within the wall (D).

papillary architecture, tufting with detached epithelial cell clusters, cytologic atypia, and occasional mitotic figures. By definition, serous tumors with focal borderline change (95% for patients with lowstage (stage I) tumors and approximately 65% for patients with high-stage (stage II–IV) tumors. Since late recurrences do occur, and follow-up is limited in many of the studies analyzed, these are conservative estimates of risk of recurrence. The management of serous borderline tumors is primarily surgical. Ovarian and uterine conservative surgery can be considered, especially in young, reproductive-aged women, although initial staging surgery is required to accurately determine the extent of disease and exclude the presence of invasive implants. Currently, there is no indication for adjuvant chemotherapy or radiation therapy for women with serous borderline tumors who have disease confined to the ovary or noninvasive extraovarian implants only. Patients with invasive implants (low-grade serous carcinoma) show poor response rates to traditional ovarian carcinoma chemotherapy.

FIG. 14.12 Serous borderline tumor with transformation to low-grade serous carcinoma. Borderline tumor (upper right aspect) is present juxtaposed to confluent invasion within the stroma.

592 SEROUS BORDERLINE TUMOR—FACT SHEET Definition n Epithelial tumor composed of hierarchically branching papillae with cellular stratification and tufting, lined by tubal-type epithelium showing limited cytologic atypia Incidence and Location n Bilateral (30%–40%) n Advanced stage (30%–40%) Morbidity and Mortality n  Prolonged, indolent course provided extraovarian implants, when present, are noninvasive n  Invasive extraovarian implants are diagosed as low-grade serous carcinoma and confer a comparatively poor prognosis n  5-year disease-specific survival 90%–95% for stage I, 65% for stage II-IV patients Age Distribution n Most common in fourth and fifth decades (mean age 46 years) Clinical Features n Often asymptomatic n Abdominal enlargement or pain secondary to torsion or rupture n Elevated serum CA125 Prognosis and Treatment n  Cystectomy or adnexectomy with preservation of uterus and remaining ovarian tissue in reproductive-age women, even when high-stage disease, provided extraovarian implants are noninvasive. However, recurrence in ipsilateral or contralateral ovary common and follow-up required n  In patients with stage I disease, micropapillary growth carries a higher risk of progression to invasive carcinoma n  Invasive implants (low-grade serous carcinoma) (80%), with transabdominal spread to involve peritoneum (with omental caking) and abdominal lymph nodes n Lungs, liver, and pleura common sites of distant metastases n Median 5 year survival rates range from 15 to 55% Geographic and Age Distribution n More common in western hemisphere n Rare in first two decades, but steady increase thereafter (mean age 56 years) Clinical Features n  Pelvic or abdominal enlargement, vague pain, urinary or gastrointestinal symptoms n Ascites n Elevated serum CA125 Prognosis and Treatment n  Amount of residual disease and stage are the most important prognostic factors n Primary surgical debulking and staging preferred n  Chemotherapy, either adjuvant or neoadjuvant (followed by interval debulking), the mainstay of therapy n  PARP inhibitors increasingly entering practice in addition to platinum and taxane chemotherapy n Despite therapy, vast majority eventually die of the disease.

serous carcinomas initially respond to chemotherapy, responses are not durable and most patients progress towards widespread dissemination involving abdomen, lung, liver, and pleura. PARP inhibitors are now part of second-line systemic treatment for patients with BRCA1/2 mutations (either germline or somatic) and other forms of homologous recombination deficiency. Good response to neoadjuvant chemotherapy is also an emerging indication for maintenance therapy with PARP inhibitors.

SEROMUCINOUS TUMORS These neoplasms, also known as “mixed Müllerian tumors,” are listed as a separate tumor type in the World Health Organization (WHO) classification. Recent insights, however, suggest that a malignant category (seromucinous carcinoma) does not exist, as these tumors can be reclassified as endometrioid (majority),

GYNECOLOGIC PATHOLOGY

HIGH-GRADE SEROUS CARCINOMA—PATHOLOGIC FEATURES Gross Findings n Solid and cystic mass with necrosis and hemorrhage n Surface excrescences and adhesions Microscopic Findings n Classic architecture: complex papillae and glands with slit-like spaces, cellular stratification, and loss of polarity n SET architecture: Solid, endometrioid, and transitional n  Pleomorphic cells with high N:C ratios, large nuclei with coarse chromatin and prominent nucleoli n Mitotic activity >12 mitoses/10 HPFs n Psammoma bodies n CRS applied to cases resected after neoadjuvant therapy Immunohistochemical Findings n PAX8, CK7, EMA, WT1, BerEP4, CA125, and CD15 positive n ER variably positive n Abnormal p53 expression n Calretinin and CK20 negative Molecular Studies n TP53 mutations n Germline or somatic BRCA1/BRCA2 mutations Differential Diagnosis n Low-grade serous carcinoma n Endometrioid adenocarcinoma n Clear cell carcinoma n Metastatic serous carcinoma of endometrium n Metastatic breast carcinoma

serous, or mucinous based on morphology, immunophenotype, and molecular features. Benign and borderline seromucinous tumors are discussed here, although they are rare and their biology and relationship to other tumor types remain to be fully elucidated.

nn BENIGN SEROMUCINOUS TUMORS Benign seromucinous tumors (cystadenoma, adenofibroma) are uncommon. They are almost always confined to the ovary.

CLINICAL FEATURES Seromucinous tumors occur over a wide age range but are most common in the reproductive age group. They may be bilateral and are frequently associated with endometriosis. Women may present with abdominal enlargement, pain, or vaginal bleeding, but most benign tumors are asymptomatic and discovered incidentally.

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CHAPTER 14  Epithelial Neoplasms of the Ovary

PATHOLOGIC FEATURES GROSS FINDINGS

Benign seromucinous tumors are composed of varying amounts of fibromatous stroma (when predominant, serous adenofibroma) and cysts (which are typically less prominent). MICROSCOPIC FINDINGS

Benign seromucinous tumors are lined by an admixture of epithelium that closely recapitulates the ciliated and secretory cells of the fallopian tube and the mucinous epithelium of the endocervix. Varying amounts of stroma (adenofibroma, cystadenofibroma) and cystic change (cystadenofibroma) are present.

ANCILLARY STUDIES IMMUNOHISTOCHEMISTRY

Seromucinous tumors express an immunohistochemical profile that overlaps with other tumor types (see seromucinous borderline tumor).

DIFFERENTIAL DIAGNOSIS Seromucinous cystadenomas are distinguished from serous epithelial (cortical) inclusion cysts on the basis of size (>1 cm). An endometriotic cyst, especially in postmenopausal women, can closely mimic a seromucinous cystadenoma, especially since the latter tumor may be seen in association with endometriosis. The presence of endometrial-type stroma in the absence of a distinctive, admixed benign proliferation of serous and mucinous cells, helps in this distinction. Borderline tumors have hierarchical papillary architecture, epithelial stratification, tufting with detached epithelial cell clusters, cytologic atypia, and occasional mitotic figures. Occasionally, serous tumors can secrete watery material resembling mucin and thus resemble a seromucinous cystadenoma, but its constituent cells do not contain intracytoplasmic mucin.

PROGNOSIS AND THERAPY Seromucinous cystadenomas, adenofibromas, and cystadenofibromas are benign. Complete excision (cystectomy or oophorectomy) is curative. To minimize surgical morbidity, laparoscopic removal is often performed.

BENIGN SEROMUCINOUS TUMORS—FACT SHEET Definition n Benign ovarian tumor composed of tubal and mucinous-type epithelium and varying amounts of stroma n  Typically prominent stromal component without grossly visible cysts: adenofibroma n  If prominent stromal component with grossly visible cysts: cystadenofibroma Incidence and Location n Uncommon benign epithelial tumor n Bilateral (20%) Morbidity and Mortality n  No significant morbidity or mortality unless torsion, rupture, or infection Age Distribution n Wide age range including premenarchal to postmenopausal women, but predominantly reproductive age Clinical Features n Often asymptomatic, incidental finding during routine examination or evaluation for endometriosis or unrelated condition Prognosis and Treatment n Benign n Simple excision (cystectomy or adnexectomy) curative

BENIGN SEROMUCINOUS TUMORS—PATHOLOGIC FEATURES Gross Findings n  Simple, smooth-walled unilocular or multilocular cyst with varying amounts of fibromatous stroma (often 90%) of adult-type granulosa cell tumors. In addition, somatic or germline DICER1 mutations have been identified in 60%–80% of Sertoli–Leydig cell tumors (intermediate and poorly differentiated) and Sertoli cell tumors. Although mutational testing for these genes is not widely available, it should be considered if the distinction is clinically relevant (for instance, cellular fibroma which is benign, from adult granulosa cell tumor which has a low-grade malignant potential and requires long-term follow-up, although in most instances a reticulin stain will suffice in this differential).

nn OVARIAN GERM CELL TUMORS Useful markers of ovarian germ cell tumors include SALL4 (Fig. 20.39) and LIN26 (positive in most malignant germ cell tumors); placental alkaline phosphatase (PLAP), D2-40, CD117, and OCT4 (positive in dysgerminoma); alpha-fetoprotein (AFP) and glypican 3 (positive in yolk sac tumor) (Fig. 20.40); and β-human chorionic gonadotropin (hCG) and GATA3 (positive in trophoblastic tumor components). OCT4, CD30, and SOX2 are positive in embryonal carcinomas, which are very rare in the ovary. Thyroglobulin and TTF1 positivity may be useful in confirming unusual forms of benign and malignant struma ovarii, including clear cell and oxyphilic forms.

CHAPTER 20  Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology

A

B FIG. 20.37 Serous tubal intraepithelial carcinoma (STIC). This lesion is characterized by abnormal (completely negative) staining with p53 (A) and a high Ki67 proliferation index exceeding 10% of the cells (B).

947

948

GYNECOLOGIC PATHOLOGY

FIG. 20.38 Granulosa cell tumor, adult type. Tumor cells are diffusely positive for inhibin.

OVARIAN GERM CELL TUMORS—FACT SHEET n n

n

 ALL4 is positive in most malignant germ cell tumors. S PLAP, OCT4, CD117, and D2-40 are characteristically positive in dysgerminoma. Glypican-3 and AFP are positive in yolk sac tumor.

nn SMALL ROUND CELL TUMORS OF THE OVARY The differential diagnosis of an ovarian small round cell tumor may be wide and immunohistochemistry, as well as molecular studies, can play an important role in the diagnosis. Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) generally exhibits diffuse nuclear positivity with an antibody against the N-terminal of WT1, although several other tumor types are also positive with this marker. Recently, it has been shown that OSCCHT is almost always associated with a germline or somatic SMARCA4 (BRG1) mutations, suggesting that these tumors are related to malignant rhabdoid tumor (and may represent a form of it). This mutation is associated with loss of staining with SMARCA4 (BRG1) antibody, and this may be a useful tool in diagnosis since there is retention of nuclear staining with this marker in most of the mimics of OSCCHT (Fig. 20.41).

TABLE 20.8 Markers of Value in Distinguishing Between Ovarian Endometrioid Adenocarcinoma and Sex Cord-Stromal Tumor Ovarian Endometrioid Adenocarcinoma

Sex Cord-Stromal Tumor

EMA

Diffuse

Negative

PAX8

Diffuse

Negative

CA125

Diffuse

Negative

Inhibin

Negative

Diffuse

Calretinin

Negative

Diffuse

SF-1

Negative

Diffuse

FOXL2

Negative

Diffuse

CD56

Negative or focal

Diffuse

These represent the most typical staining patterns, but in some cases, there are exceptions with one or more markers. EMA, Epithelial membrane antigen; SF-1, steroidogenic factor-1.

Intraabdominal desmoplastic small round cell tumor, which in females may clinically mimic an ovarian neoplasm, is characterized by positivity for a variety of epithelial, mesenchymal, and neural markers. Most tumors exhibit punctate cytoplasmic positivity with desmin and are positive with an antibody against the C-terminal of WT1. Ovarian peripheral primitive neuroectodermal tumors may be positive for CD99 and FLI-1.

CHAPTER 20  Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology

FIG. 20.39 Ovarian dysgerminoma. There is diffuse nuclear SALL4 staining.

FIG. 20.40 Ovarian yolk sac tumor. Tumor cells are strongly positive for Glypican 3.

949

950 SMALL ROUND CELL TUMORS OF THE OVARY—FACT SHEET n

n

n

 SCCHT generally exhibits diffuse nuclear positivity with an antiO body against the N-terminal of WT1 and absence of nuclear staining with BRG1. Intraabdominal desmoplastic small round cell tumor generally exhibits cytoplasmic positivity with desmin and is positive with an antibody against the C-terminal of WT1. Ovarian peripheral neuroectodermal tumors are positive for CD99 and FLI-1.

nn EPITHELIAL VERSUS MESOTHELIAL PROLIFERATIONS A panel of antibodies may assist in the sometimes-difficult distinction between an epithelial and a mesothelial proliferation involving the ovary or peritoneum. Epithelial proliferations are MOC31 and BerEP4 positive, whereas mesothelial proliferations are usually positive for calretinin (Fig. 20.42), CK5/6, thrombomodulin, HBME1, and D2-40. WT1 is also positive in mesothelial proliferations, but it is important to remember that this marker is also positive in tubal epithelium and serous neoplasms. The best combination of markers to distinguish between a serous and a mesothelial proliferation is BerEP4 (generally positive in serous and negative in mesothelial proliferations) and calretinin (generally positive in mesothelial and negative in serous proliferations). BAP1 is a recently described marker with high specificity for the diagnosis of mesothelioma: ∼65% of peritoneal mesotheliomas show loss of BAP1, whereas epithelial neoplasms and reactive mesothelial proliferations retain expression of this marker.

FIG. 20.41 Ovarian small cell carcinoma of hypercalcemic type. Loss of nuclear staining with SMARCA4 is observed. There is a positive internal control in the form of nuclear staining of endothelial cells.

GYNECOLOGIC PATHOLOGY

EPITHELIAL VERSUS MESOTHELIAL PROLIFERATIONS—FACT SHEET n

n n

 pithelial proliferations are BerEP4-positive, whereas mesothelial E proliferations are generally positive for calretinin, CK5/6, thrombomodulin, HBME1, and D2-40. WT1 is positive in serous and mesothelial proliferations. BAP1 loss is specific for mesothelioma (vs. epithelial neoplasms and reactive mesothelium).

TROPHOBLASTIC DISEASES nn MARKERS OF TROPHOBLASTIC CELLS Useful markers of trophoblastic cell populations include β-hCG, human placental lactogen (Fig. 20.43), PLAP, HSD3B1, inhibin, Mel-CAM (CD146), HLA-G, CD10, GATA3, and p63. Villous cytotrophoblast is positive for p63 and Ki67 but negative for inhibin. Syncytiotrophoblast is positive for inhibin but loses Ki67 and p63 expression. Extravillous intermediate trophoblast is positive for p63 and shows variable expression of Ki67, inhibin, and Mel-CAM. Extravillous implantation site trophoblast is positive for Mel-CAM, HLA-G, and inhibin but negative for p63 and Ki67. Because of this differential expression, trophoblastic markers are often useful in the classification of nonmolar trophoblastic proliferations (Table 20.9). GATA3, HSD3B1, and CD10 are variably positive in all trophoblast cell types and the various categories of trophoblastic neoplasia.

CHAPTER 20  Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology

951

FIG. 20.42 Reactive mesothelial proliferation around the ovary. Mesothelial cells show nuclear and cytoplasmic calretinin positivity.

FIG. 20.43 Placental site trophoblastic tumor. Mononuclear cells infiltrating a vessel wall show strong cytoplasmic positivity for human placental lactogen (HPL).

MARKERS OF TROPHOBLASTIC CELLS—FACT SHEET  arkers of trophoblastic cell populations include β-hCG, HPL, PLAP, inhibin, Mel-CAM, HLA-G, GATA3, CD10, and p63. M p57 is useful in the distinction between complete hydatidiform mole and mimickers (partial hydatidiform mole or hydropic abortion) n Negative staining in cytotrophoblast and villous mesenchyme: Complete mole n Positive staining in cytotrophoblast and villous mesenchyme: Partial mole, nonmolar gestation n Ploidy analysis or genotyping can be considered (partial mole vs. nonmolar pregnancy) n n

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GYNECOLOGIC PATHOLOGY

TABLE 20.9 Markers of Value in Nonmolar Gestational Trophoblastic Lesions hCG

Mel-CAM

hPL

HLA-G

Inhibin

P63

Ki67

Placental site nodule

Focal

Focal

Focal

Positive

Diffuse

Positive

10%

Exaggerated implantation site

Focal

Positive

Positive

Positive

Positive

Negative

≤1%

Placental site trophoblastic tumor

Focal

Diffuse

Diffuse

Positive

Positive

Negative

>1%

hCG, Human chorionic gonadotropin; hPL, human placental lactogen; HLA-G, human leukocyte antigen-G.

FIG. 20.44 Complete hydatidiform mole. There is loss of nuclear positivity of cytotrophoblast and villous mesenchyme with p57. Extravillous trophoblast (right aspect) serves as an internal positive control.

nn DIAGNOSTIC WORK-UP OF MOLAR PREGNANCY The histologic distinction between hydropic abortion, partial hydatidiform mole, and complete hydatidiform mole may be difficult. p57, which is a paternally imprinted, maternally expressed gene, is particularly useful in distinguishing between a complete mole and a partial mole or hydropic abortion. Since complete moles contain no maternal DNA, the cytotrophoblast and villous mesenchyme are negative for p57 (Fig. 20.44). In contrast, partial hydatidiform moles, hydropic abortions, and normal placenta, which contain maternal DNA, show positive nuclear staining of cytotrophoblast and villous mesenchyme with this marker. In complete hydatidiform moles, positive staining of decidua and implantation-site intermediate trophoblast acts as a positive internal control. Loss of p57 expression in cytotrophoblast and

villous mesenchyme has high correlation with diandric diploidy on sequencing-based assays. The distinction between partial mole and nonmolar gestations may require the use of molecular testing. Ploidy studies (karyotype, flow cytometry, and in situ hybridization) may be of value, as they can identify triploidy. However, the paternal versus maternal origin of the triploidy cannot be established. PCR-based DNA genotyping offers better sensitivity and specificity, as it determines ploidy as well as the paternal composition (diandric triploidy in partial hydatidiform mole). SUGGESTED READINGS General Baker, P. M., & Olwa, E. (2005). Immunohistochemistry as a tool in the differential diagnosis of ovarian tumors: an update. International Journal of Gynecological Pathology, 24, 39–55.

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Zhang, C., Zhang, P., Sung, J., et al. (2003). Overexpression of p53 is correlated with stromal invasion in extramammary Paget’s disease of the vulva. Human Pathology, 34, 880–885. Zhou, L., Rao, X., Jia, L., et al. (2014). GATA3 is expressed in vulvar Paget’s disease. Modern Pathology, 27(Suppl. 2), 1296A. Vulvovaginal Mesenchymal Lesions Iwasa, Y., & Fletcher, C. D. (2004). Cellular angiofibroma: clinicopathologic and immunohistochemical analysis of 51 cases. The American Journal of Surgical Pathology, 28, 1426–1435. McCluggage, W. G., Connolly, L. E., & McBride, H. A. (2010). HMGA2 is a sensitive but not specific immunohistochemical marker of vulvovaginal aggressive angiomyxoma. The American Journal of Surgical Pathology, 34, 1037–1042. McCluggage, W. G. (2005). A review and update of morphologically bland vulvovaginal mesenchymal lesions. International Journal of Gynecological Pathology, 24, 26–38. McCluggage, W. G., Ganesan, R., Hirschowitz, L., et al. (2004). Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series of cases with a morphological spectrum wider than previously described. Histopathology, 45, 360–368. McCluggage, W. G., Patterson, A., & Maxwell, P. (2000). Aggressive angiomyxoma of pelvic parts exhibits oestrogen and progesterone receptor positivity. Journal of Clinical Pathology, 53, 603–605. Nucci, M. R., Tallini, G., & Quade, B. J. (2001). HMGIC expression as a diagnostic marker for vulvar aggressive angiomyxoma. Modern Pathology, 14, 829(A). Nucci, M. R., Weremonicz, S., Neskey, D. M., et al. (2001). Chromosomal translocation t (8, 12) induced aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Genes Chromosomes Cancer, 32, 172–176. Preinvasive Cervical Squamous Lesions Agoff, S. N., Lin, P., Morihara, J., et al. (2003). p16 INK4A expression correlates with degree of cervical neoplasia: A comparison with Ki-67 expression and detection of high-risk HPV types. Modern Pathology, 16, 665–673. Klaes, R., Benner, A., Freidrich, T., et al. (2002). p16 (INK4A) immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. The American Journal of Surgical Pathology, 26, 1387–1399. Klaes, R., Friedrich, T., Spitkovsky, D., et al. (2002). Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. International Journal of Cancer, 92, 276–284. Kruse, A.-J., Baak, J. P. A., Helliesen, T., et al. (2002). Evaluation of MIB-1 positive cell clusters as a diagnostic marker for cervical intraepithelial neoplasia. The American Journal of Surgical Pathology, 26, 1501–1507. McCluggage, W. G., Tang, L., Maxwell, P., et al. (1996). Monoclonal antibody MIB-1 in the assessment of cervical squamous intraepithelial lesions. International Journal of Gynecological Pathology, 15, 131–136. Mittal, K. (1999). Utility of MIB-1 in evaluating cauterized cervical cone biopsy margins. International Journal of Gynecological Pathology, 18, 211–214. Mittal, K., Mesia, A., & Demopoulos, R. L. (1999). MIB-1 expression is useful in distinguishing dysplasia from atrophy in elderly women. International Journal of Gynecological Pathology, 18, 122–124. Pirog, E. C., Baergen, R. N., Soslow, R. A., et al. (2002). Diagnostic accuracy of cervical low-grade squamous intraepithelial lesions is improved with MIB-1 immunostaining. The American Journal of Surgical Pathology, 26, 70–75. Preinvasive Cervical Glandular Lesions Cameron, R. I., Maxwell, P., Jenkins, D., et al. (2002). Immunohistochemical staining with MIB-1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Histopathology, 41, 313–321.

954 Cina, S. J., Richardson, M. S., Austin, R. M., et al. (1997). Immunohistochemical staining for Ki-67 antigen, carcinoembryonic antigen, and p53 in the differential diagnosis of glandular lesions of the cervix. Modern Pathology, 10, 176–180. Ishikawa, M., Fujii, T., Nasumoto, N., et al. (2003). Correlation of p16 INK4A overexpression with human papillomavirus infection in cervical adenocarcinomas. International Journal of Gynecological Pathology, 22, 378–385. Lee, K. R., Sun, D., & Crum, C. P. (2000). Endocervical intraepithelial glandular atypia (dysplasia): a histopathologic, human papillomavirus, and MIB-1 analysis of 25 cases. Human Pathology, 31, 656–664. McCluggage, W. G., Maxwell, P., McBride, H. A., et al. (1995). Monoclonal antibodies Ki-67 and MIB-1 in the distinction of tuboendometrial metaplasia from endocervical adenocarcinoma and adenocarcinoma in situ in formalin fixed material. International Journal of Gynecological Pathology, 14, 209–216. McCluggage, W. G., & Maxwell, P. (2002). Bcl-2 and p21 staining of cervical tuboendometrial metaplasia. Histopathology, 40, 107. Negri, G., Egarter-Vigi, E., Kasal, A., et al. (2003). p16 (INK4a) is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors. The American Journal of Surgical Pathology, 27, 187–193. Pirog, E. C., Isacson, C., Szabolcs, M. J., et al. (2002). Proliferative activity of benign and neoplastic endocervical epithelium and correlation with HPV DNA detection. International Journal of Gynecological Pathology, 21, 22–26. Riethdorf, L., Riethdorf, S., Lee, K. R., et al. (2002). Human papillomaviruses, expression of p16 INK4A, and early endocervical glandular neoplasia. Human Pathology, 33, 899–904. Cervical Mesonephric Lesions Howitt, B. E., Emori, M. M., Drapkin, R., et al. (2015). GATA3 is a sensitive and specific marker of benign and malignant mesonephric lesions in the lower female genital tract. The American Journal of Surgical Pathology, 39, 1411–1419. Kenny, S. L., McBride, H. A., Jamison, J., & McCluggage, W. G. (2012). Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-β. The American Journal of Surgical Pathology, 36, 799–807. McCluggage, W. G., Oliva, E., Herrington, C. S., et al. (2003). CD10 and calretinin staining of endocervical glandular lesions, endocervical stroma and endometrioid adenocarcinoma of the uterine corpus: CD10 positivity is characteristic of, but not specific for, mesonephric lesions and is not specific for endometrioid stroma. Histopathology, 43, 144–150. Ordi, J., Nogales, F. F., Palacin, A., et al. (2001). Mesonephric adenocarcinoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation. The American Journal of Surgical Pathology, 25, 1540–1545. Ordi, J., Romagosa, C., Tavasson, F. A., et al. (2003). CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic and clear cell tumors. The American Journal of Surgical Pathology, 27, 178–186. Roma, A. A., Goyal, A., & Yang, B. (2015). Differential expression patterns of GATA3 in uterine mesonephric and nonmesonephric lesions. International Journal of Gynecological Pathology, 34(5), 480–486. Silver, S. A., Devouassoux-Shisheboran, M., Mezetti, T. P., et al. (2001). Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. The American Journal of Surgical Pathology, 25, 379–387. Cervical Gastric Type Adenocarcinomas and Benign Glandular Lesions Exhibiting Gastric Differentiation Carleton C, Hoang L, Sah S, et al. (2016). A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas. American Journal of Surgical Pathology, 40, 636–644. Karamurzin, Y. S., Kiyokawa, T., Parkash, V., et al. (2015). Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor

GYNECOLOGIC PATHOLOGY With Unusual Metastatic Patterns and Poor Prognosis. Am J Surg Pathol, 39(11), 1449–1457. Kojima, A., Mikami, Y., Sudo, T., et al. (2007). Gastric morphology and immunophenotype predict poor outcome in mucinous adenocarcinoma of the uterine cervix. The American Journal of Surgical Pathology, 31, 664–672. McCluggage WG. (2016). Recent developments in non-HPV related adenocarcinomas of the lower female genital tract and their precursors. Adv Anat Pathol, 23, 58–69. Mikami, Y., Hata, S., Melamed, J., et al. (2001). Lobular endocervical glandular hyperplasia is a metaplastic process with a pyloric gland phenotype. Histopathology, 39, 364–372. Mikami, Y., Kiyokawa, T., Hata, S., et al. (2004). Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and adenoma malignum. Modern Pathology, 17, 962–972. Mikami, Y., & McCluggage, W. G. (2013). Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant and malignant lesions. Advances in Anatomic Pathology, 20, 227–237. Pirog, E. C., Park, K. J., Kiyokawa, T., et al. (2019). Gastric-type Adenocarcinoma of the Cervix: Tumor With Wide Range of Histologic Appearances. Adv Anat Pathol, 26(1), 1–12. Talia, K. L., Stewart, C. J. R., Howitt, B. E., Nucci, M. R., & McCluggage, W. G. (2017). HPV-negative Gastric Type Adenocarcinoma In Situ of the Cervix: A Spectrum of Rare Lesions Exhibiting Gastric and Intestinal Differentiation. Am J Surg Pathol, 41(8), 1023–1033. Utsugi, K., Hira, Y., Takeshima, N., et al. (1999). Utility of the monoclonal antibody HIK1083 in the diagnosis of adenoma malignum of the uterine cervix. Gynecologic Oncology, 75, 345–348. Distinction Between Endometrial and Endocervical Adenocarcinoma Ansari-Lari, M. A., Staebler, A., Zaino, R. J., et al. (2004). Distinction of endocervical and endometrial adenocarcinomas: immunohistochemical p16 expression correlated with human papillomavirus (HPV) DNA detection. The American Journal of Surgical Pathology, 28, 160–167. Castrillon, D. H., Lee, K. R., & Nucci, M. R. (2002). Distinction between endometrial and endocervical adenocarcinoma: an immunohistochemical study. International Journal of Gynecological Pathology, 21, 4–10. Kamoi, S., Al Juboury, M. L., Akin, M. R., et al. (2002). Immunohistochemical staining in the distinction between endometrial and endocervical adenocarcinomas: another viewpoint. International Journal of Gynecological Pathology, 21, 217–223. McCluggage, W. G., & Jenkins, D. (2003). Immunohistochemical staining with p16 may assist in the distinction between endometrial and endocervical adenocarcinoma. International Journal of Gynecological Pathology, 2, 231–235. McCluggage, W. G., Sumathi, V. P., McBride, H. A., et al. (2002). A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin and estrogen receptor aids the distinction between primary endometrial and endocervical adenocarcinomas. International Journal of Gynecological Pathology, 21, 11–15. Staebler, A., Sherman, M. E., Zaino, R. J., et al. (2002). Hormone receptor immunohistochemistry and human papillomavirus in situ hybridization are useful for distinguishing endocervical and endometrial adenocarcinomas. The American Journal of Surgical Pathology, 26, 998–1006. Zaino, R. J. (2002). The fruits of our labours: distinguishing endometrial from endocervical adenocarcinoma. International Journal of Gynecological Pathology, 21, 1–3. Cervical Neuroendocrine Carcinomas Gilks, C. B., Young, R. H., Gersell, D. J., et al. (1997). Large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic study of 12 cases. The American Journal of Surgical Pathology, 21, 905–914. McCluggage, W. G., Kennedy, K., & Busam, K. J. (2010). An immunohistochemical study of cervical neuroendocrine carcinomas: neoplasms that are commonly TTF1 positive and which may express CK20 and P63. The American Journal of Surgical Pathology, 34, 525–532.

CHAPTER 20  Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology Lower Female Genital Tract Lesions Derived From Misplaced Skene Glands Kazakov, D. V., Stewart, C. J., Kacerovska, D., et al. (2010). Prostatic-type tissue in the lower female genital tract: a morphologic spectrum, including vaginal tubulosquamous polyp, adenomyomatous hyperplasia of paraurethral Skene glands (female prostate), and ectopic lesion in the vulva. The American Journal of Surgical Pathology, 34, 950–955. Kelly, P., McBride, H. A., Kennedy, K., Connolly, L. E., & McCluggage, W. G. (2011). Misplaced Skene’s glands: glandular elements in the lower female genital tract that are variably immunoreactive with prostate markers and that encompass vaginal tubulosquamous polyp and cervical ectopic prostatic tissue. International Journal of Gynecological Pathology, 30, 605–612. McCluggage, W. G., Ganesan, R., Hirschowitz, L., Miller, K., & Rollason, T. P. (2006). Ectopic prostatic tissue in the uterine cervix and vagina: report of a series with a detailed immunohistochemical analysis. The American Journal of Surgical Pathology, 30, 209–215. McCluggage, W. G., & Young, R. H. (2007). Tubulo-squamous polyp: a report of ten cases of a distinctive hitherto uncharacterized vaginal polyp. The American Journal of Surgical Pathology, 31, 1013–1019.

Typing of Endometrial Carcinomas Altrabulsi, B., Malpica, A., Deavers, M. T., Bodurka, D. C., Broaddus, R., & Silva, E. G. (2005). Undifferentiated carcinoma of the endometrium. The American Journal of Surgical Pathology, 29(10), 1316– 1321. Darvishian, F., Hummer, A. J., Thaler, H. T., et al. (2004). Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases. The American Journal of Surgical Pathology, 28(12), 1568–1578. Demopoulos, R. L., Mesia, A. F., Mittal, K., et al. (1999). Immunohistochemical comparison of uterine papillary serous and papillary endometrioid carcinoma: clues to pathogenesis. International Journal of Gynecological Pathology, 18, 233–237. Garg, K., Leitao, M. M., Jr., Wynveen, C. A., et al. (2010). p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes. Modern Pathology, 23(1), 80–92. Gilks, C. B., Oliva, E., & Soslow, R. A. (2013). Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. The American Journal of Surgical Pathology, 37(6), 874–881. Han, G., Sidhu, D., Duggan, M. A., et al. (2013). Reproducibility of histological cell type in high-grade endometrial carcinoma. Modern Pathology, 26, 1594–1604. Hoang, L. N., McConechy, M. K., Köbel, M., et al. (2013). Histotype-genotype correlation in 36 high-grade endometrial carcinomas. The American Journal of Surgical Pathology, 37(9), 1421–1432. Lax, S. F., Kendall, B., Tashiro, H., et al. (2000). The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer, 88, 814–825. McCluggage, W. G., Connolly, L. E., McBride, H. A., Kalloger, S., & Gilks, C. B. (2012). HMGA2 is commonly positive in uterine serous carcinomas and is a useful adjunct to diagnosis. Histopathology, 60, 547–553. Schlosshauer, P. W., Hedrick Ellenson, L., & Soslow, R. A. (2002). Beta-catenin and E-cadherin expression patterns in high-grade endometrial carcinoma are associated with histological subtype. Modern Pathology, 15, 1032–1037. Silva, E. G., Deavers, M. T., Bodurka, D. C., & Malpica, A. (2006). Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma? International Journal of Gynecological Pathology, 25(1), 52–58. Soslow, R. A. (2010). Endometrial carcinomas with ambiguous features. Seminars in Diagnostic Pathology, 27, 261–273. Soslow, R. A. (2013). High-grade endometrial carcinomas—strategies for typing. Histopathology, 62, 89–110.

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Talhouk A, McConechy MK, Leung S et al. (2017) Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer, 123(5), 802–813. Vang, R., Barner, R., Wheeler, D. T., et al. (2004). Immunohistochemical staining for Ki-67 and p53 helps distinguish endometrial Arias–Stella reaction from high grade carcinoma, including clear cell carcinoma. International Journal of Gynecological Pathology, 23, 223–233. Wang, T. Y., Chen, B. F., Yang, Y. C., et al. (2001). Histologic and immnophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases. Human Pathology, 32, 479–486. Distinction Between Uterine Serous Carcinoma (USC) and Ovarian/Tubal High-Grade Serous Carcinoma Al-Hussaini, M., Stockman, A., Foster, H., et al. (2004). WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing serous and ovarian endometrioid carcinoma. Histopathology, 44, 109–115. Egan, J. A., Ionescu, M. L., Eapen, E., et al. (2004). Differential expression of WT1 and p53 in serous and endometrioid carcinoma of the endometrium. International Journal of Gynecological Pathology, 23, 119–122. Goldstein, N. S., & Uzieblo, A. (2002). WT-1 immunoreactivity in uterine papillary serous carcinoma is different from ovarian serous carcinomas. American Journal of Clinical Pathology, 117, 541–545. Hashi, A., Yuminamochi, T., Murata, S.-I., et al. (2003). Wilms tumor gene immunoreactivity in primary serous carcinomas of the ­fallopian tube, ovary, endometrium and peritoneum. International Journal of Gynecological Pathology, 22, 374–377. Hwang, H., Quenneville, L., Yaziji, H., et al. (2004). Wilms tumor gene product. Sensitive and contextually specific marker of serous carcinomas of ovarian surface epithelial origin. Applied Immunohistochemistry & Molecular Morphology, 12, 122–126. McCluggage, W. G. (2004). WT1 is of value in ascertaining the site of origin of serous carcinomas within the female genital tract. International Journal of Gynecological Pathology, 23, 97–99. McCluggage, W. G., Sumathi, V. P., & Maxwell, P. (2001). CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology, 39, 273–278. Trinh, V. Q., Pelletier, M. P., Echelard, P., et al. (2019). Distinct Histologic, Immunohistochemical and Clinical Features Associated With Serous Endometrial Intraepithelial Carcinoma Involving Polyps. Int J Gynecol Pathol. 2019 Feb 14. doi: 10.1097/PGP.0000000000000591. [Epub ahead of print] PMID: 30789501 Markers Which are Positive in Endometrial Stromal Neoplasms Adegboyega, P. A., & Qiu, S. (2008). Immunohistochemical profiling of cytokeratin expression by endometrial stromal sarcoma. Human Pathology, 39, 1459–1464. Chiang, S., Lee, C. H., Stewart, C. J. R., et al. (2017). BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol, 30(9), 1251–1261. Farhood, A. I., & Abrams, J. (1991). Immunohistochemistry of endometrial stromal sarcoma. Human Pathology, 22, 224–230. Lee, C. H., Ali, R. H., Rouzbahman, M., et al. (2012). Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. The American Journal of Surgical Pathology, 36, 1562–1570. Lee, C. H., Hoang, L. N., Reyes, C., et al. (2014). Frequent immunohistochemical expression of KIT in YWHAE-FAM22 endometrial stromal sarcoma. Modern Pathology, 27, 751–757. Parra-Herran, C. E., Yuan, L., Nucci, M. R., & Quade, B. J. (2014). Targeted development of specific biomarkers of endometrial stromal cell differentiation using bioinformatics: The IFITM1 model. Mod Pathol, 27(4), 569–579. Shah, V. I., & McCluggage, W. G. (2015). Cyclin D1 does not distinguish YWHAE-NUTM2 high-grade endometrial stromal sarcoma from undifferentiated endometrial carcinoma. The American Journal of Surgical Pathology, 39, 722–724.

956 Distinction Between Endometrial Stromal and Smooth Muscle Neoplasms Busca, A., Gulavita, P., Parra-Herran, C., & Islam, S. (2018). IFITM1 outperforms CD10 in differentiating low-grade endometrial stromal sarcomas from smooth muscle neoplasms of the uterus. Int J Gynecol Pathol, 37(4), 372–378. Chu, P. G., Arber, P. A., Weiss, L. M., et al. (2001). Utility of CD10 in distinguishing between endometrial stromal sarcoma and uterine smooth muscle tumors: an immunohistochemical comparison of 34 cases. Modern Pathology, 14, 465–471. Loddenkemper, C., Mechsner, S., Foss, H.-D., et al. (2003). Use of oxytocin receptor expression in distinguishing between uterine smooth muscle tumors and endometrial stromal sarcoma. The American Journal of Surgical Pathology, 27, 1458–1462. Nucci, M. R., O’Connell, J. T., Huettner, P. C., et al. (2001). h-Caldesmon expression effectively distinguishes endometrial stromal tumors from uterine smooth muscle tumors. The American Journal of Surgical Pathology, 25, 253–258. Oliva, E., Young, R. H., Amin, M. B., et al. (2002). An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasising the importance of using a panel because of overlap in immunoreactivity for individual antibodies. The American Journal of Surgical Pathology, 26, 403–412. Parra-Herran, C. E., Yuan, L., Nucci, M. R., & Quade, B. J. (2014). Targeted development of specific biomarkers of endometrial stromal cell differentiation using bioinformatics: the IFITM1 model. Modern Pathology, 27, 569–579. Rush, D. S., Tan, J. Y., Baergen, R. N., et al. (2001). h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma. The American Journal of Surgical Pathology, 25, 253–258. Sumathi, V. P., Al-Hussaini, M., Connolly, L. E., et al. (2004). Endometrial stromal neoplasms are immunoreactive with WT-1 antibody. International Journal of Gynecological Pathology, 23, 241–247. Distinction Between Benign and Malignant Smooth Muscle Neoplasm Bennett, J. A., Weigelt, B., Chiang, S., et al. (2017). Leiomyoma with bizarre nuclei: A morphological, immunohistochemical and molecular analysis of 31 cases. Mod Pathol, 30(10), 1476–1488. Croce, S., Ducoulombier, A., Ribeiro, A., et al. (2018). Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: A comprehensive array-genomic hybridization analysis of 77 tumors. Mod Pathol, 31(5), 816–828. O’Neill, C. J., McBride, H. A., Connolly, L. E., & McCluggage, W. G. (2007). Uterine leiomyosarcomas are characterised by high p16, p53 and MIB1 expression in comparison to usual leiomyomas, benign leiomyoma variants and smooth muscle tumors of uncertain malignant potential. Histopathology, 50, 851–858. Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) Baker, R. J., Hildebrandt, R. H., Rouse, R. V., et al. (1999). Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex cord-like elements. Human Pathology, 30, 671–679. Chiang, S., Staats, P. N., Senz, J., et al. (2015). FOXL2 mutation is absent in uterine tumors resembling ovarian sex cord tumors. The American Journal of Surgical Pathology, 39, 618–623. Croce S, de Kock L, Boshari T, et al. (2016). Uterine tumor resembling ovarian sex cord tumor (UTROSCT) commonly exhibits positivity with sex cord markers FOXL2 and SF-1 but lacks FOXL2 and DICER1 mutations. Int J Gynecol Pathol, 35, 301–308. Irving, J. A., Carinelli, S., & Part, J. (2006). Uterine tumors resembling ovarian sex cord tumors are polyphenotypic neoplasms with true sex-cord differentiation. Modern Pathology, 19, 17–24. Krishnamurthy, S., Jungbloth, A. A., Busam, K. J., et al. (1998). Uterine tumors resembling ovarian sex cord tumors have an immunophenotype consistent with true sex cord differentiation. The American Journal of Surgical Pathology, 22, 1078–1082. McCluggage, W. G. (1999). Uterine tumors resembling ovarian sex cord tumors: Immunohistochemical evidence for true sex cord differentiation. Histopathology, 34, 373–380.

GYNECOLOGIC PATHOLOGY Uterine Perivascular Epithelioid Cell Tumor (PEComa) Schoolmeester, J. K., Dao, L. N., Sukov, W. R., et al. (2015). TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis. The American Journal of Surgical Pathology, 39, 394–404. Silva, E. G., Deavers, M. T., Bodurka, D. C., et al. (2004). Uterine epithelioid leiomyosarcomas with clear cells: reactivity with HMB45 and the concept of PEComa. The American Journal of Surgical Pathology, 28, 244–249. Sumpson, K. W., & Albores-Saavedra, J. (2007). HMB-45 reactivity in conventional uterine leiomyosaromas. The American Journal of Surgical Pathology, 31, 95–98. Vang, R., & Kempson, R. L. (2002). Perivascular epithelioid cell tumor (PEComa) of the uterus: a subset of HMB-45 positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. The American Journal of Surgical Pathology, 26, 1–13. Miscellaneous Uterine Mesenchymal Neoplasms Kolin, D. L., Dong, F., Baltay, M., et al. (2018). SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): A clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol, 31(9), 1442–1456. Li, F. L., Gupta, M., McCluggage, W. G., & Ronnett, B. M. (2013). Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. The American Journal of Surgical Pathology, 37, 344–355. Parra-Herran, C., Quick, C. M., Howitt, B. E., Dal Cin, P., Quade, B. J., & Nucci, M. R. (2015). Inflammatory myofibroblastic tumor of the uterus: clinical and pathologic review of 10 cases including a subset with aggressive clinical course. The American Journal of Surgical Pathology, 39, 157–168. Strickland KC, Nucci MR, Esselen KM, et al. (2016). Solitary fibrous tumor of the uterus presenting with lung metastases: a case report. Interna­tional Journal of Gynecological Pathology, 35(1):25–29. Terada, T. (2009). Gastrointestinal stromal tumor of the uterus: a case report with genetic analyses of c-kit and PDGFRA genes. International Journal of Gynecological Pathology, 28, 29–34. Primary Versus Secondary Ovarian Carcinoma Albarracin, C. T., Jafri, J., Montag, A. G., et al. (2000). Differential expression of MUC2 and MUC5AC mucin genes in primary ovarian and metastatic colonic carcinoma. Human Pathology, 31, 672–677. Berezowski, K., Stasny, J. F., & Kornstein, M. J. (1996). Cytokeratins 7 and 20 and carcinoembryonic antigen in ovarian and colonic carcinoma. Modern Pathology, 9, 426–429. Cameron, R. I., Ashe, P., O’Rourke, D. M., et al. (2003). A panel of immunohistochemical stains assists in the distinction between ovarian and renal clear cell carcinoma. International Journal of Gynecological Pathology, 22, 272–276. Chou, Y. Y., Jeng, Y. M., Kao, H. L., et al. (2003). Differentiation of ovarian mucinous carcinoma and metastatic colorectal adenocarcinoma by immunostaining with beta-catenin. Histopathology, 43, 151–156. Groisman, G. M., Meir, A., & Sabo, E. (2003). The value of cdx2 immunostaining in differentiating primary ovarian carcinomas from colonic carcinomas metastatic to the ovaries. International Journal of Gynecological Pathology, 23, 52–57. Ji, H., Isacson, C., Seidman, J. D., et al. (2002). Cytokeratins 7 and 20, Dpc4, and MUC5AC in the distinction of metastatic mucinous carcinomas in the ovary from primary ovarian mucinous tumors: Dpc 4 assists in identifying metastatic pancreatic carcinomas. International Journal of Gynecological Pathology, 21, 391–400. Ladendijk, J. A., Mullink, E. H., van Diest, P. J., et al. (1998). Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry. Differential diagnosis between colonic and ovarian carcinomas as primary sites. Human Pathology, 29, 491–497. Logani, S., Oliva, E., Arnell, P. M., et al. (2005). Use of novel immunohistochemical markers expressed in colonic adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma. Modern Pathology, 18, 19–25.

CHAPTER 20  Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology McCluggage, W. G., & Wilkinson, N. (2005). Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical features. Histopathology, 47, 231–247. McCluggage, W. G. (2000). Recent advances in immunohistochemistry in the diagnosis of ovarian neoplasms. Journal of Clinical Pathology, 3, 327–334. Park, S. Y., Kim, H. S., Hong, E. K., et al. (2002). Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Human Pathology, 33, 1078–1085. Raspollini, M. R., Amunni, G., Villanucci, A., et al. (2004). Utility of CDX-2 in distinguishing between primary and secondary (intestinal) mucinous ovarian carcinoma. Applied Immunohistochemistry & Molecular Morphology, 12, 127–131. Strickland, S., Wasserman, J. K., Giassi, A., Djordjevic, B., & Parra-Herran, C. (2016). Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary: The Added Value of SATB2 and Biomarker Discovery Through Protein Expression Database Mining. Int J Gynecol Pathol, 35(3), 191–208. Tornillo, L., Moch, H., Diener, P. A., et al. (2004). CDX-2 immunostaining in primary and secondary ovarian carcinomas. Journal of Clinical Pathology, 57, 641–643. Wauters, C. C. A.P., Smedts, F., Gerrits, L. G. M., et al. (1995). Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. Human Pathology, 26, 852–855. Werling, R. W., Yaziji, H., Bacchi, C. E., et al. (2003). CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. The American Journal of Surgical Pathology, 27, 303–310. Markers of Value in Typing Ovarian Carcinoma Al-Hussaini, M., Stockman, A., Foster, H., et al. (2004). WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing serous and endometrioid ovarian carcinoma. Histopathology, 44, 109–115. DeLair, D., Han, G., Irving, J. A., Leung, S., et al. (2013). HNF-1β in ovarian carcinomas with serous and clear cell change. International Journal of Gynecological Pathology, 32, 541–546. DeLair, D., Oliva, E., Köbel, M., Macias, A., Gilks, C. B., & Soslow, R. A. (2011). Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases. The American Journal of Surgical Pathology, 35, 36–44. Fadare, O., Zhao, C., Khabele, D., Parkash, V., Quick, C. M., Gwin, K., et al. (2015). Comparative analysis of Napsin a, alpha-methylacyl-coenzyme a racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumors. Pathology, 47, 105–111. Goldstein, N. S., & Uzieblo, A. (2002). WT-1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas. American Journal of Clinical Pathology, 117, 541–545. Iwamoto, M., Nakatani, Y., Fugo, K., Kishimoto, T., & Kiyokawa, T. (2015). Napsin A is frequently expressed in clear cell carcinoma of the ovary and endometrium. Human Pathology, 46, 957–962. Kobel, M., Kalloger, S. E., Carrick, J., et al. (2009). A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. The American Journal of Surgical Pathology, 33, 14–21. Köbel, M., Bak, J., Bertelsen, B. I., et al. (2014). Ovarian carcinoma histotype determination is highly reproducible, and is improved through the use of immunohistochemistry. Histopathology, 64(7), 1004–1013. McCluggage, W. G., Soslow, R. A., & Gilks, C. B. (2011). Patterns of p53 immunoreactivity in endometrial carcinomas: ‘all or nothing’ staining is of importance. Histopathology, 59, 786–788. Peres, L. C., Cushing-Haugen, K. L., Anglesio, M., et al. (2018). Histotype classification of ovarian carcinoma: A comparison of approaches. Gynecol Oncol, 151(1), 53–60. Shimizu, M., Toki, T., Takagi, Y., et al. (2000). Immunohistochemical detection of the Wilms’ tumor gene (WT1) in epithelial ovarian tumors. International Journal of Gynecological Pathology, 19, 158–163. Stewart, C. J., Brennan, B. A., Chan, T., & Netreba, J. (2008). WT1 expression in endometrioid ovarian carcinoma with and without associated endometriosis. Pathology, 40, 592–599.

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Yamamoto, S., Tsuda, H., Aida, S., Shimazaki, H., Tamai, S., & Matsubara, O. (2007). Immunohistochemical detection of hepatocyte nuclear factor 1beta in ovarian and endometrial clear-cell adenocarcinomas and nonneoplastic endometrium. Human Pathology, 38, 1074–1080. Diagnosis of Serous Tubal Intraepithelial Carcinoma (STIC) Carlson, J. W., Jarboe, E. A., Kindelberger, D., et al. (2010). Serous tubal intraepithelial carcinoma: Diagnostic reproducibility and its implications. International Journal of Gynecological Pathology, 29, 310–314. Visvanathan, K., Vang, R., Shaw, P., et al. (2011). Diagnosis of serous tubal intraepithelial carcinoma (STIC) based on morphologic and immunohistochemical features. A reproducibility study. The American Journal of Surgical Pathology, 35, 1766–1775. Vang, R., Visvanathan, K., Gross, A., et al. (2012). Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma. International Journal of Gynecological Pathology, 31, 243–253. Markers of Sex Cord-Stromal Tumors Al-Agha, O. M., Huwait, H. F., Chow, C., et al. (2011). FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. The American Journal of Surgical Pathology, 35, 484–494. Cao, Q. J., Jones, J. G., & Li, M. (2001). Expression of calretinin in human ovary, testis and ovarian sex cord-stromal tumors. International Journal of Gynecological Pathology, 20, 346–352. Costa, M. J., Ames, P. F., Walls, J., et al. (1997). Inhibin immunohistochemistry applied to ovarian neoplasms: a novel, effective diagnostic tool. Human Pathology, 28, 1247–1254. Deavers, M. T., Malpica, A., Liu, J., et al. (2003). Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin. Modern Pathology, 16, 584–590. Guerrieri, C., Franlund, B., Malmstrom, H., et al. (1998). Ovarian endometrioid carcinomas simulating sex cord-stromal tumors: a study using inhibin and cytokeratin 7. International Journal of Gynecological Pathology, 17, 266–271. Kommoss, F., Oliva, E., Bhan, A. K., et al. (1998). Inhibin expression in ovarian tumors and tumor-like lesions: an immunohistochemical study. Modern Pathology, 11, 656–664. Loo, K. T., Leung, A. K. F., & Chan, J. K. C. (1995). Immunohistochemical staining of ovarian granulosa cell tumors with MIC2 antibody. Histopathology, 27, 388–390. Matias-Guiu, X., Pons, C., & Prat, J. (1998). Müllerian inhibiting substance, alpha-inhibin, and CD99 expression in sex cord-stromal tumors and endometrioid ovarian carcinomas resembling sex cord-stromal tumors. Human Pathology, 29, 840–845. McCluggage, W. G., & Maxwell, P. (1999). Adenocarcinomas of various sites may exhibit immunoreactivity with anti-inhibin antibodies. Histopathology, 35, 216–220. McCluggage, W. G., & Maxwell, P. (2001). Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumors. Histopathology, 38, 403–408. McCluggage, W. G., Maxwell, P., & Sloan, J. M. (1997). Immunohistochemical staining of ovarian granulosa cell tumors with monoclonal antibody against inhibin. Human Pathology, 28, 1034–1038. Movahedi-Lankarani, S., & Kurman, R. J. (2002). Calretinin, a more sensitive but less specific marker than alpha-inhibin for ovarian sex cord-stromal neoplasms. An immunohistochemical study of 215 cases. The American Journal of Surgical Pathology, 26, 1477–1483. Pelkey, T. J., Frierson, H. F., Jr., Mills, S. E., et al. (1998). The diagnostic value of inhibin staining in ovarian neoplasms. International Journal of Gynecological Pathology, 17, 97–105. Riopel, M. A., Perlman, E. J., Seidman, J. D., et al. (1998). Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinoma. International Journal of Gynecological Pathology, 17, 46–53. Rishi, M., Howard, L. N., Bratthauer, G. L., et al. (1997). Use of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors of the ovary. The American Journal of Surgical Pathology, 21, 583–589.

958 Stewart, C. J. R., Jeffers, M. D., & Kennedy, A. (1997). Diagnostic value of inhibin immunoreactivity in ovarian gonadal stromal tumors and their histological mimics. Histopathology, 31, 67–74. Stewart, C. J. R., Nandini, C. L., & Richmond, J. A. (2000). Value of A103 (melan-A) immunostaining in the differential diagnosis of ovarian sex cord tumors. Journal of Clinical Pathology, 53, 206– 211. Yao, D. X., Soslow, R. A., Hedvat, C. V., et al. (2003). Melan-A (A103) and inhibin expression in ovarian neoplasms. Applied Immunohistochemistry & Molecular Morphology, 11, 244–249. Zhao, C., Barner, R., Vinh, T. N., McManus, K., Dabbs, D., & Vang, R. (2008). SF-1 is a diagnostically useful immunohistochemical marker and comparable to other sex cord-stromal tumor markers for the differential diagnosis of ovarian sertoli cell tumor. International Journal of Gynecological Pathology, 27, 507–514. Zhao, C., Vinh, T. N., McManus, K., Dabbs, D., Barner, R., & Vang, R. (2009). Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. The American Journal of Surgical Pathology, 33, 354–366. Ovarian Germ Cell Tumors Cheng, L., Thomas, A., Roth, C. M., et al. (2004). OCT4. A novel biomarker for dysgerminoma of the ovary. The American Journal of Surgical Pathology, 18, 1341–1346. Esheba, G. E., Pate, L. L., & Longacre, T. A. (2008). Oncofetal protein glypican-3 distinguishes yolk sac tumor from clear cell carcinoma of the ovary. The American Journal of Surgical Pathology, 32, 600–607. Small Round Cell Tumors of the Ovary Eichhorn, J. H., Young, R. H., & Scully, R. E. (1992). Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. The American Journal of Surgical Pathology, 16, 926–938. Jelinic, P., Mueller, J. J., Olvera, N., et al. (2014). Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nature Genetics, 46, 424–426. Kawrachi, S., Fukuda, T., Miyamoto, S., et al. (1998). Peripheral primitive neuroectodermal tumor of the ovary confirmed by CD99 immunostaining, karyotypic analysis and RT-PCR for EWS/FLI-1 chimeric mRNA. The American Journal of Surgical Pathology, 22, 1417–1422. Matias-Guiu, X., Prat, J., Young, R. H., et al. (1994). Human parathyroid hormone-related protein in ovarian small cell carcinoma. An immunohistochemical study. Cancer., 73, 1878–1881. McCluggage, W. G., Oliva, E., Connolly, L. E., et al. (2004). An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. International Journal of Gynecological Pathology, 23, 330–336. McCluggage, W. G. (2004). Ovarian neoplasms composed of small round cells. A review. Advances in Anatomic Pathology, 11, 288–296. Ordoñez, N. G. (1998). Desmoplastic small round cell tumor, II: an ultrastructural and immunohistochemical study with emphasis on new immunohistochemical markers. The American Journal of Surgical Pathology, 22, 1314–1327. Ramos, P., Karnezis, A. N., Craig, D. W., et al. (2014). Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nature Genetics, 46, 427–429. Riopel, M. A., Perlman, P. J., Seidman, J. D., et al. (1988). Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. International Journal of Gynecological Pathology, 17, 46–53. Witkowski, L., Carrot-Zhang, J., Albrecht, S., et al. (2014). Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nature Genetics, 46, 438–443.

GYNECOLOGIC PATHOLOGY Epithelial Versus Mesothelial Proliferations Attanoos, R. L., Webb, R., Dojcinov, S. D., et al. (2002). Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum. Histopathology, 40, 237–244. Khoury, N., Raju, U., Crissman, J. D., et al. (1990). A comparative immunohistochemical study of peritoneal and ovarian serous tumors and mesotheliomas. Human Pathology, 21, 811–819. Oparaka, R., McCluggage, W. G., & Herrington, C. S. (2011). Peritoneal mesothelial hyperplasia associated with gynaecological disease: a potential diagnostic pitfall that is commonly associated with endometriosis. Journal of Clinical Pathology, 64, 313–318. Ordoñez, N. G. (1998). Role of immunohistochemistry in distinguishing epithelial peritoneal mesothelioma from peritoneal and ovarian serous carcinomas. The American Journal of Surgical Pathology, 22, 1203–1214. Markers of Trophoblastic Cells Castrillon, D. H., Sun, D. Q., Weremowicz, S., et al. (2001). Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57 (KIP2). The American Journal of Surgical Pathology, 25, 1225– 1230. Crisp, H., Burton, J. L., Stewart, R., et al. (2003). Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57 KIP2 immunohistochemistry. Histopathology, 43, 363–373. Fukunaga, M. (2002). Immunohistochemical characterization of p57 KIP2 expression in early hydatiform moles. Human Pathology, 33, 1188–1192. Genest, D. R., Dorfman, D. M., & Castrillon, D. H. (2002). Ploidy and imprinting in hydatidiform moles. Complementary use of flow cytometry and immunohistochemistry of the imprinted gene ­product p57 KIP2 to assist molar classification. Journal of Reproductive Medicine, 47, 342–346. Jun, S.-Y., Ro, J. Y., & Kim, K.-R. (2003). p57 KIP2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. Histopathology, 43, 17–25. McCluggage, W. G., Ashe, P., McBride, H., et al. (1998). Localization of the cellular expression of inhibin in trophoblastic tissue. Histopathology, 32, 252–256. Ordi, J., Romagosa, C., Tavassoli, F. A., et al. (2003). CD10 expression in epithelial tissues and tumors of the gynecologic tract: A useful marker in the diagnosis of mesonephric, trophoblastic and clear cell tumors. The American Journal of Surgical Pathology, 27, 178–186. Shih, I. M., & Kurman, R. J. (1999). Immunohistochemical localization of inhibin-alpha in the placenta and gestational trophoblastic lesions. International Journal of Gynecological Pathology, 18, 144–150. Shih, I. M., & Kurman, R. J. (1998). Ki-67 labelling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor and choriocarcinoma. A double immunohistochemical staining technique using Ki-67 and mel CAM antibodies. Human Pathology, 29, 27–33. Shih, I. M., & Kurman, R. J. (2001). The pathology of intermediate trophoblastic tumors and tumor-like lesions. International Journal of Gynecological Pathology, 20, 31–47. Shih, I. M., & Kurman, R. J. (2004). p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. The American Journal of Surgical Pathology, 28, 1177–1183. Shih, I. M., Seidman, J. D., & Kurman, R. J. (1999). Placental site nodule and characterization of distinctive types of intermediate trophoblast. Human Pathology, 30, 687–694. Singer, G., Kurman, R. J., McMaster, M. T., et al. (2002). HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. The American Journal of Surgical Pathology, 26, 914–920. Xue, W.-C., Khoo, U.-S., Ngan, H. Y. S., et al. (2004). c-mos immunoreactivity aids in the diagnosis of gestational trophoblastic lesions. International Journal of Gynecological Pathology, 23, 145–150.

21 Cytology in the Practice of Gynecologic Pathology nn David C. Wilbur

nn INTRODUCTION Cytologic examination is an integral part of gynecologic pathology. Many of the specimens presenting to the gynecologic surgical pathology service originate as the result of abnormal cytology examinations. Moreover, in many practices, the review of concurrent cytology and surgical pathology material is performed routinely for diagnostic and quality assurance purposes. Lastly, cytologic sampling of the peritoneal cavity is complimentary to pathologic evaluation in patient staging. Thus, it is reasonable to add a chapter specifically discussing this modality to this new edition of Gynecologic Pathology. This chapter concentrates on the most important and frequently encountered diagnoses in cervicovaginal cytology, arguably the single most important cancer screening success to date. As this is not intended to be a comprehensive review, the interested reader is referred to the third edition of the Bethesda System for Reporting Cervical Cytology, published in 2015, for detailed discussions and illustrations of the entities to be described in this chapter. This chapter ends with a brief overview of peritoneal fluid examination.

nn CERVICOVAGINAL CYTOLOGY Since the original reports of clinical utility in the detection of cervical cancer by Papanicolaou and Babes in 1928, cervical cytology has become the most well-studied area in the field of cytopathology, with fine tuning to allow the detection of precursor neoplastic lesions of the lower genital tract. It is the detection, and hence eradication, of these precursor lesions that has driven the precipitous decline in cervical cancer rates (by as much as 70%) in countries where cytologic screening has been well adopted. Despite the remarkable success of cytology alone, the evolution of cervical screening programs has added other modalities, such as testing for and genotyping of human papillomavirus (HPV), the

etiologic agent of the vast majority of lower anogenital tract cancers and precursor lesions. Recently, the Food and Drug Administration has approved HPV testing for primary cervical cancer screening with cervical cytology only as a reflex test in certain situations. Moreover, the 2018 final recommendations from the US Preventive Services Task Force on cervical cancer screening recommend the following: in women 21–29 years, cytology screening every 3 years; in women 30–65 years, screening every 3 years with cytology alone or every 5 years with HPV testing alone or co-testing. This shift has led some to suggest that the role of cervical cytology in screening will disappear or be markedly transformed into an ancillary test only, whereas others suggest that cytology will remain as a frontline primary screen used in conjunction (co-testing) along with HPV detection. In this author’s opinion, it is safe to say that cervical cytology will remain a viable practice for the foreseeable future and, as important, because of its meticulous descriptions of normal and abnormal cells, it will remain the most effective modality for teaching the cytologic method (as it applies to the growing use of cytology in nongynecologic sites) to new students.

THE CYTOLOGIC METHOD Cervical cytology specimens are obtained by directly scraping cells from the surface of the uterine cervix. A variety of sampling devices have been used in the past, but optimized modern techniques currently use devices designed to well-sample the exterior of the cervix (ectocervix), transformation zone, and upper portions of the endocervical canal. The transformation zone is where HPV initially infects the cervix and where the metabolically active metaplastic process allows for neoplastic transformation. Sampling of the transformation zone, which can be proximal or distal in the cervical anatomy, depending on various factors such as patient age and hormonal status, is therefore vital in the process. 959

960 There are devices that sample all three areas in a single pass (“broom” type), whereas others are designed to work in tandem (spatula for ectocervix and distal transformation zone and endocervical brush for proximal transformation zone and endocervical canal). Any of these methods, used appropriately, will provide adequate samples for examination. Specific adequacy requirements are detailed in the current third edition of the Bethesda Atlas and will not be covered here. The use of liquid-based collection (LBC) methods has been widely adopted in the United States and in other developed countries. Although there has been a “hot” debate about whether this method improves the detection of lesions, it is fair to say that LBC has standardized the morphologic appearance of specimens, improved adequacy rates, and increased screening productivity. In addition, LBC specimens are optimized for the use of automated screening methods and for molecular analyses, both of which have added to detection sensitivity and in some cases also to increased productivity.

CYTOLOGY OF THE NORMAL CERVIX AND ENDOCERVICAL CANAL SQUAMOUS CELLS

The normal cervical squamous epithelium (ectocervix) is nonkeratinizing. It does not contain a granular layer (lacks keratohyaline granules) and does not show maturation to the level of parakeratosis or hyperkeratosis. As cytologic sampling only obtains cells from the top two to three layers, a cytologic sample from a woman of child-bearing age should show the presence of only superficial and intermediate squamous cells (Fig. 21.1). Superficial cells show abundant polygonal cytoplasm, which is most commonly eosinophilic (a feature of high-molecular-weight or mature cytokeratin structure) but may also be basophilic. The nuclei are small and pyknotic. Intermediate cells, located just below the superficial cells, also have abundant polygonal cytoplasm, which is more commonly basophilic, a feature of a less-mature cytokeratin internal skeleton structure. Intermediate cell nuclei are larger than those of superficial cells and have a discernible finely granular chromatin pattern. Intermediate cell nuclei are easily found on cervical cytology specimens and are therefore routinely used to compare to the size of other cells’ nuclei, which, as noted later, is an important exercise in judging the neoplastic potential of abnormal cells. Squamous cells of less mature origin (in the child-bearing age group) are derived from squamous metaplastic reactions of the transformation zone. Squamous metaplasia represents a spectrum of change from immature cells with small amounts of round cytoplasm

GYNECOLOGIC PATHOLOGY

and high nucleus to cytoplasmic ratio (N:C), to mature metaplastic cells having rounded cytoplasm becoming more abundant with increasing maturation, but with larger nuclei than intermediate cells. A well-sampled transformation zone will show small numbers of squamous metaplastic cells intermingled with the dominant pattern of mature intermediate and superficial cells (Fig. 21.2). In the peri- and postmenopausal periods, immature cells become more frequent in the specimen as the squamous epithelium becomes generally less mature, eventually leading to a predominance of immature squamous cells, a pattern referred to as atrophy (Fig. 21.3). GLANDULAR CELLS

Endocervical. The endocervical canal adjacent to the transformation zone is lined by a simple columnar mucin-producing epithelium. In cytologic specimens, endocervical cells can be viewed from the side giving the classic histology recapitulation or the “picket-fence” appearance or on-end in a “honey-comb” configuration (Fig. 21.4). The cells have nuclei that are slightly larger on average than an intermediate squamous cell nucleus, with some degree of nuclear size variability and distinctive “dot-like” nucleoli. The cytoplasm is frothy and clear (indicative of mucus) but may also be eosinophilic and granular. Higher in the endocervical canal, as the epithelium merges with endometrium, intermediate patterns between the two distinct epithelia emerge, including increased pseudostratification, smaller nuclei, and mucin-poor densely basophilic cytoplasm. In women over the age of 30 years, it is very common to see tubal metaplasia making up a significant proportion of the surface and deeper gland epithelium, leading to the presence of ciliated cells. Endometrial. Endometrial cells are not routinely sampled by Papanicolaou (Pap) test collection devices and therefore appear only in their spontaneously exfoliated form, typically from menses or dysfunctional cycling. Occasionally, cells from cervical endometriosis or from the corpus in cases of post–cone biopsy samples will be directly sampled and their appearance can raise concern about neoplasia (discussed later). Exfoliated endometrial cells present as three-dimensional groups (having had time to “ball-up” while traveling in endocervical mucus). The nuclei are smaller than those of the intermediate squamous cell and often show densely granular chromatin. As most exfoliated endometrial cells are degenerating, it is common to see evidence of apoptosis in the groupings. A classic menstrual appearance is the so-called “exodus” pattern with three-dimensional balls of endometrial stromal cells surrounded by endometrial epithelial cells. These groups correspond to a similar appearance commonly noted in menstrual curettage specimens

CHAPTER 21  Cytology in the Practice of Gynecologic Pathology

A

B FIG. 21.1 Normal cytology (A) and histology (B) of the ectocervical epithelium in cycling women. Cytologic sampling obtains cells from the most superficial two to three layers, and hence, superficial and intermediate cells are the only cell types obtained.

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A

B FIG. 21.2 Normal cytology (A) and histology (B) of transformation zone epithelium. In addition to superficial and intermediate cells, the presence of squamous metaplastic cells (small, round, and dense cytoplasm) indicates that this biologically important area, where human papillomavirus infects the cervix, has been sampled.

CHAPTER 21  Cytology in the Practice of Gynecologic Pathology

A

B FIG. 21.3 Atrophy. In patients with mucosal atrophy, the cytology shows predominantly small immature squamous cells (A), which may be present in isolated form (B) or in dense groups (C). When present in groups, these cells can be mistaken for high-grade squamous intraepithelial lesions. The histology of atrophy shows a very thin squamous epithelium with little or no maturation to the surface (D).

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C

D FIG. 21.3, cont’d

CHAPTER 21  Cytology in the Practice of Gynecologic Pathology

A

B FIG. 21.4 Benign endocervical epithelium. Endocervical epithelium can show several patterns cytologically, including a “honeycomb” configuration when viewed end-on (A), a “picket fence” appearance when viewed laterally (B), and as a mixture with goblet cells when intestinal metaplasia is present (C). The histologic appearance is most commonly of simple columnar epithelium with frothy mucus caps (D).

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C

D FIG. 21.4, cont’d

(Fig. 21.5). Exfoliated endometrial cells are normal in the first half of the menstrual cycle in premenopausal women; when detected in the second half of the cycle, such cells may represent functional disorders. As such, endometrial cells in this population are not reported. However, in women over age 45 years, there is a proportionately increasing risk

for an association with endometrial neoplasia. Therefore, the current recommendation is to report benign-appearing endometrial cells in this circumstance in the absence of history or when women are known to be peri- or postmenopausal. With such reports, clinicians should perform further investigations based on clinical risk factors.

CHAPTER 21  Cytology in the Practice of Gynecologic Pathology

A

B FIG. 21.5 Benign endometrial epithelium. Benign exfoliated endometrial cells present as three-dimensional clusters of uniform small cells, occasionally showing vacuoles or evidence of degeneration (A). Endometrial stromal cells present as loosely arranged groups with wispy, elongated cytoplasmic appendages (B). In menstrual specimens, degenerating three-dimensional groups of endometrial epithelium (outer layer) and stroma (inner core) can be present in cytologic (C) and histologic (D) specimens.

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C

D FIG. 21.5, cont’d

COMMON INFECTIONS AND REACTIVE EPITHELIAL CHANGES A variety of infectious organisms can be identified in Pap tests and present with specific cellular manifestations, which simplifies identification. Any insult to the nonkeratinized normal appearance of the squamous epithelium can lead to hypermaturity, including parakeratosis, hyperkeratosis, and increased numbers of

keratohyaline granules in the cytoplasm. Reactive and reparative changes to the epithelia are also common and present as two-dimensional groups of cells showing prominent nucleoli and abundant dense cytoplasm in an organized and streaming appearance often described as resembling a “school of fish.” The margins of the groups show appendages indicative of cell-to-cell cohesion (“taffy-pull cytoplasm”). Prominent cell boundaries, little nuclear overlapping, and inflammatory cells in

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A

FIG. 21.6

B

the groups complete the classic reactive/reparative morphologic appearance. When reparative changes become severe (atypical repair), they can mimic neoplasia (Fig. 21.6). Candida is the most common organism identified and in addition to the diagnostic pseudo-hyphae and yeast forms (Fig. 21.7A), squamous cells show evidence of

Reactive endocervical or squamous epithelial cells. These can both show similar changes referred to as “repair,” consisting of two-dimensional sheets with well-defined cell boundaries, prominent nucleoli, and a streaming architectural pattern with cytoplasmic appendages (A). When nuclear features become more abnormal, the designation of “atypical repair” can be made, which has many features in common with invasive carcinoma and can create a difficult morphologic differential diagnosis (B).

hypermaturity with an overall low magnification pattern of superficial cell predominance. Specific cell groups have a classic clumped or “shish-kabob” pattern with Candida pseudo-hyphae holding squamous cells tightly together as if “speared” by the organisms. Trichomonas vaginalis is a common sexually transmitted infection, which manifests typical cellular changes including hypermaturity

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A

B

FIG. 21.7 Candida and Trichomonas vaginalis. (A) Candida can present as pseudohyphae attached to groups of superficial squamous cells in a classic “spearing” pattern. (B-E) Trichomonas vaginalis organisms occur singly and in clusters. They show pear-shaped bodies with eosinophilic granules (B), flagella (C, arrows) and “comma-shaped” nuclear material (D). Clusters of organisms often involve squamous epithelial cells, obscuring their nuclei; notice the dense eosinophilic granules (E).

C

D

of squamous cells with perinuclear clear vacuoles (Fig. 21.7B). Although not specific for Trichomonas, this pattern is so commonly associated with the organism that it is often referred to as “Trich change.” The organisms are found in the clear spaces of the specimen, between the cells, and are pear-shaped, with red internal granules, comma-shaped nuclei, and flagella. Trichomonas are often present with filamentous Leptothrix organisms,

E and the latter organism can be a sentinel finding helpful in the location of the former. Ulcerated epithelia due to herpes simplex infections can be identified in cytologic specimens. The classic Cowdry type A or “ground-glass” inclusions present in multinucleated cells are most common (Fig. 21.8). Interestingly, the presence of isolated herpetic inclusions in uninucleated cells can mimic high-grade squamous intraepithelial lesion (HSIL). The presence of

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A

FIG. 21.8 Herpes simplex virus. The cytopathic effects consist of uniform ground glass nuclear inclusions presenting as isolated cells (A) or as groups of cells (B) featuring multinucleation, nuclear molding and chromatin margination.

B herpetic cells in pregnant patients is considered a “critical reporting” result in the cytology lab due to the risk of congenital infection. Actinomyces organisms can be present in cases of chronic endometritis, most commonly secondary to an intrauterine device (IUD). The typical filamentous organisms appear as three-dimensional structures and are seen in about 25% of women with IUDs. Other organisms are rare in cervical specimens.

EPITHELIAL CELL ABNORMALITIES SQUAMOUS LESIONS

Atypical Squamous Cells. Subtle changes in cells that are not definitive evidence of neoplasia, but which suggest that such may be present, have been a challenging aspect of cervical cytology specimens since their

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FIG. 21.9 Atypical squamous cells–undetermined significance (ASC-US). These cells show features suggestive, but not conclusive, of low-grade squamous intraepithelial lesion. The changes may include nuclear enlargement and hyperchromasia, abnormal keratinization, or koilocyte-like vacuoles.

inception. These changes may be both quantitative (too few abnormal cells present) or qualitative (subtle findings present in cells but which fall short of being definitive). All terminology systems prior to the current Bethesda iteration have recognized an equivocal category. This is unique to cytology as no such equivocal terminology is used in cervical histopathology. The current terminology designation is “atypical squamous cells (ASCs),” and this category is broken into two subcategories—the more common “atypical squamous cells– undetermined significance (ASC-US)” and “atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion (ASC-H).” Both of these categories should be considered not as diagnoses per se but as designations of increased risk of neoplastic disease. Hence, each of these categories has a unique management algorithm assigned to it, with the vigor of the investigation proportionate to that risk level.

ATYPICAL SQUAMOUS CELLS–UNDETERMINED SIGNIFICANCE ASC-US constitutes the most prevalent abnormal interpretation in the cervical cytology laboratory. Based on CAP reporting data, it can range from about 1% to as high as 10%, with a peak at about 5% of all cases. Its importance lies in the fact that a significant pool of high-grade disease resides in this population of equivocal cases. Data from some studies show that it is the largest category of cytologic interpretation preceding

a high-grade diagnosis. It is impossible to eliminate it by interpreting such cases “up or down” because other studies have clearly shown that with the former comes overtreatment and with the latter comes loss of sensitivity for disease. ASC-US is defined quite simply as cellular changes suggestive, but insufficient, for an interpretation of a low-grade squamous intraepithelial lesion (LSIL). These changes can be singular or combinations of features and generally occur in mature squamous epithelial cells. Features that may be seen include nuclear enlargement (1.5 to 2 times the size of an intermediate cell nucleus), irregularity, hyperchromasia, and/or irregular chromatin patterns; atypical keratinization; and incomplete changes in cells suggesting koilocytosis (Fig. 21.9). Cellular changes of severe, or atypical, repair that may be difficult to distinguish from invasive carcinoma but are far more common than cancer are also included within the ASC-US category. It is important to remember that there is no “typical” feature that makes “an ASC-US cell.” A specimen is designated as ASC-US because of the overall appearance of all the cellular material examined on a slide. This designation is routinely biased based on factors that inform the a priori risk, such as patient age, clinical history, and prior Pap and HPV test results. The triage of patients having ASC-US Pap tests is now most commonly by reflex high-risk HPV testing. ASC-US cases that are associated with a positive HPV test are referred to colposcopy (about a 15% risk of HSIL), whereas those testing negative for HPV place the patient at very low risk for high-grade disease and they are returned to routine screening.

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A

FIG. 21.10

B

ATYPICAL SQUAMOUS CELLS–CANNOT EXCLUDE A HIGHGRADE SQUAMOUS INTRAEPITHELIAL LESION ASC-H is a rare cytologic interpretation compared to ASC-US and should constitute only between 5% and 10% of ASC cases. ASC-H is defined as the presence of

Atypical squamous cells—cannot exclude high-grade squamous intraepithelial lesion (ASC-H). These cells show features suggestive but not conclusive for high-grade squamous intraepithelial lesion. This designation presents as small isolated cells with high nucleus-to-cytoplasmic ratio (A) or as groups of cells with a “syncytial-type” arrangement with nuclear overlapping (B).

cellular changes that suggest but are not definitive for HSIL. These changes most commonly occur in immature or metaplastic cells having limited amounts of cytoplasm, typically in round as opposed to polygonal shapes. The nuclei can be enlarged, irregular, or hyperchromatic and have coarse chromatin, and most commonly, the N:C ratio is high (Fig. 21.10). In addition to

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A

B

C

D FIG. 21.11 Low-grade squamous intraepithelial lesion (LSIL). LSIL presents cytologically as mature squamous cells with markedly enlarged nuclei (A) or as classic koilocytes showing enlarged irregularly shaped and hyperchromatic nuclei, often with bi- or multinucleation (B). This correlates with the cells noted in the first few layers of the histologic correlate (C, low-power magnification and D, high-power magnification).

isolated atypical cells, ASC-H can also refer to dense groups of closely packed cells with atypical nuclei or significant nuclear overlapping. This appearance is most common in specimens having atrophic cellular patterns. In addition, atypical keratinized cells with enlarged or irregular nuclei may also prompt an ASC-H designation. The risk of harboring an HSIL is significant with a Pap test interpretation of ASC-H. In the ASCUS/LSIL Triage Study of the NCI, cases interpreted as ASC-H had a 41% risk for HSIL. Because of this elevated risk, all ASC-H cases should be referred to colposcopy regardless of HPV testing result, although the results of HPV testing can be useful in post-colposcopy management.

LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION LSIL is defined as cellular changes consistent with infection by HPV with a low risk of progression to malignancy. It has a biologic and histologic correlate, also

termed LSIL, which subsumes the older designations of CIN1, slight or mild dysplasia, and koilocytosis. LSIL is not conceptually a preneoplastic lesion, but rather a risk factor: HSIL is identified on follow-up in about 15%– 20% of patients with LSIL, virtually identical to cases of ASC-US testing positive for HPV. The morphologic changes of LSIL are, in a way, an extension of those described for ASC-US. LSIL is associated with mature squamous epithelial cells, often in association with hypermaturation, including parakeratosis and hyperkeratosis. The nuclei are enlarged, often to the largest sizes associated with squamous cells at up to three to five times the area of an intermediate squamous cell nucleus (Fig. 21.11). The nuclei are hyperchromatic, irregular, and may have coarse chromatin patterns. The presence of koilocytosis, the cytopathic change specific to HPV, consists of mature cells with a clearly defined perinuclear space (halo) and atypical enlarged and hyperchromatic nuclei, often with bi- or multinucleation and/or pyknotic change (Fig. 21.11). These changes are highly

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A

B

C

D FIG. 21.12 High-grade squamous intraepithelial lesion (HSIL). HSIL presents cytologically as immature squamous cells with high nucleus-to-cytoplasmic ratio and nuclear hyperchromasia and irregularity (A). HSIL can also present as dense hyperchromatic crowded groups of similar cells with loss of polarity and nuclear overlapping (syncytial groups) (B, C). Cell blocks made from liquid-based cytology specimens can be very useful for performing immunohistochemical studies where indicated (D).

reproducible in cytology specimens—actually much more so than in histologic preparations, where glycogenated superficial cells and reactive changes can be overinterpreted as LSIL. Because of the elevated risk for an associated HSIL, just as in ASC-US/HPV positive cases, LSIL cytology should prompt referral to colposcopic examination. In as many as 50% of cases, colposcopic examination and biopsy will be negative. This reflects the fact that productive HPV infections are self-limited and resolve spontaneously in the vast majority. In 2 years of molecular follow-up to a positive HPV test, about 95% of patients become HPV test negative, consistent with clearance of infection.

HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION HSIL is considered to be a true neoplastic precursor lesion of invasive squamous cell carcinoma. A cytologic

interpretation of HSIL carries a high positive predictive value for the presence of a high-grade lesion, particularly when the HPV test is positive. Just as in LSIL, cytologic HSIL has a direct histologic correlate—also called HSIL—that subsumes the terminology of CIN2, CIN3, severe or marked dysplasia, and squamous carcinoma in situ. The cytologic features of HSIL derive from immature dysplastic squamous epithelium that shows little cytoplasmic differentiation from the base to the surface of the epithelium, in association with atypical nuclei. HSIL cytoplasm is similar to the smaller rounded dense cytoplasm present in immature metaplasia; however, nuclei are larger than the intermediate squamous cell nucleus but smaller than the nuclei of LSIL (Fig. 21.12). They are typically hyperchromatic and irregular and have coarsely granular chromatin patterns. Koilocytosis is usually not present in these immature cells as this feature represents change associated with a maturing cell. HSIL can also present as hyperchromatic crowded

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A

FIG. 21.13 High-grade squamous intraepithelial lesion. When HSIL involves endocervical glands, it can take on features of endocervical glandular neoplasia, including dense groups with palisading and columnar-like cells (A). The histology of HSIL shows cells with very little maturation present in the upper levels of the epithelium and in this example involves the endocervical glands (B).

B

groups of cells showing similar nuclear features, but with prominent overlapping, loss of group nuclear polarity, and indistinct cytoplasmic boundaries—the description of a classic “syncytial” appearance (Fig. 21.12). HSIL that involves endocervical glands and gland necks can acquire features mimicking endocervical neoplasia with group polarization appearing to be columnar and the presence of nucleoli, which are not typically present on the epithelial surface in HSIL lesions (Fig. 21.13).

INVASIVE SQUAMOUS CELL CARCINOMA The cells of invasive squamous cell carcinoma may have several different appearances. Keratinizing lesions are composed of hypermature orangeophilic cells that take elongate, spindled, or tadpole forms. Nuclei are enlarged, irregular, and densely pyknotic (Fig. 21.14). In nonkeratinizing lesions, the cells show immature

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A

B

C

D FIG. 21.14 Nonkeratinizing squamous cell carcinoma. In cytologic preparations, this presents as highly atypical cells with irregular chromatin and mitotic activity (A) or as hyperchromatic groups (B, C). In keratinizing lesions, large eosinophilic “tadpole” cells are common (D). Note the necrotic debris (tumor diathesis) clinging to the surface of the cells (D).

cytoplasm similar to HSIL, but with nuclei having greater chromatin irregularities including chromatin clearing and prominent nucleoli (Fig. 21.14). In both presentations, isolated tumor cells are common, indicative of poor inter-cellular cohesion. In addition, invasive carcinoma will show a background of amorphous material and blood due to tissue necrosis. In liquid-based specimens, this necrotic debris adheres to cell groupings (“clinging” diathesis), whereas in conventionally prepared smears, it occupies the entire background of the slide (Fig. 21.14D). In some cases, cancer cells may show more abundant dense cytoplasm, indicative of increasing functional metabolic activity. This change can cause difficulty in distinguishing carcinoma from an atypical reparative reaction, which may also show prominent nucleoli within enlarged nuclei. Lack of isolated cells and relative uniformity of the chromatin should allow for distinction in most cases.

GLANDULAR LESIONS Endocervical Adenocarcinoma in situ (AIS). This lesion is the prototypical endocervical glandular abnormality. It is relatively rare compared to squamous dysplasia, but its incidence has been increasing in the past two decades, most likely representing a combination of increased hormone use, improved endocervical canal sampling devices, and better recognition of the cytologic features. The cytologic appearance of AIS recapitulates its histology and includes pseudostratified columnar epithelial strips with epithelial rosettes (gland formations) and nuclear and cytoplasmic protrusion from group margins (feathering). Nuclei are about two times the size of the intermediate squamous cell nucleus and typically show a coarsely granular, evenly distributed chromatin pattern. Nucleoli are typically seen and may be prominent. Mitotic activity and apoptosis (nuclear breakdown granules) are also commonly present (Fig. 21.15).

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A

B

C

D FIG. 21.15 Endocervical adenocarcinoma in situ (AIS). AIS presents cytologically with pseudostratified strips (A, C) and dense polarized groups with marginal streaming of cytoplasm and nuclei (“feathering”) (B). These features recapitulate the histology of AIS (D).

Endocervical Adenocarcinoma. In the most common, or usual, type of invasive endocervical adenocarcinoma, the cytology recapitulates that of AIS with maintenance of a pseudostratified columnar or honeycombed glandular appearance but with increasing degrees of nuclear atypia including increased size, irregularity, and chromatin abnormality. A necrotic diathesis pattern is generally present. As a lesion becomes less differentiated, these typical features may be less prominent, with columnar cytoplasmic configuration in two-dimensional (directly sampled) sheets being the best indicator of an adenocarcinoma of endocervical origin (Fig. 21.16). Gastric-type endocervical adenocarcinoma differs from the usual type in that it is not associated with HPV (and hence cannot be detected by HPV testing). It can be very difficult to identify cytologically because it very closely recapitulates benign mucinous endocervical epithelium

with few atypical cells being present. In Pap test cases showing increased numbers of goblet-type columnar cells, it is very important to look closely for isolated cells with nuclear atypia and the presence of “golden-brown” mucin in the cytoplasm—a feature of gastric-type mucin. When these features are present, consideration should be given to this rare diagnosis and interpretation as “atypical glandular cells” (AGCs) is warranted (Fig. 21.17). Endometrial Adenocarcinoma. In distinction to endocervical neoplasia, which by its location is directly sampled, endometrial cancer cells are most commonly spontaneously exfoliated and travel to the sampling device suspended in the endocervical mucus. Therefore, despite having a columnar configuration in situ, endometrial lesions present as three-dimensional clusters of cells. Compared to normal endometrial cells, endometrial cancer cells have much

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A

B

C

D FIG. 21.16 Invasive endocervical adenocarcinoma (usual type). Cytologically, this shows many of the features of AIS, with the addition of increased nuclear chromatin irregularity, tumor diathesis, and the presence of increased numbers of isolated atypical columnar cells (A, B, C). The histology of endocervical adenocarcinoma shows a complex crowded architecture (D).

larger nuclei with prominent nucleoli. In addition, in patients with endometrial cancers, glandular cells with cytoplasm filled with neutrophils are commonly present. The background of the slide will often show a very finely granular (“watery”) tumor diathesis, diffuse in conventionally prepared smears and clinging in liquid-based preparations. Atypical Glandular Cells. Compared to its squamous counterpart, interpretations of AGCs are much less frequent, generally in the range of 0.5% of all specimens. However, AGC is a much more concerning designation as it has a much higher likelihood of representing a high-grade lesion than does ASC. AGC is the appropriate interpretation in cases where the cytologic features are suggestive of either an endocervical or endometrial neoplasm but are not definitive.

The most common presentations of AGC are groups of cells, often dense and hyperchromatic, which do not allow for complete evaluation of the specific features of neoplasia noted earlier. Interestingly, the most common findings on follow-up of AGC are reactive conditions and high-grade squamous dysplasias involving endocervical gland necks. Based on the low absolute prevalence of true glandular cancers, it is not surprising that most studies have reported only a minority of true glandular neoplasias found on biopsies after a cytologic interpretation of AGC. A variety of benign mimics of glandular neoplasia have been described in detail, which include tubal metaplasia (identified by presence of terminal bar and/or cilia), directly sampled lower uterine segment endometrium or cervical endometriosis (which, although cellular and composed of small blue cells, lacks

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GYNECOLOGIC PATHOLOGY

A

FIG. 21.17 Gastric-type mucinous endocervical adenocarcinoma. This presents cytologically as a subtle alteration in endocervical cell morphology with increased numbers of goblet-type cells showing frothy mucin and scattered nuclear atypia (A). Histologically, the cells of mucinous carcinoma show mild to moderate nuclear atypia and tall pale mucinous cytoplasm with distinct cell borders (gastric phenotype) (B).

B

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A

B

C

D FIG. 21.18 Pseudoneoplastic glandular lesions. Mimics of glandular neoplasia include tubal metaplasia (A), direct sampling of endometriosis or lower uterine segment (B, epithelium; C, stroma), and changes associated with intrauterine device (D).

the typical nuclear features of neoplasia), reparative changes associated with endocervical polyps, and cellular changes associated with IUD use (vacuolated cells and features of repair) (Fig. 21.18). METASTATIC TUMORS

Tumors of noncervical/nonendometrial origin can present in cervical cytology specimens. The most common origins are from ovary/pelvic peritoneum, breast, colon, and melanoma (Fig. 21.19). Metastases present either by exfoliation and passage through the fallopian tubes from peritoneal involvement or by direct extension into the cervix or vagina. In the former setting, small numbers of isolated cells or three-dimensional groups of cells will be present without diathesis (“clean” backgrounds) within the normal squamous cells. With direct

invasion, numerous tumor cells will be present in their “in situ” configuration (e.g., two-dimensional columnar/honeycomb for columnar adenocarcinomas). Abundant necrotic diathesis will be evident, and in the case of colonic carcinoma, vegetable material is often present in the background of the slide, indicative of spread via a direct fistula tract.

nn PELVIC WASH SPECIMENS Pelvic wash specimens are commonly obtained during gynecologic surgery. These specimens are collected by flushing the pelvic cavity with saline and retrieving the solution for cytologic examination. Normal elements found in pelvic washes include sheets of abraded and

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A

B

C

D FIG. 21.19 Metastases. A variety of metastatic tumors can present in Papanicolaou preparations. In exfoliated specimens, cancers present as three-dimensional clusters in a clean background without diathesis (A, B, pancreatic carcinoma). When tumors invade from contiguous organs, they show features of direct sampling (two-dimensional architecture) with evidence of diathesis. In this example, colonic carcinoma invading the vagina via a fistula is shown (C), in a background with filamentous fecal material (D).

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FIG. 21.20 Mesothelial cells. In pelvic wash specimens, benign mesothelial cells present as directly sampled two-dimensional sheets or as isolated exfoliated cells.

three-dimensional clusters of exfoliated benign mesothelium and mixed inflammatory cells (Fig. 21.20). The presence of malignant cells in a wash will change the stage in ovarian cancer to T1c3, above the T1 designation reserved for tumors confined to the ovary. High-grade serous carcinoma of tubal, ovarian, or primary peritoneal origin is the most common positive finding. This malignancy presents with three-dimensional groups displaying high-grade nuclear atypia, high nuclear-to-cytoplasmic ratio, and, often, central psammomatous calcifications (Fig. 21.21). Low-grade serous carcinoma is more likely to contain psammomatous calcifications, admixed with three-dimensional groups of relatively uniform cells with scant cytoplasm.

The status of the pelvic wash was once a staging criterion in endometrial cancer until eliminated from the International Federation of Gynecology and Obstetrics staging system; however, washes are still commonly obtained in this setting. Of particular note regarding washes in endometrial cancer, if surgery is performed laparoscopically, tumor cells from the uterine corpus can be forced into the pelvic cavity via the fallopian tubes as a consequence of the procedure. Such groups tend to be large and show intact, nonexfoliative (non-three-dimensional) features (Fig. 21.22). When such groups are present, particularly in low-grade minimally invasive tumors, explanation should be given as to the potential artificial nature of the “positive” wash specimen.

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A

FIG. 21.21 Serous carcinoma. This presents similarly in Papanicolaou tests (A) and in pelvic wash samples (B). Three-dimensional structures indicate that these cells have exfoliated and floated freely in the cervical mucus or ascitic fluid, respectively.

B

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CHAPTER 21  Cytology in the Practice of Gynecologic Pathology

FIG. 21.22 Positive washing in low-grade endometrioid carcinoma. Laparoscopic hysterectomies for low-grade, low-stage endometrioid adenocarcinomas can lead to procedural tubal regurgitation of carcinoma that may be seen in the pelvic wash samples. The presence of large groups of malignant cells in the cytology specimen with no histologic evidence of invasion should prompt this consideration.

SUGGESTED READING Arbyn, M., Bergeron, C., Klinkhamer, P., Martin-Hirsch, P., Siebers, A. G., & Bulten, J. (2008). Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol, 111, 167–177. Babkowski, R. C., Wilbur, D. C., Rutkowski, M. A., Facik, M. S., & Bonfiglio, T. A. (1996). The effects of endocervical canal topography, tubal metaplasia, and high canal sampling on the cytologic presentation of non-neoplastic endocervical cells. Am J Clin Pathol, 105, 403–410. Castle, P. E., Cox, J. T., Schiffman, M., Wheeler, C. M., & Solomon, D. (2008). Factors influencing histologic confirmation of high-grade squamous intraepithelial lesion cytology. Obstet Gynecol, 112(3), 637–645. Cox, J. T., Schiffman, M., & Solomon, D. (2003). ASCUS-LSIL Triage Study (ALTS) Group. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol, 188, 1406–1412. Crothers, B. A., Booth, C. N., Darragh, T. M., et al. (2014). False-positive Papanicolaou (PAP) test rates in the College of American Pathologists PAP education and PAP proficiency test programs: evaluation of false-positive responses of high-grade squamous intraepithelial lesion or cancer to a negative reference diagnosis. Arch Pathol Lab Med, 138, 613–619. https://doi.org/10.5858/arpa.2013-0083-CP. Darragh, T. M., Colgan, T. J., Cox, J. T., et al. (2012). Members of the LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and cervical Pathology. Arch Pathol Lab Med, 136, 1266–1297. Kusanagi, Y., Kojima, A., Mikami, Y., et al. (2010). Absence of highrisk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. Am J Pathol, 177, 2169–2175. Massad, L. S., Einstein, M. H., Huh, W. K., et al. (2013). 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis, 17, S1–S27. Nayar, R., & Wilbur, D. C. (Eds.). (2015). The Bethesda System for Reporting Cervical Cytology: Definitions, Criteria, and Explanatory Notes (3rd ed.) New York: Springer.

Nayar, R., & Wilbur, D. C. (2015). The Pap Test and Bethesda 2014. “The reports of my demise have been greatly exaggerated.” (after a quotation from Mark Twain). Acta Cytol, 59, 121–132. https:// doi.org/10.1159/000381842. Nobbenhuis, M. A., Helmerhorst, T. J., van den Brule, A. J., et al. (2001). Cytological regression and clearance of high-risk human papillomavirus in women with an abnormal cervical smear. Lancet, 358(9295), 1782–1783. Pitman, M. B., Cibas, E. S., Powers, C. N., Renshaw, A. A., & Frable, W. J. (2002). Reducing or eliminating use of the category of atypical squamous cells of undetermined significance decreases the diagnostic accuracy of the Papanicolaou smear. Cancer, 96, 128–134. Prat, J., & FIGO Committee on Gynecologic Oncology. (2015). Staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication of guidelines from the international federation of gynecology and obstetrics (FIGO). Obstet Gynecol, 126, 171–174. http://www.ncbi.nlm.nih.gov/ pubmed/26241270. Sherman, M. E., Solomon, D., & Schiffman, M. (2001). Qualification of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study. Am J Clin Pathol, 116, 386–394. Sodhani, P., Gupta, S., Singh, V., Sehgal, A., & Mitra, A. B. (2004). Eliminating the diagnosis atypical squamous cells of undetermined significance: impact on the accuracy of the Papanicolaou test. Acta Cytol, 48, 783–787. Stoler, M. H., & Schiffman, M. (2001). Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA, 285, 1500– 1505. US Preventive Services Task Force. (2018). Screening for cervical cancer. US Preventive Services Task Force recommendation statement. JAMA, 320(7), 674–686. Wang, S. S., Sherman, M. E., Hildesheim, A., Lacey, J. V., Jr., & Devesa, S. (2004). Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000. Cancer, 100, 1035–1044. Wilbur, D. C., Black-Schaffer, W. S., Luff, R. D., et al. (2009). The Becton Dickinson Focal Point GS Imaging System Clinical Trials demonstrate significantly improved sensitivity for the detection of important cervical lesions. Am J Clin Pathol, 132, 767–775.

Index

A Abscess ovarian torsion vs., 564–565 tubo-ovarian actinomycotic salpingitis vs., 512–513 endometriosis vs., 570–572, 574f Acantholytic reaction pattern, 26 Acanthotic epidermal reaction pattern, 9 lichen simplex chronicus, 12–14, 14b psoriasis, 9–12, 11b Acid fast bacilli (AFB) stain, for tuberculous salpingitis, 510 Actinomyces infection, 124–125 Actinomyces israelii, 512 Actinomyces organisms, in cytology, 971 Actinomycotic salpingitis ancillary studies of, 512 clinical features of, 512 differential diagnosis of, 512–513 infectious nongranulomatous salpingitis vs., 509 pathologic features of, 512, 512f, 513b prognosis and therapy for, 513, 513b Active (cycling) endometrium, 295, 306b–307b Acute salpingitis, 507 Adenocarcinoma adenomatoid tumor vs., 514–515 clear cell, see Clear cell (adeno)carcinoma endocervical, 258–261 cytology of, 977, 978f early invasive, 259–261 endometrial endometrioid carcinoma vs., 378 gastric-type mucinous, 268–273, 274b HPV-related, 261–268, 267b HPV-unrelated, 268–273 immunohistochemistry of, see Immunohistochemistry mesonephric, 274–277, 278b microglandular hyperplasia vs., 204–206 usual-type, 262, 263f endometrial endocervical adenocarcinoma vs., 919–924, 919b, 921t, 923f endometrioid, see Endometrioid (adeno)carcinoma metastatic endometriosis vs., 835–837 gastric-type mucinous adenocarcinoma vs., 273 pregnancy-associated changes vs., 562

Adenocarcinoma (Continued) Sertoli cell tumor vs., 690–692 Sertoli–Leydig cell tumor vs., 700–701 mucinous, see Mucinous (adeno)carcinoma salpingitis isthmica nodosa vs., 501 serous, see Serous (adeno)carcinoma vaginal, 166–171, 171b ancillary studies on, 167–168 clinical features of, 167 gross findings in, 167, 168f immunohistochemistry of, 167–168 metastatic, 168–169 microscopic findings in, 167, 169f–171f pathologic features of, 167, 172b prognosis and treatment for, 171 vaginal adenosis vs., 141 vulval, intraepithelial, see Extramammary Paget disease Adenocarcinoma in situ (AIS), cervical, 240–245, 241f, 246b ancillary studies on, 242 clinical features of, 241 colposcopic findings of, 241 cytology of, 977, 978f differential diagnosis of, 243–245, 247f gross findings in, 241 immunohistochemistry of, 242 microscopic findings in, 241, 242f–245f pathologic findings of, 241, 246b prognosis and therapy for, 245, 248f tubal and tuboendometrioid metaplasia vs., 193–194 tunnel clusters vs., 202 Adenofibroma, 516–517 ancillary studies of, 516 clinical features of, 516 differential diagnosis of, 517 pathologic features of, 516, 517f, 517b prognosis and therapy for, 517, 517b Adenoid basal carcinoma, 282–283, 284f deep glands and cysts, 201 diffuse laminar endocervical glandular hyperplasia, 209–210 ectopic prostate tissue vs., 199 lobular endocervical glandular hyperplasia, 206–209 microglandular hyperplasia, 203–206 tunnel clusters, 201–203

Note: Page numbers followed by “f” indicate figures, page numbers followed by “t” indicate tables, and page numbers followed by “b” indicate boxes.

987

988 Adenoid basal hyperplasia, of cervix, 192 adenomyoma of endocervical type, 215–216 endocervical polyp, 213–215 mesonephric remnants, 210–213 Adenoid cystic carcinoma, 282, 283f Adenoma malignum, tunnel clusters vs., 202 Adenomatoid tumor, 513 ancillary studies of, 514, 515b clinical features of, 513 differential diagnosis of, 514–515 endometrial clear cell carcinoma vs., 390 pathologic features of, 513, 514f, 515b peritoneal mesothelioma vs., 853–854 Adenomyoma atypical polypoid, see Atypical polypoid adenomyoma cervical, 290 endocervical-type, see Endocervical-type adenomyoma Müllerian, 479–481 adenomyosis vs., 487–488 ancillary studies of, 481 atypical polypoid adenomyoma vs., 483 clinical features of, 479 differential diagnosis of, 481 gross findings of, 479 immunohistochemistry of, 481 microscopic findings of, 480–481 molecular analysis of, 481 pathologic features of, 479–481, 480f, 482b prognosis and treatment for, 481, 482b Adenomyosis, 486–488 clinical features of, 486 differential diagnosis of, 487–488 fallopian tube, see Salpingitis isthmica nodosa gross findings of, 486 low-grade endometrial stromal sarcoma vs., 446–447 microscopic findings of, 487 pathologic features of, 486–487, 486f–487f, 488b prognosis and treatment for, 488, 488b Adenosarcoma cervical, 290–291, 291f metaplastic papillary tumor vs., 517 Müllerian, 472–479 ancillary studies of, 478 carcinosarcoma vs., 399–400 clinical features of, 472 differential diagnosis of, 478 endocervical polyp vs., 215 endometrial, 472–479 endometriosis vs., 198, 837 gross findings of, 473 immunohistochemistry of, 478 metaplastic papillary tumor vs., 517 microscopic findings of, 473, 474f–477f molecular analysis of, 478 pathologic features of, 473–478, 473f, 479b prognosis and treatment for, 478–479, 479b rhabdomyosarcoma vs., 470–471 with sarcomatous overgrowth, 473, 480f tubal endometriosis vs., 504–505 undifferentiated uterine sarcoma vs., 456 ovarian, 638, 638f

INDEX

Adenosis, vaginal, 141–142, 141f, 142b pathologic features of, 142b tubulosquamous polyp vs., 133–134 Adenosquamous carcinoma, 278–281, 282b ancillary studies on, 278 clinical features of, 278 differential diagnosis of, 278–281 endometrioid adenocarcinoma vs., 278–281 gross findings in, 278 microscopic findings in, 278, 280f–281f pathologic features of, 278, 282b prognosis and therapy for, 281 Adnexal involvement in endometrial carcinoma, 351–352 superficially invasive squamous cell carcinoma and, 60 Adrenocortical carcinoma, metastatic, steroid cell tumor vs., 672 Adrenocortical rests, 530–531, 531f Adult granulosa cell tumor, 673–684, 683b ancillary studies for, 675 breast carcinoma vs., 776–779 Brenner tumors vs., 633 clinical features of, 673–674 differential diagnosis of, 675–678, 683f extraovarian carcinoid tumor vs., 790 gross findings for, 674, 674f histochemistry and immunohistochemistry for, 675, 682f microscopic findings for, 675, 676f–681f molecular analysis for, 675 pathologic features of, 674–675, 684b prognosis and therapy for, 678–684 thecoma vs., 649 AEH/EIN, see Atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia Agenesis, vaginal, 120 Allergic contact dermatitis (ACD), 4–5, 4t, 5b atopic dermatitis vs., 3 clinical features of, 4 differential diagnosis of, 4 microscopic features of, 4, 5f pathologic features of, 5b prognosis and treatment for, 5 Alveolar rhabdomyosarcoma, 470 Amyloidosis ligneous vaginitis vs., 130 vaginal atrophy vs., 146 Androgenetic, term, 874 Angioleiomyoma, pathologic features of, 417–418 Angiomyofibroblastoma, 91–92, 92b ancillary studies of, 91–92 cellular angiofibroma vs., 93 clinical features of, 91 deep (aggressive) angiomyxoma vs., 100 differential diagnosis of, 91–92 gross findings of, 91 immunohistochemistry of, 91 microscopic findings of, 91, 91f pathologic features of, 91 prognosis and therapy for, 92 solitary fibrous tumor vs., 109

989

INDEX

Angiomyxoma deep (aggressive), 99–101, 100b, 911, see also Deep (aggressive) angiomyxoma superficial, 98–99, 99b, see also Superficial angiomyxoma Anovulation, 320–322, 322b clinical features of, 320 differential diagnosis of, 320–322 endometrial polyps vs., 320 gross findings of, 320 microscopic findings of, 320 ovulatory dysfunctional cycles vs., 320 pathologic features of, 320, 321f, 322b prognosis and therapy for, 322 radiologic features of, 320 Aphthous and Lipschutz ulcer, 32–34, 33b clinical features of, 32 differential diagnosis of, 33 microscopic features of, 32, 33f pathologic features of, 34b prognosis and treatment for, 33–34 Appendiceal adenocarcinomas, metastatic, 757–764, 762b ancillary features of, 759 clinical features of, 757 differential diagnosis of, 759–764 gross findings of, 757–758, 758f–759f immunohistochemistry of, 759, 763f microscopic findings of, 758–759, 760f–762f mucinous adenocarcinoma vs., 616–617 pathologic features of, 757–759, 764b Appendiceal carcinoid tumors, 759 Appendiceal mucinous neoplasms, metastatic, 938–940, 941f Arias-Stella reaction, 216, 218b, 244 ancillary studies on, 216 clinical features of, 216 differential diagnosis of, 216 endometrial clear cell carcinoma vs., 390 in gestational endometrium and pregnancy related changes, 302 pathologic features of, 216, 218b, 219f prognosis and treatment for, 216 Aromatase inhibitors, 311 Artificial displacement of epithelium invasive squamous cell carcinoma vs., 64 superficially invasive squamous cell carcinoma vs., 60 Atopic dermatitis, 3–4, 4b clinical features of, 3 differential diagnosis of, 3 microscopic features of, 3, 3f pathologic features of, 4b prognosis and treatment for, 3–4 Atrophic squamous epithelium, high-grade squamous intraepithelial lesion vs., 234–235 Atrophy, vaginal, 144–148, 148b ancillary studies on, 146 clinical features of, 144 differential diagnosis of, 146 gross findings in, 144 microscopic findings in, 144–146, 145f–147f pathologic features of, 144–146, 148b prognosis and therapy for, 146–148 vaginal intraepithelial neoplasia vs., 159–161

Atypia cytologic, 424, 428f postmenopausal squamous, 190, 232 radiation-induced, see Radiation-induced atypia reactive/reparative, see Reactive/reparative atypia Atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), 338–345, 344b ancillary studies of, 338–344 anovulation vs., 320 clinical features of, 338 differential diagnosis of, 338–344 gross findings of, 338 immunohistochemistry of, 338 microscopic findings of, 338, 339f–344f, 346f pathologic features of, 338, 345b prognosis and therapy of, 344–345 Atypical endometriosis, 569–570, 834 Atypical glandular cells (AGCs), 979–981, 981f Atypical immature metaplasia (AIM), immature squamous metaplasia vs., 187 Atypical lipomatous tumor, solitary fibrous tumor vs., 109 Atypical melanocytic nevi of genital type, 78–81, 81b clinical features of, 78 differential diagnosis of, 80 dysplastic nevi vs., 82 gross findings of, 78, 79f microscopic findings of, 78–80, 79f–80f pathologic features of, 78–80, 81b prognosis and therapy for, 81 Atypical placental site nodule (APSN), 884 Atypical polypoid adenomyoma (APA), 481–483 ancillary studies of, 482–483 clinical features of, 482 differential diagnosis of, 483 endometrial endometrioid carcinoma vs., 374–376 endometrial polyp vs., 314 endometrial squamous metaplasia vs., 326 gross findings of, 482 immunohistochemistry of, 482–483 microscopic findings of, 482 molecular studies of, 483 Müllerian adenosarcoma vs., 478 with myometrial invasion, Müllerian adenomyoma vs., 481 pathologic features of, 482, 483f–485f, 485b prognosis and treatment for, 483, 485b Atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion (ASC-H), 973–974, 973f Atypical squamous cells–of undetermined significance (ASCUS), 972, 972f Atypical verruciform lesions, lichen simplex chronicus vs., 12–13 Autoimmune oophoritis, oophoritis vs., 574, 574f

B Bacterial vaginosis, 120–121, 121b clinical features of, 120 microscopic findings in, 120, 121f pathologic features of, 120, 121b prognosis and therapy for, 120–121 Basal cell carcinoma hypertrophic lichen planus vs., 16–17 vulvar, invasive squamous cell carcinoma vs., 64–65

990 Basaloid squamous cell carcinoma, cervical, 252–254 high-grade neuroendocrine carcinoma vs., 285 bcl-2, preinvasive cervical glandular lesions, 915 Behcet disease, 34–35, 35b aphthous and Lipschutz ulcer vs., 33 clinical features of, 34 differential diagnosis of, 34 microscopic features of, 34, 35f pathologic features of, 35b prognosis and treatment of, 34–35 Benign endometrium, with diffuse stromal breakdown, ovulatory dysfunctional cycles vs., 322–324 Benign heterologous elements, carcinosarcoma vs., 399–400 Benign metastasizing leiomyoma, 437 Benign mucinous tumors, 606–608, 608b clinical features of, 606 differential diagnosis of, 607–608 gross findings of, 606, 607f microscopic findings of, 606–607 pathologic features of, 606–607, 608b prognosis and therapy of, 608 Benign seromucinous tumors, 602–604, 603b Benign serous tumors, 579–583, 582b–583b clinical features of, 579 differential diagnosis of, 579–581 gross findings of, 579, 580f–581f immunohistochemistry of, 579 microscopic findings of, 579, 582f pathologic features of, 579 prognosis and therapy of, 581–583 serous borderline tumors vs., 590–591 Benign squamous epithelium, squamous cell carcinoma vs., 255 Bethesda System, cervical lesions, 229 Bilateral salpingo-oophorectomy, hysterectomy with, 358 Biliary tree, metastatic adenocarcinoma from, 940 Blighted ovum, complete hydatidiform mole vs., 874–875 “Block” immunoreactivity, preinvasive vulvar squamous lesions and, 905–909 Borderline mucinous tumors, ovarian appendiceal carcinoma vs., 759 colorectal carcinoma vs., 752–757 metastatic pancreaticobiliary carcinoma vs., 772 Borderline tumors benign seromucinous tumors vs., 603 benign serous tumors vs., 579–581 ovarian, with implants, primary peritoneal carcinoma vs., 843 Botryoid embryonal rhabdomyosarcoma, see Embryonal rhabdomyosarcoma Breast carcinoma, metastatic, 772–780, 779b, 940 ancillary studies of, 776 clinical features of, 772–774 differential diagnosis of, 776–780 gross findings of, 774, 775f high-grade serous carcinoma vs., 601 immunohistochemistry of, 776, 779f microscopic findings of, 776, 776f–778f pathologic features of, 774–776, 780b sclerosing stromal tumors vs., 657–658

INDEX

Brenner tumors, 631–637, 637b classification of, 631t clinical features of, 632 differential diagnosis of, 633 gross findings of, 632, 632f–633f high-grade serous carcinoma vs., 601 immunohistochemistry of, 633 malignant, see Transitional cell carcinoma microscopic findings of, 632, 634f–636f pathologic features of, 632, 637b prognosis and therapy of, 633–637 urinary bladder carcinoma vs., 784–785 Broad ligament, diseases of, 530 carcinoma of, 536–537, 537b embryonic rests and ectopias of, 530–531 ependymoma of, 539–540, 539f, 540b leiomyoma of, 537–538, 537f serous borderline tumor of, 534–536, 536b Bullous pemphigoid, atopic dermatitis vs., 3

C Candida, in cytology, 969, 970f Candidiasis vaginal, 121–122, 123b ancillary studies on, 122, 122f clinical features of, 122 gross findings in, 122 microscopic findings in, 122, 122f pathologic features of, 122, 123b prognosis and therapy for, 122 vulvar, 42–45, 45b ancillary studies of, 43, 43f clinical features of, 42–43 differential diagnosis of, 43, 44f differentiated vulvar intraepithelial neoplasia vs., 56 high grade squamous intraepithelial lesion vs., 52 microscopic features of, 43 pathologic features of, 45b prognosis and treatment for, 43–45 psoriasis vs., 10–11 Carcinoembryonic antigen (CEA), endometrial vs. endocervical adenocarcinoma, 921–922 Carcinoid tumors metastatic extraovarian, see Extraovarian carcinoid tumor ovarian carcinoid tumors vs., 737 ovarian, 735–740, 739b adult granulosa cell tumor vs., 678 ancillary studies for, 737 breast carcinoma vs., 776–779 clinical features of, 735 differential diagnosis of, 737 endometrioid tumors vs., 625 extraovarian carcinoid tumor vs., 790 gross findings for, 735, 736f immunohistochemistry of, 737 microscopic findings for, 735–737, 736f–739f pathologic features of, 735–737, 739b prognosis and therapy for, 737–740 Sertoli cell tumor vs., 690–692

INDEX

Carcinosarcoma cervical, 291–292 endometrial, 397, 401b ancillary studies of, 397–399 clinical features of, 397 differential diagnosis of, 399–400 endometrial endometrioid carcinoma vs., 380 gross findings of, 397, 398f immunohistochemistry of, 397–399 leiomyosarcoma vs., 432 microscopic findings of, 397, 399f–400f molecular analysis of, 399 pathologic features of, 401b prognosis and treatment of, 400–401 rhabdomyosarcoma vs., 470–471 undifferentiated/dedifferentiated endometrial carcinoma vs., 391–392 ovarian, 639, 639f immature teratoma vs., 743 with sex cord features, Sertoli–Leydig cell tumor vs., 700–701 tubal, 526–527 clinical features of, 526 differential diagnosis of, 526 gross features of, 526 pathologic features of, 526b prognosis and therapy for, 526–527, 526b Cauterized epithelium, 244–245 CD10, endometrial stromal tumors and, 930 CDX2, colorectal carcinoma, 752 Cellular angiofibroma, 92–94, 92b ancillary studies in, 93 angiomyofibroblastoma vs., 91–92 clinical features of, 92 differential diagnosis of, 93, 911 gross findings of, 92 immunohistochemistry, 93 immunohistochemistry of, 911 microscopic findings of, 92–93, 93f molecular analysis of, 93 pathologic features of, 92–93, 92b, 94b prognosis and therapy for, 93–94 vulvovaginal smooth muscle tumors vs., 102–103 Cellular fibroma adult granulosa cell tumor vs., 675–678 stomach carcinoma vs., 765 Cellular leiomyoma endometrial stromal nodule vs., 442 highly, see Highly cellular leiomyomas pathologic features of, 415, 416f Cervical gastric-type adenocarcinomas, 919, 919b, 920f–921f Cervical keratinizing squamous cell carcinoma, epithelioid trophoblastic tumor vs., 889–890 Cervical mesonephric lesions, 915–919 Cervical stromal involvement, in endometrial carcinoma, 350–351, 354f Cervicitis, 218 eosinophilic, 220 florid reactive lymphoid hyperplasia (lymphoma-like lesion), 221–222 follicular, 218 ligneous/pseudomembranous, 221

991 Cervicitis (Continued) nonspecific chronic, 218 papillary endocervicitis, 218, 221f plasma cell, 218–220 Cervicovaginal cytology, 959–981 Cervix, 186f–187f deep glands and cysts, 201 diffuse laminar endocervical glandular hyperplasia, 209–210 lobular endocervical glandular hyperplasia, 206–209 microglandular hyperplasia, 203–206 tunnel clusters, 201–203 adenoid basal hyperplasia of, 192 adenomyoma of endocervical type, 215–216 endocervical polyp, 213–215 mesonephric remnants, 210–213 cervicitis of, 218 eosinophilic, 220 florid reactive lymphoid hyperplasia (lymphoma-like lesion), 221–222 follicular, 218 ligneous/pseudomembranous, 221 nonspecific chronic, 218 papillary endocervicitis, 218, 221f plasma cell, 218–220 endometrial carcinoma involvement primary endocervical adenocarcinoma vs., 919–924, 919b, 921t, 923f epithelial tumors of adenoid basal carcinoma, 282–283, 284f adenoid cystic carcinoma, 282, 283f adenosquamous carcinoma, 278–281, 282b glassy cell carcinoma, 280f–281f, 281–282 high-grade neuroendocrine carcinoma, small cell type, 285, 287b malignant mesenchymal, 285–290, 290b mixed, 290–292, 291f neuroendocrine tumors, 283–284 undifferentiated carcinoma, 283 glandular and gland-like conditions of, 193–194 ectopic prostate tissue, 199 endocervicosis, 199 endometriosis, 195–198 endosalpingiosis, 198 Skene’s gland, 199 tubal metaplasia, 193–194 tuboendometrioid metaplasia, 193–194 types of metaplasia, 194–195 immunohistochemistry of, see Immunohistochemistry neoplastic lesions of, 228 carcinoma, pathogenesis of, 228 colposcopy, 229, 229f endocervical adenocarcinoma, 258–261 epithelial tumors, 278–281 HPV-unrelated endocervical adenocarcinoma, 268–273 human papillomavirus in, 228 intraepithelial neoplasia, 229 squamous columnar junction in, 227, 227f transformation zone in, 227, 227f nonneoplastic lesions of, 185–226 Arias-Stella reaction, 216

992 Cervix (Continued) deciduosis, 216–217 inverted transitional cell, 193 radiation-associated atypia, 218 reactive glandular atypia, 218 reparative glandular atypia, 218 squamous, 193 squamous and squamous-like conditions of, 185–189 immature squamous metaplasia, 185–189 squamous atrophy, 189–191 transitional cell metaplasia, 191–193 uterine, 911–915 Chancre, 38 Chemotherapy Response Score (CRS) system, 599 “Chocolate cyst,” 569, 829–831 Choriocarcinoma complete hydatidiform mole vs., 875–876 epithelioid trophoblastic tumor vs., 889 nongestational, 717–719, 719b ancillary studies for, 719 clinical features of, 717 differential diagnosis of, 719 gross findings for, 717 microscopic findings for, 717–718, 718f pathologic features of, 717–718, 719b prognosis and therapy for, 719 placental site trophoblastic tumor, 894 Chorionic membranes, free, in gestational endometrium, 303 Chorionic plate, in gestational endometrium, 303 Chorionic villi, in gestational endometrium and pregnancy related changes, 303 Chronic salpingitis, 507 Chung level staging system, 174t Classic (papulosquamous) lichen planus, 15, 15t Clear cell (adeno)carcinoma cervical, 273–274, 277f Arias-Stella reaction vs., 216 mesonephric hyperplasia vs., 211–212 microglandular hyperplasia vs., 204–206 squamous cell carcinoma vs., 256–257 endometrial, 387–391 ancillary studies of, 387–390 carcinosarcoma vs., 399–400 clinical features of, 387 differential diagnosis of, 390–391 gestational endometrium and pregnancy related changes vs., 303–307 immunohistochemistry of, 387–388 microscopic findings of, 387, 388f–389f molecular analysis of, 388–390 pathologic features of, 390b ovarian, 626–631, 631b classification of, 626t clinical features of, 626 differential diagnosis of, 628–630 dysgerminoma vs., 712–713 gross findings of, 627, 627f high-grade serous carcinoma vs., 601 immunohistochemistry of, 628 juvenile granulosa cell tumor vs., 687 metastatic renal clear cell carcinoma vs., 787 microscopic findings of, 627, 628f–630f

INDEX

Clear cell (adeno)carcinoma (Continued) molecular analysis of, 628 pathologic features of, 627, 631b prognosis and therapy of, 630–631 radiographic features of, 626–627 yolk sac tumor vs., 724–726 squamous cell carcinoma vs., 256–257 tubal, 527, 822–823 papillary cystadenoma vs., 533 vaginal differential diagnosis, 153–154 microscopic findings of, 167 Müllerian papilloma vs., 153–154 prognosis and treatment, 171 yolk sac tumor vs., 178 Colorectal adenocarcinoma, metastatic, 750–757, 938–940 ancillary features of, 752 differential diagnosis of, 752–757 gross findings of, 750, 751f immunohistochemistry of, 752, 756f microscopic findings of, 751–752, 751f–755f pathologic features of, 750–752 Colposcopy, 229, 229f Complete hydatidiform mole (including invasive mole), 871–877, 877b clinical features of, 871–872 differential diagnosis of, 874–876 gross findings of, 872, 873f–874f immunohistochemistry of, 872–874 microscopic findings of, 872, 875f–877f molecular analysis of, 874 pathologic features of, 872, 878b prognosis and therapy of, 876–877 radiologic features of, 872 Condyloma acuminatum, 47–51, 48f, 50b differential diagnosis of, 48, 50f–51f microscopic features of, 47–48, 49f–50f Müllerian papilloma vs., 153–154 pathologic features of, 51b prognosis and therapy for, 48–51 Condyloma lata, 38 Contact dermatitis allergic, 4–5, 4t, 5b irritant, 4t, 5–7, 7b Corps ronds, 27 Corpus luteum cyst, endometriosis vs., 570–572 Cortex, 545 Cortical inclusion cysts, 568–569, 568f, 569b Cosmetic filler related granulomatous inflammation, Crohn disease vs., 31 Cotyledonoid leiomyoma, see Dissecting leiomyoma Crohn disease, 30–32, 32b, 132–133 clinical features of, 30–31 differential diagnosis of, 31 hidradenitis suppurativa vs., 28 microscopic features of, 31, 31f pathologic features of, 32b prognosis and treatment for, 31–32 Cyst(s) broad ligament, 531–532, 531f cortical inclusion, 568–569, 568f, 569b of follicular origin, see Follicular origin, cysts of

INDEX

Cyst(s) (Continued) vaginal, 142–144, 142b, 143f–144f, 144b, see also Hyperreactio luteinalis Cystic atrophy, nonatypical endometrial hyperplasia vs., 337 Cystic corpora lutea, 546 Cystic granulosa cell tumor, pregnancy-associated changes vs., 562 Cystic struma ovarii, follicular cysts vs., 547–550 Cytologic atypia, 424, 428f Cytology, 959–985 of atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion, 973–974, 973f of atypical squamous cells–of undetermined significance, 972, 972f cervicovaginal, 959–981 common infections, 968–971, 969f–971f epithelial cell abnormalities and, 971–972 intraepithelial lesion and high-grade, 975–976, 975f–976f low-grade, 974–975, 974f method of, 959–960 of normal cervix and endocervical canal, 960–966 glandular cells, 960–966, 965f–968f squamous, 960, 961f–964f pelvic wash specimens in, 981–983, 983f–985f reactive epithelial changes, 968–971, 969f–971f of squamous cell carcinoma, 976–981, 977f glandular lesions, 977–981, 978f–982f metastatic tumors, 981, 982f Cytotrophoblast, 717–718

D Darier disease, papular genitocrural acantholysis vs., 27 Decidual change, see Deciduosis Deciduoid mesothelioma decidual change vs., 498 pregnancy-associated changes vs., 562 Deciduosis cervical, 216–217, 220f peritoneal mesothelioma vs., 853–854 in pregnancy-associated changes, 556–557, 561f tubal, 498, 499f vaginal, 148, 148b Dedifferentiated endometrial carcinoma, 391–401 ancillary studies of, 391 carcinosarcoma vs., 399–400 clinical features of, 391 differential diagnosis of, 391–394, 399–400 endometrial endometrioid carcinoma vs., 380 immunohistochemistry of, 391 microscopic findings of, 391, 392f–394f, 399f–400f molecular analysis of, 391, 399 neuroendocrine carcinoma vs., 396 pathologic features of, 394b Deep (aggressive) angiomyxoma, 99–101, 100b, 911 ancillary studies in, 99–100 angiomyofibroblastoma vs., 91–92 cellular angiofibroma vs., 93 clinical features of, 99 differential diagnosis of, 100 fibroepithelial stromal polyp vs., 90 gross findings of, 99 immunohistochemistry of, 99

993 Deep (aggressive) angiomyxoma (Continued) mammary-type myofibroblastoma vs., 96 microscopic findings of, 99, 100f molecular analysis of, 100 pathologic features of, 99, 100b–101b prepubertal vulvar fibroma vs., 97 prognosis and therapy for, 100–101 solitary fibrous tumor vs., 109 superficial angiomyxoma vs., 98 Deep glands, and cysts, 201 Dermatofibrosarcoma protuberans, 116 Dermatophytosis candidiasis vs., 43 psoriasis vs., 10–11 Desmoplastic small round cell tumor, 865–868, 866f–867f rhabdomyosarcoma vs., 471 Desquamative inflammatory vaginitis, 128–130, 130b ancillary studies on, 129 clinical features of, 129 differential diagnosis of, 129 gross findings in, 129 pathologic features of, 129, 130b prognosis and therapy for, 130 Destructive stromal invasion, in invasive carcinoma, 259, 260f–261f Diandric diploidy, 871 Diandric triploidy, 877 Differentiated vulvar intraepithelial neoplasia (dVIN), 54–58, 58b clinical features of, 56 differential diagnosis of, 56 gross findings of, 56 high grade squamous intraepithelial lesion vs., 52–53 lichen sclerosus vs., 23 lichen simplex chronicus vs., 12–13 microscopic features of, 56, 57f–58f pathologic features of, 58b prognosis and therapy for, 57–58 Diffuse laminar endocervical glandular hyperplasia, 209–210, 209f, 210b lobular endocervical glandular hyperplasia vs., 208 pathologic features of, 210b Diffuse large B-cell lymphoma, vaginal involvement in, 175 Diffuse leiomyomatosis, 418 Disordered proliferative endometrium in anovulation, 320 nonatypical endometrial hyperplasia vs., 335–337 Dissecting leiomyoma leiomyosarcomas vs., 538 pathologic features of, 415–417, 416f Disseminated peritoneal leiomyomatosis, 868, 868f–869f Diverticulitis, actinomycotic salpingitis vs., 513 Dysgerminoma, 707–713, 713b ancillary studies for, 708–712 clinical features of, 707–708 cytology for, 708 differential diagnosis of, 712–713 embryonal carcinoma vs., 715–717 gross findings for, 708, 709f histochemistry and immunohistochemistry of, 708–710 metastatic renal clear cell carcinoma vs., 787 microscopic findings for, 708, 709f–712f molecular analysis for, 710–712

994 Dysgerminoma (Continued) pathologic features of, 708, 714b prognosis and therapy for, 713 Sertoli cell tumor vs., 690–692 yolk sac tumor vs., 726–727 Dyskeratotic cells, 14 Dysmorphic features, products of conception with, partial hydatidiform mole vs., 879–880 Dysplastic nevi, 81–83, 82b atypical melanocytic nevi of genital type vs., 80 clinical features of, 81 differential diagnosis of, 82 gross findings of, 81 melanoma vs., 84–86 microscopic findings of, 81, 82f pathologic features of, 81, 83b prognosis and therapy for, 82–83

E Early proliferative endometrium, with residual stromal breakdown, 295, 296f Early secretory endometrium, 297–298, 299f Ectopic decidual reaction, see Deciduosis Ectopic pregnancy, 502–504 clinical features of, 502 differential diagnosis of, 502–503 pathologic features of, 502, 503f, 504b prognosis and therapy for, 503–504, 504b radiologic features of, 502 Ectopic prostate tissue, 199, 201b ancillary studies on, 199 clinical features of, 199 differential diagnosis of, 199 pathologic features of, 199, 200f, 201b prognosis and treatment for, 199 Ectropion, cervical, 227, 227f Eczematous dermatitis impetiginized, candidiasis vs., 43 seborrheic dermatitis vs., 7 Embryonal carcinoma, 713–717, 717b ancillary studies for, 715 clinical features of, 713–714 differential diagnosis for, 715–717 dysgerminoma vs., 712–713 gross findings for, 714 immature teratoma vs., 741–743 immunohistochemistry of, 715, 716f microscopic findings for, 714, 714f–716f molecular analysis for, 715 pathologic features of, 714, 717b prognosis and therapy for, 717 yolk sac tumor vs., 726–727 Embryonal rhabdomyosarcoma cervical, 287–288, 289f–290f vaginal, 105–108, 106b ancillary studies in, 106 clinical features of, 105 differential diagnosis of, 106 fibroepithelial polyp, 153–154 fibroepithelial stromal polyp vs., 90 gross findings in, 105, 106f immunohistochemistry of, 106, 107f

INDEX

Embryonal rhabdomyosarcoma (Continued) microscopic findings in, 105–106, 107f Müllerian papilloma vs., 153–154 pathologic features of, 105–106, 108b prognosis and treatment for, 106–108 rhabdomyoma vs., 105 yolk sac tumor vs., 178 Emphysematous vaginitis, 128 clinical features of, 128 gross findings in, 128 microscopic findings in, 128, 129f pathologic features of, 128 prognosis and therapy for, 128 Endocervical adenocarcinoma, 258–261 cytology of, 978, 979f early invasive, 259–261 endometrial endometrioid carcinoma vs., 378 gastric-type endometrial endometrioid carcinoma vs., 378 mucinous, 268–273, 274b Müllerian adenomyoma vs., 481 HPV-related, 261–268, 267b endometrial endometrioid carcinoma vs., 378 HPV-unrelated, 268–273 immunohistochemistry of, see Immunohistochemistry mesonephric, 274–277, 278b metastatic, HPV-related type, mucinous adenocarcinoma vs, 616–617 microglandular hyperplasia vs., 204–206 usual-type, 262, 263f Endocervical adenocarcinoma in situ, 977, 978f Arias-Stella reaction vs., 216 endometriosis vs., 196, 198 Endocervical cells, cytology of, 960, 965f–966f Endocervical glands/crypts, normal, gastric type endocervical adenocarcinoma vs., 269–273 Endocervical polyps, 213–215, 215b ancillary studies on, 215 clinical features of, 213–214 differential diagnosis of, 215, 217f gross findings in, 214 microscopic findings in, 214–215, 214f Müllerian adenomyoma vs., 481 Müllerian adenosarcoma vs., 478 pathologic features of, 214–215, 215b prognosis and treatment for, 215 Endocervical-type adenomyoma, 215–216 endocervical polyp vs., 215 gastric type endocervical adenocarcinoma vs., 273 lobular endocervical glandular hyperplasia vs., 208 Endocervical-type mucinous adenocarcinoma, cervical, 262, 264f Endocervicosis, 199 Endodermal sinus tumor, see Yolk sac tumor Endometrial cells, cytology of, 960–966, 967f–968f Endometrial clear cell carcinoma, 387–391 ancillary studies of, 387–390 carcinosarcoma vs., 399–400 clinical features of, 387 differential diagnosis of, 390–391 immunohistochemistry of, 387–388 microscopic findings of, 387, 388f–389f molecular analysis of, 388–390

INDEX

Endometrial clear cell carcinoma (Continued) pathologic features of, 390b Endometrial glandular neoplasia, 333–406 atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia, 338–345, 344b ancillary studies of, 338–344 clinical features of, 338 differential diagnosis of, 338–344 gross findings of, 338 immunohistochemistry of, 338 microscopic findings of, 338, 339f–344f, 346f pathologic features of, 338, 345b prognosis and therapy of, 344–345 carcinosarcoma, 397 ancillary studies of, 397–399 clinical features of, 397 differential diagnosis of, 399–400 gross findings of, 397, 398f immunohistochemistry of, 397–399 microscopic findings of, 397, 399f–400f molecular analysis of, 399 prognosis and treatment of, 400–401 clear cell carcinoma, 387–391 ancillary studies of, 387–390 clinical features of, 387 differential diagnosis of, 390–391 immunohistochemistry of, 387–388 microscopic findings of, 387, 388f–389f molecular analysis of, 388–390 pathologic features of, 390b endometrial carcinoma, 345–358 endometrial endometrioid carcinoma, 361–378 Lynch syndrome, 358–361, 359f–360f mesonephric carcinoma, 401–402, 402f–403f mixed carcinoma, 402–403 neuroendocrine carcinoma, 394 ancillary studies of, 396 differential diagnosis of, 396–397 immunohistochemistry of, 396 microscopic findings of, 394–396, 395f pathologic features of, 396b nonatypical endometrial hyperplasia, 334–338, 334f, 337b AEH/EIN vs., 339 clinical features of, 334 differential diagnosis of, 334–337 gross findings of, 334, 334f microscopic findings of, 334, 335f–336f pathologic features of, 334, 337b prognosis and therapy of, 337–338 serous carcinoma, 381–387 ancillary studies of, 381 clinical features of, 381 differential diagnosis of, 381–387 immunohistochemistry of, 381 microscopic findings of, 381, 382f–386f molecular analysis of, 381 pathologic features of, 387b squamous cell carcinoma, 403–404 undifferentiated/dedifferentiated endometrial carcinoma, 391–401 ancillary studies of, 391 clinical features of, 391

995 Endometrial glandular neoplasia (Continued) differential diagnosis of, 391–394, 399–400 immunohistochemistry of, 391 microscopic findings of, 391, 392f–394f, 399f–400f molecular analysis of, 391, 399 pathologic features of, 394b Endometrial hyperplasia, 333, 333b atypical, 338–345, 344b ancillary studies of, 338–344 clinical features of, 338 differential diagnosis of, 338–344 gross findings of, 338 immunohistochemistry of, 338 microscopic findings of, 338, 339f–344f, 346f pathologic features of, 338, 345b prognosis and therapy of, 344–345 nonatypical, 334–338, 334f, 337b clinical features of, 334 differential diagnosis of, 334–337 gross findings of, 334, 334f microscopic findings of, 334, 335f–336f pathologic features of, 334, 337b prognosis and therapy of, 337–338 Endometrial metaplasia, 324–331 atypical endometrial hyperplasia vs., 338 endometrial endometrioid carcinoma vs., 376 nonatypical endometrial hyperplasia vs., 337 Endometrial mucinous carcinoma, endometrial endometrioid carcinoma vs., 366 Endometrial polyps, 313–314, 316b AEH/EIN vs., 339–340 ancillary studies in, 314 clinical features of, 313 differential diagnosis of, 314, 316f–317f endocervical polyp vs., 215 gross findings of, 314 microscopic findings of, 314 molecular analysis of, 314 Müllerian adenosarcoma vs., 478 with myometrial invasion, Müllerian adenomyoma vs., 481 nonatypical endometrial hyperplasia vs., 337 pathologic features of, 314, 315f, 316b prognosis and therapy for, 314 radiologic findings in, 313 Endometrial serous carcinoma, 381–387 ancillary studies of, 381 carcinosarcoma vs., 399–400 clinical features of, 381 differential diagnosis of, 381–387 immunohistochemistry of, 381 microscopic findings of, 381, 382f–386f molecular analysis of, 381 pathologic features of, 387b tubo-ovarian high-grade serous carcinoma vs., 929–930, 930b, 931f undifferentiated/dedifferentiated endometrial carcinoma vs., 392–393 Endometrial stromal carcinoma, with myometrial invasion adenomyosis vs., 487–488 AEH/EIN vs., 340 atypical polypoid adenomyoma vs., 483 Müllerian adenomyoma vs., 481

996 Endometrial stromal neoplasm, 438–453 diagnosis of, 930–933, 932f–933f, 932b smooth muscle neoplasm vs., 933–934, 933t, 934f–935f, 934b spindle cell epithelioma vs., 157 Endometrial stromal nodule (ESN), 438–443 ancillary studies of, 441–442 clinical features of, 438 differential diagnosis of, 442 gross findings of, 439–440, 439f highly cellular leiomyomas vs., 418 immunohistochemistry of, 441–442 leiomyosarcoma vs., 432 microscopic findings of, 440–441, 440f–441f molecular analysis of, 442 pathologic features of, 439–441, 443b prognosis and treatment of, 442–443, 442b Endometrial stromal sarcoma adult granulosa cell tumor vs., 675–678 cervical, 288 endometriosis vs., 837 high-grade, see High-grade endometrial stromal sarcoma low-grade, see Low-grade endometrial stromal sarcoma mesenchymal tumors of uterine corpus vs., 807–808 metastatic endometriosis vs., 837 ovarian endometrioid stromal sarcoma vs., 818–822 ovarian, 818–822, 822b ancillary studies of, 818 clinical features of, 818 differential diagnosis of, 818–822 gross findings of, 818 immunohistochemistry of, 818, 821f microscopic findings of, 818, 819f–820f pathologic features of, 818, 822b prognosis and therapy of, 822 Endometrioid adenofibroma, 625, 626b Brenner tumors vs., 633 microscopic findings of, 622, 622f Endometrioid (adeno)carcinoma, 277, 345–358, 362b cervical, mesonephric hyperplasia vs., 211–212 clinical features of, 345–346 colorectal carcinoma vs., 752 conventional component of, 377 cytology of, 985f endometrial, 361–378 ancillary studies of, 372–374 carcinoma of uterine corpus vs., 805 cervical squamous cell carcinoma vs., 255 clinical features of, 361 differential diagnosis of, 374–378 endometrial squamous metaplasia vs., 326 FIGO grading system, 361–362, 363f–366f gastric-type mucinous adenocarcinoma vs., 273 HPV-related endocervical adenocarcinoma vs., 265–266 immunohistochemistry of, 372–374 microscopic findings of, 361 molecular analysis of, 374 with mucinous differentiation, 378, 379f pathologic features of, 361, 380b primary endocervical adenocarcinoma vs., 919, 922f with villoglandular architecture, papillary metaplasia vs., 330

INDEX

Endometrioid (adeno)carcinoma (Continued) gross findings of, 345–346, 347f–349f histologic type and grade of, 356–357, 356b management of, 358 molecular classification of, 357–358 morphologic variations of, 362–372, 367f–372f, 374f–376f ovarian, 577–578, 621–626, 625b adult granulosa cell tumor vs., 678 appendiceal carcinoma vs., 762 breast carcinoma vs., 776–779 classification of, 621t clinical features of, 621 differential diagnosis of, 625 extraovarian carcinoid tumor vs., 790 gross findings of, 621, 621f high-grade serous carcinoma vs., 601 immunohistochemistry of, 624 lung carcinoma vs., 783 metastatic pancreaticobiliary carcinoma vs., 772 microscopic findings of, 622–624, 622f–624f molecular analysis of, 624–625 mucinous adenocarcinoma vs., 616–617 pathologic features of, 621–624, 626b prognosis and therapy of, 625–626 with secretory change or squamous metaplasia with clear cytoplasm, clear cell tumors vs., 628–630 Sertoli cell tumor vs., 690–692 with sex cord features, Sertoli–Leydig cell tumor vs., 700–701 yolk sac tumor vs., 724–726 precursors, 333 primary peritoneal carcinoma vs., 843 prognosis and therapy for, 346–358 stomach carcinoma vs., 765 tubal, 524–526 clinical features of, 524–525, 525f differential diagnosis of, 525 female adnexal tumor of probable wolffian origin vs., 532 florid epithelial hyperplasia vs., 506 high-grade serous carcinoma vs., 522–523 pathologic features of, 526b prognosis and therapy for, 525–526, 525b tubal endometriosis vs., 504–505 typing of, 924–929, 929b histologic typing of, 924–929, 926f–928f, 926t molecular-based, 929, 930f–931f undifferentiated/dedifferentiated, 391–401 ancillary studies of, 391 clinical features of, 391 differential diagnosis of, 391–394 endometrial endometrioid carcinoma vs., 380 immunohistochemistry of, 391 microscopic findings of, 391, 393f–394f molecular analysis of, 391 pathologic features of, 394b uterine epithelioid leiomyosarcoma vs., 432 with myometrial invasion, Müllerian adenomyoma vs., 481 PEComa vs., 461–463 uterine adenomatoid tumor vs., 489–490 uterine tumors resembling ovarian sex cord tumors vs., 460 vaginal, 167

INDEX

Endometrioid intraepithelial neoplasia, 338–345, 344b ancillary studies of, 338–344 clinical features of, 338 differential diagnosis of, 338–344 gross findings of, 338 immunohistochemistry of, 338 microscopic findings of, 338, 339f–344f, 346f mucinous neoplasia vs., 326 pathologic features of, 338, 345b prognosis and therapy of, 344–345 Endometrioma, ovarian torsion vs., 564–565 Endometriosis cervical, 195–198, 198b adenocarcinoma in situ vs., 244 ancillary studies on, 196 clinical features of, 195–196 differential diagnosis of, 196–198 gross findings in, 196 microscopic findings in, 196, 197f pathologic features of, 196, 198b prognosis and treatment for, 198 ovarian, 569–572, 572b clinical features of, 569 differential diagnosis of, 570–572 gross findings of, 569, 570f immunohistochemistry of, 570 microscopic findings of, 569–570, 571f–572f oophoritis vs., 574 pathologic features of, 569–570, 573b prognosis and therapy of, 572 peritoneal, 829–840, 839b ancillary studies of, 834 clinical features of, 829 differential diagnosis of, 835–837, 839f gross findings of, 829–831, 830f–831f immunohistochemistry of, 834 microscopic findings of, 831–834, 832f–838f pathologic features of, 829–834, 839b prognosis and therapy of, 837–840 tubal, 504–505, 531 clinical features of, 504 differential diagnosis of, 504–505 ectopic pregnancy vs., 502–503 pathologic features of, 504, 505f, 505b prognosis and therapy for, 505, 505b vaginal, 139, 139b, 140f pathologic features of, 139b vaginal adenosis vs., 141 Endometriotic cysts benign seromucinous tumors vs., 603 benign serous tumors vs., 579–581 follicular cysts vs., 551 Endometritis, 314–320, 318b ancillary studies in, 317 chronic, nonatypical endometrial hyperplasia vs., 337 clinical features of, 314–315 differential diagnosis of, 317–318 gross findings of, 317 histochemistry and immunochemistry of, 317 microscopic findings of, 317 pathologic features of, 317, 318f–319f, 320b radiologic features of, 315 treatment and prognosis for, 318–320

997 Endometrium abnormal uterine bleeding and, 313 anovulation, 320–322, 321f, 322b endometrial polyp, 313–314, 315f–317f, 316b endometritis, 314–320, 318f–319f, 318b ovulatory dysfunctional cycles (irregular secretory endometrium), 322–324, 323f, 324b exogenous hormones in, effects of, 309 aromatase inhibitors, 311 estrogens, 309 GnRH agonists and antagonists, 313 hormone replacement therapy, 309 oral contraceptives, 309, 311f pathologic features, 313b progesterone receptor modulators, 311, 312f progestins, 309, 310f selective estrogen receptor modulators, 309–311 metaplasia of, 324–325, 324b eosinophilic, 328–329, 329f mucinous, 326–328, 327f papillary, 328, 330f–331f squamous, 325–326, 325f tubal, 328, 328f nonneoplastic lesions of, 295–332, 296t normal, 295 active (cycling), 295 biopsy specimens of, 314 day 16 (periovulatory), 296–297, 298f early proliferative, 295, 296f early secretory, 297–298, 299f gestational, 302–307, 304f–306f inactive (premenarchal and postmenopausal), 307–309, 308f late secretory, 298, 301f–302f menstrual, 298, 303f mid secretory, 298, 300f proliferative, 295–296, 297f Endosalpingiosis, 545 cervical, 198 endometriosis vs., 570–572, 835–837 Enterobius vermicularis infection, tuberculous salpingitis vs., 510–511 Eosinophilic cellulitis, fixed drug eruption vs., 20 Eosinophilic cervicitis, 220 Eosinophilic metaplasia, of endometrium, 328–329 differential diagnosis of, 329 pathologic features of, 328, 328f, 329b Ependymoma of broad ligament, 539–540, 539f, 540b peritoneal mesothelioma vs., 854 Epidermal ulceration, superficially invasive squamous cell carcinoma vs., 60 Epithelial cysts, follicular cysts vs., 547–550 Epithelial metaplasia, 340, 497, 498f Epithelial neoplasms cervical, 278–281 adenoid basal carcinoma, 282–283, 284f adenoid cystic carcinoma, 282, 283f adenosquamous carcinoma, 278–281, 282b glassy cell carcinoma, 280f–281f, 281–282 high-grade neuroendocrine carcinoma, small cell type, 285, 287b malignant mesenchymal, 285–290, 290b

998 Epithelial neoplasms (Continued) mixed, 290–292, 291f neuroendocrine tumors, 283–284 undifferentiated carcinoma, 283 ovarian, 577–642, 578t mucinous tumors, 606 seromucinous tumors, 602 serous tumors, 578–579 undifferentiated carcinoma, 638, see also Intraepithelial neoplasia Epithelial versus mesothelial proliferations, 950, 950b, 951f Epithelioid angiosarcoma, epithelioid sarcoma (distal and proximal types) vs., 113–114 Epithelioid cell tumor, perivascular, see PEComa Epithelioid leiomyoma pathologic features of, 417, 417f PEComa vs., 419 Epithelioid leiomyosarcoma differential diagnosis of, 426 epithelioid sarcoma (distal and proximal types) vs., 113–114 high-grade endometrial stromal sarcoma vs., 452–453 myxoid leiomyosarcoma vs., 419 pathologic features of, 426 prognosis and treatment of, 433 Epithelioid sarcoma (distal and proximal types), 111–115, 115b ancillary studies of, 113 clinical features of, 111 differential diagnosis of, 113–114 gross findings of, 111, 112f immunohistochemistry of, 113 microscopic findings of, 111, 112f–114f molecular analysis of, 113 pathologic features of, 111, 115b prognosis and therapy for, 115 Epithelioid smooth muscle tumors endometrial clear cell carcinoma vs., 390 epithelioid trophoblastic tumor vs., 890 placental site trophoblastic tumor vs., 894–895 uterine tumors resembling ovarian sex cord tumors vs., 460, see also Epithelioid leiomyoma; Epithelioid leiomyosarcoma Epithelioid trophoblastic tumor, 887–890, 892b clinical features of, 887 differential diagnosis of, 889–890 gross findings of, 887, 889f high-grade squamous epithelial lesion vs., 237 immunohistochemistry of, 889, 893f microscopic findings of, 887–889, 890f–892f pathologic features of, 887–889, 892b placental site trophoblastic tumor, 894 prognosis and therapy of, 890 squamous cell carcinoma vs., 163–166, 255 Epithelioma, spindle cell, 154–157, 157b ancillary features of, 157 clinical features of, 154–157 differential diagnosis of, 157 microscopic findings in, 154–157, 155f–156f pathologic features of, 157b prognosis and treatment for, 157

INDEX

Epithelium squamous, see Squamous epithelium surface, 545 Erosive lichen planus, 14–15 aphthous and Lipschutz ulcer vs., 33 clinicopathologic characteristics of, 15t plasma cell vulvitis vs., 36 Erythema multiforme, 18–20, 20b aphthous and Lipschutz ulcer vs., 33 clinical features of, 18 differential diagnosis of, 18 fixed drug eruption vs., 20 microscopic features of, 18, 19f pathologic features of, 20b prognosis and treatment for, 18–20 Estrogen receptor (ER) endometrial carcinoma and, 924–925 endometrial stromal tumors and, 930 Estrogen receptor modulators, selective, 309–311 Estrogens, 309 Eutectic mixture of local anesthetics (EMLA), papular genitocrural acantholysis and, 27 Eversion, cervical, 227, 227f Ewing sarcoma, of vulva, 116 Exaggerated placental site, placental site trophoblastic tumor vs., 894 Extramammary Paget disease (EMPD), 71–77, 77b ancillary studies of, 71–73 clinical features of, 71, 72f differential diagnosis of, 74–77 gross findings of, 71 immunohistochemistry of, 71–73, 75f–76f microscopic findings of, 71, 73f–75f pathologic features of, 71, 77b prognosis and therapy for, 77 Extraovarian carcinoid tumor, metastatic, 787–790, 790b ancillary studies of, 790 clinical features of, 787–788 differential diagnosis of, 790 gross findings of, 788 immunohistochemistry of, 790 microscopic findings of, 788, 788f–789f pathologic features of, 788, 790b Extraovarian serous implants, classification of, 590t Extravillous implantation site trophoblast, 950 Extravillous intermediate trophoblast, 950

F Fallopian tube, diseases of, 497–544 inflammatory processes of, 507–510 actinomycotic salpingitis, 512–513, 512f infectious nongranulomatous salpingitis, 507, 508f–509f tuberculous salpingitis, 510–512, 511f mesenchymal lesions of, 528, 529f metastatic tumors, 528, 528f neoplastic lesions of, 513–515 benign tumors, 513 borderline malignancy and malignant tumors of, 517–518 nonneoplastic lesions of, 497, 498f decidual change, 498, 499f ectopic pregnancy, 502–504, 503f epithelial metaplasia, 497, 498f

999

INDEX

Fallopian tube, diseases of (Continued) florid epithelial hyperplasia, 505–507, 506f salpingitis isthmica nodosa, 500–502, 501f tubal endometriosis, 504–505, 505f tubal torsion, 498–500, 499f Fallopian tube prolapse, 137–139, 139b clinical features of, 137 differential diagnosis of, 138 gross findings in, 138 microscopic findings in, 138, 138f pathologic features of, 138, 139b prognosis and therapy for, 138–139 Fallopian tube torsion, 498–500 clinical features of, 498–499 differential diagnosis of, 499 ectopic pregnancy vs., 502–503 pathologic features of, 499, 499f, 500b prognosis and therapy for, 499–500, 500b FATWO, see Female adnexal tumor of probable wolffian origin Female adnexal tumor of probable wolffian origin (FATWO), 532 carcinoma of the broad ligament vs., 536–537 clinical features of, 532, 534f–535f differential diagnosis of, 532 endometrioid carcinoma vs., 525 high-grade serous carcinoma vs., 523 pathologic features of, 533b peritoneal mesothelioma vs., 854 prognosis and therapy for, 532, 533b Female genital tract pathology differential diagnosis of, 905–958, 906t–908t immunohistochemistry of, 905–958, 906t–908t molecular diagnostics in, 905–958, 906t–908t Fibroepithelial polyps condyloma acuminatum vs., 153–154 embryonal rhabdomyosarcoma vs., 153–154 Müllerian papilloma vs., 153–154 Fibroepithelial stromal polyps, 89–91, 90b ancillary studies of, 90 angiomyofibroblastoma vs., 91–92 clinical features of, 89 condyloma acuminatum vs., 48 deep (aggressive) angiomyxoma vs., 100 differential diagnosis of, 90 embryonal rhabdomyosarcoma vs., 106 gross findings of, 89 immunohistochemistry of, 90 microscopic findings of, 89–90, 89f–90f pathologic features of, 89–90, 91b prognosis and therapy for, 90–91 rhabdomyoma vs., 105 rhabdomyosarcoma vs., 471 Fibroma cellular, see Cellular fibroma ovarian, 643–648, 647b ancillary studies for, 646–647 clinical features of, 643 differential diagnosis of, 647–648 gross findings for, 643, 644f–645f histochemistry and immunohistochemistry for, 646 with marked edema, massive ovarian edema vs., 567 microscopic findings for, 644–645, 645f–646f molecular analysis of, 646–647

Fibroma (Continued) ovarian endometrioid stromal sarcoma vs., 818–822 pathologic features of, 643–645, 648b primary ovarian smooth muscle tumors vs., 817 prognosis and therapy for, 648 sclerosing stromal tumors vs., 657–658 thecoma vs., 649 Fibromatosis, ovarian, massive ovarian edema vs., 567 Fibromyxoid low-grade endometrial stromal sarcoma high-grade endometrial stromal sarcoma vs., 452–453 inflammatory myofibroblastic tumors vs., 466–469 myxoid leiomyosarcoma vs., 432 pathologic features of, 443–444, 446f Fibrosarcoma, fibroma vs., 647 Fixed drug eruption (FDE), 20–22, 22b clinical features of, 20 differential diagnosis of, 20 erythema multiforme vs., 18 microscopic features of, 20, 21f pathologic features of, 22b prognosis and treatment for, 20–22 Flat condyloma, 47–51, 48f, 50b differential diagnosis of, 48, 50f–51f microscopic features of, 47–48, 49f–50f pathologic features of, 51b prognosis and therapy for, 48–51 Florid epithelial hyperplasia clinical features of, 505–507 differential diagnosis of, 506 high-grade serous carcinoma vs., 522–523 pathologic features of, 506, 506f, 507b prognosis and therapy for, 506–507, 507b Florid reactive lymphoid hyperplasia, 221–222, 222b Florid squamous metaplasia, AEH/EIN vs., 340 Fluorescence in situ hybridization (FISH) endometrial stromal tumors and, 930 Follicular cervicitis, 218 Follicular origin, cysts of, 545–552, 551b ancillary studies of, 547 clinical features of, 545–546 cortical inclusion cysts vs., 568 differential diagnosis of, 547–551, 552f gross findings of, 546, 547f–549f immunohistochemistry of, 547 microscopic findings of, 546–547, 549f–551f pathologic features of, 546–547, 551b prognosis and therapy of, 551–552 radiologic features of, 545–546 Follicular salpingitis, salpingitis isthmica nodosa vs., 501 Fungal infections malakoplakia vs., 132 Furunculosis hidradenitis suppurativa vs., 28

G Gastric differentiation, benign glandular lesions exhibiting, 919, 919b, 920f–921f Gastric-type endocervical adenocarcinoma endometrial endometrioid carcinoma vs., 378 metastatic, stomach carcinoma vs., 765 mucinous adenocarcinoma vs., 616–617 Müllerian adenomyoma vs., 481

1000 Gastric-type mucinous adenocarcinoma, 268–273, 274b ancillary studies on, 269 clinical features of, 268 differential diagnosis of, 269–273, 275f–276f gross findings in, 268–269 histochemistry and immunohistochemistry of, 269 HPV-related adenocarcinoma vs., 265–266 microscopic findings in, 269, 270f–272f pathologic features of, 268–269, 274b prognosis and therapy for, 271f–272f, 273 Gastrointestinal stromal tumor leiomyosarcoma vs., 432 primary ovarian smooth muscle tumors vs., 817 Genital herpes, see Herpes simplex virus (HSV) infection Genital melanosis, see Mucosal lentigo Genital “melanotic” macule, see Mucosal lentigo Genotyping, in complete hydatidiform mole, 874 Geographic tumor cell necrosis, leiomyosarcoma vs., 431–432 Germ cell tumors, ovarian, 707–748, 707b, 708t dysgerminoma, 707–713 embryonal carcinoma, 713–717, 717b gonadoblastoma, 744, 744f–745f immature teratomas, 740–744, 743b immunohistochemistry of, 946–948, 948b, 949f mature cystic teratoma, 728 nongestational choriocarcinoma, 717–719 ovarian carcinoid tumors, 735–740 polyembryoma, 744, 745f struma ovarii, 731–735 teratomas, 728 yolk sac tumor, 719–728, 727b Gestation normal, with hydropic change, partial hydatidiform mole vs., 879–880 very early, gestational choriocarcinoma vs., 899–900 Gestational choriocarcinoma, 897–902, 902b clinical features of, 898 differential diagnosis of, 899–900 gross findings of, 898, 900f immunohistochemistry of, 899 microscopic findings of, 898–899, 900f–901f nongestational choriocarcinoma vs., 719 pathologic features of, 898–899, 902b prognosis and therapy of, 901–902 Gestational endometrium, 302–307, 304f–306f differential diagnosis of, 303–307 pathologic features of, 307b Gestational trophoblastic lesions, 871–904 molar, 871 nonmolar, 881–887 differential diagnosis of, 884t Giant condylomata, vulvar, invasive squamous cell carcinoma vs., 64 Glandular cells, of endocervical canal, 960–966, 965f–968f Glandular differentiation, 444 Glandular lesions of invasive squamous cell carcinoma, 977–981, 978f–981f preinvasive cervical, immunohistochemistry of, 915, 915b, 916f–918f Glandular metaplasia, AEH/EIN vs., 340 Glassy cell carcinoma, 280f–281f, 281–282

INDEX

“Gliomatosis peritonei,” 741 Glycogenated squamous epithelium, cervical, 232 GnRH agonists, 313 GnRH antagonists, 313 Gonadoblastoma ovarian, 744, 744f–745f sex cord tumor with annular tubules vs., 695 Gonadotropin-releasing hormone–treated leiomyomas, pathologic features, 411 Graft versus host disease (GVHD), 25–26, 26b clinical features of, 25 differential diagnosis of, 25 microscopic features of, 25, 26f pathologic features of, 26b prognosis and treatment for, 26 vulvovaginal chronic, 133 Granular cell tumors, 115, 116f Granulomatous reaction pattern, 28 aphthous and Lipschutz ulcer, 32–34, 33b Behcet disease, 34–35, 35b hidradenitis suppurativa, 28–30, 30b plasma cell vulvitis (Zoon vulvitis), 35–37, 37b vasculopathic, 32 Granulosa cell tumor adult-type, see Adult granulosa cell tumor juvenile, see Juvenile granulosa cell tumor mesenchymal tumors of uterine corpus vs., 807–808 ovarian carcinoid tumors vs., 737 sex cord tumor with annular tubules vs., 695 Group A Streptococcus, 124 Group B Streptococcus, 124

H Hailey-Hailey disease papular genitocrural acantholysis vs., 27 Hepatoid carcinoma, yolk sac tumor vs., 724–726 Hepatoid pattern, in yolk sac tumor, 720 Hereditary nonpolyposis colorectal cancer, see Lynch syndrome Herpes simplex virus (HSV) infection, 40–42, 42b ancillary features of, 41 aphthous and Lipschutz ulcer vs., 33 Behcet disease vs., 34 clinical features of, 40–41 differential diagnosis of, 41–42 erythema multiforme vs., 18 microscopic features of, 41, 41f pathologic features of, 42b plasma cell vulvitis vs., 36 prognosis and treatment for, 42 Hidradenitis suppurativa, 28–30, 30b clinical features of, 28 differential diagnosis of, 28 microscopic features of, 28, 29f–30f pathologic features of, 30b prognosis and treatment for, 29–30 High-grade adenosarcomas, 473 High-grade endometrial stromal sarcoma, 448–454 ancillary studies of, 451–452 clinical features of, 449 differential diagnosis of, 452–453 gross findings of, 449, 449f

INDEX

High-grade endometrial stromal sarcoma (Continued) immunohistochemistry of, 451–452 inflammatory myofibroblastic tumors vs., 466–469 microscopic findings of, 449–451, 450f–452f molecular analysis of, 452 Müllerian adenosarcoma vs., 478 pathologic features of, 454b PEComa vs., 461–463 prognosis and treatment for, 453–454, 453b undifferentiated uterine sarcoma vs., 456 undifferentiated/dedifferentiated endometrial carcinoma vs., 392–393 High-grade endometrioid carcinoma carcinosarcoma vs., 399–400 endometrial endometrioid carcinoma vs., 378–381 endometrial serous carcinoma vs., 386 undifferentiated/dedifferentiated endometrial carcinoma vs., 391–392 High-grade neuroendocrine carcinoma, small cell type, 285, 287b ancillary studies on, 285 clinical features of, 285 differential diagnosis of, 285 gross findings in, 285, 286f immunohistochemistry of, 285 microscopic findings in, 285, 286f pathologic features of, 285, 287b prognosis and therapy for, 285 squamous cell carcinoma vs., 256–257 High-grade serous carcinoma ovarian, 596–602, 602b adult granulosa cell tumor vs., 675–678 breast carcinoma vs., 776–779 clinical features of, 596–597 cytology of, 601 differential diagnosis of, 601 endometrioid tumors vs., 625 grading system for, 579t gross findings of, 597, 597f immunohistochemistry of, 601 low-grade serous carcinoma vs., 595–596 metastatic pancreaticobiliary carcinoma vs., 772 microscopic findings of, 598–601, 598f–600f molecular studies of, 601 pathologic features of, 597–601, 602b prognosis and therapy of, 601–602 with transitional morphology Brenner tumors vs., 633 urinary bladder carcinoma vs., 784–785 tubal, 521–524 clinical features of, 521 differential diagnosis of, 522–523 florid epithelial hyperplasia vs., 506 pathologic features of, 522, 523f–524f, 524b prognosis and therapy for, 523–524, 524b serous borderline tumors vs., 518 High-grade squamous intraepithelial lesion (HSIL) cervical, 233–240, 240b ancillary studies on, 233–234 clinical features of, 233 colonization of endocervical glands by, cervical adenocarcinoma in situ vs., 245

1001 High-grade squamous intraepithelial lesion (HSIL) (Continued) colposcopic features of, 233, 234f differential diagnosis of, 234–237, 236f, 238f–239f endometrial squamous metaplasia vs., 326 gross findings in, 233 immunohistochemistry of, 233–234, 237f invasive squamous cell carcinoma vs., 235–237 microscopic findings in, 233, 235f–236f pathologic findings of, 233, 240b prognosis and therapy for, 239–240 repair atypia vs., 234 cytology of, 973–974, 973f vaginal radiotherapy-associated changes and, 148 vaginal atrophy vs., 146 vulvar, 51–54, 54b ancillary studies of, 52 clinical features of, 51, 52f condyloma acuminatum vs., 48, 50f–51f differential diagnosis of, 52–53, 55f microscopic features of, 51–52, 53f–54f pathologic features of, 56b prognosis and therapy for, 54 High grade squamous intraepithelial lesion/vulvar intraepithelial lesion of usual type (HSIL/u-VIN), lichen simplex chronicus vs., 12–13 Highly cellular leiomyomas endometrial stromal nodule vs., 418 pathologic features of, 410f, 415, 416f Hilar cell hyperplasia, 556, 557f Hilar (Leydig) cell tumor, hilar cell hyperplasia vs., 556 HMGA2, immunohistochemical staining with, 911 endometrial carcinoma and, 924–925 Hormone replacement therapy, 309 HPV, see Human papillomavirus HPV-related endocervical adenocarcinoma, 261–268, 267b ancillary studies on, 264 clinical features of, 261 differential diagnosis of, 264–266 endometrial endometrioid carcinoma vs., 378 gastric-type mucinous adenocarcinoma vs., 273 gross findings in, 261, 262f immunohistochemistry of, 264, 266f–267f microscopic findings in, 261–264, 263f–265f molecular studies on, 264 pathologic features of, 261–264, 268b prognosis and therapy for, 248t, 266–268 HPV-unrelated endocervical adenocarcinoma, 268–273 clear cell, 273–274, 277f endometrioid, 277 gastric-type mucinous, 268–273, 274b mesonephric, 274–277, 278b HSV infection, see Herpes simplex virus (HSV) infection Human papillomavirus (HPV), cervical lesions and, 228 Hydatid of Morgagni, 531–532 Hydatidiform mole complete, 871–877, 877b clinical features of, 871–872 differential diagnosis of, 874–876 gross findings of, 872, 873f–874f immunohistochemistry of, 872–874 microscopic findings of, 872, 875f–877f

1002 Hydatidiform mole (Continued) molecular analysis of, 874 pathologic features of, 872, 878b prognosis and therapy of, 876–877 radiologic features of, 872 partial, 877–881, 883b clinical features of, 877 differential diagnosis of, 878–881, 881f–882f gross findings of, 878, 879f immunohistochemistry of, 878 microscopic findings of, 878, 880f molecular analysis of, 878 pathologic features of, 878, 883b prognosis and therapy of, 881 radiologic features of, 878 Hydropic abortus, complete hydatidiform mole vs., 874–875 Hymenal abnormalities, 119 Hyperplasia endometrial atypical, 338–345, 344b nonatypical, 334–338, 334f, 337b microglandular, see Microglandular hyperplasia stromal, see Stromal hyperplasia Hyperreactio luteinalis, 556–559, 560f, 564b pregnancy-associated changes vs., 562 Hypersensitivity eruptions, syphilis vs., 39–40 Hyperthecosis, stromal, 552–556, 555b clinical features of, 552–553 differential diagnosis of, 553–554 gross findings of, 553, 553f hilar cell hyperplasia vs., 556 immunohistochemistry of, 553, 554f–555f luteinized thecoma with sclerosing peritonitis vs., 654–655 microscopic findings of, 553, 553f–555f pathologic features of, 553, 555b prognosis and therapy of, 554–556 Hypertrophic lichen planus, 15, 15t Hysterectomy, leiomyoma, 421 Hysterosalpingography, 500

I Immature squamous metaplasia, 185–189, 189b ancillary studies on, 187 clinical features of, 185 differential diagnosis of, 187–189 pathologic features of, 185–187, 188f–189f, 190b prognosis and treatment for, 189 Immature teratomas, ovarian, 740–744, 743b ancillary studies for, 741 clinical features of, 740 differential diagnosis of, 741–743 gross findings for, 740, 740f immunohistochemistry of, 741 microscopic findings for, 740–741, 741f–742f molecular analysis for, 741 pathologic features of, 740–741, 743b prognosis and therapy for, 743–744 radiologic features of, 740 Immunohistochemistry, 905–958, 906t–908t diagnostic work-up of molar pregnancy, 952, 952f ovary/fallopian tube, 938–941 epithelial versus mesothelial proliferations, 950, 950b, 951f

INDEX

Immunohistochemistry (Continued) markers of value in typing of ovarian carcinomas, 941–946, 942t, 943f–945f, 945b ovarian germ cell tumors, 946–948, 948b, 949f ovarian sex cord-stromal tumors, markers of, 946, 946b, 948f, 948t primary versus secondary ovarian carcinoma, 938–941, 938f–940f, 938t, 940b, 942f, 942t serous tubal intraepithelial carcinoma, diagnosis of, 946, 946b, 947f small round cell tumors of, 948–950, 950f, 950b trophoblastic diseases, 950 markers of, 950, 951f, 951b, 952t uterine cervix, 911–915 adenocarcinoma distinction between cervical adenocarcinoma, 919–924, 919b, 921t, 923f benign glandular lesions exhibiting gastric differentiation, 919, 919b, 920f–921f cervical gastric-type adenocarcinomas, 919, 919b, 920f–921f cervical mesonephric lesions, 915–919 cervical neuroendocrine carcinomas, 924, 924b, 925f lower female genital tract lesions derived from misplaced Skene glands, 924, 926f preinvasive cervical glandular lesions, 915, 915b, 916f–918f preinvasive cervical squamous lesions, 911–915, 915b uterine corpus, 924–929 benign and malignant smooth muscle neoplasms, 934, 934b endometrial serous carcinoma and tubo-ovarian highgrade serous carcinoma, 929–930, 930b, 931f endometrial stromal and smooth muscle neoplasm vs., 933–934, 933t, 934f–935f endometrial stromal neoplasms, diagnosis of, 930–933, 932f–933f, 932b endometrioid carcinoma, typing of, 924–929, 929b miscellaneous uterine mesenchymal neoplasms, 934– 938, 938b vaginal lesions, 905–909 vulval lesions, 905–909 intraepithelial neoplasia, 908f preinvasive vulvar squamous lesions, 905–909, 909f vulvar squamous carcinomas, 909–910, 909b, 910f Implantation site, 303 Inactive endometrium, 307–309, 308f exogenous hormones vs., 309 Infections, of vulva, 37–38 candidiasis, 42–45, 45b herpes simplex virus (HSV) infection, 40–42, 42b syphilis, 38–40, 40b Infectious nongranulomatous salpingitis, 507 ancillary studies of, 508 clinical features of, 507 differential diagnosis of, 509 pathologic features of, 507–508, 508f–509f, 510b prognosis and therapy for, 509–510, 509b radiologic features of, 507 Infectious vaginitis, desquamative inflammatory vaginitis vs., 129 Inflammatory bowel disease, actinomycotic salpingitis vs., 512–513

1003

INDEX

Inflammatory diseases, vulvar, 1–46 acanthotic epidermal reaction pattern, 9 acanthotic reaction pattern, 26 classification of, 2t granulomatous reaction pattern, 28 infections, 37–38 lichenoid reaction pattern, 14 patterns, 2b spongiotic (eczematous) reaction pattern, 1–3 Inflammatory infiltrate, distribution of, 14 Inflammatory myofibroblastic tumor (IMT), 453, 466–469 ancillary studies of, 466 clinical features of, 466 differential diagnosis of, 419, 466–469 gross findings of, 466 high-grade endometrial stromal sarcoma vs., 453 immunohistochemistry of, 466, 936–937, 937f microscopic findings of, 466 molecular analysis of, 466 myxoid leiomyosarcoma vs., 432 pathologic features of, 466, 467f–468f, 469b postoperative spindle cell nodule vs., 136 prognosis and treatment for, 469, 469b smooth muscle tumors of uncertain malignant potential vs., 435 Inflammatory pseudotumor, see Inflammatory myofibroblastic tumor International Federation of Gynecologists and Obstetrics (FIGO) staging of carcinoma of ovary, fallopian tube, and peritoneum, 577, 578t of endometrial carcinoma, 346, 350b of endometrial endometrioid carcinoma, 361–362, 363f–366f of vaginal carcinoma, 166, 166t of vaginal squamous carcinoma, 162 of vulvar squamous cell carcinoma, 68b International Society for the Study of Vulvovaginal Disease (ISSVD), classification of vulvar dermatoses, 1, 2t Intestinal-type mucinous adenocarcinoma, of cervix, 262 Intraepithelial neoplasia cervical, 229 adenocarcinoma in situ, 240–245, 241f, 246b estimation of tumor size and stage, 245–250, 248t–249t, 249f general considerations for, 245–250 high-grade squamous intraepithelial lesion, 233–240, 240b low-grade squamous intraepithelial lesion, 229–233, 232b squamous cell carcinoma, 250–258, 258b terminology in, 229 tumor focality, 250, 251f endometrioid, 338–345, 344b ancillary studies of, 338–344 clinical features of, 338 differential diagnosis of, 338–344 gross findings of, 338 immunohistochemistry of, 338 microscopic findings of, 338, 339f–344f, 346f pathologic features of, 338, 345b prognosis and therapy of, 344–345

Intraepithelial neoplasia (Continued) vaginal, 157–162, 162b ancillary studies on, 159 clinical features of, 158 differential diagnosis of, 159–161 gross findings in, 158 immunohistochemistry of, 159, 160f–161f invasive squamous cell carcinoma vs., 161 microscopic findings in, 158–159, 158f–160f pathologic features of, 158–159, 162b prognosis and treatment for, 161–162 Intrauterine gestation, ectopic pregnancy vs., 502–503 Intravenous leiomyomatosis leiomyoma with intravascular intrusion vs., 437–438 low-grade endometrial stromal sarcoma vs., 446–447 microscopic findings of, 436, 437f primary ovarian smooth muscle tumors vs., 817 Invasive adenocarcinoma of endometrial or endocervical origin, endometriosis vs., 198 tubal and tuboendometrioid metaplasia vs., 193–194 Invasive carcinoma, endocervical, 259–261 clinical features of, 259 differential diagnosis of, 259–260 microscopic findings in, 259, 260f–261f pathologic features of, 250b, 259 prognosis and therapy for, 261 Invasive hydatidiform mole, 871–872, 874f Invasive squamous cell carcinoma cytology of, 976–981, 977f glandular lesions, 977–981, 978f–982f metastatic tumors, 981, 982f vulvar, 61–66, 68b clinical features of, 61 differential diagnosis of, 64–65 extramammary Paget disease vs., 74–77 gross features of, 61, 62f microscopic features of, 61–64, 63f–67f pathologic features of, 69b prognosis and therapy for, 66, 68b Invasive stratified mucin-producing carcinoma (ISMC), of cervix, 262, 264f adenosquamous carcinoma vs., 278–281 Inverse psoriasis, 9 Inverted transitional cell papilloma, 193 Irritant contact dermatitis, 4t, 5–7, 7b atopic dermatitis vs., 3 clinical features of, 5–6 differential diagnosis of, 7 microscopic features of, 6, 6f pathologic features of, 7b prognosis and treatment of, 7

J Juvenile granulosa cell tumor, 684–689, 688b ancillary studies for, 685–686 clear cell tumors vs., 628–630 clinical features of, 684 differential diagnosis of, 687 gross findings for, 684, 685f histochemistry and immunohistochemistry for, 685–686 metastatic melanoma vs., 794–797 microscopic findings for, 684–685, 685f–687f

1004 Juvenile granulosa cell tumor (Continued) molecular analysis for, 686 pathologic features of, 684–685, 688b prognosis and therapy for, 688–689 small cell carcinoma, hypercalcemic type vs., 815

K Keratinizing squamous cell carcinoma cervical, 252 well differentiated, vulvar, invasive squamous cell carcinoma vs., 64 Keratoacanthoma, vulvar, invasive squamous cell carcinoma vs., 64–65 Ki67 proliferation index of preinvasive cervical glandular lesions, 915 of vaginal intraepithelial neoplasia, 159 Koilocytosis, in vaginal intraepithelial neoplasia, 158–161 Krukenberg tumors cervical, 262 massive ovarian edema vs., 567 metastatic massive ovarian edema vs., 567 sclerosing stromal tumors vs., 657–658 sclerosing stromal tumors vs., 657–658 signet-ring stromal tumor vs., 663–664

L Large cell lymphoma, dysgerminoma vs., 712–713 Large cell neuroendocrine carcinoma cervical, immunohistochemistry, 924 endometrial, 394–396 Late secretory endometrium, 298, 301f–302f Leiomyoma with bizarre nuclei, 420 ancillary studies of, 421 clinical features of, 420–424 differential diagnosis of, 421 gross findings of, 421 immunohistochemistry of, 421 microscopic findings of, 421, 422f–423f molecular analysis of, 421 pathologic features of, 414, 421, 423b prognosis and therapy for, 421–424, 422b broad ligament, 537–538, 537f cellular, see Cellular leiomyoma cellular angiofibroma vs., 93 cervical malignant mesenchymal tumors vs., 288 intravenous leiomyomatosis vs., 437–438 spindle cell epithelioma vs., 157 with unusual anatomic distribution, 436–438 clinical features of, 436 differential diagnosis of, 437–438 microscopic findings of, 436–437 molecular analysis of, 437 pathologic features of, 436–437, 438b prognosis and therapy for, 438, 438b uterine, 407–420 ancillary studies of, 418 clinical features of, 407 differential diagnosis of, 418–419 gross findings of, 407–410, 408f–411f histochemistry of, 418, 420b

INDEX

Leiomyoma (Continued) immunohistochemistry of, 418, 420b inflammatory myofibroblastic tumors vs., 466–469 microscopic findings of, 410–418, 412f–414f molecular analysis of, 418 pathologic features of, 407–418, 420b prognosis and treatment for, 419–420, 419b treated, 411, 414f variants, 407–420 Leiomyomatosis diffuse, 418 intravenous, see Intravenous leiomyomatosis Leiomyomatosis peritonealis disseminata, primary ovarian smooth muscle tumors vs., 817 Leiomyosarcoma carcinosarcoma vs., 399–400 cervical, 287, 288f epithelioid, 424 mesenchymal tumors of uterine corpus vs., 807–808 postoperative spindle cell nodule vs., 136 tubal, 529–530 clinical features of, 529–530, 538 differential diagnosis of, 530, 538 pathologic features of, 530b, 538b prognosis and therapy for, 530, 530b, 538–539, 538b uterine, 424–433, 427f ancillary studies of, 429–431 clinical features of, 424 conventional leiomyomas vs., 418 differential diagnosis of, 431–432 gross findings of, 424, 425f–426f histochemistry of, 429 immunohistochemistry of, 429, 430f leiomyoma with bizarre nuclei vs., 421 low-grade endometrial stromal sarcoma vs., 446–447 microscopic findings of, 424–426 molecular analysis of, 430–431 pathologic features of, 424–426, 434b prognosis and treatment for, 432–433, 433b secondary (metastatic), 424 undifferentiated uterine sarcoma vs., 456 Lentigo dysplastic nevi vs., 82 hypertrophic lichen planus vs., 16–17 Leptothrix organisms, in cytology, 970 Leukemia breast carcinoma vs., 776–779 neuroendocrine carcinoma vs., 396 vaginal involvement in, 175 Leydig cell tumor, 665–667, 666b ancillary studies for, 665–666 clinical features of, 665 differential diagnosis of, 666 gross findings for, 665, 665f immunohistochemistry for, 665 microscopic findings for, 665, 666f–668f molecular analysis for, 666 pathologic features of, 665, 666b pregnancy-associated changes vs., 562 prognosis and therapy for, 667 steroid cell tumor vs., 670–672

INDEX

Lichen planus, 14–18, 17b ancillary studies of, 15 clinical features of, 14–15, 15t differential diagnosis of, 15–17 fixed drug eruption vs., 20 graft versus host disease vs., 25 lichen sclerosus vs., 23 microscopic features of, 15, 16f–17f pathologic features of, 18b prognosis and treatment for, 17–18 Lichen sclerosus, 22–25, 25b ancillary studies in, 22 clinical features of, 22 differential diagnosis of, 23 differentiated vulvar intraepithelial neoplasia vs., 56 graft versus host disease vs., 25 microscopic features of, 22, 23f–24f pathologic features of, 25b prognosis and treatment for, 23–25 vaginal atrophy vs., 146 Lichen simplex chronicus, 12–14, 14b clinical features of, 12, 12f condyloma acuminatum vs., 48 differential diagnosis of, 12–13 differentiated vulvar intraepithelial neoplasia vs., 56 lichen sclerosus vs., 23 microscopic features of, 12, 13f pathologic features of, 14b prognosis and treatment for, 14 psoriasis vs., 10–11 Lichenoid drug eruptions lichen planus vs., 15–16 plasma cell vulvitis vs., 36 Lichenoid keratosis, hypertrophic lichen planus vs., 16–17 Lichenoid reaction pattern, 14 erythema multiforme, 18–20, 20b fixed drug eruption (FDE), 20–22, 22b graft versus host disease, 25–26, 26b lichen planus, 14–18, 17b lichen sclerosus, 22–25, 25b Ligneous vaginitis, 130–131, 131b clinical features of, 130 differential diagnosis of, 130 microscopic findings in, 130, 131f pathologic features of, 130, 131b prognosis and therapy for, 131 vaginal atrophy vs., 146 Ligneous/pseudomembranous cervicitis, 221 Lipoidal salpingitis, tuberculous salpingitis vs., 510–511 Lipoleiomyoma, pathologic features of, 417 Liposarcoma dedifferentiated, solitary fibrous tumor vs., 109 vulvar, 116 Lipschutz ulcer, see Aphthous and Lipschutz ulcer Lobular endocervical glandular hyperplasia (LEGH), 206–209, 208b, 269–273 ancillary studies on, 208 clinical features of, 206 differential diagnosis of, 208 gross findings in, 206 microscopic findings in, 206, 207f pathologic features of, 206, 209b

1005 Lobular endocervical glandular hyperplasia (LEGH) (Continued) prognosis and treatment for, 208–209 tunnel clusters vs., 202 Longitudinal vaginal septa, 119 Lower uterine segment epithelium, cervical adenocarcinoma in situ vs., 244 Low-grade adenosarcoma, 473 atypical polypoid adenomyoma vs., 483 with myometrial invasion, Müllerian adenomyoma vs., 481 Low-grade appendiceal mucinous neoplasm (LAMN), mucinous borderline tumor vs., 611–612 Low-grade endometrial stromal neoplasms, 930 Low-grade endometrial stromal sarcoma adenomyosis vs., 487–488 ancillary studies of, 444–446 carcinosarcoma vs., 399–400 clinical features of, 443 differential diagnosis of, 446–448 endometrial stromal nodule vs., 442 fibromyxoid high-grade endometrial stromal sarcoma vs., 452–453 inflammatory myofibroblastic tumors vs., 466–469 myxoid leiomyosarcoma vs., 432 pathologic features of, 443–444, 446f gross findings of, 443 high-grade endometrial stromal sarcoma vs., 452–453 immunohistochemistry of, 444 intravenous leiomyomatosis vs., 437–438 leiomyosarcomas vs., 538 microscopic findings of, 443–444, 444f–445f molecular analysis of, 444–446 Müllerian adenosarcoma vs., 478 pathologic features of, 443–444, 448b prognosis and treatment for, 448, 448b uterine tumors resembling ovarian sex cord tumors vs., 460 Low-grade endometrioid carcinoma endometrial carcinoma and, 356, 924–925 endometrial endometrioid carcinoma vs., 374–378, 377f endometrial serous carcinoma vs., 381 Low-grade Müllerian adenosarcoma cervical malignant mesenchymal tumors vs., 288 endometrial polyp vs., 314 Low-grade serous carcinoma, 592–596, 596b clinical features of, 592 cytology of, 595 differential diagnosis of, 595–596 grading system for, 579t gross findings of, 592, 593f immunohistochemistry of, 595 microscopic findings of, 592–595, 594f–595f molecular analysis of, 595 pathologic features of, 592–595, 596b prognosis and therapy of, 596 serous borderline tumors vs., 590–591 Sertoli–Leydig cell tumor vs., 700–701 Low-grade squamous intraepithelial lesion (LSIL) cervical, 229–233, 232b clinical features of, 230 colposcopic features of, 230, 230f differential diagnosis of, 232 gross findings in, 230 high-grade squamous epithelial lesion vs., 232

1006 Low-grade squamous intraepithelial lesion (LSIL) (Continued) microscopic findings in, 231, 231f pathologic features of, 230–231, 233b prognosis and therapy for, 232–233 cytology of, 974–975, 974f vulvar, 47–51, 48f, 50b differential diagnosis of, 48, 50f–51f high grade squamous intraepithelial lesion vs., 52–53 microscopic features of, 47–48, 49f–50f pathologic features of, 51b prognosis and therapy for, 48–51 Lues maligna, 38 Lung carcinoma, metastatic, 780–784, 783b, 940 ancillary studies of, 780 clinical features of, 780 differential diagnosis of, 780–784 gross findings of, 780, 781f immunohistochemistry of, 780, 782f–783f microscopic findings of, 780, 781f–782f pathologic features of, 780, 783b Luteinized granulosa cell tumor, steroid cell tumor vs., 670–672 Luteinized thecoma with sclerosing peritonitis, 651–655, 655b ancillary studies for, 653 clinical features of, 651 differential diagnosis of, 653–655 fibroma vs., 647 gross findings for, 651, 652f immunohistochemistry for, 653 microscopic findings for, 651–652, 653f–654f pathologic features of, 651–652, 655b prognosis and therapy for, 655 sclerosing stromal tumors vs., 657–658 steroid cell tumor vs., 670–672 Luteoma pregnancy, 556–557, 558f, 563b steroid cell tumor vs., 670–672 thecoma vs., 649 stromal, stromal hyperplasia and hyperthecosis vs., 553–554 Lymph node metastases in endometrial carcinoma, 355–356 endometrioid carcinoma vs., 355–356 Lymphangioleiomyomatosis (LAM), intravenous leiomyomatosis vs., 437–438 Lymphangioleiomyomatosis-like PEComa, 461 Lymphangioma, adenomatoid tumor vs., 514–515 Lymphatic vascular invasion (LVI), 352 Lymphoepithelioma-like carcinoma, cervical, 255, 257f Lymphoma breast carcinoma vs., 776–779 HSV infection vs., 41–42 neuroendocrine carcinoma vs., 396 non-Hodgkin, secondary involvement by, 798 ancillary studies of, 798 clinical features of, 798 differential diagnosis of, 798 gross findings of, 798, 799f–800f immunohistochemistry of, 798 pathologic features of, 798, 798b rhabdomyosarcoma vs., 471

INDEX

Lymphoma (Continued) undifferentiated/dedifferentiated endometrial carcinoma vs., 392–393 vaginal, 175–177, 177b ancillary studies on, 175 clinical features of, 175 differential diagnosis of, 175–177 gross findings in, 175 immunohistochemistry of, 175, 176f microscopic findings in, 175, 176f–177f pathologic features of, 175, 178b primary, 175 prognosis and treatment for, 177 Lymphoma-like lesions, hematolymphoid malignancies vs., 175–177 Lymphomatoid papulosis, HSV infection vs., 41–42 Lymphoproliferative disorders, endometritis vs., 318 Lynch syndrome, 358–361, 359f–360f

M Malakoplakia, 131–132 ancillary studies on, 132 clinical features of, 132 differential diagnosis of, 132 microscopic findings in, 132, 132f prognosis and therapy for, 132 Malignant neuroectodermal tumor, immature teratoma vs., 743 Malignant rhabdoid tumor, epithelioid sarcoma (distal and proximal types) vs., 113–114 Mammary-type myofibroblastoma, 94–96, 96b ancillary studies of, 94–96 angiomyofibroblastoma vs., 91–92 cellular angiofibroma vs., 93 clinical features of, 94 differential diagnosis of, 96 gross findings of, 94, 95f immunohistochemistry of, 94 microscopic findings of, 94, 95f molecular analysis of, 96 pathologic features of, 94, 96b prognosis and therapy for, 96 vulvovaginal smooth muscle tumors vs., 102–103 Marked decidualized reaction, squamous cell carcinoma vs., 255 Massive ovarian edema, 565–568, 567b clinical features of, 565 differential diagnosis of, 567, 567f fibroma vs., 647 gross findings of, 565, 565f microscopic findings of, 565, 566f pathologic features of, 565, 567b prognosis and therapy of, 567–568 Mature cystic teratoma, ovarian, 728, 732b clinical features of, 728 gross findings for, 728, 729f microscopic findings for, 729–731, 729f–731f molecular analysis for, 731 pathologic features of, 728–731, 732b prognosis and therapy for, 731 radiologic features of, 728 Mayer-Rokitansky-Küster-Hauser syndrome, 120 Medulla, 545

INDEX

Melanocytic lesions, 77 atypical melanocytic nevi of genital type, 78–81, 81b clinical features of, 78 differential diagnosis of, 80 gross findings of, 78, 79f microscopic findings of, 78–80, 79f–80f pathologic features of, 78–80, 81b prognosis and therapy for, 81 dysplastic nevi, 81–83, 82b clinical features of, 81 differential diagnosis of, 82 gross findings of, 81 microscopic findings of, 81, 82f pathologic features of, 81, 83b prognosis and therapy for, 82–83 melanoma, 83–88, 87b ancillary studies of, 84 clinical features of, 83, 83f differential diagnosis of, 84–86 gross findings of, 83 immunohistochemistry of, 84 microscopic findings of, 83–84, 84f–86f molecular analysis of, 84 pathologic features of, 83–84, 87b prognosis and therapy for, 86–88, 87f mucosal lentigo, 77, 78f Melanoma epithelioid sarcoma (distal and proximal types) vs., 113–114 hypertrophic lichen planus vs., 16–17 juvenile granulosa cell tumor vs., 687 metastatic, 794–798, 797b ancillary studies of, 794 clinical features of, 794 differential diagnosis of, 794–798 dysgerminoma vs., 712–713 gross findings of, 794 immunohistochemistry of, 794 microscopic findings of, 794, 796f–797f nongynecologic small round blue cell sarcoma vs., 793 pathologic features of, 794 ovarian, metastatic melanoma vs., 794–797 PEComa vs., 461–463 vaginal, 172–175, 174b ancillary studies on, 172–174 clinical features of, 172 differential diagnosis of, 174 gross findings in, 172 immunohistochemistry of, 172–174, 173f microscopic findings in, 172, 173f, 174t molecular findings in, 174 pathologic features of, 172, 174b prognosis and treatment for, 174–175 vulvar, 83–88, 87b ancillary studies of, 84 atypical melanocytic nevi of genital type vs., 80 clinical features of, 83, 83f differential diagnosis of, 84–86 extramammary Paget disease vs., 74–77 gross findings of, 83 immunohistochemistry of, 84 microscopic findings of, 83–84, 84f–86f

1007 Melanoma (Continued) molecular analysis of, 84 pathologic features of, 83–84, 87b prognosis and therapy for, 86–88, 87f Menstrual endometrium, 298 endometritis vs., 317–318 Merkel cell carcinoma, vulvar, invasive squamous cell carcinoma vs., 64 Mesenchymal lesions cervical, 285–290, 290b ancillary studies on, 288 clinical features of, 287 differential diagnosis of, 288 gross features of, 287 immunohistochemistry of, 288 microscopic findings in, 287–288, 288f–290f pathologic findings of, 287–288, 290b prognosis and therapy for, 288–290 tubal, 528, 529f uterine, 407–496 vulvovaginal, 89–118 angiomyofibroblastoma, 91–92, 92b cellular angiofibroma, 92–94, 92b deep (aggressive) angiomyxoma, 99–101, 100b embryonal rhabdomyosarcoma, 105–108, 106b epithelioid sarcoma (distal and proximal types), 111–115, 115b fibroepithelial stromal polyp, 89–91, 90b immunohistochemistry, 911, 911b, 914f mammary-type myofibroblastoma, 94–96, 96b prepubertal vulvar fibroma, 96–98, 97b rhabdomyoma, 103–105, 105b solitary fibrous tumor, 108–111, 111b superficial angiomyxoma, 98–99, 99b vulvovaginal smooth muscle tumors, 101–103, 103b Mesonephric (adeno)carcinoma cervical, 274–277, 278b ancillary studies on, 276 clinical features of, 274 differential diagnosis of, 277 gross findings in, 274 immunohistochemistry of, 276 mesonephric hyperplasia vs., 211–212 microscopic findings in, 275–276, 279f molecular analysis of, 276 pathologic features of, 274–276, 278b prognosis and therapy for, 277 endometrial, 401–402, 402f–403f female adnexal tumor of probable wolffian origin vs., 532 vaginal, 167, 171f Mesonephric duct remnants of broad ligament, 530, 531f cervical, 210–213, 213b ancillary studies on, 211 clinical features of, 210 differential diagnosis of, 211–212 gross findings in, 210 microscopic findings in, 210–211, 211f–213f pathologic features of, 210–211, 213b prognosis and treatment for, 213 endometriosis vs., 570–572

1008 Mesonephric hyperplasia cervical, 210–213, 213b lobular endocervical glandular hyperplasia vs., 208 Mesothelial hyperplasia, peritoneal mesothelioma vs., 848–853, 851f–852f Mesothelioma ovarian, 822–823 uterine adenomatoid tumor vs., 489–490 Mesothelioma, malignant peritoneal, 845–857, 857b ancillary studies of, 848 clinical features of, 845 differential diagnosis of, 848–854, 851f–856f gross findings of, 845, 846f histochemistry of, 848 immunohistochemistry of, 848 microscopic findings of, 845–848, 847f–850f pathologic features of, 845–848, 857b prognosis and therapy of, 854–857 primary peritoneal carcinoma vs., 843–844 secondary involvement by, 790–793, 793b ancillary studies of, 791 clinical features of, 790 gross findings of, 790 immunohistochemistry of, 791–793 microscopic findings of, 791, 791f–792f pathologic features of, 790–791, 793b Metaplasia endometrial, 324–325, 324b endometrial endometrioid carcinoma vs., 376 eosinophilic, 328–329, 329f mucinous, 326–328, 327f nonatypical endometrial hyperplasia vs., 337 papillary, 328, 330f–331f squamous, see Squamous metaplasia tubal, 328, 328f intestinal, 194 oxyphilic, 194 pyloric, 194–195, 197f transitional cell, see Transitional cell metaplasia tubal, see Tubal metaplasia types of, 194–195 Metaplastic papillary tumor, 515–516 ancillary studies of, 515 clinical features of, 515 differential diagnosis of, 515 pathologic features of, 515, 516f, 516b prognosis and therapy for, 516, 516b serous borderline tumors vs., 518 Metastases lymph node, see Lymph node metastases vaginal, 180–183, 181f–182f primary carcinoma vs., 180–183 Metastatic carcinoma, ovarian, 749 clinical features of, 749 general features of, 749–750, 750b gross findings of, 749–750 mesenchymal tumors of uterine corpus vs., 807–808 microscopic findings of, 750 pathologic features of, 749–750, 757b prognosis and therapy of, 750

INDEX

Metastatic cervical adenocarcinoma/squamous cell carcinoma, 940 Metastatic colorectal adenocarcinoma, 938–940 endometrioid tumors vs., 625 mucinous adenocarcinoma vs., 616–617 Metastatic hepatocellular carcinoma, yolk sac tumor vs., 724–726 Metastatic mucinous adenocarcinoma, to ovary, mucinous adenocarcinoma vs., 616–617 Metastatic primary neoplasm, 749–828 from gynecologic sites, 798–803 carcinoma of uterine corpus, 803–807 mesenchymal tumors of uterine corpus, 807–808 uterine cervix, carcinoma of, 798–803 from nongynecologic sites, 750–757 appendix, 757–764 breast, 772–780 colorectal, 750–757 extraovarian carcinoid tumor, 787–790 lung carcinoma, 780–784 melanoma, 794–798 mesothelioma, malignant, secondary involvement by, 790–793 metastatic renal clear cell carcinoma, 785–787 non-Hodgkin lymphoma, secondary involvement by, 798 pancreaticobiliary tract, carcinoma of, 767–772 stomach carcinoma, 764–767 ovarian, 749 clinical features of, 749 general features of, 749–750, 750b gross findings of, 749–750 microscopic findings of, 750 pathologic features of, 749–750, 757b prognosis and therapy of, 750 Metastatic tumors, of fallopian tube, 528, 528f Metastatic urothelial carcinoma, Brenner tumors vs., 633 Metastatic uterine leiomyosarcoma, primary ovarian smooth muscle tumors vs., 817 Methotrexate, complications of, aphthous and Lipschutz ulcer vs., 33 Michaelis-Gutmann bodies, 132 Microcystic spaces, in yolk sac tumor, 675 Microcystic stromal tumor, 658–662, 662b ancillary studies for, 660–662 clinical features of, 658 differential diagnosis of, 662 gross findings for, 658 immunohistochemistry of, 660, 661f microscopic findings for, 658–659, 659f–660f molecular analysis for, 660–662 pathologic features of, 658–659, 662b prognosis and therapy for, 662 Microglandular adenocarcinomas, microglandular hyperplasia vs., 204–206 Microglandular hyperplasia, 203–206, 206b ancillary studies on, 204 cervical, 264–265 AEH/EIN vs., 340, 343f endometrioid carcinoma vs., 378 clinical features of, 203 differential diagnosis of, 204–206 gross findings in, 204

INDEX

Microglandular hyperplasia (Continued) microscopic findings in, 204, 205f mucinous metaplasia vs., 326 pathologic features of, 204, 206b Micropapillomatosis, vaginal, 159–161 Mid secretory endometrium, 298, 300f Minimal deviation adenocarcinoma, tunnel clusters vs., 202 Mitotic activity (and mitotically active tumors) of inactive endometrium, 307 leiomyoma, pathologic features of, 414–415 leiomyosarcoma, pathologic features of, 424, 429f Mixed tumors endometrial, 402–403 Müllerian, 472 epithelial cervical, 290–292, 291f ovarian, 637, 637t sex cord-stromal, 696 vaginal, 154–157 tubulosquamous polyp vs., 133–134 Molar gestational trophoblastic disease, 871 complete hydatidiform mole (including invasive mole), 871–877, 877b clinical features of, 871–872 differential diagnosis of, 874–876 gross findings of, 872, 873f–874f immunohistochemistry of, 872–874 microscopic findings of, 872, 875f–877f molecular analysis of, 874 pathologic features of, 872, 878b prognosis and therapy of, 876–877 radiologic features of, 872 partial hydatidiform mole, 877–881, 883b clinical features of, 877 differential diagnosis of, 878–881, 881f–882f gross findings of, 878, 879f immunohistochemistry of, 878 microscopic findings of, 878, 880f molecular analysis of, 878 pathologic features of, 878, 883b prognosis and therapy of, 881 radiologic features of, 878 Molar pregnancy, diagnostic work-up of, 952, 952f Morphea, lichen sclerosus vs., 23 Mucin, localized, acellular collections of, pseudomyxoma peritonei vs., 863–864 Mucinous borderline tumor, 608–613, 613b benign mucinous tumors vs., 607–608 clinical features of, 608 differential diagnosis of, 611–612 gross findings of, 608, 609f immunohistochemistry of, 609–611 microscopic findings of, 608–609, 610f–612f molecular analysis of, 611 pathologic features of, 608–609, 613b prognosis and therapy of, 613 seromucinous borderline tumors vs., 604 Mucinous carcinoid tumor, stomach carcinoma vs., 765

1009 Mucinous (adeno)carcinoma, 613–617 endometrial, 366 endometrial carcinoma and, 356, 373f primary endocervical adenocarcinoma vs., 919 ovarian, 577–578, 617b appendiceal carcinoma vs., 759 clinical features of, 613–614 colorectal carcinoma vs., 752–757 differential diagnosis of, 616–617 gross findings of, 614, 614f immunohistochemistry of, 615–616 lung carcinoma vs., 783 metastatic pancreaticobiliary carcinoma vs., 772 microscopic findings of, 614, 615f–616f molecular analysis of, 616 mucinous borderline tumor vs., 611–612 pathologic features of, 614, 617b prognosis and therapy of, 617 tubal, 527 vaginal, 167 Mucinous cystadenoma benign serous tumors vs., 579–581 with focal proliferation, mucinous borderline tumor vs., 611–612 Mucinous cystic tumor with mural nodules, 618–620, 618f–620f with pseudomyxoma peritonei, 620 Mucinous metaplasia endometrial, 326–328 differential diagnosis of, 326–328 pathologic features of, 326, 327f, 328b tubal, 497 Mucinous tumors, 606 adenocarcinoma, 613–617, 617b clinical features of, 613–614 differential diagnosis of, 616–617 gross findings of, 614, 614f immunohistochemistry of, 615–616 microscopic findings of, 614, 615f–616f molecular analysis of, 616 pathologic features of, 614, 617b prognosis and therapy of, 617 benign, 606–608, 608b clinical features of, 606 differential diagnosis of, 607–608 gross findings of, 606, 607f microscopic findings of, 606–607 pathologic features of, 606–607, 608b prognosis and therapy of, 608 borderline, 608–613, 613b benign mucinous tumors vs., 607–608 clinical features of, 608 differential diagnosis of, 611–612 gross findings of, 608, 609f immunohistochemistry of, 609–611 microscopic findings of, 608–609, 610f–612f molecular analysis of, 611 pathologic features of, 608–609, 613b prognosis and therapy of, 613 seromucinous borderline tumors vs., 604 Brenner, 631–637, 637b classification of, 631t

1010 Mucinous tumors (Continued) clinical features of, 632 differential diagnosis of, 633 gross findings of, 632, 632f–633f immunohistochemistry of, 633 microscopic findings of, 632, 634f–636f pathologic features of, 632 pathological features of, 637b prognosis and therapy of, 633–637 classification of, 606t clear cell, 626–631, 631b classification of, 626t clinical features of, 626 differential diagnosis of, 628–630 gross findings of, 627, 627f immunohistochemistry of, 628 microscopic findings of, 627, 628f–630f molecular analysis of, 628 pathologic features of, 627, 631b prognosis and therapy of, 630–631 radiographic features of, 626–627 endometrioid, 621–626, 625b classification of, 621t clinical features of, 621 differential diagnosis of, 625 gross findings of, 621, 621f immunohistochemistry of, 624 microscopic findings of, 622–624, 622f–624f molecular analysis of, 624–625 pathologic features of, 621–624, 626b prognosis and therapy of, 625–626 mixed epithelial, 637, 637t mucinous cystic tumor with mural nodules, 618–620, 618f–620f with pseudomyxoma peritonei, 620 Mucosal lentigo, 77, 78f Mucosal melanoma, dysplastic nevi vs., 82 Müllerian adenomyoma, 479–481 adenomyosis vs., 487–488 ancillary studies of, 481 atypical polypoid adenomyoma vs., 483 clinical features of, 479 differential diagnosis of, 481 gross findings of, 479 immunohistochemistry of, 481 microscopic findings of, 480–481 molecular analysis of, 481 pathologic features of, 479–481, 480f, 482b prognosis and treatment for, 481, 482b Müllerian adenosarcoma, 472–479 ancillary studies of, 478 carcinosarcoma vs., 399–400 clinical features of, 472 differential diagnosis of, 478 endocervical polyp vs., 215 endometrial, 472–479 endometriosis vs., 198, 837 gross findings of, 473 immunohistochemistry of, 478 metaplastic papillary tumor vs., 517 microscopic findings of, 473, 474f–477f molecular analysis of, 478

INDEX

Müllerian adenosarcoma (Continued) pathologic features of, 473–478, 473f, 479b prognosis and treatment for, 478–479, 479b rhabdomyosarcoma vs., 470–471 with sarcomatous overgrowth, 473, 480f tubal endometriosis vs., 504–505 undifferentiated uterine sarcoma vs., 456 Müllerian cystadenoma, pregnancy-associated changes vs., 562 Müllerian papilloma, 153–154 ancillary studies on, 153 clinical features of, 153 differential diagnosis of, 153–154 gross findings in, 153 microscopic findings in, 153, 154f pathologic features of, 153 prognosis and treatment for, 154 Müllerian-type inclusion cysts, 568 Multilocular peritoneal inclusion cysts, peritoneal mesothelioma vs., 853–854 Multiple follicular cysts, 545–546 Munro microabscesses, 9–10, 10f Myeloid sarcoma, vaginal, 175–177, 177b Myoepithelial carcinoma, epithelioid sarcoma (distal and proximal types) vs., 113–114 Myomectomy, 419, 421 Myometrium invasion, in endometrial carcinoma, 346–350, 351f–354f Myxoid leiomyoma inflammatory myofibroblastic tumors vs., 466–469 pathologic features of, 414f, 417 prognosis and treatment of, 433 Myxoid leiomyosarcoma differential diagnosis of, 426, 431f epithelioid leiomyosarcoma vs., 419 high-grade endometrial stromal sarcoma vs., 453 inflammatory myofibroblastic tumors vs., 466–469 pathologic features of, 426, 431f

N Nabothian cysts, gastric type endocervical adenocarcinoma vs., 273 Neuroendocrine carcinoma cervical, 283–284 immunohistochemistry of, 924, 924b, 925f endometrial, 394 ancillary studies of, 396 differential diagnosis of, 396–397 immunohistochemistry of, 396 microscopic findings of, 394–396, 395f pathologic features of, 396b undifferentiated/dedifferentiated endometrial carcinoma vs., 391–392 ovarian carcinoid tumors vs., 737 tubal, 527–528 vaginal, 171–172 Next-generation sequencing (NGS) panels, endometrial stromal tumors and, 930 Nodular fasciitis, 116 Nonatypical endometrial hyperplasia, 334–338, 334f, 337b AEH/EIN vs., 339 anovulation vs., 320

1011

INDEX

Nonatypical endometrial hyperplasia (Continued) clinical features of, 334 differential diagnosis of, 334–337 gross findings of, 334, 334f microscopic findings of, 334, 335f–336f pathologic features of, 334, 337b prognosis and therapy of, 337–338 Nondestructive growth, in invasive carcinoma, 259, 260f–261f Nongestational choriocarcinoma, 717–719, 719b ancillary studies for, 719 clinical features of, 717 differential diagnosis of, 719 gross findings for, 717 microscopic findings for, 717–718, 718f pathologic features of, 717–718, 719b prognosis and therapy for, 719 Non-Hodgkin lymphoma, secondary involvement by, 798 ancillary studies of, 798 clinical features of, 798 differential diagnosis of, 798 gross findings of, 798, 799f–800f immunohistochemistry of, 798 pathologic features of, 798, 798b Noninvasive desmoplastic-type implants, 585–587 Noninvasive epithelial implants, 585–587 “Noninvasive low-grade serous carcinoma,” 584 Nonmolar aneuploidy gestations, partial hydatidiform mole vs., 879–880 Nonmolar gestational trophoblastic disease differential diagnosis of, 884t epithelioid trophoblastic tumor, 887–890, 892b clinical features of, 887 differential diagnosis of, 889–890 gross findings of, 887, 889f immunohistochemistry of, 889, 893f microscopic findings of, 887–889, 890f–892f pathologic features of, 887–889, 892b prognosis and therapy of, 890 gestational choriocarcinoma, 897–902, 902b clinical features of, 898 differential diagnosis of, 899–900 gross findings of, 898, 900f immunohistochemistry of, 899 microscopic findings of, 898–899, 900f–901f pathologic features of, 898–899, 902b prognosis and therapy of, 901–902 placental site nodule, 881, 888b clinical features of, 883 differential diagnosis of, 884–886, 888f gross findings of, 883 immunohistochemistry of, 884, 887f microscopic findings of, 883–884, 885f–886f pathologic features of, 883–884, 888b prognosis and therapy of, 886–887 placental site trophoblastic tumor, 890–897, 899b clinical features of, 890–891 differential diagnosis of, 894–895, 898f gross findings of, 892, 894f immunohistochemistry of, 894, 897f microscopic findings of, 892–893, 895f–896f

Nonmolar gestational trophoblastic disease (Continued) pathologic features of, 892–893, 899b prognosis and therapy of, 895–897 radiologic features of, 891–892 Nonneoplastic lesions, of ovary, 545–576 Normal endocervical glands/crypts, gastric-type mucinous adenocarcinoma vs., 269–273 Normal glandular architecture, adenocarcinoma in situ and, 241

O Oophoritis, 572–574, 573f–574f Oral contraceptives, 309, 311f Ovarian carcinomas markers of value in typing of, 941–946, 942t, 943f–945f, 945b primary versus secondary, 938–941, 938f–940f, 938t, 940b, 942f, 942t secondary ovarian carcinoma vs., 938–941, 938f–940f, 938t, 940b, 942f, 942t Ovarian edema, massive, 565–568, 567b clinical features of, 565 differential diagnosis of, 567, 567f gross findings of, 565, 565f microscopic findings of, 565, 566f pathologic features of, 565, 567b prognosis and therapy of, 567–568 Ovarian hemorrhage, ovarian torsion vs., 564–565 Ovarian hilum, 545 Ovarian hyperstimulation syndrome, 556–557 Ovarian pulmonary-type small cell carcinoma, lung carcinoma vs., 780–783 Ovarian torsion, 564–565, 564f Ovarian vein thrombosis, ovarian torsion vs., 564–565 Ovary epithelial neoplasms of, 577–642 germ cell neoplasm of, 707–748, 707b, 708t dysgerminoma, 707–713 embryonal carcinoma, 713–717, 717b gonadoblastoma, 744, 744f–745f immature teratomas, 740–744, 743b mature cystic teratoma, 728 nongestational choriocarcinoma, 717–719 ovarian carcinoid tumors, 735–740 polyembryoma, 744, 745f struma ovarii, 731–735 teratomas, 728 yolk sac tumor, 719–728, 727b immunohistochemistry, see Immunohistochemistry nonneoplastic lesions of, 545–576 sex cord-stromal tumors of, 643–706, 644b Ovulatory dysfunctional cycles, 322–324, 324b anovulation vs., 322–324 clinical features of, 322 differential diagnosis of, 322–324 microscopic findings in, 322 pathologic features of, 322, 323f, 324b prognosis and therapy for, 324 Oxyphilic endometrioid adenocarcinoma, steroid cell tumor vs., 672

1012 P p16 endometrial carcinoma and, 924–925 endometrial vs. endocervical adenocarcinoma, 921–922 preinvasive cervical glandular lesions, 915 vulvar squamous lesions, 905–909 p53 endometrial carcinoma and, 924–925 in serous tubal intraepithelial carcinoma, 519, 522f vulvar squamous lesions, 905–909 Paget disease extramammary, 71–77, 77b ancillary studies of, 71–73 clinical features of, 71, 72f differential diagnosis of, 74–77 gross findings of, 71 immunohistochemistry of, 71–73, 75f–76f microscopic findings of, 71, 73f–75f pathologic features of, 71, 77b prognosis and therapy for, 77 vulvar, 910–911, 911b, 912f–913f Pagetoid dyskeratosis, extramammary Paget disease vs., 75–77 Pancreaticobiliary carcinoma, metastatic, 767–772, 772b, 940 ancillary studies of, 770 clinical features of, 767 differential diagnosis of, 772 gross findings of, 770 immunohistochemistry of, 770, 775f, 785f microscopic findings of, 770, 770f–774f pathologic features of, 770, 774b Papillary cystadenoma, 532–534 clinical features of, 532–533 differential diagnosis of, 533 prognosis and therapy for, 533–534 serous borderline tumor of broad ligament vs., 536 Papillary endocervicitis, 218, 221f Papillary metaplasia, of endometrium, 329–331 differential diagnosis of, 330–331 pathologic features of, 329–330, 330f–331f, 330b syncytial, 329 Papillary squamous cell carcinoma, cervical, 254 Papilloma Arias-Stella reaction, 216 deciduosis, 216–217 inverted transitional cell, 193 radiation-associated atypia, 218 reactive glandular atypia, 218 reparative glandular atypia, 218 squamous, 193 Müllerian, 153–154 Papular genitocrural acantholysis, 26–28, 28b clinical features of, 27 differential diagnosis of, 27 microscopic features of, 27, 27f pathologic features of, 28b prognosis and treatment for, 27–28 Paraovarian cysts, 531–532 Parasitic vaginitis, 125, 126f PARP inhibitors, for high-grade serous carcinoma, 601–602

INDEX

Partial hydatidiform mole (PHM), 877–881, 883b clinical features of, 877 complete hydatidiform mole vs., 876 differential diagnosis of, 878–881, 881f–882f gross findings of, 878, 879f immunohistochemistry of, 878 microscopic findings of, 878, 880f molecular analysis of, 878 pathologic features of, 878, 883b prognosis and therapy of, 881 radiologic features of, 878 PCOS, see Polycystic ovarian syndrome PEComa (perivascular epithelioid cell tumor), 288, 432, 460–466 ancillary studies of, 461 clinical features of, 460 differential diagnosis of, 461–463 epithelioid leiomyoma vs., 419 epithelioid leiomyosarcoma vs., 432 gross findings of, 461 immunohistochemistry of, 461 microscopic findings of, 461, 462f–464f molecular analysis of, 461 pathologic features of, 461, 465b prognosis and treatment of, 465–466, 465t, 465b with RAD51B rearrangement, 461 smooth muscle tumors of uncertain malignant potential vs., 435 with TFE3 rearrangement, 461 uterine, 935, 936f uterine tumors resembling ovarian sex cord tumors vs., 460 PEComatosis, 461 Pelvic wash specimens, in cytology, 981–983, 983f–985f Pemphigus vegetans, atopic dermatitis vs., 3 Pemphigus vulgaris, 133 Periovulatory endometrium, 296–297, 298f Peritoneal carcinoma, primary, 840–845, 844b ancillary studies of, 841 clinical features of, 840 differential diagnosis of, 843–844, 843f gross findings of, 840–841, 840f–841f immunohistochemistry of, 841 microscopic findings of, 841, 842f pathologic features of, 840–841, 845b prognosis and therapy of, 844–845 Peritoneal inclusions, 545 Peritoneal mesothelioma, 845–857, 857b ancillary studies of, 848 clinical features of, 845 differential diagnosis of, 848–854, 851f–856f gross findings of, 845, 846f histochemistry of, 848 immunohistochemistry of, 848 microscopic findings of, 845–848, 847f–850f pathologic features of, 845–848, 857b prognosis and therapy of, 854–857 Peritoneal serous borderline tumor, primary peritoneal carcinoma vs., 843 Peritoneal-type cysts, 568 Peritoneum, diseases of, 829–870 desmoplastic small round cell tumor, 865–868, 866f–867f disseminated peritoneal leiomyomatosis, 868, 868f–869f

INDEX

Peritoneum, diseases of (Continued) endometriosis, 829–840, 839b ancillary studies of, 834 clinical features of, 829 differential diagnosis of, 835–837, 839f gross findings of, 829–831, 830f–831f immunohistochemistry of, 834 microscopic findings of, 831–834, 832f–838f pathologic features of, 829–834, 839b prognosis and therapy of, 837–840 primary peritoneal carcinoma, 840–845, 844b ancillary studies of, 841 clinical features of, 840 differential diagnosis of, 843–844, 843f gross findings of, 840–841, 840f–841f immunohistochemistry of, 841 microscopic findings of, 841, 842f pathologic features of, 840–841, 845b prognosis and therapy of, 844–845 pseudomyxoma peritonei, 857–865, 865b ancillary studies of, 863 clinical features of, 857, 858f differential diagnosis of, 863–864 gross findings of, 858, 858f–859f immunohistochemistry of, 863 microscopic findings of, 860–863, 860f–864f pathologic features of, 858–863, 865b prognosis and therapy of, 864–865 Perivascular epithelioid cell tumor, see PEComa Persistent gestational trophoblastic disease, 876 Pilonidal sinus, hidradenitis suppurativa vs., 28 Placental mesenchymal dysplasia, partial hydatidiform mole vs., 880–881, 882f Placental site nodule, 881, 888b cervical squamous cell carcinoma vs., 255 clinical features of, 883 differential diagnosis of, 884–886, 888f gestational endometrium and pregnancy related changes vs., 303–307 gross findings of, 883 immunohistochemistry of, 884, 887f microscopic findings of, 883–884, 885f–886f pathologic features of, 883–884, 888b prognosis and therapy of, 886–887 Placental site trophoblastic tumor, 890–897, 899b clinical features of, 890–891 differential diagnosis of, 894–895, 898f endometrial clear cell carcinoma vs., 390 gross findings of, 892, 894f immunohistochemistry of, 894, 897f microscopic findings of, 892–893, 895f–896f pathologic features of, 892–893, 899b prognosis and therapy of, 895–897 radiologic features of, 891–892 Plasma cell cervicitis, 218–220 Plasma cell dyscrasia, plasma cell vulvitis vs., 36 Plasma cell vulvitis (Zoon vulvitis), 35–37, 37b clinical features of, 35–36 differential diagnosis of, 36 lichen planus vs., 15–16 microscopic features of, 36, 36f–37f pathologic features of, 37b

1013 Plasma cell vulvitis (Zoon vulvitis) (Continued) prognosis and treatment for, 36–37 syphilis vs., 39–40 Platinum-based chemotherapy, for high-grade serous carcinoma, 601–602 Polycystic ovarian syndrome (PCOS), 545–546, 549f, 551f, 552b Polyembryoma, 744, 745f Polyp(s), see Endocervical polyps; Endometrial polyps; Fibroepithelial polyps; Fibroepithelial stromal polyps Polypoid endometriosis, 569, 831 Polyvesicular pattern, in yolk sac tumor, 720 Polyvinyl alcohol–associated changes in leiomyoma, 414 Poorly differentiated carcinoma gestational choriocarcinoma vs., 900 placental site trophoblastic tumor vs., 894–895 radiotherapy-associated changes and, 148 Poorly differentiated squamous cell carcinoma epithelioid sarcoma (distal and proximal types) vs., 113–114 melanoma vs., 84–86 Positive peritoneal cytology, in endometrial carcinoma, 356 Postmenopausal squamous atypia, 190, 232 Postpartum/postabortion endometria, endometritis vs., 317–318 Pregnancy-associated changes, 556–564 clinical features of, 556–557 differential diagnosis of, 562 gross findings of, 558, 558f immunohistochemistry of, 562 microscopic findings of, 558–562, 558f–562f pathologic features of, 558–562 prognosis and treatment of, 562–564 Preinvasive vulvar squamous neoplasia, 47, 47b differentiated vulvar intraepithelial neoplasia, 54–59, 58b high grade squamous intraepithelial lesion, 51–54, 54b immunohistochemistry of, 905–909, 909f low grade squamous intraepithelial lesion, 47–51, 48f, 50b Premalignant glandular neoplasia, 333 atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia, 338–345, 344b endometrial carcinoma, 345–358 endometrial clear cell carcinoma, 387–391 endometrial endometrioid carcinoma, 361–378 endometrial serous carcinoma, 381–387 endometrioid carcinoma precursors, 333 mesonephric carcinoma, 401–402, 402f–403f mixed carcinoma, 402–403 nonatypical endometrial hyperplasia, 334–338, 334f squamous cell carcinoma, 403–404 undifferentiated and dedifferentiated endometrial carcinoma, 391–401 Prepubertal vulvar fibroma, 96–98, 97b ancillary studies of, 97 angiomyofibroblastoma vs., 91–92 cellular angiofibroma vs., 93 clinical features of, 96 differential diagnosis of, 97 gross findings of, 96 immunohistochemistry of, 97 mammary-type myofibroblastoma vs., 96 microscopic findings of, 96–97, 97f pathologic features of, 96–97, 98b prognosis and therapy for, 97–98

1014 Primary upper gastrointestinal adenocarcinomas (gastric, small intestinal, pancreatobiliary), mucinous adenocarcinoma vs., 616–617 Primitive neuroectodermal tumors (PNETs), neuroendocrine carcinoma vs., 396 Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), 357 Progesterone receptor (PR) endometrial carcinoma and, 924–925 endometrial stromal tumors and, 930 modulators, 311, 312f Progestins, 309, 310f Prolapse, vaginal, 133, 134f Proliferative endometrium, 295–296, 297f early, with residual stromal breakdown, 295–296 nonatypical endometrial hyperplasia vs., 335 Pseudobowenoid papulosis, high grade squamous intraepithelial lesion vs., 52 Pseudocarcinomatous hyperplasia, 505–506 Pseudoepitheliomatous hyperplasia superficially invasive squamous cell carcinoma vs., 60 vulvar, invasive squamous cell carcinoma vs., 64 Pseudokoilocytosis, vaginal intraepithelial neoplasia vs., 159–161 Pseudomyxoma peritonei, 857–865, 865b ancillary studies of, 863 clinical features of, 857, 858f differential diagnosis of, 863–864 gross findings of, 858, 858f–859f immunohistochemistry of, 863 microscopic findings of, 860–863, 860f–864f pathologic features of, 858–863, 865b prognosis and therapy of, 864–865 Pseudopapillary pattern, in yolk sac tumor, 720 Psoriasis, 9–12, 11b atopic dermatitis vs., 3 clinical features of, 9 differential diagnosis of, 10–11 differentiated vulvar intraepithelial neoplasia vs., 56 inverse, 9 microscopic features of, 9–10, 10f–11f pathologic features of, 12b prognosis and treatment for, 11–12 seborrheic dermatitis vs., 7 Pulmonary hamartoma, intravenous leiomyomatosis vs., 437–438 Pure sex cord tumors, 673–684 adult granuloma cell tumor, 673–684 juvenile granulosa cell tumor, 684–689 Sertoli cell tumor, 689–693 sex cord tumor with annular tubules, 693–696 Pyoderma gangrenosum, hidradenitis suppurativa vs., 28

R Radiation dermatitis, late-stage, lichen sclerosus vs., 23 Radiation-induced atypia adenocarcinoma in situ vs., 244 cervical, 218, 221f squamous cell carcinoma vs., 163–166 vaginal intraepithelial neoplasia vs., 159–161 Radiotherapy-associated changes high-grade squamous intraepithelial lesion vs., 234 vaginal, 148, 149f, 149b ligneous vaginitis and, 130

INDEX

Reactive/reparative atypia, 218, 220f adenocarcinoma in situ vs., 243–244 cytology, 968–972 serous tubal intraepithelial carcinoma vs., 520 vaginal intraepithelial neoplasia vs., 159–161 Red degeneration, leiomyoma, 408f Renal cell carcinoma, metastatic, 940 steroid cell tumor vs., 672 Renal clear cell carcinoma, metastatic clear cell tumors vs., 628–630 ovarian, 785–787 ancillary studies of, 787 clinical features of, 785 differential diagnosis of, 787 gross findings of, 785 microscopic findings of, 785, 786f–787f pathologic features of, 785 Rete cysts, benign serous tumors vs., 579 Rete ovarii, 545, 546f endometriosis vs., 570–572 tumors of, 808–811, 810b ancillary studies of, 809 clinical features of, 808–809 differential diagnosis of, 809 gross findings of, 809 immunohistochemistry of, 809 microscopic findings of, 809, 810f pathologic features of, 809, 810b prognosis and therapy of, 809–811 Reticular pattern, in yolk sac tumor, 720 Retiform Sertoli–Leydig cell tumor low-grade serous carcinoma vs., 595–596 serous borderline tumors vs., 590–591 Reverse transcription polymerase chain reaction (RT-PCR), endometrial stromal tumors and, 930 Rhabdoid differentiation, 444 Rhabdomyoma cervical malignant mesenchymal tumors vs., 288 vaginal, 103–105, 105b ancillary studies in, 105 clinical features of, 103 differential diagnosis of, 105 embryonal rhabdomyosarcoma vs., 106 gross findings of, 103 immunohistochemistry of, 105 microscopic findings of, 104f, 105 pathologic features of, 103–105, 105b prognosis and treatment for, 105 Rhabdomyosarcoma embryonal, see Embryonal rhabdomyosarcoma uterine, 469–472 clinical features of, 469 differential diagnosis of, 470–471 gross findings of, 470 immunohistochemistry of, 470 leiomyosarcoma vs., 432 microscopic findings of, 470, 471f molecular analysis of, 470 Müllerian adenosarcoma vs., 478 pathologic features of, 470, 470f, 472b prognosis and treatment for, 472b undifferentiated uterine sarcoma vs., 456 Round cell liposarcoma, rhabdomyosarcoma vs., 471

INDEX

S S-100, in vaginal melanoma, 172–174 Salpingitis isthmica nodosa (SIN), 500–502 clinical features of, 500 differential diagnosis of, 501 pathologic features of, 500, 501f, 502b prognosis and therapy for, 501–502, 501b radiologic features of, 500 tubal endometriosis vs., 504–505 Salpingo-oophorectomy, bilateral, hysterectomy with, 358 Sarcoidosis, malakoplakia vs., 132 Sarcoma fibroepithelial stromal polyp vs., 90 primary ovarian, nongynecologic small round blue cell sarcoma vs., 793 radiotherapy-associated changes and, 148 vaginal myeloid, 175–177 squamous cell carcinoma vs., 163–166, see also Embryonal rhabdomyosarcoma; Endometrial stromal sarcoma; Leiomyosarcoma Sarcoma botryoides, see Embryonal rhabdomyosarcoma Schiller–Duval bodies, 178 Schistosoma haematobium infection, tuberculous salpingitis vs., 510–511 Schistosoma mansoni infection, tuberculous salpingitis vs., 510–511 Sclerosing stromal tumor, 655–658, 658b ancillary studies for, 657 clinical features of, 655–656 differential diagnosis of, 657–658 gross findings for, 656, 656f immunohistochemistry for, 657 massive ovarian edema vs., 567 microcystic stromal tumor vs., 662 microscopic findings for, 656–657, 656f–657f pathologic features of, 656–657, 658b prognosis and therapy for, 658 stomach carcinoma vs., 765 thecoma vs., 649 Sebaceous carcinoma, extramammary Paget disease vs., 74–77 Seborrheic dermatitis, 7–9, 9b clinical features of, 7 differential diagnosis of, 7 microscopic features of, 7, 8f pathologic features of, 9b prognosis and treatment for, 9 psoriasis vs., 10–11 Seborrheic keratosis condyloma acuminatum vs., 48 high grade squamous intraepithelial lesion vs., 52 hypertrophic lichen planus vs., 16–17 Secondary ovarian carcinoma, primary ovarian carcinoma vs., 938–941, 938f–940f, 938t, 940b, 942f, 942t Secondary syphilis, plasma cell vulvitis vs., 36 Secretory cell outgrowths, 519, 521f Secretory endometrium early, 297–298, 299f imaging of, 314 late, 298, 301f–302f mid, 298, 300f nonatypical endometrial hyperplasia vs., 335

1015 Seromucinous borderline tumors, 604–606, 604b clinical features of, 604 differential diagnosis of, 604 gross findings of, 604 immunohistochemistry of, 604 low-grade serous carcinoma vs., 595–596 microscopic findings of, 604, 605f pathologic features of, 604, 606b prognosis and therapy of, 605–606 serous borderline tumors vs., 590–591 Seromucinous cystadenoma, benign seromucinous tumors vs., 603 Seromucinous tumors, 602 benign, 602–604, 603b benign mucinous tumors vs., 607–608 borderline, 604–606, 604b clinical features of, 604 differential diagnosis of, 604 gross findings of, 604 immunohistochemistry of, 604 microscopic findings of, 604, 605f pathologic features of, 604, 606b prognosis and therapy of, 605–606 Serous borderline tumor broad ligament, 534–536, 536b ovarian, 583–592, 592b clear cell tumors vs., 628–630 clinical features of, 583 cytology of, 587 differential diagnosis of, 590–591 gross findings of, 583, 583f immunohistochemistry of, 589 low-grade serous carcinoma vs., 595–596 microscopic findings of, 583–587, 584f–590f, 585b, 590t molecular analysis of, 589–590 pathologic features of, 583–587, 592b primary peritoneal carcinoma vs., 843 prognosis and therapy of, 591–592, 591f seromucinous borderline tumors vs., 604 tubal, 517–518 clinical features of, 517 differential diagnosis of, 518 pathologic features of, 517–518, 518f, 518b prognosis and therapy for, 518, 518b Serous (adeno)carcinoma endometrial, 381–387 ancillary studies of, 381 carcinosarcoma vs., 399–400 clinical features of, 381 differential diagnosis of, 381–387 immunohistochemistry of, 381 microscopic findings of, 381, 382f–386f molecular analysis of, 381 papillary metaplasia vs., 330 pathologic features of, 387b undifferentiated/dedifferentiated endometrial carcinoma vs., 392–393 ovarian, 577–578 clear cell tumors vs., 628–630 malignant mesothelioma vs., 791

1016 Serous cystadenoma cortical inclusion cysts vs., 568 endometriosis vs., 570–572 tumors of rete ovarii vs., 809 Serous epithelial (cortical) inclusion cysts benign seromucinous tumors vs., 603 benign serous tumors vs., 579–581 Serous tubal intraepithelial carcinoma, 518–521, 522f ancillary studies of, 519–520 clinical features of, 518–519 diagnosis of, 946, 946b, 947f differential diagnosis of, 520 pathologic features of, 519, 519f–520f, 521b prognosis and therapy for, 520–521, 521b Serous tumors benign, 579–583, 582b clinical features of, 579 differential diagnosis of, 579–581 gross findings of, 579, 580f–581f immunohistochemistry of, 579 microscopic findings of, 579, 582f pathologic features of, 579, 583b prognosis and therapy of, 581–583 borderline, 583–592, 592b clinical features of, 583 cytology of, 587 differential diagnosis of, 590–591 gross findings of, 583, 583f immunohistochemistry of, 589 microscopic findings of, 583–587, 584f–590f, 585b, 590t molecular analysis of, 589–590 pathologic features of, 583–587, 592b prognosis and therapy of, 591–592, 591f classification of, 579t low-grade carcinoma, 592–596, 596b clinical features of, 592 cytology of, 595 differential diagnosis of, 595–596 gross findings of, 592, 593f immunohistochemistry of, 595 microscopic findings of, 592–595, 594f–595f molecular analysis of, 595 pathologic features of, 592–595, 596b prognosis and therapy of, 596 Sertoli cell tumors, 689–693, 693b ancillary studies for, 689–690 clinical features of, 689 differential diagnosis of, 690–692 dysgerminoma vs., 712–713 extraovarian carcinoid tumor vs., 790 gross findings for, 689, 689f immunohistochemistry for, 689–690 microscopic findings for, 689, 690f–692f molecular analysis for, 690 ovarian carcinoid tumors vs., 737 pathologic features of, 689, 693b prognosis and therapy for, 692–693 Sertoli–Leydig cell tumor, 696–703, 702b clinical features of, 696 differential diagnosis of, 700–701 gross findings for, 696, 696f microscopic findings for, 696–699, 697f–702f

INDEX

Sertoli–Leydig cell tumor (Continued) ovarian carcinoid tumors vs., 737 pathologic features of, 696–699, 703b prognosis and therapy for, 701–703 yolk sac tumor vs., 727 Sex cord stromal differentiation, 444 Sex cord tumors with annular tubules, 693–696, 695b adult granulosa cell tumor vs., 678 ancillary studies for, 695 clinical features of, 693 differential diagnosis of, 695 gross findings for, 693 immunohistochemistry for, 695 microscopic findings for, 693–694, 694f molecular analysis for, 695 pathologic features of, 693–694, 695b prognosis and therapy for, 695–696 ovarian, uterine tumors resembling, 457–460 ancillary studies of, 457–458 clinical features of, 457 differential diagnosis of, 460 gross findings of, 457 immunohistochemistry of, 457–458 low-grade endometrial stromal sarcoma vs., 446–447 microscopic findings of, 457, 458f–459f molecular analysis of, 458 pathologic features of, 457, 460b PEComa vs., 461–463 prognosis and treatment of, 460, 460b ovarian endometrioid stromal sarcoma vs., 818–822 Sex cord-stromal tumors, ovarian, 643–706, 644b endometrioid tumors vs., 625 markers of, 946, 946b, 948f, 948t Signet-ring cell carcinoma, see Krukenberg tumors Signet-ring stromal tumor, 662–665, 664b ancillary studies for, 663 clinical features of, 663 differential diagnosis of, 663–664 gross findings for, 663 histochemistry and immunohistochemistry for, 663, 664f microcystic stromal tumor vs., 662 microscopic findings for, 663, 663f pathologic features of, 663, 664b prognosis and therapy for, 664–665 stomach carcinoma vs., 765 Small cell carcinoma, 394–396 cervical high-grade neuroendocrine carcinoma vs., 285 neuroendocrine carcinoma vs., 396 of hypercalcemic type, 811–816, 816b ancillary studies of, 811–815 clinical features of, 811 differential diagnosis of, 815 dysgerminoma vs., 712–713 gross findings of, 811, 811f immunohistochemistry of, 811–815 juvenile granulosa cell tumor vs., 687 lung carcinoma vs., 780–783 metastatic melanoma vs., 794–797 microscopic findings of, 811, 812f–815f molecular analysis of, 815

INDEX

Small cell carcinoma (Continued) nongynecologic small round blue cell sarcoma vs., 793 pathologic features of, 811, 816b prognosis and therapy of, 815–816 vulvar, invasive squamous cell carcinoma vs., 64–65 Small round blue cell sarcoma, nongynecologic, secondary involvement by, 793–794, 794b ancillary studies of, 793 clinical features of, 793 differential diagnosis of, 793–794 gross findings of, 793 immunohistochemistry and molecular analysis of, 793 microscopic findings of, 793, 795f pathologic features of, 793, 794b Small round cell tumors desmoplastic, see Desmoplastic small round cell tumor ovarian, 948–950, 950f, 950b Smooth muscle differentiation, 444, 447f Smooth muscle metaplasia, primary ovarian smooth muscle tumors vs., 817 Smooth muscle tumors benign vs. malignant, 934, 934b endometrial, of low or uncertain malignant potential, 433–436 ancillary studies of, 435 clinical features of, 433 differential diagnosis of, 435 endometrial stromal nodule vs., 442 gross findings of, 433 immunohistochemistry of, 435 leiomyosarcoma vs., 431–432 microscopic findings of, 433–435, 434f molecular analysis of, 435 pathologic features of, 433–435, 436b prognosis and treatment of, 435–436, 436b epithelioid, see Epithelioid smooth muscle tumors primary ovarian, 816–818, 818b ancillary studies of, 817 clinical features of, 816 differential diagnosis of, 817 gross findings of, 816 immunohistochemistry of, 817 microscopic findings of, 816–817, 817f pathologic features of, 816–817, 818b prognosis and therapy of, 817–818 uterine, inflammatory myofibroblastic tumors vs., 466–469 vulvovaginal, 101–103, 103b ancillary studies in, 102 clinical features of, 101 differential diagnosis of, 102–103 gross findings of, 101, 101f immunohistochemistry in, 102 microscopic findings of, 101–102, 102f pathologic features of, 101–102, 103b prognosis and therapy for, 103, see also Leiomyoma; Leiomyosarcoma Solitary fibrous tumor, 108–111, 111b ancillary studies in, 109 cellular angiofibroma vs., 93 differential diagnosis of, 109–111 gross findings in, 108, 108f immunohistochemistry of, 109

1017 Solitary fibrous tumor (Continued) microscopic findings in, 108, 109f–110f molecular alterations of, 109 pathologic features of, 108, 111b prognosis and therapy for, 109–111 Solitary follicular cysts, 545 endometriosis vs., 570–572 Solitary luteinized follicle cyst of pregnancy, 556–557, 559f, 563b SOX10, in vaginal melanoma, 172–174 Spindle cell epithelioma, 154–157, 157b ancillary features of, 157 clinical features of, 154–157 differential diagnosis of, 157 microscopic findings in, 154–157, 155f–156f pathologic features of, 157b prognosis and treatment for, 157 Spindle cell leiomyomas, leiomyosarcomas vs., 538 Spindle cell nodule, postoperative, 134–136, 136b ancillary studies on, 136 clinical features of, 134 differential diagnosis of, 136 gross findings in, 134 microscopic findings in, 134–136, 136f pathologic features of, 134–136, 137b prognosis and therapy for, 136 Spindle squamous cell carcinoma, vulvovaginal smooth muscle tumors vs., 102–103 Spindled endometrioid carcinoma, carcinosarcoma vs., 399–400 Spongiform pustules of Kogoj, 9–10, 10f Spongiosis, vaginal intraepithelial neoplasia vs., 159–161 Spongiotic dermatitis, 1–3 allergic contact dermatitis, 4–5, 4t, 5b atopic dermatitis, 3–4, 4b differentiated vulvar intraepithelial neoplasia vs., 56 irritant contact dermatitis, 4t, 5–7, 7b seborrheic dermatitis, 7–9, 9b Spontaneous abortions, complete hydatidiform mole vs., 874–875 Squamotransitional carcinoma, cervical, 254 Squamous atrophy, 189–191, 191b ancillary studies on, 190 clinical features of, 189–190 differential diagnosis of, 190 pathologic features of, 190, 190f, 191b prognosis and treatment for, 191 Squamous cell carcinoma cervical, 250–258, 258b adenosquamous carcinoma vs., 278–281 ancillary studies on, 255 clinical features of, 250 colposcopic features of, 250–251 differential diagnosis of, 255–257 gross findings in, 251, 251f high-grade neuroendocrine carcinoma vs., 285 high-grade squamous epithelial lesion with gland involvement vs., 255 immunohistochemistry of, 255 microscopic findings in, 251–252, 252f–254f morphologic variants of, 252–255, 254b, 256f–257f pathologic features of, 251–252, 259b

1018 Squamous cell carcinoma (Continued) placental site nodule vs., 885–886 prognosis and therapy for, 248t, 258 endometrial, 403–404 metastatic tumors, 981, 982f ovarian carcinoma of uterine cervix vs., 802–803 lung carcinoma vs., 783 vaginal, 162–166, 166b ancillary studies on, 163 clinical features of, 162 differential diagnosis of, 163–166 gross findings in, 162 immunohistochemistry of, 163 microscopic findings in, 163, 163f–165f pathologic features of, 162–163, 167b prognosis and treatment for, 166, 166t spindle cell epithelioma vs., 157 vulvar, 909–910, 910f hypertrophic lichen planus vs., 16–17 invasive, 61–66, 68b plasma cell vulvitis vs., 36 superficially invasive, 59, 61b Squamous cell carcinoma in situ, hypertrophic lichen planus vs., 16–17 Squamous columnar junction (SCJ), 227 Squamous epithelium, of normal cervix, 960, 961f–964f Squamous intraepithelial neoplasia, see Intraepithelial neoplasia Squamous lesions, as epithelial cell abnormality, 971–972 Squamous metaplasia cervical, 227, 230 associated with reactive changes, 232 immature, 233, 235 endometrial, 325–326, 325f cervical squamous metaplasia vs., 326 differential diagnosis of, 325–326 pathologic features of, 325–326, 325f, 326b immature, 185–189, 189b ancillary studies on, 187 clinical features of, 185 differential diagnosis of, 187–189 pathologic features of, 185–187, 188f–189f, 190b prognosis and treatment for, 189 Squamous morular metaplasia, carcinosarcoma vs., 399–400 Squamous neoplasms, vulvar, 47–70 Squamous papilloma, 193 Staphylococcal scalded skin syndrome, erythema multiforme vs., 18 Staphylococcus aureus, toxic shock syndrome and, 125 Steroid cell tumors, 667–673, 673b ancillary studies for, 669–670 clinical features of, 668 differential diagnosis of, 670–672 follicular cysts vs., 551 gross findings for, 668, 669f histochemistry and immunohistochemistry for, 669–670 Leydig cell tumor vs., 666 metastatic melanoma vs., 794–797 metastatic renal clear cell carcinoma vs., 787 microcystic stromal tumor vs., 662 microscopic findings for, 668–669, 669f–672f

INDEX

Steroid cell tumors (Continued) pathologic features of, 668–669, 673b pregnancy-associated changes vs., 562 prognosis and therapy for, 672–673 sclerosing stromal tumors vs., 657–658 Sertoli cell tumor vs., 690–692 stromal hyperplasia and hyperthecosis vs., 553–554 thecoma vs., 649 Stomach, metastatic adenocarcinoma of, 764–767, 765b, 940 ancillary studies of, 765 clinical features of, 764 differential diagnosis of, 765–767 gross findings of, 764, 764f immunohistochemistry of, 765 microscopic findings of, 765, 766f–769f pathologic features of, 764–765, 767b Streptococcus pyogenes, 124 Stromal hyperplasia, 552–556, 555b clinical features of, 552–553 differential diagnosis of, 553–554 fibroma vs., 647 gross findings of, 553, 553f immunohistochemistry of, 553, 554f–555f microscopic findings of, 553, 553f–555f pathologic features of, 553, 555b prognosis and therapy of, 554–556 Stromal hyperthecosis, see Hyperthecosis; stromal Stromal microinvasion, 584–585, 585b Stromal sarcoma, endometrial, see Endometrial stromal sarcoma Stromal tumors endometrial, 438 ovarian, 643 fibroma, 643–648, 647b Leydig cell tumor, 665–667, 666b luteinized thecoma with sclerosing peritonitis, 651–655, 655b microcystic stromal tumor, 658–662, 662b sclerosing stromal tumor, 655–658, 658b signet-ring stromal tumor, 662–665, 664b steroid cell tumor, 667–673, 673b thecoma, 648–651, 651b Struma ovarii, 731–735, 735b ancillary studies for, 732 benign serous tumors vs., 579–581 clinical features of, 732 differential diagnosis for, 732–733 gross findings for, 732, 733f immunohistochemistry for, 732 metastatic renal clear cell carcinoma vs., 787 microscopic findings for, 732, 733f–734f pathologic features of, 732, 735b prognosis and therapy for, 734–735 serous borderline tumors vs., 590–591 Sulfur granule, 512, 574 Superficial angiomyxoma, 98–99, 99b ancillary studies in, 98 clinical features of, 98 deep (aggressive) angiomyxoma vs., 100 differential diagnosis of, 98 gross findings of, 98 immunohistochemistry of, 98

INDEX

Superficial angiomyxoma (Continued) microscopic findings of, 98, 98f pathologic features of, 98, 99b prognosis and therapy for, 99 Superficially invasive squamous cell carcinoma, vulvar, 59, 61b clinical features of, 59 differential diagnosis of, 60 microscopic features of, 59–60, 59f–60f pathologic features of, 61b prognosis and therapy for, 60–61 “Surface papilloma,” 579, 581 Syncytiotrophoblast microscopic findings of, 717–718 trophoblastic diseases and, 950 Synovial sarcoma, of vulva, 116 Syphilis, 38–40, 40b ancillary studies of, 38 clinical features of, 38 differential diagnosis of, 39–40 microscopic features of, 38, 39f pathologic features of, 40b prognosis and treatment for, 40

T Teratoma, ovarian, 728 immature, 740–744, 743b ancillary studies for, 741 clinical features of, 740 differential diagnosis of, 741–743 gross findings for, 740, 740f immunohistochemistry of, 741 microscopic findings for, 740–741, 741f–742f molecular analysis for, 741 pathologic features of, 740–741, 743b prognosis and therapy for, 743–744 radiologic features of, 740 mature cystic teratoma, 728, 732b clinical features of, 728 gross findings for, 728, 729f microscopic findings for, 729–731, 729f–731f molecular analysis for, 731 pathologic features of, 728–731, 732b prognosis and therapy for, 731 radiologic features of, 728 ovarian carcinoid tumors, 735–740, 739b ancillary studies for, 737 clinical features of, 735 differential diagnosis of, 737 gross findings for, 735, 736f immunohistochemistry of, 737 microscopic findings for, 735–737, 736f–739f pathologic features of, 735–737, 739b prognosis and therapy for, 737–740 with sex cord features, Sertoli–Leydig cell tumor vs., 700–701 struma ovarii, 731–735, 735b ancillary studies for, 732 clinical features of, 732 differential diagnosis for, 732–733 gross findings for, 732, 733f

1019 Teratoma, ovarian (Continued) immunohistochemistry for, 732 microscopic findings for, 732, 733f–734f pathologic features of, 732, 735b prognosis and therapy for, 734–735 The Cancer Genome Atlas (TCGA), 357, 929 Thecoma, 648–651, 651b adult granulosa cell tumor vs., 675–678 ancillary studies for, 649 clinical features of, 648 differential diagnosis of, 649 fibroma vs., 647 gross findings for, 648–649, 648f histochemistry and immunohistochemistry for, 649 juvenile granulosa cell tumor vs., 687 microcystic stromal tumor vs., 662 microscopic findings for, 649, 650f molecular analysis for, 649 ovarian endometrioid stromal sarcoma vs., 818–822 pathologic features of, 648–649, 651b pregnancy-associated changes vs., 562 primary ovarian smooth muscle tumors vs., 817 prognosis and therapy for, 649–651 sclerosing stromal tumors vs., 657–658 stromal hyperplasia and hyperthecosis vs., 553–554 Thermal artifact, serous tubal intraepithelial carcinoma vs., 520 TNM Staging System, of vulvar squamous cell carcinoma, 68b Torsion, tubal, 498–500, 499f Toxic shock syndrome (TSS), 125 Transformation zone, 227 Transitional cell carcinoma high-grade serous carcinoma vs., 601 tubal, 527, 527f Transitional cell metaplasia, 191–193, 192b ancillary studies on, 191 clinical features of, 191 differential diagnosis of, 191 high-grade squamous intraepithelial lesion vs., 235 pathologic features of, 191, 192f, 192b prognosis and treatment for, 191–193 Transvaginal ultrasound, for cysts of follicular origin, 546 Transverse vaginal septa, 119 Trauma, actinomycotic salpingitis vs., 512–513 Treponema pallidum, 38 Trichomonas vaginalis, 123, 123b ancillary studies on, 123, 124f clinical features of, 123 in cytology, 969, 970f microscopic findings in, 123, 124f pathologic features of, 123, 123b Tubal intramural endometriosis, salpingitis isthmica nodosa vs., 501 Tubal metaplasia cervical, 193–194, 196b ancillary studies on, 193 clinical features of, 193 differential diagnosis of, 193–194 pathologic features of, 193, 194f–195f, 196b prognosis and treatment for, 194 endometrial, 328, 328b

1020 Tuberculosis malakoplakia vs., 132 vaginal involvement by, 125 Tuberculous salpingitis, 510–512 ancillary studies of, 510 clinical features of, 510 differential diagnosis of, 510–511 infectious nongranulomatous salpingitis vs., 509 pathologic features of, 510, 511f, 512b prognosis and therapy for, 511–512, 511b Tuboendometrioid metaplasia cervical adenocarcinoma in situ vs., 244 endometriosis vs., 196–198 Tubo-ovarian abscesses actinomycotic salpingitis vs., 512–513 endometriosis vs., 570–572, 574f Tubo-ovarian high-grade serous carcinoma, endometrial serous carcinoma vs., 929–930, 930b, 931f Tubulosquamous polyp, 133–134, 135f vaginal adenosis vs., 141 Tumor cell necrosis, 424, 428f Tunnel clusters, 201–203, 204b ancillary studies on, 202 clinical features of, 201 differential diagnosis of, 202 with a gastric phenotype, lobular endocervical glandular hyperplasia vs., 208 gastric-type mucinous adenocarcinoma vs., 269–273 gross findings in, 201 microscopic findings in, 201–202, 202f–203f pathologic features of, 201–202, 204b prognosis and treatment for, 202–203 Twin placenta, with one normal placenta, complete hydatidiform mole vs., 876

U Undifferentiated carcinoma cervical, 283 endometrial, 391–401 ancillary studies of, 391 carcinosarcoma vs., 399–400 clinical features of, 391 differential diagnosis of, 391–394, 399–400 endometrial endometrioid carcinoma vs., 380 immunohistochemistry of, 391 microscopic findings of, 391, 392f–394f, 399f–400f molecular analysis of, 391, 399 neuroendocrine carcinoma vs., 396 pathologic features of, 394b ovarian, 638 adenosarcoma, 638, 638f adult granulosa cell tumor vs., 675–678 carcinosarcoma, 639, 639f dysgerminoma vs., 712–713 tubal, 527 Undifferentiated uterine sarcoma, 454–457, 935–936, 937f ancillary studies of, 456 carcinosarcoma vs., 399–400 clinical features of, 454 differential diagnosis of, 456 gross findings of, 454 high-grade endometrial stromal sarcoma vs., 452–453

INDEX

Undifferentiated uterine sarcoma (Continued) histochemistry of, 456 immunohistochemistry of, 456 leiomyosarcoma vs., 432 microscopic findings of, 454–456, 455f molecular analysis of, 456 Müllerian adenosarcoma vs., 478 pathologic features of, 454–456, 457b prognosis and treatment for, 456–457, 457b undifferentiated uterine sarcoma vs., 456 undifferentiated/dedifferentiated endometrial carcinoma vs., 392–393 Unilocular cystic granulosa cell tumors, follicular cysts vs., 547–550 Urinary bladder carcinoma, metastatic, 784–785 ancillary studies of, 784 clinical features of, 784 differential diagnosis of, 784–785 gross findings of, 784 immunohistochemistry of, 784 microscopic findings of, 784, 784f pathologic features of, 784 Urothelial carcinoma genitourinary tract, squamous cell carcinoma vs., 255–256 squamous cell carcinoma vs., 163–166 Uterine adenomatoid tumor, 488–491 ancillary studies of, 489 clinical features of, 488 differential diagnosis of, 489–490 gross findings of, 488 immunohistochemistry of, 489 microscopic findings of, 488–489 molecular analysis of, 489 pathologic features of, 488–489, 489f–490f, 491b prognosis and treatment for, 490–491, 490b Uterine artery embolization of leiomyoma, changes associated with, 414, 415f Uterine cervix, carcinoma of, 798–803, 802b ancillary studies of, 801–802 clinical features of, 798–799 differential diagnosis of, 802–803 gross findings of, 799, 800f immunohistochemistry and molecular analysis of, 801– 802, 804f microscopic findings of, 801, 801f–803f pathologic features of, 799–801, 803b Uterine corpus carcinoma of, 803–807, 807b ancillary studies of, 805 clinical features of, 803–804 gross findings of, 804, 805f immunohistochemistry of, 805–807 microscopic findings of, 804–805, 806f pathologic features of, 804–805, 807b mesenchymal tumors of, 807–808, 808b ancillary studies of, 807 clinical features of, 807 differential diagnosis of, 807–808 gross findings of, 807 immunohistochemistry of, 807 microscopic findings of, 807, 808f pathologic features of, 807, 808b–809b

1021

INDEX

Uterine mesenchymal neoplasms, miscellaneous, 934–938, 938b Uterine polyps, benign, endocervical polyp vs., 215 Uterine tumor resembling ovarian sex cord tumor (UTROSCT), 446–447, 457–460, 934, 936f ancillary studies of, 457–458 clinical features of, 457 differential diagnosis of, 460 gross findings of, 457 immunohistochemistry of, 457–458 low-grade endometrial stromal sarcoma vs., 446–447 microscopic findings of, 457, 458f–459f molecular analysis of, 458 pathologic features of, 457, 460b PEComa vs., 461–463 prognosis and treatment of, 460, 460b UTROSCT, see Uterine tumor resembling ovarian sex cord tumor

V Vagina atrophy of, 144–148 benign neoplasms of, 153–154 adenocarcinoma, 166–171 Müllerian papilloma, 153–154 neuroendocrine carcinoma, 171–172 spindle cell epithelioma, 154–157 squamous cell carcinoma, 162–166 squamous intraepithelial lesion, 157–162 congenital anomalies of, 119 cysts of, 142–144, 142b, 143f–144f, 144b infectious and inflammatory lesions of, 120–121 Actinomyces infection, 124–125 bacterial vaginosis, 120–121 Candida albicans infection, 121–122 Crohn disease, 132–133 desquamative inflammatory vaginitis, 128–130 emphysematous vaginitis, 128 Group A Streptococcus, 124 Group B Streptococcus, 124 ligneous vaginitis, 130–131 malakoplakia, 131–132 parasitic vaginitis, 125 toxic shock syndrome, 125 Trichomonas vaginalis, 123 tuberculosis, 125 viral infections, 125–128, 127f–128f mesenchymal lesions of, 89–118 mixed tumor of, 154–157 neoplastic lesions of, 153–184 nonneoplastic diseases of, 119–152 premalignant and malignant epithelial neoplasms of, 157–162 primary malignant tumors of, 172–175 hematolymphoid malignancies, 175–177 metastases, 180–183 vaginal melanoma, 172–175 yolk sac tumor, 177–180 pseudoneoplastic and miscellaneous lesions of, 133 adenosis, 141–142 ectopic decidual reaction, 148 endometriosis, 139, 139b, 140f fallopian tube prolapse, 137–139

Vagina (Continued) postoperative spindle cell nodule, 134–136 prolapse, 133, 134f radiotherapy-associated changes, 148 tubulosquamous polyp, 133–134, 135f vault granulation tissue, 137, 137f Vaginal intraepithelial neoplasia (VAIN), 157–162, 162b ancillary studies on, 159 clinical features of, 158 differential diagnosis of, 159–161 gross findings in, 158 immunohistochemistry of, 159, 160f–161f invasive squamous cell carcinoma vs., 161 microscopic findings in, 158–159, 158f–160f pathologic features of, 158–159, 162b prognosis and treatment for, 161–162 Vaginal vault granulation tissue, 137, 137f Vaginitis desquamative inflammatory, 128–130 emphysematous, 128 ligneous, 130–131 parasitic, 125, 126f Varicella zoster virus infection, HSV infection vs., 41–42 Vascular invasion, in endometrial carcinoma, 352–355, 355f–356f Vascular leiomyoma, pathologic features of, 417–418 Vasculopathic reaction pattern, 32 Verrucous carcinoma condyloma acuminatum vs., 48 lichen simplex chronicus vs., 12–13 Vesiculobullous diseases HSV infection vs., 41–42 Villoglandular adenocarcinoma, cervical, 262, 265f Villoglandular elements, 377 Villous cytotrophoblast, trophoblastic diseases and, 950 Villous tissue, see Chorionic villi Vimentin, 921–922 Viral infections, of vagina, 125–128, 127f–128f, 127b Vulva immunohistochemistry of, see Immunohistochemistry inflammatory diseases of, 1–46 mesenchymal lesions of, 89–118 squamous neoplasms of, 47–70 Vulvar acanthosis with altered differentiation (VAAD), lichen simplex chronicus vs., 12–13 Vulvar intraepithelial neoplasia, extramammary Paget disease vs., 74–77 Vulvar lentigo, see Mucosal lentigo Vulvar squamous carcinomas, 909–910, 910f Vulvar squamous lesion, preinvasive, 905–909, 909f Vulvovaginal-gingival syndrome, 133

W Walthard nests, 497, 498f cortical inclusion cysts vs., 568 endometriosis vs., 570–572 Warts hypertrophic lichen planus vs., 16–17, see also Condyloma acuminatum Warty carcinoma, 254, 256f Warty dyskeratoma papular genitocrural acantholysis vs., 27

1022 “Wedge-shaped” hypergranulosis, 15 Well-differentiated papillary mesothelioma low-grade serous carcinoma vs., 595–596 peritoneal mesothelioma vs., 853–854 serous borderline tumors vs., 590–591 Well’s syndrome, fixed drug eruption vs., 20 Wilms tumor suppressor (WT1), 865–868

X Xanthogranulomatous reaction, tuberculous salpingitis vs., 510–511

Y Yolk sac tumor microglandular hyperplasia vs., 204–206 ovarian, 719–728 ancillary studies for, 724 clear cell tumors vs., 628–630 clinical features of, 720 differential diagnosis for, 724–727 dysgerminoma vs., 712–713 embryonal carcinoma vs., 715–717

INDEX

Yolk sac tumor (Continued) gross findings for, 720–724, 720f histochemistry and immunohistochemistry of, 724, 727f immature teratoma vs., 741–743 juvenile granulosa cell tumor vs., 687 metastatic renal clear cell carcinoma vs., 787 microscopic findings for, 720–724, 721f–726f molecular analysis for, 724 pathologic features of, 720–724, 728b prognosis and therapy for, 727–728 vaginal, 177–180, 179b ancillary studies on, 178 clinical features of, 178 differential diagnosis of, 178 gross findings in, 178 immunohistochemistry of, 178 microscopic findings in, 178, 179f–180f pathologic features of, 178, 179b prognosis and treatment for, 178–180

Z Zoon vulvitis, see Plasma cell vulvitis