Atlas of Gynecologic Surgical Pathology E-Book
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Rapidly and accurately identify gynecologic tumors and related lesions with the updated Atlas of Gynecologic Surgical Pathology. Complete with hundreds of stunning photographs and now available with online access, this visually dynamic medical reference book provides you with the know-how you need to perform state-of-the-art gynecologic diagnoses, right at your own microscope.

  • Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability. Compatible with Kindle®, nook®, and other popular devices.
  • Quickly and effortlessly find the essential information you need with summary tables, charts, and boxes throughout the text.
  • Expedite reference with a consistent approach to every entity discussed, including definitions, clinical features, gross features, microscopic features, and differential diagnoses.
  • Avoid diagnostic errors with comprehensive coverage of commonly encountered pitfalls.
  • Overcome today's toughest diagnostic challenges with guidance from internationally recognized experts in gynecologic pathology.
  • Stay completely current on the newest disease entities and updated classification schemes, and take advantage of nearly 1,000 brand-new references.
  • Ensure diagnostic accuracy and gain absolute visual clarity with the addition of 100 images.
  • Remain at the forefront of the most recently developed diagnostic methods, such as immunohistochemical diagnosis for malignant lesions and differential diagnosis of neoplastic and pseudoneoplastic lesions.
  • Access the complete contents online at Expert Consult.

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Publié par
Date de parution 11 octobre 2013
Nombre de lectures 1
EAN13 9780323188821
Langue English
Poids de l'ouvrage 11 Mo

Informations légales : prix de location à la page 0,0695€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Atlas of Gynecologic Surgical Pathology
Third Edition

Philip B. Clement, MD
Consultant Pathologist, Department of Pathology, Vancouver General Hospital, Emeritus Professor of Pathology, University of British Columbia, Vancouver, Canada

Robert H. Young, MD, FRCPath
Pathologist, James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Robert E. Scully Professor of Pathology, Harvard Medical School, Boston, USA
Copyright © 2014 Elsevier
Table of Contents
Cover image
Title page
Copyright
Dedication
Preface to the Third Edition
Glossary of Abbreviations and Acronyms
Chapter 1: Non-neoplastic Lesions and Benign Tumors of the Vulva
Human Papillomavirus (HPV) Infection INCLUDING Condyloma Acuminatum
Herpes Virus Infection (Fig. 1.5)
Other Viral Infections
Syphilis
Granuloma Inguinale
Lymphogranuloma Venereum
Chancroid
Tuberculosis
Necrotizing Fasciitis and Progressive Bacterial Synergistic Gangrene
Other Bacterial Infections
Fungal Infections and Parasitic Infestations
Lichen Sclerosus
Squamous Cell Hyperplasia, NOS (Fig. 1.9)
Other Dermatoses (Fig. 1.10)
Lentigo Simplex and Melanosis (Fig. 1.12)
Usual Melanocytic Nevi
Atypical Genital Nevi
Bartholin's Duct Cyst (Figs. 1.13–1.14)
Mucinous and Ciliated Vestibular Cysts (Fig. 1.15)
Other Cysts
Vulvar Vestibulitis
Plasma Cell Vulvitis (Zoon's Vulvitis) (Fig. 1.17)
Granulomatous Vulvitis and Vulvar Involvement by Crohn's Disease (Fig. 1.18)
Behçet's Disease
Florid Reactive Lymphoid Hyperplasia (Lymphoma-like Lesion)
Graft-Versus-Host Disease (GVHD)
Reactive Atypia and Multinucleated Keratinocytes (Figs. 1.19–1.20)
Nodular Fasciitis (Figs. 1.21–1.22)
Postoperative Spindle Cell Nodule
Lesions Related to Immobilization, Obesity, and Repetitive Trauma
Multinucleated Stromal Giant Cells (Fig. 1.23)
Adenosis
Ectopic Breast Tissue and Rarer Ectopias (Fig. 1.24)
Nodular Hyperplasia of Bartholin's Gland (Fig. 1.25)
Varices (Fig. 1.26)
Miscellaneous Rare Lesions
Papillary Hidradenoma (Hidradenoma Papilliferum) and Other Apocrine Tumors (Fig. 1.27)
Other Benign Tumors of Skin Appendage Origin
Seborrheic Keratosis (Fig. 1.28)
Benign Mammary-type Tumors (Fig. 1.29)
Benign Tumors of Bartholin's Gland and Minor Vestibular Glands
Tubulovillous Adenoma
Aggressive Angiomyxoma
Angiomyofibroblastoma (Figs. 1.34–1.37)
Cellular Angiofibroma (Fig. 1.38)
Superficial Myofibroblastoma
Prepubertal Vulvar Fibroma (Figs. 1.39–1.40)
Leiomyoma and Rhabdomyoma
Fibrous, Adipocytic, Vascular, and Neural Tumors
Superficial Angiomyxoma (Cutaneous Myxoma)
Granular Cell Tumor (Figs. 1.41–1.42)
Chapter 2: Malignant Tumors of the Vulva
Vulvar Intraepithelial Neoplasia (VIN)
Invasive Squamous Cell Carcinoma of Usual Type
Verrucous Carcinoma (Figs. 2.19–2.20)
Sarcomatoid Squamous Cell Carcinoma (Fig. 2.21)
Other Rare Variants of Squamous Cell Carcinoma
Adenocarcinoma of Mammary Type (Fig. 2.31)
Adenocarcinomas of Skin Appendage Origin (Fig. 2.32)
Rare Miscellaneous Adenocarcinomas, Malignant Myoepithelioma, and Carcinoid Tumor
Rhabdomyosarcoma
Liposarcoma
Epithelioid Sarcoma and Malignant Extrarenal Rhabdoid Tumor
Rare Sarcomas
Chapter 3: The Vagina
Condyloma Acuminatum
Vaginal Adenosis (Figs. 3.1–3.6)
Cysts (Fig. 3.7)
Prolapse of Fallopian Tube (Fig. 3.8)
Postoperative Spindle Cell Nodule
Fibroepithelial Polyp
Tubulosquamous Polyp (Fig. 3.15)
Inflammatory and Infectious Lesions (Fig. 3.16)
Endometriosis (Figs. 3.17–3.18)
Ectopias and Metaplasias
Other Tumor-like Lesions
Epithelial Tumors (Fig. 3.19)
Mixed Tumor (Spindle Cell Epithelioma) (Figs. 3.20–3.23)
Leiomyoma (Fig. 3.24)
Rhabdomyoma (Fig. 3.25)
Miscellaneous Benign Tumors
Vaginal Intraepithelial Neoplasia (VaIN) (Fig. 3.26)
Squamous Cell Carcinoma (Fig. 3.27)
Transitional and Squamotransitional Cell Carcinomas (Fig. 3.28)
Clear Cell Adenocarcinoma (Figs. 3.29–3.30)
Endometrioid Adenocarcinoma
Rare Adenocarcinomas
Small Cell Carcinoma
Embryonal Rhabdomyosarcoma (Figs. 3.31–3.34)
Leiomyosarcoma
Other Pure Sarcomas, including Extragastrointestinal Stromal Tumor
Malignant Mixed Tumors and Synovial Sarcoma
Malignant Melanoma (Figs. 3.35–3.36)
Yolk Sac Tumor (Figs. 3.37–3.39)
Hematopoietic Tumors (Fig. 3.40)
Histiocytosis X
Secondary Tumors (Fig. 3.41)
Chapter 4: Tumor-like Lesions and Benign Tumors of the Uterine Cervix
Metaplasias and Ectopias
Endocervical Glandular Hyperplasias
Mesonephric Lesions
Reactive and Reparative Lesions
Inflammatory Lesions
Infectious Lesions
Pregnancy-Related Changes
Melanotic Lesions
Miscellaneous Tumor-Like Lesions
Epithelial
Mixed Epithelial and Mesenchymal Tumors
Mesenchymal Tumors
Chapter 5: Invasive Squamous Cell Carcinoma of the Cervix and its Precursors
Basaloid Squamous Cell Carcinoma (Fig. 5.35)
Verrucous Carcinoma
Warty or Condylomatous Carcinoma
Papillary Squamous Cell Carcinoma (Figs. 5.36–5.37)
Lymphoepithelioma-like Carcinoma (Fig. 5.38)
Papillary Transitional Cell Carcinoma and Squamotransitional Cell Carcinomas (Fig. 5.39)
Sarcomatoid Squamous Cell Carcinoma (Fig. 5.40)
Mucoepidermoid Carcinoma
Chapter 6: Adenocarcinomas of the Cervix, Related Tumors, and Their Precursors
Adenocarcinoma in Situ (AIS)
Endocervical Glandular Dysplasia (EGD)
Early Invasive Adenocarcinoma (Stage Ia Adenocarcinoma)
Endocervical Adenocarcinoma, Usual Type (Figs. 6.10–6.19)
Mucinous Carcinomas, including Gastric-type Adenocarcinoma (Figs. 6.22–6.23)
Endometrioid Adenocarcinoma (Fig. 6.31)
Clear Cell Adenocarcinoma (Figs. 6.33–6.34)
Serous Adenocarcinoma (Fig. 6.35)
Mesonephric Adenocarcinoma and Malignant Mixed Mesonephric Tumors (Fig. 6.36)
Adenosquamous Carcinoma (Figs. 6.37–6.38)
Glassy Cell Carcinoma (Fig. 6.39)
Adenoid Basal Carcinoma (Adenoid Basal Epithelioma) (Figs. 6.40–6.44)
Adenoid Cystic Carcinoma (Figs. 6.45–6.46)
Typical and Atypical Carcinoid Tumors
Small Cell (Neuroendocrine) Carcinoma
Large Cell Neuroendocrine Carcinoma (Figs. 6.49–6.52)
Chapter 7: Non-neoplastic Lesions of the Uterine Corpus
Menses-related Changes (Figs. 7.1 and 7.5)
Atrophy-related Changes
Syncytial Papillary Change (Fig. 7.5)
Squamous and Morular Metaplasia (Figs. 7.6–7.7 and 7.19)
Mucinous (including Intestinal) Metaplasia (Fig. 7.8)
Ciliated (Tubal) Metaplasia (Figs. 7.9–7.10)
Eosinophilic and Oncocytic Metaplasia (Fig. 7.11)
Hobnail Cell Metaplasia
Clear Cell Metaplasia (Fig. 7.12)
Mesonephric-like Metaplasia
Arias-Stella Reaction (Fig. 7.13)
Clear Cell Change
Optically Clear Nuclei (Fig. 7.14)
Decidua (Figs. 7.15–7.16)
Effects of Exogenous Hormones (Figs. 7.17–7.20)
Heterotopic Tissues (Fig. 7.21)
Chronic Endometritis (Figs. 7.22–7.24)
Focal Necrotizing Endometritis (Fig. 7.25)
Florid Reactive Lymphoid Hyperplasia (Lymphoma-like Lesion) (Fig. 7.26)
Granulomatous Endometritis, including Effects of Thermal Ablation (Figs. 7.27–7.28)
Xanthogranulomatous Endometritis and Myometrial Xanthomatosis (Fig. 7.29)
Malacoplakia (Fig. 7.30)
Histiocytic Nodules (Fig. 7.31)
Eosinophilic Infiltrates
Mast Cell Infiltrates
Ligneous Endometritis
Pneumopolycystic Endometritis
Postoperative Spindle Cell Nodule
Intrauterine Device-related Changes, including Actinomycosis (Figs. 7.32–7.33)
Radiation-induced Changes (Fig. 7.34)
Arteritis
Viral Lesions
Microcalcification (Fig. 7.46)
Bizarre Atypia of Stromal Cells
Mesothelial Cells
Extramedullary Hematopoiesis
Congenital Myometrial Cysts
Blue Nevus
Amyloidosis
Myxoid Change of the Myometrium (Fig. 7.47)
Curettage-related Artifacts
Pseudolipomatosis (Fig. 7.48)
Vascular Pseudoinvasion and Other Artifacts Related to Laparoscopic and Robotic Hysterectomy
Stromal Signet-ring-like Cells Related to Cautery
Chapter 8: Endometrial Hyperplasia and Carcinoma
Endometrioid Carcinoma, Usual Type
Endometrioid Carcinoma, Unusual Types
Serous Carcinoma
Clear Cell Carcinoma
Mucinous carcinoma
Squamous Cell Carcinoma
Transitional Cell Carcinoma (Fig. 8.54)
Neuroendocrine Carcinomas
Other Rare Carcinomas
Undifferentiated Carcinomas of Usual (Non-Small-Cell) Type (Fig. 8.59)
Mixed Carcinomas
Chapter 9: Mesenchymal and Mixed Epithelial–Mesenchymal Tumors of the Uterine Corpus and Cervix
Leiomyoma, Usual Type
Leiomyoma Variants
Leiomyosarcoma
Smooth Muscle Tumors of Uncertain Malignant Potential
Epithelioid Smooth Muscle Tumors
Tumors of Perivascular Epithelioid Cell Origin
Benign-Appearing Smooth Muscle Tumors with Unusual Growth Patterns or Behavior
Endometrial Stromal Nodule and Endometrial Stromal Tumor with Limited Infiltration
Low-Grade Endometrial Stromal Sarcoma
Undifferentiated Endometrial Sarcoma (Fig. 9.61)
Endocervical Stromal Sarcoma
Malignant Müllerian Mixed Tumor
Müllerian Adenofibroma (Fig. 9.65)
Müllerian Adenosarcoma
Müllerian Carcinofibroma and Carcinomesenchymoma
Adenomyomas
Homologous Sarcomas
Heterologous Sarcomas
Sarcomas of Uncertain Histogenesis
Acknowledgment
Chapter 10: Trophoblastic Lesions, Miscellaneous Primary Uterine Neoplasms, Hematopoietic Neoplasms, and Metastatic Neoplasms to the Uterus
Hydatidiform Moles
Hydropic Abortus (Fig. 10.8)
Choriocarcinoma
Lesions of Intermediate Trophoblast
Tumor-Like Abnormalities of Placentation
Adenomatoid Tumor
Germ Cell Tumors
Neuroectodermal Tumors
Wilms' Tumor
Malignant Melanoma
Brenner Tumor
Lymphoma
Uterine Involvement by Leukemia (Fig. 10.31)
Plasmacytoma
Uterine Involvement by Histiocytic Disorders (Figs. 10.32–10.33)
From Genital Tract Carcinomas
From Extragenital Carcinomas (Figs. 10.34–10.36)
Chapter 11: The Fallopian Tube and Broad Ligament
Inflammatory Lesions
Epithelial Hyperplasia
Pregnancy-Related CHANGES
Metaplasias and Ectopias
Miscellaneous Tumor-Like Lesions
Benign and Borderline Epithelial Tumors
Carcinomas
Malignant Mixed Epithelial–Mesenchymal Tumors
Pure Mesenchymal Tumors
Adenomatoid Tumor
Germ Cell Tumors
Trophoblastic Tumors
Malignant Lymphoma and Leukemia
Secondary Tumors
Embryonic Rests (Figs. 11.40–11.41)
Cysts (Fig.11.42)
Other Tumor-Like Lesions
Epithelial Tumors of Müllerian Type (Fig. 11.43)
Epithelial Tumors of Definite or Probable Wolffian Origin
Ependymoma and Primitive Neuroectodermal Tumors
Mixed Epithelial–Mesenchymal Tumors (Fig. 11.45)
Soft Tissue Tumors
Miscellaneous and Secondary Tumors
Chapter 12: Tumor-like Lesions of the Ovary
Follicle Cyst
Corpus Luteum Cyst (Figs. 12.4–12.5)
Polycystic Ovarian Syndrome (Stein–Leventhal Syndrome)
Stromal Hyperthecosis
Stromal Hyperplasia
Massive Edema
Fibromatosis
Leydig Cell Hyperplasia, Hilar and Non-Hilar (Fig. 12.16)
Pregnancy Luteoma
Hyperreactio Luteinalis (Multiple Luteinized Follicle Cysts)
Large Solitary Luteinized Follicle Cyst of Pregnancy and Puerperium (Figs. 12.20–12.21)
Granulosa Cell Proliferations (Fig. 12.22)
Ectopic Decidua (Fig. 12.23)
Ovarian ‘Tumor’ of the Adrenogenital Syndrome
Bacterial Infections (Fig. 12.24)
Parasitic Infestations
Fungal Infections
Noninfectious Granulomas and Histiocytic Infiltrates
Autoimmune Oophoritis (Fig. 12.28)
Cysts, Nonfollicular
Mesothelial Proliferation
Surface Stromal Proliferation (Fig. 12.30)
Ovarian Remnant Syndrome
Torsion and Infarction (Fig. 12.31)
Ovarian Pregnancy (Fig. 12.32)
Changes Secondary to Metabolic Disease
Resistant Ovary Syndrome
Idiopathic Calcification (Fig. 12.33)
Adenomatous Hyperplasia of Rete Ovarii
Congenital Malformations and Ectopias
Other Non-Neoplastic Findings
Chapter 13: Surface Epithelial–Stromal Tumors: General Features, Serous Tumors, and Mucinous Tumors
Classification
Grading of Ovarian Carcinomas
Clinical Features and Prognostic Factors
Hereditary Ovarian Cancer
Benign Serous Tumors
Borderline Serous Tumors
High-grade Serous Carcinomas
Low-grade Serous Carcinomas (Figs. 13.35–13.40)
Intestinal-type Mucinous Tumors of Usual Type
Teratoma-associated Mucinous Tumors (Fig. 13.60)
Endocervical-like Mucinous Borderline Tumors (Figs. 13.61–13.64)
Endocervical-like Mucinous Carcinomas
Mural Nodules in Mucinous Tumors (Figs. 13.65–13.66)
Chapter 14: Surface Epithelial–Stromal Tumors: Endometrioid, Clear Cell, Transitional, Squamous, Rare, Undifferentiated, and Mixed Cell Types
Epidermoid Cyst
Squamous Cell Carcinoma
Small Cell Carcinoma, Pulmonary Type (Fig. 14.40)
Large Cell (Non-small Cell) Neuroendocrine Carcinoma (Fig. 14.41)
Hepatoid Carcinoma (Fig. 14.42)
Adenoid Cystic Carcinoma and Basaloid Carcinoma (Figs. 14.43–14.44)
Oncocytoma and Oncocytic Carcinoma
Chapter 15: Germ Cell Tumors of the Ovary
Dysgerminoma
Yolk Sac Tumor
Embryonal Carcinoma
Polyembryoma (Figs. 15.23–15.24)
Nongestational Choriocarcinoma (Figs. 15.25–15.26)
Mixed Primitive Germ Cell Tumors
Dermoid Cyst (Mature Cystic Teratoma)
Mature Solid Teratoma
Fetiform Teratoma (Homunculus)
Immature Teratoma
Struma Ovarii
Struma-derived Carcinomas (Figs. 15.48–15.49)
Insular Carcinoid
Trabecular Carcinoid
Strumal Carcinoid
Mucinous Carcinoid
Neuroectodermal Tumors
Sebaceous Tumors
Other Monodermal Teratomas
Mature Teratomas with Somatic-type Tumor
Immature Teratomas with Somatic-type Tumor
Gonadoblastoma
Mixed Germ Cell−Sex Cord–Stromal Tumors, Unclassified (Fig. 15.64)
Chapter 16: Sex Cord−Stromal and Steroid Cell Tumors of the Ovary
Granulosa Cell Tumors
Tumors in the Fibroma–Thecoma Group
Sertoli–Stromal Cell Tumors
Gynandroblastoma
Sex Cord Tumor with Annular Tubules
Sex Cord−Stromal Tumors, Unclassified
Stromal Luteoma
Leydig Cell Tumor
Steroid Cell Tumor, not otherwise Specified
Chapter 17: Miscellaneous Primary Ovarian Tumors
Leiomyoma (Fig. 17.9)
Hemangioma (Fig. 17.10)
Other Benign Soft Tissue-type Tumors
Leiomyosarcoma
Other Sarcomas, including Fibromatosis
Adenomatoid Tumor (Fig. 17.11)
Malignant Mesothelioma (Figs. 17.12–17.14)
Paraganglioma
Wilms' Tumor
Solid Pseudopapillary Tumor of Pancreatic Type (Fig. 17.15)
Melanotic Xp11 Tumor of Renal Type
Chapter 18: Metastatic Tumors of the Ovary (including Pseudomyxoma Peritonei, Hematolymphoid Neoplasms, and Tumors with Functioning Stroma)
Pancreas
Biliary Tract and Liver
Renal Tumors
Urinary Tract TUMORS
Rhabdomyosarcoma
Other Sarcomas (Fig. 18.53)
Endometrial Carcinoma (Fig. 18.54)
Cervical Carcinoma (Figs. 18.55–18.57)
Uterine Sarcomas and Choriocarcinoma (Figs. 18.58–18.59)
Fallopian Tube Tumors
Mesothelioma
Intra-abdominal Desmoplastic Small Round Cell Tumor
Malignant Lymphoma
Leukemia
Plasmacytoma
Chapter 19: Endometriosis and Lesions of the Secondary Müllerian System
General Features
Atypical endometriosis and endometriosis-associated tumors (Figs. 19.29–19.30)
Endosalpingiosis (Fig. 19.31)
Peritoneal Serous Borderline Tumors (Figs. 19.32–19.33)
Low-grade Peritoneal Serous Carcinomas, including Psammocarcinomas (Fig. 19.34)
High-grade Peritoneal Serous Carcinomas
Endocervicosis (including Müllerianosis) (Figs. 19.35–19.36)
Retroperitoneal Mucinous Tumors (Figs. 19.37–19.38)
Peritoneal Decidual Reaction
Disseminated Peritoneal Leiomyomatosis
Benign Glands of Müllerian Type
Decidua (Fig. 19.49)
Leiomyomatosis (Fig. 19.50)
Lymphangioleiomyomatosis
Chapter 20: Tumor-like Lesions and Tumors of the Peritoneum (Excluding Müllerian Lesions)
Inflammatory and Reparative Lesions
Mesothelial Lesions
Miscellaneous Lesions
Mesotheliomas
Intra-Abdominal Desmoplastic Small Round-Cell Tumor
Mesenchymal Tumors
Rare Primary Tumors
Metastatic Tumors (Figs. 20.38–20.39)
Index
Copyright

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Notices
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ISBN: 978-1-4557-7482-1
e-book ISBN: 978-0-323-18882-1
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication

To the memory of Robert E. Scully, MD


A great pathologist, a peerless investigator, a wonderful mentor, and a good friend
The third edition of this book is marked by sadness as in the last months of its preparation we lost our beloved mentor, one of the giants of pathology, Dr. Robert E. Scully. As with previous editions, we dedicate this book to him. In the following we express our debt of gratitude to him, indicate why those of us who trained with him consider him without peer as a pathologist, and why we will always have such affection for him.
Dr. Scully passed away on October 30, 2012, two months after his 91st birthday. We each had the pleasure and privilege of a close association with him for over 30 years. That experience is the defining aspect of our careers and one we will always cherish. As well as providing a unique example of practicing pathology at the highest level, his personal qualities of gentleness, kindness, and humility were an example to all who had the good fortune to know him. In addition to all he taught us, Dr. Scully allowed us free access to his treasure-trove collection of over 27,000 consultation cases and many of the illustrations in this volume are from those cases.
Dr. Scully's remarkable career has been discussed in detail elsewhere in a book recounting the history of pathology at the Massachusetts General Hospital (MGH) 1 and in recently published obituaries, but a brief summary is merited here. A Massachusetts native, Dr. Scully trained, for the most part, at Harvard Medical School and its affiliated hospitals, and was recruited to join the MGH staff by Dr. Tracy B. Mallory in 1950. He served the MGH until his retirement in the summer of 2004 with the exception of 2 years in the United States Army during the Korean War. Although he loved Boston and resided in one of its suburbs, Brookline, and then in the city center for four decades, he also enjoyed frequent travels to foreign countries where he developed many friendships. Apart from the stimulation it gave him because of his interest in other cultures, it provided a break from the great burden of work that he had for his entire career.
Dr. Scully practiced general surgical pathology until the last two decades of his career after which he focused on gynecologic and testicular pathology, although still serving as a consultant for a wide variety of cases. His diagnostic prowess is the stuff of legend at the MGH for generations of trainees and faculty who experienced his quick yet thorough eye that was applied to countless difficult cases including frozen sections. As he lived near the hospital most of his life, many senior residents who did frozen sections in evenings and weekends were buoyed by the knowledge that Dr. Scully was a short walk away and he would without fail come to their assistance should it be needed.
Dr. Scully excelled in all areas expected in an academic center, including diagnosis, teaching and research, the latter largely clinical-based studies emphasizing clinicopathologic correlation that included recognition of many new entities. As a resident he showed his academic productivity by reviewing all testicular tumors seen at the Peter Bent Brigham Hospital and coauthoring two articles that appeared in Archives of Pathology in 1948. It is humbling for us and for the reader to realize that his last publication was in 2006, a mere 58 years later! His curriculum vitae included 503 contributions, 320 of them original peer-reviewed contributions, the balance being largely chapters but also editorials and miscellaneous historical essays. His Army years resulted in a number of papers related to trauma. An interest in testicular tumors continued over the years resulting in the paradox of testicular tumors being included with the gynecologic material at the MGH.
Dr. Scully described many entities now well known and considered in these pages, among which are gonadoblastoma (the gonadal tumor of intersex) and ovarian tumors such as juvenile granulosa cell tumor, small cell carcinoma of hypercalcemic type, retiform Sertoli–Leydig cell tumor, and sclerosing stromal tumor. That some of the entities just mentioned are in the sex cord–stromal family is indicative of his lifelong great interest in that area that began in the mid-1950s when he was asked by an MGH gynecologist to co-author a book Endocrine Pathology of the Ovary 2 published in 1958. That quickly established Dr. Scully's reputation as an expert on ovarian tumors and anyone seeking an opinion on unusual morphology quickly considered him a good candidate for a second opinion. The number of consultation cases he received grew dramatically after that to reach, in the peak decades of his career, an average of about 10 a day. There was a slight bias towards ovarian tumor cases but the entire spectrum of gynecologic pathology would be encountered as well as a significant number of examples of testicular lesions and even general surgical pathology cases of diverse nature. His massive collection of sex cord–stromal tumors made his collection the source for many original papers over the years and a number of reviews in works such as the well-known Blaustein textbook. A body of studies on metastatic tumors to the ovary is also noteworthy. He was convinced for many years that most ovarian tumors associated with pseudomyxoma peritonei were metastatic from the appendix and guided a study supportive of that now widely accepted concept. Within the area of uterine mesenchymal and mixed epithelial–stromal tumors, he described new entities or made seminal contributions, which included those on müllerian adenosarcoma, uterine tumors resembling ovarian sex-cord tumors, and myxoid leiomyosarcoma. Although he felt, as we do, that the clinical, gross, and microscopic features usually led to the correct diagnosis, he was always curious and indeed wrote one of the first review articles on the immunohistochemistry of ovarian tumors. 3
Like any surgical pathologist, Dr. Scully had an abiding interest in the crucial benign versus malignant distinction, an area more important than some of the nuances of tumor morphology. In the 1970s he became aware that after operative procedures were performed on the genitourinary tract in both sexes, exuberant spindle cell proliferations could lead to misdiagnosis as sarcoma. Circa 1980 he became aware that Dr. Juan Rosai had a similar experience and had made a similar benign interpretation for his cases, and they were reported as a group in a famous paper of 1984. Mention should also be made of Dr. Scully's important role in the diethylstilbestrol (DES) story. In the mid- to late 1960s he noticed an unusual surge of MGH cases of clear cell adenocarcinoma of the vagina and cervix in young women. His comments on this unusual phenomenon prompted his clinical colleagues to be on the alert for a possible explanation. What led to the investigation of the matter was the mother of one of the young girls afflicted with clear cell carcinoma who questioned whether the drug she took during pregnancy, DES, might be related to her daughter's tumor. A clear association was soon established between in utero exposure to DES and the carcinomas and other abnormalities; many articles pertaining to this topic were published over the years.
A few years after the first edition of this book was published in 2000, Dr. Scully retired from his position as senior pathologist at the Massachusetts General Hospital and Professor of Pathology at Harvard Medical School, after a truly remarkable career spanning almost 55 years. His career, based on old-fashioned hard work, awareness of the priority of patient care, a balanced approach (including knowledge of the clinical and gross features that he rightly felt were often not given the necessary consideration), and a superb eye, is one that we can all strive to emulate. He embodied the adage of the eminent 17th century British physician Thomas Sydenham, who noted that ‘observation and experience are the standards for the physician.’ 4
We will forever hold to our conviction that no one looked at more slides of gynecologic specimens more carefully, and with greater benefit to mankind, than Dr. Scully. He will stand with another legendary figure, Dr. Robert Meyer, as one of the two giants among the illustrious individuals who have contributed to gynecological pathology. 5

Philip B. Clement, MD

Robert H. Young, MD, FRCPath

References

1. Young, R. H., Scully, R. E. Ch. 10. In: Louis D. N., Young R. H., eds. Keen Minds to Explore the Dark Continents of Disease: A History of the Pathology Services at the Massachusetts General Hospital . Beverly, MA: Memoires Unlimited Inc., 2011.
2. Morris, J. M., Scully, R. E. Endocrine Pathology of the Ovary . St Louis, MO: CV Mosby Co; 1958.
3. Scully, R. E. Immunohistochemistry of ovarian tumors. In: Russo J., Russo I., eds. Immunocytochemistry in Tumor Diagnosis . Martinus Nijhoff; 1985:293–320.
4. Power, D., Thompson, C. J. S. Chronologia Medica: A Handlist of Persons, Periods and Events in the History of Medicine . New York, NY: Paul B. Hoebler Inc; 1923.
5. Young, R. H. The rich history of gynecological pathology. Brief notes on some of its personalities and their contributions. Pathology . 2007; 39:6–25.
Preface to the Third Edition
The aims of the third edition of the Atlas of Gynecologic Surgical Pathology remain the same as those of the previous editions published in 2000 and 2008. The book is intended to be an easy-to-use practical guide to the diagnosis of lesions of the female reproductive system and peritoneum. The manner of presentation will, we hope, help the reader quickly assimilate the essential information about the numerous lesions discussed and illustrated. Each chapter begins with a heading outline so that its contents can be appreciated at a glance. The text is extensive, it being our intent that the reader will find in this volume an amount of information exceeding that in most atlases.
The text has been thoroughly revised and updated; almost 1000 new references have been added to this edition. We hope that we have achieved our goal to accurately and fairly reflect recent developments in our field, to which are added, where appropriate, personal observations based on our own experience. As much of the new information replaces rather than adds to the previous text, the word count in the third edition is only 18% greater than that of the second edition, in accord with our desire for the volume to retain its compact size and user-friendly format. Numerous space-saving abbreviations and acronyms have been used; a complete list of them appears after the table of contents. Given the availability of online search engines, we have limited the references and only cite the most important from the past 20 years, in addition to some classic older references, some of which still remain the best study of a particular lesion. There has been only a modest increase in the formally numbered figures compared to the last edition, but added to those are a significantly increased number of images as composite figures in which illustrations of a specific lesion are grouped, allowing for an economic use of space.
The emphasis in this book is on the diagnosis of neoplastic and pseudoneoplastic lesions, with a broad interpretation of ‘pseudoneoplastic’ to include all lesions that could be misinterpreted as neoplasms on clinical, gross, or microscopic examination. Although the focus is on common lesions, less common and even rare lesions are also discussed. Diagnosis of the lesions covered can in most cases be accomplished by careful evaluation of routinely stained slides, and, accordingly, the vast majority of illustrations are of such preparations. Gross examination plays an important role in evaluating specimens from the female genital tract, and we have included many gross illustrations, although space constraints preclude illustrating every entity. The clinical background may also be important when evaluating gynecologic tumors: basic features such as the age of the patient and clinical history may be crucial in formulating a differential diagnosis, especially when dealing with an ovarian tumor, and accordingly are emphasized when indicated. A detailed knowledge of the normal histology of the female reproductive system is important as a background for evaluating the pathology of this area. Some of these aspects are discussed briefly where appropriate but are not considered in detail because a standard text in this area is readily available. 1
As in the previous editions, the 20 chapters are organized by site and the text is arranged in concise, point form that highlights the cardinal clinical, gross, and microscopic features and the differential diagnoses. Immunohistochemical findings are also included, with an emphasis on those that are the most diagnostically useful, and in rare cases, even crucial to establish the correct diagnosis. The most recent FIGO (International Federation of Gynecology and Obstetrics) staging system for tumors in each major site is also included. The histological classifications used are generally those of the well-known World Health Organization classifications of tumors of the female genital tract, and with regard to the ovary, the classification used by Dr. Robert E. Scully in his second AFIP fascicle. 2
We hope that the pathologist, both in academic practice and in community practice, will find this work helpful in evaluating the numerous, often challenging specimens and perplexing microscopic patterns that may be seen in female genital tract specimens, such material accounting for a substantial proportion of the cases seen in daily practice. Additionally, it is hoped that clinicians with a particular interest in this area will also find this work a useful source of helpful information and reference material.

Philip B. Clement, MD

Robert H. Young, MD, FRCPath

References

1. Mills S. E., ed. Histology for Pathologists, fourth ed, New York, NY: Lippincott Williams & Wilkins, 2011.
2. Scully, R. E., Young, R. H., Clement, P. B. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament . Armed Forces Institute of Pathology; 1998.
Glossary of Abbreviations and Acronyms


ABC adenoid basal carcinoma
AB/PAS Alcian blue-periodic acid Schiff
ACC adenoid cystic carcinoma
ACTH adrenocorticotrophic hormone
AFP alpha-fetoprotein
AGCT adult-type granulosa cell tumor
AGN atypical genital nevus
AIM atypical immature metaplasia
AIS adenocarcinoma in situ
AJCC American Joint Cancer Committee
AML acute myelogenous leukemia
APA atypical polypoid adenomyoma
AR androgen receptor
ASC American Society of Cytopathology
ASCCP American Society for Colposcopy and Cervical Pathology
ASCUS atypical squamous cells of uncertain significance
ASR Arias-Stella reaction
BCC basal cell carcinoma
BT Brenner tumor
D&C dilatation and curettage
dVIN differentiated vulvar intraepithelial neoplasia
ER estrogen receptor
CCC clear cell carcinoma
CEA carcinoembryonic antigen
CHEC corded and hyalinized endometrioid adenocarcinoma
CIN cervical intraepithelial neoplasia
CK cytokeratin
CL cellular leiomyoma
CHM complete hydatidiform mole
CMV cytomegalovirus
CT cytotrophoblast
DES diethylstilbestrol
DPE disordered proliferative endometrium
DSRCT desmoplastic small round cell tumor
EBV Epstein–Barr virus
EC epidermoid cyst
EGFR epidermal growth factor receptor
EGD endocervical glandular dysplasia
EGIST extragastrointestinal stromal tumor
EMA epithelial membrane antigen
EMBT endocervical-like mucinous borderline tumor
ER estrogen receptor
ESN endometrial stromal nodule
ESS endometrial stromal sarcoma
EST endometrial stromal tumor
EST-LI endometrial stromal tumor with limited infiltration
ETT epithelioid trophoblastic tumor
FC follicle cyst
FATWO female adnexal tumor of probable wolffian origin
FIGO International Federation of Gynecology and Obstetrics
FISH fluorescent in situ hybridization
FSH follicle stimulating hormone
GCA giant cell arteritis
GCT granulosa cell tumor
GCDFP gross cystic disease fluid protein
GFAP glial fibrillary acidic protein
GIST gastrointestinal stromal tumor
GnRH gonadotropin releasing hormone
GnRH-a gonadotropin releasing hormone agonist
GTA gastric-type adenocarcinoma
GOG Gynecology Oncology Group
GTD gestational trophoblastic disease
GVHD graft-versus-host disease
HA hydropic abortus
HCC hepatocellular carcinoma
HDFC highly differentiated follicular carcinoma
H&E hematoxylin and eosin
hCG human chorionic gonadotropin
HCL highly cellular leiomyoma
HGPSC high-grade peritoneal serous carcinoma
HGSC high-grade serous carcinoma
HIV human immunodeficiency virus
HL hyperreactio luteinalis
HLA-G human leukocyte antigen-G
HLRCC hereditary leiomyomatosis and renal cell carcinoma syndrome
HM hydatidiform mole
HNF hepatocyte nuclear factor-1β
HNPCC hereditary nonpolyposis colonic cancer syndrome (Lynch syndrome)
hPL human placental lactogen
HPV human papillomavirus
HRHPV high-risk human papillomavirus
HSIL high-grade squamous intraepithelial lesion
HSV herpes simplex virus
IGFBP-1 insulin-like growth factor binding protein-1
IMBT intestinal-type mucinous borderline tumor
IMBT-IEC IMBT with intraepithelial carcinoma
IMT inflammatory myofibroblastic tumor
ISqCC invasive squamous cell carcinoma
ISGP International Society of Gynecological Pathologists
ISSVD International Society for the Study of Vulvar Disease
IT intermediate trophoblast
ITCP inverted transitional cell papilloma
IUD intrauterine contraceptive device
JGCT juvenile granulosa cell tumor
IVL intravenous leiomyomatosis
KS Kaposi's sarcoma
LAMN low-grade appendiceal mucinous neoplasm
LAST Lower Anogenital Squamous Terminology
LBN leiomyoma with bizarre nuclei
LCA leukocyte common antigen
LCNC large cell neuroendocrine carcinoma
LCH Langerhans' cell histiocytosis
LEEP loop electrocautery excision procedure
LGPSC low-grade peritoneal serous carcinoma
LGSC low-grade serous carcinoma
LGSMT low-grade smooth muscle tumor
LH luteinizing hormone
LMP low malignant potential
LMS leiomyosarcoma
LNI lymph node involvement
LOH loss of heterozygosity
LP lichen planus
LS lichen sclerosus
LSIL low-grade squamous intraepithelial lesion
LVSI lymphovascular space invasion
MAL mitotically active leiomyoma
MALT mucosa-associated lymphoid tumor
MEC mucoepidermoid carcinoma
MELF microcystic, elongated, fragmented
MERT malignant extrarenal rhabdoid tumor
MGH microglandular hyperplasia
mf/10 hpf mitotic figures per 10 high-power fields
MMR mismatch repair
MMRP mismatch repair proteins
MMMT malignant müllerian mixed tumor (uterus) or malignant mesodermal mixed tumor (ovary)
MPIC multilocular peritoneal inclusion cyst
MRT malignant rhabdoid tumor
MSA muscle specific actin
MSGC multinucleated stromal giant cell
NBCCS nevoid basal cell carcinoma syndrome
N : C nuclear : cytoplasmic
NMDAR anti-N-methyl D-aspartate receptor
NOS not otherwise specified
NPN necrotic pseudoxanthomatous nodule
NSE neuron-specific enolase
OC oral contraceptive
OS overall survival
OHS ovarian hyperstimulation syndrome
PAMRAG pseudoactinomycotic radiate granule
PAN polyarteritis nodosa
PAP prostatic acid phosphatase
Pap Papanicolaou
PAS periodic acid Schiff
PASD periodic acid Schiff and diastase
PCOS polycystic ovary syndrome
PCR polymerase chain reaction
PEComa perivascular epithelioid cell tumor
PES proximal epithelioid sarcoma
PFS progression-free survival
PID pelvic inflammatory disease
PIM papillary immature metaplasia
PJS Peutz–Jeghers syndrome
PLAP placental alkaline phosphatase
PHM partial hydatidiform mole
PIC peritoneal inclusion cyst
PMM peritoneal malignant mesothelioma
PNET primitive neuroectodermal tumor
POSSC primary ovarian serous surface carcinoma
PP pseudomyxoma peritonei
PR progesterone receptor
PRM progesterone receptor modulator
PSA prostatic specific antigen
PSCN postoperative spindle cell nodule
PSNP placental site nodule and plaque
PSqA postmenopausal squamous atypia
PSqCC papillary squamous cell carcinoma
PSTT placental site trophoblastic tumor
PTEN phosphatase and tensin homolog
PTHrP parathyroid hormone-related polypeptide
PVA polyvinyl alcohol
RCC renal cell carcinoma
RRSO risk-reducing salpingo-oophorectomy
SBT serous borderline tumor
SCC small cell carcinoma
SCCH small cell carcinoma of hypercalcemic type
SCH squamous cell hyperplasia
SCOUT secretory cell outgrowth
SDB Schiller–Duval body
SDTC struma-derived thyroid carcinoma
SE stromal endometriosis
SEER statistical evaluation and end results
SERM selective estrogen receptor modulator
SFT solitary fibrous tumor
SIADH syndrome of inappropriate antidiuretic hormone secretion
SIL squamous intraepithelial lesion
SLCT Sertoli–Leydig cell tumor
SCLE sex-cord like elements
SCTAT sex-cord tumor with annular tubules
SEE-FIM sectioning and extensive examination of the fimbria
SGC syncytiotrophoblastic giant cell
SIN salpingitis isthmica nodosa
SLMN sarcoma-like mural nodules
SLN sentinel lymph node
SMA smooth muscle actin
SMT smooth muscle tumor
SO sarcomatous overgrowth
SPC syncytial papillary change
SqCC squamous cell carcinoma
SqCCE squamous cell carcinoma associated with endometriosis
SqCCP squamous cell carcinoma, pure
SST sclerosing stromal tumor
ST syncytiotrophoblast
STIC serous tubal intraepithelial carcinoma
STIL serous tubal intraepithelial lesion
STCC squamotransitional cell carcinoma
STUMP smooth muscle tumor of uncertain malignant potential
TAMT teratoma-associated mucinous tumor
TC tubal carcinoma
TCC transitional cell carcinoma
TCM transitional cell metaplasia
TCN tumor cell necrosis
TEM tuboendometrioid metaplasia
TGM tris-acryl gelatin microspheres
TILT tubal intraepithelial lesion in transition
TM tubal metaplasia
UC undifferentiated carcinoma
UES undifferentiated endometrial sarcoma
uVIN usual vulvar intraepithelial neoplasia
TTF1 thyroid transcription factor
UAE uterine artery embolization
UTROSCT uterine tumor resembling ovarian sex-cord tumor
VaIN vaginal intraepithelial neoplasia
VIM vimentin
VIN vulvar intraepithelial neoplasia
VIP vasomotor inhibitory peptide
WDPM well-differentiated papillary mesothelioma
WHO World Health Organization
WT1 Wilms' tumor protein
YST yolk sac tumor
Chapter 1
Non-neoplastic Lesions and Benign Tumors of the Vulva


Viral Infections  

Human Papillomavirus (HPV) Infection including Condyloma Acuminatum 
Herpes Virus Infection 
Other Viral Infections 
Other Infections  

Syphilis 
Granuloma Inguinale 
Lymphogranuloma Venereum 
Chancroid 
Tuberculosis 
Necrotizing Fasciitis and Progressive Bacterial Synergistic Gangrene 
Other Bacterial Infections 
Fungal Infections and Parasitic Infestations 
Non-neoplastic Epithelial Disorders  

Lichen Sclerosus 
Squamous Cell Hyperplasia, NOS 
Other Dermatoses 
Squamous Papillomatosis  
Pigmented Lesions  

Lentigo Simplex and Melanosis 
Usual Melanocytic Nevi 
Atypical Genital Nevi 
Fibroepithelial Polyp (SEE Chapter 3 )  12
Cysts 

Bartholin's Duct Cyst 
Mucinous and Ciliated Vestibular Cysts 
Other Cysts 
Noninfectious Inflammatory Lesions  

Vulvar Vestibulitis 
Plasma Cell Vulvitis (Zoon's Vulvitis) 
Granulomatous Vulvitis and Vulvar Involvement by Crohn's Disease 
Behçet's Disease 
Florid Reactive Lymphoid Hyperplasia (Lymphoma-like Lesion) 
Graft-Versus-Host Disease 
Ligneous Vulvitis (see Chapter 4 ) 
Reactive Lesions  

Reactive Atypia and Multinucleated Keratinocytes 
Nodular Fasciitis 
Postoperative Spindle Cell Nodule (see Chapter 3 ) 
Lesions Related to Immobilization, Obesity, and Repetitive Trauma 
Other Non-neoplastic Lesions  

Multinucleated Stromal Giant Cells 
Adenosis 
Ectopic Breast Tissue and Rarer Ectopias 
Nodular Hyperplasia of Bartholin's Gland 
Varices 
Miscellaneous Rare Lesions 
Benign Epithelial Tumors  

Papillary Hidradenoma (Hidradenoma Papilliferum) and Other Apocrine Tumors 
Other Benign Tumors of Skin Appendage Origin 
Seborrheic Keratosis 
Benign Mammary-type Tumors 
Benign Tumors of Bartholin's Gland and Minor Vestibular Glands 
Tubulovillous Adenoma 
Site-specific Benign Mesenchymal Tumors of the Lower Genital Tract  

Aggressive Angiomyxoma 
Angiomyofibroblastoma 
Cellular Angiofibroma 
Superficial Myofibroblastoma 
Prepubertal Vulvar Fibroma 
Nonspecific Benign Mesenchymal Tumors  

Leiomyoma and Rhabdomyoma (see Chapters 2 and 3) 
Fibrous, Adipocytic, Vascular, and Neural Tumors 
Superficial Angiomyxoma (Cutaneous Myxoma) 
Granular Cell Tumor 

Viral Infections

Human Papillomavirus (HPV) Infection INCLUDING Condyloma Acuminatum


Clinical and gross features ( Fig. 1.1 )


Fig. 1.1 Condylomata acuminata. The vulva is involved by confluent condylomas.

  Sexually transmitted HPV (usually low-risk types, especially HPV type 6 or 11) is the causative agent of the common condyloma acuminatum (‘venereal wart’). The incidence of condylomas in the United States increased 4- to 5-fold between 1966 and 1981.
  Condylomas vary from those only colposcopically visible to small excrescences to large, sessile or pedunculated, white to red, cauliflower-like masses that are often multiple and occasionally confluent. They most commonly involve the vestibule and the medial aspects of the labia majora.
  There are often synchronous or metachronous condylomas, precancerous changes, or invasive squamous cell carcinoma in local sites, including the perineal and perianal skin and the mucosa of the anus, urethra, vagina, and cervix.
  The clinical course is typically protracted unless the lesions are ablated or removed. They may enlarge and increase in number during pregnancy but can regress postpartum.
  Srodon et al. classify typical condylomas as vulvar intraepithelial neoplasia (VIN) I. Although condylomas harbored a low-risk HPV in 67% of their cases, 42% contained a high-risk HPV, a finding possibly accounting for the progression of some condylomas to high-grade VIN or invasive squamous cell carcinoma.

Histological features ( Figs. 1.2 – 1.4 )


Fig. 1.2 Condyloma acuminatum. Low-power view shows typical papillary configuration.


Fig. 1.3 Condyloma acuminatum. Typical appearance; note focal koilocytotic atypia.


Fig. 1.4 Pseudobowenoid change in a condyloma (see text).

  Fully developed condylomas are characterized by simple to complex branching papillae composed of acanthotic squamous epithelium and fibrovascular cores and often an endophytic proliferation of rete pegs.
  The pathognomonic feature is the presence of koilocytes (HPV-infected keratinocytes) in the superficial layers. They are usually prominent but may be only focal or even absent. In the latter situation, a diagnosis of ‘condyloma without cytopathic effect’ has been applied, but ‘squamous papilloma, possibly condyloma’ may be preferable given the clinical implications of a condyloma diagnosis.
  Koilocytes vary in size and have a perinuclear halo of clear cytoplasm that is typically surrounded by a peripheral zone of condensed amphophilic cytoplasm. Their hyperchromatic, granular or smudgy, enlarged to shrunken nuclei have an irregular contour (‘koilocytotic atypia’); binucleated or multinucleated cells are common. Occasional mitotic figures, usually confined to the lower third of the epithelium, may be seen.
  MIB1 expression is present in the upper two-thirds of the epithelium and correlates with the presence of HPV (usually low-risk subtypes such as HPV 6 or 11). Unlike high-grade VIN ( Chapter 2 ), p16 staining is focal, cytoplasmic, and confined to the upper half of the epithelium.
  Nonspecific features include para/orthokeratosis, hypergranulosis, parabasilar hyperplasia, and an underlying superficial chronic inflammatory infiltrate.
  Variant condyloma phenotypes include:

•  Flat condyloma. These lesions are less common in the vulva than in the cervix.
•  Seborrheic keratosis (SK)-like condyloma. HPV+ SK-like lesions have also been referred to as ‘condyloma with features of SK’ (see Seborrheic Keratosis , page 19).
•  Condyloma with pseudobowenoid change. Prominent apoptosis in the superficial keratinocytes is associated with chromatin dispersal or clumping and condensation and retraction of the cytoplasm resulting in a dense hyaline globule (the residue of a dead cell). Although the appearance may suggest VIN, nuclear atypia and mitotic activity in the lower layers are absent.
  Podophyllin treatment of condylomas results in mitotic arrest in the lower epidermis, karyorrhexis, and cellular swelling. In contrast to VIN, nuclear atypia is mild and confined to the upper layers. A history of recent podophyllin treatment is obviously helpful.

Differential diagnosis


  Verruca vulgaris (HPV type 2) infection:

•  Aguilera-Barrantes found that 41% of vulvar warts in girls <5 years of age were related to HPV 2, the remainder related to HPV 6/11. The corresponding figures for adults were 3% (HPV 2) and 94% (HPV 6/11).
•  The HPV 2-related vulvar lesions, which are likely not venereally transmitted, resembled typical verruca vulgaris with marked hyperkeratosis.
•  HPV testing of vulvar warts from children can thus be helpful, especially if the histologic changes are consistent with verruca vulgaris.
  Warty VIN and warty invasive squamous cell carcinoma (SqCC). These lesions ( Chapter 2 ), in contrast to a typical condyloma, have significant nuclear atypia and mitotic figures, often abnormal, in all layers of the epithelium, typically strong and diffuse p16 staining, and in some cases, invasion.
  Verrucous carcinoma ( Chapter 2 ). These tumors (‘giant condylomas’ in the older literature) are usually large solitary tumors in older women and are usually HPV negative. They lack the fine branching papillae and koilocytosis of condylomas and have well-circumscribed deep borders formed by broad bulbous pegs.
  Papillary SqCC, not otherwise specified. These lesions are rare in the vulva ( Chapter 5 ) and are composed of obviously malignant cells that lack koilocytosis.
  Vestibular papillomatosis (page 10). The squamous papillomas of this lesion are typically confined to the vestibular area, are usually much smaller than condylomas, and typically lack koilocytosis and hyperkeratosis.
  Condyloma lata (see Syphilis , page 5).
  Epidermolytic hyperkeratosis. This lesion, characterized by acanthosis, compact papillomatous hyperkeratosis, and dissolution of the suprabasilar epithelium resulting in perinuclear clear zones, can simulate HPV infection. Keratohyaline clumping and dyskeratosis resulting in intracellular eosinophilic globules facilitate distinction from condyloma.

Herpes Virus Infection ( Fig. 1.5 )


Fig. 1.5 Herpetic ulcer of vulva. Note multinucleation and typical ground-glass nuclei.

  Most cases of herpetic vulvitis are due to the sexual transmission of herpes simplex (HSV) type 2, or less commonly, HSV type 1.
  The typical presentation is vulvar pain, inguinal lymphadenopathy, malaise, and fever. Vesicles, pustules, and painful ulcers appear sequentially. The perineum, perianal skin, cervix, vagina, and urinary tract are often synchronously involved.
  The lesions persist for 2–6 weeks and heal without scarring. Rare cases of chronic hypertrophic herpetic vulvitis may clinically simulate a neoplasm or harbor an invasive SqCC.
  Detection of HSV-2-specific antibodies confirms the diagnosis. Antibodies in many women without a history of infection indicate that subclinical infections are common.
  Cytological smears or biopsy of the base or edges of a newly formed vesicle or ulcer reveal the characteristic ground-glass nuclei or the subsequent eosinophilic intranuclear inclusions. Cells infected by HSV type 1 or herpes zoster have a similar appearance.
  Recurrent episodes are common after primary infection, although they are usually much milder and often inconspicuous and eventually tend to become less frequent.
  Vulvitis secondary to herpes zoster (varicella) infection is rare, usually occurring in postmenopausal women who present with vulvar pain that is followed by vesicles and ulcers that are usually unilateral. Recurrent episodes of pain and vesicles are common.

Other Viral Infections


  Cytomegalovirus (CMV) causes an ulcerative vulvovaginitis resembling a herpetic infection; HIV-positive women appear to be most susceptible. The characteristic CMV-inclusion bodies in epithelial and endothelial cells are detectable with routine and immunohistochemical stains, culture, or by PCR.
  Molluscum contagiosum can be venereally transmitted resulting in vulvar and perineal lesions that are often asymptomatic and overlooked by patients and physicians. The histological features are similar to those involving extravulvar sites.
  Human immunodeficiency virus (HIV) has been occasionally cultured from genital ulcers in HIV-infected women, although many genital ulcers in this population do not contain HIV. HIV may cause or exacerbate genital ulcers in HIV-infected women.
  Epstein–Barr virus is a rare cause of painful genital ulcers in women. One such patient had atypical mononucleosis.

References

Human papillomavirus infection
Aguilera-Barrantes, I., Magro, C., Nuovo, G. J. Verruca vulgaris of the vulva in children and adults: a nonvenereal type of vulvar wart. Am J Surg Pathol . 2007; 31:529–535.
Bai, H., Cviko, A., Granter, S., et al. Immunophenotype and viral (human papillomavirus) correlates of vulvar seborrheic keratosis. Hum Pathol . 2003; 34:559–564.
McLachlin, C. M., Kozakewich, H., Craighill, M., et al. Histologic correlates of vulvar human papillomavirus infection in children and young adults. Am J Surg Pathol . 1994; 18:728–735.
Nucci, M. R., Genest, D. R., Tate, J. E., et al. Pseudobowenoid change of the vulva: A histologic variant of untreated condyloma. Mod Pathol . 1996; 9:375–379.
Russell, P., Valmadre, S., Howard, V. Localised epidermolytic hyperkeratosis of the vulva: A case of mistaken identity. Pathology . 2010; 42:483–485.
Srodon, M., Stoler, M. H., Baber, G. B., et al. The distribution of low and high risk HPV types in vulvar and vaginal intraepithelial neoplasia. Am J Surg Pathol . 2006; 30:1513–1518.

Herpes virus infection
Brown, D. Herpes zoster of the vulva. Clin Obstet Gynecol . 1972; 15:1010–1014.
Corey, L., Adams, H. G., Brown, Z. A., et al. Genital herpes simplex virus infections: Clinical manifestations, course, and complications. Ann Intern Med . 1983; 98:958–972.
Kaufman, R. H., Faro, S. Herpes genitalis: Clinical features and treatment. Clin Obstet Gynecol . 1985; 28:152–163.
Koutsky, L., Stevens, C. E., Holmes, K. K., et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. New Engl J Med . 1992; 326:1533–1539.
Strehl, J., Mehlhorn, G., Koch, M. C., et al. HIV-associated hypertrophic herpes simplex genitalis with concomitant early invasive squamous cell carcinoma mimicking advanced genital cancer: Case report and literature review. Int J Gynecol Pathol . 2012; 31:286–293.

Other viral infections
Friedmann, W., Schafer, A., Kretschmer, R. CM virus infection of vulva and vagina. Geburtsh Frauenheilk . 1990; 50:729–730.
Hudson, L. B., Perlman, S. E. Necrotizing genital ulcerations in a premenarcheal female with mononucleosis. Obstet Gynecol . 1998; 92:642–644.
LaGuardia, K. D., White, M. H., Saigo, P. E., et al. Genital ulcer disease in women infected with human immunodeficiency virus. Am J Obstet Gynecol . 1995; 172:553–562.
Tyring, S. K. Molluscum contagiosum: the importance of early diagnosis and treatment. Am J Obstet Gynecol . 2003; 189(suppl. ):S12–S16.

Other Infections

Syphilis


  Syphilis is caused by the sexually transmitted spirochete Treponima pallidum . The primary lesion or chancre forms within days or several months of initial contact. The secondary phase becomes evident by 6 months as a mucocutaneous rash and papules (condyloma lata). Vulvar involvement by the gummas of tertiary syphilis is rare.
  Chancres are superficial ulcers whereas condylomata lata are nonulcerated lesions with marked acanthosis and papillomatosis, often accompanied by intraepidermal neutrophilic infiltration. In both lesions, a perivascular plasmacellular infiltrate with endothelial proliferation suggests the diagnosis, which can be confirmed by a Warthin–Starry stain to demonstrate the organisms.
  Dark-field examination or immunofluorescent staining of serum expressed from the lesions, as well as serologic studies, can also facilitate the diagnosis.

Granuloma Inguinale


  This disorder is caused by the Gram-negative bacteria Calymmatobacterium granulomatis . The primary lesions (vulvar, vaginal, or cervical) are painless papules or ulcers that appear within a month of exposure (sexual contact or fecal contamination).
  The ulcers may persist for years and mimic a neoplasm, including squamous cell carcinoma. In later stages, lymphatic spread can result in brawny edema of the vulva or parametrial or retroperitoneal involvement.
  Unlike lymphogranuloma venereum (see below), inguinal lymphadenopathy is uncommon but can be mimicked by subcutaneous inguinal abscesses that often ulcerate.
  Granulation tissue is infiltrated by neutrophils, plasma cells, and vacuolated histiocytes containing the coccoid to bacillary organisms (Donovan bodies). The latter can be demonstrated within the vacuoles by Giemsa or Warthin–Starry staining of tissue sections or touch imprints of the lesion, or by culture.

Lymphogranuloma Venereum


  This sexually transmitted disease is caused by Chlamydia trachomatis . An initial ulcer is followed by painful inguinal lymphadenitis (buboes) that can rupture and drain through the overlying skin. Later, chronic lymphatic obstruction can result in vaginal and rectal fibrosis (sometimes with strictures) and nonpitting vulvar edema.
  As the inflammatory infiltrate is nonspecific (lymphocytes, plasma cells, histiocytes including giant cells), diagnosis rests on the characteristic clinical findings, culture, immunohistochemical staining, and complement fixation tests.

Chancroid


  This sexually transmitted disease, which is caused by the Gram-negative bacillus Haemophilus ducreyi , presents with single or multiple, painful, often purulent, vulvar ulcers and tender inguinal lymphadenopathy.
  The ulcer consists of a superficial zone, a middle zone with characteristic vascular changes, and a deep zone with a lymphoplasmacellular infiltrate. Gram stains of tissue sections or smears may reveal the organisms in the superficial zone but definite diagnosis requires culture identification of the organism.

Tuberculosis


  Vulvar tuberculosis is rare and is usually due to direct or lymphatic spread from other sites in the female genital tract, involvement of which is usually a result of blood-borne spread from pulmonary tuberculosis.
  The lesion begins as a nodule that later ulcerates and may drain caseous material and pus through multiple sinuses. Epidermal hyperplasia may result in a large warty tumor-like mass (hypertrophic tuberculosis).
  There is typical granulomatous inflammation with caseation, diagnosis requires identification of the organisms ( Mycobacterium tuberculosis or occasionally atypical mycobacteria) with acid fast stains and/or culture.
  The differential diagnosis includes noninfectious forms of granulomatous vulvitis (page 14) and a foreign-body granulomatous reaction.

Necrotizing Fasciitis and Progressive Bacterial Synergistic Gangrene


  Vulvar involvement by these disorders, which represent mixed synergistic bacterial infections, is often associated with diabetes mellitus and atherosclerosis.
  Necrotizing fasciitis presents with vulvar erythema, edema, and pain, followed by rapidly progressive dark discoloration, bullae, and necrosis of the skin, subcutaneous tissue, and fascia. Toxic shock syndrome occurs in rare cases. The infection can be fatal without prompt excision of involved tissues and antibiotic therapy.
  Progressive synergistic gangrene, unlike necrotizing fasciitis, is a slowly progressive process that can involve the fascia, with less severe systemic manifestations. It is more likely to develop in postoperative wounds, whereas necrotizing fasciitis is more likely to develop at sites of minor injury.

Other Bacterial Infections


  Bartholinitis is usually caused by the sexually transmitted organisms Neisseria gonorrhoeae or Chlamydia trachomatis ; occasional cases follow vulvovaginal operations. A Bartholin's abscess, often associated with secondary infection by anaerobic bacteria, is a common complication. Toxic shock syndrome is a rare complication.
  Hidradenitis suppurativa is a chronic suppurative process of the apocrine sweat glands of the vulva and groins that often results in scarring and draining sinuses. Microscopic examination reveals acute and chronic inflammation and apocrine glands dilated with keratinaceous material. Squamous cell carcinoma has arisen in long-standing cases.
  Rare cases of vulvar bacillary angiomatosis may occur and result in a tumor-like mass. Microscopic examination reveals a lobular epithelioid vascular proliferation and hazy clumps of bacteria ( Bartonella henselae or Bartonella quintana ) that stain with the Warthin–Starry method.
  Erythrasma, a chronic infection of the vulvar and perianal skin, is due to the bacterium Corynebacterium minutissimum . The lesion is usually diagnosed by Wood's lamp examination.
  Rare cases of vulvar malakoplakia or involvement by Actinomyces israelii have been reported.

Fungal Infections and Parasitic Infestations


  Chronic fungal infections of the vulvar and perianal skin are commonly caused by Candida albicans and dermatophytes. Vulvovaginal candidiasis results in pruritic, moist, red lesions that exhibit spongiosis and intraepithelial and dermal neutrophils. PAS stains and cultures can confirm the diagnosis, but a paucity of organisms can cause false negative results.
  Rare parasitic infestations of the vulva include enterobiasis, schistosomiasis, and myiasis, the last due to infestation of the larva of the muscoid fly and sarcophaga. Enterobiasis and late cutaneous vulvar schistosomiasis can both elicit striking pseudoepitheliomatous hyperplasia that can mimic squamous cell carcinoma if the organisms are not appreciated.

References

Barnes, R., Mahood, S., Lammert, N., et al. Extragenital granuloma inguinale mimicking a soft-tissue neoplasm: A case report and review of the literature. Hum Pathol . 1990; 21:559–561.
Bhattacharya, P. Hypertrophic tuberculosis of the vulva. Obstet Gynecol . 1978; 51:21s–22s.
Farley, D. E., Katz, V. L., Dotters, D. J. Toxic shock syndrome associated with vulvar necrotizing fasciitis. Obstet Gynecol . 1993; 82:660–662.
Freinkel, A. L. Histological aspects of sexually transmitted genital lesions. Histopathology . 1987; 11:819–831.
Gallup, D. G., Freedman, M. A., Meguiar, R. V., et al. Necrotizing fasciitis in gynecologic and obstetric patients: A surgical emergency. Am J Obstet Gynecol . 2002; 187:305–311.
Kogulan, P. K., Smith, M., Seidman, J., et al. Malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: Case report and discussion of malakoplakia-associated bacteria. Int J Gynecol Pathol . 2001; 20:403–406.
Konanahalli, P., Menon, P., Walsh, M. Y., et al. Enterobius vermicularis (pinworm) infestation of the vulva: Report of 2 cases of a pseudoneoplastic lesion mimicking squamous carcinoma. Int J Gynecol Pathol . 2010; 29:490–493.
Mattox, T. F., Rutgers, J., Yoshimori, R. N., et al. Nonfluorescent erythrasma of the vulva. Obstet Gynecol . 1993; 81:862–864.
McElroy, J. Y., Gorens, M. E., Jackson, L. N., et al. Actinomyces israelii may produce vulvar lesions suspicious for malignancy. Infect Dis Obstet Gynecol . 2006; 2006:48269.
Meltzer, R. M. Necrotizing fasciitis and progressive bacterial synergistic gangrene of the vulva. Obstet Gynecol . 1983; 61:757–760.
Peters, W. A., III. Bartholinitis after vulvovaginal surgery. Am J Obstet Gynecol . 1998; 178:1143–1144.
Pratistadevi, P. K., Sing, Y., Ramburan, A., et al. Bartonella quintana -induced vulval bacillary angiomatosis. Int J Gynecol Pathol . 2012; 31:390–394.
Ramdial, P. K. Transepithelial elimination of late cutaneous vulvar schistosomiasis. Int J Gynecol Pathol . 2001; 20:166–172.
Roberts, D. B. Necrotizing fasciitis of the vulva. Am J Obstet Gynecol . 1987; 157:568–571.
Shearin, R. S., Boehike, J., Karanth, S. Toxic shock-like syndrome associated with Bartholin's gland abscess: Case report. Am J Obstet Gynecol . 1989; 160:1073–1074.
Sobel, J. D., Faro, S., Force, R. W., et al. Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol . 1998; 178:203–211.
Thomas, R., Barnhill, D., Bibro, M., et al. Hidradenitis suppurativa: A case presentation and review of the literature. Obstet Gynecol . 1985; 66:592–595.

Non-Neoplastic Epithelial Disorders




Classification *


1.  Lichen sclerosus (lichen sclerosus et atrophicus)
2.  Squamous cell hyperplasia (formerly hyperplastic dystrophy)
3.  Other dermatoses


Lichen Sclerosus


Clinical and gross features ( Fig. 1.6 )


Fig. 1.6 Lichen sclerosus, clinical appearance.

  Lichen sclerosus (LS) accounts for 30–40% of non-neoplastic epithelial vulvar lesions. It may occur at any age, including children, but is most common after the menopause.
  The etiology is unknown, but recent evidence indicates a chronic lymphocyte-mediated disease.

•  LS is associated with autoantibodies and systemic autoimmune diseases, most commonly autoimmune gastritis, Hashimoto's thyroiditis, and extragenital psoriasis.
•  Up to 50% of cases have a monoclonally rearranged T-cell receptor γ-chain gene. These monoclonal T-cells have an immunoprofile of an antigen-mediated immune response.
•  Low serum levels of dihydrotestosterone, free testosterone, and androstenedione in untreated patients and a response to topical testosterone suggest hormonal factors may also play a role.
•  A familial occurrence and HLA class II DQ antigen restrictions in some cases suggest the existence of genetic factors.
  LS may be asymptomatic but often causes pruritus, burning, and dyspareunia. Irregular, ill-defined, white patches can involve any part of the vulva. Telangiectatic vessels and melanin incontinence can result in focal red and brown areas, respectively.
  Hart et al. found that the labia minora were involved in 68% of cases, the labia majora in 60%, the clitoris in 51%, the perineum in 41%, and the posterior fourchette in 36%. Almost 90% of the lesions are multiple. Bilateral, sometimes symmetrical, lesions occur in 80% of cases.
  Vaginal involvement occurs in rare cases. Extragenital lesions occur in two-thirds of children with vulvar LS, but in only about 10% of affected adults.
  In late LS in adult women, the affected skin is shiny and wrinkled, the labia are atrophic, and the introitus is narrowed. Agglutination and scarring of the prepuce and frenulum may obscure the clitoris. Complications, especially in children, include anal fissures and perianal and genital ulcers.

Microscopic features ( Figs. 1.7 and 1.8 )


Fig. 1.7 Lichen sclerosus, typical histologic appearance.


Fig. 1.8 Lichen sclerosus with basal atypia.

  Well-developed lesions are characterized by a subepithelial homogenized zone that varies from edematous to hyalinized, with a loss of elastic fibers. This zone is usually subtended by a band of lymphocytes.
  Additional findings may include spongiosis, vacuolar alteration and squamatization of basal keratinocytes, intraepithelial lymphocytes, prominent thickening of the basement membrane, and sclerosis and/or ectasia of dermal vessels.
  Regauer et al. (2004) found a perivascular lymphocytic infiltrate and a lymphocytic vasculitis in respectively two-thirds and half of their cases of vulvar LS. These changes can be focal and subtle.
  Superimposed features of lichen simplex chronicus or squamous hyperplasia are more common than in extravulvar LS. In such cases, detached dermal squamous cell nests may suggest early invasive squamous cell carcinoma (SqCC), but unlike the latter, the nests lack atypia, are confined to the abnormal collagen, and are not associated with differentiated VIN ( Chapter 2 ).
  The often subtle findings in early LS, which may lead to underdiagnosis, include preferential involvement of adnexal structures with acanthosis and luminal hyperkeratosis and hypergranulosis. A thickened basement membrane may be appreciable, particularly with a PAS stain. Lymphocytes may be scanty.
  The presence of dyskeratosis and parakeratosis, hyperplasia, and/or basal cellular atypia (but less than that in differentiated VIN [ Chapter 2 ]) should be noted as LS with these findings and is more likely to progress to SqCC (see Behavior ).
  The basal cells are typically p53+, usually (unlike differentiated VIN) with a discontinuous pattern. In hypertrophic LS, the suprabasilar cells may also be p53+. Sadalla et al. found that p53 expression in LS did not predict progression to SqCC.

Differential diagnosis


  Lichen planus (LP). Genital involvement by LP can sometimes be difficult to distinguish from early LS. Cytoid bodies, wedge-shaped hypergranulosis, basal squamatization, and pointed rete ridges favor LP, but these findings are less common than in extravulvar LP.
  Differentiated VIN (vs LS with basilar atypia) ( Chapter 2 ).
  Postradiation fibrosis. A history of irradiation is obviously helpful. This diagnosis is also favored in the presence of more diffuse (vs band-like) fibrosis, atypical fibroblasts and endothelial cells, and thick-walled vessels.

Behavior


  Spontaneous remission may occur at puberty or postpartum. In some cases, the lesions respond to topical testosterone (or corticosteroids).
  There is growing evidence that LS is a premalignant lesion. Longitudinal studies indicate that 1% to 5% of cases of LS progress to vulvar SqCC.

•  Carli et al. (1995) found that women with LS have a lifetime cumulative risk for SqCC of 15% compared to only 0.06% for women in the general population.
•  Up to 65% of cases of differentiated VIN and invasive keratinizing SqCC are associated with synchronous LS.
•  LS lesions may be monoclonal and exhibit an increased frequency of allelic imbalance.
•  Regauer et al. (2002) found a monoclonal γ-T-cell receptor rearrangement in LS and LS-associated invasive SqCC, but not in uncomplicated LS, suggesting that a local immune dysregulation in LS may promote the development of SqCC.
•  As noted above, basal nuclear atypia in LS can occur prior to or adjacent to an invasive keratinizing SqCC, one study finding that >50% of LS cases associated with invasive SqCC had basilar atypia.
•  The frequency of p53 mutations and aneuploidy is higher in LS associated with invasive keratinizing SqCC than in uncomplicated LS.
  Patients with LS, particularly those with acanthotic or atypical LS, should be monitored for the development of invasive SqCC.

Squamous Cell Hyperplasia, NOS ( Fig. 1.9 )


Fig. 1.9 Squamous cell hyperplasia NOS.

  The term ‘squamous cell hyperplasia, NOS’ (SCH), which replaces the term ‘hyperplastic dystrophy,’ refers to epidermal hyperplasia not attributable to more specific dermatologic disorders.
  SCH has been found adjacent to 40% of SqCCs, in 20–50% of patients biopsied for a clinical diagnosis of vulvar dystrophy, and in about a third of patients with lichen sclerosus.
  A white plaque-like thickening of the involved skin may be seen clinically. The thickened epidermis may show hyperkeratosis or parakeratosis. There is normal maturation from the basal to superficial layers. Atypia is usually absent, and its presence should suggest differentiated VIN ( Chapter 2 ). Mitotic figures, if present, are confined to the basal and parabasal zones.
  There is some evidence to suggest that SCH, if not directly premalignant, may represent an early stage in vulvar carcinogenesis:

•  The lesion may abut or merge with differentiated VIN and/or invasive keratinizing SqCC ( Chapter 2 ).
•  Monoclonality and an increased expression of p53, p53 mutations, and allelic imbalance have been found in some lesions, especially in those with synchronous SqCC. Occasional lesions have contained HPV, and yet all cases studied by Santos et al. were p16 negative.
•  Patients with SCH, like those with lichen sclerosus, need to be monitored for the possible development of differentiated VIN or invasive SqCC.
  The differential diagnosis with differentiated VIN is discussed under the latter heading ( Chapter 2 ).

Other Dermatoses ( Fig. 1.10 )


Fig. 1.10 Lichen simplex chronicus.

  Almost any dermatosis can involve the vulva, the most common ones being lichen simplex chronicus, spongiotic dermatitis, psoriasis, and lichen planus.
  Lichen simplex chronicus is a common vulvar dermatosis that can follow or coexist with a wide variety of irritative and infectious factors.

•  The clinical manifestations include pruritus and burning and a leathery skin with scaly plaques and accentuated cutaneous markings.
•  Microscopic examination reveals psoriasiform hyperplasia with rete ridges that are thicker and more variable in length than in psoriasis, hypergranulosis, hyperkeratosis, and occasionally focal parakeratosis. The papillary dermis is thickened; collagen bundles may be arranged vertically, parallel to the rete ridges. Scattered dermal inflammatory cells may be present.
  Vulvar (or vulvovaginal) lichen planus can be erosive and can lead to scarring and stenosis.

•  One case of vulvar lichen planus was associated with pseudoepitheliomatous hyperplasia that progressed to squamous cell carcinoma.
•  The differential diagnosis between lichen planus and lichen sclerosus has been discussed under the latter heading.
  ‘Vulvar acanthosis with altered differentiation’ is a lesion often associated with vulvar verrucous carcinoma and is discussed under that heading ( Chapter 2 ).
  Ambros et al. state that ‘careful histories and physical examinations aid in identifying less common vulvar dermatoses. Referral to a dermatologist/dermatopathologist is indicated when the diagnosis is in doubt or if the response to treatment is poor.’

References

Ambros, R. A., Malfetano, J. H., Carlson, J. A., et al. Non-neoplastic epithelial alterations of the vulva: Recognition assessment and comparisons of terminologies used among various specialties. Mod Pathol . 1997; 10:401–408.
Carli, P., Cattaneo, A., De Magnis, A., et al. Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study. Eur J Cancer Prev . 1995; 4:491–495.
Carli, P., De Magnis, A., Mannone, F., et al. Vulvar carcinoma associated with lichen sclerosus. J Reprod Med . 2003; 48:313–318.
Carlson, J. A., Ambros, R., Malfetano, J., et al. Vulvar lichen sclerosus and squamous cell carcinoma: A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Hum Pathol . 1998; 29:932–938.
Carlson, J. A., Lamb, P., Malfetano, J., et al. Clinicopathologic comparison of vulvar and extravulvar lichen sclerosus: histologic variants, evolving lesions, and etiology of 141 cases. Mod Pathol . 1998; 11:844–854.
Chiesa-Vottero, A., Dvoretsky, P. M., Hart, W. R. Histopathologic study of thin vulvar squamous cell carcinomas and associated cutaneous lesions. Am J Surg Pathol . 2006; 30:310–318.
Eberz, B., Berghold, A., Regauer, S. High prevalence of concomitant anogenital lichen sclerosus and extragenital psoriasis in adult women. Obstet Gynecol . 2008; 111:1143–1147.
Fung, M. A., LeBoit, P. E. Light microscopic criteria for the diagnosis of early vulvar lichen sclerosus. A comparison with lichen planus. Am J Surg Pathol . 1998; 22:473–478.
Greene, L., Dulaney, E. Vulvar inflammatory dermatoses for the non-dermatopathologist: An approach for the practising surgical pathologist. Diagn Histopathol . 2010; 16:487–494.
Hammock, L. A., Barrett, T. L. Inflammatory dermatoses of the vulva. J Cutan Pathol . 2005; 32:604–611.
Hart, W. R., Norris, H. J., Helwig, E. B. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol . 1975; 45:369–377.
Jones, R. W., Rowan, D. M., Kirker, J., et al. Vulval lichen planus: progression of pseudoepitheliomatous hyperplasia to invasive vulval carcinomas. Br J Obstet Gynaecol . 2001; 108:665–666.
Lee, E. S., Allen, D., Scurry, J. Pseudoepitheliomatous hyperplasia in lichen sclerosus of the vulva. Int J Gynecol Pathol . 2003; 22:57–62.
Liegl, B., Regauer, S. p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulva intraepithelial neoplasia (d-VIN). Histopathology . 2006; 48:268–274.
Lin, M. C., Mutter, G. L., Trivijisilp, P., et al. Patterns of allelic loss (LOH) in vulvar squamous carcinoma and adjacent noninvasive epithelia. Am J Pathol . 1998; 152:1313–1318.
Lotery, H. E., Galask, R. P. Erosive lichen planus of the vulva and vagina. Obstet Gynecol . 2003; 101:1121–1125.
Niamh, L., Naveen, S., Hazel, B. Diagnosis of vulval inflammatory dermatoses: A pathologic study with clinical correlation. Int J Gynecol Pathol . 2009; 28:554–558.
O'Keefe, R. J., Scurry, J. P., Dennerstein, G., et al. Audit of 114 non-neoplastic vulvar biopsies. Br J Obstet Gynaecol . 1995; 102:780–786.
Pinto, A. P., Lin, M., Sheets, E. E., et al. Allelic imbalance in lichen sclerosus, hyperplasia, and intraepithelial neoplasia of the vulva. Gynecol Oncol . 2000; 77:171–176.
Regauer, S., Liegl, B., Reich, O. Early vulvar lichen sclerosus: a histopathological challenge. Histopathology . 2005; 47:34–37.
Regauer, S., Liegl, B., Reich, O., et al. Vasculitis in lichen sclerosus: an under recognized feature? Histopathology . 2004; 45:237–244.
Regauer, S., Reich, O., Beham-Schmid, C. Monoclonal γ-T-cell receptor rearrangement in vulvar lichen sclerosus and squamous cell carcinoma. Am J Pathol . 2002; 160:1035–1045.
Rolfe, K. J., MacLean, A. B., Crow, J. C., et al. TP53 mutations in vulval lichen sclerosus adjacent to squamous cell carcinoma of the vulva. Br J Cancer . 2003; 89:2249–2253.
Sadalla, J. C., Lourenço, S. V., Sotto, M. N., et al. Claudin and p53 expression in vulvar lichen sclersosus and squamous-cell carcinoma. J Clin Pathol . 2011; 64:853–857.
Santos, M., Montagut, C., Mellado, B., et al. Immunohistochemical staining for p16 and p53 in premalignant and malignant epithelial lesions of the vulva. Int J Gynecol Pathol . 2004; 23:206–214.
Scurry, J., Whitehead, J., Mealey, M. Histology of lichen sclerosus varies according to site and proximity to carcinoma. Am J Dermatopathol . 2001; 23:413–418.
Tate, J. E., Mutter, G. L., Boynton, K. A., et al. Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias. Am J Pathol . 1997; 150:315–322.
Ueda, Y., Enomoto, T., Myatake, T., et al. Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa. Am J Clin Pathol . 2004; 122:266–274.
van de Nieuwenhof, H. P., Bulten, J., Hollema, H., et al. Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma. Mod Pathol . 2011; 24:297–305.

Squamous Papillomatosis ( Fig. 1.11 )


  Squamous papillomatosis (squamous micropapillomatosis, vestibular papillomatosis) refers to multiple, often countless, squamous papillomas that typically involve the medial aspect of the labia minora, vulvar vestibule, hymen, introitus, and urethral meatus. One or several vestibular papillomas may be normal.


Fig. 1.11 Squamous papillomatosis. The squamous cells have clear cytoplasm due to the presence of glycogen, but are not koilocytotic.
  Women of reproductive age group are typically affected, most of whom are asymptomatic, although occasionally there is pruritus, burning, or dyspareunia. The lesions usually regress without treatment.
  The etiology is unknown; most studies have shown no association with HPV. A study finding a high frequency of HPV included koilocytic lesions that would generally be considered condylomas.
  Each papilloma is about 1 mm in diameter and 1–8 mm in length and on microscopic examination consists of bland, nonkeratinized, glycogenated squamous epithelium with a proliferation of dermal capillaries. Absence of koilocytosis is a definitional feature in most studies, allowing histological distinction from condyloma.

References

De Deus, J. M., Focchi, J., Stavale, J. N., et al. Histologic and biomolecular aspects of papillomatosis of the vulvar vestibule in relation to human papillomavirus. Obstet Gynecol . 1995; 86:758–763.
Moyal-Barracco, M., Leibowitch, M., Orth, G. Vestibular papillae of the vulva. Lack of evidence for human papillomavirus etiology. Arch Dermatol . 1990; 126:1594–1598.
Potkul, R. K., Lancaster, W. D., Kurman, R. J., et al. Vulvar condylomas and squamous vestibular micropapilloma. Differences in appearance and response to treatment. J Reprod Med . 1990; 35:1019–1022.
Wang, A. C., Hsu, J. J., Hsueh, S., et al. Evidence of human papillomavirus deoxyribonucleic acid in vulvar squamous papillomatosis. Int J Gynecol Pathol . 1991; 10:44–50.
Welch, J. M., Nayagam, M., Parry, G., et al. What is vestibular papillomatosis? A study of its prevalence, aetiology and natural history. BJOG . 1993; 100:939–942.

Pigmented Lesions


  Benign pigmented lesions of the vulva, which occur in about 10% of women, often have atypical clinical and/or histological features that may raise concern for malignant melanoma.

Lentigo Simplex and Melanosis ( Fig. 1.12 )


Fig. 1.12 Vulvar melanosis.

  Lentigo simplex refers to a lesion exhibiting benign epidermal hyperplasia, hyperpigmentation, and benign melanocytic hyperplasia. The term ‘melanosis’ is most commonly used to refer to similar hyperpigmented lesions, with or without melanocytic hyperplasia, that lack epidermal hyperplasia.
  The lesions typically occur in Caucasian women of reproductive age. In some cases they have been present for years.
  Melanotic macules involve the labia, introital area, or perineum. Lentigines are usually <5 mm, whereas areas of melanosis may reach 2 cm. Occasionally the features suggest or mimic lentigo maligna or malignant melanoma, including multifocality, an irregular margin, and variegated pigmentation.
  Microscopically, there is basilar hyperpigmentation and basilar melanocytic hyperplasia without nesting or atypia. However, some lesions designated ‘melanosis’ have lacked melanocytic hyperplasia. Acanthosis with elongation of rete pegs is present in lentigines; dermal melanophages also may be present.
  The differential diagnosis is with malignant melanoma in situ, which, unlike lentigo or melanosis, is characterized by atypical melanocytes in nests and in all layers of the epidermis. Mitotic figures may be seen in the melanocytes.

Usual Melanocytic Nevi


  Vulvar nevi, which are only one-third as common as the lesions considered in the preceding section, were found in only 2.3% of women in one study. Most vulvar nevi resemble their extravulvar counterparts and are not considered further. One epithelioid blue nevus of the vulva has been reported.
  Some vulvar melanocytic nevi overlie or are entrapped by the sclerosis of lichen sclerosus and tend to resemble persistent melanocytic nevi.

Atypical Genital Nevi


  Vulvar nevi with atypical features that differ from those of the usual dysplastic nevus have been referred to as ‘atypical melanocytic nevi of genital type’ (Clark et al.) or ‘atypical genital nevi’ (AGN) (Gleason et al.). AGN may have striking architectural and cytological atypia, but are clinically benign.
  In the study by Gleason et al., the patients had a median age of 26 years (range 6–54), and the AGN occurred on the labia majora, labia minora, and the clitoris.


Microscopic features


  A lentinginous or nested junctional component exhibits variability in the size, shape, and position of the nests, which may have a confluent band-like arrangement.

•  In addition to origin from the usual location at the rete tips, the nests may arise from the sides of rete, between rete, and from adnexal structures.
•  There is often a retraction artifact around the nests and/or cellular dyscohesion within the nests.
•  Pagetoid involvement of the upper epidermis occurs in some cases, which, in contrast to this finding in melanomas, lacks cytologic atypia and lateral extension, and is usually focal or multifocal rather than extensive or diffuse.
•  Cytological atypia of the cells in the junctional component is present, which was moderate to severe in 80% of cases in the Gleason study.
  An underlying, often large, common dermal nevus is often present that is diffusely or focally covered by the distinctive junctional component.

•  The cells in the dermal component may show atypia, but which is less common and less severe than that of the junctional component; mitotic figures are rare and maturation is typically present.
•  A broad zone of dense fibrosis within the superficial dermis is present in 40% of cases; it usually lacks the distinctive lamellar pattern of fibroplasia seen in dysplastic nevi.
  AGN must be distinguished from vulvar dysplastic nevi and superficial spreading melanoma (see Clark et al. and Gleason et al.).

References

Lentigo simplex and melanosis
Barnhill, R. L., Albert, L. S., Shama, S. K., et al. Genital lentiginosis: A clinical and histopathologic study. J Am Acad Dermatol . 1990; 22:453–460.
Sison-Torre, E. Q., Ackerman, A. B. Melanosis of the vulva. A clinical simulator of malignant melanoma. Am J Dermatopathol . 1985; 7(suppl):51–60.

Atypical genital nevi
Blickstein, I., Feldberg, E., Dgani, R., et al. Dysplastic vulvar nevi. Obstet Gynecol . 1991; 78:968–970.
Carlson, J. A., Mu, X. C., Slominski, A., et al. Melanocytic proliferations associated with lichen sclerosus. Arch Dermatol . 2002; 138:77–87.
Christensen, W. N., Friedmann, K. J., Woodruff, J. D., et al. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol . 1987; 14:87–91.
Clark, W. H., Jr., Hood, A. F., Tucker, M. A., et al. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal–stromal interactions in the biology of neoplasia. Hum Pathol . 1998; 29:S1–S24.
Gleason, B. C., Hirsch, M. S., Nucci, M. R., et al. Atypical genital nevi. A clinicopathologic analysis of 56 cases. Am J Surg Pathol . 2008; 32:51–57.
Haupt, H. M., Stern, J. B. Pagetoid melanocytosis. Histologic features in benign and malignant lesions. Am J Surg Pathol . 1995; 19:792–797.
Izquierdo, M. J., Pastor, M. A., Carrasco, L., et al. Epithelioid blue nevus of the genital mucosa: Report of four cases. Br J Dermatol . 2001; 145:496–501.
Rock, B., Hood, A. F., Rock, J. A. Prospective study of vulvar nevi. J Am Acad Dermatol . 1990; 22:104–106.

Fibroepithelial Polyp


  These lesions are most common in the vagina and are therefore discussed in Chapter 3 .

Cysts

Bartholin's Duct Cyst ( Figs. 1.13 – 1.14 )


Fig. 1.13 Bartholin's duct cyst.


Fig. 1.14 Bartholin's duct cyst. The squamous lining of the cyst (top) and normal Bartholin's gland tissue (bottom) are seen.

  Obstruction of the vestibular orifice of the Bartholin's ducts results in accumulation of secretions from the gland with cystic dilatation. The usual presentation is a lateral introital mass that may be asymptomatic or associated with dyspareunia.
  The cysts are lined by squamous, transitional, mucinous, ciliated, or flattened nonspecific epithelium. Acute and chronic inflammation is often present.
  A location consistent with Bartholin's origin and the presence of normal Bartholin's gland acini adjacent to the cyst facilitate distinction from cysts arising from minor vestibular glands (see below).

Mucinous and Ciliated Vestibular Cysts ( Fig. 1.15 )


Fig. 1.15 Mucinous vestibular cyst.

  These cysts typically present as a solitary (or occasionally multiple), sometimes painful, subcutaneous mass on the inner surfaces of the labia minora in reproductive age women.
  The cysts are usually <3 cm and are lined by a single layer of columnar mucinous epithelium, ciliated nonmucinous epithelium, squamous epithelium, or admixtures thereof. The lining cells may be ER+ and PR+.
  The cysts have traditionally been presumed to arise from the minor vestibular glands located in the anterior and posterior vestibule. To account for the typical location of the cysts, Scurry et al. suggest that minor vestibular glands also likely occur at the vulvar mucocutaneous junction (Hart's lines).

Other Cysts


  Epidermal inclusion cysts are commonly encountered in the vulva, usually the labia majora. They are lined by stratified squamous epithelium and filled with keratinaceous debris.
  Rare mesothelial cysts derived from the canal of Nuck (the incompletely obliterated processus vaginalis) are usually found in the superior aspect of the labia majora or the inguinal canal. They may be associated with, and should be distinguished from, an inguinal hernia.
  Rare mesonephric cysts occur in the lateral aspects of the vulva and have a microscopic appearance similar to that of mesonephric cysts of the vagina ( Chapter 3 ).
  Rare vulvar cysts may arise from the mammary-like glands in this site (page 17).

References

Kucera, P. R., Glazer, J. Hydrocele of the canal of Nuck. A report of four cases. J Reprod Med . 1985; 30:439–442.
Robboy, S. J., Ross, J. S., Prat, J., et al. Urogenital sinus origin of mucinous and ciliated cysts of the vulva. Obstet Gynecol . 1978; 51:347–351.
Rorat, E., Ferenczy, A., Richart, R. M. Human Bartholin gland, duct, and duct cyst. Histochemical and ultrastructural study. Arch Pathol . 1975; 99:367–374.
Scurry, J., McGrath, G. Multiple mucinous cysts on the anterior of Hart's lines of the vulva. Letter. Pathology . 2012; 44:479–480.
van der Putte, S. C. J., van Gorp, L. H. M. Cysts of mammarylike glands in the vulva. Int J Gynecol Pathol . 1995; 14:184–188.

Noninfectious Inflammatory Lesions

Vulvar Vestibulitis


Clinical features


  Vulvar vestibulitis, which affects up to 15% of patients in a general gynecologic practice, typically occurs in the reproductive age group, with a mean age of 31 years in one study.
  The diagnostic clinical feature is point tenderness of the vulvar vestibule in the absence of other identifiable causes; dyspareunia is also typically present. Vulvar erythema is found in some cases but is not a diagnostically useful feature.
  Munday et al. question whether vulvar vestibulitis is a distinct entity, and suggest that the clinical features of vulvar vestibulitis are part of a continuum within the general population and without specific findings that can be considered definitely abnormal.
  The etiology is unknown and possibly multifactorial. In most studies, HPV has been absent or identified with a frequency similar to that of control patients. Proposed pathogenetic factors include an increased number of vulvar nerve fibers, hypersensitivity to seminal fluid, deficiency of interferon-α, deficient ER expression, and enhanced synthesis of proinflammatory cytokines produced by vulvar vestibular fibroblasts.

Pathological features ( Fig. 1.16 )


Fig. 1.16 Vulvar vestibulitis. A minor vestibular gland shows squamous metaplasia and chronic inflammatory cells in the surrounding stroma.

  The histological findings have varied between studies. Although the microscopic findings can be supportive of the diagnosis, generally the diagnosis rests on the typical clinical findings.
  Some but not all studies have found a mild to severe chronic inflammatory infiltrate (T lymphocytes, plasma cells, and occasional B lymphocytes, mast cells, and monocytes), including lymphoid follicles, in the superficial dermis and surrounding the vestibular glands and ducts.

•  Jacobson-Dunlop et al. distinguished between primary and secondary vestibulitis, finding twice as many CD8+ cells and 20 times as many CD4+ positive T-cells compared to controls in 1° but not 2° vestibulitis. Patients with 2° vestibulitis, however, had more CD20+ B-cells than in controls.
•  Bornstein et al. found an increase in subepithelial mast cells, heparinase, and peripheral nerve fibers compared to asymptomatic women.
  Squamous metaplasia of the vestibular ducts and glands is found in some patients, but whether this finding is an inherent feature of the disorder is unclear.
  Complete replacement of the vestibular glands and ducts by squamous epithelium producing an invagination or cleft was considered a constant and diagnostic feature in one study. Two other studies, however, found clefts to be less common and difficult to distinguish from infoldings of surface epithelium.

Plasma Cell Vulvitis (Zoon's Vulvitis) ( Fig. 1.17 )


Fig. 1.17 Plasma cell vulvitis.

  This lesion has typical presenting features of pruritus, burning, and red, sometimes multiple, macules.
  The typical features are a predominantly plasmacellular lichenoid infiltrate, a thinned epidermis, flattened rete ridges, absence of the granular/keratin layers, spongiotic parabasal keratinocytes with spindled nuclei oriented horizontally (‘lozenge keratinocytes’), and prominent dermal blood vessels with dermal hemorrhage and hemosiderin.
  The differential diagnosis includes syphilis, lichen planus, and other chronic dermatoses.

Granulomatous Vulvitis and Vulvar Involvement by Crohn's Disease ( Fig. 1.18 )


Fig. 1.18 Granulomatous vulvitis.

  Granulomatous vulvitis is an idiopathic granulomatous vulvar inflammation that appears to be the vulvar counterpart of granulomatous cheilitis; occasional patients have both lesions.
  The lesion occurs over a wide age range and usually presents as a labial mass or labial hypertrophy. Histological examination reveals edema, fibrosis, lymphangiectasia, a mononuclear infiltrate, and non-necrotizing granulomas with giant cells.
  More common than isolated granulomatous vulvitis, but identical histologically, is vulvar involvement by Crohn's disease. There is usually a history of or synchronous onset of intestinal Crohn's disease, although rarely the vulvar involvement precedes bowel involvement. Patients presenting with granulomatous vulvitis therefore need to be monitored for the possible development of Crohn's disease.

Behçet's Disease


  Behçet's disease is a systemic vasculopathy that is most frequent in Japan and eastern Mediterranean countries. The mean age at onset is in the third decade; there is a slight male predominance.
  The disease is diagnosed by the presence of oral ulceration and any two of: genital ulceration, skin lesions (pustules or erythema nodosa-like lesions), and eye lesions (uveitis or retinal vasculitis). Synovitis and meningoencephalitis are also occasionally present.>
  The vulvar (and oral) ulcers are of minor or major aphthous or herpetiform type. Major apthous ulcers, which may lead to gangrene, heal by scarring. Healing is often followed by new ulcers.
  Microscopically there is a necrotizing vasculitis that may involve all calibers and types of dermal and subcutaneous vessels. The vasculitis may be lymphocytic or neutrophilic, and can be associated with mural fibrin deposits, mural necrosis, and thrombosis.

Florid Reactive Lymphoid Hyperplasia (Lymphoma-like Lesion)


  These lesions are very rare in the vulva; their clinical and pathological features resemble those occurring in the cervix ( Chapter 4 ). In the series by Young et al., the only vulvar case was associated with infectious mononucleosis and presented as a 1 cm crusted lesion on the labium minus.

Graft-Versus-Host Disease (GVHD)


  As the vulvovaginal area is the most common site for GVHD in the female genital tract, the findings, based on a recent study Gomez-Macias et al., are considered in this chapter.
  The most frequent clinical findings are vaginal dryness, discharge, scarring, vulvar discomfort, and dyspareunia.
  Vulvar biopsies show changes similar to GVHD in the skin, including ulceration, apoptotic bodies in the epidermal basal layer, and chronic inflammatory cells. Vaginal biopsies show inflammation, apoptotic bodies, and fibrosis. The cervical mucosa and endometrial glands may also show apoptotic bodies. Synchronous SILs and condylomas may be present.
  Immunohistochemical staining for elafin, an elastase inhibitor secreted in response to cytokines and used as a marker for GVHD in skin biopsy specimens, was found in 11 of 30 biopsies in the cited study.
Ligneous Vulvitis (see Chapter 4 )

References

Vulvar vestibulitis
Bergeron, S., Binik, Y. M., Khalife, S., et al. Vulvar vestibulitis syndrome: Reliability of diagnosis and evaluation of current diagnostic criteria. Obstet Gynecol . 2001; 98:45–51.
Bornstein, J., Cohen, Y., Zarfati, D., et al. Involvement of heparinase in the pathogenesis of localized vulvodynia. Int J Gynecol Pathol . 2008; 27:136–141.
Chadha, S., Gianotten, W. L., Drogendijk, A. C., et al. Histopathologic features of vulvar vestibulitis. Int J Gynecol Pathol . 1998; 17:7–11.
Eva, L. J., MacLean, A. B., Reid, W. M. N., et al. Estrogen receptor expression the vulvar vestibulitis syndrome. Am J Obstet Gynecol . 2003; 289:458–461.
Foster, D. C., Piekarz, K. H., Murant, T. I., et al. Enhanced synthesis of proinflammatory cytokines by vulvar vestibular fibroblasts: implications for vulvar vestibulitis. Am J Obstet Gynecol . 2007; 196:346.
Jacobson-Dunlop, E., Leclair, C., Goetsch, M., et al. Increased CD4 positive T-cell recruitment in primary chronic vestibulitis suggests potential disease triggers. [Abstract] Mod Pathol . 2011; 24:250A.
Munday, P., Green, J., Randall, C., et al. Vulval vestibulitis: a common cause of dyspareunia? BJOG . 2005; 112:500–503.
Prayson, R. A., Stoler, M. H., Hart, W. R. Vulvar vestibulitis. A histopathologic study of 36 cases, including human papillomavirus in situ hybridization analysis. Am J Surg Pathol . 1995; 19:154–160.
Pyka, R. E., Wilkinson, E. J., Friedrick, E. G., Jr., et al. The histopathology of vulvar vestibulitis syndrome. Int J Gynecol Pathol . 1988; 7:249–257.
Slone, S., Reynolds, L., Gall, S., et al. Localization of chromogranin, synaptophysin, serotonin, and CXCR2 in neuroendocrine cells of the minor vestibular glands. Int J Gynecol Pathol . 1999; 18:360–365.

Plasma cell vulvitis (Zoon's vulvitis)
Souteyrand, P., Wong, E., MacDonald, D. M. Zoon's balanitis (balanitis circumscripta plasmacellularis). Br J Dermatol . 1981; 105:195–199.

Granulomatous vulvitis and vulvar involvement by Crohn's disease
Guerrieri, C., Ohlsson, E., Ryden, G., et al. Vulvitis granulomatosa: A cryptogenic chronic inflammatory hypertrophy of vulvar labia related to cheilitis granulomatosa and Crohn's disease. Int J Gynecol Pathol . 1995; 14:352–359.

Behçet's disease
Magro, C. M., Crowson, A. N. Cutaneous manifestations of Behçet's disease. Int J Dermatol . 1995; 34:159–165.
Mangelsdorf, H. C., White, W. L., Jorizzo, J. L. Behçet's disease. Report of twenty-five patients from the United States with prominent mucocutaneous involvement. J Am Acad Dermatol . 1996; 34:745–750.

Florid reactive lymphoid hyperplasia (lymphoma-like lesion)
Young, R. H., Harris, N. L., Scully, R. E. Lymphoma-like lesions of the lower female genital tract: A report of 16 cases. Int J Gynecol Pathol . 1985; 4:289–299.

Graft-versus-host disease (GVHD)
Gomez-Macias, G. S., Stratton, P., Walter Rodriguez, B. A., et al. Does GVHD involve the female genital tract? Immunohistochemical expression of elafin as a marker of graft-versus-host disease in gynecological biopsies. [Abstract] Mod Pathol . 2012; 25:272A.

Reactive Lesions

Reactive Atypia and Multinucleated Keratinocytes ( Figs. 1.19 – 1.20 )


Fig. 1.19 Reactive atypia of vulvar epidermis.


Fig. 1.20 Multinucleated vulvar keratinocytes (see text).

  Nonspecific reactive changes within the vulvar epidermis include loss of epithelial maturation and nuclear atypia, which may suggest vulvar intraepithelial neoplasia ( Chapter 2 ). Prominent inflammation, spongiosis, lack of mitoses, MIB1 staining confined to the lower third of the epithelium, and negative staining for HPV and p16 favor a reactive lesion. Differentiated VIN, however, is typically negative for HPV and p16.
  Multinucleated keratinocytes in vulvar and extravulvar skin may reflect a defect in nuclear division in persistently rubbed skin.

Nodular Fasciitis ( Figs. 1.21 – 1.22 )


Fig. 1.21 Nodular fasciitis of vulva, sectioned surface.


Fig. 1.22 Nodular fasciitis.

  This lesion occurs over a wide age range (7–51 years), typically presenting as a painless, subcutaneous labial mass usually <4 cm in size. Local excision is usually curative, although rare lesions have recurred locally. The histological features are similar to this lesion in other sites.
  Initial misdiagnosis is common, potentially leading to inappropriate treatment. The differential diagnosis includes other reactive lesions (such as postoperative spindle cell nodule [ Chapter 3 ]) and soft tissue tumors, including aggressive angiomyxoma (page 21), angiomyofibroblastoma (page 23), and leiomyosarcoma ( Chapter 2 ).

Postoperative Spindle Cell Nodule


  Rare vulvar examples of this lesion have been reported, which is considered in Chapter 3 .

Lesions Related to Immobilization, Obesity, and Repetitive Trauma


  Vulvar lymphedema caused by obesity and immobilization may lead to vulvar enlargement that can be massive.

•  Additional findings may include giant cells, dermal fibrosis, vascular proliferation, lymphangiectasia, perivascular lymphocytes and plasma cells, and reactive epidermal changes.
•  Features favoring vulvar lymphedema over aggressive angiomyxoma (page 21) include obesity or immobilization, bilaterality, superficial location, reactive epidermal changes, perivascular inflammation, and an absence of lesional vessels of varying caliber, perivascular smooth muscle, alcianophilic stroma, and ER+ cells.
  A vulvar lesion in a paraplegic woman, interpreted as ischemic fasciitis (atypical cubital fibrodysplasia), showed ulceration, fibrinoid necrosis, and a proliferation of small vessels and atypical fibroblasts.
  Unilateral solitary nodules up to 6 cm in size may occur in the labium majus in competitive cyclists (‘cyclist’s nodule’) or equestrians. One lesion recurred.

•  There is a haphazard admixture of bland spindle-shaped fibroblasts, blood vessels, nerves, fat, and keloid-like foci. Other findings may include epithelioid or plasmacytoid myofibroblasts, lymphocytes, fat necrosis, and elastic fibers.
•  The lesional cells are ER+ and the epithelioid cells are SMA+.

References

Reactive atypia and multinucleated keratinocytes
LeBoit, P. E. Multinucleated atypia [Letter]. Am J Surg Pathol . 1996; 20:507.
McLaughlin, C. M., Mutter, G. L., Crum, C. P. Multinucleated atypia of the vulva. Report of a distinct entity not associated with human papillomavirus. Am J Surg Pathol . 1994; 18:1233–1239.

Nodular fasciitis
O'Connell, J. X., Young, R. H., Nielsen, G. P., et al. Nodular fasciitis of the vulva. A study of six cases and literature review. Int J Gynecol Pathol . 1997; 16:117–123.

Postoperative spindle cell nodule
Manson, C. M., Hirsch, P. J., Coyne, J. D. Post-operative spindle cell nodule of the vulva. Histopathology . 1995; 26:571–574.

Lesions related to immobilization, obesity, and repetitive trauma
Fadare, O., Brannan, S. M., Arin-Silasi, D., et al. Localized lymphedema of the vulva: A clinicopathologic study of 2 cases and a review of the literature. Int J Gynecol Pathol . 2011; 30:306–313.
McCluggage, W. G., Smith, J. H. F. Reactive fibroblastic and myofibroblastic proliferation of the vulva (cyclist's nodule): A hitherto poorly described vulval lesion occurring in cyclists. Am J Surg Pathol . 2011; 35:110–114.
Scanlon, R., Kelehan, P., Flannelly, G., et al. Ischemic fasciitis: An unusual vulvovaginal spindle cell lesion. Int J Gynecol Pathol . 2004; 23:65–67.

Other Non-Neoplastic Lesions

Multinucleated Stromal Giant Cells ( Fig. 1.23 )


Fig. 1.23 Multinucleated stromal giant cells. Note wreath-like arrangement of the nuclei in some cells.

  MSGCs, identical to those in fibroepithelial polyps ( Chapter 3 ), are a common incidental microscopic finding in the loose subepithelial stroma of the lower female genital tract. The cells are most common in the vulva, being present in 73% of vulvar specimens in one study.
  The cells have sparse to moderate eosinophilic cytoplasm with tapering cytoplasmic processes and multiple nuclei often with a wreath-like arrangement; mitotic figures are rarely if ever present. The cells stain for vimentin but not cytokeratin or desmin.

Adenosis


  Rare cases of introital adenosis (of tuboendometrioid type) have occurred in the Stevens–Johnson syndrome or after CO 2 laser treatment; no association with in utero exposure to diethylstilbestrol has been reported.
  A case of vulvar adenosis (‘mucinous metaplasia’) appeared as a 1 cm depressed red periclitoral lesion in a 60-year-old woman. On histological examination, columnar mucinous cells replaced the normal squamous epithelium.

Ectopic Breast Tissue and Rarer Ectopias ( Fig. 1.24 )


Fig. 1.24 Vulvar ectopic breast tissue with lactational changes in a pregnant woman.

  Although traditionally vulvar breast tissue and mammary-type lesions have been thought to arise from the embryonic milk line, currently an origin from anogenital mammary-like glands is favored.

•  Ectopic breast tissue usually occurs on the labia majora as a unilateral or bilateral, solid to cystic, subcutaneous mass; rarely there is an associated nipple. The lesions present at puberty or during pregnancy, sometimes with postpartum regression.
•  Microscopic findings include pregnancy-related lactational changes, fibrocystic changes, sclerosing adenosis, lipomatous change, pseudoangiomatous stromal hyperplasia, and benign (page 20) or malignant tumors ( Chapter 2 ).
  Rare vulvar cases of prostatic-type tissue have included a 4.5 cm mass considered of Skene's gland origin.
  A 6 cm vulvar mass (‘choristoma’) was composed mainly of salivary gland tissue with a minor component of cartilage and respiratory epithelium.
  Intestinal-type lesions have included a case of ‘intestinal heterotopia’ that presented as a vulvar ulcer in which the epidermis was replaced by colonic mucosa with subjacent smooth muscle and ganglion cells. A vulvar lesion resembling a juvenile colonic polyp has also been reported.

Nodular Hyperplasia of Bartholin's Gland ( Fig. 1.25 )


Fig. 1.25 Nodular hyperplasia of Bartholin's gland.

  This lesion occurs at an average age of 35 years (range 19–56) and presents as a solid or solid and cystic, nonencapsulated mass usually <5 cm in size. It may be related to duct obstruction.
  A proliferation with an irregular lobulated contour is composed of benign-appearing mucinous acini with (in contrast to adenomas) maintenance of the normal duct-to-acinar relationship. Inflammation, cysts, and squamous metaplasia of the ducts are often present.
  None of the lesions have recurred, even after incomplete excision.

Varices ( Fig. 1.26 )


Fig. 1.26 Vulvar varix. The lumen of a dilated vein close to the vulvar epidermis is partly filled by an organizing thrombus.

  Vulvar varices may occur alone or associated with leg varices, venous malformations (Klippel–Trenaunay–Weber syndrome and Parkes–Weber syndrome), or as a component of the pelvic congestion syndrome.
  The lesions vary from small protrusions, mainly in the labia majora, to large vulvar or perivulvar masses. They can be misdiagnosed clinically as a Bartholin’s duct cyst.

Miscellaneous Rare Lesions


  Vulvar amyloidosis is occasionally the presenting manifestation of systemic amyloidosis, and may clinically mimic an invasive squamous cell carcinoma.
  Rare vulvar examples of sebaceous hyperplasia, rheumatoid nodule, calcinosis, lymphoid hamartoma, and sclerosing lipogranuloma have been reported.

References

Multinucleated stromal giant cells
Abdul-Karim, F. W., Cohen, R. E. Atypical stromal cells of lower female genital tract. Histopathology . 1990; 17:249–253.
Pitt, M. A., Roberts, I. S. D., Agbamu, D. A., et al. The nature of atypical multinucleated stromal cells: A study of 37 cases from different sites. Histopathology . 1993; 23:137–145.

Adenosis
Coghill, S. B., Tyler, X., Shaxted, E. J. Benign mucinous metaplasia of the vulva. Histopathology . 1990; 17:373–375.
Marquette, G. P., Su, B., Woodruff, J. D. Introital adenosis associated with Stevens–Johnson syndrome. Obstet Gynecol . 1985; 66:243–245.
Sedlacek, T. V., Riva, J. M., Magen, A. B., et al. Vaginal and vulvar adenosis. An unsuspected side effect of CO 2 laser vaporization. J Reprod Med . 1990; 35:995–1001.

Ectopic breast tissue and rarer ectopias
Kazakov, D. V., Bisceglia, M., Mukensnabl, P., et al. Pseudoangiomatous stromal hyperplasia in lesions involving anogenital mammary-like glands. Am J Surg Pathol . 2005; 29:1243–1246.
Kazakov, D. V., Spagnolo, D. V., Kacerovska, D., et al. Lesions of anogenital mammary-like glands: An update. Adv Anat Pathol . 2011; 18:1–28.
Kazakov, D. V., Stewart, C. J. R., Kacerovska, D., et al. 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. Am J Surg Pathol . 2010; 34:950–955.
Lim, C., Brewer, J., Russell, P. Juvenile colonic polyp occurring in the vulva. [Letter] Pathology . 2007; 39:448–450.
Marwah, S., Berman, M. L. Ectopic salivary gland in the vulva (choristoma): Report of a case and review of the literature. Obstet Gynecol . 1980; 56:389–391.
van der Putte, S. C. J. Mammary-like glands of the vulva and their disorders. Int J Gynecol Pathol . 1994; 13:150–160.
Yeoh, G., Bannatyne, P., Kossard, S., et al. Intestinal heterotopia: An unusual cause of vulval ulceration. Case report. BJOG . 1987; 94:600–602.

Nodular hyperplasia of Bartholin's gland
Koenig, C., Tavassoli, F. A. Nodular hyperplasia, adenoma, and adenomyoma of Bartholin's gland. Int J Gynecol Pathol . 1998; 17:289–294.
Santos, L. D., Kennerson, A. R., Killingsworth, M. C. Nodular hyperplasia of Bartholin's gland. Pathology . 2006; 38:223–228.

Varices
Bell, D., Kane, P. B., Liang, S., et al. Vulvar varices: an uncommon entity in surgical pathology. Int J Gynecol Pathol . 2007; 26:99–101.

Miscellaneous rare lesions
Al-Daraji, W. I., Wagner, B., Ali, R. B. M., et al. Sebaceous hyperplasia of the vulva: a clinicopathological case report with a review of the literature. [Letter] J Clin Pathol . 2007; 60:835–837.
Appleton, M. A. C., Ismail, S. M. Ulcerating rheumatoid nodule of the vulva. J Clin Pathol . 49, 1996. [858–857].
Balfour, P. J. T., Vincenti, A. C. Idiopathic vulvar calcinosis. Histopathology . 1991; 18:183–184.
Kempson, R. L., Sherman, A. I. Sclerosing lipogranuloma of the vulva. Am J Obstet Gynecol . 1968; 101:854–856.
Kernen, J. A., Morgan, M. L. Benign lymphoid hamartoma of the vulva. Obstet Gynecol . 1970; 35:290–292.
Persoons, J. H. A., Sutorius, F. J. M., Koopman, R. J. J., et al. Vulvar paraneoplastic amyloidosis with the appearance of vulvar carcinoma. Am J Obstet Gynecol . 1999; 180:1041–1044.
Taylor, S. C., Baker, E., Grossman, M. E. Nodular vulvar amyloid as a presentation of systemic amyloidosis. J Am Acad Dermatol . 1991; 24:139.

Benign Epithelial Tumors

Papillary Hidradenoma (Hidradenoma Papilliferum) and Other Apocrine Tumors ( Fig. 1.27 )


Fig. 1.27 Hidradenoma papilliferum, low- and high-power views. In the latter, note that the epithelium consists of columnar cells and subcolumnar myoepithelial cells.

  Papillary hidradenomas are benign tumors of apocrine origin that in the vulva may arise from mammary-like glands, hence the synonymous term ‘mammary-like gland adenoma.’

•  There is usually a painless vulvar nodule in the reproductive or postmenopausal age group. Most occur on the labia majora or minora, less commonly the fourchette or clitoris.
•  Most are <2 cm in size; rarely they are multiple. In one study, 55% were cystic and 17% were ulcerated.
•  Microscopically there is a well-circumscribed to slightly infiltrative, complex proliferation of papillae, tubules, cysts, and solid areas composed of epithelial and myoepithelial cells.
•  The apocrine and nonapocrine epithelial cells occasionally exhibit mild atypia, stratification, and occasional mitoses. The myoepithelial cells, which typically subtend the epithelial cells, are usually flattened and inconspicuous, but are occasionally larger and polygonal with clear cytoplasm.
•  Unusual features include: sebaceous or squamous differentiation; foci resembling sclerosing adenosis, ductal adenoma, or sclerosing intraductal papilloma of the breast; numerous mitotic figures; inflammation; and calcification.
•  Rare cases of malignant transformation have included an adenocarcinoma in situ, an intraductal apocrine carcinoma, and a rapidly fatal adenosquamous carcinoma.
•  The differential diagnosis is with intraductal papillomas arising in ectopic breast tissue, as discussed below.
  Other benign apocrine vulvar tumors include apocrine cystadenoma, papillary apocrine fibroadenoma, apocrine tubular adenoma, and pigmented apocrine hamartoma.

Other Benign Tumors of Skin Appendage Origin


  Tumors of sweat gland origin include syringoma (including rare examples with deep dermal extension), clear cell hidradenoma, poroid hidradenoma, and benign mixed tumors (pleomorphic adenomas). The mixed tumors may also arise from myoepithelial cells in Bartholin's gland, ectopic breast tissue, or mammary-like glands. Rare pure vulvar myoepitheliomas have been reported.
  Tumors of hair follicle origin (trichogenic tumors) include pilar tumor (proliferating trichilemmal tumor, trichilemmoma), trichoepithelioma, trichoblastic fibroma, trichofolliculoma, keratoacanthoma, and inverted follicular keratosis.

•  Regauer and Nogales compared vulvar trichogenic tumors (mean age 65 years) and vulvar basal cell carcinomas (BCCs) (mean age 78 years). The trichogenic tumors formed a plaque or nodule, and unlike BCCs, lacked ulceration and clefting at the epithelial–stromal interface. BCCs lacked trichogenic differentiation and had a mucinous or granulation tissue-like stroma unlike an organized mesenchymal component in the trichogenic tumors.
•  As in extravulvar sites, vulvar keratoacanthoma and inverted follicular keratosis occasionally can be confused with squamous cell carcinoma.
•  Three cases of vulvar trichofolliculoma were associated with synchronous high-grade vulvar intraepithelial neoplasia. Two of the cases were initially misdiagnosed as invasive carcinoma.

Seborrheic Keratosis ( Fig. 1.28 )


Fig. 1.28 Seborrheic keratosis.

  Bai et al. found HPV (usually HPV 6) in 72% of cases of vulvar seborrheic keratosis (SK), leading to the designation ‘condyloma with features of seborrheic keratosis.’ MIB1 helped identify those lesions that were most likely to harbor HPV.
  In contrast, Zhang et al. found no evidence of HPV in vulvar SKs. They also found that genital and extragenital SKs could be immunoreactive for Ki-67 and p16.

Benign Mammary-type Tumors ( Fig. 1.29 )


Fig. 1.29 Fibroadenoma of mammary type.

  Benign vulvar mammary-type tumors that have arisen or presumed to arise from anogenital mammary-like glands (page 17) have included hamartomas, fibroadenomas, phyllodes tumors, and intraductal papillomas.

Benign Tumors of Bartholin's Gland and Minor Vestibular Glands


  Rare adenomas and adenomyomas of the Bartholin's gland have, in contrast to nodular hyperplasia (page 17), exhibited a haphazard proliferation of acini and tubules with loss of the normal duct-to-acinar relationship. Rare adenoid cystic carcinomas have arisen from Bartholin's gland adenomas; one was mixed with an epithelial–myoepithelial carcinoma.
  Two benign vulvar mixed tumors were considered of probable Bartholin's gland origin. Another report described a papilloma arising in a Bartholin's cyst.
  Rare adenomas (or nodular hyperplasias) of minor vestibular glands, which are typically an incidental finding in tissue removed for vestibulitis, consist microscopically of proliferations of small glands lined by mucinous columnar cells.

Tubulovillous Adenoma


  One case of enteric-type tubulovillous adenoma of the vulva has been reported in 66-year-old woman. A similar rectal tumor had been removed 6 months previously.

References

Papillary hidradenoma (hidradenoma papilliferum) and other apocrine tumors
Bannatyne, P., Elliott, P., Russell, P. Vulvar adenosquamous carcinoma arising in a hidradenoma papilliferum, with rapidly fatal outcome: Case report. Gynecol Oncol . 1989; 35:395–398.
Chen, K. T. K. Pigmented apocrine hamartoma of the vulva: A report of two cases. Int J Gynecol Pathol . 2005; 24:85–87.
Demellawy, D. E., Daya, D., Alowami, S. Vulvar apocrine tubular adenoma: An unusual location. [Letter] Int J Gynecol Pathol . 2008; 27:301–303.
Glusac, E. J., Hendrickson, M. R., Smoller, B. R. Apocrine cystadenoma of the vulva. J Am Acad Dermatol . 1994; 31:498–499.
Higgins, C. M., Strutton, G. M. Papillary apocrine fibroadenoma of the vulva. J Cutan Pathol . 1997; 23:256–260.
Scurry, J., van der Putte, S. C. J., Pyman, J., et al. Mammary-like gland adenoma of the vulva: review of 46 cases. Pathology . 2009; 41:372–378.
Shah, S. S., Adelson, M., Mazur, M. T. Adenocarcinoma in situ arising in vulvar papillary hidradenoma: Report of 2 cases. Int J Gynecol Pathol . 2008; 27:453–456.
Woodworth, H., Dockerty, M. B., Wilson, R. B., et al. Papillary hidradenoma of the vulva: A clinicopathologic study of 69 cases. Am J Obstet Gynecol . 1971; 110:501–508.

Other benign tumors of skin appendage origin
Alowami, S. O., Malik, A., Hanna, W. Vulvar poroid hidradenoma. Am J Dermatopathol . 2002; 24:523–525.
Avinoach, I., Zirkin, H. J., Glezerman, M. Proliferating trichilemmal tumor of the vulva. Case report of review of the literature. Int J Gynecol Pathol . 1989; 8:163–168.
Chen, W., Koenig, C. Vulvar keratoacanthoma: A report of two cases. Int J Gynecol Pathol . 2004; 23:284–286.
Cho, D., Woodruff, J. D. Trichoepithelioma of the vulva. A report of two cases. J Reprod Med . 1988; 33:317–319.
El Demellawy, D., Daya, D., Alowami, S. Clear cell hidradenoma: An unusual vulvar tumor. Int J Gynecol Pathol . 2008; 27:457–460.
Fukunaga, M. Myoepithelioma of the vulva. APMIS . 2003; 111:416–420.
Gilks, C. B., Clement, P. B., Wood, W. S. Trichoblastic fibroma – A report of three cases. Am J Dermatopathol . 1989; 11:397–402.
Huang, Y., Chuang, Y., Kuo, T., et al. Vulvar syringoma: A clinicopathologic and immunologic study of 18 patients and results of treatment. J Am Acad Dermatol . 2003; 48:735–739.
Kazakov, D. V., Bouda, J., Jr., Kacerovska, D., et al. Vulvar syringomas with deep extension: A potential histopathologic mimic of microcystic adnexal carcinoma. Int J Gynecol Pathol . 2011; 30:92–94.
Peterdy, G. A., Huettner, P. C., Rajarum, V., et al. Trichofolliculoma of the vulva in association with vulvar intraepithelial neoplasia: Report of three cases and review of the literature. Int J Gynecol Pathol . 2002; 21:224–230.
Regauer, S., Nogales, F. F. Vulvar trichogenic tumors. A comparative study with vulvar basal cell carcinoma. Am J Surg Pathol . 2005; 29:479–484.
Roth, L. M., Look, K. Y. Inverted follicular keratosis of the vulvar skin: A lesion that can be confused with squamous cell carcinoma. Int J Gynecol Pathol . 2000; 19:369–373.
Soh, H., Russell, P., Dalrymple, C. Benign mixed tumour of the vulva. [Letter] Pathology . 2005; 37:389–392.

Seborrheic keratosis
Bai, H., Cviko, A., Granter, S., et al. Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis. Hum Pathol . 2003; 34:559–564.
Zhang, H., Storthz, K., Malpica, A. Vulvar seborrheic keratosis, is it indeed related to HPV infection? [Abstract] Mod Pathol . 2005; 18:209A.

Benign mammary-type tumors
Baisre, A., Heller, D. S., Lee, J., et al. Fibroadenoma of the vulva. A report of two cases. J Reprod Med . 2002; 47:949–951.
Dworak, O., Reck, T., Greskotter, K. R., et al. Hamartoma of an ectopic breast arising in the inguinal region. Histopathology . 1994; 169–171.
Heffernan, T. P., Sarode, V. R., Hoffmann, B., et al. Recurrent phyllodes tumor of the vulva: A case report with review of diagnostic criteria and differential diagnosis. Int J Gynecol Pathol . 2010; 29:294–297.
Rickert, R. R. Intraductal papilloma arising in supernumerary vulvar breast tissue. Obstet Gynecol . 1980; 55:84S–87S.

Benign tumors of Bartholin's gland and minor vestibular glands
Axe, S., Parmley, T., Woodruff, J. D., et al. Adenomas in minor vestibular glands. Obstet Gynecol . 1986; 68:16–18.
Enghardt, M. H., Valente, P. T., Day, D. H. Papilloma of Bartholin's gland duct cyst: First report of a case. Int J Gynecol Pathol . 1993; 12:86–92.
Koenig, C., Tavassoli, F. A. Nodular hyperplasia, adenoma, and adenomyoma of Bartholin's gland. Int J Gynecol Pathol . 1989; 17:289–294.
Ordonez, N. G., Manning, J. T., Luna, M. A. Mixed tumor of the vulva: A report of two cases probably arising in Bartholin's gland. Cancer . 1981; 48:181–186.
Padmanaghan, V., Cooper, K. Concomitant adenoma of hybrid carcinoma of salivary gland type arising in Bartholin's gland. Int J Gynecol Pathol . 2000; 19:377–380.

Tubulovillous adenoma
Vitrey, D., Frachon, S., Balme, B., et al. Tubulovillous adenoma of the vulva. Obstet Gynecol . 2003; 102:1160–1163.

Site-Specific Benign Mesenchymal Tumors of the Lower Genital Tract


  A variety of mesenchymal tumors composed of bland fibroblastic and myofibroblastic cells occur within the soft tissues of the lower female genital tract. These tumors can be diagnostically problematic because of their overlapping histologic and immunohistochemical features.
  At least some of the tumors likely arise from hormonally responsive fibroblastic or myofibroblastic superficial stromal cells of the lower genital tract, cells that show variable expression for vimentin, smooth muscle markers, CD34, ER, and PR.
  Fibroepithelial polyps, which may be histogenetically related to the tumors in this group, are considered in Chapter 3 .

Aggressive Angiomyxoma


Clinical features


  Over 90% of these tumors, which are also referred to as deep angiomyxoma, occur in women who are usually in the reproductive age group (median age in the fourth decade).
  The typical presentation is a mass that may be vulvar, suburethral, perineal, vaginal, inguinal, gluteal, ischiorectal, retroperitoneal, or combinations thereof. The initial clinical impression is often that of a Bartholin's cyst or hernia. Rare tumors are pedunculated.
  The tumors are often much larger and deeper than initially appreciable on pelvic examination. Large tumors may fill the pelvis, tending to displace rather than invade pelvic viscera.

Pathological features ( Figs. 1.30 – 1.33 )


Fig. 1.30 Aggressive angiomyxoma, sectioned surface. The tumor is poorly circumscribed and glistening.


Fig. 1.31 Aggressive angiomyxoma. The tumor infiltrates adipose tissue.


Fig. 1.32 Aggressive angiomyxoma. Note admixture of thin- and thick-walled vessels of varying caliber within a fibromyxoid stroma.


Fig. 1.33 Aggressive angiomyxoma. Tumor cells with scanty cytoplasm and bland nuclear features are widely separated by a fibromyxoid stroma.

  The typically bulky, rubbery, and solid tumors have a lobulated to poorly circumscribed contour. The cut surface is typically glistening, gelatinous, and homogeneous, with occasional small cysts and focal hemorrhage.
  The tumors are sparsely cellular with small oval, spindle, and stellate cells interspersed in a loose myxoid stroma with delicate collagen fibrils and numerous, haphazardly scattered, variably sized vessels with thin to thick walls; the thick vessels may have hyalinized or muscular walls.
  Perivascular cuffs of collagen and bundles of smooth muscle are common; the latter may also occur unrelated to vessels.
  The lesional cells have scanty pale eosinophilic cytoplasm, small uniform nuclei, and small indistinct nucleoli; rare multinucleated cells may be present. Mitotic figures have not been observed.
  The intercellular component is weakly positive with Alcian blue and colloidal iron. Extravasated erythrocytes and sparsely distributed mast cells are commonly present.
  The tumors lack a capsule and infiltrate the surrounding soft tissue, often with entrapment of fat, skeletal muscle, and nerves.
  Unusual findings include foci resembling angiomyofibroblastoma (see below), focal increased cellularity, fibrotic areas (especially in recurrences), and admixed endometriosis.
  The tumors are reactive for vimentin, and variably for smooth muscle markers (desmin, SMA, MSA), CD34, and CD44. Nuclear staining for ER and PR is usually present.
  Unlike most other vulvovaginal mesenchymal tumors, nuclear expression for HMGA2 is found in 50% of the tumors.
  Rearrangements of the HMGA2 locus on chromosomal 12 are found in a third of tumors, and in some such cases chromosomal translocations have been identified.

Behavior


  The tumors are typically indolent but have a tendency to recur locally because of incomplete excision. Early studies found an almost 40% recurrence rate, contrasting with recurrence rates of about 10% in more recent series.
  The recurrences may appear many years postoperatively and multiple recurrences are common. Fibrotic recurrent tumor may be difficult to differentiate from normal or scar-related connective tissue.
  Only one well-documented case with hematogenous spread has been reported, in which fatal pulmonary metastases appeared after multiple local recurrences.
  GnRH-agonists or aromatase inhibitors have successfully treated unresectable primary or recurrent tumor in some cases.

Differential diagnosis


  Angiomyofibroblastoma (see next section).
  Superficial angiomyxoma (cutaneous myxoma) (see page 27). These tumors differ from aggressive angiomyoma by their superficial location, small size, circumscription, absence of thick-walled muscular vessels, presence of neutrophils, and nonreactivity for desmin, ER and PR.
  Myxoma, spindle cell lipoma, myxoid neurofibroma, fibroepithelial polyp, fibromatosis, myxoid liposarcoma, myxoid smooth muscle tumors, embryonal rhabdomyosarcoma (sarcoma botryoides), and myxoid malignant fibrous histiocytoma.

•  Aside from a myxoid stroma, all of these tumors lack the characteristic histologic appearance, including the distinctive vascular component, of aggressive angiomyxoma.
•  In addition, myxoid sarcomas usually contain non-myxoid areas and cells with greater degrees of nuclear pleomorphism and mitotic activity than seen in the aggressive angiomyxoma.

Angiomyofibroblastoma ( Figs. 1.34 – 1.37 )


Fig. 1.34 Angiomyofibroblastoma. Sectioned surface showing a well-circumscribed mass.


Fig. 1.35 Angiomyofibroblastoma, low-power view. Note well-circumscribed border.


Fig. 1.36 Angiomyofibroblastoma, medium- and high-power views. Note epithelioid tumor cells, many of which are perivascular.


Fig. 1.37 Angiomyofibroblastoma. Perivascular epithelioid tumor cells lie within adipose tissue, which was abundant in this tumor (‘lipomatous’ variant).

  These tumors occur in women of reproductive and postmenopausal age who present with a painless vulvar, or less commonly, vaginal mass that is usually <5 cm in size. The clinical diagnosis is often a Bartholin's cyst.
  These well-circumscribed tumors are composed of hypercellular zones alternating with hypocellular edematous zones in which numerous small-to-medium sized, thin-walled arborizing vessels (predominantly capillaries) are irregularly distributed. Perivascular fibrosis is common.
  The tumor cells, which may be spindled, oval, plasmacytoid (due to eccentric nuclei), or epithelioid (with eosinophilic cytoplasm), are separated by wavy strands or thick bundles of collagen. The cells form perivascular aggregates, nests or cords, or are loosely dispersed in the hypocellular areas. Fat may be present and rarely prominent (lipomatous variant). Scattered lymphocytes and mast cells are common.
  The nuclear features are typically bland, but in 40% of the cases, rare nuclei are enlarged and hyperchromatic. Occasional cells are multinucleated. Mitotic figures are absent or rare.
  The cells typically stain for vimentin and desmin, frequently for ER and PR, and occasionally for actin and CD34. HMGA2 reactivity has not been demonstrated.
  The tumors are benign although occasional tumors recur after local excision. One tumor with malignant transformation (‘angiomyofibrosarcoma’) consisted of typical angiomyofibroblastoma and high-grade sarcoma; a recurrence 2 years later was a pure sarcoma.


Differential diagnosis


  Aggressive angiomyxoma. In contrast to this tumor, angiomyofibroblastoma has circumscribed borders, is focally more cellular, has more blood vessels (that usually lack thick walls), and has plump to epithelioid tumor cells that are often perivascular. Rare hybrid neoplasms have features of both tumors.
  Cellular angiofibroma. Features favoring this diagnosis include numerous vessels with hyalinized walls and an absence of perivascular epithelioid cells.
  Angiomyofibroblastoma-like stromal reaction. A reactive lesion resembling angiomyofibroblastoma has been described in prolapsed fallopian tubes ( Chapter 11 ).

Cellular Angiofibroma ( Fig. 1.38 )


Fig. 1.38 Cellular angiofibroma.

  These tumors occur in women of reproductive or postmenopausal age who present with a superficial mass, most commonly in the vulva; rare tumors have arisen in the vagina, paravaginal region, perineum, inguinal region, or urethra. The tumors are successfully treated by local excision; one recurred locally.
  The usually well-circumscribed tumors range up to 12 cm in size (median 2.8 cm in one series) and have a solid, white, tan, or gray sectioned surface.
  Features of typical cellular angiofibromas:

•  Microscopic examination reveals a cellular proliferation of spindle cells arrayed in short intersecting fascicles; numerous small to medium-sized, thick-walled, often hyalinized, blood vessels; and short wispy collagen bundles. The spindle cells have scanty eosinophilic cytoplasm and bland nuclei. Mitotic figures are usually uncommon.
•  Fat is present in about 25% of cases but usually accounts for <5% of the tumor. Hypocellular areas of edema, myxoid change, or hyalinization may be present.
•  Uncommon findings include an infiltrative border, absence of thick-walled vessels, dilated hemangiopericytomatous vessels, vague nuclear palisading, mild cytologic atypia, multinucleated (symplastic) cells, frequent mitotic figures (up to 11 mf/10 hpf), and stromal lymphoid aggregates.
•  The spindle cells stain for vimentin, CD34, SMA, and desmin in approximately 100%, 50%, 20%, and 10% of cases, respectively, suggesting a fibroblastic rather than a myofibroblastic phenotype. Nuclear staining for ER, PR, or both is seen in half the cases.
•  Two tumors contained 13q14 deletions, suggesting a link with spindle cell lipoma and extramammary myofibroblastoma.
  Chen and Fletcher found that about 8% of vulvar cellular angiofibromas contained foci of severe atypia or sarcomatous transformation.

•  In the tumors with severe atypia, the atypical cells were usually scattered throughout the tumor but in one tumor they were localized to a discrete nodule.
•  In the tumors with severe atypia, the atypical cells were usually scattered throughout the tumor but in one tumor they were localized to a discrete nodule.
•  In the tumors with sarcomatous transformation, the latter took the form of an atypical lipomatous tumor, pleomorphic liposarcoma or nonspecific pleomorphic sarcoma.
•  The atypical and sarcomatous cells were multifocally or diffusely p16+ in contrast to absence of staining in the typical areas of the tumor.
•  Limited clinical follow-up found that none of tumors recurred or metastasized.


Differential diagnosis


  Aggressive angiomyxoma (AA). Compared to cellular angiofibroma, AA is usually larger, more deeply seated, and has infiltrative borders, diffuse hypocellularity, less prominent hyalinized blood vessels, and a more myxoid, less fibrous, intercellular component. A desmin+/CD34− phenotype favors AA.
  Angiomyofibroblastoma (AMF). Compared to cellular angiofibroma, AMF has more variable cellularity, perivascular epithelioid or plasmacytoid tumor cells, and a predominance of thin-walled vessels. A desmin+/CD34− phenotype favors AMF.
  Spindle-cell lipoma. These tumors are rare in the vulva and contain CD34+ spindle cells similar to those of cellular angiofibroma. However, in contrast to most cellular angiofibromas, they typically contain a prominent adipocytic component and inconspicuous thin-walled vessels.
  Solitary fibrous tumor (SFT). SFTs are rare in the female genital tract, but have overlapping features with cellular angiofibroma, including the presence of fat and CD34 positivity. SFTs, however, usually have more variable cellularity, dense hyaline collagen bundles, areas of hyalinization, and hemangiopericytoma-like vessels.

Superficial Myofibroblastoma


  Patients range in age from 23 to 80 (median 54) years, and typically present with a superficial polypoid or nodular mass, usually in the vagina, or uncommonly in the cervix or vulva. A history of intake of tamoxifen or other hormonal preparations is present in occasional cases. One tumor recurred locally 9 years after incomplete excision.
  The tumors range up to 6.5 cm in size, with a mean of 2.3 cm; one patient had two synchronous vaginal lesions. The well-circumscribed but unencapsulated tumors are covered by unremarkable or hyperplastic squamous epithelium that is usually separated from the tumor by a Grenz zone of uninvolved stroma.
  Microscopic examination reveals a moderately cellular proliferation of bland, mitotically inactive, ovoid, spindle, or stellate cells, often with a wavy nucleus, separated by a finely collagenous stroma.
  Although a patternless arrangement of the spindle cells usually predominates, lacelike, fascicular and storiform patterns, as well as myxoid, edematous, or hyalinized foci with thick dense collagen bundles, are also common. The deep aspects of larger tumors often contain hypercellular zones; a highly cellular focus in one tumor initially suggested a small, round, blue cell tumor.
  Thin-walled blood vessels are often concentrated within the center of the tumor; perivascular hyalinization may be seen. Larger tumors may contain occasional thick-walled vessels.
  The immunoprofile is myofibroblastic, with usual reactivity for vimentin, desmin, ER, and PR; staining for CD34, CD99, CD10, SMA, bcl-2, and calponin is present in some cases.
  Magro et al. (2012b), using FISH, found monallelic deletion of FOXO1 (in the chromosome 13q14 region) in three of five vaginal tumors (and five of seven mammary tumors).


Differential diagnosis


  Fibroepithelial polyp ( Chapter 3 ). This lesion, unlike myofibroblastoma, lacks an expansile nodular appearance and a distinct margin, is usually less cellular, often contains multinucleated stromal giant cells, and lacks both a Grenz zone and a multipatterned architecture. Distinction from cellular fibroepithelial polyps is more difficult, and the two lesions may be part of a spectrum.
  Angiomyofibroblastoma. This tumor, unlike superficial myofibroblastoma, typically contains perivascular aggregates of epithelioid or plasmacytoid cells, and usually lacks the multipatterned architecture of myofibroblastoma. The immunoprofiles of the two tumors are similar.
  Aggressive angiomyxoma. These tumors, in contrast to superficial myofibroblastomas, are usually more deeply seated, have infiltrative borders, are more myxoid and less cellular, and have blood vessels that are more prominent and variable in size.
  Cellular angiofibroma. These tumors are more diffusely cellular than superficial myofibroblastomas, and contain many thick-walled vessels and sometimes fat and lesional cells that typically are desmin negative.
  Solitary fibrous tumor. This tumor has a consistent CD34+/desmin − phenotype.

Prepubertal Vulvar Fibroma ( Figs. 1.39 – 1.40 )


Fig. 1.39 Prepubertal fibroma. The tumor is composed of hyalinized fibrous tissue, adipose tissue, and blood vessels. (Figure courtesy of Dr. Christopher Fletcher.)


Fig. 1.40 Prepubertal fibroma. Hyalinized fibrous tissue. (Figure courtesy of Dr. Christopher Fletcher.)

  This tumor (also referred to as ‘childhood asymmetric labium majus enlargement’) usually presents as a painless, unilateral, subcutaneous vulvar mass (usually in the labium majus) in prepubertal girls 3–13 years of age. One postmenopausal case has been reported.
  The tumors are 2 to 8 cm in size, and poorly circumscribed. Microscopically, there is a hypocellular proliferation of bland, mitotically inactive spindle cells separated by a variably collagenous, edematous, or myxoid matrix. The collagen appears as short, thick, wavy bundles.
  The lesional cells typically infiltrate and entrap surrounding normal vessels, fat, and nerves, and may extend up to the epithelial–stromal interface.
  The spindle cells are typically CD34+, but are negative for SMA, desmin, and S100 protein, suggesting a purely fibroblastic lesion.
  About 30% of the tumors have recurred once or twice after local excision, usually because of incomplete excision.
  The lesion has been considered either a hormonally-induced physiologic proliferation of indigenous tissues or a hamartoma.


Differential diagnosis


  Aggressive angiomyxoma. These tumors, in contrast to vulvar fibromas, occur in a postpubertal age group, usually are deeply seated, and have a diffusely myxoid matrix, perivascular smooth muscle, and desmin+ cells.
  Angiomyofibroblastoma. These tumors are well circumscribed and contain perivascular desmin+ epithelioid cells.
  Cellular angiofibroma. These tumors, in contrast to vulvar fibromas, are well circumscribed, cellular, and contain numerous blood vessels with hyalinized walls.
  Neurofibroma. These tumors, in contrast to vulvar fibromas, contain S100+ cells with wavy nuclei and many small nerve fibers throughout the lesion.
  Fibroepithelial polyp. These lesions, unlike vulvar fibromas, are polypoid, have a more heterogeneous morphology including in some cases hypercellular areas, multinucleated cells, and mitotic figures. There is no entrapment of surrounding tissues and the lesional cells are typically desmin+.

References

Site-specific benign mesenchymal tumors of the lower genital tract
McCluggage, W. G. A review and update of morphologically bland vulvovaginal mesenchymal lesions. Int J Gynecol Pathol . 2005; 24:26–38.
Nielsen, G. P., Young, R. H. Mesenchymal tumors and tumor-like lesions of the female genital tract: A selective review with emphasis on recently described entities. Int J Gynecol Pathol . 2001; 20:105–127.
Nucci, M. R., Fletcher, C. D. M. Vulvovaginal soft tissue tumors: update and review. Histopathology . 2000; 36:97–108.

Aggressive angiomyxoma
Amezcua, C. A., Begley, S. J., Mata, N., et al. Aggressive angiomyxoma of the female genital tract: A clinicopathologic and immunohistochemical study of 12 cases. Int J Gynecol Cancer . 2005; 15:140–145.
Bigby, S. M., Symmans, P. J., Miller, M. V., et al. Aggressive angiomyxoma of the female genital tract and pelvis – Clinicopathologic features with immunohistochemical analysis. Int J Gynecol Pathol . 2011; 30:505–513.
Blandamura, S., Cruz, J., Vergara, L. F., et al. Aggressive angiomyxoma: A second case of metastasis with patient's death. Hum Pathol . 2003; 34:1072–1074.
Coyne, J. D. Aggressive angiomyxoma admixed with endometriosis: A case report. Int J Surg Pathol . 2012; 20:205–207.
Fetsch, J. F., Laskin, W. B., Lefkowitz, M., et al. Aggressive angiomyxoma: A clinicopathologic study of 29 female patients. Cancer . 1996; 78:79–90.
Granter, S. R., Nucci, M. R., Fletcher, C. D. M. Aggressive angiomyxoma: Reappraisal of its relationship to angiomyofibroblastoma in a series of 16 cases. Histopathology . 1997; 30:3–10.
Medeiros, F., Erickson-Johnson, M., Keeney, G. L., et al. Frequency and characterization of HMGA1 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tract. Genes Chromosomes Cancer . 2007; 46:981–990.
Steeper, T. A., Rosai, J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol . 1983; 7:463–475.

Angiomyofibroblastoma
Cao, D., Srodon, M., Montgomery, E. A., et al. Lipomatous variant of angiomyofibroblastoma: Report of two cases and review of the literature. Int J Gynecol Pathol . 2005; 24:196–200.
Fletcher, C. D. M., Tsang, W. Y. W., Fisher, C., et al. Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma. Am J Surg Pathol . 1992; 16:373–382.
Laskin, W. B., Fetsch, J. F., Tavassoli, F. A. Angiomyofibroblastoma of the female genital tract: Analysis of 17 cases including a lipomatous variant. Hum Pathol . 1997; 28:1046–1055.
Nielsen, G. P., Rosenberg, A. E., Young, R. H., et al. Angiomyofibroblastoma of the vulva and vagina. Mod Pathol . 1996; 9:284–291.
Nielsen, G. P., Young, R. H., Dickersin, G. R., et al. Angiomyofibroblastoma of the vulva with sarcomatous transformation (‘angiomyofibrosarcoma’). Am J Surg Pathol . 1997; 21:1104–1108.
Vasquez, M. D., Ro, J. Y., Park, Y. W., et al. Angiomyofibroblastoma. A clinicopathologic study of eight cases and review of the literature. Int J Surg Pathol . 1999; 7:161–169.

Cellular angiofibroma
Chen, E., Fletcher, C. D. M. Cellular angiofibroma with atypia or sarcomatous transformation: Clinicopathologic analysis of 13 cases. Am J Surg Pathol . 2010; 34:707–714.
Iwasa, Y., Fletcher, C. D. M. Cellular angiofibroma. Clinicopathologic and immunohistochemical analysis of 51 cases. Am J Surg Pathol . 2004; 28:1426–1435.
Maggiani, F., Debiec-Rychter, M., Vanbockrijck, M., et al. Cellular angiofibroma: another mesenchymal tumour with 13q14 involvement, suggesting a link with spindle cell lipoma and (extra)-mammary myofibroblastoma. [Letter] Histopathology . 2007; 51:410–412.
McCluggage, W. G., Ganesan, R., Hirschowitz, L., et al. Cellular angiofibroma and related fibromatous lesions of the vulva: Report of a series of cases with a morphological spectrum wider than previously described. Histopathology . 2004; 45:360–368.
Nucci, M. R., Granter, S. R., Fletcher, C. D. M. Cellular angiofibroma: A benign neoplasm distinct from angiomyofibroblastoma and spindle cell lipoma. Am J Surg Pathol . 1997; 21:636–644.

Superficial myofibroblastoma
Ganesan, R., McCluggage, W. G., Hirschowitz, L., et al. Superficial myofibroblastoma of the lower female genital tract: report of a series including tumours with a vulval location. Histopathology . 2005; 46:137–143.
Laskin, W. B., Fetsch, J. F., Tavassoli, F. A. Superficial cervicovaginal myofibroblastoma: Fourteen cases of a distinctive mesenchymal tumor arising from the specialized subepithelial stroma of the lower female genital tract. Hum Pathol . 2001; 32:715–725.
Magro, G., Caltabiano, R., Kacerovská, D., et al. Vulvovaginal myofibroblastoma: Expanding the morphological and immunohistochemical spectrum. A clinicopathologic study of 10 cases. Hum Pathol . 2012; 43:243–253.
Magro, G., Righi, A., Casorzo, L., et al. Mammary and vaginal myofibroblastomas are genetically related lesions: Fluorescence in situ hybridization analysis shows deletion of 13q14 region. Hum Pathol . 2012; 43:1887–1893.
Stewart, C. J. R., Amanuel, B., Brennan, B. A., et al. Superficial cervicovaginal myofibroblastoma: A report of five cases. Pathology . 2005; 37:144–148.

Prepubertal vulvar fibroma
Ajibona, O. O., Richards, C. J., Davies, Q. A distinctive vulval fibroma of so-called prepubertal type in a postmenopausal patient. J Clin Pathol . 2007; 60:437–438.
Iwasa, Y., Fletcher, C. D. M. Distinctive prepubertal vulval fibroma. A hitherto unrecognized mesenchymal tumor of prepubertal girls: Analysis of 11 cases. Am J Surg Pathol . 2004; 28:1601–1608.
Vargas, D. O., Kozakewich, H. P. W., Boyd, T. K., et al. Childhood asymmetric labium majus enlargement mimicking a neoplasm. Am J Surg Pathol . 2005; 29:1007–1016.

Nonspecific Benign Mesenchymal Tumors

Leiomyoma and Rhabdomyoma


  Leiomyomas are discussed in Chapter 2 and rhabdomyomas in Chapter 3 .

Fibrous, Adipocytic, Vascular, and Neural Tumors


  Fibrous tumors include rare examples of desmoid tumor, fibromatosis of soft tissue type, and solitary fibrous tumor (one of which was atypical).
  Adipocytic tumors include lipomas and lipoma-variants, including spindle-cell lipoma, pleomorphic lipoma, adenolipoma, and ‘lipoblastoma-like’ tumors. The lipoblastoma-like tumors had the following features:

•  The three tumors formed well-circumscribed vulvar masses in patients 13–38 years of age. They were treated by local excision and the follow-up was uneventful.
•  The lobulated tumors were composed of uniform spindle cells in a myxoid stroma and a ‘chicken-wire’ capillary network. Signet-ring lipoblasts and mature adipocytes were also present in each tumor. None had nuclear pleomorphism, mitotic activity, or necrosis.
  Vascular tumors include glomus tumor, capillary and cavernous hemangioma, hemangioendothelioma, angiokeratoma, and lymphangioma, including lymphangioma circumscriptum.

•  In some cases, vulvar hemangiomas have been part of either the blue rubber bleb nevus syndrome or the congenital dysplastic angiopathy (Klippel–Trenaunay–Weber) syndrome.
•  Vulvar lymphangioma circumscriptum (acquired lymphangiectasia) is typically related to previous vulvar surgery, lymphadenectomy, and/or radiotherapy. Striking dermal lymphangiectasia is typically associated with marked reactive epidermal hyperplasia.
•  One case of spindle cell hemangiomatosis of the vulva was encountered in a woman with Maffucci's syndrome.
  Vulvar examples of solitary (sometimes giant) neurofibromas, neurofibromatosis, schwannomas, and paraganglioma have been reported. Vulvar involvement is rarely the presenting manifestation of neurofibromatosis.

Superficial Angiomyxoma (Cutaneous Myxoma)


  These vulvar tumors are more common in extragenital sites. The patients are usually of reproductive age (mean 21 years) who present with a slowly growing painless mass. Multiple tumors may be a manifestation of Carney's complex, although this association has not yet been found in vulvar tumors.
  The tumors are usually <5 cm in size and are well-circumscribed, nodular, multinodular or polypoid masses that involve the skin or subcutis. The sectioned surface is gelatinous.
  Microscopic examination reveals sparsely cellular nodules composed of spindle to stellate cells, delicate capillary-like vessels, and an alcianophilic myxoid matrix. The neoplastic cells have bland to mildly pleomorphic nuclei, with occasional multinucleated cells; mitotic figures are rare to absent.
  Other findings include inflammatory cells, especially neutrophils, and in some tumors, entrapped cystic epithelial inclusions likely of adnexal origin.
  The tumor cells are usually reactive for vimentin, CD34, and less commonly, actin, S100 protein, and Factor XIIIa.
  The tumors are benign but 30–40% recur due to incomplete excision, sometimes many years later.
  The differential diagnosis of these tumors with aggressive angiomyxoma is discussed under the latter heading (page 21).

Granular Cell Tumor ( Figs. 1.41 – 1.42 )


Fig. 1.41 Granular cell tumor.


Fig. 1.42 Granular cell tumor. Typical granular cells are depicted.

  Five to 15% of granular cell tumors, which are of Schwann-cell origin, arise in the vulva. Vulvar granular cell tumors, especially when multifocal, may be associated with similar tumors in extravulvar sites.
  The patients, who are usually of reproductive or postmenopausal age, present with solitary or occasionally multiple subcutaneous nodules typically in the labia majora, less commonly the clitoris or perineum. Most tumors are <4 cm in size.
  Irregular nests and sheets of eosinophilic, PAS-positive, granular cells with bland nuclei and usually <2 mf/10 hpf are intermingled with strands of collagen and occasional chronic inflammatory cells. The tumors may have a pushing or infiltrative border.
  The neoplastic cells are typically immunoreactive for S100 protein, α-inhibin, and calretinin.
  The overlying epidermis or squamous epithelium often shows striking degrees of pseudocarcinomatous hyperplasia which can be confused with a well-differentiated squamous cell carcinoma, especially in a superficial biopsy specimen in which the granular cells are sparse or absent.
  The tumors are almost always clinically benign, although some tumors recur locally. In one study, local recurrence was only associated with tumors that had an infiltrative border.
  Six malignant granular cell tumors of the vulva have been reported in patients who were 17–56 years of age. Four patients had lymph node and/or blood-borne metastases. There are no microscopic features that reliably correlated with malignant behavior.

References

Fibrous, adipocytic, vascular, and neural tumors
Allen, M. V., Novotny, D. B. Desmoid tumor of the vulva associated with pregnancy. Arch Pathol Lab Med . 1997; 121:512–514.
Biedrzycki, O. J., Singh, N., Habeeb, H., et al. Solitary fibrous tumor of the female genital tract: A case report and review of the literature. Int J Gynecol Pathol . 2007; 26:259–264.
Brown, J. V., Stenchever, M. A. Cavernous lymphangioma of the vulva. Obstet Gynecol . 1989; 73:877–879.
Busand, B., Stray-Pedersen, S., Iversen, O. H., et al. Blue rubber bleb nevus syndrome with manifestations in the vulva. Acta Obstet Gynecol Scand . 1993; 72:310–313.
Colgan, T. J., Dardick, I., O'Connell, G. Paraganglioma of the vulva. Int J Gynecol Pathol . 1991; 10:203–208.
Fernandez-Aguilar, S., Fayt, I., Noel, J. Spindle cell vulvar hemangiomatosis associated with enchondromatosis: A rare variant of Maffucci's syndrome. Int J Gynecol Pathol . 2004; 23:68–70.
Haraoka, M., Naito, S., Kumazawa, J. Clitoral involvement by neurofibromatosis: A case report and review of the literature. J Urol . 1988; 139:95–96.
Huang, H. J., Yamabe, T., Tagawa, H. A solitary neurilemmoma of the clitoris. Gynecol Oncol . 1983; 15:103–110.
Lae, M. E., Pereira, P. F., Keeney, G. L., et al. Lipoblastoma-like tumour of the vulva: Report of three cases of a distinctive mesenchymal neoplasm of adipocytic differentiation. Histopathology . 2002; 40:505–509.
Lewis, F. M., Lewis-Jones, M. S., Toon, P. G., et al. Neurofibromatosis of the vulva. Br J Dermatol . 1992; 127:540–541.
McNeely, T. B. D. Angiokeratoma of the clitoris. Arch Pathol Lab Med . 1992; 116:880–881.
Nielsen, G. P., Young, R. H. Fibromatosis of soft tissue type involving the female genital tract. Int J Gynecol Pathol . 1997; 16:383–386.
Pantanowitz, L., Henneberry, J. M., Otis, C. N., et al. Adenolipoma of the external genitalia. Int J Gynecol Pathol . 2008; 27:297–300.
Reis-Filho, J. S., Milanezi, F., Soares, M. F., et al. Intradermal spindle cell/pleomorphic lipoma of the vulva: Case report and review of the literature. J Cutan Pathol . 2002; 29:59–62.
Sonobe, H., Ro, J. Y., Ramos, M., et al. Glomus tumor of the female external genitalia: A report of two cases. Int J Gynecol Pathol . 1994; 13:359–364.
Stewart, C. J. R., Chan, T., Platten, M. Acquired lymphangiectasia (‘lymphangioma circumscriptum’) of the vulva: A report of eight cases. Pathology . 2009; 41:448–453.
Tjaden, B. L., Buscema, J., Haller, J. A., Jr., et al. Vulvar congenital dysplastic angiopathy. Obstet Gynecol . 1990; 75:553–554.
Vogel, A. M., Alesbury, J. M., Burrows, P. E., et al. Vascular anomalies of the female external genitalia. J Pediatr Surg . 2006; 41:993–999.

Superficial angiomyxoma (cutaneous myxoma)
Fetsch, J. F., Laskin, W. B., Tavassoli, F. A. Superficial angiomyxoma (cutaneous myxoma). A clinicopathologic study of 17 cases arising in the genital region. Int J Gynecol Pathol . 1997; 16:325–334.

Granular cell tumor
Althausen, A. M., Kowalski, D. P., Ludwig, M. E., et al. Granular cell tumors: A new clinically important histologic finding. Gynecol Oncol . 2000; 77:310–313.
Papalas, J. A., Shaco-Levy, R., Robboy, S. J., et al. Isolated and synchronous vulvar granular cell tumors: A clinicopathologic study of 17 cases in 13 patients. Int J Gynecol Pathol . 2010; 29:173–180.
Ramos, P. C., Kapp, D. S., Longacre, T. A., et al. Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review. Int J Gynecol Cancer . 2000; 10:429–434.
Wolber, R., Wilkinson, E., Talerman, A., et al. Granular cell tumors of the vulva with pseudocarcinomatous hyperplasia: A comparative morphological analysis with squamous cell carcinoma. Int J Gynecol Pathol . 1991; 10:59–66.

* Formulated by the International Society for the Study of Vulvar Disease (ISSVD) and the International Society of Gynecological Pathologists (ISGP).
Chapter 2
Malignant Tumors of the Vulva


Squamous Cell Carcinoma and its Precursors  

Vulvar Intraepithelial Neoplasia 
Invasive Squamous Cell Carcinoma of Usual Type 
Verrucous Carcinoma 
Sarcomatoid Squamous Cell Carcinoma 
Other Rare Variants of Squamous Cell Carcinoma 
Paget's Disease  
Carcinoma of Bartholin's Gland  
Other Adenocarcinomas and Related Tumors  

Adenocarcinoma of Mammary Type 
Adenocarcinomas of Skin Appendage Origin 
Rare Miscellaneous Adenocarcinomas, Malignant Myoepithelioma, and Carcinoid Tumor 
Basal Cell Carcinoma  
Merkel Cell Tumor  
Malignant Melanoma  
Benign and Malignant Smooth Muscle Tumors  
Other Sarcomas  

Rhabdomyosarcoma 
Liposarcoma 
Epithelioid Sarcoma and Malignant Extrarenal Rhabdoid Tumor 
Rare Sarcomas 
Yolk Sac Tumor and Other Germ Cell Tumors  
Hematopoietic Tumors  
Langerhans' Cell Histiocytosis  
Secondary Tumors  

Squamous Cell Carcinoma and Its Precursors

Vulvar Intraepithelial Neoplasia (VIN)


Terminology


  The two main types of VIN each have their own distinctive clinical and pathological features.

•  The much more common type is referred to variously as usual, classic, undifferentiated, or bowenoid VIN, and includes basaloid and warty subtypes. Usual VIN (uVIN) is used here as it was adopted by the International Society for the Study of Vulvar Disease (ISSVD).
•  The VIN terminology has also been incorporated recently into the LAST standardization project for HPV-associated lesions (see Chapter 5).
•  The second major type is differentiated VIN (dVIN), previously referred to as ‘simplex’ VIN.
  Although traditionally VIN has been graded I, II, or III, the new ISSVD terminology eliminates grading because VIN I has an unproven precancerous potential, and usually corresponds to a condyloma. ‘VIN’ is now reserved for differentiated VIN and high-grade uVIN (formerly usual VIN II or III).
  Challenging this approach, Srodon et al. found high-risk HPVs in 42% of uVIN I lesions, supporting the continued use of that term. High-risk HPV, however, was not found in condylomas, suggesting that the latter differed from uVIN I. Similar results were found by Skapa et al.

Clinical features of usual VIN


  The incidence of uVIN has almost doubled over the past few decades, with a striking increase in younger women; most of those currently affected are <40 years of age.
  Risk factors include evidence of HPV (such as condyloma acuminatum) and herpes infection, HIV-positivity, smoking, and sexual factors identical to those for cervical cancer ( Chapter 5 ). Some cases are associated with lichen sclerosus, although the latter is more closely associated with dVIN.
  The typical presentation is a pruritic, burning, or asymptomatic, white, pink, red, or pigmented lesion that may be plaque-like, papular, or verruciform, and which may be clinically misinterpreted as a non-neoplastic epithelial disorder (vulvar ‘dystrophy’) ( Chapter 1 ).
  Involved sites in decreasing order of frequency are labia minora, posterior forchette, labia majora, perianal skin, and periclitoral skin. The lesions are multifocal in 40–80% of cases.
  Synchronous or metachronous HPV-related intraepithelial or invasive squamous neoplasms are present in other sites in up to half the cases, including the cervix, vagina, urethra, perineum, and anus. Some multifocal lesions are clonal.
  Maniar et al. found that uVINs (containing high-risk HPV) in immunocompromised patients may be contiguous to a condyloma (containing low-risk HPV), indicating independent lesions.

Pathological features of usual VIN and its variants ( Figs. 2.1 – 2.8 )


Fig. 2.1 VIN III. White, focally erythematous, plaque-like and polypoid lesions are seen.


Fig. 2.2 Usual VIN III. The surface is hyperkeratotic.


Fig. 2.3 High-grade uVIN. Note full-thickness atypia and abnormal mitotic figures.


Fig. 2.4 Pagetoid VIN.


Fig. 2.5 High-grade uVIN, immunostain for p16. There is nuclear staining throughout all layers of the epidermis.


Fig. 2.6 High-grade uVIN with bulbous projections into the dermis, an appearance largely due to tangential sectioning, but which is sometimes misinterpreted as superficial invasion.


Fig. 2.7 High-grade uVIN, warty type.


Fig. 2.8 High-grade uVIN, warty type. There is full-thickness atypia with koilocytotic cells in the superficial layers.

  The normal epithelial maturation is lost due to replacement by keratinocytes with increased N : C ratio and variable nuclear pleomorphism, hyperchromasia, chromatin clumping, multinucleation, and mitotic figures, including abnormal mitoses. The cells are typically aneuploid.

•  Dyskeratotic cells, corps ronds (apoptotic bodies), and poorly formed keratin pearls may be seen. The affected epithelium may be acanthotic, parakeratotic, hyperkeratotic, or combinations thereof.
•  Skin appendages, most commonly pilosebaceous units, are commonly involved. Tangential sectioning of involved appendages should not be misinterpreted as invasion (see below).
•  HPV (usually HPV16, less commonly HPV18, 31, 33) and diffuse moderate to strong reactivity for p16 are present in most high-grade lesions, as are full-thickness staining for MIB1 and ProEx C. In contrast to dVIN, p53 staining is focal and present in only a minority of cases.
•  uVIN may abut or merge with a condyloma. Dysplastic cells in the basal and parabasal layers of an otherwise typical or flat condyloma warrant a diagnosis of uVIN within the condyloma.
•  Dermal deposits of amyloid can be seen in rare cases.
  uVIN can be subdivided into basaloid and warty (condylomatous) variants, but as these variants are often synchronous, can overlap in appearance, and lack clinically significant differences, their separate recognition is of doubtful value. Both types contain high-risk HPV.

•  The basaloid variant has a flat, sometimes keratotic, surface and is composed of small uniform basaloid cells with scanty cytoplasm, ill-defined cell membranes, large hyperchromatic nuclei, clumped chromatin, inapparent nucleoli, and numerous mitoses; the appearance resembles typical CIN3 ( Chapter 5 ).
•  The warty variant is typically acanthotic with a spiky or warty surface and large cells with copious eosinophilic cytoplasm, marked nuclear pleomorphism, and multinucleated cells. Corps ronds, dyskeratotic cells, and koilocytotic cells are common. There is superficial maturation and para-/hyperkeratosis. Wide rete pegs extend into the stroma.
  The term ‘bowenoid papulosis’ has been applied to usually multiple, red to brown papules occurring typically in young, often pregnant, women.

•  The microscopic appearance varies from typical uVIN to those with dysplastic keratinocytes scattered within a background of more normal-appearing cells.
•  Lesions may spontaneously regress, but as many as 20% recur. Rarely the lesion is synchronous with, or progresses to, invasive squamous cell carcinoma.
•  As bowenoid papulosis has neither a predictable behavior nor a distinctive microscopic appearance, the continued use of the term has been discouraged.
  Pagetoid VIN (pagetoid Bowen's disease) is an uncommon pattern.

•  Neoplastic keratinocytes with moderate amounts of pale cytoplasm are disposed singly or in small nests within a background non-neoplastic keratinocytes, and can involve all layers of the epidermis and skin appendages.
•  The neoplastic cells, like those of Paget's disease but unlike those of other types of VIN, are usually CK7+/CK19+. Unlike Paget's disease, however, the cells lack intracellular mucin and are p16+/CEA−/ CAM5.2− / GCDFP-15−. These findings also help distinguish pagetoid Bowen's disease from synchronous uVIN and Paget's disease.
  Rare but otherwise typical cases of VIN exhibit mucinous differentiation in the form of cells with mucin-rich cytoplasm and eccentric, small regular nuclei.
  Chafe et al. found foci of unsuspected invasion in almost 20% of uVIN lesions, but in most of the cases the invasion was <1 mm in depth. Women with unsuspected invasion were older than those without it (mean age 58 years vs 39 years).

•  Appendigeal involvement by, and tangential sectioning of, uVIN are common and may mimic invasion. Evidence of a residual appendage, a well-circumscribed border, a continuous basement membrane (highlighted by laminin and/or collagen IV positivity), and absence of a desmoplastic stroma facilitate the diagnosis.
•  Spiegel has found that the presence of stromal and/or intraepithelial eosinophils in a biopsy specimen with VIN warrants additional sections and levels to exclude invasion.

Behavior of usual VIN


  After local treatment, up to 50% of cases of uVIN persist or recur, usually within 5 years. Recurrence has correlated with smoking, multifocality, positive resection margins, and laser (vs surgical) treatment.
  Progression to invasive squamous cell carcinoma (SqCC) is less common than in dVIN, occurring in 5–6% of treated women and 10–15% of untreated women. Progression occurs over a longer period compared to dVIN, and the risk is increased with age and in immunocompromised women.
  As noted above, spontaneous regression of uVIN may occur, particularly in pregnant or postpartum women, especially those with the clinical findings of bowenoid papulosis.

Clinical features of differentiated VIN


  dVIN (which is considered VIN III, as noted above) accounts for 5–10% of VIN. It is rarely diagnosed in pure form, possibly due to a short intraepithelial phase. It is usually found adjacent to an invasive SqCC, 60–85% of dVIN lesions being associated with a synchronous or metachronous invasive SqCC, usually of keratinizing type.
  These findings indicate that dVIN is the likely precursor of many or most HPV-negative invasive SqCCs, and, as noted above, is associated with a greater risk of invasion than uVIN.
  dVIN usually occurs in postmenopausal women. It may be asymptomatic or cause pruritis and/or a visible lesion. The latter are usually less conspicuous than those of uVIN, appearing as single or multiple gray–white areas with a rough surface or ill-defined white plaques or nodules.
  In contrast to uVIN, dVIN is preceded by and/or coexists with squamous hyperplasia, lichen simplex chronicus, lichen sclerosus, or combinations thereof, in 80% of cases. These lesions, which may show atypia, are putative precursors of dVIN.

Microscopic features of differentiated VIN ( Figs. 2.9 – 2.11 )


Fig. 2.9 Differentiated VIN. The epidermis is acanthotic with elongated and branching rete ridges, one of which contains a keratin pearl.


Fig. 2.10 Differentiated VIN. Note atypia of basal cells. The suprabasilar keratinocytes have abundant eosinophilic cytoplasm, vesicular nuclei, and macronucleoli.


Fig. 2.11 Differentiated VIN, p53 stain. Most of the cells in the lower half of the epidermis show intense nuclear immunoreactivity.

  dVIN is often a subtle finding that is microscopically underdiagnosed due to its high degree of differentiation. One study found that 42% of lesions preceding SqCC initially diagnosed as lichen sclerosus were dVIN.
  The epidermis is usually thickened and parakeratotic, often with elongated and branching rete ridges.
  Except for the basal layer, the involved epithelium is composed of enlarged squamous cells with abundant eosinophilic cytoplasm, prominent intercellular bridges, and large vesicular nuclei with macronucleoli. Dyskeratotic cells may be present.
  The abnormal squamous cells typically extend deeply into the epidermis (or its rete ridges), where they encroach on the basal cells and form whorls or keratin pearls.
  The large keratinocytes contrast with the smaller basal cells that have irregular hyperchromatic nuclei with mild to severe atypia. Mitotic figures are most commonly found in the basilar cells, but also may be present in the upper layers.
  Intraepithelial mast cells are common and may be diagnostically helpful as they are not found in benign cutaneous lesions, such as lichen sclerosus.
  dVIN often abuts lichen sclerosus and/or squamous hyperplasia. The lichen sclerosus may show atypia, particularly in the lower epidermis, with nuclear enlargement, prominent nucleoli, and occasional normal or abnormal mitotic figures. The cytoplasm of the atypical cells may be pale and vacuolated, potentially mimicking Paget's disease.
  Other findings may include prominent spongiosis, involvement of pilosebaceous units, a chronic inflammatory cell infiltrate, and dermal fibrosis.
  Subtle foci of microinvasion may be present, and their presence may be a clue to the presence of overlying dVIN. The invasive foci consist of small nests of large keratinocytes originating from the basilar epidermis or rete ridges, sometimes with an inflammatory or desmoplastic reaction.
  p53 reactivity is typically present in at least the lower third of the involved epidermis. MIB1 reactivity is intense but, in contrast to uVIN, it is confined to the basal and parabasal layers. The neoplastic cells are typically negative for HPV and p16.
  dVIN is typically associated with TP53 mutations, and in some cases the same mutations are present in adjacent areas of invasive SqCC, supporting a genetic relationship between the two lesions.
  In a study of HPV-negative invasive SqCCs, Ordi et al. identified a basaloid form of dVIN that accounted for 8% of the VIN. Unlike dVIN, the epidermis is replaced by a homogeneous population of basaloid keratinocytes with the same immunoprofile as that of typical dVIN, facilitating distinction from classic VIN. The associated invasive SqCCs included keratinizing and basaloid types.

Behavior of differentiated VIN


  In two studies, van de Nieuwenhof et al. (2009 and 2011) found that dVIN had a greater risk of progression to invasive SqCC than uVIN. A third of dVIN lesions progressed and within a shorter period (mean 28 months) than with uVIN lesions that progressed to invasive SqCC.

Differential diagnosis of usual and differentiated VIN


  Condylomas with pseudobowenoid change and condylomas with podophyllin effect ( Chapter 1 ).
  Inflammatory and reactive atypia and multinucleated keratinocytes ( Chapter 1 ).
  Lichen sclerosus or squamous cell hyperplasia with atypia (vs dVIN).

•  Features favoring or indicating dVIN include prominent parakeratosis, a thickened epidermis with elongated and branching rete, abnormal keratinocytes with large vesicular nuclei, macronucleoli, abundant eosinophilic cytoplasm, squamous whorls, and keratin pearls.
•  Strong continuous p53 staining of basilar cells, sometimes with suprabasilar extension of the staining, also favors dVIN.
  Paget's disease and radial growth of malignant melanoma.

•  In both disorders, the malignant cells are usually individually disposed and surrounded by benign keratinocytes. Glands and/or signet-ring cells may be seen in Paget's disease.
•  Special stains will show mucin, CEA, and CK7 in Paget's cells, and S100 and HMB45 in melanoma cells. As noted above, pagetoid VIN may also be CK7 positive, but other markers noted above facilitate its distinction from Paget's disease.
•  The rare form of VIN with mucinous differentiation, unlike Paget's, contains dysplastic keratinocytes.

Invasive Squamous Cell Carcinoma of Usual Type


Clinical features


  These tumors (ISqCCs) account for 90% of vulvar cancers and 5% of gynecological cancers.
  Two pathogenetic pathways exist:

•  An HPV-related pathway, which usually occurs in premenopausal women, leads to warty and basaloid ISqCCs. It is commonly associated with one or more of: HPV infection (including a history of genital warts), uVIN, smoking, cervical cancer risk factors, immunosuppression, and squamous neoplasia of the cervix or vagina.
•  A p53-related pathway, which usually occurs in women in the seventh to eighth decades of life, leads to keratinizing ISqCC. It is usually not related to HPV but is associated with one or more of: dVIN, lichen sclerosus, squamous cell hyperplasia, and p53 mutations.
•  The two pathways may act in synchrony: almost 40% of LS-associated ISqCCs were HPV+ in one study. Similarly, a third of keratinizing ISqCCs in another study were associated with uVIN. Some tumors are negative for both HPV and p53, suggesting the existence of other pathogenetic factors. Some vulvar ISqCCs have complicated chronic hidradenitis suppurativa.
  Patients usually present with a vulvar mass that may be pruritic or painful or bleeds; a groin mass is an occasional presentation. A persistent ulcer may be the only presenting finding, particularly in a postmenopausal woman. Because patient and/or physician delay is common, 30–40% of vulvar ISqCCs are not treated until they are stage III or IV ( Table 2.1 ).

Table 2.1
FIGO staging of carcinoma of the vulva Stage 0 Carcinoma in situ; intraepithelial carcinoma Stage I Tumor confined to the vulva and/or perineum, ≤2 cm in greatest dimension  Ia Depth of invasion not exceeding 1 mm *  Ib Depth of invasion >1 mm Stage II Tumor confined to the vulva and/or perineum, >2 cm in greatest dimension Stage III Tumor invades any of the following: lower urethra, vagina, anus, and/or unilateral regional lymph node metastasis Stage IVa Tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa; and/or is fixed to bone; and/or bilateral regional lymph node metastasis Stage IVb Any distant metastasis including pelvic lymph nodes
* The depth of invasion is defined as the distance of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla, to the deepest point of invasion.

Pathologic features ( Figs. 2.12 – 2.18 )


Fig. 2.12 Invasive squamous cell carcinoma forms an exophytic mass (bottom) that is associated with lichen sclerosus (white areas, left and top).


Fig. 2.13 Squamous cell carcinoma with superficial invasion. Left: Small nests of invasive tumor lie within a loose reactive stroma. Right: The invasive nests at the bottom of the field show greater maturation than the overlying VIN.


Fig. 2.14 Invasive keratinizing squamous cell carcinoma associated with lichen sclerosus (top right).


Fig. 2.15 Invasive keratinizing squamous cell carcinoma.


Fig. 2.16 Invasive keratinizing squamous cell carcinoma with a prominent fibromyxoid stromal response, which was an adverse prognostic finding in one study.


Fig. 2.17 Invasive squamous cell carcinoma, basaloid type.


Fig. 2.18 Two uncommon findings in vulvar squamous cell carcinomas: acantholysis resulting in gland-like spaces (left) and cells with clear (glycogen-rich) cytoplasm (right).

  Clinical and gross examination reveals a raised, white, sometimes warty, sometimes ulcerated mass, which involves, in descending order of frequency, the labia majora, the labia minora, the perineal body and the posterior fourchette, and the clitoris. About 10% of lesions are multifocal.
  As noted above, the three main histologic subtypes of ISqCC are keratinizing, basaloid, and warty, which occasionally coexist; some tumors have overlapping features. Keratinizing ISqCCs account for 65–80% of vulvar ISqCCs and basaloid and warty ISqCCs combined account for the remaining 20–35%.
  Keratinizing ISqCCs resemble typical ISqCCs in other sites. They may be papillary or polypoid, and are usually well or moderately differentiated, with varying degrees of squamous maturation and keratin formation and an absence of koilocytosis.

•  Common adjacent lesions include typical or atypical lichen sclerosus, squamous hyperplasia, and dVIN (or uncommonly, uVIN).
•  Most tumors are p53+ and exhibit TP53 mutations, which may also be present in foci of synchronous dVIN; p16 staining is usually absent or weak and focal. PCR testing usually reveals no HPV, although HPV has been present in a minority of tumors in some studies.
  Basaloid and warty ISqCCs.

•  Basaloid ISqCCs are composed of basaloid cells with scanty cytoplasm that typically grow in bands, sheets, or nests within a desmoplastic stroma. Focal cytoplasmic maturation and keratinization can occur, usually with an abrupt transition with the basaloid cells.
•  Warty ISqCCs resemble warty VIN except for invasion as bulbous or irregular jagged nests, often with prominent keratinization. The koilocytotic tumor cells have pleomorphic to bizarre, often multiple, nuclei with irregular contours that vary from hyperchromatic and shrunken to those with clumped or smudged chromatin.
•  In both types, contiguous uVIN is present in 80% of cases.
•  The tumor cells typically show strong diffuse p16 staining (due to the presence of HPV), but are usually negative for p53.
  There is no widely accepted grading system for vulvar ISqCCs.

•  Kurman et al. grade keratinizing ISqCCs as well differentiated (discrete nests with central keratinization and cells with low-grade nuclear features), poorly differentiated (diffuse stromal infiltration as small nests and cords, little or no keratinization, high-grade nuclear features), and moderately differentiated (features intermediate between the well and poorly differentiated tumors). Basaloid and warty ISqCCs are not graded.
•  The Gynecology Oncology Group (GOG) grade keratinizing ISqCCs on the proportion of the tumor that is ‘undifferentiated’ (UC) (small cells with scanty cytoplasm infiltrating as small nests or cords): grade 1, no UC; grade 2, 1–30% UC; grade 3, 31–50% UC; grade 4, >50% UC.
  Rush et al. found that staining for cytokeratin and collagen IV facilitated the diagnosis of very superficial invasion. In contrast to VIN, early invasive nests had an absent or discontinuous investment by basement membrane.

Differential diagnosis


  Amelanotic malignant melanoma. This diagnosis is indicated by the presence of a junctional component, absence of keratinization, and positivity for S100 and HMB-45.
  Epithelioid sarcoma (see corresponding heading). Findings favoring this diagnosis are a deep location, zonal necrosis, rhabdoid cells, positivity for mesenchymal antigens, and an absence of VIN and keratinization.
  Basal cell carcinoma (vs basaloid ISqCC). Features favoring basal cell carcinoma include a lobular well-circumscribed contour, low-grade atypia, peripheral palisading, and an absence of VIN.
  Metastatic small cell carcinoma and Merkel cell tumor (vs basaloid ISqCC). These tumors tend to have a highly infiltrative pattern (often with single cell invasion), smaller cells with scanty cytoplasm, and positivity for neuroendocrine markers.
  Verrucous carcinoma (vs warty SqCCs and papillary keratinizing SqCCs). Features indicating verrucous carcinoma (see corresponding heading) include absent or minimal cytologic atypia, usual absence of koilocytosis, and a well-circumscribed deep border formed by rounded bulbous masses.

Behavior and prognostic factors


  Prognostically adverse clinical factors include increasing stage ( Table 2.1 ) with 5-year survival rates of 85–98%, 60–85%, 40–74%, and 10–30% for stages I to IV, respectively; older age; smoking; and fixed or ulcerated groin nodes.
  Prognostically adverse pathologic features of the primary tumor are increasing tumor diameter, increasing depth of invasion, increasing grade, and lymphovascular space invasion.

•  Tumors invading ≤1 mm (measured from point of origin of invasive cells, or, if this is not possible, from the most superficial dermal papilla adjacent to the tumor's deepest focus of invasion) are stage Ia ( Table 2.1 ) and have a <1% risk of nodal spread, whereas that for tumors invading 1.1–3 mm and 3.1–5 mm was 6% and 20%, respectively (Yoder et al.).
•  Other adverse prognostic factors of the primary tumor found in some studies have included basaloid subtype, multifocality, associated uVIN, infiltrative (vs pushing) pattern of invasion, perineural invasion, minimal mononuclear inflammatory infiltrate, a fibromyxoid stromal response (Ambros et al.), p53 overexpression, diffuse MIB1 staining, and increased EGFR gene copy numbers.
•  Allo et al. found that HPV status and p16 and p53 staining had no effect on survival.
  Lymph node involvement is an important prognostic factor.

•  The inguinofemoral nodes are involved in 30–40% of cases, with bilateral involvement in about one-third of these. de Hullu et al. found that the predictive value of a negative inguinal sentinel lymph node was 100%. The pelvic lymph nodes are involved in 5% of cases overall, in about 25% of cases with involved inguinofemoral nodes, and rarely if ever when the inguinal nodes are negative.
•  Recurrences develop in 50% of patients with involved inguinofemoral nodes. These women have a 40% 5-year survival vs 85% for those with negative nodes.
•  Involvement of ≥three inguinofemoral nodes, bilateral nodal involvement, extranodal tumor, and pelvic nodal involvement are additional adverse prognostic factors.
•  Cytokeratin staining detected micrometastases in inguinal nodes in 23% and 42% of patients in two studies. In one of these studies, the patients with involved nodes had an almost 20-fold increased risk of recurrence compared to those with negative nodes.
•  Regauer (2009) found that cytokeratin staining was helpful in detecting micrometastases in sentinel nodes, including single tumor cells and anucleate cells. Single tumor cells were particularly common in women with lichen sclerosus (LS)-associated ISqCCs.
  Piura et al. found extravulvar recurrences were associated with a poor survival compared to those with a vulvar recurrence (12% vs 62%, respectively).
  Spiryda et al. found that aggressive locally recurrent tumors were often associated with persistent high-grade VIN and LS. Regauer (2011) found that almost 50% of LS-related ISqCCs recurred within residual anogenital LS.

Verrucous Carcinoma ( Figs. 2.19 – 2.20 )


Fig. 2.19 Verrucous carcinoma. Note well-circumscribed deep border.


Fig. 2.20 Verrucous carcinoma. Note bland nuclear features.

  Verrucous carcinomas (VCs) are rare, highly differentiated SqCCs. Most or all appear to be unrelated to both HPV and Tp53 mutations. Some VCs have been associated with one or more of: lichen sclerosus, lichen simplex chronicus, and a distinctive type of acanthosis described below.
  VCs typically occur in women in the late reproductive and postmenopausal age groups who present with pain, pruritus, and a large, gray–white, fungating mass on the labia majora.
  A delay in diagnosis may occur if previous biopsies of the tumor are misdiagnosed as squamous papilloma or condyloma. In the largest series, two-thirds of the tumors were stage II or higher.
  The tumors have a papillary architecture with prominent acanthosis, hyperkeratosis, and a deep pushing invasive border composed of broad bulbous pegs. Koilocytosis is absent.
  The neoplastic squamous cells have abundant eosinophilic cytoplasm and absent to mild nuclear atypia. Mitoses, if present, are confined to the basal layers, as are most MIB1+ cells.
  Nascimento et al. use the term ‘vulvar acanthosis with altered differentiation’ to refer to a distinctive noninvasive squamous proliferation that often abuts VCs and that may be a precursor or risk factor for VC. This lesion consists of marked acanthosis with variable verruciform architecture, loss of the granular layer with superficial epithelial cell pallor, and multilayered parakeratosis.
  VCs should be distinguished from condyloma ( Chapter 1 ), warty carcinoma (see corresponding heading), and papillary but otherwise conventional SqCCs that are distinguishable from VCs by the presence of more than mild nuclear atypia and an infiltrative border.
  VCs may invade local structures; high-stage tumors are occasionally fatal. However, the tumors rarely, if ever, metastasize. Metastases should prompt thorough sampling of the primary tumor to exclude a component of conventional ISqCC that rarely arises in an otherwise typical VC and that may focally mimic VC.

Sarcomatoid Squamous Cell Carcinoma ( Fig. 2.21 )


Fig. 2.21 Sarcomatoid squamous cell carcinoma. Most of the tumor cells are spindle-shaped and lie within a fibrotic stroma. A nest of typical squamous cell carcinoma is also present (upper left).

  About 10 sarcomatoid ISqSCs of the vulva have been reported, mostly in postmenopausal women. Two tumors were associated with lichen sclerosus. Most tumors are high stage and/or associated with recurrence; at least two were fatal.
  Microscopically, high-grade spindle cells merge with foci of more typical ISqCC.
  The differential diagnosis is with a sarcoma or spindle cell melanoma. Merging of the spindle cells with typical ISqCC, focal keratinization, and CK+ spindle cells facilitate the diagnosis. A caveat is that the spindle cells may be CK− and vimentin+.

Other Rare Variants of Squamous Cell Carcinoma


  Acantholytic ISqCCs have prominent spaces that can simulate glands (‘adenoid’ or ‘pseudoglandular’ SqCC) or vascular spaces (‘pseudoangiosarcomatous’ SqCC). These tumors may be more aggressive than typical ISqCCs.
  Rare ISqCCs have numerous tumor giant cells creating a resemblance to giant cell carcinomas in other sites.
  One vulvar plasmacytoid ISqCC has been reported. The tumor cells expressed a variety of epithelial markers as well as some plasma cell markers.
  Two vulvar carcinosarcomas have been reported in which the carcinomatous component was squamous; the sarcomatous component was osteosarcoma in one case and leiomyosarcoma in the other.
  Three lymphoepithelioma-like carcinomas of the vulva have been reported. All were EBV−. One tumor recurred locally and in inguinal lymph nodes 4 months after resection.

References

Vulvar intraepithelial neoplasia
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van de Nieuwenhof, H. P., Hebeda, K. M., Bulten, J., et al. Specific intraepithelial localization of mast cells in differentiated vulvar intraepithelial neoplasia and its possible contribution to vulvar squamous cell carcinoma development. Histopathology . 2010; 57:351–362.
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Invasive squamous cell carcinoma: general features
Ambros, R. A., Malfetano, J. H., Mihm, M. C., Jr. Clinicopathologic features of vulvar squamous cell carcinomas exhibiting prominent fibromyxoid stromal response. Int J Gynecol Pathol . 1996; 15:137–145.
Ansink, A. C., Krul, M. R. L., De Weger, R. A., et al. Human papillomavirus, lichen sclerosus, and squamous cell carcinoma of the vulva: Detection and prognostic significance. Gynecol Oncol . 1994; 52:180–184.
Chiesa-Vottero, A., Dvoretsky, P. M., Hart, W. R. Histopathologic study of thin vulvar squamous cell carcinomas and associated cutaneous lesions. Am J Surg Pathol . 2006; 30:310–318.
Convicini, F., Venturoli, S., Ambretti, S., et al. Presence and type of oncogenic human papillomavirus in classic and in differentiated vulvar intraepithelial neoplasia and keratinizing vulvar squamous cell carcinoma. J Med Virol . 2005; 77:102–106.
Herod, J. J. O., Shafi, M. I., Rollason, T. P., et al. Vulvar intraepithelial neoplasia with superficially invasive carcinoma of the vulva. Br J Obstet Gynaecol . 1996; 103:453–456.
Hording, U., Daugaard, S., Junge, J. F., et al. Human papillomaviruses and multifocal genital neoplasia. Int J Gynecol Pathol . 1996; 15:230–234.
Joura, E. A., Losch, A., Haider-Angeler, M. G., et al. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women. J Reprod Med . 2000; 45:613–615.
Kurman, R. J., Toki, T., Schiffman, M. H. Basaloid and warty carcinomas of the vulva. Distinctive types of squamous cell carcinoma frequently associated with human papillomaviruses. Am J Surg Pathol . 1993; 17:133–145.
Leibowitch, M., Neill, S., Pelisse, M., et al. The epithelial changes associated with squamous cell carcinoma of the vulva: A review of the clinical, histological and viral findings in 78 women. Br J Obstet Gynaecol . 1990; 97:1135–1139.
Lerman, E., Matias-Guiu, X., Lee, S. J., et al. Squamous cell carcinoma of the vulva: Study of ploidy, HPV, p53, and pRb. Int J Gynecol Pathol . 1999; 18:191–197.
Magrina, J. F., Gonzalez-Bosquet, J., Weaver, A. L., et al. Squamous cell carcinoma of the vulva Stage IA: Long-term results. Gynecol Oncol . 2000; 76:24–27.
Pinto, A. P., Miron, A., Yassin, Y., et al. Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma. Mod Pathol . 2010; 23:404–412.
Piura, B., Masotina, A., Murdoch, J., et al. Recurrent squamous cell carcinoma of the vulva: A study of 73 cases. Gynecol Oncol . 1993; 48:189–195.
Riethdorf, S., Neffen, E. F., Cviko, A., et al. P16 INK4a expression as biomarker for HPV 16-related vulvar neoplasia. Hum Pathol . 2004; 35:1477–1483.
Rush, D., Hyjek, E., Baergen, R. N., et al. Detection of microinvasion in vulvar and cervical intraepithelial neoplasia using double immunostaining for cytokeratin and basement membrane components. Arch Pathol Lab Med . 2005; 129:747–753.
Santos, M., Landolfi, S., Olivella, A., et al. p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol . 2006; 30:1347–1356.

Invasive squamous cell carcinoma: behavior and prognostic factors
Allo, G., Mulligan, A. M., Ghazarian, D., et al. HPV DNA in-situ hybridization, p16 and p53 in a cohort of 128 vulvar squamous cell carcinomas. [Abstract]. Mod Pathol . 2012; 25:23A.
de Hullu, J. A., Hollema, H., Piers, D. A., et al. Sentinel lymph node procedure is highly accurate in squamous cell carcinoma of the vulva. J Clin Oncol . 2000; 18:2811–2816.
Drew, P. A., Al-Abad, M. A., Orlando, C. A., et al. Prognostic factors in carcinoma of the vulva: A clinicopathologic and DNA flow cytometric study. Int J Gynecol Pathol . 1996; 15:235–241.
Homesley, H. D., Bundy, B. N., Sedlis, A., et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (A Gynecologic Oncology Group Study). Am J Obstet Gynecol . 1991; 164:997–1004.
Homesley, H. D., Bundy, B. N., Sedlis, A., et al. Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (A Gynecologic Oncology Group Study). Gynecol Oncol . 1993; 49:279–283.
Knopp, S., Holm, R., Tropé, C., et al. Occult lymph node metastases in early stage vulvar carcinoma patients. Gynecol Oncol . 2005; 99:383–388.
Narayansingh, G. V., Miller, I. D., Sharma, M., et al. The prognostic significance of micrometastases in node-negative squamous cell carcinoma. Br J Cancer . 2005; 92:222–224.
Regauer, S. Histopathological work-up and interpretation of sentinel lymph nodes removed for vulvar squamous cell carcinoma. Histopathology . 2009; 55:174–181.
Regauer, S. Residual anogenital lichen sclerosus after cancer surgery has a high risk for recurrence: A clinicopathological study of 75 women. Gynecol Oncol . 2011; 123:289–294.
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Verrucous carcinoma
Gualco, M., Bonini, S., Foglia, G., et al. Morphologic and biologic studies of ten cases of verrucous carcinoma of the vulva supporting the theory of a discrete clinico-pathologic entity. Int J Gynecol Cancer . 2003; 13:317–324.
Japaze, H., Van Dinh, T., Woodruff, J. D. Verrucous carcinoma of the vulva: Study of 24 cases. Obstet Gynecol . 1982; 60:462–466.
Nascimento, A. F., Granter, S. R., Cviko, A., et al. Vulvar acanthosis with altered differentiation. A precursor to verrucous carcinoma. Am J Surg Pathol . 2004; 28:638–643.

Sarcomatoid squamous cell carcinoma
Choi, D., Lee, J., Lee, S., et al. Squamous cell carcinoma with sarcomatoid features of the vulva: A case report and review of the literature. Gynecol Oncol . 2006; 103:363–367.
Santos-Briz, A., Antúnez, P., López-Rios, F., et al. Human papillomavirus-negative spindle cell carcinoma of the vulva associated with lichen sclerosus. Case report and literature review. Am J Dermatopathol . 2002; 24:135–138.
Steeper, T. A., Rosai, J. Squamous cell carcinoma with sarcoma-like stroma of the female genital tract. Cancer . 1983; 52:890–898.

Other rare variants of squamous cell carcinoma
Adam, P., Zettl, A., Zollner, U., et al. Metastasizing vulvar carcinosarcoma with squamous carcinomatous and leiomyosarcomatous differentiation: Genetic evidence of clonal origin. Hum Pathol . 2005; 36:1143–1147.
Horn, L., Liebert, U. G., Edelmann, J., et al. Adenoid squamous carcinoma (pseudoangiosarcomatous carcinoma) of the vulva: A rare but highly aggressive variant of squamous cell carcinoma – report of a case and review of the literature. Int J Gynecol Pathol . 2008; 27:288–291.
Niu, W., Heller, D. S., D'Cruz, C. Lymphoepithelioma-like carcinoma of the vulva. J. Lower Genit Tract Dis . 2003; 7:184–186.
Santos, L. D., Krivanek, M. J., Chan, F., et al. Pseudoangiosarcomatous squamous cell carcinoma of the vulva. [Letter]. Pathology . 2006; 38:581–583.
Sluvkin, I. I., Schink, J. C., Warner, T. F. Lymphoepithelioma-like carcinoma of the vulva: A case report. J. Lower Genit Tract Dis . 2003; 7:136–139.
Tran, T. A., Carlson, J. A. Plasmacytoid squamous cell carcinoma of the vulva. Int J Gynecol Pathol . 2008; 27:601–605.
Wilkinson, E. J., Croker, B. P., Friedrich, E. G., Jr., et al. Two distinct pathologic types of giant cell carcinoma of the vulva. A report of two cases. J Reprod Med . 1988; 33:519–522.

Paget's Disease


Clinical features ( Fig. 2.22 )


Fig. 2.22 Paget's disease with extensive involvement of the vulva.

  Paget's disease (PD), which accounts for about 1% of vulvar cancers, occurs in the late reproductive and postmenopausal age groups, with median and mean ages in the seventh decade. PD may be present for years before a diagnostic biopsy is performed.
  The usual presentation is that of pruritic or burning, eczematoid, erythematous, weeping patches interspersed with white (hyperkeratotic) or ulcerated areas. Early lesions are usually confined to the labia, but longstanding lesions may also involve the mons, clitoris, urethra, perianal area, and medial aspect of the thighs.
  About 30% of patients have a synchronous or metachronous internal carcinoma, most commonly of the breast or genitourinary system (uterine cervix, urinary bladder). With rare exceptions (see next section), these tumors are unrelated to the vulvar disease.

Histogenesis


  About 95% of cases begin as a primary cutaneous in situ carcinoma, likely originating from adnexal stem cells, the cells of the poral portion of the sweat ducts, or from mammary-like glands ( Chapter 1 ). Involvement of skin appendages reflects pagetoid spread of the tumor cells or multifocal disease, not an underlying sweat gland carcinoma.
  Less than 5% of cases represent secondary vulvar involvement by a regional internal cancer, most commonly arising in the anorectal region or urinary tract. A primary rectal adenocarcinoma should be excluded in cases with vulvar and perianal involvement.

Microscopic features ( Figs. 2.23 – 2.28 )


Fig. 2.23 Paget's disease. There is involvement of adnexal structures (arrow).


Fig. 2.24 Paget's disease. There is typical pagetoid involvement of the epidermis.


Fig. 2.25 Paget's disease with signet-ring-type tumor cells (arrow). There is a suggestion of gland lumina in the two largest nests of tumor cells (bottom left and bottom center).


Fig. 2.26 Paget's disease with prominent squamous cell hyperplasia. The Paget cells are not clearly visible at this low magnification, but could be overlooked even on higher power magnification because of the marked squamous proliferation.


Fig. 2.27 Paget's disease with superficial invasion, CK7 stain. The tumor cells in the epidermis and the invasive cells in the dermis are intensely CK7+ in contrast to the negatively staining keratinocytes in the epidermis.


Fig. 2.28 Paget's disease with prominent adnexal involvement that could be misinterpreted as invasion.

  Large malignant epithelial cells are disposed singly, in clusters, and occasionally as glands within the epidermis. The concentration of tumor cells is usually greatest in the basal layer, but in most cases, all epidermal layers are involved. The pilosebaceous units and the poral and dermal portions of sweat ducts are involved in almost all cases.
  The typical Paget cell has a vesicular nucleus with a prominent nucleolus and abundant pale amphophilic cytoplasm that usually contains mucin demonstrable with mucin stains, but it may be scanty and difficult to find in a small biopsy specimen. Signet-ring cells with abundant cytoplasmic mucin may also be present, and can be numerous in invasive foci.
  Involvement is typically much more extensive and more multifocal than is appreciable on clinical or gross examination; cutaneous resection margins are commonly involved.
  Paget cells are diffusely and strongly CK7+, which is an excellent marker for in situ and invasive Paget cells and facilitates their distinction from hyperplastic and malignant squamous cells, which are CK7−.

•  Paget cells are also usually CEA+, CAM 5.2+, GCDFP+, MUC1+, and AR+ (but ER− and PR−). Her-2/neu positivity has been found in 40–60% of cases; some tumors are p53+, a finding that correlated with dermal invasion in one study.
•  Rarely, strongly p16+ Paget cells can efface keratinocytes mimicking high-grade VIN (Sah et al.).
•  Vulvar PD secondary to spread from a regional cancer has the immunoprofile of the primary tumor. These tumors may be CK7+, but in contrast to vulvar Paget's, are typically CK20+ and GCDFP−. Tumors of colorectal origin are also CDX2+ and those of urothelial origin are often uroplakin-III+.
  In a third of cases, dermal invasion (often unsuspected clinically) is found on microscopic examination.

•  The detection of rare invasive cells in the superficial dermis can be facilitated by staining for CK7.
•  The depth of invasion in millimeters (measured from the basement membrane) and the presence or absence of lymphatic invasion should be noted in the pathology report.
  Brainard and Hart found that a third of their cases of vulvar PD had a superimposed squamous proliferation categorized, in order of frequency, as papillomatous squamous cell hyperplasia (SCH), SCH not otherwise specified, and fibroepithelioma-like SCH.

•  These changes can result in a misdiagnosis of a benign squamous lesion if Paget cells are rare, or a malignant squamous lesion if Paget cells are numerous and diffusely distributed.
•  In several cases, small dermal nests of squamous cells simulated microinvasive squamous carcinoma.
  Rare cases of vulvar PD are associated with other vulvar lesions, such as synchronous VIN, ISqCC, or malignant melanoma.

Differential diagnosis


  Pagetoid VIN (see corresponding heading).
  VIN with mucinous differentiation. The presence of dysplastic and p16+ squamous cells supports this diagnosis.
  In situ malignant melanoma. In contrast to Paget cells, melanoma cells lack mucin and stain for one or more of S100, HMB-45, and Melan-A, but not CK7. As cytoplasmic melanin can occur in Paget cells, it is not a differential feature.
  Rarer lesions in the differential diagnosis (see Kohler et al.) include pagetoid Spitz nevus, clear cells of Toker, pagetoid dyskeratosis ( Chapter 4 ), clear cell papulosis, epidermal involvement by sebaceous carcinoma, Merkel cell carcinoma, eccrine porocarcinoma, cutaneous T-cell lymphoma, and lesions of Langerhans' cells (histiocytosis X, Langerhans' cell microabscesses).

Behavior


  Intraepidermal recurrence occurs in up to 60% of cases due to incomplete excision; rarely, recurrences are within the vaginal and cervical mucosa. The risk of recurrence does not correlate with resection margin status.
  Multiple recurrences may occur over a period of many years. Rarely, there is progression to invasive PD during the follow-up period.
  Minimal dermal invasion (<1 mm), with rare exceptions, does not appear to affect prognosis, whereas tumors with deeper invasion may spread to inguinal nodes and other sites with a potentially fatal outcome. One study found that invasion did not increase the risk of local recurrence.
  Other findings that may increase the risk of local recurrence include acantholysis within the epidermal tumor and her-2/neu expression.

References

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Kohler, S., Rouse, R. V., Smoller, B. R. The differential diagnosis of pagetoid cells in the epidermis. Mod Pathol . 1998; 11:79–82.
Lloyd, J., Evans, D. J., Flanagan, A. M. Extension of extramammary Paget disease of the vulva to the cervix. J Clin Pathol . 1999; 52:538–540.
Plaza, J. A., Torres-Cabala, C., Ivan, D., et al. HER-2/neu expression in extramammary Paget disease: A clinicopathologic and immunohistochemistry study of 47 cases with and without underlying malignancy. J Cutan Pathol . 2009; 36:729–733.
Richter, C. E., Hui, P., Buza, N., et al. HER-2/NEU overexpression in vulvar Paget disease; the Yale experience. J Clin Pathol . 2010; 63:544–547.
Sah, S. P., McCluggage, W. G. Florid vulval Paget disease exhibiting p16 immunoreactivity and mimicking classic VIN. Int J Gynecol Pathol . 2013; 32:221–227.
Shaco-Levy, R., Bean, S. M., Vollmer, R. T., et al. Paget disease of the vulva: A histochemical study of 56 cases correlating pathologic features and disease course. Int J Gynecol Pathol . 2010; 29:69–78.
Wilkinson, E. J., Brown, H. M. Vulvar Paget disease of urothelial origin: A report of three cases and a proposed classification of vulvar Paget disease. Hum Pathol . 2002; 33:549–554.
Zhang, C., Zhang, P., Sung, J., et al. Overexpression of p53 is correlated with stromal invasion in extramammary Paget's disease of the vulva. Hum Pathol . 2003; 34:880–885.

Carcinoma of Bartholin's Gland ( Figs. 2.29 – 2.30 )


  These tumors, which account for <5% of vulvar carcinomas, occur in the reproductive and postmenopausal age groups; the median age in the largest series was 50 years. HPV has been found in Bartholin's gland carcinomas of squamous and transitional type.


Fig. 2.29 In situ and invasive squamous cell carcinoma of Bartholin's gland. The Bartholin's duct (lumen, lower right) is lined focally by squamous cell carcinoma in situ (top center and top right). Invasive squamous cell carcinoma is present in lower left. Note residual Bartholin's gland acini.


Fig. 2.30 Adenoid cystic carcinoma of Bartholin's gland.
  Chamlian's and Taylor's criteria for the diagnosis are: 1) transition between the normal gland and tumor; or 2) the tumor involves the area of Bartholin's gland, is histologically compatible with Bartholin origin, and there is no evidence of a primary tumor elsewhere.
  The presentation may include a mass, pain, pruritis, bleeding, discharge, or combinations thereof. In as many as 50% of patients, there is an initial misdiagnosis of Bartholin's gland cyst or abscess, resulting in diagnostic delay. In a large series, the FIGO stages were I in 25%, II in 42%, III in 28%, and IV in 5%.
  The approximate frequencies of the most common histologic subtypes are: squamous cell carcinoma (which rarely is in situ), 40%; adenocarcinoma NOS, 25%; and adenoid cystic carcinoma (ACC), 12%.
  Rarer types have included adenosquamous carcinoma, transitional cell carcinoma, epithelial–myoepithelial carcinoma, and undifferentiated carcinoma, including small cell neuroendocrine carcinoma (one with paraganglioma-like features). Single examples of Merkel cell carcinoma, clear cell adenocarcinoma, and a salivary gland-type basal cell adenocarcinoma have also been reported.
  In one large series, 40% of patients had nodal spread. Distant metastases (lungs, bone) may also occur, particularly in ACCs.
  The 5-year survival rate (after wide local excision, inguinal lymphadenectomy, and in some cases, irradiation) was approximately 85% (all histologic subtypes) in two series. Patients with ACCs may have multiple local recurrences and distant metastases occurring over many years, with a 10-year survival of 60%.

References

Balat, Ö., Edwards, C. L., Delclos, L. Advanced primary carcinoma of the Bartholin gland: Report of 18 patients. Eur J Gynaecol Oncol . 2001; 22:46–49.
Chamlian, D. L., Taylor, H. B. Primary carcinoma of Bartholin's gland. A report of 24 patients. Obstet Gynecol . 1972; 39:489–494.
Copeland, L. J., Sneige, N., Gershenson, D. M., et al. Adenoid cystic carcinoma of Bartholin gland. Obstet Gynecol . 1986; 67:115–120.
Copeland, L. J., Sneige, N., Gershenson, D. M., et al. Bartholin gland carcinoma. Obstet Gynecol . 1986; 67:794–801.
Félix, A., Moura Nunes, J. F., Soares, J. Salivary gland-type basal cell adenocarcinoma of presumed Bartholin's gland origin. Int J Gynecol Pathol . 2002; 21:194–197.
Felix, J. C., Cote, R. J., Kramer, E. E. W., et al. Carcinoma of Bartholin's gland. Histogenesis and the etiological role of human papillomavirus. Am J Pathol . 1993; 142:925–933.
Jones, M. A., Mann, E. W., Caldwell, C. L., et al. Small cell neuroendocrine carcinoma of Bartholin's gland. Am J Clin Pathol . 1990; 94:439–442.
Khoury-Collado, F., Elliott, K. S., Lee, Y., et al. Merkel cell carcinoma of the Bartholin's gland. Gynecol Oncol . 2005; 97:928–931.
Lim, K. C. -K., Thompson, I. W., Wiener, J. J. A case of primary clear cell adenocarcinoma of Bartholin's gland. BJOG . 2002; 109:1305–1307.
McCluggage, W. G., Aydin, N. E., Wong, N. A. C. S., et al. Low-grade epithelial–myoepithelial carcinoma of Bartholin gland: report of 2 cases of a distinctive neoplasm arising in the vulvovaginal region. Int J Gynecol Pathol . 2009; 28:286–292.
Yang, S. V., Lee, J., Kim, W., et al. Adenoid cystic carcinoma of the Bartholin's gland: Report of two cases and review of the literature. Gynecol Oncol . 2006; 100:422–425.

Other Adenocarcinomas and Related Tumors

Adenocarcinoma of Mammary Type ( Fig. 2.31 )


Fig. 2.31 Mammary-type adenocarcinoma of the vulva. The tumor grows in a trabecular and cord-like pattern beneath a normal epidermis (extreme right).

  Rare vulvar adenocarcinomas that resemble primary mammary carcinomas likely arise directly from mammary-like glands in this site or from ectopic breast tissue ( Chapter 1 ). Rarely these patients have had BRCA mutations.
  The patients are usually in the late reproductive and postmenopausal age groups. The tumors are often clinically malignant, including inguinal lymph node involvement.
  Most tumors resemble typical invasive ductal carcinomas, although rare mucinous (colloid) carcinomas, invasive lobular (or tubulolobular) carcinomas, and in situ ductal carcinomas have been reported. Pagetoid involvement of the overlying epidermis occurs in rare cases. The tumors are typically ER+, PR+, and GCDFP+.
  The differential is with primary vulvar apocrine carcinomas and metastatic carcinoma from the breast. Absence of a history of primary breast carcinoma and an association with ectopic breast tissue or mammary-like glands facilitate the diagnosis. ER+ and PR+ staining favors a breast-type carcinoma over one of cutaneous adnexal origin.

Adenocarcinomas of Skin Appendage Origin ( Fig. 2.32 )


Fig. 2.32 Mucinous adenocarcinoma of the vulva. Nests of tumor cells lie within abundant extracellular mucin.

  Vulvar adenocarcinomas of suspected or proven eccrine origin have included mucinous adenocarcinomas with abundant intra- and extracellular mucin (and in one case, neuroendocrine differentiation); clear cell hidradenocarcinoma; eccrine porocarcinoma; malignant eccrine spiradenoma (including one with carcinosarcomatous transformation); microcystic adnexal carcinoma; and an adenocarcinoma arising in a chondroid syringoma.
  In addition to apocrine carcinomas that may arise from mammary-type glands (see previous section), some vulvar apocrine carcinomas may arise from apocrine sweat glands.
  Some vulvar adenosquamous carcinomas have resembled extravulvar tumors of presumed sweat gland or hair sheath origin. The tumors are aggressive with a fatal outcome in 80% of patients.
  Rare vulvar sebaceous carcinomas have been reported.

Rare Miscellaneous Adenocarcinomas, Malignant Myoepithelioma, and Carcinoid Tumor


  Rare vulvar adenocarcinomas or adenosquamous carcinomas have been postulated to be of cloacogenic origin. Some have had enteric differentiation, including goblet cells. Other rare types have included:

•  A tumor resembling a polymorphous low-grade adenocarcinoma of salivary gland origin involved the vulva and vagina of a 32-year-old woman. It was initially misdiagnosed as an adenoid cystic carcinoma.
•  Rare vulvar adenocarcinomas have a putative origin from Skene's glands. Two were adenoid cystic carcinomas and a third was prostatic-type adenocarcinoma that was PSA+.
•  An encapsulated solid and papillary carcinoma with neuroendocrine differentiation occurred in a 40-year-old woman.
  Two malignant myoepitheliomas of the vulva were composed of epithelioid and/or spindle cells (and in one, squamous cells) with nuclear pleomorphism and brisk mitotic activity. The lesional cells stained with both epithelial and myoid markers.
  Srivastava et al. reported three clear cell vulvar carcinoid tumors in middle-aged women. The tumors were composed exclusively of clear cells arranged in nests separated by fibrovascular septa. The tumor cells were chromogranin+ and NSE+. There was no evidence of malignant behavior on follow-up.

References

Adenocarcinoma of mammary type
Abbott, J. J., Ahmed, I. Adenocarcinoma of mammary-like glands of the vulva. Report of a case and review of the literature. Am J Dermatopathol . 2006; 28:127–133.
Castro, C. Y., Deavers, M. Ductal carcinoma in-situ arising in mammary-like glands of the vulva. Int J Gynecol Pathol . 2001; 20:277–283.
Chung-Park, M., Liu, C. Z., Giampoli, E. J., et al. Mucinous adenocarcinoma of ectopic breast tissue of the vulva. Arch Pathol Lab Med . 2002; 126:1216–1218.
Fernandez-Figueras, T., Michal, M., Kazakov, D. V. Mammary-type tubulolobular carcinoma of anogenital mammary-like glands with prominent stromal elastosis. [Letter] Am J Surg Pathol . 2010; 34:1224–1226.
Lamb, A., Darus, C. J., Skripenova, S., et al. Association of primary breast cancer of the vulva with herediitary breast and ovarian cancer. J Clin Oncol . 2013; 31:e231–e232.

Adenocarcinomas of skin appendage origin
Adegboyega, P. A. Eccrine porocarcinoma of the vulva: A case report and review of the literature. Int J Gynecol Pathol . 2011; 30:95–100.
Alsaad, K. O., Obaidat, N., Dube, V., et al. Vulvar apocrine adenocarcinoma: A case with nodal metastasis and intranodal mucinous differentiation. Pathol Res Pract . 2009; 205:131–135.
Biedrzycki, O. J., Rufford, B., Wilcox, M., et al. Malignant clear cell hidradenoma of the vulva: Report of a unique case and review of the literature. Int J Gynecol Pathol . 2008; 27:142–146.
Buhl, A., Landow, S., Lee, Y. -C., et al. Microcystic adnexal carcinoma of the vulva. Gynecol Oncol . 2001; 82:571–574.
Genner, O., Piura, B., Segal, S., et al. Adenocarcinoma arising in a chondroid syringoma of vulva. Int J Gynecol Pathol . 2003; 22:398–400.
Ghamande, S. A., Kasnzica, J., Griffiths, T., et al. Mucinous adenocarcinomas of the vulva. Gynecol Oncol . 1995; 57:117–120.
Hou, JL., Wu, L. Y., Zhang, H. T., et al. Clinicopathologic characteristics of 12 patients with vulvar sweat gland carcinoma. Int J Gynecol Cancer . 2010; 20:874–878.
Khan, Z., Misra, G., Fiander, A. N., et al. Sebaceous carcinoma of the vulva. BJOG . 2003; 110:227–228.
Rahilly, M. A., Beattie, G. J., Lessells, A. M. Mucinous eccrine carcinoma of the vulva with neuroendocrine differentiation. Histopathology . 1995; 27:82–86.
Underwood, J. W., Adcock, L. L., Okagaki, T. Adenosquamous carcinoma of skin appendages (adenoid squamous cell carcinoma, pseudoglandular squamous cell carcinoma, adenoacanthoma of sweat gland of Lever) of the vulva. Cancer . 1978; 42:1851–1858.
Wick, M. R., Goellner, J. R., Wolfe, J. T., III., et al. Vulvar sweat gland carcinomas. Arch Pathol Lab Med . 1985; 109:43–47.

Rare miscellaneous adenocarcinomas, malignant myoepithelioma, and carcinoid tumor
Kennedy, J. C., Majmudar, B. Primary adenocarcinoma of the vulva, possibly cloacogenic. A report of two cases. J Reprod Med . 1993; 38:113–116.
Meenakshi, M., McCluggage, W. G. Myoepithelial neoplasms involving the vulva and vagina: Report of 4 cases. Hum Pathol . 2009; 40:1747–1753.
Pongtippan, A., Malpica, A., Levenback, C., et al. Skene's gland adenocarcinoma resembling prostatic adenocarcinoma. Int J Gynecol Pathol . 2003; 23:71–74.
Rhatigan, R. M., Mojadidi, Q. Adenosquamous carcinomas of the vulva and vagina. Am J Clin Pathol . 1973; 59:208–217.
Rodriguez, A., Isaac, M. A., Hidalgo, E., et al. Villoglandular adenocarcinoma of the vulva. Gynecol Oncol . 2001; 83:409–411.
Srivastava, S. A., Wang, Y., Vallone, J., et al. Primary clear cell carcinoid tumors of the vulva. Am J Surg Pathol . 2012; 36:1371–1375.
Ueda, Y., Mandai, M., Matsumura, N., et al. Adenoid cystic carcinoma of Skene glands: A rare origin in the female genital tract and the characteristic clinical course. Int J Gynecol Pathol . 2012; 31:506–600.
Willén, R., Békássy, Z., Carlén, B., et al. Cloacogenic adenocarcinoma of the vulva. Gynecol Oncol . 1999; 74:298–301.
Young, S., Leon, M., Talerman, A., et al. Polymorphous low-grade adenocarcinoma of the vulva and vagina: A tumor resembling adenoid cystic carcinoma. Int J Surg Pathol . 2003; 11:43–49.
Zhang, C., Quddus, M. R., Sung, C. J., et al. Vulvar encapsulated solid papillary carcinoma with neuroendocrine differentiation: A case report. Int J Surg Pathol . 2012; 20:97–100.

Basal Cell Carcinoma ( Fig. 2.33 )


  Basal cell carcinomas (BCCs) account for only 2–3% of vulvar carcinomas. They typically occur in elderly women; the mean age in a large series was 76 years. A third of women in one series had a synchronous or metachronous extravulvar BCC. Some vulvar BCCs have abutted another, sometimes more significant tumor, such as squamous cell carcinoma or Paget's disease.


Fig. 2.33 Basal cell carcinoma. Solid (right) and adenoid (left) patterns are seen.
  A localized irritation, soreness, or pruritis, and a nodular, polypoid, ulcerated, pigmented or nonpigmented lesion, up to 6.5 cm in size, is usually found on the labium majus.
  Vulvar BCCs are histologically identical to typical cutaneous BCCs, and can include superficial, solid, and adenoid types. Rare basosquamous cell carcinomas (mixed basal cell-squamous cell carcinomas) have been reported. BCCs tested for HPV have been negative.
  The differential diagnosis is with basaloid squamous carcinomas (see corresponding heading) and trichogenic tumors ( Chapter 1 ).
  Vulvar BCCs are usually cured by wide local excision. Occasional tumors recur locally and rare tumors have metastasized to regional lymph nodes or have spread hematogenously and/or have been fatal.

References

Benedet, J. L., Miller, D. M., Ehlen, T. G., et al. Basal cell carcinoma of the vulva: Clinical features and treatment results in 28 patients. Obstet Gynecol . 1997; 90:765–768.
Feakins, R. M., Lowe, D. G. Basal cell carcinoma of the vulva. A clinicopathologic study of 45 cases. Int J Gynecol Pathol . 1997; 16:319–324.
Gibson, G. E., Ahmed, I. Perianal and genital basal cell carcinoma: A clinicopathologic review of 51 cases. J Am Acad Dermatol . 2001; 45:68–71.
Kimball, K. J., Straughn, J. M., Conner, M. G., et al. Recurrent basosquamous cell carcinoma of the vulva. Gynecol Oncol . 2006; 102:400–402.
Mulvany, N. J., Rayoo, M., Allen, D. G. Basal cell carcinoma of the vulva: A case series. Pathology . 2012; 44:528–533.
Regauer, S., Nogales, F. F. Vulvar trichogenic tumors. A comparative study with vulvar basal cell carcinoma. Am J Surg Pathol . 2005; 29:479–484.

Merkel Cell Tumor


  Rare vulvar Merkel cell tumors have occurred in women 28 to 79 years of age who usually presented with a labial mass.
  The tumors pathologically resemble Merkel cell tumors in other sites. One otherwise typical tumor showed both squamous and glandular differentiation.
  The tumors are more aggressive than their extravulvar counterparts as almost all have had widespread metastases and a fatal clinical course.
  One vulvar neuroendocrine tumor, which lacked the typical features of Merkel cell tumor, was reported as a ‘neuroendocrine carcinoma with paraganglioma-like features.’

References

Gil-Moreno, A., Garcia-Jimenez, A., Gonzalez-Bosquet, J., et al. Merkel cell carcinoma of the vulva. Gynecol Oncol . 1997; 64:526–532.
Hierro, I., Blanes, A., Matilla, A., et al. Merkel cell (neuroendocrine) carcinoma of the vulva. A case report with immunohistochemical and ultrastructural findings and review of the literature. Pathol Res Pract . 2000; 196:503–509.
Nuciforo, P. G., Fraggetta, F., Fasani, R., et al. Neuroendocrine carcinoma of the vulva with paraganglioma-like features. [Letter]. Histopathology . 2004; 44:304–306.
Scurry, J., Brand, A., Planner, R., et al. Vulvar Merkel cell tumor with glandular and squamous differentiation. Gynecol Oncol . 1996; 62:292–297.

Malignant Melanoma


Clinical features ( Fig. 2.34 )


Fig. 2.34 Malignant melanoma. The tumor is pigmented.

  These tumors, which account for 5–10% of vulvar cancers (and 3–7% of melanomas), are most common in older women, with a mean age of >60 years in most studies, but may occur as early as the second decade of life.
  Wechter et al. found that 55% of their patients had atypical extravulvar nevi and 15% of patients had a family history of cutaneous melanoma.
  A mass, pruritus, bleeding, or a change in a pre-existing lesion are the most common presentations. The usual locations, in descending order of frequency, are the labia majora, the clitoris, and the labia minora; only 15% arise in hair-bearing areas. Multifocal lesions occur in one- to two-thirds of cases.
  The typical lesion is a plaque or nodule, often with a serpiginous border, that may be diffusely pigmented, focally pigmented, or nonpigmented. Ulceration is present in almost half the tumors. The clinical appearance can be mimicked by a benign pigmented lesion ( Chapter 1 ).
  As many as 70% of patients have stage III or IV disease at presentation.

Microscopic features ( Figs. 2.35 – 2.36 )


Fig. 2.35 Malignant melanoma, lentiginous in situ component.


Fig. 2.36 Malignant melanoma, invasive spindle-cell component.

  In the largest study, 57% were of mucosal acral lentiginous type, 22% were of nodular type, 12% were unclassified, and 4% were of superficial spreading type (an order opposite to that of extravulvar cutaneous melanomas). Rare vulvar melanomas take the form of a malignant blue nevus.
  The invasive component is of spindle cell type, epithelioid type, or mixed spindle–epithelioid type in approximately equal proportions. Cytoplasmic melanin can vary from copious to absent. Striking neurotropism and/or desmoplasia is common in lentiginous tumors.
  Microscopic evidence of an associated nevus, melanosis, or atypical melanocytic hyperplasia may be present. The origin of vulvar melanomas from a pre-existing nevus, however, is much less common than in extravulvar melanomas; such tumors are usually of superficial spreading type, or less commonly, of nodular type.
  HPV, including type 16, has been demonstrated in occasional cases.
  The depth of invasion should be assessed by at least one of the following:

•  Breslow's method. Raber et al. found that 14.6% of tumors were ≤0.75 mm, 14.6% were 0.76–1.5 mm, 25.6% were 1.51–3 mm, 11% were 3.01–4 mm, and 34.2% were >4 mm. The mean Breslow depth in another study (Wechter et al.) was 2.8 mm.
•  Clark's levels. Raber et al. found that 2.4% were level I, 12.2% were level II, 17.1% were level III, 51.2% were level IV, and 17.1% were level V.
•  The modification of Clark's levels proposed by Chung et al. for vulvar MMs: level II, invasion <1 mm; level III, 1–2 mm invasion; level IV, >2 mm invasion (levels I and V are as described by Clark). Chung et al. found that 24% of tumors were level II, 15% were level III, 46% were level IV, and 15% were level V.
  The American Joint Committee on Cancer staging (AJCC) for melanomas incorporates depth. Stage I: <1.5 mm depth or Clark's level III and no metastases; stage II: >1.5 but <4 mm or Clark's level IV and no metastases, stage III: >4 mm or Clark's level V or nodal metastases; stage IV: distant metastases.

Differential diagnosis


  Atypical genital nevi and dysplastic nevi ( Chapter 1 ).
  Paget's disease or pagetoid VIN vs radial growth phase of malignant melanoma; the differential features are considered under those headings. The tumor cells of both these lesions can contain melanin pigment, and thus its presence does not aid in the differential diagnosis.
  Poorly differentiated SqCC or adenocarcinoma (vs the invasive component of an epithelioid melanoma) and sarcoma (vs spindle cell melanoma). The presence of a malignant junctional component, cytoplasmic melanin pigment, and positivity for S100 and HMB-45 facilitate the diagnosis.
  As in other sites, the diagnosis of melanoma should always be considered when a poorly differentiated malignant vulvar tumor proves difficult to classify on microscopic examination.

Behavior and prognostic factors


  Local recurrence (which may include the urethra), often as melanoma in situ, occurs in as many as one-third of cases due to persistence of the radial growth phase.
  Lymphatic and hematogenous spread is common.
  The 5-year survival in most studies has varied from 28–50%; it was 47% in the largest study.
  Prognostic factors (many of which are interrelated) include:

•  Depth of invasion (which correlates highly with lymph node spread). Raber et al. found 5-year survivals for tumors >1.5 mm deep to be 20% compared to 69% for tumors ≤1.5 mm. The 10-year survival rates by Clark's levels in a Mayo Clinic study were 100% (level II), 83% (level III), 65% (level IV), and 23% (level V).
•  Lymph node involvement. In a SEER study, those with 0, 1, and 2 or more positive lymph nodes had survival rates of 68%, 29%, and 19.5%, respectively.
•  AJCC staging. This was the only independent prognostic factor in a large GOG study of vulvar melanomas.
•  Other factors correlating with poor prognosis and/or lymph node spread have included older patient age, black ethnicity, FIGO stage, ulceration, a clitoral or bilateral location, multifocality, tumor size, clinical amelanosis, epithelioid cell type, mitotic rate, lymphovascular space invasion, and nondiploidy.

References

Benda, J. A., Platz, C. E., Anderson, B. Malignant melanoma of the vulva: A clinical-pathologic review of 16 cases. Int J Gynecol Pathol . 1986; 5:202–216.
Bradgate, M. G., Rollason, T. P., McConkey, C. C., et al. Malignant melanoma of the vulva: A clinicopathological study of 50 women. Br J Obstet Gynaecol . 1990; 97:124–133.
Chung, A. F., Woodruff, J. M., Lewis, J. L., Jr. Malignant melanomas of the vulva. A report of 44 cases. Obstet Gynecol . 1975; 45:638–646.
Lotem, M., Anteby, S., Peretz, T., et al. Mucosal melanoma of the female genital tract is a multifocal disorder. Gynecol Oncol . 2003; 88:45–50.
Phillips, G. L., Bundy, B. N., Okagaki, T., et al. Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group. Cancer . 1994; 73:2626–2632.
Raber, G., Mempel, V., Jackisch, C., et al. Malignant melanoma of the vulva. Report of 89 patients. Cancer . 1996; 78:2353–2358.
Ragnarsson-Olding, B. K., Kanter-Lewensohn, L. R., Lagerlof, B., et al. Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females. Clinical observations and histopathologic features. Cancer . 1999; 86:1273–1284.
Ragnarsson-Olding, B. K., Nilsson, B. R., Kanter-Lewensohn, L. R., et al. Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females. Predictors of survival. Cancer . 1999; 86:1285–1293.
Raspagliese, F., Ditto, A., Paladini, D., et al. Prognostic indicators in melanoma of the vulva. Ann Surg Oncol . 2000; 7:738–742.
Rohwedder, A., Philips, B., Malfetano, J., et al. Vulvar malignant melanoma associated with human papillomavirus DNA. Am J Dermatopathol . 2002; 24:230–240.
Scheistroen, M., Trope, C., Kaern, J., et al. Malignant melanoma of the vulva. Evaluation of prognostic factors with emphasis on DNA ploidy in 75 patients. Cancer . 1995; 75:72–80.
Spatz, A., Zimmermann, U., Bachollet, D., et al. Malignant blue nevus of the vulva with late ovarian metastases. Am J Dermatopathol . 1998; 20:408–412.
Sugiyama, V. E., Chan, J. K., Shin, J. Y., et al. Vulvar melanoma. A multivariable analysis of 644 patients. Obstet Gynecol . 2007; 110:296–301.
Wechter, M. E., Gruber, S. B., Haefner, H. K., et al. Vulva melanoma: A report of 20 cases and review of the literature. J Am Acad Dermatol . 2004; 50:554–562.

Benign and Malignant Smooth Muscle Tumors


Clinical features


  Vulvar smooth muscle tumors are uncommon and occur over a wide age range, but most occur in the fourth and fifth decades. They usually present as a painless, sometimes longstanding, mass that may clinically mimic a Bartholin's cyst.
  Tumors in pregnant women may enlarge during pregnancy, consistent with their usual content of estrogen and progesterone receptors.
  In occasional cases, a vulvar mass present for years has rapidly enlarged. The histological findings in some of these tumors have suggested transformation of a leiomyoma to a leiomyosarcoma.
  Rare cases of vulvar leiomyomatosis, some familial, have been reported. The vulvar tumors are multiple and ill-defined; there may be prominent clitoral involvement. Some patients have had synchronous or metachronous leiomyomatosis of the esophagus or urinary bladder and/or Alport's syndrome.

Pathological features ( Figs. 2.37 – 2.39 )


Fig. 2.37 Myxoid leiomyoma.


Fig. 2.38 Leiomyosarcoma, spindle-cell type.


Fig. 2.39 Leiomyosarcoma, epithelioid-cell type.

  Tumors that are benign or of low malignant potential tend to be small (3–5 cm) and well circumscribed, whereas leiomyosarcomas (LMS) tend to be >5 cm and infiltrative. Leiomyomas usually have a whorled sectioned surface; LMS may be focally hemorrhagic and/or necrotic.
  Most tumors are composed of spindle cells growing in intersecting fascicles. Less commonly, there is a prominent or pure component of epithelioid cells with eosinophilic or clear cytoplasm.
  A myxoid and/or hyaline stroma (‘myxohyaline’ pattern) is disproportionately common, and may be even more common in pregnancy. The neoplastic cells within this stroma may result in a plexiform pattern.
  The histologic distinction of leiomyomas with atypical features from LMS has not been completely established because of their rarity.

•  Tumors with three or more of the following are considered LMS: ≥5 cm in size, infiltrative margins, ≥5 mf/10 hpf, and moderate to severe atypia. Additionally, tumor cell necrosis, especially when associated with any of the other features, should raise concern for LMS.
•  ‘Atypical smooth muscle tumor’ is appropriate for tumors with atypia, mitotic activity, and/or infiltrative margins that do not fulfill LMS criteria. Such tumors should be excised with a 1 cm margin of normal tissue and receive long-term follow-up because they can recur locally, sometimes years later. The recurrent tumor may be more atypical, mitotic, or infiltrative than the primary tumor.
  The differential diagnosis (see Nielsen et al.) includes aggressive angiomyxoma, angiomyofibroblastoma, myxoid malignant fibrous histiocytoma, nerve sheath tumors, glomus tumors, myoepithelial tumors, and malignant melanoma.

References

Fred-Oginski, W., Lovecchio, J. L., Farahani, G., et al. Malignant myxoid sarcoma of the Bartholin gland in pregnancy. Am J Obstet Gynecol . 1995; 175:1633–1635.
Newman, P. L., Fletcher, C. D. M. Smooth muscle tumours of the external genitalia: Clinicopathological analysis of a series. Histopathology . 1991; 18:532–539.
Nielsen, G. P., Rosenberg, A. E., Koerner, F. C., et al. Smooth-muscle tumors of the vulva: A clinicopathological study of 25 cases and review of the literature. Am J Surg Pathol . 1996; 20:779–793.
Nucci, M. R., Fletcher, C. D. M. Vulvovaginal soft tissue tumors: Update and review. Histopathology . 2000; 36:97–108.
Tavassoli, F. A., Norris, H. J. Smooth muscle tumors of the vulva. Obstet Gynecol . 1979; 53:213–217.

Other Sarcomas

Rhabdomyosarcoma


  The vulva is the rarest site for these tumors in the lower female genital tract, the most common site being the vagina ( Chapter 3 ) followed by the uterine cervix. Some tumors with vulvar involvement may arise in the adjacent perineum.
  The tumors almost always occur in the first two decades of life. Embryonal rhabdomyosarcomas (sarcoma botryoides) are the most common type but alveolar rhabdomyosarcomas also occur. The latter type appears to be more common in adult women.
  The prognosis is good if treated by chemotherapy and excision. In one study, eight of nine patients were disease-free at 4 to 10 years and one was alive with probable disease at 2.5 years. Adult patients may have a worse prognosis.

Liposarcoma


  These rare tumors usually occur in middle-aged women who present with a painless vulvar mass.
  In the only series of vulvar liposarcomas, five of the six cases were >3 cm in maximal dimension and three were grossly well demarcated.

•  Four tumors were well-differentiated liposarcoma/atypical lipoma based on variation in adipocyte size, adipocyte nuclear atypia, and occasional lipoblasts.
•  The other two tumors had an unusual appearance with an admixture of neoplastic bland spindle and round cells, adipocytes showing variation in size, and numerous bivacuolated lipoblasts.
•  None of the six tumors recurred after local excision, although the follow-up was limited.
  Rare examples of pleomorphic and myxoid leiomyosarcoma of the vulva have been reported. One myxoid leiomyosarcoma, in a 15-year-old girl, recurred as a fatal poorly differentiated round cell liposarcoma.

Epithelioid Sarcoma and Malignant Extrarenal Rhabdoid Tumor


  Most of these rare sarcomas arising in the vulva, Bartholin's gland, perineum, and pelvic soft tissues have been of proximal type (PES). Even rarer are vulvar tumors reported as malignant extrarenal rhabdoid tumor (MERT).

•  PESs and MERTs have similar morphological, immunohistochemical, and ultrastructural features, including an absence of the INI1 gene product, leading some authors to consider them identical.
•  Contrarily, Tholpady et al. note that MERTs, unlike PESs, have an exclusive population of rhabdoid cells, lack immunoreactivity for dysadherin, and are almost always rapidly fatal.
•  The following text summarizes the features of the vulvar tumors reported in the literature as PES.
  The tumors usually present in the reproductive age group as a subcutaneous and/or deep soft tissue mass.
  The tumor cells, which are often in a multinodular pattern, have prominent epithelioid and/or rhabdoid features and marked cytologic atypia.
  Necrosis is common, but the granuloma-like pattern of typical epithelioid sarcoma is present only rarely. Prominent granulomatous changes can result in an initial misdiagnosis of an inflammatory lesion.
  PESs typically stain for cytokeratin, epithelial membrane antigen, vimentin, and as noted above, dysadherin; some tumors are also CD34+.
  PESs are more aggressive than typical epithelioid sarcomas, often with early lymphatic or hematogenous spread, and a fatal outcome in 50% of the cases.

Rare Sarcomas


  Approximately 40 vulvar cases of dermatofibrosarcoma protuberans have been reported.

•  The patients, who have ranged from 22–83 (mean 44) years of age, usually present with a non-tender vulvar mass, most commonly involving a labium majus.
•  The tumors have ranged up to 15 cm in size and are similar microscopically and immunohistochemically to their extravulvar counterparts. About 10% of the tumors have contained foci of fibrosarcoma in the primary or recurrent tumor.
•  Approximately 30% of the tumors recur locally; only a few have metastasized. Some tumors have responded to imatinib therapy.
  Cases have been reported of rare vulvar examples of malignant fibrous histiocytoma (including the giant cell variant), malignant schwannoma, fibrosarcoma (including the low-grade myxoid variant), vascular tumors (angiosarcoma, Kaposi's sarcoma, hemangioendothelioma, hemangiopericytoma), synovial sarcoma (typical and monophasic), alveolar soft part sarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor, myxoid and mesenchymal chondrosarcomas, pleomorphic hyalinizing angiectatic tumor, malignant myoepithelioma, and ‘myofibroblastic sarcoma’.
  Malignant vulvar phyllodes tumors are much rarer than their benign counterparts ( Chapter 1 ). These tumors can exhibit marked atypia and mitotic activity of the stromal component, heterologous elements, and sarcomatous overgrowth.

References

Rhabdomyosarcoma
Andrassy, R. J., Hays, D. M., Raney, R. B., et al. Conservative surgical management of vaginal and vulvar pediatric rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg . 1995; 30:1034–1037.
Copeland, L. J., Sneige, N., Stringer, A., et al. Alveolar rhabdomyosarcoma of the female genitalia. Cancer . 1985; 56:849–855.
Ferguson, S. E., Gerald, W., Barakat, R. R., et al. Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults. Am J Surg Pathol . 2007; 31:383–389.
Hays, D. M., Shimada, H., Raney, R. B., Jr., et al. Clinical staging and treatment results in rhabdomyosarcoma of the female genital tract among children and adolescents. Cancer . 1988; 61:1893–1903.

Liposarcoma
Brooks, J. J., LiVolsi, V. A. Liposarcoma presenting on the vulva. Am J Obstet Gynecol . 1987; 156:73–75.
Donnellan, R., Moodley, M. Vulval myxoid liposarcoma. Int J Gynecol Cancer . 2001; 11:321–322.
Nucci, M. R., Fletcher, C. D. M. Liposarcoma (atypical lipomatous tumors) of the vulva: A clinicopathologic study of six cases. Int J Gynecol Pathol . 1998; 17:17–23.

Epithelioid sarcoma and malignant extrarenal rhabdoid tumor
Guillou, L., Wadden, C., Coindre, J. -M., et al. ‘Proximal-type’ epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol . 1997; 21:130–146.
Perrone, T., Swanson, P. E., Twiggs, L., et al. Malignant rhabdoid tumor of the vulva: Is distinction from epithelioid sarcoma possible? A pathologic and immunohistochemical study. Am J Surg Pathol . 1989; 13:848–858.
Tholpady, A., Lonergan, C. L., Wick, M. R. Proximal-type epithelioid sarcoma of the vulva: Relationship to malignant extrarenal rhabdoid tumor. Int J Gynecol Pathol . 2010; 29:600–604.

Rare sarcomas
Edelweiss, M., Malpica, A. Dermatofibrosarcoma protuberans of the vulva: A clinicopathologic and immunohistochemical study of 13 cases. Am J Surg Pathol . 2010; 34:393–400.
El Damellawy, D., Saleh, R., Daya, D., et al. Malignant giant cell tumor of the vulva. Int J Gynecol Pathol . 2010; 29:93–97.
Fakokunde, A., Yoong, W., Bajekal, N. Vulva hemangiopericytoma: Case report and literature review. J Obstet Gynaecol . 2004; 24:94–95.
Fong, Y. E., Lopez-Terrada, D., Zhai, Q. J. Primary Ewing sarcoma/peripheral primitive neuroectodermal tumor of the vulva. Hum Pathol . 2008; 39:1535–1539.
Fu, L., Lau, S., Roy, I., et al. Phyllodes tumor with malignant stromal morphology of the vulva: A case report and review of the literature. Int J Gynecol Pathol . 2011; 30:198–202.
Guirguis, A., Kanbour-Shakir, A., Kelley, J. Epithelioid angiosarcoma of the mons after chemoradiation for vulvar cancer. Int J Gynecol Pathol . 2007; 26:265–268.
Hinze, P., Feyler, S., Berndt, J., et al. Malignant myoepithelioma of the vulva resembling a rhabdoid tumor. Histopathology . 1999; 25:50–54.
Laartz, B. W., Cooper, C., Degryse, A., et al. Wolf in sheep's clothing: advanced Kaposi sarcoma mimicking vulvar abscess. South Med J . 2005; 98:475–477.
Lin, J., Yip, K. M. H., Maffulli, N., et al. Extraskeletal mesenchymal chondrosarcoma of the labium majus. Gynecol Oncol . 1996; 60:492–493.
McCluggage, W. G., Sumathi, V. P., Nucci, M. R., et al. Ewing family of tumours involving the vulva and vagina: Report of a series of four cases. J Clin Pathol . 2007; 60:674–680.
Nirenberg, A., Östör, A. G., Slavin, J., et al. Primary vulvar sarcomas. Int J Gynecol Pathol . 1995; 14:55–62.
Roth, T. M., Fratkin, J., Woodring, T. C., et al. Low-grade myofibroblastic sarcoma of the vulva. Gynecol Oncol . 2004; 92:361–364.
Santa Cruz, M. R., Proctor, L., Thomas, D. B., et al. Extraskeletal myxoid chondrosarcoma: A report of a gynecologic case. Gynecol Oncol . 2005; 98:498–501.
Santala, M., Suonio, S., Syrjanen, K., et al. Malignant fibrous histiocytoma of the vulva. Gynecol Oncol . 1987; 27:121–126.
Shen, J. T., d'Ablaing, G., Morrow, C. P. Alveolar soft part sarcoma of the vulva: Report of a first case and review of literature. Gynecol Oncol . 1982; 13:120–128.
Strayer, S. A., Yum, M. N., Sutton, G. P. Epithelioid hemangioendothelioma of the clitoris: A case report with immunohistochemical and ultrastructural findings. Int J Gynecol Pathol . 1992; 11:234–239.
Sumathi, V. P., Fisher, C., Williams, A., et al. Synovial sarcoma of the vulva and vagina: A clinicopathologic and molecular genetic study of 4 cases. Int J Gynecol Pathol . 2011; 30:84–91.
Terada, K. Y., Schmidt, R. W., Roberts, J. A. Malignant schwannoma of the vulva. A case report. J Reprod Med . 1988; 33:969–972.

Yolk Sac Tumor and Other Germ Cell Tumors


  Eight vulvar yolk sac tumors have been reported in females 1–26 years of age. The tumors presented as a labial or clitoral mass and had a typical microscopic appearance. Three of six patients with follow-up died within a year despite excision and combination nonplatin chemotherapy.
  One vulvar choriocarcinoma has been reported in a 31-year-old woman with an elevated hCG. There was no evidence of an extravulvar tumor or ectopic gestation. Excision of the tumor and chemotherapy were curative.
  One of the two reported vulvar teratomas was in a 38-year-old woman. It resembled a grade 3 immature ovarian teratoma and had spread to an inguinal lymph node. There was no evidence of disease 18 months after combined-modality treatment. The second case was a mature teratoma that formed a pedunculated mass in a newborn and was successfully excised.

References

Çakmak, M., Sava , Ç., Özba ar, D., et al. Congenital vulvar teratoma in a newborn. J Pediatr Surg . 2001; 36:620–621.
Flanagan, C. W., Parker, J. R., Mannel, R. S., et al. Primary endodermal sinus tumor of the vulva: A case report and review of the literature. Gynecol Oncol . 1997; 66:515–518.
Mamoon, N., Mushtaq, S., Akhter, N., et al. Immature teratoma of the vulva with an inguinal lymph node metastasis: Report of a case and review of literature. Int J Gynecol Pathol . 2010; 29:197–200.
Weiss, S., Amit, A., Schwartz, M. R., et al. Primary choriocarcinoma of the vulva. Int J Gynecol Cancer . 2001; 11:251–254.

HematopoIetic Tumors


  The vulva, including the Bartholin's gland, is rarely the site of a primary lymphoma or is the initial site of involvement in women with widespread lymphoma or acute or chronic myeloblastic leukemia. Secondary vulvar involvement by either a previously diagnosed lymphoma (see Secondary Tumors) or a myelocytic or lymphocytic leukemia also occurs.
  Most primary vulvar lymphomas occur in adult women who usually present with a vulvar nodule, swelling, or induration, occasionally with localization to the clitoris or Bartholin's gland. Rare patients are HIV+ or are iatrogenically immunosuppressed. Most of the tumors have been Ann Arbor stage IE or less commonly IIE.

•  The tumors are usually diffuse large B-cell type. Rare types have included follicular large B-cell type, lymphoplasmacytic type, peripheral T-cell type, diffuse mixed cell type, plasmablastic, or Hodgkin's. A case of vulvar Hodgkin's disease occurred in a woman with long-standing Crohn's disease and recurrent anogenital fistulas.
•  A minority of patients have died of tumor despite treatment.
  One case of a solitary mastocytoma of the vulva, which occurred in a 6-year-old girl, has been reported.

References

Er ahin, Ç., Omeroglu, G., Potkul, R. K., et al. Myeloid sarcoma of the vulva as the presenting symptom in a patient with acute myeloid leukemia. Gynecol Oncol . 2007; 106:259–261.
Ferry, J. A. Lymphomas of the female genital tract. In: Extranodal lymphomas . New York: Saunders; 2011:259–281.
Shaungshoti, S., Shuangshoti, S., Pintong, J., et al. Solitary mastocytoma of the vulva: Report of a case. Int J Gynecol Pathol . 2003; 22:401–403.
Tjalma, W. A. A., Van de Velde, A. L. R., Schroyens, W. A. M. Primary non-Hodgkin's lymphoma in Bartholin's gland. Gynecol Oncol . 2002; 87:308–309.
Van den Broecke, R., Van Droogenbroek, J., Dhont, M. Vulvovaginal manifestation of acute myeloblastic leukemia. Obstet Gynecol . 1996; 88:735.
Vang, R., Madeiros, L. J., Malpica, A., et al. Non-Hodgkin's lymphoma involving the vulva. Int J Gynecol Pathol . 2000; 19:236–242.
Winnicki, M., Gariepy, G., Sauthier, P. G., et al. Hodgkin lymphoma presenting as a vulvar mass in a patient with Crohn disease: a case report and literature review. J Low Genit Tract Dis . 2009; 13:110–114.

Langerhans' Cell Histiocytosis


  The vulva is most commonly involved in patients with known systemic disease, but occasionally it is the presenting site. The latter cases are summarized here.
  The patients were 2–91 years of age, and usually presented with a nodule or mass that was occasionally ulcerated and/or pruritic.
  On post-treatment follow-up, there was no extravulvar spread in two-thirds of the cases, although in a few cases there were one or more local recurrences. In the other third of cases, the disease subsequently disseminated, with a fatal course in one case.

References

Axiotis, C. A., Merino, M. J., Duray, P. H. Langerhans cell histiocytosis of the female genital tract. Cancer . 1991; 67:1650–1660.
Montero, A. J., Diaz-Montero, C. M., Malpica, A., et al. Langerhans cell histiocytosis of the female genital tract: A literature review. Gynecol Oncol . 2003; 13:381–388.
Padula, A., Medeiros, J., Silva, E. G., et al. Isolated vulvar Langerhans cell histiocytosis: Report of two cases. Int J Gynecol Pathol . 2004; 23:278–283.

Secondary Tumors


  These tumors accounted for 8% of malignant vulvar tumors in one hospital-based series. In the largest series (Neto et al.), 90% of the patients were peri- or postmenopausal. The labium majus is most commonly involved; less common sites are the labium minus, the clitoris, an episiotomy scar, or Bartholin's gland.
  Most tumors complicated by vulvar metastases are high stage when initially diagnosed. In one series, the primary tumor and the vulvar metastases were diagnosed synchronously in 25% of cases. Rarely, vulvar metastases are the presenting manifestation of an occult primary tumor as exemplified by a urothelial carcinoma of the bladder presenting as vulvar Paget's disease.
  In the series by Neto et al., the primary site was known in 90% of cases, about half of which were of gynecologic origin and the other half of nongynecologic origin.

•  The tumors of gynecologic origin, in order of frequency, were cervical, ovarian, endometrial, and vaginal carcinomas.
•  Most of the tumors of nongynecologic origin, in order of frequency, were colorectal carcinomas, breast carcinomas, or malignant melanomas. Rare primary sites include lung, anus, bladder, urethra, and pancreas.
  The differential diagnosis of metastatic breast carcinoma includes primary mammary-type carcinomas of the vulva (see corrresponding heading). Metastatic adenocarcinomas involving the epidermis can potentially mimic Paget's disease. The paucity of singly disposed intraepidermal cells, the presence of extensive invasion, and the absence of the typical immunoprofile of Paget's disease favor metastasis.
  In the Neto et al. study, 52 of the 60 patients with follow-up died of disease within 1–81 months (median 7.5 months) of the diagnosis of the metastasis.
  Vang et al. found eight cases of metastatic lymphoma to the vulva from their own files and the literature. The most common type was diffuse large B-cell lymphoma, with rare cases of follicular small cleaved cell type, small lymphocytic type, peripheral T-cell lymphoma, and mycosis fungoides.

References

Dehner, L. P. Metastatic and secondary tumors of the vulva. Obstet Gynecol . 1973; 42:47–57.
Mazur, M. T., Hseeuh, S., Gersell, D. J. Metastases to the female genital tract: Analysis of 325 cases. Cancer . 1984; 53:1978–1985.
Neto, A. G., Deavers, M. T., Silva, E. G., et al. Metastatic tumors of the vulva: A clinopathologic study of 66 cases. Am J Surg Pathol . 2003; 27:799–804.
Reyes, M. C., Park, K. J., Lin, O., et al. Urothelial carcinoma involving the gynecologic tract: A morphologic and immunohistochemical study of 6 cases. Am J Surg Pathol . 2012; 36:1058–1065.
Vang, R., Madeiros, L. J., Malpica, A., et al. Non-Hodgkin's lymphoma involving the vulva. Int J Gynecol Pathol . 2000; 19:236–242.
Chapter 3
The Vagina


Tumor-like Lesions 

Condyloma Acuminatum 
Vaginal Adenosis 
Cysts 
Prolapse of Fallopian Tube 
Postoperative Spindle Cell Nodule 
Fibroepithelial Polyp 
Tubulosquamous Polyp 
Inflammatory and Infectious Lesions 
Endometriosis 
Ectopias and Metaplasias 
Other Tumor-like Lesions 
Benign Tumors 

Epithelial Tumors 
Mixed Tumor (Spindle Cell Epithelioma) 
Aggressive Angiomyxoma, Angiomyofibroblastoma, Cellular Angiofibroma, and Myofibroblastoma (see Chapter 1 ) 
Leiomyoma 
Rhabdomyoma 
Miscellaneous Benign Tumors 
Malignant Tumors 

Vaginal Intraepithelial Neoplasia 
Squamous Cell Carcinoma 
Transitional and Squamotransitional Cell Carcinomas 
Clear Cell Adenocarcinoma 
Endometrioid Adenocarcinoma 
Rare Adenocarcinomas 
Small Cell Carcinoma 
Embryonal Rhabdomyosarcoma 
Leiomyosarcoma 
Other Pure Sarcomas, including Extragastrointestinal Stromal Tumor 
Malignant Mixed Tumors and Synovial Sarcoma 
Malignant Melanoma 
Yolk Sac Tumor 
Hematopoietic Tumors 
Histiocytosis X 
Secondary Tumors 

Tumor-Like Lesions

Condyloma Acuminatum


  Vaginal condylomas are similar to their vulvar counterparts ( Chapter 1 ) except for the more frequent occurrence of flat condylomas in the vagina.
  Vaginal condylomas may have a ‘spiked’ surface due to asperities or minute surface projections that contain capillaries and scanty stroma. Diffuse vaginal involvement by such lesions has been referred to as ‘condylomatous vaginitis.’

Vaginal Adenosis ( Figs. 3.1 – 3.6 )


Fig. 3.1 Vaginal adenosis and clear cell adenocarcinoma within a vaginectomy–hysterectomy specimen. The vagina is on the right and the uterus is on the left. The two flat red areas on the vaginal mucosa are areas of adenosis. The polypoid red vaginal mass (bottom) is a clear cell carcinoma.


Fig. 3.2 Adenosis, papillary and glandular patterns. A focal microglandular pattern is seen, most prominently in the top left.


Fig. 3.3 Adenosis. Glands separated by vaginal stroma are lined by tuboendometrioid epithelium. One gland is partly replaced by metaplastic squamous epithelium.


Fig. 3.4 Adenosis. Glands are lined by mucinous epithelium.


Fig. 3.5 Adenosis. A gland is lined by tubal-type epithelium.


Fig. 3.6 Adenosis with florid squamous metaplasia resulting in numerous squamous pegs. Residual gland lumens are present (bottom center) within several pegs.

  Prior to the use of diethylstilbestrol (DES), vaginal adenosis was a rare finding in the reproductive and postmenopausal age groups. In contrast, adenosis is found in a third of asymptomatic girls or young women exposed in utero to DES. Adenosis has also been associated with CO 2 laser vaporization or topical 5-fluorouracil treatment of condylomas and the Stevens–Johnson syndrome.
  On clinical examination, the vaginal mucosa is red and granular and fails to stain with iodine. The upper third of the vagina is almost always affected; the middle third is involved in about 10% of cases and the lower third in only 2% of cases.
  In 20% of DES-exposed females, congenital malformations of the cervix and vagina accompany the adenosis. Rare patients with diffuse vaginal adenosis unrelated to DES exposure have had an imperforate hymen.
  Microscopically, benign columnar epithelium of endocervical or tubo-endometrioid type replaces the normal squamous epithelium or forms glands within the superficial stroma. Tubo-endometrioid epithelium is particularly common in the lower vagina and within glands.
  Rare findings in adenosis include:

•  Papillae (papillary adenosis); microglandular hyperplasia secondary to oral contraceptive use or pregnancy; Arias-Stella reaction in pregnancy; and intestinal metaplasia.
•  Dysplastic changes (including adenocarcinoma in situ) that usually occur in tubo-endometrioid adenosis adjacent to clear cell adenocarcinomas, supporting the view that these changes are premalignant in at least some cases.
  The glands typically undergo replacement by metaplastic squamous epithelium with the formation of squamous pegs. Striking examples of this process may be misconstrued as invasive squamous cell carcinoma.

•  The pegs and small mucin-filled spaces (mucin ‘droplets’) within the pegs or surface squamous epithelium may be the only clues to the diagnosis of adenosis.
•  The glycogen-poor metaplastic squamous epithelium is gradually converted to an epithelium that is indistinguishable from normal glycogen-rich, vaginal squamous epithelium.
  Adenosis is rarely complicated by the development of a vaginal or cervical adenocarcinoma, which is usually of clear cell type or by vaginal intraepithelial neoplasia.

Cysts ( Fig. 3.7 )


Fig. 3.7 Gartner's (mesonephric) duct cyst that was in the lateral wall of the vagina. Note cuboidal to flattened lining cells devoid of cilia and intracellular mucin.

  These uncommon lesions occur in the reproductive and postmenopausal age groups and usually present as a symptomatic mass or an incidental clinical finding.
  The cysts are of the following types:

•  Mullerian-type cysts that are located anywhere in the vagina but are most common anteriolaterally. They are lined by endocervical-type, tubal, or endometrioid epithelium; focal metaplastic squamous epithelium may also be present. Most of these cysts probably arise from adenosis.
•  Epithelial inclusion cysts, lined by squamous epithelium and containing keratin; most of these arise in sites of a previous episiotomy or laceration.
•  Mesonephric (Gartner's duct) cysts, lined by cuboidal to flattened, nonciliated epithelial cells that lack cytoplasmic mucin. These cysts likely arise from mesonephric remnants within the lateral vaginal walls.
•  Endometriotic cysts ( Chapter 19 ) and cysts of Bartholin's duct origin ( Chapter 1 ).

Prolapse of Fallopian Tube ( Fig. 3.8 )


Fig. 3.8 Prolapsed fallopian tube. The tubal plicae contain a dense chronic inflammatory cell infiltrate.

  Tubal prolapse occasionally occurs after hysterectomy, which is usually a vaginal hysterectomy. A lesion at the vaginal apex simulating granulation tissue is typically seen.
  A misdiagnosis of papillary adenocarcinoma may occur if there is reactive atypia of the tubal epithelial cells. The presence of tubal plicae and ciliated epithelial cells with a mostly benign appearance facilitate the diagnosis.
  Rarely a prolapsed fallopian tube has exhibited focal features resembling angiomyofibroblastoma ( Chapter 1 ) or aggressive angiomyxoma ( Chapter 1 ), potentially leading to a misdiagnosis.

Postoperative Spindle Cell Nodule


Clinical features


  This lesion (PSCN) is a pseudosarcomatous spindle cell lesion that develops shortly after an operation on the lower genitourinary tract. In the female reproductive tract, PSCNs most often involve the vagina; rare vulvar and endometrial examples have also been reported.
  PSCNs are detected in the surgical site 1–12 weeks postoperatively. Upper vaginal PSCNs usually follow a vaginal hysterectomy, whereas those in the lower vagina or vulva usually follow an episiotomy.
  The post-excision follow-up is benign. Rare local recurrences have been successfully treated by re-excision.

Pathological features ( Fig. 3.9 )


Fig. 3.9 Postoperative spindle cell nodule of the vagina within an episiotomy scar. Note spindle cells with bland nuclei and numerous mitotic figures.

  Soft polypoid masses, which are usually <4 cm in size, are composed of spindle cells arranged in intersecting fascicles, often with a network of small blood vessels. The cells have plump, vesicular nuclei with one or two prominent nucleoli but lack significant cytological atypia. Mitotic figures are often numerous, with as many as 50 mf/10 hpf.
  Limited infiltration of the surrounding normal tissue may occur. There may be overlying ulceration with a deeper neutrophilic infiltrate and a chronic inflammatory infiltrate, and commonly, focal hemorrhage and edema.
  PSCNs are usually immunoreactive for vimentin, desmin, SMA, and surprisingly, cytokeratin.

Differential diagnosis with well-differentiated leiomyosarcoma


  This distinction may be difficult on microscopic examination as leiomyosarcomas may exhibit no more cytological atypia and may be less mitotic than a PSCN. A history of a recent operation in the site of the lesion strongly favors a diagnosis of PSCN over that of leiomyosarcoma.
  Sarcomas with mitotic rates as high as those in PSCNs usually exhibit significant nuclear atypia. Also, the prominent network of small blood vessels in PSCNs is not a feature of leiomyosarcoma.

Fibroepithelial Polyp


Clinical features


  The vagina is the commonest site of these lesions; less commonly they involve the vulva, or rarely the cervix. The polyps usually occur in women of reproductive and postmenopausal age (rarely in infants) who may be asymptomatic, have postcoital bleeding, or notice a mass.
  About 20% of the patients are pregnant at the time of diagnosis and an additional 10% have received hormonal treatment (estrogen, oral contraceptives, tamoxifen, or a hormonal agent of unspecified type), suggesting a possible hormonal etiology in some cases.
  Local excision is almost always curative. In the rare cases in which the lesions recur, re-excision is successful. In pregnant patients, the polyps may regress during the puerperium.

Pathological features ( Figs. 3.10 – 3.14 )


Fig. 3.10 Fibroepithelial polyps.


Fig. 3.11 Fibroepithelial polyp. The stromal cells, some of which are multinucleated, are separated by an edematous stroma.


Fig. 3.12 Fibroepithelial polyp. High-power view showing mononuclear and multinucleated stromal cells. The nuclei in some of the latter have a wreath-like configuration (top left).


Fig. 3.13 Fibroepithelial polyp with sarcomatoid stromal giant cells, low- and high-power views.


Fig. 3.14 Fibroepithelial polyp with cellular stroma, low- and high-power views.

  The polyps are usually single but can be multiple and numerous, especially in pregnancy. They range from sessile to pedunculated to villiform, are soft to rubbery, and gray–pink. Occasional vaginal polyps have a botryoid appearance. Most polyps are <4 cm in size but occasionally are as large as 12 cm.
  The polyps are usually covered by unremarkable, but occasionally koilocytotic or dysplastic squamous epithelium. The stroma is fibrous to edematous and usually sparsely cellular. The vessels are thin-walled (sometimes dilated) to thick-walled; the latter type vessels are usually located more centrally within the lesion.
  There is usually no distinct margin with the underlying normal tissue and the lesion usually extends to the squamous epithelium, without a Grenz zone.
  The polygonal to spindle to stellate stromal cells usually have scanty pale cytoplasm and tapering cytoplasmic processes with typically bland and mitotically inactive nuclei. Cells with multiple (or multilobed) nuclei are often present and the latter may be disposed in a wreath-like arrangement.
  Occasional polyps, especially during pregnancy, exhibit features that can raise concern for malignancy (‘pseudosarcoma botryoides’): striking cellularity, which is often greater in the center of the lesion; bizarre, hyperchromatic, multiple or multilobed nuclei with prominent nucleoli; and mitotic figures (usually <3 but rarely >5 mf/10 hpf) that may be abnormal.
  The stromal cells typically stain for vimentin, desmin, and ER and PR, and have ultrastructural features of fibroblasts and myofibroblasts.

Differential diagnosis


  Aggressive angiomyxoma ( Chapter 1 ). Unlike usual fibroepithelial polyps, these tumors are less likely to be polypoid, are typically bulky and deeply seated, contain numerous blood vessels of various sizes (including thick-walled vessels), often exhibit smooth muscle differentiation, have infiltrative borders, and have only rare multinucleated cells. The distinction between the two lesions, however, may be difficult in a superficial biopsy specimen.
  Sarcoma botryoides. Features favoring this diagnosis over a fibroepithelial polyp with stromal atypia include an age <5 years; a history of rapid growth; a cambium layer containing small mitotically active cells with scanty cytoplasm and hyperchromatic nuclei (or similar cells elsewhere in the lesion); invasion of the squamous epithelium; cells with cytoplasmic cross-striations; and staining for skeletal muscle markers.
  Superficial myofibroblastoma ( Chapter 1 ).

Tubulosquamous Polyp ( Fig. 3.15 )


Fig. 3.15 Tubulosquamous polyp. Well-circumscribed squamous nests (some containing necrotic material) are separated by a hypocellular fibrous stroma. Note a few small tubules immediately subjacent to the surface squamous epithelium (top center).

  These lesions occur in postmenopausal, or less commonly, late reproductive, age groups. They are usually found in the upper vagina and <3 cm in size.
  Microscopic examination reveals well-circumscribed nests of bland epithelial cells within a hypocellular fibrous stroma.

•  Most of the nests are composed of glycogenated or non-glycogenated squamous cells, often with central necrosis, calcification, keratinization, or combinations thereof.
•  Small tubules are also present, usually at the periphery of the squamous nests, and are lined by cuboidal cells with pale cytoplasm, sometimes with intracellular mucin.
•  Uncommon findings have included prominent basaloid epithelial differentiation, sebaceous glands, and mucinous and goblet cell differentiation.
•  The epithelial elements are positive for cytokeratins and ER and in some cases, PAP and/or PSA.
  Kelly et al. suggest that these polyps, as well as rare examples of ectopic prostate tissue in the vagina, are derived from eutopic or ectopic Skene's glands.
  Aside from ectopic prostate tissue, the differential diagnosis includes vaginal Brenner tumor and benign mixed tumor (spindle cell epithelioma). Contrasting features of the latter include a location near the hymenal ring and a predominant cellular spindle cell component.

Inflammatory and Infectious Lesions ( Fig. 3.16 )


Fig. 3.16 Vaginitis emphysematosa. Note cystic spaces with foreign-body giant cell reaction.

  Rare cases of vaginal involvement by lichen sclerosus ( Chapter 1 ) and Darier's disease have been reported. The latter can result in an abnormal Pap smear.
  Tuberculosis, mycoses (cryptococcosis, histoplasmosis), schistosomiasis, malacoplakia, xanthogranulomatous inflammation, a tumor-like mass caused by a granulomatous reaction to keratin, mucicarminophilic histiocytosis, and ligneous inflammation (see Chapter 4 ) have been reported in the vagina.
  A vaginal fibrohistiocytic reaction with a storiform pattern mimicked a fibrous histiocytoma except for the presence of a foreign-body reaction to polarizable material.
  Emphysematous vaginitis is a self-limiting lesion in the reproductive and postmenopausal age groups. Gas-filled cystic spaces subjacent to the squamous epithelium are lined by foreign-body giant cells and chronic inflammatory cells. The cervix and/or vulva can also be involved. The pathogenesis is obscure; at least some cases appear to be caused by gas-forming bacteria.

Endometriosis ( Figs. 3.17 – 3.18 )


Fig. 3.17 Polypoid endometriosis. Multiple tan polyps replace the vaginal mucosa.


Fig. 3.18 Polypoid endometriosis. Several polyps composed of endometrial glands and stroma are covered by vaginal squamous epithelium.

  Superficial vaginal endometriosis, which typically involves the vault, is rarer than its cervical counterpart, but is similar to the latter microscopically, in its predilection for involving sites of prior trauma, and in its lack of associated pelvic endometriosis.
  Deep vaginal endometriosis is more common and is typically associated with pelvic endometriosis and involvement of the cul-de-sac and rectovaginal septum. When extensive this process may form nodular or polypoid mucosal masses (polypoid endometriosis) on the posterior vaginal wall.
  The differential diagnosis of vaginal endometriosis, particularly of the superficial type, includes vaginal adenosis of the tuboendometrial variety; the latter, however, lacks endometrial stroma and the other stigmata of endometriosis.
  The presence of endometriosis adjacent to a vaginal tumor favors a primary rather than a metastatic tumor. The former include endometrioid or clear cell adenocarcinoma (see separate headings in this chapter), endometrial stromal sarcoma, or adenosarcoma. Endometriosis-associated tumors are considered in more detail in Chapter 19 .

Ectopias and Metaplasias


  Transitional cell metaplasia, similar to that occurring more commonly in the cervix ( Chapter 4 ), occasionally occurs in the vagina, sometimes in association with a transitional cell neoplasm.
  Mucinous epithelium other than that seen in adenosis (see Vaginal Adenosis) may occur in the vagina:

•  Rare cases of vaginal endocervicosis ( Chapter 19 ) have been reported. In one of them, the typical benign endocervical-like glands of endocervicosis merged with an adenocarcinoma.
•  Replacement of the vaginal epithelium by metaplastic mucinous epithelium occurred in a woman with cervical agenesis. The mucinous epithelium, which was focally atypical, involved the entire genital tract.
  Rare vaginal examples of ectopic skin (including cutaneous appendages), isolated sebaceous glands, and thyroid/parathyroid tissue occur. One case of vaginal prostatic tissue has also been described with features similar to this lesion in the uterine cervix ( Chapter 4 ).
  Ectopic decidua within the vagina in pregnant women has clinically mimicked carcinoma in some cases. The histological features are similar to those of eutopic decidua and ectopic decidua in other sites.

Other Tumor-like Lesions


  Multinucleated stromal giant cells, identical to those within fibroepithelial polyps, are a common incidental microscopic finding in the loose subepithelial stroma of the lower female genital tract, especially the vulva ( Chapter 1 ) but were also found in the vagina in 12% of cases in one autopsy study.
  Mesonephric remnants and/or mesonephric hyperplasia ( Chapter 4 ) occur in the vagina and can be associated with an abnormal Papanicolaou (Pap) smear.
  Benign pigmented lesions of the vaginal mucosa include melanosis, blue nevus of usual and cellular type, atypical melanocytic hyperplasia, and ochronosis.
  Fadare has described ‘vaginal stromal sclerosis’ in women 50 to 62 years of age who had dyspareunia, vaginal atrophy, and a vaginal nodule or plaques. The lesions consisted of subepithelial zones of sparse fibroblastic stromal cells separated by collagen and elastic fibers.
  Rare examples of vaginal involvement by retroperitoneal fibrosis have been documented.

References

Condyloma acuminatum
Roy, M., Meisels, A., Fortier, M., et al. Vaginal condylomata: A human papilloma virus infection. Clin Obstet Gynecol . 1981; 24:461–483.

Vaginal adenosis
Bornstein, J., Kaufman, R. H., Adam, E., et al. Human papillomavirus associated with vaginal intraepithelial neoplasia in women exposed to diethylstilbestrol in utero. Obstet Gynecol . 1987; 70:75–80.
Bornstein, J., Sova, Y., Atad, J., et al. Development of vaginal adenosis following combined 5-fluorouracil and carbon dioxide laser treatments for diffuse vaginal condylomatosis. Obstet Gynecol . 1993; 81:896–898.
Emberger, M., Lanschuetzer, C. M., Laimer, M., et al. Vaginal adenosis induced by Stevens–Johnson syndrome. J Eur Acad Dermatol Venereol . 2006; 20:896–898.
Hansen, K., Egholm, M. Diffuse vaginal adenosis. Three cases combined with imperforate hymen and haematocolpos. Acta Obstet Gyencol Scand . 1975; 54:287–292.
Merchant, W. J., Gale, J. Intestinal metaplasia in stilbestrol-induced vaginal adenosis. Histopathology . 1993; 23:373–376.
Robboy, S. J., Hill, E. C., Sandberg, E. C., et al. Vaginal adenosis in women born prior to the diethlystilbestrol era. Hum Pathol . 1986; 17:488–492.
Robboy, S. J., Kaufman, R. H., Prat, J., et al. Pathologic findings in young women enrolled in the National Cooperative Diethystilbestrol Adenosis (DESAD) Project. Obstet Gynecol . 1979; 53:309–317.
Robboy, S. J., Young, R. H., Welch, W. R., et al. Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring. Cancer . 1984; 54:869–875.
Robboy, S. J., Welch, W. R. Microglandular hyperplasia in vaginal adenosis associated with oral contraceptives and prenatal diethylstilbestrol exposure. Obstet Gynecol . 1977; 49:430–434.

Cysts
Deppisch, L. M. Cysts of the vagina. Classification and clinical correlations. Obstet Gynecol . 1975; 45:632–637.
Pradham, S., Tobon, H. Vaginal cysts: A clinicopathologic study of 41 cases. Int J Gynecol Pathol . 1986; 5:35–46.

Prolapse of fallopian tube
Ellsworth, H. S., Harris, J. W., McQuarrie, H. G., et al. Prolapse of the fallopian tube following vaginal hysterectomy. JAMA . 1973; 224:891–892.
Michal, M., Rokyta, Z., Mejchar, B., et al. Prolapse of the fallopian tube after hysterectomy associated with exuberant myofibroblastic stromal response: A diagnostic pitfall. Virchows Arch . 2000; 437:436–439.
Silverberg, S. G., Frable, W. J. Prolapse of fallopian tube into vaginal vault after hysterectomy. Arch Pathol . 1974; 97:100–103.
Varnholt, H., Otis, C. N., Nucci, M. R., et al. Fallopian tube prolapse mimicking aggressive angiomyxoma. Int J Gynecol Pathol . 2005; 24:292–294.
Wheelock, J. B., Schneider, V., Goplerud, D. R. Prolapsed fallopian tube masquerading as adenocarcinoma of the vagina in a postmenopausal woman. Gynecol Oncol . 1985; 21:369–375.

Postoperative spindle cell nodule
Kay, S., Schneider, V. Reactive spindle cell nodule of the endocervix simulating uterine sarcoma. Int J Gynecol Pathol . 1985; 4:255–257.
Manson, C. M., Hirsch, P. J., Coyne, J. D. Post-operative spindle cell nodule of the vulva. Histopathology . 1995; 26:571–574.
Proppe, K. H., Scully, R. E., Rosai, J. Postoperative spindle cell nodules of genitourinary tract resembling sarcomas. Am J Surg Pathol . 1984; 8:101–108.
Wick, M. R., Brown, B. A., Young, R. H., et al. Spindle-cell proliferations of the urinary tract. An immunohistochemical study. Am J Surg Pathol . 1988; 12:379–389.

Fibroepithelial polyp
Al-Nafussi, A. I., Rebello, G., Hughes, D., et al. Benign vaginal polyp: A histological, histochemical and immunohistochemical study of 20 polyps with comparison to normal vaginal subepithelial layer. Histopathology . 1992; 20:145–150.
Hartman, C., Sperling, M., Stein, H. So-called fibroepithelial polyps of the vagina exhibiting an unusual but uniform antigen profile characterized by expression of desmin and steroid hormone receptors but no muscle-specific actin or macrophage markers. Am J Clin Pathol . 1990; 93:604–608.
Mucitelli, D. R., Charles, E. Z., Kraus, F. T. Vulvovaginal polyps. Histologic appearance, ultrastructure, immunocytochemical characteristics, and clinicopathologic correlations. Int J Gynecol Pathol . 1990; 9:20–40.
Nucci, M. R., Young, R. H., Fletcher, C. D. M. Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower female genital tract: An underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol . 2000; 24:231–240.
Ostor, A. G., Fortune, D. W., Riley, C. B. Fibroepithelial polyps with atypical stromal cells (pseudosarcoma botryoides) of vulva and vagina. A report of 13 cases. Int J Gynecol Pathol . 1988; 7:351–360.

Tubulosquamous polyp
Kelly, P., McBride, H. A., Kennedy, K., et al. Misplaced Skene's glands: Glandular elements in the lower female genital tract that are variably immunoreactive with prostatic markers and that encompass vaginal tubulosquamous polyp and cervical ectopic prostatic tissue. Int J Gynecol Pathol . 2011; 30:605–612.
McCluggage, W. G., Young, R. H. Tubulo-squamous polyp: A report of ten cases of a distinctive hitherto uncharacterized vaginal polyp. Am J Surg Pathol . 2007; 31:1013–1019.
Tong, B., Clarke, B. A., Ghazarian, D. Tubulo-squamous polyp with mucinous and goblet cell differentiation: A unique morphologic variant. [Letter] Int J Gynecol Pathol . 2011; 30:518–519.

Inflammatory and infectious lesions
Diac, M., Hanoch, J., McIndoe, A., et al. Keratin induced granulomatous disease of the vagina mimicking a malignant tumor. BJOG . 2005; 111:389–390.
Fishman, A., Ortega, E., Girtanner, R. E., et al. Malacoplakia of the vagina presenting as a pelvic mass. Gynecol Oncol . 1993; 49:380–382.
Kogulan, P. K., Smith, M., Seidman, J., et al. Malakoplakia involving the abdominal wall, urinary bladder, vagina, and vulva: Case report and discussion of malakoplakia-associated bacteria. Int J Gynecol Pathol . 2001; 20:403–406.
Kramer, K., Tobon, H. Vaginitis emphysematosa. Arch Pathol Lab Med . 1987; 111:746–749.
Kuo, T., Hsueh, S. Mucicarminophilic histiocytosis: A polyvinylpyrrolidone (PVP) storage disease simulating signet-ring cell carcinoma. Am J Surg Pathol . 1984; 8:418–428.
Ladefoged, C., Lorentzen, M. Xanthogranulomatous inflammation of the female genital tract. Histopathology . 1988; 13:541–551.
Longinotti, M., Schieffer, Y. M., Kaufman, R. H. Lichen sclerosus involving the vagina. Obstet Gynecol . 2005; 106:1217–1219.
Nogales-Ortiz, F., Tarancon, I., Nogales, F. The pathology of female genital tract tuberculosis. Obstet Gynecol . 1979; 53:422–428.
Snover, D. C., Phillips, G., Dehner, L. P. Reactive fibrohistiocytic proliferation simulating fibrous histiocytoma. Am J Clin Pathol . 1981; 76:232–235.
Strate, S. M., Taylor, W. E., Forney, J. P., et al. Xanthogranulomatous pseudotumor of the vagina: Evidence of a local response to an unusual bacterium (mucoid Escherichia coli). Am J Clin Pathol . 1983; 79:637–643.
Suarez-Penaranda, J. M., Antunez, J. R., Del Rio, E., et al. Vaginal involvement in a woman with Darier's disease: A case report. Acta Cytol . 2005; 49:469–470.

Endometriosis
Gardner, H. L. Cervical and vaginal endometriosis. Clin Obstet Gynecol . 1966; 9:358–372.
Parker, R. L., Dadmanesh, F., Young, R. H., et al. Polypoid endometriosis: A clinicopathological analysis of 24 cases and a review of the literature. Am J Surg Pathol . 2004; 28:285–297.

Ectopias and metaplasias
Anjarwala, S., Rollason, T. P., Rooney, N., et al. Atypical mucinous metaplasia and intraepithelial neoplasia of the female genital tract – A case report and review of the literature. Int J Gynecol Cancer . 2007; 17:1147–1150.
Belousova, I. E., Kazakov, D. V., Michal, M. Ectopic sebaceous glands in the vagina. Int J Gynecol Pathol . 2005; 24:193–195.
Kurman, R. J., Prabha, A. C. Thyroid and parathyroid glands in the vaginal wall. Am J Clin Pathol . 1973; 59:503–507.
Martinka, M., Allaire, C., Clement, P. B. Endocervicosis presenting as a painful vaginal mass. Int J Gynecol Pathol . 1999; 18:274–276.
Mathie, J. G. Vaginal deciduosis simulating carcinoma. J Obstet Gynaecol Br Empire . 1957; 64:720–721.
McCluggage, W. G., Ganesan, R., Hirschowitz, L., et al. Ectopic prostatic tissue in the uterine cervix and vagina: Report of a series with detailed immunohistochemical analysis. Am J Surg Pathol . 2006; 30:209–215.
McCluggage, W. G., Price, J. H., Dobbs, S. P. Primary adenocarcinoma of the vagina arising in endocervicosis. Int J Gynecol Pathol . 2001; 20:399–402.

Other tumor-like lesions
Abdul-Karim, F. W., Cohen, R. E. Atypical stromal cells of lower female genital tract. Histopathology . 1990; 17:249–253.
Bottles, K., Lacey, C. G., Miller, T. R. Atypical melanocytic hyperplasia of the vagina. Gynecol Oncol . 1984; 19:226–230.
Fadare, O. Vaginal stromal sclerosis: A distinctive stromal change associated with vaginal atrophy. Int J Gynecol Pathol . 2011; 30:295–300.
Gatcliffe, T. A., Soto-Wright, V., Kasznica, J. Vaginal hyperpigmentation due to ochronosis. Obstet Gynecol . 2003; 101:1066–1068.
Heah, J. T. C. Idiopathic retroperitoneal fibrosis involving the vagina: Case report. BJOG . 1979; 86:407–410.
Tobon, H., Murphy, A. I. Benign blue nevus of the vagina. Cancer . 1977; 40:3174–3176.
Tsukuda, Y. Benign melanosis of the vagina and cervix. Am J Obstet Gynecol . 1976; 124:211–212.
Welsh, T., Fu, Y. S., Chan, J., et al. Mesonephric remnants or hyperplasia can cause abnormal Pap smears: A study of three cases. Int J Gynecol Pathol . 2003; 22:121–126.

Benign Tumors

Epithelial Tumors ( Fig. 3.19 )


Fig. 3.19 Müllerian papilloma of infancy.

  Most benign papillary squamous lesions of the vagina are condylomas. Noncondylomatous squamous papillomas are rare in the vagina and are similar to those occurring in the cervix ( Chapter 4 ). Vestibular squamous papillomatosis is considered in Chapter 1 .
  Rare papillomas of the vaginal mucosa, usually in children, resemble müllerian papillomas of the cervix ( Chapter 4 ), and may clinically and histologically suggest embryonal rhabdomyosarcoma.

•  Two otherwise similar papillomas that were mural (nonmucosal) consisted of papillae, glands, and solid areas; the lesional cells had eosinophilic cytoplasm and bland nuclei.
•  One müllerian papilloma recurred many times over a 40-year period, eventually progressing to a clear cell carcinoma.
  Occasional tubulovillous adenomas resembling colonic tubulovillous adenomas occur in the vagina. Most have contained goblet cells (with enteric mucin) and Paneth cells. Some have contained foci of high-grade dysplasia or merged with an adenocarcinoma.
  Ovarian-type benign epithelial–stromal tumors occurring in the vagina have included rare Brenner tumors (some of which, in retrospect, are probably examples of a tubulo-squamous polyp) and endometrioid papillary cystadenofibroma.

Mixed Tumor (Spindle Cell Epithelioma) ( Figs. 3.20 – 3.23 )


Fig. 3.20 Benign mixed tumor (spindle cell epithelioma). Note well-circumscribed border.


Fig. 3.21 Benign mixed tumor (spindle cell epithelioma). Nests of mature squamous cells are separated by sheets of spindle cells.


Fig. 3.22 Benign mixed tumor (spindle cell epithelioma). A cord-like pattern and nests of squamous cells (top) are shown.


Fig. 3.23 Benign mixed tumor (spindle cell epithelioma), cytokeratin stain. The spindle cells are immunoreactive for cytokeratin.

  These rare tumors of uncertain histogenesis occur near the hymenal ring in women of reproductive or postmenopausal age. They are typically an incidental clinical finding or the patient notices a slowly enlarging, painless mass. Occasional tumors have recurred after local excision.
  The tumors are usually <5 cm in size, typically well circumscribed, and immediately subjacent to the vaginal squamous epithelium. The sectioned surface is usually solid, gray to white, and sometimes focally myxoid.
  The characteristic microscopic appearance is a predominant to exclusive component of spindle cells in intersecting fascicles; vague whorls, cords, nests, and hyaline spherules may also be seen. Obvious epithelial elements in the form of nests of mature squamous epithelium (sometime with keratinization) and glands lined by mucinous or nonspecific epithelium are usually present, but may be scanty and found only after serial sectioning.
  The spindle cells have scanty cytoplasm, round to spindled nuclei, fine chromatin, indistinct nucleoli, and rare to absent mitoses. The cellularity varies with the amount of intercellular alcianophilic material and collagen.
  The spindle cells typically stain for epithelial markers (AE1/3, CK7), mesenchymal markers (MSA, desmin, h-caldesmon), CD10, and PR.
  Ultrastructural findings suggest that these tumors are purely epithelial rather than mixed epithelial–stromal tumors.
  The differential diagnosis includes smooth muscle and endometrial stromal tumors, the immunoprofiles of which partly overlap with that of the mixed tumor. The typical location of the tumor and the usual admixture of well-differentiated epithelial elements with the spindle cells facilitate the diagnosis.
Aggressive Angiomyxoma, Angiomyofibroblastoma, Cellular Angiofibroma, and Myofibroblastoma (see Chapter 1 )

Leiomyoma ( Fig. 3.24 )


Fig. 3.24 Leiomyoma with bizarre nuclei.

  Leiomyomas are the most common vaginal mesenchymal tumor. They typically occur in the reproductive and postmenopausal age groups. Larger tumors may cause pain, dyspareunia, bleeding, dystocia, or urinary tract symptoms. The tumors can arise anywhere in the vagina.
  The gross and microscopic features are similar to those occurring in the uterus ( Chapter 9 ). The tumors are usually submucosal and composed of spindle cells or occasionally epithelioid cells. About 10% of tumors have foci of myxoid change. Rare leiomyomas have bizarre nuclei.
  Tumors in pregnancy may show increased mitotic activity. Rare tumors may recur in one or more pregnancies, suggesting hormone dependency.
  The differential diagnosis is usually with leiomyosarcoma. Tumors with moderate to marked atypia and ≥5 mf/10 hpf should be considered leiomyosarcoma; such tumors only rarely metastasize, but may recur locally. Extragastrointestinal stromal tumors are also in the differential diagnosis.

Rhabdomyoma ( Fig. 3.25 )


Fig. 3.25 Rhabdomyoma, low- and high-power views.

  These rare benign tumors of the female genital tract are most common in the vagina. They typically present in women in the reproductive or postmenopausal age groups as a small (<3 cm) smooth, solitary, submucosal mass. They are cured by local excision.
  Most of the tumors are covered by intact squamous epithelium and are composed of variable numbers of benign, amitotic, skeletal muscle cells (eosinophilic cytoplasm, cross-striations, positivity for skeletal muscle markers) that appear round or strap-shaped depending on the plane of section. There is a variable amount of vascular fibromyxoid stroma.
  The tumors should be thoroughly sampled as rare tumors have had an admixed component of rhabdomyosarcoma or had an appearance intermediate between the two lesions.
  Differential diagnosis:

•  Fibroepithelial polyps. These lesions lack skeletal muscle differentiation.
•  Embryonal rhabdomyosarcoma. These tumors, in contrast to rhabdomyomas, occur in infants or children, exhibit rapid growth, and have a cambium layer, mitotic activity, and an infiltrative border.

Miscellaneous Benign Tumors


  Rare vaginal examples of dermoid cyst, adenomatoid tumor, myxoma, solitary fibrous tumor, angiomyolipoma, mesenchymoma (containing skeletal and smooth muscle and fat), hemangioma, glomus tumor, neurofibroma (including one with rhabdomyomatous differentiation [‘Triton’ tumor]), schwannoma (typical and cellular), granular cell tumor, and paraganglioma have been reported.
  Two vaginal myoepitheliomas occurred in women in their fifth decade. Both lesions were circumscribed nodules subjacent to the squamous epithelium and composed of spindle and/or epithelioid cells with bland nuclear features. The lesional cells stained with both epithelial and myoid markers.

References

Epithelial tumors
Abu, J., Nunns, D., Ireland, D., et al. Malignant progression through borderline changes in recurrent müllerian papilloma of the vagina. [Letter] Histopathology . 2003; 42:510–517.
Ben-Izhak, O., Munichor, M., Malkin, L., et al. Brenner tumor of the vagina. Int J Gynecol Pathol . 1998; 17:79–82.
Fox, H., Wells, M., Harris, M., et al. Enteric tumours of the lower female genital tract: A report of three cases. Histopathology . 1988; 12:167–176.
Kerner, H., Munichor, M. Papillary müllerian cystadenofibroma of the vagina. Histopathology . 1997; 30:84–86.
Lüttges, J. E., Lübke, M. Recurrent benign müllerian papilloma of the vagina. Immunohistochemical findings and histogenesis. Arch Gyneol Obstet . 1994; 255:157–160.
McCluggage, W. G., Nirmala, V., Radhakumari, K. Intramural müllerian papilloma of the vagina. Int J Gynecol Pathol . 1999; 18:94–95.
Peña-Fernández, M., Abdulkader-Nallig, I., Novo-Domínguez, A., et al. Vaginal tubulovillous adenoma: A clinicopathologic and molecular study with review of the literature. Int J Gynecol Pathol . 2013; 32:131–136.
Shaco-Levy, R., Benharroch, D. Vaginal Brenner tumor. Int J Gynecol Pathol . 2013; 32:238–241.

Mixed tumor (spindle cell epithelioma)
Branton, P. A., Tavassoli, F. A. Spindle cell epithelioma, the so-called mixed tumor of the vagina. A clinicopathologic, immunohistochemical, and ultrastructural analysis of 28 cases. Am J Surg Pathol . 1993; 17:509–515.
Oliva, E., Gonzalez, L., Dionigi, A., et al. Mixed tumors of the vagina: An immunohistochemical study of 13 cases with emphasis on cell of origin and potential aid in differential diagnosis. Mod Pathol . 2004; 17:1243–1250.
Sirota, R. L., Dickersin, G. R., Scully, R. E. Mixed tumors of the vagina. A clinicopathologic analysis of eight cases. Am J Surg Pathol . 1981; 5:413–422.

Leiomyoma
Bianchi, S. A., O'Tooke, V. E., Fung, C., et al. Bizarre leiomyoma of the vagina: Report of a case. Int J Gynecol Pathol . 2000; 19:186–187.
Rywlin, A. M., Simmons, R. J., Robinson, M. J. Leiomyoma of vagina recurrent in pregnancy: A case with apparent hormone dependency. Southern Med J . 1969; 62:1449–1451.
Tavassoli, F. A., Norris, H. J. Smooth muscle tumors of the vagina. Obstet Gynecol . 1979; 53:689–693.

Rhabdomyoma
Iversen, U. M. Two cases of benign vaginal rhabdomyoma. APMIS . 1996; 104:575–578.
Jacques, S. M., Lawrence, W. D., Malviya, V. K. Uterine mixed embryonal rhabdomyosarcoma and fetal rhabdomyoma. Gynecol Oncol . 1993; 48:272–276.
Wertheim, R. A., Krebs, H. -B., Frable, W. J. Intermediate form of cervical fetal rhabdomyoma? Diagn Gynecol Obstet . 1982; 4:57–62.

Miscellaneous benign tumors
Azzopardi, J. G., Eusebi, V., Tison, V., et al. Neurofibroma with rhabdomyomatous differentiation: Benign ‘Triton’ tumour of the vagina. Histopathology . 1983; 7:561–572.
Brustman, H. Paraganglioma of the vagina: Report of a case. Pathol Res Pract . 2007; 203:189–192.
Chen, K. T. K. Angiomyolipoma of the vagina. Gynecol Oncol . 1990; 37:302–304.
Egley, C. C., Fox, J. S. Vaginal myxoma presenting as acute urinary retention. Obstet Gynecol . 1989; 73:882–883.
Ellison, D. W., MacKenzie, I. Z., McGee, J. O. D. Cellular schwannoma of the vagina. Gynecol Oncol . 1992; 46:19–21.
Koskela, O. Granular-cell myoblastoma of the vagina. Ann Chir Gynaecol Fenn . 1964; 53:270–273.
Lorenz, G. Adenomatoid tumor of the ovary and vagina. Zentralbl Gynakol . 1978; 100:1412–1416.
Mann, S., Russell, P., Wills, E. J., et al. Benign vaginal mesenchymoma showing mature skeletal muscle, smooth muscle, and fatty differentiation. Int J Surg Pathol . 1996; 4:49–54.
Meenakshi, M., McCluggage, W. G. Myoepithelial neoplasms involving the vulva and vagina: Report of 4 cases. Hum Pathol . 2009; 40:1747–1753.
Moldavsky, M., Stayerman, C., Turani, H. Vaginal glomus tumor presented as a painless cystic mass. Gynecol Oncol . 1998; 69:172–174.
Placide, N., Robert, S. Solitary fibrous tumor of the vagina: A case report with review of the literature. Int J Surg Pathol . 2012; 20:101–104.
Rezvani, F. F. Vaginal cavernous hemangioma in pregnancy. Obstet Gynecol . 1997; 89:824–825.
Siu, S. -S. N., Tam, W. -H., To, K. -F., et al. Is vaginal dermoid cyst a rare occurrence or a misnomer? Ultrasound Obstet Gynecol . 2003; 21:404–406.
Terada, S., Suzuki, N., Tomimatsu, N., et al. Vaginal schwannoma. Arch Gynecol Obstet . 1992; 251:203–206.

Malignant Tumors

Vaginal Intraepithelial Neoplasia (VaIN) ( Fig. 3.26 )


Fig. 3.26 VaIN III.

  VaIN is only 1% as common as its cervical counterpart (CIN). It tends to occur in an older age group, although its frequency is increasing in younger women. The usual presentation is an abnormal Pap smear.
  There is usually a prior or synchronous preinvasive or invasive squamous neoplasm of the cervix or vulva; Venokurova et al. found that in some cases these may represent multicentric clonal lesions. Other risk factors include immunosuppression, smoking, prior pelvic irradiation, and adenosis.
  The upper third of the vagina is usually involved. The lesion may be macroscopically abnormal (raised, roughened, white, pink) or only appreciable colposcopically. About 50% of lesions are multifocal.
  The microscopic and immunohistochemical features are as those for CIN ( Chapter 5 ).

•  LSIL (low-grade squamous intraepithelial lesion) is now synonymous with VaIN I, and HSIL (high-grade squamous intraepithelial lesion) collectively denotes VaIN II and VaIN III. The VaIN terminology has also been incorporated recently into the LAST standardization project for HPV-associated lesions (Chapter 5).
•  HPV DNA is detected in the tumor cells in at least 80% of cases; Srodon et al. have found that even VaIN 1 lesions can contain high-risk HPV.
  VaIN is usually treated by excision, laser ablation, topical chemotherapy, or ultrasonic surgical aspiration. Local recurrence is more likely with nonextirpative treatment. Rarely VaIN progresses to invasive squamous cell carcinoma, a finding that may be more likely in VaIN that follows pelvic irradiation for an unrelated lesion.
  Ki-67 and p16 staining, as with CIN ( Chapter 5 ), can facilitate the differential diagnosis of VaIN with reactive atypia, postirradiation atypia, atrophy, transitional cell metaplasia, and immature squamous metaplasia within adenosis. Hampl et al., however, found that only 62% of vaginal HSILs were p16+ (vs 85% for vulvar HSILs and 90% of cervical HSILs).

Squamous Cell Carcinoma ( Fig. 3.27 )


Fig. 3.27 Vaginal squamous cell carcinoma in a vaginectomy–hysterectomy specimen. Note polypoid mass in the upper vagina.

  Vaginal squamous cell carcinomas (SqCCs) account for about 90% of primary vaginal cancers and 1% of cancers of the female genital tract. The ratio of vaginal to cervical SqCC is about 1 : 50.
  The risk factors are those for VaIN as well as multiple sexual partners, early age at first intercourse, and antibodies to HPV16. About 80% of vaginal SqCCs contain HPV DNA, most commonly HPV 16/18. Up to half the patients have a history of hysterectomy for benign disease or cervical squamous neoplasia.
  The patients are usually in the late reproductive or postmenopausal age groups; 10% are <40 years of age. The presenting features include vaginal bleeding or discharge, urinary symptoms, abnormal cytology, a mass, or combinations thereof.
  Most tumors arise in the upper third of the vagina and vary from polypoid to ulcerating, and microscopically resemble typical keratinizing or nonkeratinizing cervical SqCCs ( Chapter 5 ).
  Uncommon variants include verrucous ( Chapter 2 ), warty ( Chapter 5 ), papillary ( Chapter 5 ), sarcomatoid ( Chapter 5 ), lymphoepithelioma-like carcinomas ( Chapter 5 ), and squamotransitional cell carcinomas (see next section).
  Fuste et al. found that almost all HPV+ tumors are p16+ and are usually nonkeratinizing, warty, or basaloid subtypes.
  The most important prognostic factor is stage ( Table 3.1 ). Survival figures from a Stanford study of patients treated with radiation were 94% (stage I), 80% stage II, 50% (stage III), and 0% (stage IV).

Table 3.1
FIGO staging of carcinoma of the vagina Stage 0 Carcinoma in situ (VIN III). Stage I The carcinoma is limited to the vaginal wall. Stage II The carcinoma has involved the subvaginal tissue but tumor has not extended to the pelvic wall. Stage III The carcinoma has extended to the pelvic wall. Stage IV The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum.  IVa Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis.  IVb Spread to distant organs.

•  Hellman et al. found that older age and tumors ≥4 cm were also adverse prognostic factors. Low histologic grade, tumor size <3 cm, and an absence of lymphatic invasion have been favorable prognostic factors in some studies.
•  The term ‘microinvasive SqCC,’ proposed for tumors that invade <2.5 mm, has not been uniformly adopted; such tumors are occasionally fatal.
•  Larsson et al. found that women with HPV+ tumors, especially HPV16+ tumors, had a better survival than those with HPV− tumors.

Transitional and Squamotransitional Cell Carcinomas ( Fig. 3.28 )


Fig. 3.28 Papillary transitional cell carcinoma, low- and high-power views.

  Rare vaginal carcinomas with transitional cell differentiation have been either pure transitional cell carcinomas (TCCs) or squamotransitional cell carcinomas (STCCs).
  Pure vaginal TCCs resemble urinary tract TCCs, and some have been associated with the latter and/or vaginal transitional cell metaplasia. One tumor had a CK7+/CK20+ phenotype. Most of the reported tumors were noninvasive and indolent; rare invasive tumors have had nodal metastases.
  Vaginal STCCs have clinical and morphological features that overlap with papillary SqCCs. In some cases, there is a synchronous or metachronous HSIL and/or an invasive SqCC of the vagina or cervix. A CK7+/CK20− phenotype is typical; HPV 16 was found in one tumor.

Clear Cell Adenocarcinoma ( Figs. 3.29 – 3.30 )


Fig. 3.29 Clear cell carcinoma. This small and superficial tumor has a tubulocystic pattern.


Fig. 3.30 Clear cell carcinoma admixed with vaginal adenosis (the more darkly stained glands).

  Vaginal clear cell carcinomas (CCCs) were very rare prior to the use of diethlystilbestrol (DES) in the early 1950s; most occurred in postmenopausal women. Some arose from vaginal endometriosis.
  Subsequently, about 400 vaginal CCCs were reported by 1994, mostly in adolescents and young adults (median age 19 years). Approximately 80% of these patients were exposed in utero to DES or another type of synthetic estrogen. The ratio of vaginal to cervical DES-related CCCs is 2 : 1.
  Larger CCCs may cause bleeding; asymptomatic small tumors are often found during an examination prompted by a DES history. The upper third of the anterior vaginal wall (the most common site of adenosis) is usually involved; rare tumors are multicentric. CCCs involving the cervix and vagina (as with other carcinomas involving both sites) are classified as cervical ( Chapter 6 ).
  CCCs range from microscopic to large polypoid, nodular, flat, or ulcerated tumors. Small tumors may not be seen colposcopically if covered by intact mucosa, but may be palpable.
  The microscopic features are identical to CCCs in other sites of the female genital tract ( Chapters 6 , 8 , and 14 ). Adenosis, which may be atypical, usually abuts the tumor.
  The differential diagnosis includes microglandular hyperplasia and Arias-Stella reaction, both of which may occur in vaginal adenosis (see Differential Diagnosis under these headings in Chapter 4 ).
  About 15% of stage I tumors and 40% of stage II tumors have spread to lymph nodes at the time of presentation. About a third of the recurrences are extra-abdominal (vs 10% for vaginal SqCCs).
  The survival rates are 90% for stage I tumors and almost 100% for small incidentally discovered tumors. DES-related CCCs have a better prognosis than sporadic CCCs, a difference that appears to be unrelated to tumor stage or size.

Endometrioid Adenocarcinoma


  Endometrioid adenocarcinoma of the vagina is the second most common type of vaginal adenocarcinoma after clear cell carcinoma.
  The patients in a recent study were 45–81 years of age and usually presented with vaginal bleeding. About half the tumors were at the vaginal apex. Sixty percent were stage I and the rest were stage II or IV. Low stage tumors were associated with a favorable prognosis.
  The tumors were mostly typical endometrioid carcinoma. Uncommon to rare features included focal squamous or mucinous metaplasia, small nonvillous papillae, a microglandular hyperplasia-like pattern ( Chapter 8 ), and a minimal deviation pattern of invasion.
  Two-thirds of the tumors were associated with endometriosis, a finding that helps distinguish them from metastatic adenocarcinomas, including metastatic endometrial endometrioid carcinoma, the most likely mimic.

Rare Adenocarcinomas


  Rare cases of vaginal adenocarcinoma in situ (AIS) have followed treatment for cervical AIS. One tumor contained signet-ring cells with pagetoid invasion of the squamous epithelium.
  Mucinous adenocarcinomas, some with an enteric or gastric phenotype, may arise in the vagina; some are periurethral. An association with DES and/or adenosis, endocervicosis, an enteric-type adenoma, or a Crohn's-related rectovaginal fistula has been occasionally found. Two tumors had a component of small cell carcinoma (see Small Cell Carcinoma ).
  Rare vaginal serous carcinomas, adenosquamous carcinomas, adenoid basal carcinomas, and adenoid cystic carcinomas have been reported. The differential diagnosis of serous carcinoma includes rare examples of the latter arising in the urethra or urethral diverticulum.
  Rare adenocarcinomas arise from the periurethral Skene's glands and may present as a primary vaginal tumor. These tumors may resemble prostatic adenocarcinoma including staining for PSA.
  Several mesonephric tumors have arisen in the vagina or paravaginal tissues, including one resembling a female adnexal tumor ( Chapter 11 ), two adenocarcinomas, and a malignant mesonephric mixed tumor ( Chapter 6 ).
  As >90% of vaginal adenocarcinomas are metastatic, an extravaginal primary tumor should be clinically excluded before categorizing the vaginal tumor as primary, especially if it is of an unusual type and/or lacks an association with a potential precursor lesion.

Small Cell Carcinoma


  Vaginal small cell (neuroendocrine) carcinomas are rare and usually occur in postmenopausal women (range 32–78 years). One tumor was preceded by VaIN, another mimicked a Bartholin's gland abscess, and one ACTH-producing tumor was associated with Cushing's syndrome. Most of the patients had stage II–IV disease and died of tumor, usually within 2 years of presentation.
  Most of the tumors histologically resembled their counterparts in the uterine cervix ( Chapter 6 ). One tumor was TTF+ and another, which was CK20+, was considered a Merkel cell carcinoma. Two tumors were associated with an intestinal-type adenocarcinoma (in one there was also synchronous VaIN) and one tumor was associated with vaginal adenosis.

Embryonal Rhabdomyosarcoma ( Figs. 3.31 – 3.34 )


Fig. 3.31 Embryonal rhabdomyosarcoma (sarcoma botryoides). A polypoid botryoid mass fills the vagina. (Figure courtesy of Dr. Richard Voet. Reproduced with permission from Color Atlas of Gynecologic Pathology, Mosby Elsevier, 1997.)


Fig. 3.32 Embryonal rhabdomyosarcoma. The surface of the tumor is papillary and has a subepithelial cellular zone (cambium layer).


Fig. 3.33 Embryonal rhabdomyosarcoma. There is pagetoid spread of tumor cells into the squamous epithelium.


Fig. 3.34 Embryonal rhabdomyosarcoma. Small round tumor cells with scanty cytoplasm (right) are admixed with strap-shaped cells with eosinophilic cytoplasm (left).

  These tumors are the most common vaginal cancer in infants and young children. About 90% occur in the first 5 years of life (mean 1.8 years); rare examples occur in young adults and postmenopausal women.
  The presenting features are vaginal bleeding and a vaginal mass that is typically soft, edematous, and nodular, papillary, or polypoid (‘sarcoma botryoides’), often with protrusion through the introitus.
  Microscopically, a densely cellular zone (cambium layer) of primitive, small, mitotic cells subtends the squamous epithelium, which may be invaded by the tumor cells. Beneath the cambium layer is a less cellular edematous zone in which similar small cells and rhabdomyoblasts are identified. Small foci of hyaline cartilage may also be present.
  The rhabdomyoblasts, which may be sparse, vary from round to strap-shaped and have eosinophilic cytoplasm with, in most cases, cross-striations. Immunoreactivity for desmin and more specifically, skeletal muscle markers (myoglobin, myogenin, myoD1) facilitate the diagnosis. Nuclear staining for myoD1 and myogenin is the most specific, but not present in all tumors.
  The differential diagnosis includes fibroepithelial polyp with atypical cells and rhabdomyoma, which both lack the cambium layer and the primitive small cells of rhabdomyosarcoma.
  The tumors can invade local structures and metastasize to regional lymph nodes or distant sites. Combination chemotherapy, irradiation, and/or surgery have achieved cure rates of 90–95%.

Leiomyosarcoma


  These rare tumors (LMSs), which occur in the third to ninth decades (average age 47 years), usually present as a mass; occasional patients have been pregnant.
  LMSs accounted for only 8% of cases in the only large series of vaginal smooth muscle tumors (Tavassoli and Norris).

•  The LMSs were 3 to 4 cm in size; none were obviously malignant on gross examination. The mitotic rates were 5 to 16 mf/10 hpf and the atypia ranged from mild (one tumor), to moderate (three tumors), to severe (one tumor). Only one had an infiltrative border.
•  All five tumors recurred locally after conservative excision. One tumor metastasized (the only tumor with infiltrative borders) with death 10 months after diagnosis.
•  These findings suggest that a vaginal smooth muscle tumor with 5 or more mf/10 hpf and moderate or severe atypia should be considered LMS, although such tumors only rarely metastasize.
  In two other studies, most patients presented with larger, more advanced stage tumors; 10 of the 13 tumors in these two series were fatal. Ciaravino et al. found an overall 5-year survival of 43%, with stage being the only independent predictor of survival.
  One paravaginal LMS composed of epithelioid cells, some with a signet-ring appearance, had a myxoid stroma. The tumor was fatal 22 months after presentation.
  Vaginal leiomyosarcomas should be distinguished from extragastrointestinal stromal tumors (see next section).

Other Pure Sarcomas, including Extragastrointestinal Stromal Tumor


  Rare vaginal examples of endometrial stromal sarcoma, alveolar soft part sarcoma, angiosarcoma (some postirradiation, some epithelioid), malignant fibrous histiocytoma, malignant rhabdoid tumor, neurofibrosarcoma, malignant schwannoma, synovial sarcoma (see next section), and Ewing's sarcoma/peripheral neuroectodermal tumor have been reported.
  The one reported vaginal perivascular epithelioid cell tumor was initially misdiagnosed as an embryonal rhabdomyosarcoma.
  Two vaginal ‘hemangiopericytomas’ have been reported, although the histologic features of these tumors in our opinion favor extrauterine low-grade endometrial stromal sarcoma.
  Extragastrointestinal stromal tumors (EGISTs) can present as a vaginal, rectovaginal, or vulvovaginal mass; several tumors recurred. In contrast to most smooth muscle tumors, EGISTs are CD117+, often CD34+, but negative for desmin, ER, and PR.

Malignant Mixed Tumors and Synovial Sarcoma


  Rare malignant müllerian mixed tumors (MMMT) (carcinosarcomas) and adenosarcomas have arisen in the vagina and resembled their uterine counterparts. Some of the vaginal adenosarcomas (typical and with sarcomatous overgrowth) were associated with vaginal endometriosis. One MMMT was associated with VaIN and contained HPV in both the carcinomatous and sarcomatous components.
  Light microscopic and ultrastructural findings in one vaginal malignant mixed tumor suggested a mesonephric origin.
  Several vaginal synovial sarcomas have been reported.

Malignant Melanoma ( Figs. 3.35 – 3.36 )


Fig. 3.35 Malignant melanoma, in situ lentiginous component, which was associated with invasion (not shown).


Fig. 3.36 Malignant melanoma, epithelioid cell type.

  Vaginal melanomas represent 0.3–1% of all melanomas and 3–5% of vaginal cancers.
  The tumors occur from the third to the ninth decades; most patients are postmenopausal (mean age 60 years). Vaginal bleeding or a mass is the usual presenting feature. Some tumors have been preceded by melanocytic hyperplasia (‘melanosis’). One patient had paraneoplastic cerebellar degeneration.
  Almost half the tumors occur in the lower third of the vagina; some of these also involve the vulva (vulvovaginal melanoma). The anterior and lateral vaginal walls are most commonly involved. The tumors are nodular to polypoid, and often ulcerated. Their typical pigmentation suggests the diagnosis, although some tumors are nonpigmented.
  Vaginal melanomas resemble mucosal melanomas in other sites, including the usual presence of a junctional in situ component, typically of lentiginous type with epidermal nests of atypical spindled melanocytes. The invasive component may be spindled, epithelioid, or mixed.
  Gupta et al. found positivity for S100, tyrosinase, MART-1, and HMB-45 in 96%, 81%, 77%, and 62% of tumors, respectively.
  The prognosis is generally poor because of deep invasion and/or advanced stage. Five-year survival rates range from 0% to 30%. In one study, 43% of patients with tumors ≤3 cm survived 5 years compared to 0% of those with tumors >3 cm.
  Differential diagnosis:

•  A poorly differentiated malignant vaginal tumor without squamous or glandular differentiation should suggest malignant melanoma. Positivity for the above markers and negative staining for cytokeratin facilitate the diagnosis in problematic cases.
•  An in situ component excludes metastatic melanoma and helps distinguish an amelanotic melanoma from a sarcoma or carcinoma.
•  Benign pigmented lesions lack the atypia, mitotic activity, and invasion of melanomas.

Yolk Sac Tumor ( Figs. 3.37 – 3.39 )


Fig. 3.37 Yolk sac tumor in a vaginectomy–hysterectomy specimen. A polypoid mass is present in the lower vagina (extreme left).


Fig. 3.38 Yolk sac tumor, reticular pattern.


Fig. 3.39 Yolk sac tumor, reticular pattern.

  These rare tumors (YSTs) account for 90% of extragonadal YSTs in the female genital tract. Some tumors involve both the vagina and cervix; one tumor was paravaginal.
  The tumors usually occur in children <3 years who typically present with vaginal bleeding or discharge and a vaginal mass. The serum AFP is usually elevated.
  The tumors are usually <5 cm in size, polypoid or sessile, and sometimes ulcerated, with soft, friable, and white to gray–tan sectioned surfaces, and focal hemorrhage and necrosis.
  The microscopic features are identical to ovarian YSTs ( Chapter 15 ).
  Over 50% of patients reported in the older literature died of disease despite radical surgical therapy. Currently, combination chemotherapy, with or without conservative surgical removal, achieves a cure in most cases.

Hematopoietic Tumors ( Fig. 3.40 )


Fig. 3.40 Lymphoma. The neoplastic cells are in small nests or singly disposed cells within a fibrotic stroma.

  Primary vaginal lymphoma is much less common than secondary lymphomatous involvement.

•  The age range is from 19 to 79 (mean 50 years). The usual presentation is vaginal bleeding or discharge, pain, dyspareunia, a mass, or symptoms related to urethral compression. Clinical/gross examination reveals an ill-defined, rubbery to firm, gray–white thickening or induration of the vaginal wall. Local extension to the cervix, rectovaginal septum, and pelvic side walls may be present.
•  Most tumors are of the diffuse large B-cell type, but rare cases of follicular mixed small and large cell lymphoma, diffuse mixed lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and angiocentric T-cell lymphoma have been reported. Rare tumors are EBV+.
•  Sclerosis, as in cervical lymphomas, is often prominent in diffuse large B-cell lymphomas. Some tumors may have a storiform pattern and spindle cell morphology.
•  Vaginal lymphomas are often misdiagnosed. The differential diagnosis is the same as for cervical lymphomas ( Chapter 10 ).
•  Unlike patients with secondary lymphomatous vaginal involvement, most patients with Ann Arbor stage I disease have a favorable prognosis following radiation and/or chemotherapy. In a study of seven cases, all were free of disease at last follow-up, although one patient had a relapse at 5 years.
  Rare vaginal myeloid sarcomas have been reported, about half of which have had acute myelogenous leukemia at the time of diagnosis. Of the 11 reported cases, eight of nine patients with follow-up died of disease, all but one within 16 months of presentation.
  Rare vaginal plasmacytomas and one case of vaginal involvement by angiofollicular lymphoid hyperplasia (Castleman's disease) have been reported.

Histiocytosis X


  Rare cases of vaginal involvement by histiocytosis X have been documented. In some of these cases, the vaginal involvement was followed by progressive disease. In other cases, the vaginal lesions followed oral or cutaneous lesions or diabetes insipidus.

Secondary Tumors ( Fig. 3.41 )


Fig. 3.41 Pagetoid invasion of vaginal epithelium by transitional cell carcinoma. The primary tumor was in the urinary bladder.

  One review found that 84% of invasive vaginal carcinomas were secondary, usually from tumors in other pelvic sites that included, in order of frequency, cervix, endometrium, colon and rectum, ovary, vulva, and urinary bladder or urethra. Even 75% of vaginal SqCCs were secondary, usually from the cervix or vulva.

•  Usually the spread is by direct invasion or lymphatics, the primary tumor is clinically evident or has already been treated, and the diagnosis is straightforward. In some cases, the metastatic tumor has a pagetoid pattern within the vaginal squamous epithelium.
•  Reyes et al. reported primary urothelial carcinomas of the bladder or renal pelvis with vaginal spread as in situ or invasive disease. The history is diagnostically crucial because of histologic and immuno histochemical overlap with primary vaginal carcinomas. Positivity for CK20 and urothelial markers is also helpful.
•  An association with endometriosis with an adenocarcinoma favors a primary tumor, which is usually of clear cell or endometrioid type.
  Spread of trophoblast to the vagina can occur in gestational trophoblastic disease. Vaginal involvement occurs in up to 50% of cases of uterine choriocarcinoma. In molar gestations, vaginal nodules consist of typical molar villi or avillous trophoblast. Vaginal nodules of intermediate trophoblast may also occur in normal pregnancies.
  Vaginal metastases may be the presenting sign of a distant tumor such as in the kidney, breast, pancreas, stomach, or a cutaneous malignant melanoma. Metastatic renal cell carcinoma may occur years after nephrectomy and mimic a vaginal clear cell carcinoma. Findings indicating the latter include vaginal adenosis or endometriosis, a tubulocystic pattern, hobnail cells, mucin, an absence of a sinusoidal vascular pattern, and a CD10−/RCC marker− immunoprofile.

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Malignant mixed tumors and synovial sarcoma
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Shevchuk, M. M., Fenoglio, C. M., Lattes, R., et al. Malignant mixed tumor of the vagina probably arising in mesonephric rests. Cancer . 1978; 42:214–223.
Toyoshima, M., Akahira, J., Moriya, T., et al. Primary vaginal adenosarcoma with sarcomatous overgrowth. Gynecol Oncol . 2004; 95:759–761.

Malignant melanoma
Cobellis, L., Calabrese, E., Stefanon, B., et al. Malignant melanoma of the vagina. A report of 15 cases. Eur J Gynaecol Oncol . 2000; 21:295–297.
Gupta, D., Malpica, A., Deavers, M. T., et al. Vaginal melanoma. A clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol . 2002; 26:1450–1457.
Kerley, S. W., Blute, M. L., Keeney, G. L. Multifocal malignant melanoma arising in vesicovaginal melanosis. Arch Pathol Lab Med . 1991; 115:950–952.
Van Nostrand, K. M., Lucci, J. A., III., Schell, M., et al. Primary vaginal melanoma: Improved survival with radical pelvic surgery. Gynecol Oncol . 1994; 55:234–237.

Yolk sac tumor
Copeland, L. J., Sneige, N., Ordonez, N. G., et al. Endodermal sinus tumor of the vagina and cervix. Cancer . 1985; 55:2558–2565.
Liebhart, M. Histopathological diagnosis of vaginal endodermal sinus tumors in infants. Int J Gynecol Pathol . 1986; 5:217–222.
Young, R. H., Scully, R. E. Endodermal sinus tumor of the vagina: A report of nine cases and review of the literature. Gynecol Oncol . 1984; 18:380–392.

Hematopoietic tumors
Doss, L. L. Simultaneous extramedullary plasmacytomas of the vagina and vulva. A case report and review of the literature. Cancer . 1978; 41:2468–2474.
Ferry, J. A. Lymphomas of the female genital tract. In: Extranodal lymphomas . New York: Saunders; 2011:259–281.
Gaunt, G. A., Gostout, B. S., Remstein, E., et al. Pelvic Castleman disease presenting as vaginal occlusion. Obstet Gynecol . 2002; 100:1082–1085.
Harris, N. L., Scully, R. E. Malignant lymphoma and granulocytic sarcoma of the uterus and vagina. A clinicopathologic analysis of 27 cases. Cancer . 1984; 53:2530–2645.
Perren, T., Farrant, M., McCarthy, K., et al. Lymphomas of the cervix and upper vagina: A report of five cases and a review of the literature. Gynecol Oncol . 1992; 44:87–95.
Policarpio-Nicolas, M. L. C., Valente, P. T., Aune, G. J., et al. Isolated vaginal myeloid sarcoma in a 16-year-old girl. Ann Diagn Pathol . 2012; 16:374–379.
Yoshinaga, K., Akahira, J. -I., Nikura, H., et al. A case of primary mucosa-associated lymphoid tissue lymphoma of the vagina. Hum Pathol . 2004; 35:1164–1166.

Histiocytosis X
Axiotis, C. A., Merino, M. J., Duray, P. H. Langerhans cell histiocytosis of the female genital tract. Cancer . 1991; 67:1650–1660.

Secondary tumors
Chagpar, A., Kanthan, S. C. Vaginal metastases of colon cancer. Am Surg . 2001; 67:171–172.
Gupta, D., Neto, A. G., Deavers, M. T., et al. Metastatic melanoma to the vagina: Clinicopathologic and immunohistochemical study of three cases and literature review. Int J Gynecol Pathol . 2003; 22:136–140.
Haines, M. Hydatidiform mole and vaginal nodules. J Obstet Gynaecol Brit Emp . 1955; 62:6–11.
Reyes, M. C., Park, K. J., Lin, O., et al. Urothelial carcinoma involving the gynecologic tract: A morphologic and immunohistochemical study of 6 cases. Am J Surg Pathol . 2012; 36:1058–1065.
Tarraza, H. M., Jr., Meltzer, S. E., DeCain, M., et al. Vaginal metastases from renal cell carcinoma: Report of four cases and review of the literature. Eur J Gynaecol Oncol . 1998; 19:14–18.
Chapter 4
Tumor-like Lesions and Benign Tumors of the Uterine Cervix


TUMOR-LIKE LESIONS 

Metaplasias and Ectopias 

Squamous Metaplasia 
Transitional Cell Metaplasia 
Tubal, Tuboendometrioid, and Endometrioid Metaplasia 
Endometriosis 
Endocervicosis 
Endosalpingiosis 
Deep Glands and Cysts 
Intestinal Metaplasia 
Oxyphilic Metaplasia 
Ectopic Prostatic Tissue and Ectopic Skene's Glands 
Other Ectopias 
Endocervical Glandular Hyperplasias 

Tunnel Clusters 
Microglandular Hyperplasia 
Diffuse Laminar Endocervical Glandular Hyperplasia 
Lobular Endocervical Glandular Hyperplasia 
Adenoid Basal Hyperplasia 
Mesonephric Lesions 

Mesonephric Remnants 
Mesonephric Hyperplasia 
Mesonephric Ductal Hyperplasia 
Reactive and Reparative Lesions 

Postbiopsy Pseudoinvasion of Squamous Epithelium 
Reactive and Reparative Atypia 
Pagetoid Dyskeratosis 
Radiation-induced Atypia 
Changes Secondary to Extravasation of Mucin 
Postoperative Spindle Cell Nodule (see Chapter 3 ) 
Pseudoactinomycotic Radiate Granules 
Inflammatory Lesions 

Typical Cervicitis 
Papillary Endocervicitis 
Follicular Cervicitis 
Florid Reactive Lymphoid Hyperplasia (Lymphoma-like Lesion) 
Plasma Cell Cervicitis 
Histiocytic Infiltrates and Noninfectious Granulomas 
Changes Related to Cautery and Monsel's Solution 
Eosinophilic Cervicitis 
Ligneous Cervicitis 
Pyoderma Gangrenosum 
Arteritis 
Infectious Lesions 

Viral Lesions 
Bacterial Lesions 
Parasitic Lesions 
Pregnancy-related Changes 

Ectopic Decidua 
Arias-Stella Reaction 
Placental Site Nodules and Plaques (see Chapter 10 ) 
Cervical Pregnancy 
Melanotic Lesions 

Blue Nevus 
Mucosal Melanosis 
Miscellaneous Tumor-like Lesions 

Multinucleated Stromal Giant Cells 
Signet-ring-like Epithelial Cells 
Amyloidosis 
Psammomatous Calcification 
Myxoid Change (see Chapter 7 ) 
Extramedullary Hematopoiesis (see Chapter 7 ) 
BENIGN TUMORS 

Epithelial 

Endocervical Polyps 
Squamous Papilloma 
Inverted Transitional Cell Papilloma 
Müllerian Papilloma 
Mixed Epithelial and Mesenchymal Tumors 

Adenofibroma 
Villous and Villoglandular Adenoma 
Adenomyoma of Endocervical Type 
Mesenchymal Tumors 

Tumor-Like Lesions

Metaplasias and Ectopias

Squamous Metaplasia ( Figs. 4.1 – 4.2 )


Fig. 4.1 Florid squamous metaplasia in a cervical polyp.


Fig. 4.2 Florid squamous metaplasia.

  This normal process within the transitional zone of postpubertal women results in the replacement of endocervical surface and glandular epithelium by squamous epithelium. Florid squamous metaplasia within endocervical glands or endocervical polyps can simulate invasive squamous cell carcinoma.
  Features favoring squamous metaplasia include a superficial location; nests of cells with smooth contours consistent with replaced endocervical glands; bland nuclear features; no stromal response; the presence of residual mucinous epithelial cells, gland lumina, or luminal mucin; and absence of dysplasia in the adjacent squamous epithelium.
  Immature squamous metaplasia is considered in Chapter 5 .

Transitional Cell Metaplasia ( Fig. 4.3 )


Fig. 4.3 Transitional cell metaplasia. The nuclei are elongated and appear to be ‘streaming’. Some nuclei have grooves.

  This process (TCM) is typically an incidental microscopic finding in postmenopausal and occasionally premenopausal women and normal prepubertal subjects. TCM may present with an abnormal Pap smear, but the distinctive appearance of the cells on smears allows their separation from an SIL, atrophy, and tubal metaplasia.
  TCM in postmenopausal women and in females receiving androgen therapy for gender reassignment suggests hypoestrinism as a cause in some cases. One case was associated with the adrenogenital syndrome and cervical ectopic prostatic tissue.
  TCM usually involves the ectocervical epithelium, less commonly the surface or glandular epithelium of the endocervix and transformation zone. Occasionally, the involved epithelium may invaginate into the underlying stroma that may result in isolated stromal nests of transitional cells.
  The epithelium is replaced by multiple layers of cells with pale, uniform, oval to spindle nuclei that are usually oriented vertically in the deeper layers, and horizontally (with a streaming or whorled pattern) superficially. Perinuclear halos may be present. A superficial layer of ‘umbrella’ cells is a rare finding.
  The N : C ratio is usually high and the nuclei have finely stippled chromatin, inconspicuous nucleoli, and occasional longitudinal nuclear grooves; mitotic figures are rare to absent. Rarely, the cells have superimposed dysplastic changes.
  TCM stains for CK13, CK17, and CK18, findings similar to those of urothelial transitional cell epithelium, but unlike the latter, CK20 is negative.
  The lack of normal maturation can suggest an HSIL, but that diagnosis is excluded by the bland nuclear features and absent or rare mitotic figures.
  The numerous layers of cells and nuclear grooves distinguish transitional cell metaplasia from atrophic squamous epithelium, although the cells of the latter occasionally appear transitional.

Tubal, Tuboendometrioid, and Endometrioid Metaplasia

General features


  Tubal metaplasia (TM) refers to the replacement of the endocervical columnar epithelium by tubal-type epithelium. Less commonly, the epithelium is intermediate in appearance between tubal and endometrioid epithelium (tuboendometrioid metaplasia, TEM), or rarely, it is purely endometrioid (endometrioid metaplasia, EM).
  These metaplasias are usually an incidental microscopic finding, but in some cases may account for abnormal cells in a Pap smear.
  TM was found in 21% of cone biopsy and 62% of hysterectomy specimens in one study. TEM was found in 26% of post-cone biopsy hysterectomy specimens in one series, suggesting that it is a reparative response in some cases.
  Vang et al. reported an unusual form of TM that was associated with in utero exposure to diethylstilbestrol (DES) (see below).

Microscopic features ( Figs. 4.4 – 4.6 )


Fig. 4.4 Tubal metaplasia. The glands vary in size and shape, and some are cystic. The periglandular stroma is more cellular than normal endocervical stroma.


Fig. 4.5 Tubal metaplasia. Most of the epithelial cells are ciliated.


Fig. 4.6 Tubo-endometrioid metaplasia within a previous cone biopsy site. Left: The tuboendometrioid glands (top) contrast with the normal endocervical glands. Right: Note admixture of ciliated and nonciliated cells within a tuboendometrioid gland.

  In TM, the endocervical surface or glandular epithelium is replaced by a single layer of admixed ciliated, nonciliated, and peg cells. TEM is similar to TM except for the presence of fewer ciliated cells. The nonciliated columnar cells of TM and TEM may have apical snouts.
  The glands involved by TM and TEM are usually similar to normal endocervical glands in size, shape, and distribution. Unusual findings in TM and TEM include variability in gland size and shape, cystic dilatation, focal crowding, a deep location (see Deep Glands and Cysts ), and periglandular stromal hypercellularity or edema.
  Vang et al. reported three cases of TM associated with in utero DES exposure with a haphazard pseudoinfiltrative pattern and involvement of the resection margins. In one case there was moderate atypia and mitotic activity.
  TM and TEM are distinguished from adenocarcinoma in situ (AIS) by an admixture of cell types, a usual absence of atypia, and an absence or paucity of mitotic figures, and from invasive adenocarcinoma by the usual absence of an infiltrative pattern. TM and TEM can occasionally be focally p16+ but without the strong diffuse staining of AIS.
  Rarely TM may merge with atypical TM and ciliated AIS ( Chapter 6 ).

Differential diagnosis


  Typical endometriosis of the cervix (see below). In contrast to TEM or EM, endometrial-type periglandular stroma is usually present in endometriosis, but may be sparse and partly obscured by inflammatory cells. Distinction between TM with cellular stroma and atrophic endometriosis may be impossible in some cases but is of no clinical importance.
  Ciliated AIS ( Chapter 6 ). This lesion is distinguished from TM and TEM by the presence of malignant nuclear features.
  Low-grade endocervical glandular dysplasia (EGD). Subtle or incompletely developed cases of TM that are difficult to recognize may be diagnosed as low-grade EGD, a diagnosis we avoid ( Chapter 6 ).
  Mesonephric hyperplasia (see corresponding heading) with endometrioid-like glands. The usual deep location of the process and admixture of more typical mesonephric tubules with their colloid-like luminal secretions facilitate the diagnosis.

Endometriosis ( Figs. 4.7 – 4.8 )


Fig. 4.7 Superficial cervical endometriosis. Left: A focus of endometriosis subtending normal endocervical glands could be misinterpreted as a tunnel cluster, but note endometriotic stroma within the focus. Center: Higher power view showing hyperchromatic mucin-poor cells that could suggest endocervical glandular dysplasia or adenocarcinoma in situ. Right: A different focus of endocervical endometriosis. Note endometriotic stroma as well as occasional mitotic figures in the glandular cells.


Fig. 4.8 Stromal endometriosis of endocervix at low- and high-power magnifications. Note hemorrhage between the endometriotic stromal cells. The appearance could suggest a diagnosis of Kaposi's sarcoma.

  Cervical endometriosis may be superficial (mucosal) or deep. The superficial form is often localized to areas of prior biopsy or cautery, suggesting implantation of menstrual endometrium or trauma-induced metaplasia. Deep cervical endometriosis is usually an extension of cul-de-sac involvement associated with typical pelvic endometriosis.
  Superficial endometriosis is usually an incidental microscopic finding, but occasionally it can cause a thickened, granular, or hemorrhagic mucosa, or result in an abnormal Pap smear. The lesion is almost always confined to the superficial one-third of the cervical wall, most often just beneath the surface epithelium.
  The endometriotic glands are typically well spaced and round to oval but occasionally may show irregularity in size and shape and crowding. They most commonly resemble the glands of a proliferative or weakly proliferative endometrium, including the presence of occasional mitotic figures, but occasionally have a secretory appearance.
  Endometriotic stromal cells are usually obvious although they may be sparse and/or obscured by edema, hemorrhage, and inflammation.

•  The presence of the characteristic small arterioles and extravasated erythrocytes can facilitate the recognition of the stromal component in such cases.
•  Special stains may help but are rarely needed. Reticulin and trichrome stains reveal that endometriotic stroma typically has dense reticulin and sparse collagen with the opposite findings in normal endocervical stroma. Endometriotic stromal cells are CD10+/CD34−, whereas endocervical stromal cells exhibit the opposite findings, although some periglandular endocervical stromal cells may stain for CD10.
  If endometriosis is not recognized microscopically, reactive atypia and/or mitotic activity in the endometriotic glands and their occasional p16 positivity may suggest endocervical glandular dysplasia or AIS.

•  An absence of both marked nuclear atypia and numerous apoptotic bodies and recognition of the endometriotic nature of the stromal cells facilitate the diagnosis. Also, the p16 staining is usually more focal than in AIS.
•  Additionally, the epithelial cells of endometriotic glands are strongly bcl2+, whereas those of AIS are bcl2−.
  Stromal endometriosis, an uncommon variant of endometriosis, is characterized by an exclusive component of endometriotic stroma.

•  Well-circumscribed foci within the superficial cervical stroma are composed of endometrial stromal cells, small blood vessels, and extravasated erythrocytes.
•  The differential diagnosis is most commonly with cervical involvement by endometrial stromal sarcoma. The lesion's small size, superficial location, and absence of the permeative growth and vascular invasion facilitate the diagnosis.
•  Is some cases, the appearance may cause concern for Kaposi's sarcoma (KS), although we are unaware of any reports documenting cervical KS. The latter is favored in the presence of a fascicular arrangement of mitotically active spindle cells with hyaline globules and an HSV8+/CD10−/ER− immunoprofile.

Endocervicosis ( Figs. 4.9 – 4.10 )


Fig. 4.9 Endocervicosis. Endocervical-type glands with an irregular size and shape lie within the outer wall of the cervix.


Fig. 4.10 Endocervicosis. Endocervical-type glands are surrounded by a reactive stroma, an appearance that initially raised concern for minimal-deviation adenocarcinoma (adenoma malignum).

  This term refers to the presence of ectopic benign-appearing endocervical-type glands ( Chapter 19 ). Occasionally the outer cervical wall and paracervical connective tissue are involved. In such cases, an infiltrative pattern, a stromal response to extravasated mucin, and the deep location of the glands may suggest adenoma malignum (minimal deviation adenocarcinoma) ( Chapter 6 ).
  Features distinguishing endocervicosis from adenoma malignum include the absence of a mucosal-based adenocarcinoma merging with the deep lesion, the absence of overtly dysplastic or malignant glands, and the occasional admixture of other benign müllerian-type glands, endometriotic stroma, or both.

Endosalpingiosis ( Fig. 4.11 )


Fig. 4.11 Endosalpingiosis. Glands lined by tubal-type epithelium lie within the deep endocervical stroma.

  Endosalpingiosis is considered in Chapter 19 . Although uterine involvement is typically confined to the uterine serosa, endosalpingiosis rarely can involve the wall of the cervix and lower corpus resulting in a clinically evident mass and a thickened wall with multiple cysts on gross examination.
  In one case, extensive mural endosalpingiosis of the uterine cervix was initially interpreted as minimal deviation adenocarcinoma. The absence of a mucosal-based tumor, the admixture of cell types including ciliated cells, and the absence of more than mild nuclear atypicality facilitate the diagnosis.

Deep Glands and Cysts ( Figs. 4.12 – 4.13 )


Fig. 4.12 Deep nabothian cysts.


Fig. 4.13 Deep nabothian cysts.

  Otherwise typical endocervical glands and their cystic counterparts (nabothian cysts) uncommonly extend into the outer third of the cervical wall. Deep glands are an incidental microscopic finding, but deep nabothian cysts may result in a striking gross appearance.
  In contrast to the glands of adenocarcinoma ( Chapter 6 ), deep glands and cysts are usually widely spaced, relatively uniform in size and shape, and lack cytologic atypia and a periglandular stromal response.

Intestinal Metaplasia


  Intestinal metaplasia is characterized by the presence of goblet and occasionally argentaffin cells within the endocervical glands.
  The finding is rare in a pure (nondysplastic) form, as it is usually associated with nuclear features of AIS (intestinal type of AIS) ( Chapter 6 ).

Oxyphilic Metaplasia ( Fig. 4.14 )


Fig. 4.14 Atypical oxyphilic metaplasia.

  Oxyphilic metaplasia is an incidental microscopic finding of no clinical significance. The change is invariably focal, involving only a few glands or even a single gland.
  The endocervical glandular or surface epithelium is replaced by a single layer of large, often cuboidal cells with dense, eosinophilic, focally vacuolated cytoplasm. The cells have enlarged hyperchromatic, often variably sized nuclei but usually without mitotic figures.
  A lack of cellular stratification, marked atypia, and mitoses facilitates distinction from endocervical glandular dysplasia and AIS. These lesions also usually lack abundant oxyphilic cytoplasm.

Ectopic Prostatic Tissue and Ectopic Skene's Glands ( Figs. 4.15 – 4.16 )


Fig. 4.15 Ectopic prostatic tissue.


Fig. 4.16 Ectopic prostatic tissue. Gland with squamous metaplasia (left). The gland is immunoreactive for prostate-specific antigen (right).

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