Gynecologic Pathology: An Atlas of Essential Pathology for Gynecologists Ivan Damjanov, Fang Fan, Ossama Tawfik
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Vulva1

 
NORMAL ANATOMY AND HISTOLOGY
Vulva represents the external part of the female genital organs. It consists of the mons pubis, the labia majora and labia minora, the clitoris, and the vestibule of the vagina (Fig. 1.1). Vulva includes the external orifice of the urethra and the accessory mucous glands.
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Figure 1.1: Normal vulva.
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The aspects of normal anatomy and histology that are most important for the understanding of vulvar pathology are as follows:
  • The vulva is covered with skin that is similar to the skin on other parts of the body.
    • Many vulvar diseases are similar to skin diseases affecting other parts of the body.
  • Vulvar skin is partially covered with pubic hair which covers the mons pubis and lateral sides of the labia majora.
    • Infections of the hair follicles of the pubic area are similar to infections of other hairy parts of the body.
  • Histologically, the skin covering the vulva is composed of squamous epithelium. The squamous epithelium of the mons pubis, labia majora and minora undergoes surface keratinization (Fig. 1.2).
    • Squamous epithelium is resistant to bacterial infections but can be infected by viruses (e.g. Human popillomavirus—HPV) or fungi (e.g. Candida albicans).
    • Most of the tumors of the vulva are squamous cell neoplasms.
  • Epithelium covering the vestibule is continuous with the epithelium of vaginal mucosa, which is also a hormone sensitive squamous epithelium. Vulvar mucosa resembles vaginal epithelium and does not show keratinization.
    • Keratinization of vestibular mucosal squamous epithelium is an abnormal finding.
  • The vaginal vestibule contains tubular and alveolar glands, the most important of which are the major vestibular glands–vulvovaginal (Bartholin) and periurethral (Skene) glands.
    • Bacteria can enter the ducts and infect the glandular epithelium (e.g. Bartholin's gland abscess).
  • The vulva is closely related to the terminal parts of the urinary and gastrointestinal tract (anus).
    • Vulvar infections are often related to bacteria from the anus or lower urinary tract.
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Figure 1.2: Vulva: Normal histology.
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OVERVIEW OF PATHOLOGY
The most important diseases of the vulva are classified as follows:
  • Inflammatory diseases
  • Cysts
  • Neoplastic diseases
 
Inflammatory Diseases
Inflammatory diseases may be infectious, immune-mediated, related to mechanical factors or exogenous irritants, or may have no identifiable causes (Box 1.1).
  1. Infections of vulva: These can occur in an isolated form or together with involvement of the entire female genital tract or the entire body (Box 1.2).
  2. Genital herpes: It is the most common sexually transmitted disease of the vulva. Typically, it presents in form of small grouped vesicles. Fluid accumulates inside the tissue clefts formed inside the epithelium (Fig. 1.3). These vesicles tend to recur and usually ulcerate and heal without scarring.
  3. Condyloma acuminatum or genital wart: It is a exophytic epithelial lesion related to HPV infection. Condylomata lata are usually caused by HPV-6, and less commonly by HPV-11. Like other HPV viruses, these two DNA viruses cause proliferation of squamous epithelium with koilocytic changes (Fig. 1.4). Condylomata acuminata do not progress to neoplasia.
  4. Hidradenitis suppurativa: It is a bacterial infection of the apocrine glands attached to the hairy part of the vulva (Fig. 1.5).
  5. Non-neoplastic epithelial disorders: These include several chronic vulvar diseases of noninfectious origin that are classified as follows:
    • Lichen sclerosus: This disease of unknown etiology accounts for approximately one-third of all vulvar nonneoplastic chronic diseases (Box 1.3 and Fig. 1.6).
    • Squamous cell hyperplasia: It usually presents clinically as a leukoplakia or erythroplakia and could be mistaken for carcinoma (Box 1.4 and Fig. 1.7).
    • Chronic vulvar dermatitis: This group of diseases includes many forms of systemic dermatitis such as psoriasis or lichen planus. Histologically, these diseases produce the same change as in the skin of other parts of the body.
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Figures 1.3A and B: Herpes virus infection: A. Low-power view of an intraepidermal herpetic vesicle. B. Higher power view of a cluster of multinucleated giant cells with typical intranuclear inclusions.
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Figures 1.4A to C: Condyloma acuminatum of vulva: A. The lesion is characterized by papillomatosis, acanthosis and hyperkeratosis. B. Prominent acanthosis and hyperkeratosis. C. Typical koilocytes are noted with raisinoid hyperchromatic nuclei surrounded by a perinuclear cytoplasmic halo.
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Figure 1.5: Hidradenitis suppurativa: Extensive marked acute and chronic inflammation in dermis and subcutaneous tissue with abscess formation and a trapped hair shaft (arrow).
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Figures 1.6A and B: Lichen sclerosus: A. The vulva is focally covered with pale white plaque-like lesions with focal ecchymosis and ulceration. B. Microscopic features include hyperkeratosis with a loss of rete ridges, subepidermal homogenized zone of edema and hyalinization, and a band of chronic inflammation.
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Figure 1.7: Squamous cell hyperplasia (keratosis): The microscopic features include epithelial thickening with acanthosis, hyperkeratosis, and a prominence of the stratum granulosum. Note the absence of nuclear atypia. Mitoses are sparse and limited to the basal layer.
 
CYSTS
Cysts develop from embryonic remnants, invagination of the epidermis, or due to an obstruction of the vulvar gland ducts.
  1. Epidermoid cysts: These are the most common vulvar cysts. These cysts are similar to those occur in the other parts of the body. They are lined by squamous epithelium and filled with keratinous debris.
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  2. Bartholin gland cyst: It results from obstruction of the major duct (Box 1.5 and Fig. 1.8). Despite the obstruction, the glands continue secreting mucus that accumulates inside the cyst. It occurs chiefly during the reproductive ages.
 
Neoplastic Diseases
  1. Vulvar intraepithelial neoplasia (VIN): It represents a spectrum of squamous intraepithelial lesions of the vulvar skin characterized by disordered squamous maturation, nuclear abnormalities, and mitotic figures (Box 1.6). VIN is almost invariably associated with human papillomavirus infection, most commonly HPV type 16.
The degree of atypia and dysplasia of VIN is pathologically graded as mild, moderate or severe. In VIN 1, atypia is confined to the lower third of the epithelium (Fig. 1.9). In VIN 2, atypia involves the basal and middle thirds of the epithelium (Fig. 1.10).
In VIN 3, the atypia involves the entire thickness of the epithelium (Fig. 1.11). The lesions may be classified as warty, showing surface keratinization and papillomatosis, or basaloid, when flat and showing intraepithelial changes similar to those in the cervix.
  1. Invasive squamous cell carcinoma: It is the most common malignant tumor of the vulva (Box 1.7) and occurs more frequently in older women. Typically, it evolves in the background of VIN. The tumor is composed of invasive squamous cells of varying degrees of differentiation (Figs 1.12 to 1.19 and Box 1.8).
The prognosis depends on the stage of the tumor and the presence or absence of metastases. Other parameters such as histologic grade, type, and DNA ploidy are also included in the pathology report as they carry certain prognostic significance.
  1. Extramammary Paget's disease: It is an intraepithelial carcinoma characterized by distinctive large malignant cells growing along the epidermal basal layer (Fig. 1.20). It presents clinically as red and eczematoid lesions resemble dermatosis. In contrast to mammary Paget's disease (typically associated with underlying ductal carcinoma), ductal or glandular carcinoma can rarely be demonstrated underneath the epithelium involved by Paget's disease of the female genital tract. It may histologically resemble malignant melanoma, which must be excluded before the diagnosis of extramammary Paget's disease is made.
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Figures 1.8A to C: Bartholin's gland and Bartholin's gland cyst A. The normal gland is composed of mucous glands and excretory ducts. B. Bartholin's gland cyst. It is located in labia minora and forms a protruding mass. Obstruction of the duct is accompanied by inflammation, imparting the inflamed cyst a red color. C. Microscopically, the cyst is lined by transitional or squamous epithelium.
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Figures 1.9A and B: Vulvar intraepithelial neoplasia 1 (VIN 1): A. Squamous dysplasia is minimal and limited to the basal layers of epithelium. Koilocytes are signs of HPV infection. B. Cytologic smear of low grade intraepithelial neoplasia contains cells that have enlarged, hyperchromatic nuclei and show koilocytic features.
  1. Melanocytic tumors: These include benign melanocytic nevi and malignant melanomas.
    • Melanocytic nevus: Congenital and acquired nevi (moles) occur in the vulva, usually in the labia majora. These nevi have the same features as nevi in other locations (Fig. 1.21).
    • Malignant melanoma: This rare tumor accounts for 5 to 10% of vulvar malignancies and is the second most common malignant tumor at this site. Pathologically, it has the same features as skin melanomas in other sites (Box 1.9 and Figs 1.21 to 1.23).
  2. Mesenchymal tumors and tumor-like lesions: They are rare. The most important lesions are as follows:
    • Fibroepithelial polyp: This superficially located polypoid vulvar lesion is composed of loose myxoid stroma covered by normal squamous epithelium (Fig. 1.24).
    • Aggressive angiomyxoma: This tumor often presents as a bulky vulvar mass no sharp margins. The mean age at diagnosis is 30 years, but the tumor may also occur in older or younger women, and even in children. Clinically, it mimics a Bartholin's gland cyst or hernia. The tumor is composed of spindle or stellate shaped cells arranged in myxoid stroma around thin-walled and thick-walled blood vessels (Fig. 1.25). These cells have immunohistochemical features characteristic of smooth muscle cells.
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      Figures 1.10A and B: Vulvar intraepithelial neoplasia 2 (VIN 2): A. Squamous dysplasia involves the lower two thirds of the epithelial layer, which also shows marked koilocytic changes and scattered mitoses. B. Pap smear shows dysplastic squamous cells with a high nuclear-cytoplasmic ratio and hyperchromatic nuclei.
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      Figures 1.11A and B: Vulvar intraepithelial neoplasia 3 (VIN 3): A. Low-power view showing the transition between normal and dysplastic epithelium. Notice the full thickness dysplasia of the epithelium and the absence of stromal invasion. B. High-power view showing loss of normal maturation, nuclear pleomorphism, hyperchromasia, and increased mitotic activity throughout the entire thickness of epithelium.
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      Figure 1.12: Invasive squamous cell carcinoma. Radical vulvectomy specimen showing bilateral fungating ulcerative lesions on both sides of the vulva.
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      Figure 1.13: Invasive squamous cell carcinoma of vulva: The tumor shows marked stromal invasion. The tumor thickness is measured from the surface or the granular layer of epithelium to the deepest point of invasion. The depth of invasion is measured from the epithelial stromal junction of the adjacent most superficial dermal papillae to the deepest point of invasion.
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      Figure 1.14: Well-differentiated, invasive squamous cell carcinoma of vulva. The tumor is keratinized and shows moderate nuclear atypia.
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      Figure 1.15: Poorly-differentiated, invasive non-keratinizing squamous cell carcinoma of vulva. Sheets of anaplastic tumor cells show no keratinization.
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      Figure 1.16: Poorly-differentiated, invasive keratinizing squamous cell carcinoma of vulva. Sheets of anaplastic tumor cells evoke a desmoplastic stromal response. Individual cell keratinization is present.
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      Figure 1.17: Poorly-differentiated, invasive non-keratinizing squamous cell carcinoma of vulva. High-power view shows marked anaplasia and frequent atypical mitosis.
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      Figure 1.18: Poorly-differentiated, invasive non-keratinizing squamous cell carcinoma of vulva. Lymphatic spaces contain tumor cells (arrow).
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      Figure 1.19: Moderately-differentiated, invasive keratinizing squamous cell carcinoma of vulva. There is perineural invasion by tumor cells.
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      Figures 1.20A and B: Extramammary Paget's disease of vulva: A. The epidermis contains groups of cells and single large pale tumor cells that differ from the surrounding squamous cells. B. Immunohistochemical stain for epithelial membrane antigen (EMA) highlights the Paget's cells in the epidermis.
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      Figure 1.21: Intradermal nevus: Benign melanocytic nevus cells are noted in the dermis.
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      Figure 1.22: Radical vulvectomy specimen with malignant melanoma: The tumor shows areas of brown pigmentation, hemorrhage, and necrosis. The green ink was added during dissection to indicate the visible margins of this tumor.
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      Figure 1.23: Malignant melanoma of vulva: Sheets of large malignant cells with atypical nuclei and prominent nucleoli. Occasional melanin pigmentation is seen.
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      Figure 1.24: Fibroepithelial polyp: The lesion is composed of benign squamous epithelium and benign fibrovascular stroma. The epidermis shows with no cellular atypia or koilocytic changes.
    • Angiomyofibroblastoma: This rare benign vulvar tumor usually presents as a well-demarcated small nodule measuring less than 5 cm in diameter. It is composed of thin-walled blood vessels surrounded by rings of spindle-shaped cells bordered by less cellular acellular spaces (Fig. 1.26). The spindle cells are epithelioid myofibroblasts, which have eosinophilic cytoplasm and stain immunohistochemically with antibodies to smooth muscle markers (e.g. desmin or smooth muscle cell actin).
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      Figure 1.25: Aggressive angiomyxoma of vulva: Hypocellular fibromyxoid stroma contains prominent medium-sized blood vessels.
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      Figure 1.26: Angiomyofibroblastoma of vulva: The tumor is moderately cellular and consists of spindle-shaped myofibroblasts surrounded by fibrotic extracellular matrix. There are scattered small blood vessels.
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    • Angiosarcoma: This form of sarcoma rarely occurs in the vulva. It is usually hemorrhagic and necrotic and bleeds easily. It is composed of malignant endothelial cells and is similar to angiosarcomas in other locations (Fig. 1.27).
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Figures 1.27A and B: Angiosarcoma of vulva: A. Partial vulvectomy specimen with a cross-section showing dermal and subcutaneous tissue involvement by a hemorrhagic ill-defined tumor. B. There are numerous vascular spaces lined by large atypical malignant endothelial cells.