Vulva
7 October 2007
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Vulva - table of contents
Primary references, embryology, normal anatomy
Congenital abnormalities, inflammatory lesions, infection, case reports
Benign non-neoplastic disorders: Bartholin’s cyst, Behcet’s disease, leukoplakia, lichenification, lichen planus, lichen sclerosus, multinucleated atypia, squamous cell hyperplasia, vulvar dystrophy, vulvar hypertrophy with lymphedema
Benign or non-neoplastic tumors: angiomyofibroblastoma, benign skin adnexal tumors, bowenoid papulosis, cellular angiofibroma, fibroepithelial polyp, genital nevus, hidradenoma papilliferum, hypertrophic HSV, leiomyoma, melanocytic nevi, mixed tumor, mucosal polyp, pseudosarcomatous fibroepithelial stromal polyps, squamous papilloma, vulvar vestibular papillomatosis
Premalignant lesions: atypical melanocytic nevi of genital type, condyloma, differentiated vulvar intraepithelial neoplasia, dysplastic nevi, vulvar intraepithelial neoplasia
Malignant neoplasms: aggressive angiomyxoma, Bartholin’s gland carcinoma, basal cell carcinoma, basaloid carcinoma, Bowen’s disease, carcinoma-general, case reports, epithelioid sarcoma, leiomyosarcoma, melanoma, Merkel cell carcinoma, metastases, Paget’s disease, pigmented lesions, squamous cell carcinoma, verrucous carcinoma, warty carcinoma
Staging, features to report
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), Sep 1977 to Mar 2003
Archives of Pathology and Laboratory Medicine (Archives), Oct 1975 to Jan 2003
Human Pathology (Hum Path), Mar 1970 to Feb 2003
Modern Pathology (Mod Path), Jan 1988 to Feb 2003
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Please refer to these primary references for more detailed discussions and photographs
Germ cells arise from yolk sac at 4 weeks, migrate to urogenital ridge at 5-6 weeks, then mesothelium of urogenital ridge proliferates to form epithelium and stroma of gonad, incorporating the germ cells
At 6 weeks, lateral mullerian ducts (paramesonephric ducts) form from fusion of coelomic lining epithelium, proximal portion forms fallopian tubes, caudal portion fuses to form uterus, upper vagina
Urogenital sinus forms lower vagina and vestibule, fuses with mullerian ducts
In men, mullerian inhibitory substance from testes causes regression of mullerian ducts and paired wolffian (mesonephric) ducts form epididymis and vas deferens
If no functional testes, mullerian ducts persist and mesonephric duct regresses; mesonephric duct vestiges may persist as Gartner duct cysts in cervix or vagina
Vulva: immediately external to vagina; composed of mons pubis, clitoris, labia minora, labia majora, vulvar vestibule, vestibulovaginal bulbs, urethral meatus, hymen, Bartholin’s and Skene’s glands and ducts, vaginal introitus
Bartholin’s gland: major vestibular gland, tubuloalveolar structure with mucus-secreting columnar cells and urothelial lined duct
Clitoris: erectile tissue similar to corpora cavernosa of penis; lymphatics drain to deep inguinal nodes
Hymen: nonkeratinized stratified squamous epithelium
Labia majora: keratinized stratified squamous epithelium with hair follicles and eccrine, apocrine and sebaceous glands
Labia minora: nonkeratinized stratified squamous epithelium, usually no adnexae
Minor vestibular glands: simple tubular glands with mucus-secreting columnar cells that merge with stratified squamous epithelium of vestibule
Skene’s glands: periurethral glands analogous to prostate; mucus secreting columnar epithelium merges with duct urothelium, then stratified squamous epithelium of vestibule
Vulvar lymphatics: drainage for all but clitoris is to superficial inguinal nodes
Ectopic mammary tissue
Occurs along primitive milk line, from axilla to groin; may be source of papillary hydradenoma
May develop benign or malignant processes of ordinary breast tissue
Proposed criteria for primary breast carcinoma in vulva: histology consistent with breast carcinoma, non-neoplastic breast tissue or DCIS present in vulva, supportive immunohistochemistry (ER+, PR+, GCDFP-15+, HER2+), no carcinoma in ordinary breast tissue or other organs, inability to locate other primary carcinoma of vulvar glands or skin appendages
Case report of mucinous (colloid) adenocarcinoma, Archives 2002;126:1216
Micro images: mucinous carcinoma
Septate or double vagina
Associated with failure of fusion of distal mullerian ducts, double uterus (uterus didelphys)
Crohn’s disease
May be associated with perineal disease or vulvar fistulas
May be separated from anal lesions by normal tissue
Gross: hyperemia, edema, ulceration
Micro: noncaseating granulomas
Necrotizing fasciitis
Diabetic women
High mortality
Treatment: wide excision
Nonspecific vulvitis
Associated with blood dyscrasias, uremia, diabetes, malnutrition, avitaminoses
Vasculitis, isolated
Case report at Mod Path 1994;7:610
Vestibular adenitis
Inflammation of vestibular glands in vulvar vestibule submucosa
Produces small ulcerations
Treatment: surgical removal of mucosa
Vulvar vestibulitis
Chronic inflammation of lamina propria and periductal connective tissue of vestibule
Candida
Causes vulvovaginitis; 10% of women are carriers
Risk factors: diabetes, oral contraceptives, pregnancy
Clinical: small white surface patches with leukorrhea and itching
Diagnosis: see hyphae on wet mount
Garderella vaginalis
Small gram negative rods, implicated in vaginitis when other causes can't be found
Granuloma inguinale
Caused by Calymmatobacterium granulomatis, an encapsulated, non-motile, gram negative rod
Soft granulomatous area enlarges by peripheral extension and ulcerates
Micro: Donovan bodies (small round encapsulated bodies within histiocytes), seen best with silver or Giemsa stains; also pseudoepitheliomatous hyperplasia, plasma cells, histiocytes, small abscesses
DD: squamous cell carcinoma, soft tissue neoplasm if it spreads to retroperitoneum
Herpes simplex virus
Sexually transmitted disease characterized by labial ulcers with punched out centers
Extremely painful (“heartbreak of herpes”)
Papules in vulva, progress to vesicles, later coalescent ulcers
Also affects vagina and cervix
Usually HSV2 in young women
1/3 are symptomatic (lesions 3-7 days after sex); lesions heal in 1-3 weeks, but virus is latent in regional nerve ganglia
2/3 suffer recurrences (less painful)
High risk of transmission to neonate during vaginal birth, especially if active primary infection
Case report of associated necrotizing lymphadenitis, Archives 1985;109:1043
Micro: multinucleated giant cells with molding, ground glass nuclei
Human papillomavirus (HPV)
HPV subtypes 6,8,11,13 associated with papillary lesions
HPV subtypes 16, 18, 31, 33 associated with flat lesions
HPV 16 produces E6 protein that binds to p53 and E7 protein that binds to Rb protein
Koilocytotic atypia is a viral cytopathic effect, often NOT present in vulvar condylomas
Verrucopapillary lesions, even in children/young adults, are likely to be HPV associated, AJSP 1994;18:728
Lymphogranuloma venereum
Caused by Chlamydia trachomatis, L1-L3 serotypes
Sexually transmitted disease
Initial small ulcer at site of contact, then inguinal adenopathy with stellate abscesses surrounded by epithelioid histiocytes, then scarring, fistulas and strictures of urethra, vagina, rectum
Squamous cell carcinoma or adenocarcinoma may be engrafted on lymphogranulomatous structures
Diagnosis: Frei test (intradermal skin test), complement fixation, immunofluorescence
Molluscum contagiosum
Sexually transmitted disease that affects vulva only
Micro: molluscum bodies
Mycoplasma
Causes spontaneous abortions and chorioamnionitis
Neisseria gonorrhea
Affects entire gynecologic tract in adults except vagina; only children get vaginitis
Causes infertility
Begins in Bartholin’s glands or other vestibular or periurethral glands, then spreads to cervix, tubes, ovaries
Micro: acute suppurative reaction, inflammation within mucosa and submucosa only
Pelvic inflammatory disease
Clinical syndrome due to various bacteria
Compared to N. gonorrhea, exudates are less with Staphylococcal or Streptococcal infections or coliforms, but infection extends throughout wall to serosa and may cause bacteremia
Complications: infertility, peritonitis, intestinal obstruction due to adhesions, bacteremia
Syphilis
Primary syphilis has painless chancre, usually initial occurs in vulva in women
Chancre composed of plasma cells, lymphocytes, histiocytes, covered by zone of ulceration with neutrophils and necrosis; also endarteritis
Adjacent lymph nodes are enlarged with plasma cells, endarteritis within or outside capsule, fibrosis (capsular, pericapsular), follicular hyperplasia
Primary and secondary syphilis are infectious
Trichomonas vaginalis
Large, flagellated, ovoid protozoan
Diagnose in wet mount
15% of women in sexually transmitted disease clinic are infected
Purulent discharge, local discomfort, "strawberry" cervix (fiery red with thin epidermis)
Infection limited to epithelium and lamina propria
Benign non-neoplastic disorders
Often secondary to gonorrhea or other acute inflammation, which causes abscess then obstruction of duct
Painful; may be huge; seen in all ages, but often women age 40 or more
May be associated with accessory breast tissue
May have mucocele-like changes, Hum Path 1978;9:111
Treatment: excise in older women because of risk of adenoid cystic carcinoma; otherwise marsupialize
Micro: squamous and urothelial epithelium common, but may be destroyed by inflammatory infiltrate; still see residual mucinous glands with nonsulfated sialomucin; may have calcifications resembling malakoplakia
Oral ulcers, genital ulcers, ophthalmic inflammation
Prolific endothelial proliferation causes vascular occlusion
Clinical term, means vitiligo (loss of pigment); pathologists should NOT use this term
Causes include inflammatory dermatosis (psoriasis, chronic dermatitis), lichen planus, lichen simplex chronicus, lichen sclerosus, squamous cell hyperplasia, carcinoma-in-situ / Paget’s disease, invasive carcinoma
Changes due to scratching
Accentuation of normal lines of skin
Associated with squamous cell hyperplasia
A final common pathway of many itchy/scratchy diseases
aka Wickham’s striae
White, lacy, reticular lesion
Itching causes hyperkeratosis
Chronic, recurring, relapsing
Rarely have oral lesions
Micro: lymphocytic infiltrate
Chronic atrophic vulvitis
Persistent/progressive inflammatory dermatosis of unknown etiology with predilection for vulva; may be perianal
Usually age 40 years or older (more common after menopause)
Rare in children, may involute spontaneously at puberty
May be familial; associated with autoimmune diseases
Very itchy and scratchy skin
Not a premalignant lesion, but associated with well differentiated squamous cell carcinoma - in one study, 9% developed VIN, 21% developed invasive squamous cell carcinoma (mean 4 years later), Hum Path 1998;29:932
Gross: atrophic skin resembles cigarette paper (crinkly atrophy); often with loss of labia; also white/red ill-defined patches
Micro: severe hyperkeratosis; thin epidermis, loss of rete pegs, homogenized band of dense fibrosis at papillary dermis, chronic inflammation around vessels (particularly eosinophils), often band like
Proposed minimal histologic criteria: presence of vacuolar interface reaction pattern in conjunction with dermal sclerosis (homogenized and hyalinized eosinophilic collagen bundles) of any thickness intervening between the inflammatory infiltrate and epithelium and or vessel walls, Mod Path 1998;11:844
DD: allergic contact dermatitis
Usually young women
Micro: multinucleated epithelioid cells in lower to middle epithelial layers, containing 2-10 nuclei, often prominent nucleoli; no surface atypia, no hyperchromasia or pleomorphism; no significant inflammation
Negative stains: HSV
Molecular: HPV negative
Reference: AJSP 1994;18:1233
Squamous cell hyperplasia (keratosis)
Associated with cancer, but not considered premalignant unless VIN present
Do not appear to be precursor to HIV negative squamous cell carcinoma, Hum Path 1996;27:389
Suggested to diagnose as dermatosis, not a squamous hyperplasia, Mod Path 1997;10:401
Micro: epithelial hyperplasia and hyperkeratosis; increased mitotic figures in basal and prickle cell layers; mild dermal chronic inflammation; no atypia
Unrelated disorders that present as irregular patchy areas of thickened skin and severe itching
Often white skin (leukoplakia), but may be red
Easily traumatized
Suggested to diagnose as dermatosis, not as vulvar dystrophy, Mod Path 1997;10:401
Kraurosis: accompanied by soft tissue atrophy
Mixed vulvar dystrophy: squamous hyperplasia and lichen sclerosus
Vulvar hypertrophy with lymphedema
Case report of 43 year old quadriplegic woman with bilateral vulvar enlargement, Archives 2000;124:1697
Micro: hypocellular proliferation of fibroblastic cells in edematous-myxoid stroma, vessels with perivascular collagen deposition, ectatic tortuous lymphatics; no true thick-walled vessels
Micro images: image1, image2, image3
DD: aggressive angiomyxoma
Angiokeratoma of clitoris, Archives 1992;116:880
Desmoid tumor associated with pregnancy, Archives 1997;121:512
Extrapulmonary sugar tumor, Mod Path 2001;14:615
Granular cell tumor of clitoris, AJSP 1986;10:497
Lymphoma, T cell, in renal allograft recipient, AJSP 1993;17:842
Malakoplakia of Bartholin’s glands, Archives 1986;110:757
Neurofibromatosis, AJSP 1989;13:873
Phyllodes tumor, recurrent, in aberrant breast tissue, AJSP 1993;17:946
Solitary fibrous tumors, Mod Path 1997;10:1028
Sweat gland carcinomas, Archives 1985;109:43
Synovial sarcoma, Mod Path 1996;9:970
Undifferentiated sweat gland carcinoma mimicking epithelioid sarcoma, AJSP 1991;15:990
Benign or non-neoplastic tumors
Benign vulvar tumor, first described in 1992, AJSP 1992;16:373
Case report of sarcomatous transformation, AJSP 1997;21:1104
No reported recurrences after excision
Gross: well circumscribed, 0.5 to 12.0 cm
Micro: circumscribed tumor with alternating hypercellular and hypocellular areas, spindle cells and plump stroma cells with eosinophilic cytoplasm that aggregate around small blood vessels; may have binucleated or multinucleated cells; minimal stromal mucin, rare/no red blood cell extravasation, no atypia; rare/no mitotic figures; mast cells common
Positive stains: vimentin, desmin
Negative stains: actin, keratin, S100
EM: well developed rough endoplasmic reticulum, Golgi apparatus, intermediate filaments, pinocytotic vesicles
DD: angiomyxoma (not circumscribed, less cellular, fewer vessels, no hyalinized vessels, infrequent plump stromal cells, stromal mucin, RBC extravasation)
Reference: Mod Path 1996;9:284
Benign pilar tumor, syringoma, warty dyskeratoma
Type of vulvar intraepithelial neoplasia
Multiple small papules, often pigmented, in vulva of young women
Grossly resemble verrucae
Does not progress to invasive carcinoma, but may recur
Distinction between Bowen’s disease/CIS and bowenoid papulosis can usually be made clinically
Micro: atypia up to carcinoma in-situ, non-invasive; dysplastic cells arise in background of orderly epithelium with sparing of acrotrichium
Positive stains: HPV, p53
Women ages 39-50 years
Resemble labial or Bartholin’s gland cyst
First described in 1997, benign behavior in 2 of 2 cases
Gross: usually < 3 cm, well circumscribed
Micro: cellular neoplasm composed of uniform, bland, spindled cells, numerous thick walled and often hyalinized vessels, rare adipocytes; brisk mitotic activity
Positive stains: vimentin
Negative stains: CD34, S100, actin, desmin, EMA
DD: aggressive angiomyxoma, angiomyofibroblastoma, spindle cell lipoma, solitary fibrous tumor, perineuroma, leiomyoma
Reference: AJSP 1997;21:636
Loose myxoid stroma covered by squamous epithelium
May have bizarre, multinucleated stromal cells
Positive stains: desmin (often)
Prominent junctional nests with large cells
Seen in young women;
May be overdiagnosed as melanoma (usually age 50+)
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Aka papillary hidradenoma
Benign, small, sharply circumscribed nodule covered by normal skin, often on labia majora or interlabial folds
May ulcerate through skin and simulate carcinoma
May derive from ectopic mammary tissue (resembles intraductal papilloma)
Case report with associated intraductal apocrine breast cancer (GCDFP-15+, ER+, PR+), Archives 1991;115:1249
Micro: well differentiated, complex papillary glandular pattern with some stratification and pleomorphism; myoepithelial layer usually present
Hypertrophic herpes simplex virus in HIV positive patient
Rare; chronic hyperproliferative plaque or mass that clinically resembles malignancy
In vulva or perianal region
Case reports: Case of Week #53, 44 year-old African American man with a hypertrophic gluteal cleft plaque (J Drugs Dermatol 2003;2:198, free full text)
Treatment: often ineffective, often recurs
Gross images: vulvar mass
Micro: epithelial hyperplasia, brisk infiltrate of lymphocytes and plasma cells
Micro images: vulvar mass #1; #2; HSV immunostain
Positive stains: HSV
References: Dis Colon Rectum 2005;48:2289, BHIVA Conf 2005 Apr 20-23;11:PA8
Diagnosis: only 1 of these criteria (if 2, atypical leiomyoma; if 3, leiomyosarcoma): 5 cm+, infiltrative markers, 5+ mitotic figures/10 HPF, moderate/severe cytologic atypia, AJSP 1996;20:779
Treatment: conservative excision with long-term, careful follow up
Positive stains: ER, PR
Common in labia majora, usually intradermal or compound in adults
Aka chondroid syringoma
Benign, but looks different from mixed tumors elsewhere
Benign stroma covered with squamous epithelium
Pseudosarcomatous fibroepithelial stromal polyps
Resemble fibroepithelial stromal polyps of vagina, cervix and vulva, but with bizarre morphology, frequent mitoses (>10/10 HPF), atypical mitotic figures or hypercellularity
Median age 32, range 16-75 years
Often in pregnant patients
May recur locally; no metastases
Positive margin status, which is common, apparently not associated with recurrence
Gross: often multiple lesions, particularly in pregnant women
Positive stains: desmin
DD: aggressive angiomyxoma: deep, prominent vascular pattern cuffed by myoid bundles
angiomyofibroblastoma: well circumscribed subserosal nodule, no atypia, stromal cells cluster around vessels, which usually have delicate walls
botyroid embryonal rhabdomyosarcoma: early childhood, submucosal hypercellular zone/cambium layer, rhabdomyoblasts, myoglobin+, myogenin+
cellular angiofibroma: well circumscribed, less polypoid, diffusely vascular with hyalinized walls, no atypical stromal cells, desmin-
DFSP: CD34+, desmin-, storiform throughout
leiomyosarcoma: clear boundary of tumor cells with epithelium, smooth muscle differentiation
low grade endometrial stromal sarcoma: vessels resemble spiral arterioles, no central vascular core, thick bands of collagen in starburst pattern, dot like staining of desmin or keratin
MPNST: perivascular accentuation, 50% are S100+