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Vulva
Author: Nat Pernick, M.D. (see Authors page)
Last revised: 12 May 2012, last major update March 2003
Copyright: (c) 2003-2010, PathologyOutlines.com, Inc.
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 (7th 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 reports: 30 year old woman with 2 cm circumscribed mass (Case of Week #241);
80 year old woman with sarcomatous transformation (Am J Surg Pathol 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+)
top
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+
Reference: AJSP 2000;24:231
Papillary vulvar lesions without atypia
May contain HPV by
PCR
No microscopic features of condyloma
Vulvar vestibular papillomatosis
Lesions resemble condyloma but most are HPV negative
May be normal anatomic variant
Micro: like fingers, not like stalks of condylomas
Premalignant lesions
Atypical melanocytic nevi of the genital type
Usually on vulva (labia minora or clitoral region), also perineum, rarely mons pubis, axilla, male genitalia
Median age 25 years
Micro: nonspecific stromal pattern
DD: melanoma
Reference: Hum Path 1998;29 (1 Suppl 1):S1
Sexual transmitted disease, lesions may be multiple and coalesce
Vulvar, vaginal, perianal, perineal
Different from condyloma latum of syphilis
Flat condyloma more common than condyloma accuminatum
MIB staining present in 2+ epithelial cells in upper 2/3 of epithelium anywhere within the lesion, AJSP 2000;24:1393
Regress, except in immunocompromised
Treatment: CO2 laser, podophyllin application (for one week, causes epidermal pallor, keratinocyte necrosis, increased mitotic figures)
Micro: complex papillary arrangement of well differentiated squamous cells with intact basement membranes, well vascularized connective tissue stalk or flat lesion; T lymphocytes; acanthosis, hyperkeratosis, parakeratosis; orderly maturation but koilocytotic atypia (nuclear hyperchromasia, enlargement, pleomorphism and cytoplasmic cavitation), no other significant atypia, no atypical mitotic figures
May have pseudobowenoid changes resembling podophyllin effect or VIN (superficial keratinocytes in various stages of apoptosis, nuclear degenerative changes of absence of nuclear membrane and dispersed chromatin), Mod Path 1996;9:375
Molecular: diploid, tetraploid, octaploid
DD: vulvar intraepithelial neoplasia (abnormal mitotic figures, lack of maturation, nuclear pleomorphism, enlargement and hyperchromasia), squamous papillomas (no atypia)
Differentiated vulvar intraepithelial neoplasia
Maturation, variable hyperplasia, keratinization and parabasal atypia
Variable HPV
More common on labia majora than labia minora
Micro: stroma has concentric eosinophilic fibroplasia or lamellar fibroplasia, Hum Path 1998;29(1 Suppl 1):S1
Vulvar intraepithelial neoplasia (VIN)
Premalignant lesion
Incidence has markedly increased recently; becoming more common in women 20 to 35 years
Frequently coexists with HPV infection
Multifocal
VIN1 to VIN3 (carcinoma in situ / Bowen’s disease)
Malignant neoplasms
Bland appearing, slow growing, perineal lesions that may present at vulvar mass and simulate a Bartholin’s gland cyst
Usually teens/young adults, rarely children; occurs in men in scrotum
Recurs locally in ischiorectal or retroperitoneal space, perhaps due to incomplete excision, Hum Path 1985;16:621
Treatment: wide local excision
Case Reports: 28 year old woman with vulvar tumor (Case of the Week #181)
Gross: gelatinous, ill defined mass, larger and deeper than fibroepithelial polyp
Micro: spindled and stellate cells in hypocellular myxomatous stroma, no/rare mitotic figures, no atypia; thick walled vessels with dilated lumina and occasional hyaline thickening of adventitia; extravasation of red blood cells common; no bizarre stromal cells; often deep, prominent vascular pattern cuffed by myoid bundles
Positive stains: actin
Negative stains: S100, factor 8, CEA, keratin
EM: primitive mesenchymal cells with fibroblastic features
DD: vulvar hypertrophy with lymphedema
Nodular masses in labia majora in elderly, may be large and ulcerate
Solid, keratotic, adenoid types
Note: basal cell carcinoma may exhibit abrupt squamous differentiation of pilar type, but doesn’t affect prognosis
Rare nodal metastases seen with deeply invasive lesions
DD: basaloid carcinoma, basaloid changes in Bowen’s disease, invasive squamous cell carcinoma
Micro: relatively uniform population of small, ovoid cells with high N/C ratio resembling VIN 3; peripheral pallisading, resembles counterpart in upper aerodigestive tract; may have adenoid cystic component; associated with VIN
Molecular: HPV positive
Reference: AJSP 1993;17:133
Aka carcinoma in situ; a type of vulvar intraepithelial neoplasia
10% progress to invasive carcinoma if untreated
Treatment: wide local excision if localized; tumor at margin predicts recurrence
Gross: slightly elevated, plaque-like, red velvety appearance, centered on labia majora, may extend to perineum and anus
Micro: full thickness disorganization of epithelium with hyperkeratosis, parakeratosis, acanthosis, multinucleated dyskeratotic cells, abnormal mitotic figures throughout full thickness; has intracellular bridges; often involves intraepidermal portion of hair follicle (acrotrichium), but spares counterpart in sweat gland (acrosyringium)
Positive stains: p53
Molecular: often aneuploid; HPV-16 positive
95% squamous cell carcinoma; also basal cell, melanoma, adenocarcinoma
HPV related (90% are HPV 16, 18)
Multicentric, associated with VIN III (CIS/Bowen’s disease)
May regress or progress; progression more common in elderly and immunocompromised
Carcinomas associated with lichen sclerosus or squamous hyperplasia are usually HPV-, p53+ and have poor prognosis
Tumors with prominent keratinization are often confused with dermatitis or eczema
Risk of metastases is related to size, depth, angiolymphatic invasion
Survival: 60% if 2 cm in diameter or less after vulvectomy and lymphadenectomy; <10% with positive lymph nodes or larger tumors
More aggressive in vulva than in distal extremities, perhaps due to rhabdoid features at this site
Resembles malignant rhabdoid tumor
May recur locally (65%) or metastasize (75%), usually to lymph nodes, Mod Path 2001;14:655
Most die of disease (65%)
Micro: sheets of large epithelioid cells with marked cytologic atypia including prominent nucleoli, resembling poorly differentiated carcinoma, usually no granuloma-like pattern; often rhabdoid phenotype with intracytoplasmic inclusions
Positive stains: vimentin, keratin, EMA (85%), p53 (80%), HMB45 (25%), CEA (10%), CD99 (25%)
Negative stains: S100, CD31
EM: inclusions in rhabdoid cells are intermediate filaments
DD: synovial sarcoma (biphasic, CD34-), angiosarcoma (CD31+, EMA-), melanoma (S100+, HMB45+), MPNST (S100+), extrarenal rhabdoid tumor, undifferentiated carcinoma (usually connection to epidermis or adnexae, squamous or glandular differentiation, CD34-)
Reference: AJSP 1997;21:130, AJSP 1989;13:848
Proposed criteria is 3 of these features: 5 cm or larger, infiltrative markers, 5+ mitotic figures/10 HPF, moderate/severe cytologic atypia, AJSP 1996;20:779
Treatment: wide excision, long-term careful follow-up
Positive stains: ER, PR
Age 50+; much less frequent than squamous cell carcinoma
Associated with melanosis, Archives 1991;115:950
Most lesions are advanced (Clark’s level III, IV)
Treatment: radical vulvectomy with bilateral inguinal nodal dissection or wide local excision for small lesions with depths of 1.75 mm+
5 year survival 35% (poor prognosis for mucosal melanomas)
Prognostic factors: nodes, level / thickness
Gross: large, infiltrating, variegated; nodular areas may be less pigmented
Micro: radial growth phase melanomas have fibroplasia with a plaque like lymphocytic infiltrate and diffuse eosinophilic fibroplasias; thick or deeply invasive vertical growth phase melanomas have fibroplasia with angiogenesis or an absence of evidence for parenchymal stromal reciprocal interactions, Hum Path 1998;29(1 Suppl 1):S1
Clark’s levels:
Level I - in situ
Level II - extends into superficial papillary dermis
Level III - fills and expands the papillary dermis
Level IV - invades the reticular dermis
Level V - invades into fat or other deeper tissues
Breslow measurements:
Invasion < Invasion <0.75 mm from deep border of granular layer
Invasion 0.76 mm to 1.5 mm from deep border of granular layer
Invasion >1.5 mm from deep border of granular layer
Chung Modification of Breslow Measurement
1 - Intraepithelial (melanoma in situ)
2 - Invasion of < 1 mm into dermis or lamina propria
3 - Invasion 1-2 mm into subepithelial tissue
4 - Invasion > 2 mm into fibrous or fibromuscular tissue
5 - Extension into subcutaneous fat
Very aggressive
May be associated with Bowen’s disease
50% from cervix; also endometrium, kidney, gastrointestinal tract
Malignant glandular tumor of vulva, either primary (vulva only, a sweat gland carcinoma arising from acrosyringium or carcinoma of basal layer differentiating along eccrine lines) or secondary (due to adenocarcinoma of anorectum, urothelium, prostate)
Crusting, weeping, oozing lesion; may be erythematous
Recurrences common due to residual disease
Only rarely causes death
In vulva and perianal region, lesion is red, crusted, sharply demarcated, usually on labia majora (also male perineum)
Good prognosis if no invasive disease present since does not metastasize, although may recur as invasive disease
May be associated with VIN
May recur in split thickness skin graft
Note: in breast, presence of Paget’s cells almost always indicates an underlying carcinoma, and intradermal cells are usually mucin negative
In vulva, 70-85% of cases are primary (no underlying carcinoma) and are usually mucin positive
Primary vulvar Paget’s is usually positive for CK7 and GCDFP-15, negative for CK20
Vulvar Paget’s secondary to anorectal carcinoma is usually positive for CK20, negative for CK7, GCDFP-15
Vulvar Paget’s secondary to urothelial carcinoma is usually positive for CK7, CK20 and uroplakins UP-III, negative for GCDFP-15, Hum Path 2002;33:545
May originate from apocrine glands (GCDFP-15 positive), aberrant embryonic cells of sweat gland lineage or ectopic cells from Bartholin’s glands (similar mucin phenotypes)
Case report of pseudoinvasive disease, Archives 1998;122:471
Rarely detected by pap smear, Archives 1988;112:941
Treatment: excise margin of normal skin and subcutaneous tissue to include all sweat glands (may not identify microscopic disease at surgery)
Micro: large pale staining tumor cells, usually in lower epidermis, in nests, glandular spaces or continuously along basement membrane; also in pilosebaceous ducts and sweat glands, tumor cells have abundant cytoplasm, large nuclei, prominent nucleoli; may see cleft between tumor cells and overlying keratinocytes; basal layer still present around outside of clusters, gland formation may be present; may have intracytoplasmic melanin, lichenoid lymphocytic infiltrates in papillary dermis; associated with fibroepithelioma-like hyperplasia (9%) or papillomatous hyperplasia (AJSP 2000;24:543); also associated with carcinoma in situ of sweat glands
May resemble invasive disease due to marked intraepithelial proliferation with deep invaginations, tangential sectioning of rete pegs, papillary dermis stroma resembling desmoplastic response, Archives 1998;122:471
Primary vulvar Paget cells tend to be large with abundant pale cytoplasm, round vesicular nuclei, prominent nucleoli, no/rare mitoses
Vulvar Paget cells secondary to urothelial carcinoma resemble high-grade urothelial cells, with anaplastic nuclear features, variable nuclear shapes, coarse irregular chromatin, infrequent/nonprominent nucleoli, high mitotic rate
Vulvar Paget cells secondary to anorectal carcinoma resemble gastrointestinal glands with stratified columnar cells, goblet cells and intraluminal necrosis
Positive stains: CEA, mucicarmine, CAM5.2, B72.3, GCDFP-15, S100 (30%), MUC1, MUC5AC, CK7, UP-III (secondary to urothelial carcinomas)
Negative stains: PAS, Alcian blue, HMB45, CK20 (usually for primary cases)
EM: glandular differentiation
DD: melanoma (has intercellular bridges), invasive carcinoma
References: AJSP 2001;25:1469 (mucin gene expression), AJSP 1984;8:43 (immunostains study), AJSP 1977;1:193
Melanoma, melanosis (lentigo simplex), VIN III (gray/blue), nevus, atypical nevomelanocytic lesions of young women (highly atypical cells which mature, good prognosis, looks like acral-lentiginous melanoma)
95% of vulvar carcinomas
Mean age 60-74, rare in women younger than 30 years
Risk factors: large number of sexual partners, cigarette smoking, immunodeficiency, genital granulomatous disease, cervical carcinoma (? field effect)
Two types: HPV related (younger women, often basaloid or warty histology with VIN of similar histology) and non-HPV related (usually HPV-16, older women, usually keratinizing, associated with vulvar dystrophies)
Usually on labia majora, also labia minora, clitoris
20% metastasize to regional nodes; labial tumors to superficial inguinal nodes, clitoral tumors to deep inguinal nodes
Note: enlarged, hyperplastic nodes are common source of clinical error in assessment
Clitoral tumors are associated with lichen sclerosis, often have a prominent fibromyxoid stromal response and usually are not associated with VIN 3
Treatment: wide local excision with 1 cm margins if small, superficial (3 mm) and well differentiated; or radical vulvectomy with bilateral lymph node dissection; advanced cases have iliac lymphadenectomy, pelvic extenteration; radiation therapy also used
Prognosis: 5 year survival 50-75%; based on lymph node status (most important), tumor size, depth; extracapsular nodal spread and size of metastatic focus also important
Case report: keratinizing squamous cell carcinoma with adjacent carcinoma in situ, HPV negative, in 26 year old woman, Archives 2001;125:267
Gross/micro images: image1
Micro: usually well differentiated; tumors on clitoris may be more anaplastic; VIN often present at margins
High grade lesions may show focal glandular differentiation, but don’t call adenosquamous
Molecular: loss of 4p13, 3p, 5q; gains of 3q, 8p, Mod Path 2001;14:377; HPV +, Hum Path 1991;22:711
Microinvasive squamous cell carcinoma
Depth of invasion < 5 mm; however, may still need inguinal lymphadenectomy
Controversial concept
Aka giant condyloma of Bushki/Lowenstein
A well differentiated squamous cell carcinoma, similar to counterpart in aerodigestive tract
Note: if infiltrative or atypia present, cannot call verrucous
Very good prognosis, but may die of local invasion (metastases extremely unusual)
DO NOT RADIATE (radiation causes dedifferentiation in some)
Some call hybrid if features of verrucous and squamous carcinoma
Gross: may be huge, typically is exophytic, invades locally
Micro: "baggy pants" pattern (broad bulbous masses, pushing into underlying stroma); not infiltrative, no atypia
Molecular: HPV negative
DD: condyloma accuminatum, conventional squamous cell carcinoma (infiltrative, cytologic atypia)
Warty (condylomatous) carcinoma
Usually women age 60 or less, higher percentage of black women than with keratinizing squamous cell carcinoma
Resembles condyloma microscopically
Treat with radiation
Report: depth, cleft involvement, perineural invasion; other changes (severe dysplasia, etc.)
Micro: tumor cells display marked pleomorphism, atypia, enlargement and multinucleation, associated with koilocytotic atypia in adjacent epithelium; invades via single cells or clusters of cells, NOT the broad front of verrucous carcinoma; associated with VIN
Molecular: HPV often detected
Reference: AJSP 1993;17:133
Includes tumors with primary site of growth in vulva only; excludes mucosal melanoma
AJCC 7th edition reflects new staging adopted by FIGO in 2008
Primary tumor (T) and FIGO stage in ( )
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ (preinvasive carcinoma) – no longer part of FIGO classification
T1a (IA): Lesions 2 cm or less in size, confined to the vulva or perineum, and with stromal invasion 1.0 mm or less
T1b (IB): Lesions more than 2 cm in size OR any size with stromal invasion more than 1.0 mm, confined to the vulva or perineum
T2 (II): Tumor of any size with extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement)
T3 (IVA): Tumor of any size with extension to any of the following: upper/proximal 2/3 of urethra, upper/proximal 2/3 of vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone
Notes:
(1) The depth of invasion is measured from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion
(2) FIGO uses classification T2/T3, defined as T2 in TNM
(3) FIGO uses classification T4, defined as T3 in TNM
Regional lymph nodes (N) and FIGO stages in ( )
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: One or two regional lymph nodes with the following features:
N1a (IIIA): 1 lymph node metastasis 5 mm or less
N1b (IIIA): 1 lymph node metastasis 5 mm or greater
N2 (IIIB): Regional lymph node metastasis with the following features:
N2a (IIIB): Three or more lymph node metastases each less than 5 mm
N2b (IIIB): Two or more lymph node metastases 5 mm or greater
N2c (IIIC): Lymph node metastasis with extracapsular spread
N3 (IVA): Fixed or ulcerated regional lymph node metastasis
Note: The site and laterality of lymph node metastases should be described
Distant Metastasis (M) and FIGO stages in ( )
M0: No distant metastasis
M1 (IVB): Distant metastasis (including pelvic lymph node metastasis)
Stage grouping
Stage 0: Tis N0 M0
Stage I: T1 N0 M0
Stage IA: T1a N0 M0
Stage IB: T1b N0 M0
Stage II: T2 N0 M0
Stage IIIA: T1-T2 N1a-b M0
Stage IIIB: T1-T2 N2a-b M0
Stage IIIC: T1-T2 N2c M0
Stage IVA: T1-T2 N3 M0 or T3 any N M0
Stage IVB: M1
Note: FIGO no longer includes Stage 0 (Tis)
Anatomic site and location
Size
Depth of invasion (squamous cell carcinoma: from epithelial-stromal junction of adjacent most superficial dermal papilla to deepest point of invasion)
Histologic type
Histologic grade
Pagetoid spread
Type of invasion (infiltrating, pushing, mixed)
Angiolymphatic invasion
Adjacent organs
Margins
Presence of precancerous lesions
Presence of vulvar dystrophies
Descriptive features (ulcers, etc.)
Lymph nodes: total, number positive, location, tumor size
Involvement or not of adjacent tissue
Reference: Archives 2000;124:51
End of Vulva chapter