Carcinoma of the Vulva

Postgraduate-Level Review from Berek & Novak's Gynecology

EPIDEMIOLOGY AND INCIDENCE

• Predominantly affects postmenopausal women; most common anogenital cancer in women >70 years
• 5-year survival rate: 72% in the United States
• Most cases are diagnosed at early stage
• Incidence of in situ vulvar cancer is increasing worldwide, driven largely by young women who account for 75% of in situ cases
• Squamous cell carcinomas: >80% of all primary vulvar malignancies
• Melanomas, adenocarcinomas, basal cell carcinomas, Paget disease, and sarcomas are less common

ETIOLOGY AND PATHOGENESIS

Pathway 1 - HPV-Related (Basaloid/Warty Type)

• Comprises ~40% of vulvar SCC
• Tends to be multifocal, occurs in younger patients
• Associated with: HPV infection (especially HPV-16, HPV-33, HPV-18), usual-type VIN (uVIN), immunosuppression, cigarette smoking
• A meta-analysis of 5,015 vulvar cancers showed 40% prevalence of HPV overall; nearly 80% of warty/basaloid cancers are HPV-positive
• Epidemiologic risk factors similar to cervical cancer: multiple lower genital tract neoplasias, immunosuppression, smoking
• Nine-valent HPV vaccine has potential to prevent up to 90% of HPV-associated vulvar cancers

Pathway 2 - Non-HPV-Related (Keratinizing/Differentiated/Simplex Type)

• Comprises ~60% of cases
• Tends to be unifocal, occurs in older patients
• Associated with: lichen sclerosus, chronic inflammatory dermatoses, differentiated-type VIN (dVIN)
• Adjacent lichen sclerosus or dVIN found in >80% of keratinizing carcinomas
• Population-based study: 36-fold increased risk of vulvar cancer for women with lichen sclerosus
• Incidence of lichen sclerosus has nearly doubled over the past 20 years (7.4 to 14.6 per 100,000 woman-years)
• Cumulative incidence of SCC in women with lichen sclerosus: 6.7%; concurrent VIN and age ≥70 years are independent risk factors
• Molecular studies show: aneuploid DNA content, p53 overexpression, high Ki67 expression, monoclonal keratinocyte expansion

Vulvar Intraepithelial Neoplasia (VIN) as Precursor

• High-grade VIN (HSIL) is the recognized precancerous lesion
• Review of 3,322 patients with high-grade VIN: 9% progression to cancer in untreated and 3.8% in treated cases
• VIN is found adjacent to basaloid/warty vulvar SCC in >80% of cases
• 10-20% of vulvar carcinoma in situ lesions harbor an occult invasive component

Additional Risk Factors

• CIN and prior cervical cancer history
• Alcohol consumption, obesity
• Immunosuppression
• Northern European ancestry

TYPES OF INVASIVE VULVAR CANCER

1. Squamous Cell Carcinoma (>80%)

• Presents most often as a visible lesion or ulcer on the vulva
• Long prediagnostic symptom period is common (median ~12 months)
• Symptoms: pruritus, mass, pain, bleeding, discharge
• Any persistent vulvar lesion must be biopsied - delay in biopsy is the most common cause of delayed diagnosis

• Biopsy is mandatory - never treat a vulvar lesion empirically without biopsy
• Colposcopy-directed or Keyes punch biopsy of suspicious areas
• Complete evaluation of the lower genital tract (cervix, vagina) for associated neoplasia

1. Direct extension to adjacent structures (vagina, urethra, anus)
2. Lymphatic spread to regional inguinofemoral lymph nodes (primary route)
   • Initial spread is to superficial inguinal nodes, then to deep femoral nodes, then to pelvic nodes (external iliac)
   • Contralateral nodal spread can occur, especially with midline or bilateral lesions
   • Clitoral and anterior labial tumors may spread directly to deep femoral and pelvic nodes, potentially bypassing inguinal nodes
3. Hematogenous spread: late, to lungs, liver, bone

• Without groin node metastases: >90% 5-year survival
• With groin node metastases: ~50% 5-year survival
• Recurrence in the groin is almost universally fatal
• Other prognostic factors: tumor size, depth of stromal invasion, presence of lymphovascular space invasion (LVSI), surgical margin status, extracapsular nodal extension

• Invasion ≤1.0 mm (Stage IA/T1a): nodal metastases are extremely rare (<1%) - groin dissection is omitted
• Invasion >1.0 mm: risk of nodal metastases increases substantially - groin dissection required

TREATMENT

Management Philosophy (The Paradigm Shift)

1. Individualization of treatment for all patients
2. Vulvar conservation for unifocal tumors with otherwise normal vulva
3. Omission of groin dissection for microinvasive tumors (T1a: ≤2 cm diameter, ≤1 mm stromal invasion)
4. Elimination of routine pelvic lymphadenectomy
5. Sentinel lymph node (SLN) procedure to eliminate complete inguinofemoral lymphadenectomy in node-negative patients
6. Separate groin incisions (triple-incision technique) to improve wound healing
7. Omission of contralateral groin dissection in patients with lateral T1 lesions and negative ipsilateral nodes
8. Preoperative chemoradiation for advanced disease to avoid exenteration
9. Postoperative chemo-radiation for patients with multiple positive groin nodes

Microinvasive Vulvar Cancer (T1a - Stage IA)

• Criteria: tumor ≤2 cm in diameter, stromal invasion ≤1 mm, no LVSI
• Treatment: radical local excision only - no groin dissection needed
• Risk of lymph node metastases is <1%

Early Vulvar Cancer (T1b - Stage IB)

• Radical local excision (hemivulvectomy or modified radical vulvectomy)
• Inguinofemoral lymphadenectomy is required
• Surgical margin: at least 8 mm from tumor (pathologically clear margins reduce local recurrence)
• Sparing surgery allows excellent local control as long as pathologic margins are ≥8 mm
• For unifocal lateral lesions (>1 cm from midline): ipsilateral groin dissection only if nodes are negative
• For midline or bilateral lesions: bilateral groin dissection required

• Suitable for: unifocal tumors <4 cm diameter with clinically negative nodes
• Must be performed in experienced hands (learning curve)
• Uses radioactive tracer (Tc-99m nanocolloid) ± blue dye
• If SLN is negative on frozen section: complete inguinofemoral lymphadenectomy can be avoided
• GROINSS-V trial validated safety and feasibility

Early T2 Vulvar Cancer

• Vulvar conservation can be extended to selected T2 patients
• Tumors involving posterior vulva and lower vagina, where preservation of anus, clitoris, and urethra is feasible, are suitable for conservative resection
• More advanced T2: radical vulvectomy and/or chemoradiation; when distal urethra or anus involved, preoperative chemoradiation preferred over primary exenteration

Closure of Large Defects

1. Leave open to granulate (6-8 weeks); may hasten with vacuum-assisted wound closure
2. Full-thickness rotational/advancement fasciocutaneous flaps: rhomboid flap, mons pubis pedicle flap, pudendal thigh flap, V-Y advancement flap
3. Myocutaneous flaps for large defects: gracilis myocutaneous graft, vertical rectus abdominis muscle flap

Advanced Disease: Large T2 and T3 Primary Tumors

• Historically required pelvic exenteration + radical vulvectomy + inguinofemoral lymphadenectomy (very high morbidity)
• Modern approach: preoperative chemoradiation (cisplatin-based) to shrink tumor, followed by limited surgical resection
• This avoids exenteration in many patients
• 5-fluorouracil (5-FU) and/or cisplatin used as radiation sensitizers

Groin Node Management

• Complete inguinofemoral lymphadenectomy remains the standard for clinically node-positive or T1b+ disease
• Must dissect both superficial inguinal AND deep femoral nodes (femoral node metastases with negative inguinal nodes can occur)
• The saphenous vein should be preserved if possible
• Postoperative radiation to groins is indicated for patients with ≥2 positive inguinal nodes or any extracapsular nodal extension (reduces groin recurrence risk)

Recurrent Vulvar Cancer

• Often salvageable with surgery (re-excision or radical vulvectomy)
• Selected cases: chemoradiation
• Prognosis better than groin recurrence

• Almost universally fatal
• Aggressive multimodality approaches (surgery + radiation + chemotherapy) for palliation

• Cisplatin-based chemotherapy; limited response rates
• Immunotherapy/targeted therapy under investigation

2. MELANOMA OF THE VULVA

• Second most common vulvar malignancy (~5-10%)
• Most common in older Caucasian women
• Most arise on the labia minora or clitoris

• Three types: superficial spreading, nodular, and acrolentiginous melanoma
• ABCDEs apply (Asymmetry, Border, Color, Diameter, Evolution)

• Uses the AJCC TNM system (Breslow thickness and Clark level are key)
• Breslow thickness: most important prognostic factor
  • Stage IA: <1.0 mm, no ulceration
  • Stage IB: 1.0-2.0 mm without ulceration, or <1.0 mm with ulceration
  • Stage II: 2.0-4.0 mm
  • Stage III: ≥N1 (nodal involvement)
  • Stage IV: distant metastases

• Wide local excision with adequate margins
• Sentinel lymph node biopsy for lesions >1 mm (same principles as cutaneous melanoma)
• Complete lymph node dissection for SLN-positive cases

• Nivolumab (PD-1 inhibitor): frequently recommended for lymph node involvement; more effective and less toxic than ipilimumab
• Ipilimumab (CTLA-4 inhibitor): associated with improved disease-free survival compared with interferon alfa in BRAF wild-type patients; combined nivolumab + ipilimumab yields 55% objective response rate vs. 11% with nivolumab alone
• BRAF V600 mutant tumors: adjuvant targeted therapy with dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor)

• 5-year overall survival for vulvar melanoma: 50-60%
• SEER data: disease-specific survival for localized, regional, and distant disease = 76%, 39%, and 22%, respectively
• Independent favorable prognostic factors: localized disease, negative lymph nodes, younger age
• Propensity for late recurrences - 5-year survival may not reflect cure

3. BARTHOLIN GLAND CARCINOMA

• Rare; arises from Bartholin gland epithelium
• Diagnosis often delayed because it mimics a Bartholin gland cyst or abscess
• Clinical Rule: Any Bartholin gland mass in a woman >40 years should be excised and sent to pathology

• Accounts for 2-7% of vulvar cancers

• Squamous cell carcinoma (most common from duct epithelium)
• Adenocarcinoma (from glandular epithelium)
• Transitional cell carcinoma
• Adenoid cystic carcinoma (unique - discussed separately)

• Radical local excision with bilateral groin lymph node dissection
• Adjuvant radiation may be used

Adenoid Cystic Carcinoma of the Bartholin Gland

• Slow-growing, locally invasive
• Tendency for perineural invasion and late distant metastases (especially to lung)
• Wide local excision; relatively poor response to radiation

4. OTHER ADENOCARCINOMAS

Adenosquamous Carcinoma

• Contains both glandular and squamous elements
• More aggressive than pure SCC; high rate of nodal metastases

Basal Cell Carcinoma

• Very rare; arises from basal cells of vulvar skin
• Rarely metastasizes
• Treatment: wide local excision; no groin dissection needed unless deep invasion or nodal involvement

Verrucous Carcinoma

• Locally invasive, cauliflower-like appearance
• Very low metastatic potential
• Treatment: radical local excision
• Do not irradiate - radiation may induce anaplastic transformation to aggressive SCC

5. PAGET DISEASE OF THE VULVA

• Nonsquamous intraepithelial neoplasia
• Presents as pruritic, erythematous, eczematoid lesion with white islands
• Characteristic "strawberries and cream" appearance
• Most often an intraepithelial adenocarcinoma (primary Paget disease)
• Must exclude an underlying invasive adenocarcinoma and associated distant carcinoma (breast, GI, genitourinary)
• Treatment: wide local excision; high recurrence rate due to subclinical extension beyond visible margins

6. VULVAR SARCOMA

• Leiomyosarcoma is most common
• Rhabdomyosarcoma in children
• Treatment: wide surgical excision; chemotherapy for rhabdomyosarcoma (VAC regimen)

7. RARE VULVAR MALIGNANCIES

• Lymphomas (primary extranodal)
• Endodermal sinus tumor (yolk sac tumor)
• Merkel cell carcinoma (neuroendocrine; aggressive)
• Dermatofibrosarcoma protuberans (low-grade spindle cell tumor)

8. METASTATIC TUMORS OF THE VULVA

• Rare; most common primary sites: cervix, endometrium, vagina, ovary, urethra, breast, rectum, kidney
• Treatment is palliative; prognosis determined by primary tumor

PREMALIGNANT LESIONS: VIN AND VULVAR DYSTROPHIES

Classification of Vulvar Epithelial Diseases (ISSVD)

• Lichen sclerosus
• Squamous hyperplasia (formerly hyperplastic dystrophy)
• Other dermatoses

• VIN 1 (mild dysplasia)
• VIN 2 (moderate dysplasia)
• VIN 3 / HSIL (severe dysplasia / carcinoma in situ)
• Paget disease
• Melanocytic tumors (noninvasive)

KEY PROGNOSTIC PRINCIPLES (Summary)

COMPLICATIONS OF TREATMENT