The Bethesda Handbook of Clinical Oncology

Kristen P. Zeligs and Christina M. Annunziata

EPIDEMIOLOGY

Vulvar cancer is the fourth most common gynecologic cancer, accounting for 5% of all female genital tract malignancies.

A total of 5,950 new cases and 1,110 deaths from vulvar cancer were projected for 2016.

It is most frequently diagnosed in postmenopausal women, with a median age of diagnosis of 68 years.

One in 333 (0.3%) women will be diagnosed with vulvar cancer during her lifetime (2.4 per 100,000 women per year in the United States).

The rate of vulvar cancer has remained stable over the past 20 years, however the incidence of its precursor (vulvar intraepithelial neoplasia 3) has doubled.

ETIOLOGY AND RISK FACTORS

Two independent pathways of vulvar carcinogenesis are felt to exist currently: the first related to human papillomavirus (HPV) infection and the second related to disorders of chronic inflammation (e.g. vulvar dystrophy) or autoimmune processes. Premalignant lesions of the vulva, collectively known as vulvar high-grade squamous intraepithelial lesions (HSIL) or VIN 2/3, are linked to HPV DNA in 70% to 80% of cases. However, the association between HPV and vulvar cancer is observed less frequently, with only 40% to 60% of vulvar cancers testing positive on molecular analysis for HPV DNA (most commonly HPV subtypes 16 and 33). Vulvar cancers not associated with HPV infection often are associated with vulvar dystrophies, most commonly lichen sclerosus and squamous cell hyperplasia.

Risk Factors

Vulvar high-grade squamous intraepithelial lesions (VIN 2/3) increase the risk of development of invasive vulvar cancer.

Other risk factors include cigarette smoking, vulvar dystrophies (e.g., lichen sclerosus), VIN or CIN, HPV infection, prior history of cervical cancer, immunodeficiency disorders (e.g., HIV), and Northern European ancestry.

HISTOLOGY

Squamous cell carcinomas (SCCs) constitute >90% of cases.

Melanomas constitute 5% to 10% of cases.

The remainder of tumor types include basal cell carcinoma, sarcoma, extramammary Paget’s disease, and Bartholin gland adenocarcinoma.

VULVAR SQUAMOUS CELL CARCINOMA

Vulvar SCC is commonly indolent, with slow extension and late metastases. Signs and symptoms in order of decreasing frequency are pruritus, mass, pain, bleeding, ulceration, dysuria, and discharge. Many patients are asymptomatic. A synchronous second malignancy is found in up to 22% of patients with vulvar SCC (most commonly, cervical cancer).

Diagnostic Workup

Biopsy must include adequate tissue to determine histology and grade, depth of invasion, and stromal reaction present.

Use of colposcopy following application of 5% acetic acid solution is helpful in delineating multifocal lesions, which occur in 5% of cases.

Cystoscopy, proctoscopy, chest x-ray, and intravenous urography should be performed as needed based on the extent of disease.

Suspected bladder or rectal involvement must be biopsied.

If invasive disease is present, detailed pelvic exam in addition to pelvic and abdominal imaging with PET/CT or MRI should be performed to assess deep and pelvic lymph nodes (LNs).

Indications for Excisional Biopsy of Vulvar Lesions

Any gross lesion

Red, white, dark brown, or black skin patches

Areas firm to palpation

Pruritic, tingling, or bleeding lesions

Any nevi in the genital tract

Enlarged or thickened areas of Bartholin glands, especially in postmenopausal women

Location and Metastatic Spread Pattern of Vulvar SCC

Vulvar SCC is found on

•The labia majora in 50% of cases

•The labia minora in 15% to 20% of cases

•The clitoris and perineum in rare cases

Vulvar SCC tends to grow locally via direct extension to nearby structures (e.g., vagina, urethra, clitoris, anus), with early spread to inguinal, femoral, and pelvic LNs.

Hematogenous spread occurs late in the course of disease and is rare in patients without inguinofemoral LN involvement.

Inguinal and femoral LV involvement is the most important prognostic factor for survival.

Staging

Vulvar cancer is a surgically staged disease. The revised 2014 FIGO staging system is as follows:

•Stage I: Tumor confined to the vulva

•IA: Lesions ≤2 cm in size, confined to the vulva or perineum, and with stromal invasion ≤1.0 mm, no nodal metastasis

•IB: Lesions >2 cm in size or with stromal invasion >1.0 mm, confined to the vulva or perineum, and with negative nodes

•Stage II: Tumor of any size with extension to adjacent perineal structures (lower 1/3 urethra, lower 1/3 vagina, anus) with negative nodes

•Stage III: Tumor of any size with or without extension to adjacent perineal structures (lower 1/3 urethra, lower 1/3 vagina, anus) with positive inguinofemoral LNs

•IIIA: (i) With one LN metastasis (≥5 mm), or (ii) 1 to 2 LN metastasis (es) (<5 mm)

•IIIB: (i) With two or more LN metastases (≥5 mm), or (ii) three or more LN metastases (<5 mm)

•IIIC: With positive nodes with extracapsular spread

•Stage IV: Tumor invades other regional or distant structures

•IVA: Tumor invades any of the following: (i) upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (ii) fixed or ulcerated inguinofemoral LNs

•IVB: Any distant metastasis including pelvic LNs

Prognosis and Survival

Survival depends on stage, LN involvement, depth of invasion, structures involved, and tumor location.

LN metastases are related to tumor size (>4 cm is associated with 30% to 50% rate of inguinofemoral metastases), clinical stage, and depth of invasion.

5-year overall survival ranges from 70% to 93% in patients without LN involvement to 25% to 41% for those with LN involvement.

Studies suggest a high overall incidence of local recurrence following primary surgical treatment. Disease presence at the excised tumor margin has been postulated as a significant prognostic factor for recurrence.

Management

Vulvar Intraepithelial Neoplasia 2/3

Therapeutic options are based on individual patient need and can include any of the following:

Surgical excision (e.g., wide local excision, skinning vulvectomy)

Laser ablation

Pharmacologic treatment (topical imiquimod, cidofovir, or 5-FU cream)

Recurrences are seen in up to 35% of women regardless of initial treatment modality. The most common sites of recurrence are perineal skin and clitoral hood.

Invasive cancer is present in 10% to 22% of women with VIN on initial biopsy, thus surgical excision (where additional pathologic specimen can be evaluated) should be treatment of choice if patient has any risk factors for invasive disease.

Stage I (lesions confined to vulva)

≤1 mm depth of invasion (stage IA): wide local excision

•Excise down to inferior fascia of urogenital diaphragm.

•Strive for 1–2 cm clear margins to minimize risk of local recurrence.

•No inguinofemoral lymphadenectomy (LND) or sentinel lymph node biopsy (SNLB) necessary.

> 1 mm depth of invasion (stage IB): wide local excision + inguinofemoral LND versus SLNB

•Ipsilateral inguinofemoral LND for lateral lesions (located ≥2 cm from vulvar midline).

•Bilateral inguinofemoral LND for centrally located lesions.

•SNLB is an emerging technique in early-stage vulvar cancer and may obviate the need for full nodal dissections in many women. SNLB can be offered to patients with vulvar cancer if tumor diameter is <4 cm, >1 mm depth of invasion, no palpable LNs, unifocal disease, and surgeon has sufficient expertise.

•Patients with close or positive surgical tumor margins (<8 mm from tumor) can undergo re-resection or, if unresectable, adjuvant radiation therapy (RT).

Special Considerations

Poor surgical candidates can be treated with chemoradiation, achieving long-term survival.

Surgical complications include mortality (2% to 5%), wound breakdown or infection, sepsis, thromboembolism, chronic leg lymphedema (use of separate incision for the groin LN dissection reduces wound breakdown and leg edema), urinary tract infection, stress urinary incontinence, and poor sexual function.

Stage II

Modified radical vulvectomy (hemivulvectomy if possible) and bilateral inguinofemoral LND if ≥1 cm of negative margins can be achieved with preservation of midline structures.

Adjuvant RT is recommended for women with no LN involvement on LND in the presence of additional risk factors to include: tumor size >4 cm, close tumor margins (≤8 mm), lymphovascular invasion, depth of invasion, or spray/diffuse pattern of invasion.

Stage III (Inguinofemoral LN Involvement)

Modified radical vulvectomy and bilateral inguinofemoral LND are standard.

Adjuvant chemoradiation is recommended for women with involved LNs, and most commonly involves Cisplatin 40 mg/m² concurrently with RT to the inguinal, external iliac, internal iliac, and obturator regional bilaterally.

Stage IVA

Radical vulvectomy and bilateral inguinofemoral lymphadenectomy can be used if ≥1 cm of negative margins can be achieved with preservation of midline structures.

As in stage II and III vulvar cancers, adjuvant chemoradiation is recommended for women with LN involvement or surgical margins <8 mm.

Neoadjuvant chemoradiation, with cisplatin concurrently with RT to the vulva, groin, and LNs, may improve operability and should be considered in patients with

•Anorectal, urethral, or bladder involvement

•Disease fixed to the bone

•Gross inguinal or femoral LN involvement

Special Considerations

Management of positive groin nodes: Positive LNs require RT to primary tumor/groin/pelvis + concurrent chemotherapy.

Suggested doses of localized adjuvant radiation are 45 to 50 Gy.

Neoadjuvant chemoradiation can be used in stages III and IV disease to improve the operability of the tumor. Recent GOG trials have successfully used cisplatin and 5-FU concurrently with RT.

Patients with inoperable disease can achieve long-term survival with radical chemoradiation therapy.

Radiation fraction size of ≤180 cGy has been proven to minimize the radiation complication rate (i.e., late fibrosis, atrophy, telangiectasia, and necrosis). Total doses of 54 to 65 Gy should be used.

Radical vulvectomy and pelvic exenteration are not commonly used due to extensive morbidity and uncertain survival benefit.

Stage IVB (Metastatic) and Recurrent Disease

Therapy recommendations depend on sites of metastasis or recurrent disease and disease-related symptoms. All patients should be considered for clinical trials.

Distant metastasis or recurrence: RT for locoregional control/symptom palliation and/or chemotherapy or best supportive care. Chemotherapy choices for advanced, recurrent/metastatic disease commonly include cisplatin, cisplatin/vinorelbine, or cisplatin/paclitaxel. These patients are also appropriate candidates for clinical trials.

If recurrence is confined locally to the vulva (and LNs are clinically negative), radical excision and unilateral or bilateral inguinofemoral LND (if not done prior) may be employed. This should be followed by RT +/- concurrent chemotherapy if LNs are found to be surgically positive or surgical margins are positive.

Patients with recurrence in groin LNs who have not undergone prior RT can undergo resection of positive LNs +/- inguinofemoral LND followed by RT +/– concurrent chemotherapy

VERRUCOUS CARCINOMA

Variant of SCC with distinctive cauliflower-like features of vulvar lesions.

Verrucous carcinoma is very rare and can be confused with condyloma acuminatum because of an exophytic growth pattern.

It is locally destructive and rarely metastasizes.

It is associated with HPV type 6.

The main treatment is surgery. LN dissection is of questionable value unless LNs are obviously involved. Radiation therapy is contraindicated because it is ineffective and can potentially lead to more aggressive disease.

PAGET DISEASE

Characterized by preinvasive lesions.

Most frequent symptoms include pruritus, tenderness, or vulvar lesions (i.e., “red velvet,” hyperemic, well-demarcated, thickened lesions with areas of induration and excoriation).

Can be associated with underlying adenocarcinoma of the vulva (1% to 2%). Although Paget disease is histologically a preinvasive disease locally, it should be treated with radical wide local excision, as with other vulvar malignancies. Patients require radical excision, often with intraoperative frozen section confirmation of clear margins, because microscopic disease often extends beyond the gross visual margin observed by the operating surgeon.

MALIGNANT MELANOMA

Malignant melanoma of the vulva is a rare tumor (representing 5% of all melanoma cases and 5% to 10% of primary vulvar neoplasms).

Most melanomas are located on the labia minora and clitoris.

Prognosis depends on size of lesion and depth of invasion.

Staging of malignant melanoma is the same as for skin melanoma.

Suggested therapy is radical vulvectomy with inguinal and pelvic lymphadenectomy, although there is a current trend toward a more conservative approach. For most well-demarcated lesions, 2 cm margins are suggested for thin (up to 7 mm) lesions and 3 to 4 cm margins for thicker lesions.

BARTHOLIN GLAND ADENOCARCINOMA

Adenocarcinoma of the Bartholin gland is a very rare tumor (1% of all vulvar malignancies).

Peak incidence is in women in their mid-60s.

Enlargement of the Bartholin gland area in postmenopausal women requires evaluation for malignancy with biopsy.

Therapy includes radical vulvectomy with wide excision to achieve adequate margins and inguinal lymphadenectomy.

Basal Cell Carcinoma

The natural history and therapeutic approach for basal cell carcinoma are similar to those for primary tumors seen in other sites (i.e., wide local excision).