Anne M. Noonan and Christina M. Annunziata
EPIDEMIOLOGY
■Vulvar cancer accounts for <5% of all female genital malignancies.
■A total of 4,490 new cases and 950 deaths from vulvar cancer were projected for 2012.
■It is most frequent in women in the seventh decade of life, but is occasionally diagnosed in women younger than 40 years.
■One in 368 women will be diagnosed with vulvar cancer during their lifetime (2.3 per 100,000 women per year in the United States).
ETIOLOGY AND RISK FACTORS
The etiology of vulvar cancer remains unclear, but potentially involves two distinct diseases associated with the following:
■Human papillomavirus (HPV) DNA, especially type 16
•Can be detected in 80% of intraepithelial lesions
•Found in 10% to 15% of invasive vulvar cancers (especially squamous cell)
■Chronic inflammation
•Venereal or granulomatous lesions
•Lichen sclerosus (coexists with up to 25% of vulvar cancers)
•Squamous hyperplasia (hyperplastic dystrophy) or lichen simplex chronicus
•Paget disease of the vulva (preinvasive)
Risk Factors
■Vulvar intraepithelial neoplasia (VIN), especially high grade (VIN III), increases the risk of development of invasive vulvar cancer.
■Other risk factors include prior history of cervical cancer, immunodeficiency disorders (e.g., HIV), and cigarette smoking.
■Classic risk factors such as hypertension, diabetes mellitus, and obesity are probably associated with aging and are not truly independent risk factors for this malignancy.
HISTOLOGY
■Squamous cell carcinomas (SCCs) constitute >90% of cases.
■Melanomas constitute <10% of cases.
■The remainder of tumor types include adenocarcinoma, basal cell carcinoma, verrucous carcinoma, sarcoma, clear cell carcinoma, and other rare tumors.
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.
Diagnostic Workup
■Biopsy must include adequate tissue to determine histology and grade, depth of invasion, and stromal reaction present.
■Colposcopy using 5% acetic acid solution may be necessary to delineate suspected multifocal lesions.
■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, 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, with subsequent spread to inguinal, femoral, and pelvic LNs.
■Hematogenous spread rarely occurs without LN involvement.
Staging
■Vulvar cancer is a surgically staged disease. The revised 2009 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 (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes
•Stage III: Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower 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 (2/3 upper urethra, 2/3 upper vagina), 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.
■Statistics based on the pathologic status of the inguinal LNs and the size of the primary lesion:
•Lesions <2 cm in greatest dimension without LN involvement (stage I): 77% 5-year survival
•Lesions of any size with unilateral LN (stage III): 31% 5-year survival
Management
Stage 0 (VIN)
Therapeutic options are based on individual patient need.
■Wide local excision, laser ablation, or both
■Skinning vulvectomy with or without grafting
■CO2 laser total superficial vulvectomy
■Topical treatments include
•5-FU cream: response rate (RR) 40% to 75%
•Five percent imiquimod: RR approximately 50% to 70%
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.
Stage I
■<1 mm invasion (stage IA): wide local excision
•Excise down to inferior fascia of urogenital diaphragm.
•Strive for 2 cm clear margins to minimize risk of local recurrence.
■>1 mm invasion (stage IB):
•Modified radical vulvectomy with ipsilateral superficial inguinal lymphadenectomy for lesions located laterally.
•Bilateral inguinofemoral node dissection for centrally located lesions.
•Sentinel LN biopsy is an emerging technique in early-stage vulvar cancer and may obviate the need for full nodal dissections in many women.
Special Considerations
■Poor surgical candidates can be treated with radiation therapy, 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 and bilateral inguinofemoral lymphadenectomy can be used if ≥1 cm of negative margins can be achieved with preservation of midline structures.
■Adjuvant radiation therapy is recommended for women with more than one positive LN or surgical margins <1 cm.
Stage III
■Modified radical vulvectomy and bilateral inguinofemoral lymphadenectomy are standard.
■Adjuvant radiation therapy or chemoradiation is recommended for women with involved LNs, thick tumors (>5 mm), lymphovascular invasion, or close surgical margins <1 cm.
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 radiation therapy is recommended for women with more than one positive LN or surgical margins <1 cm.
■Neoadjuvant chemoradiation, with 5-FU or 5-FU plus cisplatin, may improve operability.
Special Considerations
■Management of positive groin nodes: One LN requires no further therapy. Two or more LNs can be treated with groin and pelvic radiation therapy, based on data from the GOG randomized trial in which improved survival was documented with this therapy compared to pelvic LN dissection.
■Suggested doses of localized adjuvant radiation are 45 to 50 Gy.
■Neoadjuvant chemoradiation can be used in stage III and IV disease to improve the operability of the tumor. Recent GOG trials have successfully used cisplatin and 5-FU concurrently with radiation.
■Patients with inoperable disease can achieve long-term survival with radical chemoradiation therapy.
■When radiation is given as primary definitive treatment, it is suggested that the addition of 5-FU with cisplatin or mitomycin C be considered.
■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: No standard systemic chemotherapy is available for metastatic disease. These patients are appropriate candidates for clinical trials. Agents such as cisplatin, methotrexate, cyclophosphamide, bleomycin, and mitomycin C have shown a partial RR of only 10% to 15% and are of short duration (a few months). Trials evaluating the efficacy of paclitaxel in vulvar cancer are ongoing.
■Pelvic node metastasis or local recurrence can be treated with the following:
•Wide local (re)excision with or without radiation (5-year survival of 56% if regional LNs are negative).
•In cases with small, localized recurrence, radiation with or without 5-FU can be curative.
■Inguinal nodes can be subjected to radiation and surgery.
VERRUCOUS CARCINOMA
■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 (5% of all melanoma cases).
■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.
■Therapy includes radical vulvectomy with wide excision to achieve adequate margins and inguinal lymphadenectomy.
Adenoid Cystic Carcinoma
■Adenoid cystic carcinoma is a very rare tumor.
■It is characterized by frequent local recurrences and very slow progression.
■Recommended therapy is wide local excision with ipsilateral 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).
REVIEW QUESTIONS
1.A 74-year-old woman presents to her primary care physician with an 18-month history of pruritus vulvae, difficulty with urination, and hard left inguinal mass. Pelvic examination reveals an erythematous ulcerating lesion on the labia majora extending on to the urethral orifice and labia minora bilaterally. On vaginal examination there is a hard mass palpable anteriorly. CT scan reveals extension into the lower posterior bladder and wall and involvement of the left inguinal and pelvic LNs. Biopsy of the vulvar lesion reveals a poorly differentiated SCC arising from the vulva. She has a history of depression and mild hypertension. What is the most appropriate treatment?
A.Tamoxifen
B.Pelvic exenteration
C.Chemoradiation to vulva and inguinal area followed by resection of any residual disease on the vulva
D.Vaginal brachytherapy
E.A and B
2.A 72-year-old female with a history of stage IVB SCC of the vulva treated 1 year ago with chemoradiation followed by resection of residual disease on the labia minora now presents to the ER with urinary retention, reduced appetite, and hard mass in the right lower abdomen. Serum chemistries and CBC are normal. Urethral catheterization is performed to relieve her urinary retention. On CT scan she has recurrence of her disease in the pelvis with involvement of the urethra causing a stricture and right-sided pelvic LN mass within the radiation port. She lives alone and was working as a secretary until her admission. She has no other significant comorbidities. What is the most appropriate next step?
A.Repeat external beam radiotherapy to the pelvis
B.Referral for a clinical trial
C.Carboplatin plus bevacizumab
D.Aromatase inhibitor
E.None of the above
3.A 69-year-old female with a history of stage I screen-detected ER- and PR-positive breast cancer treated 5 years ago with lumpectomy and adjuvant radiation therapy followed by 5 years of anastrozole presents for routine follow-up. On review of systems she reports a 6-month history of itching of the vulva. On examination there is a 0.5 cm erythematous raised lesion. Colposcopy and biopsy reveal VIN with no evidence of invasive disease. What is the most appropriate treatment?
A.Radical vulvectomy
B.Cisplatin 50 mg/m2 IV every 3 weeks
C.No therapy. Observation only is required
D.Vaginal brachytherapy
E.Laser ablation
Suggested Readings
1.DiSaia PJ, Creasman WT. Clinical Gynecologic Oncology. 5th ed. St. Louis: Mosby; 1997.
2.FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix and endometrium. Int J Gynecol Obstet. 2009;105:103-104.
3.Jhingran A, Russell AH, Seiden MV, et al. Cancer of the cervix, vulva, and vagina. In: Abeloff MD, Armitage JO, Niederhuber JE, et al., eds. Abeloff’s Clinical Oncology. 4th ed. Philadelphia, PA: Churchill Livingstone; 2008.
4.Moore DH, Koh WJ, McGuire WP, Wilkinson EJ. Vulva. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, eds. Principles and Practice of Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2009:553-590.
5.Nash JD, Curry S. Vulvar cancer. Surg Oncol Clin N Am. 1998;7(2):335-346.
6.National Cancer Institute Physician Data Query website. http://cancer.gov/cancertopics/types/vulvar
7.SEER Stat Fact Sheets: Vulva 2012. http://seer.cancer.gov/statfacts/html/vulva.html