Bethesda Handbook of Clinical Oncology, 2nd Edition
Christina M. Annunziata*
Michael J. Birrer†
*Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
†Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, Rockville, Maryland
- Vulvar cancer accounts for 4% of all female genital malignancies; 4,000 new cases were projected for 2003.
- It is most frequent in women between 65 and 75 years old, and is occasionally diagnosed in women younger than 40 years.
ETIOLOGY AND RISK FACTORS
- The etiology remains unclear and potentially involves two distinct diseases associated with
- human papillomavirus (HPV) DNA, especially type 16, found in 80% of intraepithelial lesions and 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), and Paget disease (preinvasive, see below).
- Vulvar intraepithelial neoplasia (VIN), especially high grade (VIN III), increases risk for development of vulvar cancer.
- Classic risk factors such as hypertension, diabetes mellitus, and obesity most probably represent conditions associated with aging and are not truly independent risk factors for this malignancy.
Squamous cell carcinomas (SCCs) constitute more than 90% of cases, and melanomas constitute less than 10% of cases. The remainder are adenocarcinoma, basal cell carcinoma, verrucous carcinoma, sarcoma, 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.
- Biopsy, cystoscopy, proctoscopy, chest x-ray (CXR), and i.v. urography, if needed, based on the extent of disease
- Suspected bladder or rectal involvement must be biopsied.
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 Squamous Cell Carcinoma
- Vulvar squamous cell carcinoma is found on the labia majora in 50% of cases and on the labia minora in 15% to 20%; the remainder of these cancers are on the clitoris and perineum.
- The carcinoma tends to grow locally, with subsequent spread to inguinal, femoral, and pelvic lymph nodes (LNs). Hematogenous spread usually takes place after LN involvement.
- Vulvar cancer is a surgically staged disease (see Table 20.1).
TABLE 20.1. Premalignant Lesions
Prognostic Factors and Survival (True for Most Histologies)
- Survival depends on stage, LN involvement, depth of invasion, structures involved, and tumor location.
- Survival is most dependent on the pathologic status of the inguinal LNs and on the size of the primary lesion (lesions <2-cm in greatest dimension, inguinal LN(-), show 98% 5-year survival; lesions of any size, three or more unilateral LN(+) or two or more bilateral LN(+), show 29% 5-year survival).
- LN metastases are related to tumor size, clinical stage, and depth of invasion.
The following therapeutic approaches are equally effective:
- Wide local excision, laser beam therapy, or combination of the two
- Skinning vulvectomy with or without grafting.
In some cases, a 5% 5-fluorouracil (5-FU) cream can be used [response rate (RR) is 50% to 60%], but it is not the first choice of therapy.
Recurrences are seen regardless of type of procedure used for initial treatment (most common sites are perianal skin, presacral area, and clitoral hood).
- Less than 1-mm invasion: wide local excision
- From 1-mm to 5-mm invasion: modified radical vulvectomy with ipsilateral superficial inguinal lymphadenectomyfor lesions located laterally, and bilateral node dissection for centrally placed 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.
- 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.
Modified radical vulvectomy and bilateral inguinal lymphadenectomy can be used if at least 1 cm of negative margins can be achieved with preservation of midline structures.
Stages III and IV
The management of stage III and IV disease is shown in Fig. 20.1. Special considerations:
- Management of positive groin nodes: one LN requires no further therapy, whereas two or more LNs can be treated with groin and pelvic radiation therapy (based on data from GOG randomized trial in which improved survival was documented with this therapy as 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 been successful with the use of cisplatin and 5-FU concurrently with radiation.
- Patients with inoperable disease can achieve long-term survival with radical radiation 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 less than or equal to 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.
FIG. 20.1. Management algorithm for stages III and IV disease. (From DiSaia PJ, Creasman WT. Clinical gynecologic oncology, 5th ed. St. Louis: Mosby, 1997:222, with permission.)
Recurrent and Metastatic Disease
- Treatment and outcome depend on site and extent of recurrence.
- Local recurrencecan be treated with wide local reexcision 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.
- Another option is radical vulvectomy and pelvic exenteration.
- Groin nodescan be subjected to radiation and surgery.
- Distant 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 they are of short duration a (few months). Trials evaluating the efficacy of paclitaxel in vulvar cancer are ongoing.
- Verrucous carcinoma is very rare and can be confused with condyloma acuminátum because of 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 is contraindicated because it is not effective and can potentially lead to more aggressive behavior.
- Paget disease is characterized by preinvasive lesions.
- The most frequent symptoms include pruritus, tenderness, or vulvar lesions (i.e., hyperemic, well-demarcated, thickened lesions, with areas of induration and excoriation).
- Paget disease can be associated with underlying adenocarcinoma of the vulva (1% to 2%). These patients should be treated the same way as are patients with other vulvar malignancies.
- Malignant melanoma is a rare tumor (5% of all melanoma cases).
- Most melanomas are located on the labia minora and clitoris.
- Prognosis depends on the size of the lesion and on the depth of invasion.
- Staging of malignant melanoma is the same as for skin melanoma.
- The suggested therapy is radical vulvectomy with inguinal and pelvic lymphadenectomy (lately the tendency is for 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 are suggested for thicker lesions.
- Adenocarcinoma of the Bartholin gland is a very rare tumor (1% of all vulvar malignancies).
- Its peak incidence is in women in their mid-60s.
- Enlargement of the Bartholin gland area in postmenopausal women requires evaluation for malignancy.
- The 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.
- The 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).
We would like to thank Dr. Helen Frederickson for her critical review of this chapter.
DiSaia PJ, Creasman WT. Clinical gynecologic oncology, 5th ed. St. Louis: Mosby, 1997.
Moore RG, DePasquale SE, Steinhoff MM, et al. Sentinel node identification and the ability to detect metastatic tumor to inguinal lymph nodes in squamous cell cancer of the vulva. Gynecol Oncol 2003; 89(3):475–479.
Montana GS, Thomas GM, Moore DH, et al. Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2000;48(4): 1007–1013.
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NCI-PDQ Page. at: http://www.cancernet.nci.nih.gov/clinpdq/soa/Cervical_cancer_Physician.html, 2003.