The most common etiology of vulvar cancer involves infection with the Human Papilloma Virus (HPV). In this group of women there is an association with high-risk sexual activity, increased rates of tobacco use, and younger age. The remaining cases are seen mostly in elderly patients, does not have an apparent association to HPV infection, is not preceded by vulvar dysplasia, and is commonly found adjacent to chronic dystrophic or inflammatory lesions. There are also a small proportion of vulvar cancers classified as melanoma, sarcoma, or basal cell lesions. For squamous cancers, management is consistent regardless of cause.
Vulvar cancer accounts for approximately 5% of all female genital malignancies. It occurs in about 2.5 per 100,000 women-years in developed countries but is 2-3 times more frequent in underdeveloped countries.  With the exception of the rare sarcomas, this cancer appears most frequently in women aged 65-75 years, and, in some series, almost half of the patients are aged 70 years or older. Vulvar cancer can appear in younger patients, and, in some large cancer referral institutions, approximately 15% of all vulvar cancers occur in women younger than 40 years. These young patients tend to have early microcarcinomas, which may be associated with diffuse intraepithelial neoplasia of the vulva.
As the population ages, the incidence of vulvar cancer may be increasing slowly. In a recent annual report, almost 50% of patients reported to have vulvar cancer were aged 70 years or older, with 15% aged 80 years or older. In most series, an extended delay in diagnosis appears to occur mainly because the patient does not seek medical attention for many months or because the lesion is treated medically for months, without biopsy for definitive diagnosis.
Although there is no screening for vulvar neoplasia or vulvar cancer, immunization with the quadrivalent or 9-valent HPV vaccine and smoking cessation have been shown to decrease the rates of disease. 
Histological evaluation is a prerequisite before planning definitive therapy for changes in the epithelium of the vulva, whether pigmentation, hypertrophy, or lump or mass occurs. Many techniques can be used in the office setting to obtain adequate tissue for pathological evaluation. A dermal punch biopsy can be used as it is used elsewhere on the skin. If a lesion is small, excision may not only be diagnostic but also therapeutic. A local anesthetic is usually sufficient, and sutures are placed as needed.
Aside from invasive vulvar cancer, biopsy may identify VIN. These are further classified into low-grade squamous intraepithelial lesion of the vulva (vulvar LSIL), high-grade squamous intraepithelial lesion of the vulva (vulvar HSIL), and differentiated type VIN.
Most vulvar cancer is squamous in origin. Because the vulva is covered with skin, any malignancy that appears elsewhere on the skin also can occur on the vulva. Melanoma is the second most frequent histological type, but this represents less than 5% of vulvar cancers.
Squamous vulvar cancer can have many different growth characteristics. It can occur in an area of epithelial neoplasia that develops into a small nodule, which may break down and ulcerate. Small, warty, or cauliflower-like growths may arise and be confused with condyloma acuminata. Squamous carcinomas can appear in a background of atrophic changes (ie, lichen sclerosis) or in hypertrophic epithelium. Long-term pruritus, lumps, or masses on the vulva are present in most patients with invasive vulvar cancer.
The cancer can appear anywhere on the vulva, although about three fourths arise primarily on the labia. The rarer types, such as Bartholin gland carcinomas, tend to be localized to that specific region. Because the vulva is rich in lymphatics, metastasis to the inguinal lymph node can occur early in the process. Lymph node involvement is directly related to the depth of stromal invasion, as well as to the size of the primary lesion. Fortunately, bilateral inguinal nodal involvement without ipsilateral side involvement is unusual. This has therapeutic indications. The disease is usually localized and well demarcated; however, in advanced disease, determining the exact site of origin is impossible. Multifocal patterns with invasive cancer are unusual, although kissing lesions can occur as isolated lesions. Unilateral lesions appear to be the norm, particularly in postmenopausal patients.
The clinical evaluation of possible inguinal lymph node metastasis is very imprecise. In 1988, the International Federation of Gynecology and Obstetrics (FIGO) adopted a surgical staging system based on the primary tumor, regional lymph node, remote metastases (TNM) classification system. In 2008, FIGO revised the staging of vulvar cancer. [3, 4]
Table 1. Carcinoma of the Vulva: FIGO nomenclature (Open Table in a new window)
|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 with negative nodes|
|II||Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes|
|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 lymph nodes|
(i) With 1 lymph node metastasis (≥5 mm), or
(ii) 1-2 lymph node metastasis(es) (< 5 mm)
(i) With 2 or more lymph node metastases (≥5 mm), or
(ii) 3 or more lymph node metastases (< 5 mm)
|IIIC||With positive nodes with extracapsular spread|
|IV||Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures|
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 lymph nodes
|IVB||Any distant metastasis including pelvic lymph nodes|
|*The depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent, most superficial dermal papilla to the deepest point of invasion.|
A small primary lesion on the vulva (ie, < 2 cm) with superficial invasion (ie, < 1 mm from the epithelial stromal junction of the adjacent, most superficial dermal papillae) has essentially no risk of lymph node metastasis. Consequently, these lesions can be treated with wide local excision, ensuring that adequate surgical margins are present (not only on the skin but also deep margins).
Treatment is recommended for all women with vulvar HSIL because of the risk for occult invasion. Wide local excision is the preferred initial treatment method, but there is evidence that topical imiquimod is also effective. Indole-3-carbinol also appears to be safe but may not be as effective as imiquimod or surgery.  In cases where invasive cancer is not suspected, laser ablation is acceptable.
In a review of randomized controlled trials that assessed medical interventions in adult women diagnosed with high-grade vulval intraepithelial neoplasia (VIN), imiquimod appears to be effective; however, but its safety needs further examination. Indole-3-carbinol also appears to be safe but may not be as effective as imiquimod or surgery. 
In larger lesions (ie, stage IB or greater or with stromal invasion >1 mm), the incidence of ipsilateral inguinal lymph node involvement increases as the depth of invasion, as well as the gross size, increases. Consequently, inguinal lymphadenectomy is part of the primary surgical procedure. This can be performed through a small separate inguinal incision, removing the lymph nodes above the cribriform fascia and in the opening of the fascia at the fossa ovalis. If the results are negative on frozen section of these lymph nodes, then a modified partial vulvectomy is the only treatment necessary. If the results on frozen section of the ipsilateral lymph nodes are positive, then most physicians suggest removing the lymph nodes on the contralateral inguinal area as well.
The lesion itself can be treated conservatively, with a partial vulvectomy. Performing complete vulvectomy is an outdated treatment unless the cancer is present bilaterally. If clitoral involvement is present, lymphatic drainage can be direct to the pelvic lymph nodes. Studies have demonstrated that, even with clitoral involvement, the deep lymph nodes are not involved unless the inguinal nodes have evidence of metastasis also. Pelvic lymphadenectomy is largely discontinued, even in cases of lymph node involvement. A large, prospective, randomized study conducted by the Gynecologic Oncology Group (GOG) noted that patient survival rates are better if the pelvic and inguinal area is treated with radiation postsurgically, as compared to patients treated with pelvic lymphadenectomies, even when the pelvic nodes are not involved. [6, 4] Incidence of lymph node metastasis seems to be increased if vascular lymphatic space is involved.
In women with locally advanced vulvar cancer, no significant differences in survival or adverse events were found when primary chemoradiation or neoadjuvant chemoradiation were compared with primary surgery. However, these findings were based on small numbers and few studies in this Cochrane review.  Good, quality studies that compare primary treatments in locally advanced vulvar cancer are needed.
Contemporary data suggest that the overall 5-year survival rate of patients with stage I epidermoid invasive cancer is 85-90%. The survival rate decreases with increasing stage; however, an approximate 5-year survival rate of 40% can be obtained, even in patients with lymph node metastasis.
In a review of the National Cancer Data Base, patients with positive inguinal lymph nodes were found to have 5-year survival rates of 64% with 2-cm lesions and 43% with lesions greater than 2 cm. In patients with primary lesions of any size, the survival rate was identical whether 1 lymph node was positive or 2-3 lymph nodes were positive (55% vs 59%). The survival rate in patients with 4 or more positive nodes was only 33% at 5 years. The 5-year survival rate of patients with 1 positive node, without radiation, was 68% and was 56% with radiation. If 2 or more lymph nodes were positive, the survival rate was 46% without radiation therapy and 48% with radiation. 
The 2006 Annual Report noted a 5-year survival rate of 82% in patients with negative lymph nodes who were treated with surgery only, compared to 72% for patients treated with surgery and radiation. If lymph nodes were positive, the survival rate was 48% in patients treated with surgery alone, compared to 31% in patients treated with surgery plus radiation. These studies raise the question of whether or not postoperative radiation therapy is as advantageous as the GOG study noted.
More than 80% of recurrences appear within the first 2 years after therapy, and they may be either local or distant. Because many reoccurring lesions appear locally and near the site of the primary lesion, initial close follow-up is necessary. Visual examination provides the best follow-up.
Local recurrences are more common in patients with large primary tumors than in patients with metastatic disease in the lymph nodes, and local occurrences can appear when the margins are clear on the original operative specimen. Local recurrences can be managed successfully in many instances by repeat local excision and/or interstitial radiation.
Recurrent lesions in the lymph node area, as well as in distant sites, are difficult to treat, and survival rates are poor. If recurrences appear in the inguinal area, excision with or without radiation therapy may be beneficial. Distant metastasis are treated most effectively with chemotherapy, with cisplatin as the drug of choice, and 30% response rates have been achieved in reports.
Melanoma is the second most common invasive cancer occurring in the vulva, but its occurrence is rare. Melanoma probably arises from a lesion containing a junctional or compound nevus. Consider pigmented lesions on the vulva suspicious if they are blue-black in color, have a jagged or fuzzy border, are raised or ulcerated, or are larger than approximately 1 cm. Melanomas may be misdiagnosed as undifferentiated squamous carcinoma, particularly if they are amelanotic. Most melanomas are located on the labia minora or clitoris, and prognosis is related to the size of the lesion and the depth of invasion. The Clark classification commonly used for melanoma elsewhere on the skin is of prognostic benefit for melanoma of the vulva. The Breslow modification expresses invasion in micrometers compared with location of different skin structures.
Approximately 3% of all melanomas are located in the genital tract. Melanoma of the vulva accounts for 5-7% of invasive vulvar cancers and has an estimated annual incident rate of 1 per 1,000,000 women. The disease can affect women of all ages (eg, women aged 7-97 y in 1 study) but is more common in the older population, with almost half of the patients aged 70 years or older. More than 90% of melanomas occur in white women.
In the past, this lesion was treated with radical vulvectomy and bilateral inguinal lymphadenectomy. In recent years, more conservative treatment, such as has been practiced for this lesion elsewhere on the body, has become more common. A radical local excision with 2-cm margins appears to be adequate for most well-circumscribed lesions. Whether inguinal lymphadenectomy should be performed for this cancer is undecided at present. Obviously, if lymph nodes are involved, this finding is not only diagnostic but also prognostic. If lymph nodes are negative, the patient may be reassured. Lymph node involvement is directly related to the depth of invasion. If the disease is intraepithelial, the cure rate is close to 100% and is reported to be as high as 99% with invasion of 1.5 mm or less. The survival rate drops to 65-70% if the lesion invades 1.5-4 mm.
Medical management for metastatic disease continues to be experimental. If the melanoma recurs locally in the vulvar area, reexcision may be adequate therapy, with long-term survival.
Paget disease of the vulva is rare. It occurs in women in the seventh decade of life but can occur in young patients. Symptoms of pruritus and tenderness or identification of a vulvar lesion occur most frequently. The patient may experience symptoms for several years before seeking medical advice. The lesion may be localized to one labium or involve the entire vulvar epithelium. It may extend to the perirectal area, buttocks, inguinal area, or mons. It has been observed extending into the vagina. Because of its rarity, frequency data are unavailable.
Clinical and histological features
Vulvar lesions usually are hyperemic, and they may be demarcated sharply and thickened with foci of excoriation and induration. The vulvar skin may be thick, leading to the impression of leukoplakia with the cake icing effect. This classic finding almost is pathognomonic for Paget disease. The lesion is usually superficial and is considered an intraepithelial lesion, although an underlying adenocarcinoma may be associated with Paget disease. Older literature suggests that underlying adenocarcinoma occurs in about a quarter of cases, but more recent data find less association of Paget disease with an underlying adenocarcinoma.
Obtain adequate biopsies to make an accurate diagnosis. Histologically, it commonly presents with large cells of clear cytoplasm in a heavy lymphocytic infiltration in the dermis; it can be confused with amelanotic melanoma. If any thickened indurated area is present, then obtain adequate deep biopsy in order to rule out adenocarcinoma.
If only intraepithelial Paget disease is present, wide local excision is adequate treatment. Histological evaluation of the epithelium extends, in many instances, far beyond the visual limits of the lesion, and, therefore, wide adequate margins are necessary to remove the lesion. If an underlying adenocarcinoma is present, then treat the lesion as invasive squamous cell carcinoma is treated. If tumor cells are present at the margin of the excision, then recurrence can be quite high. Some investigators obtain frozen section of the margins and, if positive, continue to obtain wider margins. Unfortunately, even with negative margins, recurrences are possible, and new lesions can be treated in the same manner as the primary disease (ie, wide local excision). These may occur years after diagnosis of the primary lesion.
Currently, intraepithelial Paget disease and Paget disease with an underlying adenocarcinoma are thought to be 2 separate entities. The cases of patients who were diagnosed with Paget disease and who refused primary treatment have been followed for over a decade without development of an underlying adenocarcinoma. As with other vulvar lesions, frequent visual examinations are necessary in order to determine disease-free status.