Malignant Vulvar Lesions

INTRODUCTION

Background

Although older literature suggests a possible association between vulvar carcinoma and venereal or granulomatous lesions, more contemporary data suggests that this relationship does not exist. People of all cultures and races report vulvar malignancies. Gravity and parity do not appear to be involved in its pathogenesis. Although human papillomavirus (HPV) has been suspected in the etiology of squamous carcinoma of the vulva, in truth, the cause of cancer of the vulva is unknown.

Frequency

Vulvar cancer accounts for approximately 5% of all female genital malignancies. It occurs in about 1.5 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 the recent Annual Report, more than 50% of patients reported to have vulvar cancer were aged 70 years or older, with 20% aged 80 years or older. In most series, an extended delay in diagnosis appears to occur mainly because the patient will not seek medical attention for many months or because the lesion is treated medically for months, without biopsy for definitive diagnosis.

Diagnosis

Histological evaluation is a prerequisite before planning definitive therapy for changes in the epithelium of the vulvar, 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 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 usually is sufficient, and sutures are placed as needed.

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 cauliflowerlike growths may arise and be confused with condyloma acuminata. Squamous carcinomas can appear in a background of atrophic changes (lichen sclerosis) or in hypertrophic epithelium. Long-term pruritus, lumps, or masses on the vulva are present in most patients with invasive vulvar cancer.

Metastasis

The cancer can appear anywhere on the vulva, although about three fourths will arise primarily on the labia. The more rare 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 usually is 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 1995, FIGO instituted a subclassification of stage I.

Carcinoma of the Vulva: FIGO nomenclature

Stage Characteristics
Stage 0 Carcinoma in situ; intraepithelial neoplasia grade III
Stage I Lesion ?/font>2 cm; confined to the vulva or perineum; no nodal metastasis
Stage Ia Lesion ?/font>2 cm; confined to the vulva or perineum and with stromal invasion ?/font>1 mm*; no nodal metastasis
Stage Ib Lesion ?/font>2 cm; confined to the vulva or perineum and with stromal invasion >1 mm*; no nodal metastasis
Stage II Tumor >2 cm in greatest dimension; confined to the vulva and/or perineum; no nodal metastasis
Stage III Tumor of any size with adjacent spread to the lower urethra and/or vagina or anus and/or unilateral regional lymph node metastasis
Stage IVa Tumor invasion of any of the following: upper urethra, bladder mucosa, rectal mucosa, and/or pelvic bone and/or bilateral regional node metastases
Stage 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.

Treatment

A small primary lesion on the vulva (<2 cm) with superficial invasion (<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).

In larger lesions (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 these lymph nodes are negative on frozen section, then a modified partial vulvectomy is the only treatment necessary. If 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 is 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. Incidence of lymph node metastasis seems to be increased if vascular lymphatic space is involved.

Prognosis

Contemporary data suggest that the overall 5-year survival of patients with stage I epidermoid invasive cancer is 85-90%. Survival 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, survival was identical whether 1 lymph node was positive or 2-3 lymph nodes were positive (55% vs 59%). Survival with 4 or more positive nodes was only 33% at 5 years. The 5-year survival of patients with 1 positive node, without radiation, was 68% and was 56% with radiation. If 2 or more lymph nodes were positive, survival was 46% without radiation therapy and 48% with radiation.

The 2000 Annual Report noted a 5-year survival of 86% in patients with negative lymph nodes who were treated with surgery only, compared to 65% for patients treated with surgery and radiation. If lymph nodes were positive, survival was 61% in patients treated with surgery alone, compared to 40% 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.

Follow-up

More than 80% of recurrences will appear within the first 2 years after therapy and may either be local or distant. Because many reoccurring lesions will 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 is 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 @

Background

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 all ages (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 Caucasian women.

Treatment

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, cure is close to 100% and reported to be as high as 99% with invasion of 1.5 mm or less. This rate drops to 65-70% survival 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 @

Background

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 are observed 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 is 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 usually is 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 finds 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 melanotic melanoma. If any thickened indurated area is present, then obtain adequate deep biopsy in order to rule out adenocarcinoma.

Treatment

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 will 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.

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