Although these cancers are rare, they can be even more deadly than melanomas appearing on other parts of the body and more easily overlooked. To detect these malignancies early on, have any suspicious lesions promptly biopsied.
Even though malignant melanoma of the vulva is a relatively rare disease, its prognosis is usually poor, with survival dependent upon tumor thickness or level of infiltration. Early diagnosis is therefore imperative and key to managing these cancers. The importance of using vulvar biopsies liberally cannot be overstressed. The gynecologist also must understand the differential diagnosis of the pigmented or dark vulvar lesion, as well as some of the subtle differences between benign and malignant lesions. (Vaginal melanomas, which are extremely rare, will be discussed at the end of this article.)
Most large academic centers will see only 10 to 20 patients with vulvar malignant melanoma in a 10-year period.1 Although this disease is the second most frequently occurring neoplasm of the vulva, it accounts for only 4.8% of vulvar cancers, and 3% to 7% of all melanomas in females.2 This incidence may be higher than expected when one considers that the vulva accounts for only 1% to 2 % of the total surface area of the skin. Some authors have hypothesized that the vulvar skin has a more complex skin surface, which makes it more susceptible to squamous cell cancers and melanomas.3 Other studies have shown a reduced incidence of melanomas, however, suggesting no predisposition.4
The average patient with vulvar melanomas is over 60, with most women presenting between the ages of 50 and 80.3 In contrast, the mean age for cutaneous melanomas is between 30 and 40 years, with one third of cases occurring before age 45. Symptoms of vulvar malignant melanomas are similar to those seen in squamous cell cancers. Most women will present with either a noticeable lesion or pruritus. Other symptoms include bleeding, ulceration, or discharge. In our series from the University of Miami/Jackson Memorial Hospital, almost one half of all lesions were asymptomatic, and many were picked up on routine exam.2 Occasionally, patients will present with a melanoma arising in a pre-existing nevus, but in Clark's original studies, only 8% to 9% of the melanomas were associated with a nevus.5
For squamous cell cancers of the vulva, most series report that patients wait between 2 and 16 months before seeking medical attention, while physicians delay up to 12 months before diagnos-ing them. The delay in treating melanomas is thought to be about the same, with subtle or amelanotic lesions more likely to be overlooked.2 Figure 1 shows the vulva of a patient who went to her primary care physician with a new growth just above her clitoris. The woman's primary care physician removed the original lesion, which measured less than 1 cm, but did not send it for evaluation by a pathologist. The patient returned approximately 2 to 3 months later, after the lesion began to bleed. This time a biopsy was performed and a diagnosis of melanoma was made. At the time of surgery, the woman was found to have a total of four positive bilateral lymph nodes.
Malignant melanomas are generally dark lesions, but can have a varied appearance. Dark lesions that are brown, black, purple, and multicolored account for approximately 10% of all vulvar disease.6 The clinician's differential diagnosis should include lentigo, carcinoma in situ or Bowenoid papullosis, hemangiomas, ecchymosis, and other vascular diseases, acanthosis nigricans, nevi melanoma, and other uncommon conditions. One of the most common pigmented lesions of the vulva is the lentigo, which is an abnormal concentration of melanocytes in one area of the skin. It produces an excessive amount of melanin compared with that found in the surrounding skin. Lentigo may be freckle-like or have fuzzy borders, but is not a raised lesion. It is a benign lesion that is only important because it may be confused with other more serious conditions. Occasionally, pigmented superficial spreading melanoma (SSM) may have a similar appearance to lentigo.
Dismiss no mole. It is important that the gynecologist always maintain an adequate level of suspicion. In general, consider for biopsy any pigmented or dark lesion, particularly if its borders are indistinct or spreading, or if the lesion is raised. The bluish-black lesion of malignant melanoma is particularly pathognomonic. If the lesion is amelanotic, however, or has minimal pigmentation, it can sometimes be confused with a squamous lesion. For example, the lesion shown in Figure 2 could be mistaken for a squamous cell cancer but is actually a superficial spreading vulvar melanoma. Maximum invasion was in the nodular area and the lesion also appeared amelanotic. Moreover, the surrounding tissue was reported to be invasive superficial spreading melanoma in situ and atypical melanocytic hyperplasia. The upper right pigmented lesion was an associated compound nevus with focal atypia. Colposcopically, however, the lesion had the appearance of squamous CIS with microinvasion.
Paget's disease vs. melanoma. Other lesions that can be confused with melanomas of the vulva include Paget's disease and dysplastic nevi. Immunohistochemistry can help the pathologist to distinguish between Paget's disease and melanoma. Typically, Paget's cells show immunoreactivity for carcinoembryonic antigen (CEA), whereas melanoma cells do not. Melanoma cells usually show positivity for S-100 protein or melanoma-specific antigen. Special stains for detecting melanin are not usually helpful since amelanotic melanomas may be lacking in melanin, whereas Paget's cells may contain melanin.7
Excisional biopsy is better. An excisional biopsy is preferable whenever possible, as it will allow the pathologist to gauge the maximum depth of invasion and help determine subsequent treatment for the patient. If an excisional biopsy is not feasible initially, an incisional one should be done with a 5- to 7-mm dermatologic punch biopsy (Keyes punch biopsy). It is important to take the biopsy from the most nodular area, since this is usually the site of deepest penetration. The biopsy should extend into the subcutaneous tissue for evaluation of the depth of invasion. Numerous studies have shown that an incisional biopsy does not affect prognosis. Routine removal of a vulvar nevus is usually not recommended, as long as the patient is willing to do self-monitoring. In general, you should remove lesions if patients have either large nevi or a history of premalignant nevi.
Several systems are used for staging malignant melanomas anywhere on the body. The first one reported onalbeit the classification that is the least helpful in predicting prognosiswas based upon the clinical and histolopathologic features of the lesion.8 This histologic staging, based on morphology, histology, and growth patterns, includes superficial spreading, nodular (NM); lentigo maligna (LMM); acral lentiginous (ALM) and unclassified lesions. SSMs account for the majority of vulvar melanomas, although one will occasionally see the nodular or acral lentiginous types. Other classifications include clinical staging, staging based on histologic depth of penetration, and TNM.
Growth patterns for melanomas are either radial or vertical, with the radial growth phase usually preceding the vertical one. Radial growth can either be along the basement membrane or can fill the entire epidermis. It is now believed that most melanomas have an in situ or superficially invasive phase of several years. Vertical growth starts when the tumor takes on more aggressive biologic properties.
Superficially spreading melanomas. These tend to be less than 2.5 cm and to have an arch-like outline with an irregular border. The lesion ranges from slightly to definitely elevated and its color varies greatly. Not only may it be brown, black, pink, rose, or gray/white, but the colors tend to be placed haphazardly. The growth pattern is both horizontal and vertical and it may consist of numerous small tumor nodules. When it occurs on the vulva, this type of melanoma may be much more difficult to recognize (Figure 2), particularly when lesions arise on mucous membranes. The pedunculated form shown in Figure 3 is an unusual variation of this disease. This patient, who waited approximately 6 months before seeking medical attention, obviously presented with a large growth on her mons pubis.
Nodular melanoma. Distinguished by being elevated throughout, NM may appear as a dark, blueberry-like lesion or a raised plaque that is uniformly discolored. The colors tend toward deep blue, purple, black, or dark brown. Histologically, there is very little intraepidermal growth, and the lesion typically arises at the dermoepidermal junction. NMs of the vulva (Figure 4) have a very similar appearance. Since this lesion is known for early deep penetration, the prognosis is generally poorer.
Lentigo maligna and acral lentiginous melanomas. Usually a relatively flat lesion, LMM typically occurs in sun-exposed areas, like the head and neck. On rare occasion, it can appear on the vulva. This type tends to be larger than the cutaneous superficial spreading kind, measuring between 3 and 6 cm. Its varied coloration is similar to that seen in SSM. ALM, on the other hand, occurs at cutaneous junctions and on the palms and soles. Although similar to LMM, its biologic behavior is more aggressive. On rare occasions, it can appear on the vulva.
Unclassified lesions. These tumors account for only about 5% of all melanomas.
In 1969, in order to better predict the outcome of patients with localized disease, Clark and associates correlated prognosis to five anatomic levels of invasion.5 They defined their categories as: Level I: All the tumor cells are above the basement membrane, or confined to the epidermis (in situ melanoma); Level II: The neoplastic cells have broken through the basement membrane and extend into the papillary dermis, but have not reached the reticular dermis; Level III: The neoplastic cells completely fill the papillary dermis; Level IV: The cells enter the reticular dermis; and Level V: The cells penetrate into the subcutaneous fat.
Clark showed that survival was inversely proportional to the level of invasion, and that recurrences and metastasis were proportional to the invasion level. There were several inherent problems in using Clark's levels to determine prognosis, however. The first was difficulty in differentiating between an advanced level II and a level III lesion. Also, levels III and IV varied greatly in thickness, whereas levels I, II, and V tended to be more uniform in thickness. One of the major problems with Clark's microstaging system for vulvar melanomas stems from the clitoris and labia having differing morphology from the rest of the skin of the body; hence some of these levels of invasion do not apply.
Approximately 1 year after Clark, Breslow was better able to correlate the thickness or depth of invasion of the melanoma with prognosis.9 Using ocular micrometer, he measured the thickest portion of the melanoma from the surface of intact epithelium to the deepest point of invasion. Until recently, Breslow's staging was the most common staging system for melanomas. But Chung and colleagues have now devised a modified Clark's system that is designed specifically for the staging of vulvar melanomas.10 They substituted the measurement of tumor thickness in multiples of 1 mm for the middle three Clark levels. Chung and colleagues argued that most of the vulva lacked well-defined papillary dermis (Table 1 compares all three.).
The literature on vulvar melanomas contains only one prospective study conducted by the Gynecologic Oncology Group (GOG). They applied the American Joint Committee on Cancer (AJCC) staging for cutaneous melanomas (Table 2) to vulvar melanomas, found this staging to be most predictive of survival, and concluded that the AJCC staging should be used for vulvar melanomas.11 The GOG found that Breslow's staging was the second most predictive. Using the AJCC staging, the 5-year survival rate was 85% for stage I, 40% for stage II, and 25% for stage III. In the same study, FIGO staging was not found to be very predictive of survival. Even though many cancer centers use TNM staging for malignant melanomas of the vulva, TNM is also not as predictive of survival as Breslow's and others that stage by depth. Overall, the survival for vulvar melanomas does not appear to be as good as for those appearing elsewhere. The reason for this is that more women with vulvar melanomas present with advanced disease, and many are older when they present.
Over the past three decades there has been a trend towards more conservative surgical treatment of squamous cancers and malignant melanomas of the vulva.12 In the early 1970s, melanomas were treated by an en bloc radical vulvectomy, bilateral inguinal-femoral lymphadenectomy, and retroperitoneal pelvic lymphadenectomy. Shortly thereafter, pelvic node dissections were performed only if Cloquet's node was positive, or if there was clitoral involvement. By the end of the 1970s, pelvic lymphadenectomy was abandoned for the most part. Over the next two decades, there has been a trend towards even more conservative treatment. Multiple studies have now questioned the role of radical vulvectomy in many of the vulvar melanomas.
The role of lymphadenectomy. Patients in whom cutaneous melanomas penetrate less than 1 mm have been shown to have a 5-year survival rate of at least 98%.13 Regional lymphadenectomy is therefore not recommended for these lesions. As with melanoma lesions elsewhere on the body, it is now felt that wide local excision alone is the best treatment for vulvar lesions of less than 0.76 mm of invasion. There is an emerging concept of radical wide local excision for deeper lesions. With deeper lesions, the depth of excision still needs to be at least 1 to 2 cm. The role of lymphadenectomy in deeper lesions is still under debate. Some authors argue that the cure rate may be the same if lymphadenectomy is performed expectantlythat is, subsequent removal takes place only once positive lymph nodes are clinically evident. For wide local excision, it is generally recommended that margins be at least 1.0 to 2.0 cm. Larger margins have not improved survival.3 The issue of whether smaller margins can be used has not really been addressed in the gynecologic literature. Breslow reported on 62 cutaneous lesions with less than 0.76-mm depth of invasion.14 Some 32% of these patients had a resection margin of 1 cm or less. The width of the margins ranged from 0.1 to 5.15 cm. None of these patients had a local recurrence over a 5-year period.
When the odds of survival are less clear cut. The management of vulvar lesions with 1.0 to 4.0 mm of invasion is less clear cut, since patients with an intermediate thickness ranging from 1.0 to 4.0 mm have a 60% chance of occult regional metastasis, but only a 20% chance of distant metastasis.13 Therefore, if melanomas spread directly to the regional lymph nodes, one might expect improved survival from elective lymphadenectomy. At the time of initial presentation, lesions thicker than 4.0 mm have a 60% chance of regional node metastasis and a 70% chance of occult distant disease.13 Survival rates for these patients tend to be poor as a result of distant metastasis. Regional lymphadenectomy will probably not help these women, unless it is to remove grossly positive nodes, and no further metastasis has occurred. Two large studies on cutaneous melanomas did not show a survival benefit to elective lymphadenectomy.15,16 In these studies survival was the same whether the lymphadenectomy was not performed, performed at a later date, or took place when the patient developed clinical evidence of nodal disease. The GOG study was also unable to draw any conclusions about the benefits of elective groin-node dissection in vulvar melanomas.
More individualized and less radical surgery for vulvar cancers has continued into the 1990s with the development of sentinel node biopsy (intraoperative lymphatic mapping).17,18 Sentinel node biopsy for patients with primary cutaneous melanomas was first introduced in the 1990s. It was thought that this approach would identify the subset of women with regional nodal metastasis who would particularly benefit from lymphadenectomy and also would spare numerous patients from more radical surgery. The primary tumor is injected with isosulfan blue dye, and the first drainage point is then identified, usually within minutes of injection. This node, or collection of nodes, is sampled and sent for frozen section. If the node(s) is negative, no further dissection is done; if positive, a regional lymphadenectomy is performed.
In one of the largest series on cutaneous melanomas, Morton and colleagues were able to identify a sentinel node in 82% of a total of 237 patients. All patients underwent a regional lymphadenectomy. Positive nonsentinel nodes were found in only two patients. There were no positive nodes in 34 patients who had a negative sentinel node.19 In a cooperative study, only two of 132 patients (1.5%) had a recurrence following a negative sentinel node. To date, the procedure of lymphatic node mapping has been shown to be fairly accurate. Advantages include a lower morbidity as a result of less radical surgery. However, the role of this technique has yet to be completely determined and its application is probably best confined to clinical studies at this time.
In the past, malignant melanoma was generally considered to be radioresistant. There is now sufficient biologic and clinical evidence to show the reverse.20,21 Although surgery remains the treatment of choice for most malignant melanomas, there is now evidence that radiation can be effectively used in certain situations, such as the patient in whom surgery would result in significant cosmetic or functional disability. Retrospective and Phase II prospective studies have shown that both elective and adjuvant radiation therapy improves local and regional control, particularly for thick primary lesions, nodal involvement, and mucosal melanomas. In most of these cases, radiation therapy has not been shown to improve 5-year survival.
For the most part, adjuvant chemotherapy, immunotherapy, and vaccines have not improved survival.22 Only adjuvant alpha interferon has been shown to increase disease-free and overall survival.23 Additional randomized prospective trials are needed to further evaluate dosage, duration, and treatment regimens. The most active chemotherapy agent for the treatment of malignant melanomas is dacarbazine (DTIC). At best, the response rates are around 20%.22 The average duration of response is only 5 to 6 months, and complete responses occur in less than 1% to 2% of the patients.
Melanomas of the vagina are extremely rare, with nodular lesions being the most frequently seen form of the disease. Because there are so few cases, no prospective study has really addressed the issue of staging. However, the FIGO staging system is probably the most commonly used. In a retrospective study, lesions smaller than 3 cm were found to have a significantly better survival rate. The benefits of radical or exenterative procedures in treating these lesions are unclear, as the two largest retrospective studies on vaginal melanomas produced conflicting conclusions.24,25
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