Melanoma and Other Skin Cancers

Staging and Prognosis of Melanoma

A great deal of information is available regarding factors that correlate with clinical outcome in patients with melanoma. In patients with clinically localized disease, the most important prognostic factors are Breslow's thickness, mitotic rate, ulceration, and SLN status. Overall, however, 85% of melanoma patients present with clinically normal lymph nodes. In clinically node-negative patients, most investigators have found the microscopic degree of invasion of the melanoma, or microstaging, to be of critical importance in predicting outcome (Tables 1 and 2; Figure 1).

Microstaging

Primary melanoma

Three microscopic characteristics of primary melanoma are now incorporated into the new American Joint Committee on Cancer (AJCC) staging system for melanoma, as each contributes significantly to predicting risk of regional lymph node involvement and long-term risk of metastatic disease and death.

Breslow's thickness. First described by Alexander Breslow, this method of describing tumor thickness measures from the top of the granular layer of the epidermis to the deepest contiguous tumor cell at the base of the lesion using a micrometer in the microscope eyepiece. It is the primary determinant of T staging and has the highest prognostic value of any primary tumor characteristic. In the 2010 AJCC 7th Edition Cancer Staging Manual (which was released in 2009, with revisions implemented in January 2010), Clark's level was removed from stage groupings, as it is not predictive of outcome when the three cardinal features are considered.

TABLE 1TNM staging for cutaneous melanoma

TABLE 2Anatomic stage groupings for cutaneous melanoma

FIGURE 1Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for stages I and II melanoma. For patients with stage III disease, survival curves are shown comparing (C) the different N categories and (D) the stage groupings.

Ulceration. The presence of ulceration in a primary melanoma is one of the strongest negative predictive factors for long-term survival. Ulceration is defined as the lack of a complete epidermal layer overlying the melanocytic lesion. The presence of ulceration essentially upstages affected patients to the next highest T level. In other words, a patient with a 1.1- to 2-mm melanoma that is ulcerated will carry the same long-term prognosis as a patient with a 2.1- to 4-mm melanoma that does not have ulceration. The likelihood of finding ulceration is directly related to tumor depth: Patients with thin melanomas (≤ 1 mm) have a 6% rate of ulceration, whereas those with > 4-mm melanomas have a 63% incidence of ulceration. Along with tumor depth, ulceration is integral to determining a patient's long-term prognosis and is an independent predictor of patient outcome.

Mitoses. The presence of mitotic figures in the dermal component of a primary melanoma has been shown in several institutional series to confer poor prognosis. In the 2010 staging classification for melanoma, the presence of ≥ 1 mitosis/mm² has been added as a modifier of risk for patients with T1 melanomas, as it is in this group that the presence of mitoses has the greatest influence on management.

Mitototic rate

In the 2010 AJCC staging system, the mitotic rate was identified as an independent predictor of survival for primary melanoma < 1 mm in Breslow thickness. It is defined as the number of dividing cells identified within 1 mm². The most powerful cutoff was < 1/mm² vs > 1/mm². Indeed, in more than 10,000 patients with early melanoma, mitotic rate was second only to Breslow thickness as a survival determinant.

Clark's level

Wallace Clark and associates devised a system to classify melanomas according to the level of invasion relative to histologically defined landmarks in the skin. Although Clark's levels correlate with prognosis (lesions with deeper levels of invasion have a greater propensity for recurrence), the inherent problem with Clark's system is that the thickness of the skin and hence the distance between the various landmark dermal layers varies greatly in different parts of the body. When initially described, the Clark's level was a standard way to stage patients with melanoma and predict outcome. Over the years, it has proven much less reliable than Breslow thickness, and the 2002 AJCC staging system was used only for lesions < 1 mm. In the 2010 AJCC staging system, the mitotic index has replaced the Clark's level in staging lesions < 1 mm. The Clark's level is only used when mitotic index is unavailable for lesions < 1 mm.

Regional Lymph Node Involvement

In patients with intermediate-risk melanoma (1 to 4 mm in thickness), lymph node involvement is the strongest prognostic indicator in the staging of melanoma. Patients with nodal involvement at the time of their diagnosis have significantly decreased survival compared with node-negative patients. There is a direct relationship between the depth of invasion of the primary lesion and the potential for lymph node involvement. Among node-positive patients, the prognosis is more favorable in those with microscopic as opposed to macroscopic or clinically apparent disease. In addition, the increased number of nodes involved is associated with decreased survival in both microscopically detected and clinically apparent regional nodal metastasis. The worst prognosis occurs in patients with large, matted regional lymph nodes, whose outcome is similar to that of patients with stage IV disease.

In the 2010 version of the AJCC staging system, there was no change in nodal basin staging. Importantly, despite reports from some centers that a low burden of disease in the regional node predicts no additional nodal metastasis, the current staging system does not identify a minimal nodal tumor burden that would be considered essentially negative.

Melanoma of Unknown Primary

Melanoma of unknown primary (MUP) occurs in up to 5% of patients who present to tertiary cancer referral centers. Lymphadenopathy is the most common clinical presentation, followed by identification of visceral metastases and cutaneous nodules. Patients should be evaluated by a dermatologist and should undergo a complete physical examination, including an anorectal and genital evaluation. A CT scan of the chest, abdomen, and pelvis and/or a whole-body PET scan are useful for staging patients with MUP. In the absence of other sites of disease, surgical resection of the metastatic lesion (or complete regional lymphadenectomy) is appropriate. In the absence of symptoms, an ophthalmologic consultation is probably not warranted unless liver metastases are the only site of disease, given the propensity for ocular melanoma to metastasize to this site.

Single dermal nodules with no identifiable primary lesion are typically treated in a fashion similar to that of primary melanomas, with wide local excision and regional nodal evaluation SLNB if appropriate. The prognosis for patients who present with MUP is similar to that for somewhat more favorable patients with metastatic disease from a known primary (AJCC M1a).

Clinical and Pathologic Staging

TABLE 3Differences between the 6th edition (2002) and the 7th edition (2010) of the AJCC melanoma staging system

TNM staging system

The melanoma staging committee of the AJCC revised the TNM staging system to reflect more accurately the impact of statistically significant prognostic factors that were validated in a multi-institution sample of 38,918 melanoma patients. The AJCC 2010 Staging System is shown in Tables 1, 2, and 3. Survival curves from the AJCC Melanoma Staging Database comparing different T categories and stage groupings for stages I and II melanoma are shown in Figure 1; in addition, for patients with stage III disease, survival curves in this figure compare the different N categories and the stage groupings.

Changes in the staging system are summarized in Table 3. The most significant change to the 2010 AJCC staging classification is the replacement of Clark's level by presence of mitoses in the stage I group. This involves the use of mitotic rate in the staging of patients with clinically localized melanoma ≤ 1 mm. Patients without ulceration and a mitosis < 1/mm² are categorized as T1a, whereas those with > 1/mm² are T1b.

For patients with stage IV disease (distant metastases), there are few long-term survivors, but more favorable survival is associated with soft-tissue sites (vs lung or visceral sites) and normal LDH.

Other Prognostic Factors

Age

Overall, patients who are ≥ 65 years old have a survival rate that is decreased by 10% to 15% compared with their younger counterparts. This trend has been demonstrated in numerous studies. A different relationship between age and risk of lymph node involvement is emerging, however. Data from the prospective Sunbelt Melanoma Trial and retrospective studies reveal that younger patients are significantly more likely to have a positive SLN biopsy than older patients with similar lesions.

Gender

Many studies have identified improved survival in women vs men with melanoma, when stratified by stage. The reasons for this are unclear.

Anatomic location

There is a correlation between anatomic location and prognosis of primary melanoma. Those with lesions on the back, upper arms, neck, and scalp (BANS area) have a worse prognosis than those with lesions on the extremities. Men are more likely to develop truncal melanomas, whereas women are most likely to develop melanoma on their extremities.

Desmoplastic melanoma

Desmoplastic melanomas represent a less common but clinically distinct spindle cell variant of melanoma with dense fibrosis and frequent neurotropism. Clinically, they are raised, firm nodules that are amelanotic in up to 40% of patients, commonly leading to a delay in diagnosis.They are usually deep lesions but have a more favorable prognosis than do conventional melanomas of similar Breslow thickness. The association of desmoplastic melanoma with local recurrence may be due to the fact that many of these lesions are misdiagnosed and undertreated, with regard to an appropriate radial margin of excision.

Additionally, although many desmoplastic melanomas are deeply invasive at the time of diagnosis, they are less likely to involve regional lymph node basins. Patients with "pure" desmoplastic melanoma are extremely unlikely to harbor regional nodal metastasis, and SLN biopsy is unlikely to provide useful information. Patients with "mixed" desmoplastic melanoma, containing a component of conventional melanoma, have a risk of regional nodal metastasis that is approximately half that of patients with conventional melanoma, and SLN mapping should be considered in these patients.

Despite the fact that these lesions are often relatively thick at presentation, patients with desmoplastic melanomas have survival rates that are favorable compared with patients who have conventional melanomas of a similar depth.

Angiolymphatic invasion

Defined as invasion of tumor cells into the wall and/or lumen of vessels or lymphatics of the dermis or deeper structures, angiolymphatic invasion is uncommon in melanoma. However, this finding is clearly associated with more aggressive tumors. Multiple large studies have shown worsened long-term survival and more frequent lymph node involvement in patients with angioinvasive melanomas. Patients with vascular invasion in their primary melanoma have a threefold risk of lymph node involvement and a reduction in 5-year survival by as much as 50% compared with matched patients without vascular invasion.

Regression

The finding of regression represents a host immune response to invasive melanoma. Areas where invasive cells may have once existed are replaced by inflammatory reaction and fibrosis, which may make it impossible to determine the precise depth of the initial lesion histologically. There is continuing debate regarding the prognostic importance of regression; however, many clinicians believe that thin lesions that show signs of regression should be given higher consideration for surgical nodal staging, given the fact that the initial lesion may have originally been more deeply invasive. Although some studies have shown that regressed lesions have a higher propensity for lymph node metastases than nonregressed primary tumors of the same thickness, this finding has not been universally observed. Indeed, a recent retrospective single-institution study demonstrated no increased risk of SLN metastasis in patients with regressed melanoma, suggesting that SLNB should not be performed for lesions that would otherwise not be considered for the procedure based on the presence of regression.

Tumor-infiltrating lymphocytes

Variable numbers of tumor-infiltrating lymphocytes (TILs) are observed in melanoma. Tumors with a high number of TILs should carry an improved prognosis, presumably because of the active host response to tumor. In fact, many studies have shown this tendency. The absence of TILs in the primary melanoma has been associated with a higher risk of positive SLNs in a recent, large, single-institution study. In addition, as Azimi et al reported (J Clin Oncol 2012), the quantification of TIL within the primary tumor was shown to predict survival in patients with clinically localized disease. (High-grade TIL infiltration was associated with improved survival.)