The incidence of melanoma is increasing faster than that of any other cancer. Fortunately, most melanomas (approximately 80%) are diagnosed at early localized stages, and surgery alone is curative. For patients at high risk for recurrence, a systemic approach to treatment may be necessary to reduce risk, and for some with more advanced or widespread melanoma, treatment may be palliative in nature in an effort to reduce or improve symptoms.
Proper staging of melanoma is crucial for defining prognosis and for determining the optimal treatment approach. Several cancer staging systems are used worldwide; one of the most common staging systems is the tumor-node-metastasis (TNM) classification endorsed by the American Joint Committee on Cancer (AJCC). The TNM system classifies cancers, including melanoma, by the size and extent of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence or absence of distant metastasis (M), supplemented in recent years by carefully selected (nonanatomic) prognostic factors (Edge et al., 2010, p. 3). This system of classifying cancer by TNM status determines clinical Stage I, II, III, or IV for every cancer.
With regard to melanoma specifically, the T category is based on the thickness (or depth) of the primary melanoma measured in millimeters, and is further subcategorized to include the presence or absence of ulceration and mitotic rate-two very important prognostic features of a primary melanoma (Table 1). The N category (Table 2) is determined by the presence and extent of regional lymph node involvement, and is further subcategorized according to number of involved lymph nodes and whether the metastases were macroscopic or microscopic (palpable or determined by sentinel-node evaluation, respectively). In-transit and satellite metastases are also included in the N staging. The M category (Table 3) is determined by the presence or absence of distant metastases (including skin), by site of disease, and serum LDH level.
Melanomas without regional lymphatic spread are designated as Stage I or II. The staging of node-negative melanomas is based on the thickness (or depth) of the primary lesion at the time of definitive excision (Table 4). It also includes the presence or absence of ulceration, with the absence of ulceration defined as an intact epidermal layer overlying the melanoma. Thickness and ulceration are pathological features determined by microscopic examination. Before 2010, definition for T1 or thin melanomas (<1 mm) incorporated Breslow depth in addition to depth of invasion (Clark's level). According to Balch et al. (2009), a multivariate analysis of 4,861 T1 melanomas, tumor thickness, mitotic rate, and ulceration were the most powerful predictors of survival outcome for T1 melanoma patients, and the level of invasion was no longer statistically significant when mitotic rate and ulceration were included in the analysis. On the basis of this observation, in the 2010 staging system, Clark's level has been replaced by mitotic rate. As shown in Figure 1, with increasing thickness, the mortality rate increases, and within each level of thickness, ulceration confers a poorer prognosis.
Stage III melanoma is defined by involvement of (spread to) regional lymph nodes and/or the presence of satellite and/or in-transit metastases. Lymphatic metastases within 2 cm of the primary lesion are designated satellite metastases; those located more than 2 cm from the primary melanoma but before the first echelon of draining lymph nodes are designated in-transit metastases (Lawrence & Rubin, 2009). For melanomas that have spread to lymph nodes, the presence of ulceration of the primary tumor retains its prognostic significance; in other words, the prognostic features of the primary lesion are still considered in determining a patient's prognosis. The burden of tumor in the lymph nodes is highly predictive of outcome and is represented by the number of metastatic lymph nodes (Figure 2) and whether the involvement is microscopic (clinically inapparent before surgery) or macroscopic (clinically apparent; Lawrence & Rubin, 2009). The outcomes of these categories of nodal involvement are shown in Table 5. Stage IV melanoma represents distant metastatic spread and is stratified according to sites of involvement and serum LDH level. On the basis of these T, N, and M criteria, patients can be grouped according to prognosis. Long-term survival is rare in metastatic melanoma but is seen in up to 20% of patients with M1a disease (skin and nodal involvement only).
The definition of "high risk" is somewhat ambiguous; however, depth of the primary lesion (also known as Breslow depth), presence of ulceration, and nodal involvement, including microscopic involvement versus macroscopic involvement, are the major prognostic indicators that enable clinicians to determine a patient's individualized risk. These factors are included in the AJCC staging guidelines (Edge et al., 2010). Changes to the latest edition reflect a more accurate understanding of certain features that impact a patient's prognosis.
The seventh edition of the Cancer Staging Manual is effective for cancer cases diagnosed on or after January 1, 2010. The seventh edition includes evidence-based revisions that further clarify the TNM classifications and stage grouping criteria, reflecting an improved understanding of the disease. These recommendations are based on a multivariate analysis of approximately 38,000 patients with melanoma, 30,946 with Stages I, II, and III melanoma and the remainder with Stage IV melanoma (Balch et al., 2009).
The recommendations for changes were the result of an evidence-based analysis of the patients from the database. Essentially, there were four primary changes to the melanoma staging system:
1. mitotic rate per square millimeter is now to be used for categorizing T1 melanoma;
2. immunohistochemical (IHC) detection of nodal metastases is allowed;
3. there is no lower threshold for staging N+ disease; and
4. because of the large variability between clinical and pathological staging, a standard recommendation for sentinel-node staging as standard patient care is encouraged and should be required before clinical trial entry (Flaherty, Agarwala, & Rubin, 2009).
Mitotic rate, a measure of tumor proliferation in the dermis, is defined by the number of mitosis per square millimeter and indicates the number of cells that are in the process of dividing (mitosis) in a specified amount of melanoma tissue. Data from the Melanoma Staging Database clearly demonstrate an inverse relationship between mitotic rate and survival. In other words, the higher the mitotic rate, the more aggressive the lesion, and the higher the risk for metastases and subsequent death. Analysis of the Melanoma Staging Database has identified mitotic rate as a powerful and independent predictor of survival (Balch et al., 2009). Mitotic rate is now a required component of the staging system and will be used as the primary criterion for defining T1b melanomas. Clark's level will no longer be considered in the definition of T1 lesions, as discussed earlier in the manuscript. The exception to this would be only if mitotic rate cannot be determined in a nonulcerated T1 lesion; in this case, Clark's level may be used.
The second notable change in the latest AJCC melanoma staging guidelines includes the use of IHC detection of nodal metastases. The presence of nodal involvement historically has been determined by standard hematoxylin and eosin-stained sectioning; however, with the increasing availability of IHC staining to detect melanoma-associated antigens, it is now possible to consistently detect nodal metastases in just a few aggregate of cells (0.1 mm or less), an extremely low volume of tumor (Balch et al., 2009; Edge et al., 2010). Although it is recommended that both hematoxylin and eosin and IHC be performed, the AJCC considers IHC alone acceptable to determine the presence of microscopic nodal metastases, as long as the diagnosis is based on at least one melanoma-associated marker (such as HMB-45, Melan-A/MART 1) and the cells have malignant morphologic features that can be detected in the IHC-stained slides. Prognosis for patients with cutaneous melanoma is dependent on the number of involved regional nodes and the thickness of the primary tumor. As most patients who now present with Stage III melanoma do so with clinically uninvolved nodes and micrometastases diagnosed by sentinel-node biopsy, this change in practice involving the use of IHC translates into more refined and favorable survival estimates for patients with Stages IB-IIIA melanoma (Balch et al., 2009).
Staging is a way to determine the extent of involvement of the cancer. Another change in the new melanoma guidelines involves the difference between clinical and pathological staging. There are two types of staging for melanoma: clinical and pathological. Clinical staging is determined by microstaging of the primary as well as clinical evidence and/or radiologic evidence of metastases (results of CAT or PET scans, MRI, or ultrasound). Pathological staging includes the clinical staging, in addition to biopsy information from nodal or other visceral organ biopsies, if any. Pathological Stage 0 or Stage IA patients do not require nodal evaluation (i.e., sentinel-node evaluation); thus, they will not have information about nodal biopsies.
Significant differences in survival rates have been identified in patients who were clinically staged compared with those whose nodal disease was staged pathologically and those survival differences were statistically significant among all T categories except stage T4b (Edge et al., 2010, p. 328). Therefore, the AJCC Melanoma Staging Committee now recommends that sentinel lymph node biopsy be performed as a staging procedure in patients for whom the information will be useful in planning subsequent treatments and follow-up regimens (Balch et al., 2009). The risk for regional nodal involvement increases with increasing thickness of the primary melanoma. On the basis of this observation, the AJCC advocates that sentinel-node staging be a requirement for clinical trial entry for patients presenting with clinical Stage IB or II disease.
As there is now the widespread use of IHC to determine nodal involvement, another change to the 2010 AJCC staging guidelines for melanoma includes no lower threshold for node-positive disease. The ability to detect even the tiniest tumor burden by IHC has led researchers to question just how much tumor burden is clinically significant. Evidence published in the melanoma literature demonstrates that even small volumes (e.g., 0.1 mm or less [just a few cells] are associated with a worse prognosis over time (Balch et al., 2009). This observation contradicts a prior held belief that isolated tumor cells in the lymph nodes, particularly in the subcapsular sinus, are of no adverse biological significance.
CONCLUSION
The revisions to the AJCC staging system, along with advances in technology, allow patients with melanoma to be staged more precisely (Flaherty et al., 2009). More precise staging enables a greater understanding of an individual's risk for metastases and therefore the best recommendations for further treatment and follow-up, with the ultimate goal being increased survival.
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