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:
- mitotic rate per square millimeter is now to be used for categorizing T1 melanoma;
- immunohistochemical (IHC) detection of nodal metastases is allowed;
- there is no lower threshold for staging N+ disease; and
- 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.
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.
Balch, C. M., Gershenwald, J. E., Soong, S., Thompson, J. F., Atkins, M. B., Byrd, D. R., et al. (2009). Final version of 2009 AJCC melanoma staging and classification. Journal of Clinical Oncology
Edge, S. B., Byrd, D. R., Compton, C. C., Fritz, A. G., Greene, F. L., Trotti, A. (Eds). 2010. AJCC cancer staging manual
(7th ed.). New York: Springer.
Flaherty, K. T., Agarwala, S. S., & Rubin, K. M. (2009). Adjuvant therapy for malignant melanoma. Targeted pathways to antitumor potential and better outcomes. Oncology Nursing News
Lawrence, D., & Rubin, K. (2008). Melanoma. In B. A. Chabner, T. J. Lynch, & D. L. Longo (Eds.), Harrison's manual of oncology
. New York: McGraw-Hill.
Editor's Note: The American Cancer Society provides an excellent explanation, useful for patients and clinicians, on how melanoma is staged, using the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system. http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-skin-cancer-staging (retrieved November 1, 2010).
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
AJCC; Clinical Staging; Melanoma; Pathological Staging