The prognostic importance of tumor mitotic rate for patients with primary cutaneous melanoma.

The prognosis for patients who present with localized primary cutaneous melanoma depends on a number of clinical and histologic features. Among the latter, tumor thickness as measured by the method of Breslow has been established as the most important parameter for predicting clinical outcome.1–5 A number of other histologic features, such as ulceration, microanatomic levels of invasion, and tumor mitotic rate (TMR) have been the subjects of many studies over the past 30 years. Their relative importance continues to be evaluated as pitfalls of prior study designs become recognized and more sophisticated and rigorous analytical methods are employed. The Australian pathologist Vincent McGovern was one of the pioneers in the search for prognostic parameters that can be deduced from the light microscopic analysis of primary cutaneous melanomas and one of the first to suggest that TMR may have predictive value.5,6 Numerous subsequent studies have yielded conflicting results on the significance of TMR. Recent data from the Sydney Melanoma Unit (SMU), however, have redrawn attention to the potential predictive value of TMR.4 In a multivariate analysis of 3661 patients seen at the SMU between 1983 and 2001, TMR was found to be second only to tumor thickness as the most powerful independent predictor of survival. The strength of the SMU data comes from a large number of patients with long-term clinical follow-up and careful attention to methodological detail, in particular with regard to the way TMR was measured and analyzed. For measuring TMR, the authors followed the guidelines of the 1982 Pathology Workshop chaired by Vincent McGovern in Sydney.5 They recorded TMR as the total number of mitoses/mm in the invasive melanoma component with the highest TMR (“mitotic hot spot”). Previously, many pathologists had assessed mitoses per high-power field (HPF). Even nowadays, several pathologists still use this method, but it is imprecise for study and staging purposes when multiple pathologists are involved using different microscopes, because the area of an HPF varies between microscopes. With regard to analyzing the predictive value of TMR, the team at the SMU examined this parameter as a continuous variable as well as in different groupings. This flexibility in their approach paid off. No significant difference in survival was seen when TMR was studied as a continuous variable. A better result was seen with groupings and depended on the type of grouping (0, 1–4, 5–10, and 11 mitoses/mm versus 0–1, 2–4, and 5 mitoses/mm). The prognostic value of TMR was strongest when patients with a TMR of 0 mitoses/mm were compared with those with a TMR of 1 or more mitoses/ mm. Putting patients with TMRs of 0 and 1 mitoses/ mm together into the same group diminished the predictive value of this parameter.4 The impact of the method for recording and analyzing TMR on its prognostic value is further illustrated in the article by Francken et al. in this issue of Annals of Surgical Oncology.6 They present data from a unique cohort of 1317 patients seen at the SMU between 1957 and 1982 for cutaneous melanoma, whose follow-up was long. The melanomas had been reviewed by Vincent McGovern and were analyzed by current members of the SMU for the prognostic value of TMR and its dependency on the method of assessment. TMR was confirmed as a prognostic factor,6 but its significance was less than in the previously reported and above-mentioned SMU data set from the 1983 to 2001 Received February 6, 2004; accepted February 19, 2004. From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Address correspondence and reprint requests to: Klaus J. Busam, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-794-6224; e-mail: busamk@mskcc.org.