Melanoma Controversies: Clinical Significance of Nodal Micrometastases and the Future of Melanoma Vaccines

Abstract

There is no greater impediment to progress in the sciences than the desire to see it take place too quickly.—G.C. Lichtenberg (1742–1799), German physicist, philosopher Failure after long perseverance is much grander than never to have a striving good enough to be called a failure.—George Eliot [Mary Ann Evans] (1819 –1880), British novelist Progress is not an illusion, it happens, but it is slow and invariably disappointing.—George Orwell (1903–1950), British novelist In this issue of World Journal of Surgery, Leong et al. [1] evaluate the clinical significance of lymph node metastases in melanoma detected by sentinel lymph node (SLN) biopsy, and Spagnoli et al. [2] review the progress in development of active antigen-specific immunotherapy. These articles provide a convenient excuse to reflect upon the progress in melanoma staging and treatment. Leong and colleagues studied 363 patients with cutaneous melanoma for whom they have a median follow-up of 4.8 years. Sentinel nodes were evaluated by routine histopathology with hematoxylin and eosin (H&E) staining and immunohistochemical stains. However, the first 294 patients did not undergo immunohistochemistry (IHC) testing for evaluation of the sentinel nodes. Therefore the nodal metastases detected by H&E staining alone in these 294 patients likely represent larger and more obvious foci of metastatic disease in the lymph node. Overall, 18% of their patients had positive sentinel nodes. Mortality was significantly associated with sentinel lymph node status as well as lymphovascular invasion, ulceration, mitotic index, and Breslow thickness. This is yet another study indicating that SLN biopsy can accurately stage the regional lymph nodes and that SLN status is an independent prognostic factor predicting recurrence and survival. Most (80–85%) patients with a ‘‘positive’’ SLN have only a single SLN that contains metastatic disease. With serial section histopathology and IHC analysis, it is possible to identify extremely small foci of microscopic disease within the SLN—sometimes even single cells. Do patients with a few melanoma cells in the SLN have the same prognosis as those whose disease is measured in millimeters? Until recently, there had been little controversy over the clinical significance of nodal micrometastases in melanoma. It was thought by many that adequate data were available to substantiate the fact that patients with a positive sentinel node detected by histology or IHC had a worse prognosis. On the other hand, the clinical significance of nodal micrometastases in breast cancer has generated enormous controversy. Do nodal micrometastases in melanoma have a different significance than they do in breast cancer? To shed light on this issue, several investigators have now evaluated various means of measuring the microscopic tumor burden in the sentinel nodes of melanoma patients and have found a strong correlation with disease-free and overall survival [3–6]. It is becoming increasingly clear that it is no longer sufficient to simply call sentinel nodes ‘‘positive’’ or ‘‘negative’’—it is likely that the amount and pattern of microscopic disease in the lymph node has important prognostic significance. Whether micromorphometry-based classification systems [3, 4] or other means of classifying the tumor burden in the sentinel node [5, 6] ultimately are the best way to evaluate SLN pathology remains to be determined. Nonetheless, there may be some minimum volume and distribution of melanoma cells in the SLN that have little impact on prognosis. We may also find ageand gender-related differences in the clinical significance of minimal nodal disease. It is therefore imperative that future studies incorporate careful analysis of the tumor burden in the sentinel nodes. Why is this so important? Because it affects treatment decisions, including the decision to perform a completion lymph node dissection and the decision to give adjuvant therapy. Completion lymph node dissection is currently recommended for patients with a positive sentinel node, regardless of the amount of the tumor burden in the lymph node [7, 8]. The rate of finding additional positive lymph nodes upon completion lymph node dissection ranges from 12% to 14% for the lowest-risk group of patients—those who have had positive sentinel nodes detected only by IHC [8, 9]. Whether patients can safely avoid the potential morbidity of completion lymph node dissection is a topic being Correspondence to: Kelly M. McMasters, M.D., Ph.D., e-mail: mcmasters@louisville.edu World J. Surg. 29, 681–682 (2005) DOI: 10.1007/s00268-005-1113-7