BERLIN — Look for a big jump in the number of melanoma patients diagnosed with stage III disease beginning early next year, when the new American Joint Committee on Cancer classification system takes effect.
The new AJCC system endorses immunohistochemical detection of nodal metastases, and there will no longer be a lower limit for the definition of nodal disease, Dr. Claus Garbe explained at the annual congress of the European Academy of Dermatology and Venereology.
“In allowing micrometastases to be defined through immunohistochemistry, it means isolated tumor cells which weren't previously considered to be stage III are now considered to be N+. So even one metastatic cell is now enough,” said Dr. Garbe, professor of dermatology at the University of Tübingen (Germany).
The clinical implication of this revision is that a lot more radical lymphadenectomies will be performed, since that is a recommended part of the management of stage III disease. Likewise, patients who have immunohistochemically defined micrometastatic stage III disease will need to be offered an adjuvant therapy, as it is also standard in stage III melanoma, he continued.
From the audience reaction in Berlin, this redefinition of what constitutes stage III melanoma is likely to be the most controversial change coming in the melanoma section of AJCC 2010 (“AJCC to Institute New Melanoma Staging System,” March 2009, p. 1).
“It worries me enormously that one positive cell on immunohistochemistry will be stage III melanoma. And it worries me enormously that we're going to be doing more nodal dissections in the absence of any supporting evidence,” commented Dr. J.M. Thomas, who is professor of surgery at Royal Marsden Hospital in London.
Dr. Jean-Jacques Grob, president of the European Association of Dermato-Oncology, said he is troubled by the prospect of considerable difficulties in comparing data from studies using the new criteria for stage III disease with historical data.
“And applying the same therapeutic principles used in the old stage III patients to the new ones is perhaps not a good idea,” added Dr. Grob, professor of dermatology at the University of Marseille (France).
Other audience members complained that the AJCC change is premature in light of recent evidence from the Rotterdam melanoma study group that micrometastases less than 0.1 mm in diameter carry essentially as good a prognosis as no micrometastases at all.
“My guess is that this is not the end of the story,” Dr. Garbe replied to the critics.
For example, he and his coworkers will soon publish a study showing a near-linear inverse relationship between the number of metastatic cells found upon immunostaining of a completely dissected lymph node and prognosis.
Also, there are two highly pertinent ongoing clinical trials—one in Germany, and the U.S.-based Multicenter Selective Lymphadenopathy Trial-2—that have randomized patients after a positive sentinel lymph node biopsy to radical lymph node dissection or observation, he noted.
“I think these trials will help us to determine whether it's really useful to do radical lymphadenectomy for micrometastases. Currently we don't have a basis in evidence, we just have consensus surgical recommendations,” Dr. Garbe continued.
In addition to the hot-button issue of the broadened criteria for stage III melanoma, other coming changes in the 2010 AJCC melanoma classification system include:
▸ Mitotic rate will make its debut as an independent prognostic factor. It is to be routinely determined histopathologically. A finding of one or more mitoses/mm
This new criterion is based upon a multivariate regression analysis that involved more than 10,000 melanoma patients in which mitotic rate ran a close second to tumor thickness as a predictor of 10-year mortality, with ulceration a distant third.
The old nomenclature, expressed as mitoses per 10 high-power fields, is out. The new terminology is mitoses/mm
▸ Clark's level of invasion is being eliminated from the new classification scheme based upon insufficient prognostic value.
▸ Isolated metastases arising in skin, subcutaneous tissue, or lymph nodes from an unknown primary site are to be classified as stage III, not stage IV as often occurred before. These soft-tissue metastases from a melanoma of unknown primary, or MUP, have been shown to carry a prognosis akin to regional metastases, not the distant metastases which define stage IV disease.
The 655-page seventh edition of the AJCC Staging Manual, which was recently published by Springer, goes into effect next year.