Up to now, melanoma patients whose tumors had spread to regional lymph nodes were deemed a fairly homogeneous group. In the widely used staging system of the American Joint Committee on Cancer, node-positive patients were put into one, largely undifferentiated groupingstage III.
However, that has changed dramatically with the publication of the final version of the AJCCs new staging system for melanoma. Posted in June on the Committees Web site and destined for the sixth edition of the AJCC Cancer Staging Manual, the new system revamps criteria in stages I through IV. Some of the major changes are seen in the node-positive, stage III group, which now includes six subgroups and an intricate set of criteria for determining which patients fall into which subgroups.
The result is a system that reflects differences in prognosis among stage III patients much more precisely than before, said Charles Balch, M.D., who chaired the AJCCs melanoma staging committee. It also reflects the growing amount of data on micrometastases that have come from lymph node mapping and biopsy in the past few years.
And perhaps most important, the new system reinforces the growing importance of having such pathologic data for the accurate staging of melanoma (and thus for a more accurate system on which to base evaluations of therapy). The committee concluded, in fact, that any patient with a tumor of 1 mm or more in thickness should have sentinel node biopsy and lymphadenectomy if the patient is considering a clinical trial, Balch said.
What swayed the AJCC were findings of wide variations in survival among node-positive patients who are staged pathologically. Ten-year survival, for instance, ranges from 12% to 69% according to data from the 13 major centers and cooperative groups represented on the staging committee.
"I think these are very profound numbers," Balch said. "We used to think this was a homogeneous group."
Patients at the high end of that range, with 5-year-survival rates of 60% to 70%, are likely to have only one microscopic nodal metastasis. Such patients are assigned to stage IIIA. Patients with more pathologically detected nodes and/or other less favorable prognostic factors were placed in either IIIB or IIIC. Patients with clinically determined positive nodes are placed in separate groups. (See sidebar below.)
In general, the new stage III subgroups are based on number of involved nodes, the presence or absence of ulceration in the primary tumor, and whether the lymph node metastases are macro (defined as those found through clinical examination or radiologically) or micro (found only on histopathologic examination).
Although the new system represents a major new direction for melanoma staging, it too is expected to evolve. "Ten years from now we are going to know much more [about micrometastases] than we do now," said Vernon Sondak, M.D., of the University of Michigan Medical Center, the discussant for several melanoma papers presented at the May meeting of the American Society of Clinical Oncology in New Orleans.
Data on micrometastases continue to come from the growing number of lymphatic mapping procedures and sentinel node biopsies performed for melanoma. One question these data may someday answer is how best to detect micrometastases. The conventional method is bisection of the nodes followed by hematoxylin and eosin staining, but several studies have shown that more specialized pathologic techniques could improve detection and disease staging, said Jeffrey Gershenwald, M.D., a staging committee member from the University of Texas M. D. Anderson Cancer Center, Houston. These include serial sectioning with immunostaining and use of reverse-transcriptase polymerase chain reaction to detect tyrosinase mRNA.
The Sunbelt Melanoma Trial, now under way at M. D. Anderson and two other centers, is looking at the conventional histology versus use of PCR to detect nodal micrometastases.
Regardless of whether a trial is addressing micrometastasis issues directly, the use of pathologic staging is important, Balch said. That is because the more precise staging is essential to understand variations in response to treatment. "Otherwise you get either artificially exaggerated or artificially diminished survival rates that you ascribe to treatment when actually the staging is skewing the numbers."
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