• © 2010 by American Society of Clinical Oncology

Reply to J.M. Thomas et al

As described in the Journal of Clinical Oncology article¹ cited by Thomas et al,² the American Joint Commission on Cancer (AJCC)/International Union Against Cancer melanoma staging committee used the term tumor burden as a dichotomous variable to operationally stratify regional nodal metastases as either clinically evident (ie, macroscopic) or clinically occult (ie, microscopic, and most often detected by the sentinel lymph node [SLN] biopsy). In our report, classification according to this schema was associated with highly significant differences in prognosis and survival rates.¹ Databases used from 18 sites worldwide consistently recorded the number of regional nodes that contained metastases. However, at least in part as a result of the significant evolution of SLN pathologic techniques during the past decade, uniformly collected data on the size of microscopic metastases (ie, SLN microscopic tumor burden) was not readily available; as such, we could not additionally examine this cohort of patients with stage IIIA/IIIB disease. Because these data are being prospectively collected, we anticipate they will be included in our analysis for the eighth edition of the Cancer Staging Manual.

Regarding the comment related to a threshold to define N+ melanoma, there has never been a 0.2 mm lower cut point in either the previous sixth edition or the current seventh edition of the Cancer Staging Manual. The melanoma staging committee, which included among its members authors of the papers cited by Thomas et al, carefully and thoroughly examined the available evidence and reached the unanimous consensus included in the seventh edition melanoma staging chapter. Specifically, “the concept that isolated tumor cells in the lymph nodes (especially in subcapsular sinuses) are of no adverse biologic significance cannot be substantiated for melanoma at this time, and a lower threshold of clinically insignificant nodal metastases has not been defined based on any evidence known to the AJCC Melanoma Task Force membership. These findings are in contrast to the findings often cited from breast cancer where micrometastases of less than 0.2 mm are defined as not clinically relevant and therefore not used as a criterion for staging node-positive breast cancer.”^3p332 Thus, we did not make an arbitrary decision, as suggested by Thomas et al, but accurately stated that there was insufficient evidence to define such a boundary. Remarkably, Thomas et al have no data on this subject either and are simply expressing their opinion. They selectively refer to some published articles, two of which simply refer to letters expressing opinions, and they fail to cite other studies—in melanoma and breast cancer—that demonstrate that even isolated tumor cells (ie, < 0.2 mm) have prognostic significance.^4,5 The AJCC melanoma staging committee has recently completed a multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma that demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, particularly among those with microscopic metastases. Importantly, the number of tumor-containing nodes was the most significant independent predictor of survival in patients with nodal micrometastases.⁶

In their letter, Thomas et al unfortunately blur the important distinction that must be made between accurate staging and treatment decision making. It is inevitable, if not desirable, not only that the melanoma staging system will be additionally refined on the basis of future evidence-based analyses but also that melanoma treatment paradigms will also evolve to reflect our improved understanding of melanoma biology and the anticipated availability of better treatment options (medical and/or surgical). Thomas et al fail to adequately appreciate that SLN biopsy was designed as a surgical staging procedure to be used to define the histologic status of regional lymph nodes. Because tumor-containing lymph nodes, if present, are excised as part of this procedure, an analysis of survival outcome between those patients with minimal tumor burden compared with those without node involvement would be confounded by a possible treatment effect of the staging procedure. Thus, we disagree with their contention that the only justification for making a recommendation to include even minimal tumor burden in the N+ category would be the inclusion of survival curves for patients with T2/T3N0 disease versus T2/T3N less than 0.1 mm to prove that the survival of these two groups was significantly different. Rules for cancer staging are limited to criteria that are reproducible and can be confirmed by multiple investigators in a standardized manner so that they may be applicable worldwide. The studies published to date regarding microscopic SLN tumor burden represent important early forays into this important arena, although they were not considered to be confirmed by the expert melanoma panel; therefore, they were not adopted by the AJCC or the International Union Against Cancer for the current seventh edition of the melanoma staging system.