Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis

In a recent article, Taran and Heenan maintained that metastasis from Clark level 2 cutaneous malignant melanoma (CMM) “is rare, if it occurs at all,” a conclusion based on the examination of all pathology reports of patients diagnosed with a primary malignant melanoma at the Cancer Registry of Western Australia between 1982–1996.1 They found that no level 2 CMM in their data set was > 1 mm thick. There were 1716 patients with a CMM that measured ≤ 1 mm in thickness, 67 of whom developed metastases within a follow-up period of 7–15 years. After excluding 18 patients with multiple CMMs, 5 of the remaining 49 patients with metastases were found to have a level 2 CMM. All five patients displayed focal to extensive regression; therefore the authors concluded that the assessment of level of invasion may have been inaccurate, with these CMMs being invasive to level 3 or 4 before the onset of regression. We would like to present corresponding figures from the Sydney Melanoma Unit (SMU) database, which contains the records of nearly 19,500 melanoma patients treated between January 1950 and July 2001 at Royal Prince Alfred, St. Vincent's, and Sydney Hospitals. All pathology slides were reviewed by specialists from the Department of Anatomical Pathology at the Royal Prince Alfred Hospital who had extensive experience in melanoma pathology. Metastases developed in 164 of 2761 patients with Clark level 2 CMMs who had only a single Stage I or II lesion (American Joint Committee on Cancer/International Union Against Cancer staging system) over a follow-up period of 1–45 years. Approximately 22% of these metastasizing CMMs were > 1 mm thick, with 50% of the latter having a polypoid architectural pattern. Early, intermediate, or late regression was found in 73% of metastasizing level 2 CMMs, a figure that was nearly identical to the proportion with regression in 2597 nonmetastasizing level 2 CMMs (74%). In the majority of metastasizing level 2 CMMs displaying regression (57%), the regression was at the early stage. We previously have shown that in very thin CMMs (< 0.5 mm), evidence of regression did not constitute a risk for recurrence.2 Part of the discrepancy between the current results and those of Taran and Heenan appears to lie in pathologic definitions and interpretation of Clark levels 2 and 3 and the presence or absence of regression. Interobserver variability in reporting the level of invasion is referred to by Taran and Heenan.1 Some of our metastasizing level 2 CMMs were > 1 mm thick and some of these were polypoid. Such CMMs may be associated with expansion but not filling of the papillary dermis by melanoma cells and the cells may not reach the papillary/reticular dermal interface and hence can be designated as level 2. Although we accept that some authors regard such polypoid CMMs as level 3,3, 4 applying the criteria of Clark et al.5 (as used by Taran and Heenan in their study1), such CMMs are level 2. Furthermore, some of our metastasizing level 2 CMMs measuring > 1 mm thick were acral lesions, which may become this thick as a result of their epidermal thickening. The definition of regression used by Taran and Heenan1 encompasses the definitions of intermediate and late regression as used by the SMU. Because our analysis also included CMMs with early regression (defined as the presence of tumor-infiltrating lymphocytes), the proportion of CMMs displaying regression in our metastasizing level 2 CMMs was not comparable to that in the study by Taran and Heenan.1 The SMU is a major referral center for melanoma in New South Wales and therefore is not population-based like the Cancer Registry of Western Australia. However, it appears from our results that metastases from level 2 CMMs are not as uncommon as maintained by Taran and Heenan.1 Although the majority of these metastasizing CMMs displayed regression, this alone could not explain their metastatic potential. We conclude that it is injudicious to dismiss level 2 CMMs as having practically no metastatic potential.