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About BRAF Mutations and p16 Expression in Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Author's Reply.

In Reply: We have read with interest the comments of Ugen and colleagues suggesting the usefulness of complementary BRAF mutation and p16 and ki67 immunohistochemistry results in our series of 11 melanomas associated with or mimicking cellular blue nevi.1 We have also read the study of Yilmaz et al2 reporting BRAF mutations in blue-like melanomas, which was published shortly before our work. We are grateful to have the opportunity to share complementary data from our study. In both of our cases that were wild-type for GNAQ and GNA11 (cases 6 and 7), we also found a wild-type status of BRAF by sequencing techniques. It is also noteworthy that both of these cases had a benign adjacent component (blue nevus) and that BRAF mutations have not been often identified in benign blue lesions including in the study of Yilmaz and colleagues (0/35). In the study of Held et al3 such mutations were present in deep penetrating nevi (3/15). Saldanha et al identified 3 mutated cases in 3/25 blue nevi. It is thus possible to have BRAF-mutated malignant melanomas that morphologically resemble the cases from our study, but it remains to be determined whether they also display class I/II array comparative genomic hybridization (aCGH) profiles and are associated with BAP1 expression loss. So far, this has not been the case in our experience (unpublished data). We are more inclined to believe that other mutations in protein G-like genes or pathway could be present in our 2 cases such as the recently described p.D630Y PLCB4 mutations in uveal melanomas. Regarding p16 expression, Ugen and colleagues suggested that it could possibly be used as a diagnostic tool as in other types of melanocytic lesions. This was evaluated in 8/11 of our cases (not performed in cases 5, 6, and 9). Seven of 11 showed a heterogenous p16 expression; only in case 1 was p16 lost in the malignant component and retained in the benign area but was not correlated with a detectable homozygous deletion of the gene by aCGH. Moreover, aCGH data displayed very few heterozygous losses of chromosome 9 (1/11, case 10) where CDKN2A is located (9p21). These results do not suggest a striking interest of p16 immunohistochemistry in blue-like melanomas compared with BAP1, but nonetheless a case did show an expression loss only in the malignant component. A similar query regarding ki-67 was also formulated by the authors. These data were available in all cases and ranged from 7% to 30% with a mean of 18%. By comparison, the proliferative index in the benign component was always low (<5%). This suggests that ki-67 could be useful to separate benign from malignant components in the setting of blue nevi. However, we found this staining often difficult to evaluate due to the limited areas of benign melanocytes. The study of both BAP1 and ki-67 seems a more reliable combination than that of p16 and BAP1. We strongly encourage other teams worldwide to publish their molecular results in these rare tumor types.