Fluorescence In Situ Hybridization for Melanoma Diagnosis: A Review and a Reappraisal.

Although conventional histopathological examination is the undisputable mainstay for the diagnosis of melanocytic skin neoplasms, fluorescence in situ hybridization (FISH) has the potential to provide important information to morphologically challenging cases. The standard melanoma FISH test targeting RREB1 (6p25), MYB (6q23), CCND1 (11q13), and centromere 6 is an effective compromise between cost, technical complexity, and sensitivity. The authors use the standard FISH-positivity as a tie-breaker for challenging melanocytic neoplasms mainly in a non-Spitzoid morphologic context because the currently available test leaves several unresolved issues: namely, a relatively low diagnostic accuracy in morphologically ambiguous melanocytic neoplasms; a relatively low sensitivity and specificity in Spitzoid neoplasms; and the occurrence of false positives due to tetraploidy in Spitz nevi and in nevi with an atypical epithelioid component. Under investigation is currently a new melanoma probe cocktail targeting RREB1 (6p25), C-MYC (8q24), CDKN2A (9p21), and CCND1 (11q13). However, CDKN2A is a significant parameter only if lost in homozygosis, and this complicates the interpretation of the results. Furthermore, the new melanoma probe cocktail has been tested on cases of atypical Spitzoid proliferations with fatal outcomes which at present are too few to allow definite conclusions. The authors propose the implementation of a FISH algorithm (standard 4-probe test followed by either C-MYC or CDKN2A/centromere 9) to assist the histopathological diagnosis and minimize the technical problems. Nevertheless, because the diagnostic accuracy of the FISH technique is far from being absolute, the overall clinicopathological context must always guide the decision-making process about the management of morphobiologically ambiguous melanocytic proliferations.