Abstract

The evolution of melanocytic neoplasms is led by complex sequence of molecular events. However, literature on correlations between morphology and copy number variation remains scant in melanomagenesis. For that reason, we conducted a retrospective study of 62 melanocytic neoplasms (4 benign, 10 borderline and 48 malignant). We reviewed the whole slide images of representative H&E-stained section of each case. We compared 6 histologic parameters with copy number variations (CNV) in RREB1 gain, CDKN2A loss, MYC gain, and MYB loss. The histologic parameters evaluated were infiltrative growth pattern, pagetoid spread, myxoid stroma, predominance of spindle cell, rhabdoid features (>4 under 200x magnification) and large nucleoli (detected at 100x magnification). CNV were detected by a novel digital droplet PCR method, and also confirmed by chromosomal microarray analysis. The Kruskal-Wallis test and Fisher’s Exact test were used in the statistical analysis to assess for associations between the histologic parameters and CNV. MYC gain was associated with infiltrative growth pattern (p=0.029), myxoid stroma (p=0.02), rhabdoid features (p<0.01), and large nucleoli (p=0.01). Pagetoid spread was associated with loss of CDKN2A (p=0.02) and RREB1 gain was associated with spindle cell morphology (p<0.01). All these associations were statistically significant with both tests. Our results suggests that recognizing certain histologic features can help in predicting specific molecular events in melanomagenesis. As therapy for advanced melanoma increasingly targets molecular changes, morphologic-genomic correlations could prove increasingly relevant in future cases. Future work could confirm these findings, and examine the mechanisms by which copy number alterations lead to these morphologic changes.