Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features

Abstract

Spitz nevus is a benign melanocytic neoplasm that can be difficult or impossible to histologically distinguish from melanoma. We have recently described copy number increases of chromosome 11p in a subset of Spitz nevi. To study the molecular and histological features of this group, we studied 102 Spitz nevi for 11p copy number increases using fluorescence in situ hybridization (FISH) on tissue arrays. Copy number increases of at least threefold were found in 12 cases (11.8%) and involved the HRAS gene on chromosome 11p. Sequence analysis of HRAS showed frequent oncogenic mutations in cases with copy number increase (8/12 or 67%), contrasting with rare HRAS mutations in cases with normal HRAS copy numbers (1/21 or 5%, P: < 0.0001). Tumors with 11p copy number increases were larger, predominantly intradermal, had marked desmoplasia, characteristic cytological features, and had an infiltrating growth pattern. Proliferation rates in the majority of these cases were low to absent. HRAS activation by either mutation or copy number increase alone could explain several of the histological features that overlap with those of melanoma. We speculate that HRAS activation in the absence of co-operating additional genetic alterations drives the partially transformed melanocytes of these Spitz nevi into senescence or a stable growth arrest. Although there is no data suggesting that Spitz nevi with HRAS activation are at risk for progression to melanoma, future studies are warranted to assess their biological behavior more accurately.

Figure 1.

Histological features associated with copy number increase of 11p (A–D). A: Compound, predominantly intradermal Spitz nevus. B: Melanocytes with ample amphophilic cytoplasm and vesicular nuclei with prominent nucleoli between haphazardly arranged collagen fibers. C: Melanocytes with pleomorphic nuclei singly and in clusters between thickened collagen fibers. D:. Cells are surrounded by a fine eosinophilic rim (arrowheads and inset). E: Dual-color FISH with a probe containing HRAS (green signals) and a reference probe for chromosome 11q (red signals) showing a central nest of melanocytes with multiple green signals surrounded by normal cells. F: Sequence profile of a portion of exon 2 of HRAS showing a A→T mutation of codon 61 (boxed).