Ambiguous melanocytic tumors with loss of 3p21

Abstract

Germline loss-of-function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of 1 allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus-like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.

Figure 1

A typical nevus with BAP1 loss, case 13. This nevus is dome shaped, lacks a junctional component, and contains an infiltrative lymphocytic infiltrate. The constituent cells contain abundant glassy eosinophilic cytoplasm and have distinct cellular membranes. The melanocytes and their nuclei demonstrate a broad range of sizes, and the eccentric placement of the nucleus is more readily appreciated in larger melanocytes.

Figure 2

Kiss of Death. The largest melanocytes within our cases often were observed to be in contact with neighboring lymphocytes. The melanocytes being “kissed” by lymphocytes demonstrated eccentric placement of their nucleus away from the adjacent lymphocyte, resulting in a plasmacytoid appearance.

Figure 3

Blue nevus like melanoma with BAP1 loss and cellular blue nevus cytomorphology, case 15. Left. Low power view demonstrates the typical architecture of a blue nevus. Upper right. High power view demonstrates fusiform cells with scant cytoplasm. Lower right. BAP1 immunostaining demonstrates loss of BAP1 in the neoplastic melanocytes. BAP1 staining is preserved in the epithelium.

Figure 4

A Spitz nevus with BAP1 loss and a junctional component, case 4. Nests of large spitzoid melanocytes as seen in the dermis are present within an effaced epidermis.

Figure 5

NRAS^Q61R mutant Spitz nevus with BAP1 loss, case 17. The tumor has a similar overall configuration to Spitz nevi with BAP1 loss and BRAF^V600E mutation, with cells arranged in a dermal nodule. There is more pigmentation within this tumor than in the cases with BRAF^V600E mutation, not only in melanophages near the base of the lesion, but also within the constituent melanocytes.