Benign and Intermediate-grade Melanocytic Tumors With BRAF Mutations and Spitzoid Morphology

Abstract

The current classification of Spitz neoplasms in the World Health Organization (WHO), Fourth Edition defines Spitz neoplasms as melanocytic proliferations with characteristic Spitz morphology and a Spitz-associated genomic fusion or HRAS mutation. In contrast, melanocytic neoplasms with BRAF mutations are considered typical of common acquired nevi, dysplastic nevi, and melanomas from intermittent sun-damaged skin. However, increased utilization of ancillary testing methods such as BRAF V600E immunohistochemistry and sequencing studies have made apparent a subgroup of benign-grade and intermediategrade melanocytic neoplasms with Spitzoid morphology that harbor BRAF V600E mutations. We refer to these cases as BRAF mutated and morphologically Spitzoid (BAMS) nevi and tumors. Two experienced dermatopathologists reviewed a series of 36 BAMS nevi/tumors. Cases in which a diagnosis of melanoma was favored were excluded. The histomorphologic, clinical, and molecular findings were assessed by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing using validated gene panels. Characteristics of BAMS nevi/tumors were compared with a control set of Spitz tumors with previously reported fusion proteins. BAMS nevi/tumors had a decreased proportion of Kamino bodies (P = 0.03) and a higher proportion of cytoplasmic pigmentation (P < 0.00001). There were no differences in other morphologic features such as the silhouette, epidermal hyperplasia, pagetosis, and cytologic atypia compared with fusion-induced Spitz tumors. In 6/17 cases where nextgeneration sequencing studies were available, recurrent mutations in the KMT gene family were seen. This was higher than the proportion of such mutations seen in fusion Spitz tumors and lower than the frequency in cutaneous melanoma.

Clinical, Morphologic, and Molecular Features of Benign and Intermediate-grade Melanocytic Tumors With Activating Mutations in MAP2K1

“…Other classes of melanocytic neoplasms have been identified, which closely mimic Spitz. This includes BAP1 -associated melanocytic tumors and some sets of BRAF -mutated melanocytic nevi/tumors referred to as BAMS ( BRAF -mutated and morphologically spitzoid) melanocytic neoplasms 39 . However, there are some distinctions.…”

“…This includes BAP1associated melanocytic tumors and some sets of BRAFmutated melanocytic nevi/tumors referred to as BAMS (BRAF-mutated and morphologically spitzoid) melanocytic neoplasms. 39 However, there are some distinctions. BAP1 melanocytic tumors often have a biphenotypic appearance with a component of conventional nevus combined with a population of epithelioid melanocytes typically in the dermis with spitzoid features.…”

TERT Promoter Mutational Analysis as an Ancillary Diagnostic Tool for Diagnostically Challenging Melanocytic Neoplasms

“…Mutations in the TERT promoter gene are frequent in various cancers including melanoma (17%-71%), where they have been shown to be a key mechanism for sustained upregulation of telomerase to maintain the capability of infinite cell growth. 5,7,[10][11][12][13] The proliferative potential of normal cells is limited by gradual loss of nucleotide repeats at chromosomal ends (telomeres) during each cell division, leading to cell senescence and eventual cell death. TERT enzyme compensates for DNA erosion by adding TTAGGG sequences to chromosome termini, thereby preventing telomere shortening and cell senescence.…”

“…DNA sequencing was performed on formalin-fixed paraffin-embedded tissue via one of the 3 methods: digital droplet PCR at the Northwestern molecular pathology lab, Illumina Hiseq. 4000 System with Tempus xT assay, 7 or a previously described pipeline using Sanger sequencing. 8 The following methods were used for Northwestern sequencing: primers and probes from Bio-Rad were specific for the 2 most common TPMs (c.-124C > T C228T and c.-146C > T C250T) (Chr5:1295228 and Chr5:1295250, respectively).…”

An Atypical Deep Penetrating Nevus With Mutations in Beta Catenin, BRAF V600E , and IDH1 R132C in an 8-Year-Old Boy

“…7,8 Although the presence of an expansile melanocytic proliferation in childhood with an epithelioid morphology raises the possibility of a Spitz tumor, BRAF V600E mutations are generally not considered to be a feature of true Spitz tumors, other than in the distinct setting of BAP1 loss neoplasms 9 or recently described rare BRAF mutated and morphologically spitzoid tumors. 10 BRAF V600E mutation has been found in 50% of DPNs 11 and 33% of atypical DPNs. 3 The mutation in CTNNB1 found in this tumor is typical of the missense mutations in exon 3 of CTNNB1 gene found in DPN that lead to genetic activation of the beta-catenin pathway.…”