Spitz melanoma is a distinct subset of spitzoid melanoma

Abstract

Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations such a kinase fusions or HRAS mutations. It is unclear what fraction of 'spitzoid melanomas' defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an eight-year period and performed high coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only 9 cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with a MAPK activating mutation and those without. Both Spitz melanoma and spitzoid melanomas in which a MAPK activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK activating mutations. The MAPK activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1 and KIT while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the 'spitzoid melanomas' comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Expanding spectrum of “spitzoid” lesions: a small series of 4 cases with MAP2K1 mutations

“…MAP2K1 mutations seem to be associated with intermediate or malignant spitzoid tumors both in our own cases and in a previously reported case [4]. This is also supported by the description of a case of spitzoid melanoma by Raghavan et al [9]. They reported a MAP2K1 mutation co-occurring with an HRAS mutation, mutations in CDKN2A, ARID1A, and NOTCH2, and a gain of chromosome 6p.…”

BRAF fusion Spitz neoplasms; clinical morphological, and genomic findings in six cases

“…the literature, there are few detailed clinical, morphological, and molecular descriptions of BRAF fusion Spitz neoplasms are still sparse. [3][4][5][6][7][8][9][10][11] The mean patient age among the six cases in this study was 32 years with a range of 10 to 65 years. This was greater than the mean patient age in the total cohort of Spitz neoplasms (20.…”

“…(Table 4). [3][4][5][6][7][8][9][10][11] This is a greater proportion of cases to develop metastatic disease relative to most of the other Spitz fusion categories such as NTRK1, NTRK3, and ALK. 7,[19][20][21][22][23][24] This is consistent with some previous studies which noted that BRAF fusions were among the char- In our review of the literature, there were seven studies describing the morphological features of Spitz neoplasms with BRAF fusion, which in total included 40 cases.…”

Eruptive Spitz nevus, a striking example of benign metastasis

“…Additional pathogenic mutations were not identified. We analyzed the genomic copy number of the tumors using the sequencing data as previously described 13 . The Spitz nevus from the left inferior buttock demonstrated copy loss of chromosome 12q, but no other copy number alterations.…”