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

Abstract

The molecular background of a significant proportion of spitzoid neoplasms is still unknown. Recently, activating mutations in MAP2K1 have been described in a few spitzoid lesions, but not in benign Spitz nevi. We report four cases of melanocytic tumors with spitzoid features in which a MAP2K1 mutation was detected. The lesions did not show a single distinct phenotype and ranged from benign to malignant. Two cases resembled desmoplastic Spitz nevi. Based on the combination of morphological, immunohistochemical, and molecular findings, one case was classified as benign, one as probably benign, possibly intermediate low-grade (MELTUMP—melanocytic tumor of unknown malignant potential), one case was classified as intermediate (MELTUMP), and one case was considered a superficial spreading melanoma with spitzoid features. Based on this, we conclude that MAP2K1 mutations can indicate a spitzoid genetic signature and can be found in both benign and malignant spitzoid neoplasms.

Spitz nevus with a novel TFG‐NTRK2 fusion: The first case report of NTRK2‐rearranged Spitz/Reed nevus

“…As oncogenic gene alterations other than kinase gene fusions, HRAS point mutations are found in approximately 15% of all Spitz neoplasms 8 . In addition, more recent studies reported MAP2K1 mutations in a subset of spitzoid lesions 4,9‐11 . All these genetic anomalies are present in a mutually exclusive pattern.…”

“…8 In addition, more recent studies reported MAP2K1 mutations in a subset of spitzoid lesions. 4,[9][10][11] All these genetic anomalies are present in a mutually exclusive pattern. Herein, we present the first case of Spitz nevus with a NTRK2 rearrangement, which is a novel TFG-NTRK2 fusion.…”

Conceptual Evolution and Current Approach to Spitz Tumors

“…In more recent years, genomic studies have shown that most Spitz neoplasms harbor serine–threonine kinase mutations (HRAS, or more rarely MAP2K1) or receptor tyrosine and serine–threonine kinase fusions (ALK, ROS1, NTRK1, NTRK3, MAP3K8, more rarely BRAF, RET, MET, NTRK2, ERB4, FGFR1, MAP3K3, PRKDC) [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Of note, BRAF or MAP3K8-fused cases may pursue a more aggressive course compared with tyrosine kinase–fused cases, especially in the presence of TERT promoter mutations.…”

“…The diagnosis of Spitz tumors may be difficult on clinical, dermoscopic, and histologic grounds [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Clinically, they may present either as pigmented, hypopigmented, or non-pigmented lesions.…”

“…Histologic diagnosis is currently based on microscopic characteristics (large spindle and/or epithelioid cells), possibly confirmed by an immunohistochemical or molecular evaluation of the genetic profile, including the presence of HRAS/MAP2K1 mutations and receptor tyrosine/serine–threonine kinase fusions. Importantly, Spitz tumors do not harbor GNAQ/GNA11 mutations, occurring in blue tumors, CTNNB1 mutation or APC loss, observed in deep penetrating tumors, PRKAR1A or PRKCA mutations, common in pigmented epithelioid melanocytomas, and BAP1 inactivation, characteristic of BAP1-inactivated melanocytic tumors [ 36 , 38 ] ( Table 1 ). By definition, Spitz melanoma has a kinase-fusion or HRAS aberration, while it does not carry the driver mutation of a conventional melanoma, such as BRAF/NRAS or NF1 mutation.…”