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

Abstract

Fusions of ALK, ROS1, NTRK1, NTRK3, RET, MET, MERTK, FGFR1, ERBB4, LCK, BRAF, MAP3K8, MAP3K3, and PRKDC and mutation of HRAS have so far been discovered as the genetic alterations associated with the pathogenesis of Spitz neoplasms. This report presents the first case of NTRK2‐rearranged Spitz/Reed nevus. The patient was a 39‐year‐old male with a pigmented macule rapidly growing on his shoulder. Histopathologically, the lesion was a junctional melanocytic nevus composed of large nests of spindled melanocytes with abundant eosinophilic cytoplasm associated with a hyperplastic epidermis. These findings fulfilled the diagnostic criteria of a pigmented spindle cell nevus of Reed (variant of Spitz nevus). Immunohistochemistry for pan‐Trk revealed diffuse cytoplasmic positivity in the tumor cells, but immunoexpression of ALK, ROS1, and BRAF V600E was not seen. A novel, in‐frame, TFG‐NTRK2 fusion was identified by RNA sequencing. This case report expands the list of genetic alterations in Spitz neoplasms and the spectrum of NTRK2‐rearranged tumors.

Spitz Tumor With SQSTM1::NTRK2 Fusion: A Clinicopathological Study of 5 Cases

“…[11][12][13][14][15] To date, only a single case of NTRK2-rearranged Spitz tumor has been documented. 16 We hereby report a series of 5 melanocytic lesions harboring SQSTM1::NTRK2 fusion, extending the molecular and morphological features of Spitz neoplasms.…”

“…All tumors harbored a SQSTM1::NTRK2 fusion. To the best of our knowledge, only 2 cases of NTRK2rearranged melanocytic neoplasms have been reported to date, each having a different fusion partner, namely TFG::NTRK2 fusion 16 and TRAF2::NTRK2 fusion. 20 The first reported case of an NTRK2-rearranged melanocytic neoplasm was a primary melanoma with TRAF2::NTRK2 fusion.…”

“…20 The second reported case with a TFG::NTRK2 fusion was Spitz nevus. 16 The neoplasm was a 4-mm pigmented, rapidly growing, lesion on the shoulder of a 39-year-old man. Histologically, the tumor was a junctional melanocytic proliferation composed of large, spindled melanocytes with eosinophilic cytoplasm and elongated or oval nuclei arranged in large solid nests.…”

“…Most nests contained abundant melanin pigment in the cytoplasm conferring a Spitz/Reed morphology. 16 The NTRK proto-oncogene family comprises 3 members, namely NTRK1, NTRK2, and NTRK3, which encode tropomyosin or tyrosine receptor kinases (TRKs), a receptor family composed of 3 transmembrane proteins, namely TRKA, TRKB, and TRKC. [21][22][23] These receptors are expressed mainly in the nervous system and play an important role in its development through the regulation of cell proliferation, differentiation, apoptosis, and survival of neurons, but can also be found in other cell types and tissues, including monocytes, lung, bone, and pancreatic beta cells.…”

“…To the best of our knowledge, only 2 cases of NTRK2 -rearranged melanocytic neoplasms have been reported to date, each having a different fusion partner, namely TFG::NTRK2 fusion 16 and TRAF2::NTRK2 fusion. 20…”