Clinical, morphologic and genomic findings in Spitz tumors with RET fusion: a series of 31 cases.

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Tác giả: Arnaud De la Fouchardiere, Michele Donati, Pedram Gerami, Keisuke Goto, Dimitrios Goutas, Dmitry V Kazakov, Thibault Kervarrec, Julie Lemahieu, Siebe Loontiens, Nicolas Macagno, Boulos Mansour, Daniel Nosek, Shantel Olivares, Giuseppe Perrone, Daniel Pissaloux, Joni Van der Meulen

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 552488

RET-fused Spitz neoplasms are rare and poorly characterized. We describe clinical, histologic and molecular findings of 31 Spitz neoplasms with RET fusion diagnosed as 16 Spitz nevus (SN), 13 atypical Spitz tumors (AST) and 2 Spitz melanoma (SM). The lesions mainly occurred in children and young adults of both sexes with predilection for the extremities. Microscopically, there were mainly symmetrical compound melanocytic neoplasms with a dome-shaped/slightly raised silhouette predominantly composed of epithelioid, spindled and/or smaller nevoid melanocytes arranged in confluent nests. Dyscohesive melanocytes within the nests in the upper part of the lesions, prominent Kamino bodies, giant multinucleated melanocytes, variable pigmentation and increased vascularity with vascular ectasia were frequent features. RNA sequencing detected 9 different 5' (N-terminus) fusion partners, including KIF5B (n= 8), LMNA (n= 7), CCDC6 (n= 6), OPTN (n= 3), MYO5A (n= 2) and NCOA4, ERC1, MYH9, AGAP3 (n= 1). Of these, OPTN::RET and AGAP3::RET represent novel fusions, and 3 further 5' fusion partners, namely NCOA4, ERC1 and MYH9 have never been reported in Spitz tumors. Although as a whole group, the tumors showed a heterogenous histopathologic presentation, correlation of the morphological features and the 5' fusion partners demonstrated certain associations. Nevoid melanocytes were exclusively encountered in cases with KIF5B fusion partner. Neuroid-like appearances with intersecting fascicles of spindled cells typified both MYO5A-fused cases. Epithelioid melanocyte population dominated cases with LMNA and CCDC6 fusion partners. Transepidermal elimination/floating intraepidermal nests of pigmented both spindled and epithelioid melanocytes were observed in the OPTN subgroup. The remaining cases with less frequent 5' fusion partners manifested in general more atypical histopathologic features, including nuclear pleomorphism, high mitotic count, atypical mitoses and sheet-like growth pattern. Melanoma fluorescence in situ hybridization (FISH) Probe Kit targeting RREB1, MYC, CDKN2A, and CCND1, was negative for copy number variation in 4 cases tested, including 2 cases with complete p16 nuclear loss on immunohistochemistry. Array comparative genomic hybridization (aCGH) performed in 3 lesions detected numerous segmental chromosomal imbalances in 2 cases diagnosed SM. DNA and RNA sequencing detected several further genomic alterations, including POU2F3 overexpression in 3 highly pigmented lesions. Further studies are needed to confirm possible correlations between the microscopic features and a particular fusion partner (or additional genetic events) in RET-fused Spitz neoplasms.
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