Department of Dermatology, Feinberg School of Medicine, Northwestern University.
Tempus Labs Inc., Chicago, IL.
Am J Surg Pathol. 2018 Aug;42(8):1042-1051. doi: 10.1097/PAS.0000000000001074.
Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. However, to date, there is little data in the literature focused on the molecular characterization of PSCN of Reed with next-generation sequencing. We analyzed a total of 129 melanocytic neoplasms with RNA sequencing including 67 spitzoid neoplasms (10 Spitz nevi, 44 atypical Spitz tumors, 13 spitzoid melanomas) and 23 PSCN of Reed. Although only 2 of 67 (3.0%) of spitzoid lesions had NTRK3 fusions, 13 of 23 (57%) of PSCN of Reed harbored NTRK3 fusions with 5' partners ETV6 (12p13) in 2 cases and MYO5A (15q21) in 11 cases. NTRK3 fusions were confirmed with a fluorescent in situ hybridization break-apart probe. The presence of a NTRK3 fusion correlated with younger age (P=0.021) and adnexal extension (P=0.001). Other minor fusions identified in PSCN of Reed included MYO5A-MERTK (2), MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3 leading to a total of 78% with fusions. Our study suggests that the majority of PSCN of Reed are the result of genomic fusions, and the most frequent and characteristic genomic aberration is an NTRK3 fusion.
最近对 Spitz 样肿瘤的分子研究发现，ROS1、ALK、RET、BRAF、NTRK1、MET 和 NTRK3 的激酶融合是早期起始的基因组事件，这些融合相互排斥。Reed 色素性梭形细胞痣（PSCN）是 Spitz 的一种形态变异型，其组织学特征可能与黑色素瘤有关，因此诊断极具挑战性。它们发生在年轻患者中，与阳光照射无关，且早期快速生长阶段类似于 Spitz 痣，提示融合也可能在这些病变中起重要作用。然而，迄今为止，文献中关于 Reed 色素性梭形细胞痣的分子特征分析很少涉及下一代测序。我们共分析了 129 例含有 RNA 测序的黑素细胞肿瘤，包括 67 例 Spitz 样肿瘤（10 例 Spitz 痣、44 例非典型 Spitz 肿瘤、13 例 Spitz 样黑色素瘤）和 23 例 Reed 色素性梭形细胞痣。尽管仅有 67 例 Spitz 样病变中的 2 例（3.0%）存在 NTRK3 融合，但 23 例 Reed 色素性梭形细胞痣中有 13 例（57%）存在 NTRK3 融合，其中 5' 伙伴为 ETV6（12p13）的有 2 例，为 MYO5A（15q21）的有 11 例。NTRK3 融合通过荧光原位杂交断裂探针得到证实。NTRK3 融合的存在与年龄较小（P=0.021）和附属器扩展（P=0.001）相关。Reed 色素性梭形细胞痣中还发现了其他较小的融合，包括 MYO5A-MERTK（2）、MYO5A-ROS1、MYO5A-RET 和 ETV6-PITX3，总共 78%存在融合。我们的研究表明，大多数 Reed 色素性梭形细胞痣是基因组融合的结果，最常见和特征性的基因组异常是 NTRK3 融合。
