Sikl's Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
Bioptical Laboratory, Pilsen, Czech Republic.
Am J Dermatopathol. 2020 Aug;42(8):578-592. doi: 10.1097/DAD.0000000000001632.
ALK-fused spitzoid neoplasms represent a distinctive group of melanocytic lesions. To date, few studies addressed genetic and chromosomal alterations in these lesions beyond the ALK rearrangements. Our objective was to study genetic alterations, including ALK gene fusions, telomerase reverse transcriptase promoter (TERT-p) mutations, chromosomal copy number changes, and mutations in other genes. We investigated 29 cases of Spitz lesions (11 Spitz nevi and 18 atypical Spitz tumors), all of which were ALK immunopositive. There were 16 female and 13 male patients, with age ranging from 1 to 43 years (mean, 18.4 years). The most common location was the lower extremity. Microscopically, all neoplasms were polypoid or dome shaped with a plexiform, predominantly dermally located proliferation of fusiform to spindled melanocytes with mild to moderate pleomorphism. The break-apart test for ALK was positive in 17 of 19 studied cases. ALK fusions were detected in 23 of 26 analyzable cases by Archer FusionPlex Solid Tumor Kit. In addition to the previously described rearrangements, 3 novel fusions, namely, KANK1-ALK, MYO5A-ALK, and EEF2-ALK, were found. Fluorescence in situ hybridization for copy number changes yielded one case with the loss of RREB1 among 21 studied cases. TERT-p hotspot mutation was found in 1 of 23 lesions. The mutation analysis of 271 cancer-related genes using Human Comprehensive Cancer Panel was performed in 4 cases and identified in each case mutations in several genes with unknown significance, except for a pathogenic variant in the BLM gene. Our study confirms that most ALK fusion spitzoid neoplasms can be classified as atypical Spitz tumors, which occurs in young patients with acral predilection and extends the spectrum of ALK fusions in spitzoid lesions, including 3 hitherto unreported fusions. TERT-p mutations and chromosomal copy number changes involving 6p25 (RRB1), 11q13 (CCND1), 6p23 (MYB), 9p21 (CDKN2A), and 8q24 (MYC) are rare in these lesions. The significance of mutation in other genes remains unknown.
ALK 融合棘皮瘤是一组独特的黑素细胞病变。迄今为止，很少有研究探讨这些病变除 ALK 重排以外的遗传和染色体改变。我们的目的是研究遗传改变，包括 ALK 基因融合、端粒酶逆转录酶启动子（TERT-p）突变、染色体拷贝数变化以及其他基因的突变。我们研究了 29 例 Spitz 病变（11 例 Spitz 痣和 18 例非典型 Spitz 肿瘤），这些病变均为 ALK 免疫阳性。患者 16 例为女性，13 例为男性，年龄 1 至 43 岁（平均 18.4 岁）。最常见的部位是下肢。显微镜下，所有肿瘤均呈息肉状或圆顶状，有一个由梭形至纺锤形黑素细胞组成的丛状、主要位于真皮的增生，有轻度至中度多形性。19 例研究病例中的 17 例 ALK 分离试验阳性。通过 Archer FusionPlex Solid Tumor Kit 检测到 26 例可分析病例中的 23 例存在 ALK 融合。除了先前描述的重排外，还发现了 3 种新的融合，即 KANK1-ALK、MYO5A-ALK 和 EEF2-ALK。21 例研究病例中有 1 例出现 RREB1 拷贝数丢失。23 例病变中有 1 例存在 TERT-p 热点突变。使用 Human Comprehensive Cancer Panel 对 271 个癌症相关基因进行突变分析，在 4 例病例中发现了除 BLM 基因的致病性变异外，其他基因的突变，这些基因的突变意义不明。本研究证实，大多数 ALK 融合棘皮瘤可归类为非典型 Spitz 肿瘤，发生于肢端偏好的年轻患者，扩展了棘皮瘤中 ALK 融合的范围，包括 3 种以前未报道的融合。TERT-p 突变和涉及 6p25（RRB1）、11q13（CCND1）、6p23（MYB）、9p21（CDKN2A）和 8q24（MYC）的染色体拷贝数变化在这些病变中很少见。其他基因的突变意义仍不清楚。
