Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.
最近研究发现Spitz肿瘤中活化性激酶融合是与HRAS及BRAF突变相互排斥的早期致癌事件。本研究报道32例伴有ALK融合的一系列Spitz肿瘤（包括6例 Spitz痣、22例非典型Spitz肿瘤和4例 Spitz样黑色素瘤），患者年龄从5个月至64岁（中位年龄12岁）。肿瘤通常表现为四肢外生性丘疹和偶有色素沉着。除了在其他类型肿瘤中已经描述过的ALK融合方式（NPM1-ALK和TPR-ALK）外，在这一系列的Spitz肿瘤中我们鉴定出了2种新的ALK融合方式（CLIP1-ALK和GTF3C2-ALK）。19例肿瘤阵列比较基因组杂交显示出很高频率的2号染色体异常（63%，ALK所在染色体），37%的病例显示染色体1p缺失。伴有ALK融合的Spitz肿瘤显示独特的组织病理学特征。胖梭形黑素细胞、细丝状胞浆和增大的细胞核，瘤细胞裂隙状和小囊泡状排列。这些黑色素细胞通常沿长轴排列或放射状纺锤样排列。肿瘤常常楔形或下缘呈球根状延伸到真皮或皮下组织（分别为45%和17%）。浸润性生长方式常常出现在肿瘤周边并可被ALK免疫组化证实。总之，伴有ALK重排的Spitz肿瘤显示有独特的组织病理学特征，这些特征有助于提高这些具有挑战性肿瘤的准确分类。