The category of ALK-rearranged mesenchymal neoplasms has been evolving rapidly, with reports of morphologically diverse lesions of cutaneous, soft tissue, and visceral origin. While some of these represent morphologically defined entities harboring recurrent ALK fusions (inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma), others are unclassified by morphology with variable overlap with the tyrosine kinase family of neoplasia and their underlying ALK fusions cannot be suspected based on morphology. We herein report 3 cases that expand the anatomic, morphologic, and genotypic spectrum of ALK-rearranged unclassified neoplasms. Patients were all adults aged 46 to 69 (median: 63) who presented with a mass located in the gingiva, subcutis of the back, and submucosal posterior pharyngeal wall. The tumor size ranged from 1 to 2.7 cm (median: 1.6). Conservative surgery was the treatment in all patients. Follow-up was available for one patient who remained disease-free at 14 months. Histologically, all tumors displayed large polygonal cells with foamy to granular and lipogenic-like microvacuolated copious cytoplasm and medium-sized round nuclei with 1 or 2 prominent nucleoli. Mitoses and necrosis were not seen. The initial diagnostic impression was PEComa, inflammatory rhabdomyoblastic tumor and unclassified pseudolipogenic neoplasm. Strong cytoplasmic ALK was detected by immunohistochemistry in all cases. Other positive markers include Cathepsin K (2/2), desmin (1/3), focal MyoD1 (1/1), focal SMA (1/3), and focal EMA (1/2). Targeted RNA sequencing revealed ALK fusions with exon 20 (2 cases) and exon 19 (one case) of ALK fused to RND3 (exon 3), SQSTM1 (exon 6), and desmin (intron 6). Methylation profiling in the desmin-fused case (initially diagnosed as inflammatory rhabdomyoblastic tumor) revealed an inflammatory myofibroblastic tumor match with a low confidence score of 0.5 and a flat copy number variation (CNV) profile. No NF1 mutation was detected in this case, altogether excluding an inflammatory rhabdomyoblastic tumor. Our study highlights and expands the morphologic and anatomic diversity of ALK-fused neoplasms and documents novel fusion partners (RND3 and desmin).

中文翻译：

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ALK 重排的间充质肿瘤具有突出的泡沫/假脂肪生成细胞形态：扩大了 ALK 融合肿瘤的表型谱和新型融合伴侣的报告。


ALK 重排间充质肿瘤的类别一直在迅速发展，据报道皮肤、软组织和内脏起源的病变形态多样。虽然其中一些代表形态学上定义的携带复发性 ALK 融合的实体（炎性肌纤维母细胞瘤和上皮样纤维组织细胞瘤），但其他一些未按形态学分类，与肿瘤的酪氨酸激酶家族有可变重叠，并且不能根据形态学怀疑其潜在的 ALK 融合。我们在此报告 3 例病例，这些病例扩展了 ALK 重排未分类肿瘤的解剖学、形态学和基因型谱。患者均为 46 至 69 岁的成年人 （中位数： 63），表现为位于牙龈、背部皮下和咽后壁粘膜下层的肿块。肿瘤大小从 1 到 2.7 cm 不等 （中位数： 1.6）。保守手术是所有患者的治疗方法。1 例患者在 14 个月时仍无病，可进行随访。组织学上，所有肿瘤均显示大多边形细胞，具有泡沫状至颗粒状和脂肪生成样微空泡状大量细胞质和中等大小的圆形细胞核，具有 1 或 2 个突出的核仁。未见有丝分裂和坏死。初步诊断印象为 PEComa 、炎性横纹肌母细胞瘤和未分类的假性脂肪生成肿瘤。在所有病例中，通过免疫组化检测到强细胞质 ALK。其他阳性标志物包括组织蛋白酶 K （2/2）、结蛋白 （1/3）、局灶性 MyoD1 （1/1）、局灶性 SMA （1/3） 和局灶性 EMA （1/2）。靶向 RNA 测序显示 ALK 与 ALK 的外显子 20 （2 例） 和外显子 19 （1 例） 融合与 RND3 （外显子 3） 、 SQSTM1 （外显子 6） 和结蛋白 （内含子 6） 融合。 结蛋白融合病例 （最初诊断为炎性横纹肌母细胞瘤） 中的甲基化分析显示炎性肌成纤维细胞瘤匹配，置信度评分为 0.5 且拷贝数变异 （CNV） 谱平坦。在这种情况下未检测到 NF1 突变，完全排除炎性横纹肌成细胞肿瘤。我们的研究突出并扩展了 ALK 融合肿瘤的形态学和解剖学多样性，并记录了新的融合伴侣 （RND3 和 desmin）。