Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Pathology, Oregon Health & Science University, Portland, OR, USA.
Mod Pathol. 2021 Jan;34(1):95-103. doi: 10.1038/s41379-020-0623-z. Epub 2020 Jul 15.
Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months-55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3-NTRK1 (n = 3), TPR-NTRK1, LMNA-NTRK1, and ETV6-NTRK3 (n = 2), and SPECC1L-NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.
由 NTRK 融合驱动的间叶性肿瘤在临床上和形态上具有异质性。随着越来越多的临床病理实体与 NTRK 融合相关联，识别 NTRK 融合的诊断和预测价值尚不确定。最近，具有 NTRK 融合的胃肠道间叶性肿瘤被描述为胃肠道间质瘤（GIST），但此类肿瘤的分类学仍存在争议。我们报告了 8 例涉及胃肠道的具有 NTRK1 或 NTRK3 重排的间叶性肿瘤。这些肿瘤发生在 6 名儿童和 2 名成人中，男性 5 例，女性 3 例（年龄 2 个月至 55 岁；中位年龄 3.5 岁），涉及小肠（n=4）、胃（n=2）、直肠（n=1）和肠系膜（n=1）。临床结果各不相同，从相对惰性（n=2）到侵袭性疾病（n=2）。形态上，肿瘤具有异质性，可分为以下三组：（1）婴儿纤维肉瘤累及胃肠道（n=4），富含 NTRK3 融合；（2）低级别 CD34 阳性、S100 蛋白阳性梭形细胞肿瘤，与 NTRK1 融合相关（n=2）；（3）未分类的高级别梭形细胞肉瘤，与 NTRK1 融合（n=2）。通过免疫组织化学，肿瘤表现为弥漫性 pan-TRK 表达，强度不同，缺乏特定的分化线。4 例表达 CD34，其中 3 例与 S100 蛋白共表达。SOX10、KIT 和 DOG1 的表达始终缺失。分子遗传学检测发现 TPM3-NTRK1（n=3）、TPR-NTRK1、LMNA-NTRK1 和 ETV6-NTRK3（n=2）以及 SPECC1L-NTRK3 基因融合。我们的结论是，对于没有明确分化线的胃肠道间叶性梭形细胞瘤的评估，应包括 NTRK 改变的检测，特别是在儿科患者中。具有 NTRK 重排的胃肠道间叶性肿瘤在临床上和形态上具有异质性，很少（如果有的话）与 GIST 相关。
