胃肠道间质瘤(GIST)是最常见的胃肠道间质瘤,有原癌基因,受体酪氨酸激酶(c-kit),或PDGFRα突变在约85%的病例中检测到。无c-kit或血小板衍生生长因子受体α(PDGFRα)突变的GIST被认为是野生型(WT),它们不同的分子变化和生物学行为仍然不确定。它们通常对酪氨酸激酶抑制剂(TKIs)不敏感。最近,一些分子改变,包括神经营养酪氨酸受体激酶(NTRK)融合,很少有WTGIST病例报道。这项新发现为在GIST的这些亚型中使用原肌球蛋白受体激酶(TRK)抑制剂治疗打开了窗口。在这里,我们报告了1例NTRK融合WT高危GIST的新病例,患者盆腔肿块较大(大尺寸20cm).肿瘤被切除了,和组织病理学显示纺锤体为主的形态与局灶性上皮样区域,粘液样基质组织,和明显的淋巴浸润,三级淋巴结构。在50个没有核多态性的高功率场中量化了10个有丝分裂。DOG1表现出强烈和弥漫性阳性,CD117显示中度阳性。琥珀酸脱氢酶亚基B(SDHB)被保留,Pan-TRK为局灶性阳性(核模式),增殖指数Ki-67为7%。下一代测序(NGS)检测到ETV6::NTRK3融合,荧光原位杂交(FISH)证实了这一发现,显示NTRK3重排。此外,NGS发现RB1突变。随访CT扫描显示腹膜结节提示腹膜播散,和恩替尼(一种TRK抑制剂)给药。经过3个月的随访,新的CT扫描显示完全缓解.根据我们的结果和文献中的案例,到目前为止,具有NTRK融合的GIST非常罕见;因此,进一步的筛查研究,包括更多WTGIST病例,可能会增加发现额外病例的可能性。本病例可能为TRK抑制剂的潜在引入提供新的见解,以治疗具有NTRK融合的GIST。此外,在这种情况下,大量的淋巴浸润的存在可能促使进一步研究免疫疗法作为一种可能的额外治疗选择。
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.