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Purpose <p>This study aimed to characterize the clinicopathological, immunophenotypic, and molecular features of gastrointestinal stromal tumors (GISTs) harboring <i>NTRK</i> fusions and to evaluate their diagnostic, prognostic, and therapeutic implications.</p> Methods <p>Twenty-six cases of <i>KIT/PDGFRA/SDH/BRAF</i> wild-type GISTs were evaluated using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) for <i>NTRK1/2/3</i>, and next-generation sequencing (NGS). Transcriptome analysis was performed on all <i>NTRK</i> fusion-positive cases. Seven <i>KIT</i>-mutant GISTs served as controls. Clinicopathological parameters, IHC profiles, genetic alterations, and treatment responses were analyzed, supplemented by a literature review.</p> Results <p>Five of the 26 wild-type GISTs harbored <i>NTRK</i> fusions, all confirmed by NGS as <i>ETV6::NTRK3</i>. Pan-TRK IHC showed 100% sensitivity and 66.7% specificity. All five patients were male; four tumors were intestinal and one gastric. Four cases were high-risk and one very low-risk. Two cases recurred post-resection, showing additional mutations and copy number variations (CNVs). Preliminary evidence from transcriptome sequencing pointed to the possibility that <i>NTRK</i> fusion-positive GISTs represented a heterogeneous group and showed similarities in their molecular profiles to common <i>KIT</i>-mutant GISTs. Both recurrent patients received multi-line TKI therapy (imatinib, sunitinib, regorafenib, ripretinib) with disease progression; one subsequently achieved remission with larotrectinib.</p> Conclusion <p><i>NTRK</i> fusion-positive GISTs are rare and exhibit distinct clinicopathological characteristics. FISH and NGS are reliable detection methods, while pan-TRK IHC has limited specificity. Co-occurring genetic alterations may confer aggressive behavior. These tumors respond to TRK inhibition but are resistant to conventional TKIs, underscoring the need for molecularly guided therapy.</p>

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Clinicopathologic and molecular spectrum of gastrointestinal stromal tumor (GIST) with NTRK fusion and marked response to larotrectinib in GIST with NTRK fusion: a case report

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Yanying Shen,
  • Qi Peng,
  • Jinxuan Wen,
  • Linxi Yang,
  • Lingyan Zhu,
  • Yiming Chen,
  • Qiang Liu,
  • Lisha Wang,
  • Jinjuan Yao,
  • Anqi Li,
  • Ming Wang,
  • Zebing Liu

摘要

Purpose

This study aimed to characterize the clinicopathological, immunophenotypic, and molecular features of gastrointestinal stromal tumors (GISTs) harboring NTRK fusions and to evaluate their diagnostic, prognostic, and therapeutic implications.

Methods

Twenty-six cases of KIT/PDGFRA/SDH/BRAF wild-type GISTs were evaluated using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) for NTRK1/2/3, and next-generation sequencing (NGS). Transcriptome analysis was performed on all NTRK fusion-positive cases. Seven KIT-mutant GISTs served as controls. Clinicopathological parameters, IHC profiles, genetic alterations, and treatment responses were analyzed, supplemented by a literature review.

Results

Five of the 26 wild-type GISTs harbored NTRK fusions, all confirmed by NGS as ETV6::NTRK3. Pan-TRK IHC showed 100% sensitivity and 66.7% specificity. All five patients were male; four tumors were intestinal and one gastric. Four cases were high-risk and one very low-risk. Two cases recurred post-resection, showing additional mutations and copy number variations (CNVs). Preliminary evidence from transcriptome sequencing pointed to the possibility that NTRK fusion-positive GISTs represented a heterogeneous group and showed similarities in their molecular profiles to common KIT-mutant GISTs. Both recurrent patients received multi-line TKI therapy (imatinib, sunitinib, regorafenib, ripretinib) with disease progression; one subsequently achieved remission with larotrectinib.

Conclusion

NTRK fusion-positive GISTs are rare and exhibit distinct clinicopathological characteristics. FISH and NGS are reliable detection methods, while pan-TRK IHC has limited specificity. Co-occurring genetic alterations may confer aggressive behavior. These tumors respond to TRK inhibition but are resistant to conventional TKIs, underscoring the need for molecularly guided therapy.