Abstract
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.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-025-01146-6.