GISTs with NTRK Gene Fusions: A Clinicopathological, Immunophenotypic, and Molecular Study

SIMPLE SUMMARY: Wild-type GISTs are generally not sensitive to tyrosine kinase inhibitors. Tropomyosin receptor kinase inhibitors have been approved to be effective in multiple cancers with neurotrophic tyrosine receptor kinase (NTRK) fusions. Although NTRK fusions are rare in wild-type GISTs, the unambiguous diagnosis can bring clinical benefits to the patients. The immunohistochemistry staining of Pan-TRK, next-generation sequencing or fluorescence in situ hybridization have been used to screen NTRK fusions in a few cases of wild-type GIST, and each technique has its advantages and drawbacks. This study aimed to identify NTRK fusions in wild-type GISTs with the above three methods and explore the clinicopathological and genetic features of GISTs with NTRK functions based on our patients and the literature. The findings from this study provide new evidence to establish a clinical protocol for screening GISTs with NTRK fusions and an overall view of the clinicopathological characteristics of GISTs with NTRK fusions. ABSTRACT: The most common mutations in gastrointestinal stromal tumors (GISTs) are KIT or PDGFRA mutations. Recently, neurotrophic tyrosine receptor kinase (NTRK) fusions have been reported in WT GISTs, which increased interest in introducing tropomyosin receptor kinase (TRK) inhibitors as treatments for GISTs with NTRK fusions. Hence, we aimed to screen NTRK fusions in WT GISTs; we used fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) to screen NTRK fusions in 46 WT GISTs and evaluate each method. We further reviewed NTRK fusion-positive GISTs from the literature and performed clinical and pathological analyses; two GISTs with an ETV6-NTRK3 fusion (5%) were identified, while only one (50%) was positive for Pan-TRK expression. On the other hand, among the six GISTs with Pan-TRK-positive expression, only one (17%) harbored NTRK fusion. The literature review revealed the strong consistency between FISH and NGS and the limited value of Pan-TRK IHC in screening NTRK fusions in GISTs. In addition, the clinical and pathological analysis showed that GISTs with NTRK rearrangement occurred less frequently in the stomach, were more frequently larger in size, and the epithelioid type presented with a higher risk of recurrence. The NTRK3 fusion has been more common than the NTRK1 fusion in GISTs to date; our study identified two ETV6-NTRK3 fusions in 46 WT GISTs. Compared with FISH and IHC, NGS is preferred for screening WT GISTs, including NTRK rearrangements. However, since GISTs with NTRK fusions are rare, further studies including more samples and mechanistic investigations should be conducted in the future.