Gastrointestinal Stromal Tumors: Histopathological Spectrum, Molecular Subtypes, and Implications for Targeted Therapy

: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and represent a paradigm of precision oncology in which histopathology and molecular profiling directly inform diagnosis, prognosis, and therapeutic strategy. Arising from the interstitial cells of Cajal or their precursors, GISTs display a wide morphological spectrum, including spindle cell, epithelioid, mixed, and rare histologic variants, often requiring immunohistochemical confirmation with KIT (CD117), DOG1, and CD34. Molecular characterization reveals a limited but clinically decisive range of driver mutations, most commonly in KIT and PDGFRA, with additional subsets involving SDH deficiency, NF1 alterations, and rare mutations such as BRAF, KRAS, or NTRK fusions. These molecular signatures underpin distinct biological behaviors, prognostic categories, and therapeutic sensitivities. Risk stratification incorporates tumor size, mitotic rate, anatomical location, and tumor rupture to predict recurrence and guide adjuvant therapy decisions. Targeted tyrosine kinase inhibitors (TKIs) have transformed GIST management, with imatinib as the foundational first-line therapy and subsequent agents, sunitinib, regorafenib, avapritinib, and ripretinib, addressing primary or secondary resistance driven by diverse mutational patterns. Nevertheless, challenges persist, including imatinib-resistant PDGFRA D842V mutations, SDH-deficient tumors lacking actionable kinase alterations, and the emergence of polyclonal secondary resistance due to heterogeneous KIT adenosine triphosphate (ATP)-binding pocket or activation loop mutations. Emerging therapeutic directions include next-generation kinase inhibitors, heat shock protein inhibitors, immunotherapy, metabolic and epigenetic targeting, and biomarker-driven individualized treatment strategies. This review synthesizes contemporary advances in the histopathological, molecular, and therapeutic landscape of GISTs, emphasizing an integrated diagnostic approach and highlighting ongoing efforts to overcome therapeutic resistance and optimize personalized care.