Preoperative tyrosine kinase inhibitors risks bowel anastomotic healing in patients with advanced primary and recurrent/metastatic gastrointestinal stromal tumors— A rose has its thorns

Background: The combination of tyrosine kinase inhibitors (TKIs) and surgery has created a paradigm shift for advanced primary and metastatic gastrointestinal stromal tumors (GISTs). However, the associated surgical morbidity rate is reportedly high, which we hypothesized is attributable to the adverse effects of the previous use of TKIs on bowel anastomosis healing. Methods: A total of 613 GIST patients with (n = 108) and without (n = 505) preoperative TKI treatment were enrolled. Propensity score matching compared the surgical morbidities and mortalities between the two cohorts. An animal model was used to elucidate the relevant mechanism. Results: After propensity score matching, the incidence and severity of surgical complications were higher in patients with preoperative TKIs than in those without (34% vs 10%, p < 0.0001; grades 3–5, 16% vs 2%, p < 0.0001). Specifically, the incidence of bowel anastomosis leakage was increased in those with versus those without preoperative TKI (18% vs 6%, p = 0.032). A constellation of mucosal shedding, shortening of villus height and crypt depth, and disarrayed epithelial lining of the bowel was observed with preoperative TKI treatment. The animal model showed that bowel anastomosis healing was weakened by imatinib through the downregulation of Col1A1, Col3A1, and MMPs. Conclusions: Impaired bowel anastomosis healing was responsible for the extraordinarily high surgical morbidity rate of patients with GIST after TKI treatment. The mechanism involved altered tissue microarchitecture and dysregulated Col1A1, Col3A1, and MMP expressions.