Molecular profiling and perioperative management of inflammatory myofibroblastic tumors at a single institution.

Abstract

e23519 Background: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm often driven by kinase fusions, most commonly involving anaplastic lymphoma kinase (ALK). Although tyrosine kinase inhibitors (TKIs) have demonstrated activity in unresectable IMT, the role of targeted therapy perioperatively is not well established. We evaluated the molecular profiles and clinical outcomes of IMTs at a single institution, describing the prevalence of actionable gene fusions and use of neoadjuvant targeted therapy. Methods: We performed a retrospective review of all patients with IMT at Columbia University Irving Medical Center from 2005 to 2025. Clinical and treatment data were analyzed. RNA-based fusion testing was performed on archival tumor specimens when available, and prior DNA/RNA sequencing results were reviewed when available. Results: Twenty-seven IMT patients were included. 59% were male and the average age at diagnosis was 41 years (range 1.5-81). Tumors arose in multiple sites, including the lung (22%), kidney (15%), head and neck (15%), and gastrointestinal tract (15%). 14 tumors underwent successful RNA-based sequencing, of which 12 (86%) harbored kinase fusions. ALK fusions were present in 9 (64%), ROS1 in 2 (14%), and a VCAN-IL23R fusion in one case. FN1-ALK was the most common fusion subtype (n=3), all occurring in bladder IMTs. Surgical resection was the primary treatment for 26/27 patients. Four patients received neoadjuvant therapy. Two patients with ALK-rearranged IMTs were treated with neoadjuvant ALK inhibition, resulting in one complete metabolic response (alectinib) and one partial response (crizotinib) prior to resection. The VCAN-IL23R case demonstrated recurrence and progression despite multimodal therapy. Two additional patients developed recurrence managed surgically. Conclusions: Kinase fusions were common (86% of sequenced tumors) and molecularly diverse in this IMT cohort, supporting routine use of RNA-based fusion profiling. Despite the high prevalence of actionable alterations, TKI use remained limited. The favorable responses to neoadjuvant ALK inhibition demonstrate the potential role for perioperative targeted therapy. The aggressive clinical phenotype seen in the VCAN-IL23R fusion case suggests that rare non-ALK fusions may represent biologically distinct IMT subsets with limited treatment options. Together, these findings support earlier incorporation of molecular testing with expanded investigation of rare gene fusions and highlight the need for prospective evaluation of perioperative TKI strategies. IMT molecular fusion profiles. Fusion Type N (%) Fusion partner(s) Tumor location Age range ALK 9 (64) FN1 (3), CLTC, MCC, TMP4, CLIP2, CSTF3, KIF5B Bladder (3), lung (3), head/neck (2), breast 2-77 ROS1 2 (14) FN1, TFG Lung, small intestine 13-18 IL23R 1 (7) VCAN Liver 12 No fusion detected 2 (14) N/A Epididymis, head/neck 70-78