Molecular Heterogeneity and Clinicopathologic Correlations in Inflammatory Myofibroblastic Tumors of the Urinary Bladder: A Study of 20 Cases With Predominant FN1::ALK Fusions and Novel Kinase Rearrangements.

Abstract

Inflammatory myofibroblastic tumors (IMTs) of the urinary bladder are rare mesenchymal neoplasms with an incompletely defined molecular spectrum. This integrated clinicopathologic and molecular study of 20 bladder IMTs utilized immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and targeted RNA sequencing to characterize their molecular drivers. Clinically, patients (mean age 45 y) presented with hematuria (85%) and cystoscopic polypoid/nodular masses; despite muscularis propria invovlement (55%) or perivesical soft tissue extension (5%), clinical outcomes were excellent (90% disease-free survival; mean follow-up 32.6 mo), with 2 recurrences managed by repeat resection. Histologically, the tumors exhibited mixed growth patterns: compact spindle cell (75%), myxoid (50%), and hypocellular fibrous (20%), with 45% showing combined features. IHC revealed ALK positivity in 90% (18/20) of cases, predominantly diffuse cytoplasmic staining (17/18), while keratins (AE1/AE3 and/or CAM5.2) were positive in 83.3%. Molecular analysis identified ALK rearrangements in 87.5% (14/16) of FISH-tested cases (signal separation: 13% to 42%) and gene fusions in 88.9% (16/18) of RNA-sequenced cases, with FN1::ALK being the predominant fusion (75%, 12/16). Rare fusions included VCL::ALK , DCTN1::ALK , PPFIBP1::ALK , and a novel TFG::ROS1 (confirmed by RT-PCR and Sanger sequencing). Distinct genotype-phenotype correlations emerged: myxoid morphology strongly associated with FN1::ALK (87.5%, 7/8), while hypocellular fibrous patterns enriched non- FN1 fusions (75%, 3/4). The predominance of FN1::ALK fusions, sharing identical breakpoints ( ALK exons 18 to 19) with pseudosarcomatous myofibroblastic proliferations of the urinary bladder, alongside expanded molecular diversity (non- FN1/ROS1 fusions), supports their classification as a biological continuum of ALK -driven bladder mesenchymal neoplasms. These findings broaden the molecular genetic spectrum of bladder IMTs and advocate for histology-guided molecular testing to identify kinase fusions, reinforcing conservative management for these typically indolent tumors.