Inflammatory rhabdomyoblastic tumor: Clinicopathologic and genomic features, association with neurofibromatosis type 1, and progression to rhabdomyosarcoma.

Inflammatory rhabdomyoblastic tumor (IRMT) is a rare myogenic neoplasm with a morphologic spectrum and incompletely defined clinical behavior. It is characterized by a prominent inflammatory infiltrate, skeletal muscle differentiation, and recurrent near-haploidization, with occasional progression to rhabdomyosarcoma. Its relationship with neurofibromatosis type 1 (NF1) remains incompletely understood, despite recurrent NF1 alterations and reports of IRMT arising in patients with NF1. We analyzed five IRMTs: three conventional tumors, one tumor with increased mitotic activity without overt malignant features, and one malignant tumor. Two arose in patients with clinically overt NF1 and Targeted next-generation sequencing identified pathogenic NF1 alterations in four out of five tumors, supporting an association between IRMT and NF1. Whole-genome sequencing demonstrated near-haploid genomes in conventional IRMTs, whereas the malignant tumor showed whole-genome duplication, genome-wide loss of heterozygosity, and homozygous CDKN2A inactivation. When included with other genomically characterized and published conventional IRMTs and malignant progressions, integrated data supports a view in which near-haploidization represents the genomic background of conventional IRMT, with complete CDKN2A inactivation and whole-genome duplication as candidate contributors to malignant progression. Although this small retrospective series cannot establish temporal sequence or causality, our findings provide additional clinicopathologic and molecular support for an association between IRMT and NF1 and further characterize the genomic alterations associated with malignant progression. Complete CDKN2A loss and whole-genome duplication should be regarded as candidate progression-associated findings requiring validation in larger cohorts and longitudinal and functional studies.