Biological heterogeneity in adult IRF4-rearranged large B-cell lymphoma: Stratification by age and anatomical site.

Large B-cell lymphoma (LBCL) with IRF4 rearrangement (LBCL-IRF4-R) is a rare subtype predominantly diagnosed in children and young adults. Whether adult LBCL cases with IRF4 rearrangement (IRF4-R) should be classified as LBCL-IRF4-R remains unclear. Clinicopathological and molecular features of 61 adult LBCL cases with IRF4-R were analyzed and compared to diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), to assess biological heterogeneity. The 61 cases grouped by patient age and site were classified as follows: Group 1 included 13 patients aged ≤40 years, whose features supported LBCL-IRF4-R, showing favorable outcomes with high frequencies of IGH::IRF4 fusion and IRF4 mutations. Group 2 comprised 37 patients aged >40 years with tumors at usual sites; 17 early-stage cases largely retained LBCL-IRF4-R characteristics, whereas three other early-stage cases showed molecular or clinical features more consistent with DLBCL, NOS with IRF4-R. Twelve advanced-stage cases showed aggressive behavior with adverse DLBCL, NOS-associated mutations (e.g., TP53), suggesting classification as follicular lymphoma grade 3A (FL-3A) and DLBCL with IRF4-R or DLBCL, NOS with IRF4-R. Five cases lacked sufficient data for definitive classification. Group 3 included 11 patients aged >40 years with tumors at unusual extranodal sites; except for one case classified as LBCL-IRF4-R, the remaining 10 cases showed aggressive clinical behavior with frequent MYD88 mutations, favoring classification as FL-3A and DLBCL with IRF4-R or DLBCL, NOS with IRF4-R. These findings support a multidimensional approach that integrates age, tumor site, and clinicomolecular features to refine classification, enhance risk stratification, and guide personalized management in adult LBCL cases with IRF4-R.