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

Abstract 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.