Craniofacial Involvement Is Associated With Poor Prognosis in Extranodal Diffuse Large B-Cell Lymphoma

The craniofacial region represents a distinct yet poorly understood pattern of extranodal involvement in diffuse large B-cell lymphoma (DLBCL). However, the prognostic significance and molecular characteristics of craniofacial involvement in extranodal DLBCL (EN-DLBCL) remain unclear. This study included 164 patients with EN-DLBCL, comprising 98 with craniofacial involvement (CFI) and 66 without. Prognostic factors and survival, as well as relapse and other clinical factors, were analyzed. Targeted next-generation sequencing was performed in 87 cases. Patients with CFI had significantly inferior 5-year progression-free survival (p = 0.0097) and overall survival (p = 0.0088), and CFI remained an independent adverse prognostic factor after adjustment for International Prognostic Index (IPI). Sequencing showed that MYD88, TMSB4X, and PCLO mutations were more frequent in the CFI group. Among the recurrently mutated genes in patients with CFI, only BTG2 mutation was associated with both inferior PFS and OS, whereas no significant prognostic effect was observed in patients without CFI. Immunohistochemistry further demonstrated significantly lower BTG2 expression in BTG2-mutant samples than in wild-type samples (p = 0.008). These findings indicate that CFI defines a clinically unfavorable subset of EN-DLBCL with distinct molecular features and that BTG2 alteration may serve as a candidate biomarker for risk stratification in this setting.