Clinicopathologic Heterogeneity and Prognostic Determinants in Pediatric Chronic Active Epstein–Barr Virus Infection

Objective: Chronic active EBV infection (CAEBV) is a rare but life-threatening Epstein–Barr virus-driven T/natural killer (NK)-cell lymphoproliferative disorder with heterogeneous clinicopathologic features and poorly defined prognostic markers. We aimed to characterize the histopathologic spectrum of pediatric CAEBV and assess its correlation with clinical outcomes. Methods: We retrospectively analyzed 101 CAEBV patients, assessing clinical features, histopathologic grading, immunophenotype and treatment outcomes. Results: Pathologic grading revealed proliferative (Grade-1, 52.5%), borderline (Grade-2, 32.7%) and neoplastic (Grade-3, 14.9%) lesions. Immunophenotypically, 71.3% were T-cell type, while 28.7% exhibited mixed T/NK-cell type, with higher-grade showing increased T/NK-cell mixed immunophenotypes (60.0% in Grade-3 vs. 11.3% in Grade-1, P < 0.001). Multisite biopsies identified spatial heterogeneity, with extramedullary sites demonstrating higher-grade disease than bone marrow. Key clinical and laboratory parameters showed no significant association with histopathologic grade or immunophenotype ( P > 0.05 for most comparisons). Initial chemotherapy achieved responses in 64.4% of patients, with lower efficacy in higher-grade disease (Grade-1: 71.7% vs. Grade-3: 33.3%; P = 0.022). Immunophenotype did not influence response (T-cell: 69.4% vs. T/NK-cell: 51.7%; P = 0.093). Hematopoietic stem cell transplantation was performed in 85.1% of cases, with Grade-1 cases demonstrating superior transplant eligibility (94.3% vs. 75.8%–73.3%, P = 0.024). With a 3-year overall survival of 75.1% ± 4.3% for the entire cohort, hematopoietic stem cell transplantation recipients had superior survival (86.0%) versus nontransplanted patients (6.7%) ( P = 0.001). Pathologic grade significantly predicted outcomes, with Grade-1 patients demonstrating the highest survival (84.9% ± 4.9% vs. 63.2%–66.7% for Grades 2 and 3; P = 0.033), while immunophenotype showed no prognostic impact ( P = 0.385). Conclusions: These findings highlight the prognostic value of histopathologic grading and the need for multisite biopsies to guide risk stratification and therapy.