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

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.

We retrospectively analyzed 101 CAEBV patients, assessing clinical features, histopathologic grading, immunophenotype and treatment outcomes.

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).

These findings highlight the prognostic value of histopathologic grading and the need for multisite biopsies to guide risk stratification and therapy.