Tumor microenvironment composition in pediatric classical Hodgkin lymphoma is modulated by age and Epstein-Barr virus infection.

Classical Hodgkin lymphoma (cHL) is characterized by a small number of neoplastic cells in a background of reactive cells. Children and adults differ in constitution and functionality of the immune system and it is possible that there may be age-related differences in tumor microenvironment composition in cHL. One hundred children with pediatric cHL were studied. Tumor-infiltrating lymphocytes were analyzed by immunohistochemistry (IHC) and image analysis. Epstein-Barr virus (EBV) status was determined by EBER-specific in situ hybridization and IHC. Results were analyzed in the context of age-group, histological characteristics and clinical follow-up. EBV-status was not associated with age-group. Children<10 years and EBV+ cases were characterized by a more intense T cell infiltrate, exhibiting a cytotoxic/Th1 profile, characterized by higher numbers of CD3+, CD8+, TIA1+ and TBET+ lymphocytes. Extranodal disease (p=0.016) and high number of GranzymeB+ lymphocytes (p=0.04) were independently associated with reduced progression-free survival (PFS). Yet, in EBV+ cases, improved outcome was observed in cases with low numbers of FOXP3+ lymphocytes (p=0.046), FOXP3/CD8 ratio<1 (p=0.021) and TBET/CMAF ratio<1 (p=0.017). By contrast, in EBV- cases, poor survival was observed in cases with extranodal disease (p=0.028), MC subtype (p=0.009) and high numbers of TIA1+ (p=0.044) and GranzymeB+ (p=0.04) lymphocytes. The results suggest that in EBV+ cHL an effective immune response directed against viral or tumor antigens may be triggered in the tumor microenvironment and that physiological and age-related changes of the immune system may also modulate the tumor microenvironment in pediatric cHL.