Tumor Microenvironment In Pediatric Hodgkin Lymphoma: Clues for Disease Biology

Abstract 2681

The non-malignant elements in Hodgkin lymphoma (HL) tissue are very prominent and represent a reactive process either directly against or induced by tumor cells. Thus far, only clinical characteristics have been used in the risk assessment of HL. Biologic markers of disease remain largely unidentified. This study examined cellular immunologic features of the tumor microenvironment in pediatric HL patients seen at a single children's hospital since 1997 for whom flow cytometric evaluation at diagnosis was available. Retrospective chart review was conducted to gather other relevant clinical and laboratory data on the cases. Student t-test, nonparametric Mann-Whitney U and Kruskal-Wallis tests, and Pearson's correlation analysis were used for statistical evaluation. Thirty-one patients, 14 male and 17 female, with a median age of 14 years (range 3–17) were included in the study. Twenty-one cases were nodular sclerosis (NS) [71% female, with a median age of 14 years], 6 mixed cellular (MC) [17% female, with a median age of 11 years] and 4 undetermined subtype. While T cells were predominant in nodular sclerosis (NS), the infiltrate was B cell-rich in mixed cellular (MC) subtype. CD4+ T cells were significantly higher in NS (55 vs. 30.5; p=0.01) and, conversely, CD8+ cells in MC (21.3 vs. 11.3; p=0.02). Consistently, CD4/CD8 ratio was significantly higher in NS (9.6 vs. 1.6; p=0.02). All of the MC tumors were in situ EBV-positive, compared to only 24% of NS tumors (p=0.008). The WBC and absolute lymphocyte count were higher in NS compared with MC, 12×10⁹/L vs. 6.1×10⁹/L and 3.9×10⁹/L vs. 1.5×10⁹/L, respectively. Occurrence of primary continuous complete remission (CCR) without recurrence or refractoriness was significantly higher in MC group (p=0.009). Higher hemoglobin, DR+CD38+ lymphocyte percentage and lower CD4/CD8 ratio were also predictive of primary CCR status (p<0.05) in the entire study group. In the NS group, higher DR+CD38+ lymphocyte percentage was again associated with primary CCR (p=0.004). In this group, there was also an association between primary CCR and higher hemoglobin level (p=0.053). While DR+CD38+ lymphocyte percentage negatively correlated with CD4/CD8 ratio, there was positive correlation with WBC. Finally, the immunophenotype characteristics of the EBV-positive NS cases were intermediate to the MC group and EBV-negative NS cases. Albeit a small series, these results point to striking tumor microenvironment differences between NS and MC subtypes and EBV status-associated patterns. Moreover, DR+CD38+ lymphocyte proportion and CD4/CD8 ratio appear to be associated with the risk status of childhood HL, suggesting their potential role as prognostic biologic factors.