Precursor cells and implications of a T-cell inflamed immune response in the pre-malignant setting in Hodgkin lymphoma

The etiology of classical Hodgkin lymphoma (cHL) is largely unknown. High serum CD30-levels are associated with increased risk of cHL. Epstein-Barr virus (EBV) is detectable in the tumor cells in 1/3 of cHL cases in the Western world. The PD-1 pathway (T-cell inflamed immune response) might contribute to the pathogenesis by enabling pre-malignant CD30+ or EBV + cells to evade immune surveillance. We aimed to investigate if high infiltrations of CD30+, PD-1+, PD-L1+ and EBV + cells in benign lymph nodes from patients that later develop cHL (cases) (n = 15) were associated with risk of cHL compared to controls (n = 45) with benign lymph nodes from patients that did not develop cHL. Pathology registries including 3500 cH L patients were screened. Lymph nodes were stained with immunohistochemistry and in situ hybridization and the risk for cHL calculated with logistic regression. High CD30-expression by B- and T-cells was associated with a decreased risk of cHL [(OR = 0.10, 95 % CI:0.03-0.39) and (OR = 0.13, 95 % CI:0.01-0.71), respectively], which remained significant for CD30 + B-cells (OR = 0.15, 95 % CI:0.03-0.60) in multivariate analyses. Amount of PD-1+, PD-L1+ and EBV + cells were not statistically significantly associated with risk of cHL. However, the amount of PD-L1+ leukocytes tended to be higher in cases later developing cHL (OR = 2.84, 95 % CI:0.61-12.61). High proportions of potential precursors to cHL, i.e. CD30 + B-cells in benign lymph nodes are not associated with an increased risk of cHL, while a tendency for a T-cell inflamed immune response, i.e. abundant PD-L1+ cells, was observed in biopsies taken prior to the cHL diagnosis.