Epidemiological evidence for the role of puberty and immune senescence in Hodgkin lymphoma aetiology from 1992 Danish cases

Current epidemiological thinking is that classic Hodgkin lymphoma (cHL) comprises multiple aetiologically distinct disease entities that may in part be defined by either histological subtype or the presence of Epstein-Barr virus (EBV) in the malignant cells, or by both. This study aimed to advance our understanding of epidemiological differences between cHL subtypes, in particular EBV-positive and EBV-negative cHL. We retrospectively collected and EBV-typed 1992 cHL primary tumour tissues from among all 2811 patients diagnosed with incident HL in Denmark in the period 1990 through 2010 'Hodgkin lymphoma in Denmark' [HOLYDAN] project. Based on characteristics of retrieved samples combined with additional information from national registers, we projected nationwide age-, sex-, histology- and EBV-specific cHL incidence rates. The analyses demonstrated age- and sex-dependent variation in histology- and EBV-tumour status-specific cHL incidence rates, details of which yielded new aetiological clues. cHL incidence increased markedly around the age of puberty, irrespective of histological subtype and EBV status. The incidence of all subtypes of cHL increased with age after age 50 years, with the exception of EBV-negative nodular sclerosis cHL in females, which therefore showed a single peak in incidence and was higher than in males among young adults. These results were obtained in a small homogeneous population and might, therefore, only apply to rich, industrialised, Western populations. Nevertheless, we propose that puberty creates an immunological host environment conducive to cHL development irrespective of EBV status and histology, and that age-related decline in immune function facilitates the development of both EBV-positive and EBV-negative cHL.