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Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46 Page 136

HL lesions are histologically unusual among malignant diseases in that the neoplastic cells, the so-called
Hodgkin/Reed-Sternberg (HRS) and their variants, constitute only a small fraction of the tumour lesion,
[14]
typically a few percent in cHL . Instead, the tumour lesions are entirely dominated by an admixture of
[14]
inflammatory and accessory cells in which the malignant cells are scattered . Based on the architecture of
the TME, cHL is further divided into four subtypes, specifically mixed cellularity (MC), nodular sclerosis
[14]
(NS), lymphocyte rich (LR) and lymphocyte depleted (LD) cHL . The appreciation of these main
histological types is important to the discussion of aetiological heterogeneity in cHL which rests primarily
though not exclusively on epidemiological considerations.

Variation in HL incidence patterns suggests epidemiological heterogeneous variants
[2]
HL incidence varies by age both within and between populations . Epidemiologically, the age-specific
incidence distribution of HL in most settings has historically been construed as a mixture of two
archetypical patterns, suggested to be characteristic of socio-economically affluent and deprived settings,
respectively, in early survey data .
[15]
In affluent western countries age-specific cHL incidence tends to follow a bimodal distribution with
separate peaks in adolescents and young adults (AYA) and in older adults, respectively. In deprived settings
in contrast, there is no incidence peak in AYA but rather an incidence peak in younger children, which is
then followed by an incidence peak in older adults .
[15]

It is implicitly understood from these associations that the age-specific incidence distributions are dynamic,
especially in the first four decades of life [2,16] . Thus, in conjunction to societal development from deprived to
an affluent setting an AYA HL incidence peak emerged, e.g., in Singapore . Further illustrations of this
[17]
phenomenon based on data from the United States, Slovenia, Finland, Estonia and Japan are discussed in
[16]
Ref. .
Age, histology and tumour viral-status as markers of aetiologically distinct cHL variants
The conspicuous variation in age-specific incidence of HL along with other epidemiological and clinical
differences fostered the first notion of aetiological heterogeneity in HL. Specifically, it was suggested that HL
in children, in AYA, and in older adults were epidemiologically, possibly causally different [18,19] .

To this day, epidemiological studies continuously consider age at diagnosis as an important characteristic to
understand the natural history of cHL. Increasingly often, however, age at diagnosis is combined with either
or both of two other features, tumour histology and tumour Epstein-Barr virus (EBV) status also suspected
of defining aetiologically distinct cHL variants [2,16] .

The incidence peak among AYA in affluent populations is mostly made up of NS cHL [2,16,20] . In contrast, MC
cHL is more commonly seen in children and older adults, in socio-economically deprived settings and in
patients with immune deficiencies [2,16,21] . In combination with other data pointing to different
epidemiological characteristics it has therefore been suggested that MC and NS cHL represent aetiologically
distinct entities [2,16,20] .

Epstein-Barr virus and cHL
The contrasting incidence peaks among children in socio-economically deprived and among AYA in socio-
economically affluent populations, respectively, led to speculations about HL being causally associated with
a common childhood infectious agent whose oncogenic potential increases with age at exposure [15,22,23] .