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Page 135 Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46

INTRODUCTION
Hodgkin lymphoma (HL) is almost exclusively a B-cell malignancy annually diagnosed in an estimated
[1]
83,000 individuals worldwide . The age-distribution of HL is unusual among cancers, by being bi- or tri-
modal with a substantial number of cases in children, adolescents and young adults, and older adults,
[2]
respectively . Thus, HL spans the full spectrum from paediatric to geriatric malignancy and is believed to
[2]
encompass entities of different aetiologies .
The treatment of HL is one of the success stories of modern oncology. The application of increasingly
effective and gentle radiotherapy since the 1950s and subsequently combination chemotherapy and
combined modality treatment have increased 5-year survival after HL from less than 10% to 90% or more
[3,4]
today .

Today, most patients can potentially be cured even when diagnosed with advanced stage disease provided
[3]
access to modern health care . However, despite the generally favourable prognosis HL, both directly and
indirectly, remains associated with increased morbidity and mortality. First, even with current state-of-the-
[5]
art first-line treatment remission is not achieved for all patients and in other patients the disease relapses .
The prognosis for this non-negligible group of patients with refractory or relapsing disease, e.g., 15% of all
HL patients in Sweden in the period 1992-2009, is considerably less favourable [3,4,6] . Secondly, follow-up
studies of HL survivors continuously demonstrate a high frequency of a wide variety of adverse effects of the
treatment and of the disease, accompanied by reduced quality of life and life expectancy [7-10] . E.g., not so long
ago more early-stage HL patients died from long-term treatment complications, than from the lymphoma
itself . The excess morbidity and mortality, too, are particularly pronounced in the stratum of patients
[3,4]
with relapsing or refractory disease [7,11] .

Oncologists therefore face the difficult task of devising treatment strategies which simultaneously improve
or maintain current HL cure rates and reduce the risk of long-term adverse effects of treatment among the
survivors. Owing to the generally good outcomes achievable with current protocols there has been no
strong incentive to investigate if even better results could be obtained by considering HL aetiology in
treatment allocation.

However, this attitude may change following the successful introduction of novel treatment modalities into
cHL treatment, which targets tumour cell characteristics and/or tumour cells’ interaction with the
surrounding micro-environment, i.e., the tumour micro-environment (TME) . The notion that aetiology
[12]
would matter to HL treatment and treatment outcome hinges on the assumption that aetiologically
heterogeneous variants of HL exist and that these exhibit differences that are therapeutically relevant.

Here, we provide a broad-brush picture aimed at motivating and pointing the way for renewed research
into risk stratification considering HL aetiology. To do so in a concise and accessible way we have omitted
many interesting details and viewpoints and deliberately used a compact set of references, making intensive
use of a few other reviews.

CLASSIFICATION OF HODGKIN LYMPHOMA
The current WHO classification of tumours of haematopoietic and lymphoid tissues recognizes two
immunophenotypically distinct HL variants, i.e., classical HL (cHL) and nodular lymphocyte predominant
[2]
HL of these, cHL constitutes some 95% of all HL cases . The two types of HL are considered
[13]
aetiologically, pathologically and clinically different , and in the following only cHL is considered.
[13]