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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 138

Traditional stratification of cHL treatment
First-line treatment of patients with cHL today generally consists of chemotherapy with or without
radiotherapy, while patients with refractory or relapsing disease receive further chemotherapy and possibly
autologous stem cell transplantation, and most recently also brentuximab vedotin, pembrolizumab and
Nivolumab [6,41] .

First-line treatment allocation is determined by stage of disease and scoring of established prognostic
factors. Here, different staging systems have been used over time, most recently the Cotswolds modification
[42]
of the Ann Arbor classification introduced in 1989, and the Lugano classification finalised in 2014 . Thus,
depending on extent and location of disease patients are classified with early (stages I and II) or advanced-
stage disease (stages III and IV). Staging is supplemented by different sets of characteristics known to have
prognostic significance. In early-stage disease these factors include age, mediastinal tumour size, number of
nodal sites and extra-nodal involvement, sedimentation rate, and the presence of specific - socalled B -
symptoms [43,44] . For patients with advanced disease, characteristics influencing treatment allocation include
[43]
age, stage, male sex, white blood cell count, lymphocyte and albumin and haemoglobin concentrations .

While patient survival was previously found to vary by tumour histology in univariate analyses and it
[45]
therefore was among prognostic factors in early-stage HL, it does not retain practical significance with
modern treatment and in the presence of other prognostic factors using contemporary modelling
techniques. Today it is therefore not considered by most centres and cooperative groups [43,44] .

Tumour EBV status is not and has not previously been considered a prognostic factor in cHL treatment
protocols. Presumably, the combination of a rare outcome (due to the good prognosis) in a rare disease and
an assumed complicated association through interactions between tumour aetiology and outcome has made
the gains from such analyses of tumour aetiology too uncertain to make the undertaking worthwhile in
prospective studies. Also, histological and clinical presentation of cHL at diagnosis does not vary sufficiently
by tumour EBV status to allow for inference from studies considering prognostic significance of clinical
presentation alone [12,32] .

Therefore, to evaluate the clinical significance of cHL EBV-status and histological subtype one must resort
to retrospective studies and/or historical data concerning treatments no longer used. The bulk of such
[32]
studies predating 2012 regarding EBV-status was recently reviewed and meta-analysed . In combination,
there was little to suggest from these studies that cHL outcome vary by tumour EBV-status whether with
respect to event-free, disease-specific or overall survival . While this could be due to methodological
[32]
differences between studies [e.g., setting, study populations (trials, other), definition of cHL EBV status,
types of treatment, etc.], it is also entirely plausible that clinical significance of cHL EBV status may vary
between age groups considering the model for EBV-positive cHL pathogenesis. Such variation may easily
escape detection in crude univariate meta-analyses, and on the other hand, may be hard to detect in suitably
stratified analyses due to lack of statistical power.

Still, it is of some interest that albeit with some nuances, the three largest populations-based studies all
suggested that compared with EBV-negative cHLs, EBV-positive cHLs may carry a better prognosis in
younger adult patients and a worse prognosis in older adult patients, whether the outcomes considered were
[48]
overall or disease-specific survival [46,47] . or failure-free and relative survival . Patients included in the studies
were diagnosed in 1988-2000 in the United States or Europe, but information on specific types of
chemotherapy administered was reported in only one of these three studies where it did not vary by tumour
[48]
EBV status . Still, the lack of specific treatment information adds an additional layer of complications to