Understanding Classic Hodgkin Lymphoma and Its Challenges

Classic Hodgkin lymphoma (CHL), a subtype of Hodgkin lymphoma (HL), is a cancer that originates in the lymphatic system, the network of vessels and nodes that helps the body fight infections. Named after Thomas Hodgkin who first described it in 1832, CHL is characterized by the presence of large, abnormal cells called Hodgkin and Reed-Sternberg (HRS) cells amid a sea of reactive immune cells. While CHL accounts for about 90% of all HL cases, traditionally viewed as a single entity, recent advances suggest greater complexity. In Canada, approximately 1,150 new cases are diagnosed annually, with around 650 in men and 500 in women, according to the Canadian Cancer Society. Survival rates have improved dramatically to over 85% five-year relative survival, thanks to multi-agent chemotherapy like ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) combined with radiation, but relapses and treatment toxicities remain concerns, especially for younger patients.

The disease predominantly affects young adults aged 20-40 and older adults over 55, showing a bimodal distribution. In British Columbia, BC Cancer, the province's leading cancer agency, handles a significant portion of these cases, emphasizing research-driven care. Despite high cure rates, the one-size-fits-all approach overlooks underlying biological variations that could explain differing responses to therapy.

The Groundbreaking BC Cancer Research Initiative

A landmark study led by researchers at BC Cancer, published on January 30, 2026, in Cancer Discovery, challenges the uniform view of CHL. Titled "Multidimensional Characterization of Tumor–Immune Architecture Reveals Clinically Relevant Classic Hodgkin Lymphoma Subtypes," the paper introduces the HLGen classification system, identifying four distinct subtypes: CST, CN913, STB, and CN2P. This work, spearheaded by principal investigator Dr. Christian Steidl—executive director of research at BC Cancer and professor of pathology at the University of British Columbia (UBC)—and lead author Dr. Tomohiro Aoki (formerly a postdoctoral fellow at BC Cancer, now at Princess Margaret Cancer Centre), integrates cutting-edge technologies to map the tumor microenvironment (TME).

The research builds on prior genomic efforts at BC Cancer's Centre for Lymphoid Cancer, where Steidl's lab has pioneered biomarker discovery in lymphomas. Funded by the BC Cancer Foundation, Terry Fox Research Institute, Canadian Cancer Society, Genome Canada, and Genome BC, it analyzed tumors from multiple cohorts, revealing how genetic mutations shape immune interactions.

Advanced Methods Unlocking Subtype Secrets

To dissect CHL's heterogeneity, the team employed multimodal profiling: single-cell sequencing of malignant HRS cells, spatial transcriptomics to map gene expression in tissue context, and imaging mass cytometry for protein-level immune cell phenotyping. This systems-level approach captured the unique TME of CHL, where HRS cells (only 0.1-1% of cells) co-opt surrounding non-malignant cells like T cells, macrophages, and B cells to evade immunity.

Spatial analysis highlighted compartmentalization: HRS cells cluster with FOXP3+ regulatory T cells in immunosuppressive niches. Genetic profiling identified recurrent mutations, such as CSF2RB in the CST subtype, driving oncogenic signaling and TARC (thymus and activation-regulated chemokine) secretion, which recruits suppressive immune cells.

Decoding the Four CHL Subtypes

• CST Subtype: Defined by CSF2RB mutations, leading to TARC overexpression. This creates a suppressive TME with exhausted T cells, correlating with poorer progression-free survival. Functional models confirmed dysregulated JAK-STAT signaling.
• CN913 Subtype: Features NF-κB pathway alterations, with dense macrophage infiltration. Associated with aggressive behavior but potential responsiveness to immune checkpoint inhibitors.
• STB Subtype: Shows stromal-rich architecture, B-cell dominant TME, linked to indolent course and better outcomes.
• CN2P Subtype: Plasma cell-enriched, with TP53 mutations, indicating high-risk features and need for intensified therapy.

These subtypes exhibit distinct mutational landscapes, gene signatures, and spatial immune profiles, validated across international cohorts.

Clinical Relevance and Patient Outcomes

The subtypes predict clinical behavior: CST patients have higher relapse risk post-ABVD, while STB fares better. In a validation cohort of 200+ patients, HLGen subtypes associated with event-free survival differences (p<0.01). Dr. Aoki noted, "By defining biologically meaningful subtypes, we can better understand tumor behavior and immune response, guiding therapy selection." This stratification could refine risk groups beyond IPS (International Prognostic Score), sparing low-risk patients from overtreatment.

In Canada, where HL incidence is stable at 2-3 per 100,000, subtype-aware approaches could reduce long-term toxicities like infertility and secondary cancers, critical for young patients comprising 40% of cases.

Implications for Personalized Medicine in Canada

HLGen paves the way for precision oncology. For CST, targeting CSF2RB-JAK or TARC pathways (e.g., PD-1 inhibitors like nivolumab, approved for relapsed HL) shows promise. Trials could test subtype-specific regimens, integrating brentuximab vedotin for CN913's NF-κB profile. BC Cancer's role exemplifies Canada's strength in lymphoma research, with UBC pathology labs driving genomic innovation.

The study aligns with CIHR's precision medicine push, potentially influencing national guidelines via Canadian Cancer Trials Group. Patients benefit from biomarker-driven trials, reducing trial-and-error.

BC Cancer and UBC's Leadership in Lymphoma Research

BC Cancer, under Steidl's direction since 2018, hosts the Centre for Lymphoid Cancer, sequencing thousands of lymphomas. Steidl, a Germany-trained pathologist, joined UBC in 2008, authoring 200+ papers. Collaborators include UBC's Brad Nelson (Victoria) and Ryan Morin (SFU). This UBC-affiliated work underscores British Columbia's research ecosystem, supported by Genome BC.

As part of Provincial Health Services Authority, BC Cancer integrates research with care, treating 80% of BC's cancer patients. The study received the Karl Musshoff Prize at the 2024 International Symposium on Hodgkin Lymphoma.

Broad Impacts on Canadian Cancer Care

Canada's HL survival exceeds global averages, but subtypes explain 10-20% relapse variability. Integrating HLGen into routine diagnostics (e.g., NanoString panels) could enhance PET-guided therapy. Economically, personalized approaches cut costs by avoiding ineffective treatments, vital amid rising cancer incidence (projected 15% by 2030).

Future Directions and Ongoing Trials

Prospective validation in RATHL-like trials is next, with BC Cancer planning HLGen-based arms. Emerging therapies: bispecific antibodies (e.g., afuceslen) for CN2P, CAR-T for refractory cases. Dr. Steidl envisions, "This work challenges the traditional view of HL as uniform, opening doors to tailored therapies." International collaboration via Lunenburg Lymphoma Phase Group will standardize HLGen.

In Canada, expect subtype profiling in precision oncology hubs like Vancouver Prostate Centre model.

Photo by Jana Ohajdova on Unsplash

Patient Perspectives and Actionable Insights

For patients, seek centres like BC Cancer offering genomic profiling. Advocate for trials via Lymphoma Canada. Lifestyle: maintain fitness pre-chemo to mitigate fatigue. Researchers urge early biopsy for subtype ID, empowering informed decisions.