New Molecular Insights Support Diagnosis of Hodgkin Lymphoma

Hodgkin lymphoma is the most common cancer in adolescents aged 15–19 and also affects adults over 55, typically presenting with enlarged lymph nodes. However, distinguishing it from related B-cell lymphomas can be challenging when tumor morphology overlaps and malignant cells are sparse, highlighting the need for clearer molecular criteria to support pathology workflows and test selection.

New findings now show that tumor cells in Hodgkin lymphoma exist in a blocked developmental state with distinctive immune-evasion features, pointing to potential diagnostic markers.

Weill Cornell Medicine (New York, NY, USA) researchers analyzed Hodgkin and Reed‑Sternberg cells using transcriptome sequencing to define their developmental state and immune‑escape mechanisms. The team concluded that these malignant cells represent B cells aborted on the path to plasma‑cell differentiation because they cannot produce immunoglobulins. The analysis reframes Hodgkin lymphoma as a cancer of failed cellular maturation rather than solely unchecked proliferation.

Investigators profiled gene expression from 18 primary tumors and four cell lines, comparing Hodgkin lymphoma with primary mediastinal B‑cell lymphoma (PMBL). The Hodgkin lymphoma transcriptome more closely resembled multiple myeloma, a plasma‑cell malignancy, than other lymphomas. Genes in the unfolded protein response (UPR) pathway were unusually active, consistent with cellular stress in cells unable to secrete antibodies.

The study also delineated immune‑evasion strategies relevant to laboratory assessment. Hodgkin lymphoma cells downregulated SLAM‑family ligands, including CD48, undermining natural killer (NK) cell recognition; tumors also contained fewer NK cells and exhibited mechanisms to evade T cells. The findings nominate proteins linked to the UPR as differentiating markers; for example, PDIA6 was specifically upregulated in Hodgkin lymphoma and could help distinguish it from conditions with similar presentations.

The work was published April 22 in Blood Cancer Journal. Collaborating institutions referenced in the study include Memorial Sloan Kettering Cancer Center and New York University, alongside Weill Cornell Medicine. The authors indicate that these molecular features could support development of improved diagnostic criteria.

"Hodgkin lymphoma cells were assumed to originate from B cells that are in the process of developing the ability to produce immunoglobulins in the germinal center," said Dr. Ethel Cesarman, professor of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell, who co-led this research.

"In this study, we now see that they were on the pathway to differentiating into plasma cells and that process has been aborted because they cannot produce immunoglobulins, as normal plasma cells do," said Dr. Cesarman.

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