Objective:

To identify molecular features of Hodgkin and Reed–Sternberg (HRS) cells that may support diagnosis, improve understanding of classic Hodgkin lymphoma (cHL) biology, and inform treatment strategies.

Key Findings:

• HRS cells exhibit significant reprogramming and loss of typical B-cell features.
• Activation of the unfolded protein response (UPR) was observed in HRS cells, not in other related lymphomas.
• Strong expression of PDIA6 in HRS cells suggests its potential as a diagnostic marker.
• HRS cells show reduced expression of NK cell recognition molecules, including CD48, indicating immune evasion.
• Distinct differences in pathways between HRS cells and primary mediastinal B-cell lymphoma were identified.

Interpretation:

The findings suggest that HRS cells have unique molecular characteristics that could aid in diagnosis and understanding of cHL, particularly regarding immune evasion and cellular stress responses, with implications for future research.

Limitations:

• The study focused on a limited number of patient samples (18), which may affect generalizability.
• Viral involvement was only assessed for Epstein–Barr virus, limiting the scope of viral pathogen analysis.
• The need for larger sample sizes in future studies is essential to validate findings.

Conclusion:

Targeted sequencing of HRS cells can reveal diagnostic markers and clarify disease mechanisms, potentially leading to improved diagnostic tools for cHL and informing clinical applications.