Advances in Hodgkin Lymphoma (HL)

Dear Colleagues,

Despite the high overall cure rates, approximately 15–20% of patients with classic Hodgkin lymphoma (cHL) either relapse or fail to respond to frontline therapy. Diagnostic uncertainty remains a major challenge due to the absence of disease-specific biomarkers and the significant morphologic and immunophenotypic overlap with other lymphomas and reactive conditions. The tumor microenvironment (TME), which constitutes the bulk of the tumor mass, exhibits profound heterogeneity shaped by cell composition, age, EBV status, and spatial immune architecture, all of which influence prognosis and therapeutic response but are not yet integrated into clinical practice. Treatment resistance to brentuximab vedotin and PD-1 inhibitors arises from a combination of tumor-intrinsic mechanisms and a highly immunosuppressive TME, yet no predictive biomarkers are in routine use. This Special Issue 1) critically examines unresolved issues across cHL diagnosis and treatment; 2) discusses the variability in disease extent and presentation, as well as diagnostically ambiguous grey-zone cases that blur classification boundaries; and 3) highlights emerging opportunities, including the development of molecular diagnostics, TME-targeted therapies, and integrative technologies such as spatial transcriptomics and ctDNA profiling, which may enable personalized treatment and improved risk stratification in relapsed and refractory cHL.

Table of contents for this Special Issue:

• Hodgkin Lymphoma: Classification, WHO Fifth Ed. and ICC Proposals
• Tumour Morphology of Classic Hodgkin Lymphoma
• HRS Cell Phenotype, Genotype, and Cell of Origin
• Functional Observations on Tumour Tissue and Classic Hodgkin Lymphoma Tumour Cell Lines.
• The Classic Hodgkin Lymphoma Tumour Microenvironment: Its Role in Promoting Tumour Growth and Immune Escape
• How Immunologic and Genetic Biomarkers Impact Classic Hodgkin Lymphoma Diagnosis
• The Role of Cd40/Cd40l and Interferon Regulatory Factor 4 in Classic Hodgkin Lymphoma Microenvironment
• Epstein–Barr Virus-Associated Classic Hodgkin Lymphoma
• Classic Hodgkin Lymphoma in Patients Living with HIV Infection
• Primary Refractory and Early Relapsed Classic Hodgkin Lymphoma
• Strategies for Therapeutic Targeting Based on the Tumour Microenvironment

In summary, this Special Issue will focus on current evidence, unresolved questions, biomarker-driven diagnosis, and rational immunotherapy integration by addressing the following topics:

1. Diagnostic ambiguity: Lack of a pathognomonic marker of cHL; morphological overlap with grey-zone lymphomas and EBV-driven proliferations.
2. Resistance mechanisms: Predictors of failure for standard ABVD, brentuximab vedotin, and PD-1 blockade remain undefined; lack of biomarkers to guide clinical decisions.
3. Microenvironmental complexity: Spatial and single-cell studies reveal prognostic immune niches (e.g., CXCR5⁺ HRS–CXCL13⁺ macrophage axis), yet these insights have not been translated into routine risk stratification or therapy.
4. Translational opportunities: Circulating tumour DNA, refined imaging, and next-generation patient-derived models promise improved monitoring and drug testing but require validation.

Prof. Dr. Antonino Carbone
Guest Editor

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• classic Hodgkin lymphoma
• diagnostic challenges
• tumour microenvironment
• variability in disease extent
• TME-targeted therapies
• personalized treatment
• relapsed/refractory cHL