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Advances in Hodgkin Lymphoma (HL)
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Advances in Hodgkin Lymphoma (HL)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: 15 July 2026 | Viewed by 9508

Special Issue Editor

Prof. Dr. Antonino Carbone

E-Mail Website
Guest Editor
Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, 33081 Aviano, Italy
Interests: hematopathology; Hodgkin lymphoma; non-Hodgkin lymphoma; HIV-associated lymphoma; virus-associated lymphoma; post-transplant lymphoma; pathology; immunohistochemistry; tumour microenvironment; telepathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

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Published Papers (4 papers)

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Research

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18 pages, 1629 KB  
Article
Routine Imaging Surveillance After Frontline ABVD Improves Outcome in High-Risk Hodgkin Lymphoma
by Novella Pugliese, Marco Picardi, Annamaria Vincenzi, Claudia Giordano, Anna Lucania, Alessandro Severino, Claudia Salvatore, Massimo Mascolo, Paola Della Cioppa and Fabrizio Pane
Cancers 2025, 17(19), 3242; https://doi.org/10.3390/cancers17193242 - 6 Oct 2025
Cited by 1 | Viewed by 902
Abstract
Background/Objectives: Despite the high complete response (CR) rate to first-line therapy, approximately one-third of patients with advanced-stage Hodgkin lymphoma (HL) eventually relapse. In up to 30–50% of cases, relapses are subclinical, i.e., initially detected only by imaging procedures. However, there is no [...] Read more.
Background/Objectives: Despite the high complete response (CR) rate to first-line therapy, approximately one-third of patients with advanced-stage Hodgkin lymphoma (HL) eventually relapse. In up to 30–50% of cases, relapses are subclinical, i.e., initially detected only by imaging procedures. However, there is no definitive consensus on the optimal surveillance strategy for high-risk HL patients. Methods: The purpose of this cohort study is to evaluate the long-term outcome of stage II-B/IV HL patients who relapsed under routine imaging surveillance (imaging cohort) compared to those who relapsed under conventional clinical monitoring (standard cohort). Follow-up in the imaging cohort systematically included FDG-PET/CT, ultrasonography, and/or chest X-ray. At relapse, patients were treated with the same approach (salvage therapy and autologous hematopoietic stem cell transplantation [AHSCT]) in both cohorts. Results: A total of 123 high-risk HL patients were assessed at their first relapse: 80 in the imaging cohort and 43 in the standard cohort. The 2-year event-free survival (EFS) was significantly higher in the imaging cohort compared to the standard cohort (70% vs. 37.2%, respectively; p = 0.001). Similarly, the CR rate following salvage treatment was greater in the imaging cohort as compared to the standard cohort (68.8% vs. 41.9%, respectively; p < 0.004). These differences were due to the capability of routine imaging surveillance to detect disease with more limited extension (early onset of clinically silent relapses) as compared to standard clinical monitoring, which was associated with relapsed disease in a more advanced stage. Conclusions: Our findings suggest that routine imaging surveillance in patients with high-risk HL leads to improved EFS detecting relapses, which were characterized by more favorable prognostic factors (low tumor burden), thus enabling the timely administration of salvage therapy. Full article
(This article belongs to the Special Issue Advances in Hodgkin Lymphoma (HL))
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Review

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14 pages, 704 KB  
Review
Systemic Therapy for Advanced-Stage Hodgkin Lymphoma
by Varun Iyengar, Kishan Patel and Alison Moskowitz
Cancers 2026, 18(12), 1919; https://doi.org/10.3390/cancers18121919 - 12 Jun 2026
Abstract
Advanced-stage classic Hodgkin lymphoma (cHL) represents one of the major success stories in modern oncology, with long-term survival now exceeding 80% for most patients. In this review, we examine the evolution of frontline therapy for advanced-stage cHL, tracing the transition from empiric combination [...] Read more.
Advanced-stage classic Hodgkin lymphoma (cHL) represents one of the major success stories in modern oncology, with long-term survival now exceeding 80% for most patients. In this review, we examine the evolution of frontline therapy for advanced-stage cHL, tracing the transition from empiric combination chemotherapy to contemporary, biologically informed treatment strategies. We begin by revisiting the early development of multiagent chemotherapy regimens, including MOPP and ABVD. These regimens established, for the first time, that advanced lymphoma could be cured with systemic therapy. We then discuss efforts to improve outcomes through treatment intensification, which culminated in the development of BEACOPP-based approaches that improved disease control at the cost of substantial acute and long-term toxicity. Subsequently, the incorporation of functional imaging ushered in the era of PET-adapted therapy, enabling dynamic treatment modification based on early response and providing a framework to better balance efficacy with toxicity reduction. Finally, we review the integration of novel agents, including brentuximab vedotin and PD-1 blockade, which have reshaped the frontline treatment landscape and further improved outcomes for high-risk patients while challenging historical chemotherapy paradigms. Collectively, the treatment history of advanced-stage cHL reflects a broader evolution in oncology: from maximizing cytotoxic intensity toward increasingly personalized strategies designed to optimize cure while minimizing long-term harm. Ongoing efforts focused on biomarker-driven risk stratification and the utilization of circulating tumor DNA are poised to further refine this balance in the coming decade. Full article
(This article belongs to the Special Issue Advances in Hodgkin Lymphoma (HL))
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18 pages, 1288 KB  
Review
Hodgkin Reed-Sternberg Cells of Classic Hodgkin Lymphoma: Morphology, Phenotype, Genotype, and Cell of Origin
by Annunziata Gloghini, Daniele Lorenzini, Chiara Costanza Volpi, Desirè Viola Trupia and Giancarlo Pruneri
Cancers 2026, 18(9), 1446; https://doi.org/10.3390/cancers18091446 - 30 Apr 2026
Viewed by 795
Abstract
Classic Hodgkin lymphoma (cHL) is a distinctive B-cell malignancy defined by the presence of scarce but pathobiologically dominant Hodgkin Reed-Sternberg (HRS) cells within an inflammatory tumor microenvironment (TME). Although representing less than 10% of total tumor cellularity, HRS cells shape the TME by [...] Read more.
Classic Hodgkin lymphoma (cHL) is a distinctive B-cell malignancy defined by the presence of scarce but pathobiologically dominant Hodgkin Reed-Sternberg (HRS) cells within an inflammatory tumor microenvironment (TME). Although representing less than 10% of total tumor cellularity, HRS cells shape the TME by recruiting and functionally polarizing immune and stromal elements through cytokine- and chemokine-mediated signaling. Morphologically, HRS cells are large, atypical, often binucleated or multinucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm, giving rise to the classic “owl’s eye” appearance. Distinct morphological variants—including lacunar, mummified, mononuclear, and anaplastic forms—contribute to the histopathologic diversity across cHL subtypes such as nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted disease. The immunophenotype of HRS cells is equally characteristic, with strong and uniform CD30 expression, frequent CD15 positivity, reduced expression of B-cell markers (CD20, CD79A/B), and partial retention of PAX5, reflecting profound lineage dysregulation. Aberrant expression of activation markers and immune-evasion molecules, including PD-L1 driven by recurrent 9p24.1 amplification, underscores their capacity for immune escape. Genetically, HRS cells display alterations affecting NF-κB, JAK/STAT, and PI3K/AKT pathways, facilitated by somatic mutations, chromosomal gains, and epigenetic remodeling that silence B-cell-defining genes. Despite reprogramming, clonality and somatic hypermutation patterns confirm their origin from germinal center B-cells, even in EBV-associated cases. Collectively, the morphology, phenotype, and genotype of HRS cells reveal a complex pathogenic network in which intrinsic oncogenic pathways and extrinsic TME interactions co-operate to sustain malignant transformation. Understanding these integrated mechanisms provides a biological foundation for current therapeutic strategies. Full article
(This article belongs to the Special Issue Advances in Hodgkin Lymphoma (HL))
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18 pages, 2312 KB  
Review
Hodgkin Lymphoma Classification—From Historical Concepts to Current Refinements
by Antonino Carbone and Mohamed N. Alibrahim
Cancers 2025, 17(17), 2929; https://doi.org/10.3390/cancers17172929 - 7 Sep 2025
Cited by 4 | Viewed by 7006
Abstract
The current classification of Hodgkin lymphoma (HL) is the result of an integrated approach that combines the evaluation of morphological patterns, immunophenotypic characteristics, molecular features, and clinical presentation. Evolving from its origins based solely on histological observation to the latest updates in the [...] Read more.
The current classification of Hodgkin lymphoma (HL) is the result of an integrated approach that combines the evaluation of morphological patterns, immunophenotypic characteristics, molecular features, and clinical presentation. Evolving from its origins based solely on histological observation to the latest updates in the WHO 5th Edition, this system has become an essential tool for accurate diagnosis and personalized therapeutic strategies. Each subtype of classic HL (cHL)—nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted—exhibits distinctive pathological and clinical features, now better understood through multidisciplinary studies and international collaborations. HL also includes nodular lymphocyte-predominant HL (NLPHL), a distinct entity with unique morphologic, immunophenotypic, and clinical features. A hallmark morphological feature of cHL is the presence of Hodgkin and Reed-Sternberg (HRS) cells, large and often multinucleated cells derived from B lymphocytes that have lost their typical B-cell phenotype. Identifying these cells is critical for diagnosis and for differentiating HL from other hematologic malignancies. HL is characterized by the rarity of malignant cells, a high curability rate, and a rich immune cell microenvironment that is both shaped and exploited by the tumor. Understanding these core aspects paves the way for exploring the role of immunologic and genetic biomarkers in refining classification, enhancing diagnosis, improving prognostic assessment, and guiding therapy for patients with cHL. Full article
(This article belongs to the Special Issue Advances in Hodgkin Lymphoma (HL))
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