Classic Hodgkin Lymphoma: Biology-Driven Disease Model
- 1Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Italy
- 2Former Senior Scientist at the Department of Advanced Diagnostics, Fondazione IRCCS, Istituto Tumori Milano, 20133 Milano, Italy
Abstract
Background/Objectives: Classic Hodgkin lymphoma (cHL) is a unique lymphoid neoplasm in which rare malignant Hodgkin and Reed–Sternberg (HRS) cells orchestrate an extensive, spatially organized immune and inflammatory microenvironment that determines diagnosis, prognosis, and therapeutic sensitivity. This review summarizes recent advances in the biopathology, diagnosis, and prognostic stratification of classic Hodgkin lymphoma, with particular emphasis on the emerging molecular subtyping framework proposed by Aoki and colleagues, which is not yet clinically validated, and on the proposed concept of classic Hodgkin lymphoma as a systemic immunobiological disease. Methods: In this narrative review, we examined the literature on classic Hodgkin lymphoma biology, the tumor immune microenvironment, diagnostic and prognostic biomarkers, and molecular classification, prioritizing studies published through to mid-2026 and distinguishing established evidence from observational associations, preclinical findings, meeting abstracts, ongoing trials, and hypotheses, including single-cell, spatial, and liquid biopsy technologies, and integrating the authors’ own recent work on immune and inflammatory biomarkers and on the systemic immunobiological features of classic Hodgkin lymphoma. Results: Hodgkin and Reed–Sternberg cells sustain disease through constitutive NF-κB and JAK/STAT signaling, 9p24.1-driven PD-L1/PD-L2 overexpression, and secretion of chemokines and cytokines that recruit and functionally reprogram CD4+ T cells, regulatory T cells, macrophages, and stromal cells. Multidimensional profiling integrating malignant-cell genomics, spatial transcriptomics, and imaging mass cytometry has led to the proposal of four molecular subtypes of classic Hodgkin lymphoma (CST, CN913, STB, and CN2P), each defined by distinct genomic drivers and immune architecture, a hypothesis-generating framework that awaits prospective validation. Classic Hodgkin lymphoma has been proposed to be a systemic immunobiological disorder, with circulating tumor DNA, thymus and activation-regulated chemokine (TARC/CCL17), and peripheral immune signatures associated with disease activity beyond the lymph node; these markers are promising but remain investigational. Diagnosis is evolving from morphology-based assessment toward precision immunopathology integrating spatial and digital pathology, while prognosis is progressively incorporating tissue-based, circulating, spatial, and molecular biomarkers into integrated risk models that are, for the most part, still investigational and are being tested in biomarker-directed clinical trials. Conclusions: The convergence of molecular subtyping, spatial immunobiology, systemic disease biology, and liquid biopsy may reshape the diagnostic and prognostic landscape of classic Hodgkin lymphoma, suggesting a potential transition from anatomically defined, morphology-based assessment toward integrated, biology-driven precision medicine. This transition has unfolded stepwise, from tissue-based immunophenotyping and spatial biomarkers, through circulating markers such as ctDNA and TARC/CCL17, to genomically defined molecular subtypes now being linked to systemic immune readouts and tested in biomarker-directed trials. Prospective validation, assay standardization, and evidence of clinical utility are required before these approaches can enter routine practice.
Related
- Successful treatment with BrECADD in a patient with Dubin-Johnson syndrome and classic Hodgkin lymphoma: a case report.
- Immunohistochemistry for c-MET, HLA class II, and CD68 does not show prognostic value in early-stage classic Hodgkin lymphoma patients in the EORTC-GELA H9 intergroup randomised trial
- Circulating tumor DNA in Hodgkin lymphoma: biological classification, molecular residual disease, and integration with PET response
- On closing the gap: anti-PD-1-based salvage in relapsed/ refractory classical Hodgkin lymphoma. Comment on: “Mind the gap: anti-PD-1 salvage before autologous transplantation in classical Hodgkin lymphoma”
- Spatial associations among Reed sternberg, Hodgkin and immune cells in Hodgkin lymphoma
BibTeX
@article{carbone2026classic,
title = {{Classic Hodgkin Lymphoma: Biology-Driven Disease Model}},
author = {Antonino Carbone and Annunziata Gloghini},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213592},
url = {https://www.mdpi.com/2072-6694/18/21/3592},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Classic Hodgkin Lymphoma: Biology-Driven Disease Model
AU - Antonino Carbone
AU - Annunziata Gloghini
PY - 2026
DA - 2026/11/09
JO - Cancers
DO - 10.3390/cancers18213592
UR - https://www.mdpi.com/2072-6694/18/21/3592
AB - Background/Objectives: Classic Hodgkin lymphoma (cHL) is a unique lymphoid neoplasm in which rare malignant Hodgkin and Reed–Sternberg (HRS) cells orchestrate an extensive, spatially organized immune and inflammatory microenvironment that determines diagnosis, prognosis, and therapeutic sensitivity. This review summarizes recent advances in the biopathology, diagnosis, and prognostic stratification of classic Hodgkin lymphoma, with particular emphasis on the emerging molecular subtyping framework proposed by Aoki and colleagues, which is not yet clinically validated, and on the proposed concept of classic Hodgkin lymphoma as a systemic immunobiological disease. Methods: In this narrative review, we examined the literature on classic Hodgkin lymphoma biology, the tumor immune microenvironment, diagnostic and prognostic biomarkers, and molecular classification, prioritizing studies published through to mid-2026 and distinguishing established evidence from observational associations, preclinical findings, meeting abstracts, ongoing trials, and hypotheses, including single-cell, spatial, and liquid biopsy technologies, and integrating the authors’ own recent work on immune and inflammatory biomarkers and on the systemic immunobiological features of classic Hodgkin lymphoma. Results: Hodgkin and Reed–Sternberg cells sustain disease through constitutive NF-κB and JAK/STAT signaling, 9p24.1-driven PD-L1/PD-L2 overexpression, and secretion of chemokines and cytokines that recruit and functionally reprogram CD4+ T cells, regulatory T cells, macrophages, and stromal cells. Multidimensional profiling integrating malignant-cell genomics, spatial transcriptomics, and imaging mass cytometry has led to the proposal of four molecular subtypes of classic Hodgkin lymphoma (CST, CN913, STB, and CN2P), each defined by distinct genomic drivers and immune architecture, a hypothesis-generating framework that awaits prospective validation. Classic Hodgkin lymphoma has been proposed to be a systemic immunobiological disorder, with circulating tumor DNA, thymus and activation-regulated chemokine (TARC/CCL17), and peripheral immune signatures associated with disease activity beyond the lymph node; these markers are promising but remain investigational. Diagnosis is evolving from morphology-based assessment toward precision immunopathology integrating spatial and digital pathology, while prognosis is progressively incorporating tissue-based, circulating, spatial, and molecular biomarkers into integrated risk models that are, for the most part, still investigational and are being tested in biomarker-directed clinical trials. Conclusions: The convergence of molecular subtyping, spatial immunobiology, systemic disease biology, and liquid biopsy may reshape the diagnostic and prognostic landscape of classic Hodgkin lymphoma, suggesting a potential transition from anatomically defined, morphology-based assessment toward integrated, biology-driven precision medicine. This transition has unfolded stepwise, from tissue-based immunophenotyping and spatial biomarkers, through circulating markers such as ctDNA and TARC/CCL17, to genomically defined molecular subtypes now being linked to systemic immune readouts and tested in biomarker-directed trials. Prospective validation, assay standardization, and evidence of clinical utility are required before these approaches can enter routine practice.
SN - 2072-6694
ER -