{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:28:23Z","timestamp":1792596503985,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Classic Hodgkin lymphoma (cHL) has traditionally been conceptualized as a malignancy confined to lymphoid tissues, with disease extent defined primarily by anatomical staging systems. While this framework has guided clinical management for decades, it incompletely captures the biological complexity of cHL. Emerging evidence from molecular, immunological, and translational studies supports a reinterpretation of cHL as a systemic immunobiological disease rather than a purely nodal malignancy. A defining feature of cHL is the rarity of malignant Hodgkin and Reed\u2013Sternberg (HRS) cells, which orchestrate a highly structured tumor microenvironment through constitutive activation of signaling pathways, including NF-\u03baB and JAK\/STAT, and through expression of immune checkpoint ligands. Beyond local effects, HRS cells secrete cytokines, chemokines, and extracellular vesicles that enter the systemic circulation, promoting widespread immune reprogramming. This includes T-cell exhaustion, expansion of regulatory T cells, and activation of immunosuppressive myeloid populations, which collectively shape host immunity beyond the lymph node. Circulating tumor DNA (ctDNA) and soluble mediators such as thymus and activation-regulated chemokine (TARC\/CCL17) provide measurable evidence of systemic disease activity and enable dynamic monitoring of tumor burden. These biological insights help explain key clinical features of cHL, including constitutional (\u201cB\u201d) symptoms, extranodal involvement, and heterogeneous patterns of treatment response and resistance. Importantly, integration of ctDNA kinetics, peripheral immune profiling, and functional imaging offers a multidimensional framework for disease assessment that overcomes the limitations of conventional staging systems. Therapeutically, the efficacy of immune checkpoint inhibitors underscores the central role of systemic immune dysregulation, while emerging biomarker-driven strategies support adaptive and personalized approaches to treatment. Collectively, these findings support a paradigm shift toward understanding cHL as a systemic immunobiological disease. This framework has important implications for disease monitoring, therapeutic decision-making, and future research, paving the way for biology-driven, precision medicine approaches in cHL.<\/jats:p>","DOI":"10.3390\/cancers18111813","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"1813","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Classic Hodgkin Lymphoma Beyond the Lymph Node: A Systemic Immunobiological Paradigm"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-639X","authenticated-orcid":false,"given":"Antonino","family":"Carbone","sequence":"first","affiliation":[{"name":"Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7226-1942","authenticated-orcid":false,"given":"Annunziata","family":"Gloghini","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnostics, Fondazione IRCCS, Istituto Tumori Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1148\/78.4.553","article-title":"The radical radiotherapy of regionally localized Hodgkin\u2019s disease","volume":"78","author":"Kaplan","year":"1962","journal-title":"Radiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nrc2542","article-title":"The biology of Hodgkin\u2019s lymphoma","volume":"9","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/ajh.26717","article-title":"Hodgkin lymphoma: 2023 update on diagnosis, risk-stratification, and management","volume":"97","author":"Ansell","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification","volume":"32","author":"Cheson","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2017). TNM Classification of Malignant Tumours, John Wiley & Sons. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41572-020-0189-6","article-title":"Hodgkin lymphoma","volume":"6","author":"Connors","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/path.2711","article-title":"The classical Hodgkin\u2019s lymphoma microenvironment and its role in promoting tumour growth and immune escape","volume":"221","author":"Aldinucci","year":"2010","journal-title":"J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1182\/blood-2018-02-833806","article-title":"Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?","volume":"132","author":"Carbone","year":"2018","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1182\/blood.2024027355","article-title":"A comprehensive genetic study of classic Hodgkin lymphoma using circulating tumor DNA","volume":"146","author":"Pirosa","year":"2025","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1182\/blood-2017-11-812073","article-title":"Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma","volume":"131","author":"Spina","year":"2018","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40364-025-00881-0","article-title":"Soluble cytokines enhance risk prediction across all stages of classical Hodgkin lymphoma","volume":"14","author":"Maco","year":"2026","journal-title":"Biomark. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e794","DOI":"10.1097\/HS9.0000000000000794","article-title":"Immune Biomarkers in the Peripheral Blood and Tumor Microenvironment of Classical Hodgkin Lymphoma Patients in Relation to Tumor Burden and Response to Treatment","volume":"6","author":"Mulder","year":"2022","journal-title":"Hemasphere"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101514","DOI":"10.1016\/j.beha.2023.101514","article-title":"Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment","volume":"36","author":"Masel","year":"2023","journal-title":"Best. Pract. Res. Clin. Haematol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cristaldi, V., Terzi di Bergamo, L., Patruno, L., Kallikourdis, M., Cassanmagnago, G.A., Corrado, F., Calabretta, E., Condoluci, A., di Trani, M., and Rahal, D. (2025). The immune cell dynamics in the peripheral blood of cHL patients receiving anti-PD1 treatment. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1518107"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1002\/ajh.27470","article-title":"Hodgkin lymphoma: 2025 update on diagnosis, risk-stratification, and management","volume":"99","author":"Ansell","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/s41375-021-01204-6","article-title":"Molecular biology of Hodgkin lymphoma","volume":"35","author":"Weniger","year":"2021","journal-title":"Leukemia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1182\/blood-2010-05-282780","article-title":"Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma","volume":"116","author":"Green","year":"2010","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zanelli, M., Fragliasso, V., Parente, P., Bisagni, A., Sanguedolce, F., Zizzo, M., Broggi, G., Ricci, S., Palicelli, A., and Foroni, M. (2024). Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126447"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrc3774","article-title":"The tumour microenvironment in B cell lymphomas","volume":"14","author":"Scott","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"794","DOI":"10.3324\/haematol.2015.132761","article-title":"The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints","volume":"101","author":"Vardhana","year":"2016","journal-title":"Haematologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/j.1365-2796.2008.02032.x","article-title":"Inflammatory cells and immune microenvironment in malignant lymphoma","volume":"264","author":"Enblad","year":"2008","journal-title":"J. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.1182\/bloodadvances.2025015837","article-title":"Serum TARC: A biomarker for early detection or exclusion of relapse in classic Hodgkin lymphoma","volume":"9","author":"Teesink","year":"2025","journal-title":"Blood Adv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zijtregtop, E.A.M., van der Strate, I., Beishuizen, A., Zwaan, C.M., Scheijde-Vermeulen, M.A., Brandsma, A.M., and Meyer-Wentrup, F. (2021). Biology and Clinical Applicability of Plasma Thymus and Activation-Regulated Chemokine (TARC) in Classical Hodgkin Lymphoma. Cancers, 13.","DOI":"10.3390\/cancers13040884"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/s41591-020-1006-1","article-title":"A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma","volume":"26","author":"Cader","year":"2020","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/s41375-021-01421-z","article-title":"Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma","volume":"36","author":"Thelen","year":"2022","journal-title":"Leukemia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2033433","DOI":"10.1080\/2162402X.2022.2033433","article-title":"CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma","volume":"11","author":"Veldman","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1158\/2326-6066.CIR-23-0547","article-title":"T-cell States, Repertoire, and Function in Classical Hodgkin Lymphoma Revealed through Single-Cell Analyses","volume":"12","author":"Chen","year":"2024","journal-title":"Cancer Immunol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1182\/blood-2018-04-843714","article-title":"Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment","volume":"132","author":"Cader","year":"2018","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1111\/bjh.13198","article-title":"Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up-front with a risk-adapted strategy","volume":"168","author":"Romano","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Alibrahim, M.N., Carbone, A., Alsaleh, N., and Gloghini, A. (2025). Immune Checkpoint Molecules in Hodgkin Lymphoma and Other Hematological Malignancies. Cancers, 17.","DOI":"10.3390\/cancers17142292"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lau, H.C., and Kwong, Y.L. (2026). Immune Checkpoint Blockade in Hematological Malignancies: Current Status and Future Directions. Cancers, 18.","DOI":"10.3390\/cancers18030485"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.anndiagpath.2005.07.014","article-title":"Hodgkin lymphoma presenting with exclusive or preponderant pulmonary involvement: A clinicopathologic study of 5 new cases","volume":"10","author":"Rodriguez","year":"2006","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/PAI.0000000000000628","article-title":"PD-L1 Immunohistochemistry Highlights Bone Marrow Involvement by Classic Hodgkin Lymphoma in Staging Biopsies: Implications for Diagnosis and Tumor Microenvironment Alterations","volume":"27","author":"Xing","year":"2019","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1136\/jclinpath-2019-205967","article-title":"Differing reflections of paediatric classical Hodgkin\u2019s lymphoma on local and distant immunological microenvironments: A flow cytometric study","volume":"73","author":"AlQanber","year":"2020","journal-title":"J. Clin. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.hoc.2025.12.001","article-title":"Circulating Tumor DNA Assessment in Classic Hodgkin Lymphoma: Ready for Primetime?","volume":"40","author":"Zamrik","year":"2026","journal-title":"Hematol. Oncol. Clin."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13045-025-01673-7","article-title":"Circulating tumor DNA in lymphoma: Technologies and applications","volume":"18","author":"Fu","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13046-024-03108-6","article-title":"Hodgkin lymphoma and liquid biopsy: A story to be told","volume":"43","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"105679","DOI":"10.1016\/j.humpath.2024.105679","article-title":"Clinical use of circulating tumor DNA analysis in patients with lymphoma","volume":"156","author":"Bisig","year":"2025","journal-title":"Hum. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/jha2.826","article-title":"Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG-PET\/CT","volume":"5","author":"Cereceda","year":"2024","journal-title":"EJHaem"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/s41586-023-06903-x","article-title":"Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling","volume":"625","author":"Alig","year":"2024","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"104503","DOI":"10.1016\/j.critrevonc.2024.104503","article-title":"Minimal residual disease testing for classical Hodgkin lymphoma: A comprehensive review","volume":"204","author":"Arai","year":"2024","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1080\/10428194.2024.2389210","article-title":"Prospects for liquid biopsy approaches in lymphomas","volume":"65","author":"Jamal","year":"2024","journal-title":"Leuk. Lymphoma"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/bjh.19162","article-title":"Baseline circulating tumour DNA and interim PET predict response in relapsed\/refractory classical Hodgkin lymphoma","volume":"204","author":"Calabretta","year":"2024","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Oral, K., and Uysal, A. (2026). The Prognostic Significance of the Systemic Inflammation Response Index (SIRI) and HALP Score in Hodgkin\u2019s Lymphoma. Diagnostics, 16.","DOI":"10.3390\/diagnostics16070980"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Renner, C., and Stenner, F. (2018). Cancer Immunotherapy and the Immune Response in Hodgkin Lymphoma. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00193"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1411087","article-title":"PD-1 blockade with nivolumab in relapsed or refractory Hodgkin\u2019s lymphoma","volume":"372","author":"Ansell","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1056\/NEJMoa1510093","article-title":"Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin\u2019s Lymphoma","volume":"374","author":"Johnson","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_48","first-page":"475","article-title":"The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin\u2019s disease","volume":"91","author":"Gallamini","year":"2006","journal-title":"Haematologica"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S1470-2045(16)30167-X","article-title":"Nivolumab for classical Hodgkin\u2019s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial","volume":"17","author":"Younes","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed\/Refractory Classic Hodgkin Lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1200\/JCO.2017.76.0793","article-title":"Nivolumab for Relapsed\/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial","volume":"36","author":"Armand","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1007\/s00277-025-06328-8","article-title":"Molecular profiling of cell-free DNA from classic Hodgkin lymphoma patients identifies potential prognostic clusters and corresponds with disease dynamics","volume":"104","author":"Veltmaat","year":"2025","journal-title":"Ann. Hematol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"217076","DOI":"10.1016\/j.canlet.2024.217076","article-title":"Metabolic reprogramming in tumor immune microenvironment: Impact on immune cell function and therapeutic implications","volume":"597","author":"Liu","year":"2024","journal-title":"Cancer Lett."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1813\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:40:45Z","timestamp":1780317645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":53,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111813"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111813","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]}}}