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Hodgkin's lymphoma (C81)

Hodgkin lymphoma is a malignant lymphoid neoplasm characterized by the presence of abnormal Reed–Sternberg cells within an inflammatory cellular background. It arises from B lymphocytes, most commonly originating in germinal center B cells, and typically involves the lymphatic system, including lymph nodes, spleen, and other lymphoid tissues. Hodgkin lymphoma is broadly divided into classical Hodgkin lymphoma and the less common nodular lymphocyte-predominant subtype, with classical disease accounting for the majority of cases. The disease often presents with painless lymphadenopathy, particularly in the cervical or mediastinal regions, and may be accompanied by constitutional “B symptoms” such as fever, drenching night sweats, and unintentional weight loss. Pathophysiologically, malignant Reed–Sternberg cells evade immune destruction and secrete cytokines and chemokines that recruit inflammatory cells, creating a tumor microenvironment that both supports tumor survival and contributes to systemic symptoms. Epstein–Barr virus infection is associated with a subset of cases, particularly in immunocompromised individuals. Diagnosis is established through excisional lymph node biopsy demonstrating characteristic Reed–Sternberg cells with appropriate immunophenotypic markers, including CD15 and CD30 positivity in classical Hodgkin lymphoma. Hodgkin lymphoma is considered one of the most curable malignancies, with treatment typically involving combinations of chemotherapy, radiation therapy, targeted therapy, and increasingly immune checkpoint inhibitors such as PD-1 blockade.

Causes

The etiology of Hodgkin lymphoma is multifactorial and involves a combination of genetic susceptibility, immune dysregulation, and environmental or infectious influences. The disease arises from malignant transformation of B lymphocytes, most commonly germinal center B cells that acquire genetic and epigenetic abnormalities allowing uncontrolled survival and proliferation. Infection with Epstein-Barr virus infection is strongly associated with a subset of cases, particularly mixed cellularity and immunocompromised-associated disease, where viral proteins may promote abnormal B-cell activation and resistance to apoptosis. Additional risk factors include immunodeficiency states such as HIV infection, prior organ transplantation, autoimmune disease, family history of lymphoma, and certain inherited genetic predispositions affecting immune regulation. Although the precise initiating events remain incompletely understood, disruption of normal B-cell maturation and immune surveillance ultimately leads to the emergence of Reed–Sternberg cells, which orchestrate the inflammatory tumor microenvironment characteristic of Hodgkin lymphoma.

Pathophysiology

The pathophysiology of Hodgkin lymphoma centers on the malignant transformation of germinal center B lymphocytes into Reed–Sternberg cells, which represent the defining neoplastic cells of the disease. Although these malignant cells constitute only a small proportion of the tumor mass, they profoundly alter the surrounding immune microenvironment through secretion of cytokines, chemokines, and growth factors that recruit inflammatory cells such as lymphocytes, eosinophils, macrophages, and plasma cells. Reed–Sternberg cells commonly exhibit activation of signaling pathways including NF-κB, JAK/STAT, and PD-1/PD-L1 immune checkpoint pathways, promoting cellular survival, proliferation, immune evasion, and resistance to apoptosis. In some cases, latent Epstein-Barr virus infection contributes to oncogenic signaling and impaired immune control. The resulting inflammatory milieu produces many of the systemic symptoms of the disease, including fever, night sweats, pruritus, and weight loss. Progressive lymph node enlargement and spread through contiguous lymphatic pathways may eventually involve extranodal organs such as the spleen, liver, bone marrow, and lungs.

Clinical features

The clinical features of Hodgkin lymphoma most commonly include painless lymphadenopathy, particularly involving the cervical, supraclavicular, or mediastinal lymph nodes. Enlarged nodes are typically firm, rubbery, and persistently enlarged over time. Many patients develop constitutional “B symptoms,” including unexplained fever, drenching night sweats, and unintentional weight loss, which may reflect cytokine release from the tumor microenvironment and are associated with more advanced disease. Additional symptoms can include fatigue, pruritus, anorexia, and alcohol-induced pain in affected lymph nodes, a relatively uncommon but classic feature. Mediastinal involvement may produce cough, chest discomfort, or dyspnea due to compression of thoracic structures. As the disease progresses, extranodal involvement of the spleen, liver, bone marrow, or lungs may occur, leading to hepatosplenomegaly, cytopenias, or systemic illness. Because early symptoms may be nonspecific, diagnosis often depends on persistent lymph node enlargement prompting further evaluation and biopsy.

Diagnosis

The diagnosis of Hodgkin lymphoma is established through histopathologic examination of involved lymphoid tissue, most commonly obtained by excisional lymph node biopsy. The hallmark finding is the presence of Reed–Sternberg cells within an inflammatory cellular background composed of lymphocytes, eosinophils, plasma cells, and macrophages. In classical Hodgkin lymphoma, Reed–Sternberg cells typically express CD30 and CD15 surface markers while showing weak or absent expression of typical B-cell markers. Imaging studies such as PET/CT and contrast-enhanced CT scanning are used to determine the extent of nodal and extranodal involvement and to stage the disease according to the Ann Arbor classification system. Laboratory evaluation may reveal anemia, elevated erythrocyte sedimentation rate, leukocytosis, eosinophilia, or abnormalities associated with systemic inflammation. Bone marrow biopsy may be performed in selected cases with suspected marrow involvement. Accurate staging and risk stratification are essential because treatment selection and prognosis depend heavily on disease extent and the presence of constitutional “B symptoms.”

Mechanism of action videos

Biological pathways

  • Transport of connexons to the plasma membrane
  • Translocation of SLC2A4 (GLUT4) to the plasma membrane
  • The role of GTSE1 in G2/M progression after G2 checkpoint
  • Selective autophagy
  • Sealing of the nuclear envelope (NE) by ESCRT-III
  • Recycling pathway of L1
  • Recruitment of NuMA to mitotic centrosomes
  • RHO GTPases activate IQGAPs
  • Protein folding
  • Prefoldin mediated transfer of substrate to CCT/TriC
  • Post-chaperonin tubulin folding pathway
  • Post NMDA receptor activation events
  • PKR-mediated signaling
  • Nuclear Envelope (NE) Reassembly
  • Mitotic G2-G2/M phases
  • Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
  • Kinesins
  • Intraflagellar transport
  • Interferon Signaling
  • HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
  • Gap junction trafficking and regulation
  • Gap junction trafficking
  • Gap junction assembly
  • G2/M Transition
  • Formation of tubulin folding intermediates by CCT/TriC
  • Factors involved in megakaryocyte development and platelet production
  • EML4 and NUDC in mitotic spindle formation
  • Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding
  • Chaperonin-mediated protein folding
  • Cargo trafficking to the periciliary membrane
  • Carboxyterminal post-translational modifications of tubulin
  • COPI-independent Golgi-to-ER retrograde traffic
  • Assembly and cell surface presentation of NMDA receptors
  • Antimicrobial mechanism of IFN-stimulated genes
  • Aggrephagy
  • Activation of AMPK downstream of NMDARs
  • Resolution of Sister Chromatid Cohesion
  • MHC class II antigen presentation
  • COPI-mediated anterograde transport
  • Mitotic Prometaphase

Clinical trials

  • A Phase 1b/2 Proof-of-Concept Study of the Combination of ACP-196 (Acalabrutinib) and Pembrolizumab in Subjects With Hematologic Malignancies
  • Fitness-adapted, Pembrolizumab-based Therapy for Untreated Classical Hodgkin Lymphoma Patients 60 Years of Age and Above (cHL 001)
  • Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA)
  • A Phase I/II Open-Label Multi-Centre Master Protocol to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or in Combination With Other Anticancer Agents in Participants With Mature B-Cell Malignancies
  • Phase 1 Study of Autologous Anti-CD45 CAR T Cells in Combination With CD45 Base Edited HSPCs in Patients With Relapsed or Refractory Hematologic Malignancies
  • Cord Blood Transplantation in Children and Young Adults With Hematologic Malignancies
  • A Randomized Phase 3 Interim Response Adapted Trial Comparing Standard Therapy With Immuno-oncology Therapy for Children and Adults With Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma
  • A Phase 1 Multicenter, Open Label Trial Evaluating the Safety and Efficacy of DuoCAR20.19.22-D95 in Adult Patients With Relapsed or Refractory B-cell Malignancies
  • An Extension Study of Venetoclax for Subjects Who Have Completed a Prior Venetoclax Clinical Trial
  • NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Ensartinib in Patients With Tumors Harboring ALK or ROS1 Genomic Alterations
  • A Phase I Study With an Expansion Cohort/Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients With Relapsed/Refractory Hodgkin Lymphoma
  • A Pilot Phase I Study of Atezolizumab (MPDL3280A) in Combination With Immunogenic Chemotherapy (Gemcitabine-Oxaliplatin) and Rituximab for Transformed Diffuse Large B-Cell Lymphoma
  • A Phase 1 Study of Nivolumab in Combination With ASTX727 in B-cell Lymphoma (NHL or HL) With an Expansion Cohort in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) and Hodgkin Lymphoma (HL)
  • A Two Cohort Randomized Study for Patients With High Risk (Phase II) and Standard Risk (Phase III) Classical Hodgkin Lymphoma in First Relapse
  • A Phase I Study of Ibrutinib (PCI-32765) in Combination With Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma
  • An Exploratory Clinical Study to Evaluate the Safety and Efficacy of GI001 in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (r/r B-NHL)
  • NOVA-BCL6-1, A First-in-Human, Multicenter Phase 1a/1b Study to Investigate Safety, Tolerability, Pharmacokinetics, and Efficacy of LY4584180 in Adult Participants With Previously Treated Hematologic Malignancies
  • Randomized Phase II/III Study of Venetoclax (ABT199) Plus Chemoimmunotherapy for MYC/BCL2 Double-Hit and Double Expressing Lymphomas
  • A Phase I Study to Investigate the Safety of the Ubiquitin Activating Enzyme Inhibitor TAK-243 in Adult Solid Tumor and Lymphoma Patients
  • A Pilot Study of Subcutaneous Mosunetuzumab With or Without Polatuzumab Vedotin and Obinutuzumab for Untreated Indolent B-Cell Non-Hodgkin Lymphoma
  • A Phase II Study of Talimogene Laherparepvec Followed by Talimogene Laherparepvec + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors
  • NORM: Nodular Lymphocyte-Predominant Hodgkin Lymphoma Patients Treated in a Randomized Phase 2 Trial With Either Rituximab or Mosunetuzumab
  • Phase 1/Expansion Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma
  • A Phase 1 Study of Mosunetuzumab With Polatuzumab Vedotin and Lenalidomide (M+Pola+Len) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
  • A Phase 1b Study Evaluating the Safety, Tolerability, and Preliminary Anti-tumor Activity of NT-I7 (Efineptakin Alfa), a Long-acting Human IL-7, Post-Axicabtagene Ciloleucel or Post-Lisocabtagene Maraleucel in Subjects With Relapsed/Refractory Large B-cell Lymphoma
  • NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Erdafitinib in Patients With Tumors Harboring FGFR1/2/3/4 Alterations
  • An Open-label, Multi-Center, Single-arm Prospective Clinical Trial to Evaluate Efficacy, Safety, and Pharmacokinetics of Gamunex®-C Plus Standard Medical Treatment to Prevent Infections in Participants With Secondary Antibody Deficiency Associated With Chronic Lymphocytic Leukemia, Multiple Myeloma, or Non-Hodgkin Lymphoma
  • A Randomized Phase 2 Study of CDX-1127 (Varlilumab) in Combination With Nivolumab in Patients With Relapsed or Refractory Aggressive B-cell Lymphomas
  • Nivolumab for Relapsed or Refractory Disease Post Chimeric Antigen Receptor T-Cell Treatment in Patients With Hematologic Malignancies
  • A Pilot Study of Weekly Brentuximab Vedotin or Brentuximab Vedotin Plus Nivolumab Every 3 Weeks in Patients With CD30+ Malignancies Refractory to Every ≥ 3 Week Brentuximab Vedotin
  • A Pilot Study of Loncastuximab Tesirine in Specific Populations of Relapsed/Refractory B-Cell Malignancies
  • A Phase II Randomized, Placebo-Controlled, Multicenter Trial to Evaluate the Protective Function of a CMV-MVA Triplex Vaccine in Recipients of an Allogeneic Hematopoietic Stem Cell Transplant
  • A Phase 2 Study of Loncastuximab Tesirine Plus Mosunetuzumab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma
  • Pembrolizumab and Involved Site Radiation Therapy for Early Stage Relapsed or Primary Refractory Hodgkin Lymphoma
  • Pralatrexate and Bendamustine With 3 Gy TBI as a New Reduced Intensity Conditioning (RIC) Regimen for Allogeneic HCT for T-Cell Lymphoma Patients Who Are in Untreated R/R, or in Remission With MRD
  • A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies
  • Continuing Treatment for Participants Who Have Participated in a Prior Protocol Investigating CC-122
  • A Phase 2 Study to Evaluate the Efficacy and Safety of MK-1026 in Participants With Hematologic Malignancies
  • A Phase 3, Randomized, Open Label Study Evaluating the Efficacy and Safety of Odronextamab (REGN1979), an Anti-CD20 x Anti-CD3 Bispecific Antibody, Versus Standard of Care Therapy in Participants With Relapsed/Refractory Aggressive B-cell Non-Hodgkin Lymphoma (OLYMPIA-4)
  • A Phase 1b Study of JNJ-80948543 in Combination With Other CD3 T-Cell Engagers (TCEs) in Participants With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoid (R/R B-Cell NHL) Malignancies

Therapeutic area: Oncology

Hodgkin's Lymphoma (C81)