Classic Hodgkin lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Lymphocyte-Rich Classic Hodgkin Lymphoma.Other relevent pages include: HAEM4:Nodular Sclerosis Classic Hodgkin Lymphoma
Note: author needs to merge Nodular Sclerosis Classic Hodgkin Lymphoma, Lymphocyte-Rich Classic Hodgkin Lymphoma, Mixed Cellularity Classic Hodgkin Lymphoma, Lymphocyte-Depleted Classic Hodgkin Lymphoma
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
Xiaolin Hu, Ph.D., GeneDx
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | B-cell lymphoid proliferations and lymphomas |
| Family | Hodgkin lymphoma |
| Type | N/A |
| Subtype(s) | Classic Hodgkin lymphoma |
Related Terminology
| Acceptable | N/A |
| Not Recommended | Hodgkin disease |
Gene Rearrangements
No characteristic chromosomal rearrangements have been reported for lymphocyte-rich classical Hodgkin's lymphoma.
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
Recurrent chromosomal imbalances are characteristic of CHL and contribute to its pathogenesis. Frequent gains include 2p (REL), 9p24.1 (JAK2, CD274/PDL1, PDCD1LG2/PDL2), and 17q21 (MAP3K14), while recurrent losses include 6q23–q24 (TNFAIP3). These alterations support activation of NF-κB and JAK/STAT pathways, as well as immune evasion.
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 2p | gain | 2p13 | REL | P | No | REL amplification promotes NF-κB signaling activation that promotes HRS cell survival and proliferation.[1][2][3] |
| 9p | Gain | 9p24.1 | CD274 (PD-L1), PDCD1LG2 (PD-L2), JAK2 | T, P | Yes [4] | 9p24.1 amplification drives PD-L1/PD-L2 overexpression leading to immune suppression. Relevant for immune checkpoint inhibitor therapy [4][5] |
| 17q | Gain | 17q21 | MAP3K14 | P | No | MAP3K14 (NIK) gain activates alternative NF-κB signaling [3] |
| 19q | Gain | 19q13.3 | RELB | P | No | Overexpression of RELB leads to enhanced NF-kB signaling and HRS cell survival. [6] |
| 20q | Gain | 20q13 | CD40 | P | No | Over expression of CD40 activates NF-kB signaling, promotes proliferation and immune evasion.[7][8] |
| 6q | Loss | 6q23-24 | TNFAIP3 | P | No | Loss of TNFAIP3 (A20), a negative regulator of NF‑κB, enhance NF-kB signling [9] |
| 13q | Loss | 13q14 | RB1 | P | No | loss of tumor suppressors and contribute to HRS cell survival |
The table below seems duplicated, can be deleted?
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| 2p [10][11] | Gain | chr2 | Unknown | Unknown | Unknown | It can result in REL (2p16), CD40 (20q13) [10] | |
| 9p [10][11] | Gain | chr9 | Unknown | Unknown | Unknown | It can result in JAK2, CD274 (PDL1) and PDCD1LG2 (PDL2) mutations. The amplification of 9p24.1 is critical to CD274/PDCD1LG2 gain of function[10] | |
| 17q [10][11] | Gain | chr17 | Unknown | Unknown | Unknown | it can result in MAP3K14 (17q21) mutation[10] | |
| 19q [10][11] | Gain | chr19 | Unknown | Unknown | Unknown | It can result in RELB (19q13) mutation[10] | |
| 20q [10][11] | Gain | chr20 | Unknown | Unknown | Unknown | CD40 is the lesion of 20q13[10] | |
| 6q [10][11] | Loss | chr6 | Unknown | Unknown | Unknown | ||
| 13q [10][11] | Loss | chr13 | Unknown | Unknown | Unknown |
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| Aneuploidy | Chromosomal instability | Common | P | No | Common in HRS cells; associated with genomic instability and disease progression (PMID: 7632954) |
| Hypertetraploidy | Chromosomal duplication leading to genome-wide imbalance | Recurrent (5–20%) | P | No | Frequently observed in CHL; reflects chromosomal instability (PMID: 7632954) |
| Recurrent chromosomal imbalances (e.g., 2p, 9p, 17q gains; 6q loss) | Deregulated NF-κB and JAK/STAT signaling; immune evasion | Common (>20%) | P,T | Yes (PMID: 19380639, 20628145) | Involves REL, JAK2, PD-L1, PD-L2, TNFAIP3; contributes to pathogenesis and guides immunotherapy potential |
The below table can be deleted?
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| Aneuploidy, hypertetraploidy | No | unkonwn | unknown | Common in HRS cells; contributes to genomic instability (PMID: 7632954) |
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| TNFAIP3 | Inactivating mutation | Tumor Suppressor Gene | Recurrent (5-20%) | P | No | Loss of function mutations disrupt NF-κB regulation (PMID: 19380639) |
| SOCS1 | Frameshift and nonsense mutations | Tumor Suppressor Gene | Recurrent (5-20%) | P | No | SOCS1 mutations activate JAK/STAT signaling (PMID: 24531327) |
| STAT6 | Missense mutations | Oncogene | Recurrent (5-20%) | P | No | STAT6 mutations drive cytokine signaling alterations (PMID: 24531327, 29650799) |
| B2M | Inactivating mutations | Tumor Suppressor Gene | Rare (<5%) | P | No | Loss of MHC class I expression aids immune evasion (PMID: 21368758) |
| CIITA | Inactivating mutations | Tumor Suppressor Gene | Rare (<5%) | P | No | Loss of MHC class II expression aids immune evasion (PMID: 21368758) |
| XPO1 | Missense mutations | Oncogene | Rare (<5%) | Unknown | No | Emerging evidence of role in CHL pathogenesis (PMID: 33686198) |
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
No characteristic gene mutations have been reported for lymphocyte-rich classical Hodgkin's lymphoma.
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Global downregulation of B-cell transcription factors (OCT2, BOB1, PU.1) and epigenetic silencing of B-cell program genes (PMID: 19465900, 14694522)
Genes and Main Pathways Involved
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| REL, TNFAIP3, NFKBIA, MAP3K14 | NF-κB signaling | Constitutive activation of classical and alternative NF-κB pathways promotes HRS cell survival (PMID: 19380639, 33686198) |
| JAK2, STAT6, SOCS1 | JAK/STAT signaling | Dysregulation leads to proliferation and survival of HRS cells (PMID: 24531327, 29650799) |
| CD274 (PD-L1), PDCD1LG2 (PD-L2), B2M | Immune evasion | Upregulation of PD-L1/PD-L2 and loss of MHC I/II expression enables immune escape (PMID: 20628145, 21368758) |
| EBV LMP1, LMP2A | Viral oncogenesis | LMP1 mimics CD40 signaling, LMP2A mimics BCR signaling to promote HRS cell survival in EBV+ CHL (PMID: 9501091, 17682125) |
Genetic Diagnostic Testing Methods
- Immunohistochemistry for CD30, CD15, PAX5, and EBV (EBER in situ hybridization) (PMID: 2477085, 6946981)
- 9p24.1 copy number assessment (FISH or NGS) may be used in refractory/relapsed cases to evaluate PD-L1/PD-L2 amplification for potential immunotherapy (PMID: 29394125).
- TR clonality assays can help exclude T-cell lymphomas in challenging differential diagnoses (PMID: 24128129).
- Targeted NGS panels for NF-κB and JAK/STAT pathway mutations (PMID: 33686198)
Familial Forms
Familial aggregation and monozygotic twin concordance suggest genetic predisposition (PMID: 26311361, 34208754)
Additional Information
N/A
Links
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References
- ↑ Joos, Stefan; et al. (2002-02-15). "Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2". Blood. 99 (4): 1381–1387. doi:10.1182/blood.v99.4.1381. ISSN 0006-4971. PMID 11830490.
- ↑ Martín-Subero, José I.; et al. (2002-02-15). "Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma". Blood. 99 (4): 1474–1477. doi:10.1182/blood.v99.4.1474. ISSN 0006-4971. PMID 11830502.
- ↑ 3.0 3.1 Steidl, Christian; et al. (2010-07-22). "Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome". Blood. 116 (3): 418–427. doi:10.1182/blood-2009-12-257345. ISSN 1528-0020. PMID 20339089.
- ↑ 4.0 4.1 Green, Michael R.; et al. (2010-10-28). "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". Blood. 116 (17): 3268–3277. doi:10.1182/blood-2010-05-282780. ISSN 1528-0020. PMC 2995356. PMID 20628145.
- ↑ Roemer, Margaretha G. M.; et al. (2016-08-10). "PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 34 (23): 2690–2697. doi:10.1200/JCO.2016.66.4482. ISSN 1527-7755. PMC 5019753. PMID 27069084.
- ↑ Slovak, Marilyn L.; et al. (2011-05-15). "Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal distinct copy number alterations in chemosensitive versus refractory Hodgkin lymphoma". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 17 (10): 3443–3454. doi:10.1158/1078-0432.CCR-10-1071. ISSN 1557-3265. PMC 3096736. PMID 21385932.
- ↑ Alibrahim, Mohamed N.; et al. (2024-12-05). "Pathobiological Features and Therapeutic Opportunities Linked to TNF Family Member Expression in Classic Hodgkin Lymphoma". Cancers. 16 (23): 4070. doi:10.3390/cancers16234070. ISSN 2072-6694. PMC 11640334 Check
|pmc=value (help). PMID 39682256 Check|pmid=value (help). - ↑ De Re, Valli; et al. (2019-10-02). "Classical Hodgkin's Lymphoma in the Era of Immune Checkpoint Inhibition". Journal of Clinical Medicine. 8 (10): 1596. doi:10.3390/jcm8101596. ISSN 2077-0383. PMC 6832444. PMID 31581738.
- ↑ Schmitz, Roland; et al. (2009-05-11). "TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma". The Journal of Experimental Medicine. 206 (5): 981–989. doi:10.1084/jem.20090528. ISSN 1540-9538. PMC 2715030. PMID 19380639.
- ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 Wang, Hao-Wei; et al. (2019-01). "Diagnosis of Hodgkin lymphoma in the modern era". British Journal of Haematology. 184 (1): 45–59. doi:10.1111/bjh.15614. ISSN 1365-2141. PMC 6310079. PMID 30407610. Check date values in:
|date=(help) - ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 Steidl, Christian; et al. (2010-07-22). "Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome". Blood. 116 (3): 418–427. doi:10.1182/blood-2009-12-257345. ISSN 1528-0020. PMID 20339089.
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Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.
*Citation of this Page: “Classic Hodgkin lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/11/2026, https://ccga.io/index.php/HAEM5:Classic_Hodgkin_lymphoma.