HAEM5:Classic Hodgkin lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This 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

No characteristic chromosomal rearrangements have been reported for lymphocyte-rich classical Hodgkin's lymphoma.

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.)

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 (PMID: 19380639)
9p	Gain	9p24.1	CD274 (PD-L1), PDCD1LG2 (PD-L2), JAK2	T, P	Yes (PMID:20628145)	9p24.1 amplification drives PD-L1/PD-L2 overexpression, relevant for immune checkpoint inhibitor therapy (PMID: 20628145, 27069084)
17p	Gain	17q21	MAP3K14	P	No	MAP3K14 (NIK) gain activates alternative NF-κB signaling (PMID: 19380639)
6q	Loss	6q23-24	TNFAIP3	P	No	Loss of TNFAIP3 (A20) disrupts NF-κB regulation (PMID: 19380639)

There is no typical findings for lymphocyte-rich classical Hodgkin's lymphoma, the main features are also seen in other classical Hodgkin's lymphoma subtypes.

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	Gain		chr2	Unknown	Unknown	Unknown	It can result in REL (2p16), CD40 (20q13)
9p	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
17q	Gain		chr17	Unknown	Unknown	Unknown	it can result in MAP3K14 (17q21) mutation
19q	Gain		chr19	Unknown	Unknown	Unknown	It can result in RELB (19q13) mutation
20q	Gain		chr20	Unknown	Unknown	Unknown	CD40 is the lesion of 20q13
6q	Loss		chr6	Unknown	Unknown	Unknown
13q	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
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

No characteristic chromosomal patterns have been reported for lymphocyte-rich classical Hodgkin's lymphoma.

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

N/A

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)
• Targeted NGS panels for NF-κB and JAK/STAT pathway mutations (PMID: 33686198)
• 9p24.1 copy number assessment for PD-L1/PD-L2 amplification in refractory disease (PMID: 29394125)

Familial Forms

Familial aggregation and monozygotic twin concordance suggest genetic predisposition (PMID: 26311361, 34208754)

Additional Information

N/A

Links

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References

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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 07/11/2025, https://ccga.io/index.php/HAEM5:Classic_Hodgkin_lymphoma.