Classic Hodgkin Lymphoma

Cancer MONDO:0009348 Pathograph 24 Show in embeddings browser Lymphoma

Classic Hodgkin lymphoma is a B-cell lymphoma characterized histologically by the presence of Hodgkin cells and multinucleated Reed-Sternberg cells.

Ask OpenScientist

Ask a research question about Classic Hodgkin Lymphoma. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Definitions
8
Pathophys.
1
Histopath.
4
Phenotypes
24
Pathograph
11
Genes
5
Medical Actions
2
Differentials
1
Datasets
2
Trials
1
Deep Research
📘

Definitions

1
Pathologic definition of classic Hodgkin lymphoma
Classic Hodgkin lymphoma is defined by neoplastic Hodgkin/Reed-Sternberg cells in a dense inflammatory background and is now understood to arise from germinal center B cells despite loss of many canonical B-cell markers.
CASE_DEFINITION General pathologic and molecular definition of classic Hodgkin lymphoma
Show evidence (1 reference)
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers."
This review provides a concise disease definition centered on the hallmark HRS cell and its germinal center B-cell derivation.
⚙

Pathophysiology

8
Germinal Center B-Cell Origin of HRS Cells
The malignant Hodgkin/Reed-Sternberg cell is derived from germinal center B cells but loses many typical B-cell features during transformation.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
Downstream
Cytokine and Chemokine-Mediated Microenvironment Remodeling Transformed HRS cells remodel a supportive inflammatory niche.
Show evidence (1 reference)
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers."
This directly supports the germinal center B-cell origin of the malignant HRS cell.
Mutation-Driven JAK/STAT Activation
Recurrent mutations in classic Hodgkin lymphoma activate JAK/STAT signaling programs that support tumor-cell survival and cytokine-responsive growth.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
JAK2 hgnc:6192 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee. STAT6 hgnc:11368 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT6 (hgnc:11368). hgnc:11368 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: SOMATIC
cell surface receptor signaling pathway via JAK-STAT GO:0007259 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology.
Downstream
Cytokine and Chemokine-Mediated Microenvironment Remodeling JAK/STAT signaling supports inflammatory niche formation.
Show evidence (1 reference)
PMID:29340061 SUPPORT Human Clinical
"However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others."
This genomic study directly supports recurrent genetic lesions affecting JAK/STAT signaling in classic Hodgkin lymphoma.
Mutation-Driven NF-kappaB Activation
Recurrent lesions affecting negative regulators and upstream activators of NF-kappaB signaling drive constitutive survival signaling in Hodgkin/Reed-Sternberg cells. The lesions are of two opposite kinds and both are bound here: destructive mutations in the negative regulators TNFAIP3 and NFKBIA, and copy-number gains of the positive regulators REL and MAP3K14.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
TNFAIP3 hgnc:11896 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNFAIP3 (hgnc:11896). hgnc:11896 is a gene from the HUGO Gene Nomenclature Committee. NFKBIA hgnc:7797 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NFKBIA (hgnc:7797). hgnc:7797 is a gene from the HUGO Gene Nomenclature Committee. REL hgnc:9954 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves REL (hgnc:9954). hgnc:9954 is a gene from the HUGO Gene Nomenclature Committee. MAP3K14 hgnc:6853 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MAP3K14 (hgnc:6853). hgnc:6853 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: SOMATIC
canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology.
Downstream
Cytokine and Chemokine-Mediated Microenvironment Remodeling NF-kappaB signaling sustains the inflammatory tumor niche.
PD-1 Ligand-Mediated Immune Evasion Constitutive NF-kappaB signaling cooperates with checkpoint-ligand upregulation to promote immune escape.
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3,..."
This review directly supports recurrent somatic lesions in NF-kappaB pathway regulators, including TNFAIP3 and NFKBIA, as core mechanisms in Hodgkin lymphoma.
EBV LMP1-Mediated NF-kappaB Activation
In Epstein-Barr virus-positive classic Hodgkin lymphoma, viral latent membrane protein 1 mimics active CD40 signaling and drives NF-kappaB activation in Hodgkin/Reed-Sternberg cells.
canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology.
Downstream
Cytokine and Chemokine-Mediated Microenvironment Remodeling EBV-driven NF-kappaB activation reinforces the inflammatory tumor niche.
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor."
This directly supports EBV LMP1 as a mechanism of NF-kappaB activation in EBV-positive classical Hodgkin lymphoma.
Cytokine and Chemokine-Mediated Microenvironment Remodeling
HRS cells persist within a dense inflammatory infiltrate that they actively recruit and shape through cytokine and chemokine signaling.
chemokine production GO:0032602 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased chemokine production (GO:0032602). GO:0032602 is a biological process from the Gene Ontology.
Downstream
PD-1 Ligand-Mediated Immune Evasion The inflammatory niche is coupled to ineffective anti-tumor immunity.
Lymphadenopathy The HRS-supported inflammatory niche contributes to bulky nodal enlargement.
Fever Cytokine-rich tumor inflammation contributes to B symptoms including fever.
Night Sweats Cytokine-rich tumor inflammation contributes to B symptoms including night sweats.
Weight Loss Cytokine-rich tumor inflammation contributes to systemic B symptoms including weight loss.
Show evidence (1 reference)
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow."
This review directly supports the dependence of classic Hodgkin lymphoma on cytokine and chemokine-mediated microenvironmental remodeling.
PD-1 Ligand-Mediated Immune Evasion
Near-universal 9p24.1 copy gain increases PD-1 ligand expression on HRS cells and contributes to immune escape in classic Hodgkin lymphoma. The two genes in the amplicon that carry the effect are CD274 (PD-L1) and PDCD1LG2 (PD-L2); they are altered concordantly rather than one at a time.
CD274 hgnc:17635 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD274 (hgnc:17635). hgnc:17635 is a gene from the HUGO Gene Nomenclature Committee. PDCD1LG2 hgnc:18731 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDCD1LG2 (hgnc:18731). hgnc:18731 is a gene from the HUGO Gene Nomenclature Committee.
Negative Regulation of T Cell Mediated Immunity GO:0002710 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Negative Regulation of T Cell Mediated Immunity (GO:0002710). GO:0002710 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:31816062 SUPPORT Human Clinical
"HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands."
This study directly links recurrent 9p24.1 gains in HRS cells to elevated PD-1 ligand expression and immune evasion.
PMID:27069084 SUPPORT Human Clinical
"Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci"
Names the two 9p24.1 genes bound on this node and establishes that they are altered concordantly, which is why both are recorded rather than CD274 alone.
Mutation-Driven MHC Class I Loss
One of two genetically separate antigen-presentation arms, split from its class II sibling because the two reach the same immune-evasion endpoint by different immunological routes. Recurrent somatic B2M lesions disrupt beta-2-microglobulin, the invariant light chain every class I molecule needs to reach the cell surface, so HRS cells lose surface MHC class I and with it direct CD8 cytotoxic T-cell recognition. This is not the same mechanism as checkpoint-ligand-mediated inhibition of the T cells that do still recognise the tumour.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
B2M hgnc:914 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves B2M (hgnc:914). hgnc:914 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: SOMATIC
antigen processing and presentation of peptide antigen via MHC class I GO:0002474 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased antigen processing and presentation of peptide antigen via MHC class I (GO:0002474). GO:0002474 is a biological process from the Gene Ontology.
Downstream
PD-1 Ligand-Mediated Immune Evasion Loss of surface class I removes the CD8 cytotoxic recognition arm, so the residual anti-tumour response that the checkpoint axis acts on is the MHC-class-II-dependent one.
Show evidence (3 references)
PMID:29394125 SUPPORT Human Clinical
"Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation."
Establishes perturbed antigen presentation as an immune-evasion mechanism in cHL separate from the 9p24.1 checkpoint-ligand gains.
PMID:29394125 SUPPORT Human Clinical
"PD-1 receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells."
Supports loss of MHC class I expression on HRS cells as a reported feature, and is the source this node's description is graded against - the paper reports deficiencies of class I expression rather than its abolition.
PMID:31816062 SUPPORT Human Clinical
"recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1"
Places B2M among the recurrent somatic alterations of flow-sorted HRS cells.
Mutation-Driven MHC Class II Loss
The class II counterpart. CIITA, the MHC class II transactivator, is recurrently broken or fused in a subset of classic Hodgkin lymphoma, so class II expression is lost and with it CD4 T-cell recognition. This arm is the one that bears on treatment: it is HRS-cell MHC class II expression, not class I, that predicts complete remission on PD-1 blockade, which is why the two arms are curated as separate nodes rather than as one antigen-presentation node.
germinal center B cell CL:0000844 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germinal center B cell (CL:0000844). CL:0000844 is a cell type from the Cell Ontology.
CIITA hgnc:7067 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CIITA (hgnc:7067). hgnc:7067 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: SOMATIC
antigen processing and presentation of peptide antigen via MHC class II GO:0002495 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased antigen processing and presentation of peptide antigen via MHC class II (GO:0002495). GO:0002495 is a biological process from the Gene Ontology.
Downstream
PD-1 Ligand-Mediated Immune Evasion Class II status governs what blocking the PD-1 axis can achieve: HRS-cell MHC class II expression is what predicts complete remission on PD-1 blockade, while class I expression is not.
Show evidence (2 references)
PMID:21368758 SUPPORT Human Clinical
"genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%)"
Supports recurrent CIITA disruption in classic Hodgkin lymphoma as the lesion behind this node.
PMID:21368758 SUPPORT Human Clinical
"CIITA is an essential transactivator of MHC class II expression"
Establishes CIITA's role as the transactivator MHC class II expression depends on, which is what makes its disruption a class II rather than a class I lesion.
✶

Histopathology

1
Hodgkin/Reed-Sternberg Cells in a Dense Inflammatory Background VERY_FREQUENT
Classic Hodgkin lymphoma shows scattered Hodgkin/Reed-Sternberg cells within a dense reactive inflammatory infiltrate rather than sheets of tumor cells.
Show evidence (1 reference)
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow."
This review directly supports the hallmark microscopic pattern of sparse HRS cells embedded in an inflammatory background.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Classic Hodgkin Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Cardiovascular 1
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32433447 SUPPORT Human Clinical
"Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
This directly supports lymphadenopathy as the classic presenting feature of Hodgkin lymphoma.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32433447 SUPPORT Human Clinical
"Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
This abstract explicitly names fever as part of the B-symptom complex.
Constitutional 1
Night Sweats HP:0030166 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night sweats (HP:0030166). HP:0030166 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32433447 SUPPORT Human Clinical
"Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
This presentation-focused abstract explicitly lists night sweats among the classic B symptoms of Hodgkin lymphoma.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32433447 SUPPORT Human Clinical
"Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
This abstract explicitly names weight loss as one of the classic B symptoms.
🧬

Genetic Associations

11
TNFAIP3 (Somatic Loss-of-Function Mutation)
Gene: TNFAIP3 hgnc:11896 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNFAIP3 (hgnc:11896). hgnc:11896 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3,..."
This review directly identifies TNFAIP3 as a recurrently mutated negative regulator of NF-kappaB signaling in Hodgkin lymphoma.
NFKBIA (Somatic Loss-of-Function Mutation)
Gene: NFKBIA hgnc:7797 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NFKBIA (hgnc:7797). hgnc:7797 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3,..."
This review directly identifies NFKBIA as a recurrently mutated negative regulator of NF-kappaB signaling in Hodgkin lymphoma.
B2M (Somatic Mutation)
Gene: B2M hgnc:914 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is B2M (hgnc:914). hgnc:914 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:31816062 SUPPORT Human Clinical
"Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases."
This genomic study identifies recurrent B2M mutations as one of the characteristic immune-evasion-associated lesions in classic Hodgkin lymphoma.
CIITA (Somatic Rearrangement/Fusion)
Gene: CIITA hgnc:7067 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CIITA (hgnc:7067). hgnc:7067 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:21368758 SUPPORT Human Clinical
"In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%)."
This study directly supports recurrent CIITA genomic breaks in a subset of classic Hodgkin lymphoma.
CD274 (9p24.1 copy gain) (Somatic Copy-Number Gain)
Gene: CD274 hgnc:17635 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD274 (hgnc:17635). hgnc:17635 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:31816062 SUPPORT Human Clinical
"HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands."
This directly supports recurrent 9p24.1 copy gain as a defining genetic immune-evasion lesion in classic Hodgkin lymphoma.
PMID:27069084 SUPPORT Human Clinical
"We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL"
Names CD274 as one of the two 9p24.1 genes whose alterations were assayed in cHL biopsies.
PDCD1LG2 (9p24.1 copy gain) (Somatic Copy-Number Gain)
Gene: PDCD1LG2 hgnc:18731 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDCD1LG2 (hgnc:18731). hgnc:18731 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:27069084 SUPPORT Human Clinical
"Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci"
Establishes concordant alteration of the PD-L2 (PDCD1LG2) locus with PD-L1 across the cHL cohort.
JAK2 (Somatic alteration activating JAK/STAT signaling)
Gene: JAK2 hgnc:6192 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:27069084 SUPPORT Human Clinical
"In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling."
Places JAK2-STAT signalling as an amplifier of PD-1 ligand abundance in cHL alongside the copy-number gain.
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"Among the most fre - quent are amplifications of 9p24.1 locus, affecting JAK2, PD-L1 and PD-L2 genes"
Places JAK2 inside the same 9p24.1 amplicon as the two PD-1 ligand genes, which is the claim this record's notes make about the shared locus.
STAT6 (Somatic Mutation)
Gene: STAT6 hgnc:11368 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT6 (hgnc:11368). hgnc:11368 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:31816062 SUPPORT Human Clinical
"recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1"
Lists STAT6 among the recurrent somatic alterations identified in flow-sorted HRS cells.
REL (Somatic Copy-Number Gain)
Gene: REL hgnc:9954 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is REL (hgnc:9954). hgnc:9954 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)"
Identifies REL copy-number gain as a recurrent NF-kappaB-activating lesion in Hodgkin lymphoma.
MAP3K14 (Somatic Copy-Number Gain)
Gene: MAP3K14 hgnc:6853 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MAP3K14 (hgnc:6853). hgnc:6853 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:27221964 SUPPORT REVIEW SYNTHESIS Other
"copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)"
Identifies MAP3K14 copy-number gain as a recurrent NF-kappaB-activating lesion in Hodgkin lymphoma.
KLHDC8B (Germline predisposition in familial classic Hodgkin lymphoma)
Gene: KLHDC8B hgnc:28557 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KLHDC8B (hgnc:28557). hgnc:28557 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (5 references)
PMID:19706467 SUPPORT Human Clinical
"We tested KLHDC8B as a candidate gene for cHL and found that a 5'-UTR polymorphism responsible for decreasing its translational expression is associated with cHL in probands from other families with cHL and segregates with disease in those pedigrees"
The primary human genetic evidence: a KLHDC8B regulatory variant associated with and segregating in multiple classic Hodgkin lymphoma pedigrees.
PMID:19706467 SUPPORT In Vitro
"Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its reduced expression in the formation of cHL's signature RS cell."
Supplies the mechanistic link from reduced KLHDC8B to the binucleate Reed-Sternberg morphology.
PMID:22988245 SUPPORT In Vitro
"We recapitulated the major pathologic features of the Reed-Sternberg cell and concluded that KLHDC8B is essential for mitotic integrity and maintenance of chromosomal stability."
Independent functional replication across three cell types, and the reason the mechanistic story for this predisposition gene is unusually specific for the disease it predisposes to.
+ 2 more references
💊

Medical Actions

5
ABVD-Based Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632 Regimen: ABVD regimenNCI Thesaurus (NCIT) Relation: this regimen component is this clinical intervention This regimen component is ABVD regimen (NCIT:C9509). NCIT:C9509 is a clinical intervention from the NCI Thesaurus. Ontology label: ABVD Regimen NCIT:C9509
Agent: doxorubicin CHEBI:28748 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxorubicin (CHEBI:28748). CHEBI:28748 is a therapeutic agent from Chemical Entities of Biological Interest. bleomycin CHEBI:22907 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses bleomycin (CHEBI:22907). CHEBI:22907 is a therapeutic agent from Chemical Entities of Biological Interest. vinblastine CHEBI:27375 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vinblastine, annotated with vincaleukoblastine (CHEBI:27375). CHEBI:27375 is a therapeutic agent from Chemical Entities of Biological Interest. dacarbazine CHEBI:4305 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dacarbazine (CHEBI:4305). CHEBI:4305 is a therapeutic agent from Chemical Entities of Biological Interest.
Combination chemotherapy with ABVD remains a standard systemic treatment backbone for Hodgkin lymphoma.
Show evidence (2 references)
NCIT:C411 SUPPORT Other
"Dacarbazine | Accepted_Therapeutic_Use_For | - | - | Carcinoid cancer; Hodgkins disease; Islet cell carcinoma; Melanoma; Neuroblastoma; Soft tissue sarcoma"
NCI Thesaurus asserts accepted therapeutic use of dacarbazine for Hodgkin's disease; it is the dacarbazine component of the ABVD regimen.
PMID:31894937 SUPPORT Other
"Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin,..."
This treatment review identifies ABVD-containing combination chemotherapy as a standard treatment approach for Hodgkin lymphoma.
Radiation Therapy
Action: Radiation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Radiation Therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. NCIT:C15313
Platform: Radiotherapy
Radiotherapy is used with chemotherapy in selected Hodgkin lymphoma treatment strategies.
Show evidence (1 reference)
PMID:31894937 SUPPORT Other
"Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin,..."
This review explicitly states that radiotherapy is used in combination treatment regimens for Hodgkin lymphoma.
Brentuximab Vedotin
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: brentuximab vedotin NCIT:C66944 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses brentuximab vedotin (NCIT:C66944). NCIT:C66944 is a therapeutic agent from the NCI Thesaurus.
CD30-directed antibody-drug conjugate therapy has activity in relapsed or refractory classic Hodgkin lymphoma and is commonly combined with chemotherapy.
Show evidence (1 reference)
PMID:39039881 SUPPORT INDIRECT Human Clinical
"Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin's lymphoma in children."
Supports brentuximab vedotin as an active CD30-targeted therapy in relapsed or refractory disease. Marked INDIRECT because the cited series is 10 children, so it does not by itself establish the activity of the drug across the adult classic Hodgkin lymphoma population this entry describes.
Pembrolizumab
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: pembrolizumab NCIT:C106432 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses pembrolizumab (NCIT:C106432). NCIT:C106432 is a therapeutic agent from the NCI Thesaurus.
PD-1 blockade with pembrolizumab is active in relapsed or refractory classic Hodgkin lymphoma.
Mechanism Target:
INHIBITS PD-1 Ligand-Mediated Immune Evasion — Pembrolizumab blocks PD-1 signaling and counteracts PD-1 ligand-mediated suppression of anti-tumor T-cell activity in classic Hodgkin lymphoma.
Show evidence (1 reference)
PMID:28441111 SUPPORT Human Clinical
"Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease."
The clinical activity of pembrolizumab supports inhibition of PD-1 ligand-mediated immune evasion as a therapeutically relevant mechanism in relapsed or refractory classic Hodgkin lymphoma.
Show evidence (1 reference)
PMID:28441111 SUPPORT Human Clinical
"Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease."
This phase II trial supports pembrolizumab as an effective PD-1-blocking therapy in relapsed or refractory classic Hodgkin lymphoma.
Nivolumab
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: nivolumab NCIT:C68814 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nivolumab (NCIT:C68814). NCIT:C68814 is a therapeutic agent from the NCI Thesaurus.
PD-1 blockade with nivolumab, aligned to the disease's 9p24.1-driven checkpoint biology. The evidence carried in this entry is the CheckMate 205 registration record, which fixes the drug, disease and treated population; the efficacy of PD-1 blockade in relapsed or refractory classic Hodgkin lymphoma is evidenced here by the pembrolizumab phase II trial.
Mechanism Target:
INHIBITS PD-1 Ligand-Mediated Immune Evasion — Nivolumab blocks PD-1 signaling and counteracts checkpoint-mediated immune escape in classic Hodgkin lymphoma.
Show evidence (1 reference)
clinicaltrials:NCT02181738 SUPPORT INDIRECT Human Clinical
"The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants."
Shows that a PD-1-blocking antibody was taken into trial in this disease. Marked INDIRECT because the registration record reports no result, so the claim that blockade reverses PD-1 ligand-mediated immune evasion rests on the pembrolizumab trial above rather than on this record.
Show evidence (1 reference)
clinicaltrials:NCT02181738 SUPPORT INDIRECT Human Clinical
"The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants."
Establishes that nivolumab was tested in previously treated and newly diagnosed classical Hodgkin lymphoma. Marked INDIRECT because this is the registration record's statement of purpose: it fixes the drug, disease and population but reports no outcome, so it does not on its own establish efficacy.
🔬

Diagnosis

3
Open Lymph Node Biopsy
Tissue diagnosis is preferably established with open lymph node biopsy.
Show evidence (1 reference)
PMID:31894937 SUPPORT Other
"An open lymph node biopsy is preferred for diagnosis."
This review explicitly states that open lymph node biopsy is the preferred diagnostic procedure for lymphoma.
Immunohistochemistry for classical Hodgkin lymphoma markers
Diagnosis of classic Hodgkin lymphoma is supported by the characteristic immunophenotype of CD30, CD15, and PAX5 expression with absence of CD45 and T-lineage markers.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Markers: CD30, CD15, PAX5, CD45
Show evidence (1 reference)
PMID:26839195 SUPPORT Other
"Classical Hodgkin lymphoma has a characteristic immunophenotype in most cases, with expression of CD30, CD15, and PAX-5, and absence of CD45 and T-lineage markers."
This pathology review abstract directly supports the diagnostic immunophenotypic profile used in classic Hodgkin lymphoma.
PET/CT-Based Lugano Staging
PET/CT is integrated into Lugano staging to define disease extent and guide treatment selection.
Show evidence (1 reference)
PMID:31894937 SUPPORT Other
"The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment."
This review supports PET/CT-based Lugano staging as a standard part of lymphoma diagnosis and management.
📊

Prevalence

1
All lymphomas in the Western world
15-25
Show evidence (1 reference)
PMID:34075767 SUPPORT REVIEW SYNTHESIS Other
"Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world."
This review quantifies the proportion of all lymphomas represented by classic Hodgkin lymphoma in Western populations.
🦠

Infectious Agent

1
Epstein-Barr Virus
Epstein-Barr virus is associated with a subset of classic Hodgkin lymphoma cases, with heterogeneity in association linked to the host immune context.
Human gammaherpesvirus 4 NCBITaxon:10376 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:29799516 SUPPORT Other
"The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level."
This review supports EBV as a relevant but non-universal infectious cofactor in classic Hodgkin lymphoma.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Classic Hodgkin Lymphoma:

Nodular lymphocyte predominant Hodgkin lymphoma Not Yet Curated MONDO:0044778
Overlapping Features NLPHL is a major pathologic differential because it can overlap morphologically with classic Hodgkin lymphoma while differing in immunophenotype and clinical behavior.
Distinguishing Features
  • NLPHL retains a B-cell program with LP cells rather than classic Hodgkin/Reed-Sternberg cells.
  • NLPHL requires careful separation from classic Hodgkin lymphoma because management and biologic behavior differ.
Show evidence (1 reference)
PMID:34208705 SUPPORT Other
"NLPHL also shows overlap with other lymphomas, particularly, classic Hodgkin lymphoma and T-cell lymphomas."
This review explicitly identifies classic Hodgkin lymphoma as a diagnostic overlap and differential consideration for NLPHL.
Primary mediastinal large B-cell lymphoma Not Yet Curated MONDO:0020323
Overlapping Features PMBCL is a relevant mediastinal differential because it shares B-cell lineage features and overlapping immune-evasion biology with classic Hodgkin lymphoma, especially in mediastinal presentations.
Distinguishing Features
  • PMBCL typically presents as a rapidly enlarging anterior mediastinal mass with preserved B-cell surface marker expression.
  • Classic Hodgkin lymphoma is defined by Hodgkin/Reed-Sternberg cells in an inflammatory background rather than a diffuse large B-cell phenotype.
Show evidence (1 reference)
PMID:34590432 SUPPORT Other
"Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive large B cell lymphoma originating in the mediastinum, that mainly expresses B cell surface molecules, such as CD19, CD20, CD22, andCD79a."
This supports PMBCL as a clinically and pathologically distinct mediastinal B-cell lymphoma that must be separated from classic Hodgkin lymphoma.
📊

Related Datasets

1
Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Stenberg cells reveals escape from NK cell recognition and an unfolded protein response geo:GSE301492
Bulk RNA-seq resource profiling flow-sorted primary Hodgkin/Reed-Sternberg cells, matched intratumoral non-neoplastic B cells, and cell lines to define malignant-cell transcriptional programs and immune-evasion biology in classic Hodgkin lymphoma.
human BULK RNA SEQ n=18
Conditions: classic Hodgkin lymphoma Hodgkin/Reed-Sternberg cells matched intratumoral non-neoplastic B cells
Show evidence (1 reference)
GEO:GSE301492 SUPPORT Human Clinical
"To discover the molecular features that distinguish cHL, we deployed flow cytometric cell sorting and low-input RNA sequencing to generate full transcriptome data from viable, isolated Hodgkin and Red-Sternberg (HRS) cells from eighteen primary tumors, alongside matched intra-tumoral..."
This GEO series directly provides a patient-derived transcriptomic resource focused on malignant HRS cells and matched intratumoral B cells in classic Hodgkin lymphoma.
🔬

Clinical Trials

2
NCT02181738 PHASE_II COMPLETED
Multi-cohort phase II nivolumab study in previously treated or newly diagnosed classical Hodgkin lymphoma.
Show evidence (1 reference)
clinicaltrials:NCT02181738 SUPPORT Human Clinical
"The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants."
This directly supports active clinical development of nivolumab in classical Hodgkin lymphoma.
NCT00265889 PHASE_II COMPLETED
Phase II tandem autologous stem-cell transplantation study for primary progressive or poor-risk recurrent Hodgkin lymphoma.
Show evidence (1 reference)
clinicaltrials:NCT00265889 SUPPORT Human Clinical
"Giving two autologous stem cell transplants (one after the other) may be an effective treatment for Hodgkin's lymphoma."
This supports autologous transplantation as an actively studied salvage strategy in poor-risk recurrent Hodgkin lymphoma.
{ }

Source YAML

click to show 
name: Classic Hodgkin Lymphoma
creation_date: "2026-04-12T03:59:32Z"
category: Cancer
categories:
- Hematologic Malignancy
- B-cell Neoplasm
- Hodgkin Lymphoma
synonyms:
- classical Hodgkin lymphoma
- classical Hodgkin's lymphoma
- classic Hodgkin disease
- CHL
disease_term:
  preferred_term: classic Hodgkin lymphoma
  term:
    id: MONDO:0009348
    label: classic Hodgkin lymphoma
parents:
- Lymphoma
description: >-
  Classic Hodgkin lymphoma is a B-cell lymphoma characterized histologically by
  the presence of Hodgkin cells and multinucleated Reed-Sternberg cells.
definitions:
- name: Pathologic definition of classic Hodgkin lymphoma
  definition_type: CASE_DEFINITION
  description: >-
    Classic Hodgkin lymphoma is defined by neoplastic Hodgkin/Reed-Sternberg
    cells in a dense inflammatory background and is now understood to arise from
    germinal center B cells despite loss of many canonical B-cell markers.
  scope: General pathologic and molecular definition of classic Hodgkin lymphoma
  evidence:
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers."
    explanation: This review provides a concise disease definition centered on the hallmark HRS cell and its germinal center B-cell derivation.
prevalence:
- population: All lymphomas in the Western world
  percentage: "15-25"
  evidence:
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world."
    explanation: This review quantifies the proportion of all lymphomas represented by classic Hodgkin lymphoma in Western populations.
infectious_agent:
- name: Epstein-Barr Virus
  infectious_agent_term:
    preferred_term: Human gammaherpesvirus 4
    term:
      id: NCBITaxon:10376
      label: Human gammaherpesvirus 4
  description: >-
    Epstein-Barr virus is associated with a subset of classic Hodgkin lymphoma
    cases, with heterogeneity in association linked to the host immune context.
  evidence:
  - reference: PMID:29799516
    reference_title: "Epstein Barr Virus-Associated Hodgkin Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level."
    explanation: This review supports EBV as a relevant but non-universal infectious cofactor in classic Hodgkin lymphoma.
pathophysiology:
- name: Germinal Center B-Cell Origin of HRS Cells
  description: >-
    The malignant Hodgkin/Reed-Sternberg cell is derived from germinal center B
    cells but loses many typical B-cell features during transformation.
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  evidence:
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers."
    explanation: This directly supports the germinal center B-cell origin of the malignant HRS cell.
  downstream:
  - target: Cytokine and Chemokine-Mediated Microenvironment Remodeling
    description: Transformed HRS cells remodel a supportive inflammatory niche.
- name: Mutation-Driven JAK/STAT Activation
  genetic_context:
    variant_origin: SOMATIC
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  description: >-
    Recurrent mutations in classic Hodgkin lymphoma activate JAK/STAT signaling
    programs that support tumor-cell survival and cytokine-responsive growth.
  genes:
  - preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  - preferred_term: STAT6
    term:
      id: hgnc:11368
      label: STAT6
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  evidence:
  - reference: PMID:29340061
    reference_title: "Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others."
    explanation: This genomic study directly supports recurrent genetic lesions affecting JAK/STAT signaling in classic Hodgkin lymphoma.
  downstream:
  - target: Cytokine and Chemokine-Mediated Microenvironment Remodeling
    description: JAK/STAT signaling supports inflammatory niche formation.
- name: Mutation-Driven NF-kappaB Activation
  genetic_context:
    variant_origin: SOMATIC
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  description: >-
    Recurrent lesions affecting negative regulators and upstream activators of
    NF-kappaB signaling drive constitutive survival signaling in Hodgkin/Reed-Sternberg cells.
    The lesions are of two opposite kinds and both are bound here: destructive
    mutations in the negative regulators TNFAIP3 and NFKBIA, and copy-number
    gains of the positive regulators REL and MAP3K14.
  genes:
  - preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  - preferred_term: NFKBIA
    term:
      id: hgnc:7797
      label: NFKBIA
  - preferred_term: REL
    term:
      id: hgnc:9954
      label: REL
  - preferred_term: MAP3K14
    term:
      id: hgnc:6853
      label: MAP3K14
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-κB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)."
    explanation: This review directly supports recurrent somatic lesions in NF-kappaB pathway regulators, including TNFAIP3 and NFKBIA, as core mechanisms in Hodgkin lymphoma.
  downstream:
  - target: Cytokine and Chemokine-Mediated Microenvironment Remodeling
    description: NF-kappaB signaling sustains the inflammatory tumor niche.
  - target: PD-1 Ligand-Mediated Immune Evasion
    description: Constitutive NF-kappaB signaling cooperates with checkpoint-ligand upregulation to promote immune escape.
- name: EBV LMP1-Mediated NF-kappaB Activation
  conforms_to: "viral_oncogenesis#Host Tumor Suppressor Inactivation and Signaling Hijack"
  description: >-
    In Epstein-Barr virus-positive classic Hodgkin lymphoma, viral latent
    membrane protein 1 mimics active CD40 signaling and drives NF-kappaB
    activation in Hodgkin/Reed-Sternberg cells.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-κB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor."
    explanation: This directly supports EBV LMP1 as a mechanism of NF-kappaB activation in EBV-positive classical Hodgkin lymphoma.
  downstream:
  - target: Cytokine and Chemokine-Mediated Microenvironment Remodeling
    description: EBV-driven NF-kappaB activation reinforces the inflammatory tumor niche.
- name: Cytokine and Chemokine-Mediated Microenvironment Remodeling
  conforms_to: "tumor_promoting_inflammation#Pro-Tumorigenic Inflammatory Microenvironment"
  description: >-
    HRS cells persist within a dense inflammatory infiltrate that they actively
    recruit and shape through cytokine and chemokine signaling.
  biological_processes:
  - preferred_term: chemokine production
    modifier: INCREASED
    term:
      id: GO:0032602
      label: chemokine production
  evidence:
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow."
    explanation: This review directly supports the dependence of classic Hodgkin lymphoma on cytokine and chemokine-mediated microenvironmental remodeling.
  downstream:
  - target: PD-1 Ligand-Mediated Immune Evasion
    description: The inflammatory niche is coupled to ineffective anti-tumor immunity.
  - target: Lymphadenopathy
    description: The HRS-supported inflammatory niche contributes to bulky nodal enlargement.
  - target: Fever
    description: Cytokine-rich tumor inflammation contributes to B symptoms including fever.
  - target: Night Sweats
    description: Cytokine-rich tumor inflammation contributes to B symptoms including night sweats.
  - target: Weight Loss
    description: Cytokine-rich tumor inflammation contributes to systemic B symptoms including weight loss.
- name: PD-1 Ligand-Mediated Immune Evasion
  conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
  description: >-
    Near-universal 9p24.1 copy gain increases PD-1 ligand expression on HRS
    cells and contributes to immune escape in classic Hodgkin lymphoma. The
    two genes in the amplicon that carry the effect are CD274 (PD-L1) and
    PDCD1LG2 (PD-L2); they are altered concordantly rather than one at a time.
  genes:
  - preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  - preferred_term: PDCD1LG2
    term:
      id: hgnc:18731
      label: PDCD1LG2
  biological_processes:
  - preferred_term: Negative Regulation of T Cell Mediated Immunity
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
    modifier: INCREASED
  evidence:
  - reference: PMID:31816062
    reference_title: "Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands."
    explanation: This study directly links recurrent 9p24.1 gains in HRS cells to elevated PD-1 ligand expression and immune evasion.
  - reference: PMID:27069084
    reference_title: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci"
    explanation: >-
      Names the two 9p24.1 genes bound on this node and establishes that they are
      altered concordantly, which is why both are recorded rather than CD274 alone.
- name: Mutation-Driven MHC Class I Loss
  genetic_context:
    variant_origin: SOMATIC
  description: >-
    One of two genetically separate antigen-presentation arms, split from its
    class II sibling because the two reach the same immune-evasion endpoint by
    different immunological routes. Recurrent somatic B2M lesions disrupt
    beta-2-microglobulin, the invariant light chain every class I molecule needs
    to reach the cell surface, so HRS cells lose surface MHC class I and with it
    direct CD8 cytotoxic T-cell recognition. This is not the same mechanism as
    checkpoint-ligand-mediated inhibition of the T cells that do still recognise
    the tumour.
  genes:
  - preferred_term: B2M
    term:
      id: hgnc:914
      label: B2M
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  biological_processes:
  - preferred_term: antigen processing and presentation of peptide antigen via MHC class I
    modifier: DECREASED
    term:
      id: GO:0002474
      label: antigen processing and presentation of peptide antigen via MHC class I
  evidence:
  - reference: PMID:29394125
    reference_title: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation."
    explanation: >-
      Establishes perturbed antigen presentation as an immune-evasion mechanism in
      cHL separate from the 9p24.1 checkpoint-ligand gains.
  - reference: PMID:29394125
    reference_title: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PD-1 receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells."
    explanation: >-
      Supports loss of MHC class I expression on HRS cells as a reported feature,
      and is the source this node's description is graded against - the paper
      reports deficiencies of class I expression rather than its abolition.
  - reference: PMID:31816062
    reference_title: "Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1"
    explanation: Places B2M among the recurrent somatic alterations of flow-sorted HRS cells.
  downstream:
  - target: PD-1 Ligand-Mediated Immune Evasion
    description: >-
      Loss of surface class I removes the CD8 cytotoxic recognition arm, so the
      residual anti-tumour response that the checkpoint axis acts on is the
      MHC-class-II-dependent one.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of CD8 cytotoxic T-cell recognition of HRS cells
- name: Mutation-Driven MHC Class II Loss
  genetic_context:
    variant_origin: SOMATIC
  description: >-
    The class II counterpart. CIITA, the MHC class II transactivator, is
    recurrently broken or fused in a subset of classic Hodgkin lymphoma, so class
    II expression is lost and with it CD4 T-cell recognition. This arm is the one
    that bears on treatment: it is HRS-cell MHC class II expression, not class I,
    that predicts complete remission on PD-1 blockade, which is why the two arms
    are curated as separate nodes rather than as one antigen-presentation node.
  genes:
  - preferred_term: CIITA
    term:
      id: hgnc:7067
      label: CIITA
  cell_types:
  - preferred_term: germinal center B cell
    term:
      id: CL:0000844
      label: germinal center B cell
  biological_processes:
  - preferred_term: antigen processing and presentation of peptide antigen via MHC class II
    modifier: DECREASED
    term:
      id: GO:0002495
      label: antigen processing and presentation of peptide antigen via MHC class II
  evidence:
  - reference: PMID:21368758
    reference_title: "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%)"
    explanation: Supports recurrent CIITA disruption in classic Hodgkin lymphoma as the lesion behind this node.
  - reference: PMID:21368758
    reference_title: "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CIITA is an essential transactivator of MHC class II expression"
    explanation: >-
      Establishes CIITA's role as the transactivator MHC class II expression
      depends on, which is what makes its disruption a class II rather than a
      class I lesion.
  downstream:
  - target: PD-1 Ligand-Mediated Immune Evasion
    description: >-
      Class II status governs what blocking the PD-1 axis can achieve: HRS-cell
      MHC class II expression is what predicts complete remission on PD-1
      blockade, while class I expression is not.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of CD4 T-cell recognition of HRS cells
    evidence:
    - reference: PMID:29394125
      reference_title: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In contrast, HRS cell expression of MHC class II was predictive for complete remission."
      explanation: >-
        Supports the directed relation recorded on this edge: class II
        antigen-presentation status, specifically, governs the outcome of blocking
        the PD-1 axis.
    - reference: PMID:29394125
      reference_title: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HRS cell expression of \u03b22-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy."
      explanation: >-
        The contrast that motivates splitting the two arms: class I status does
        not predict the outcome that class II status does.
histopathology:
- name: Hodgkin/Reed-Sternberg Cells in a Dense Inflammatory Background
  finding_term:
    preferred_term: Hodgkin/Reed-Sternberg cells in a dense inflammatory background
    term:
      id: NCIT:C12660
      label: Reed-Sternberg Cell
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Classic Hodgkin lymphoma shows scattered Hodgkin/Reed-Sternberg cells within
    a dense reactive inflammatory infiltrate rather than sheets of tumor cells.
  evidence:
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow."
    explanation: This review directly supports the hallmark microscopic pattern of sparse HRS cells embedded in an inflammatory background.
phenotypes:
- category: Lymphatic
  name: Lymphadenopathy
  description: >-
    Classic Hodgkin lymphoma usually presents with nodal enlargement and
    contiguous nodal spread.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:32433447
    reference_title: "Classic Hodgkin Lymphoma: A Nonclassic Presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
    explanation: This directly supports lymphadenopathy as the classic presenting feature of Hodgkin lymphoma.
- category: Constitutional
  name: Night Sweats
  description: >-
    Night sweats are part of the classical B-symptom complex at presentation.
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
  evidence:
  - reference: PMID:32433447
    reference_title: "Classic Hodgkin Lymphoma: A Nonclassic Presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
    explanation: This presentation-focused abstract explicitly lists night sweats among the classic B symptoms of Hodgkin lymphoma.
- category: Constitutional
  name: Weight Loss
  description: >-
    Unintentional weight loss is a classical B symptom of active disease.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:32433447
    reference_title: "Classic Hodgkin Lymphoma: A Nonclassic Presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
    explanation: This abstract explicitly names weight loss as one of the classic B symptoms.
- category: Constitutional
  name: Fever
  description: >-
    Fever is a classical B symptom that may accompany nodal disease.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:32433447
    reference_title: "Classic Hodgkin Lymphoma: A Nonclassic Presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever."
    explanation: This abstract explicitly names fever as part of the B-symptom complex.
diagnosis:
- name: Open Lymph Node Biopsy
  description: >-
    Tissue diagnosis is preferably established with open lymph node biopsy.
  evidence:
  - reference: PMID:31894937
    reference_title: "Lymphoma: Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An open lymph node biopsy is preferred for diagnosis."
    explanation: This review explicitly states that open lymph node biopsy is the preferred diagnostic procedure for lymphoma.
- name: Immunohistochemistry for classical Hodgkin lymphoma markers
  description: >-
    Diagnosis of classic Hodgkin lymphoma is supported by the characteristic
    immunophenotype of CD30, CD15, and PAX5 expression with absence of CD45 and
    T-lineage markers.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: CD30, CD15, PAX5, CD45
  evidence:
  - reference: PMID:26839195
    reference_title: "Atypical Phenotypes in Classical Hodgkin Lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Classical Hodgkin lymphoma has a characteristic immunophenotype in most cases, with expression of CD30, CD15, and PAX-5, and absence of CD45 and T-lineage markers."
    explanation: This pathology review abstract directly supports the diagnostic immunophenotypic profile used in classic Hodgkin lymphoma.
- name: PET/CT-Based Lugano Staging
  description: >-
    PET/CT is integrated into Lugano staging to define disease extent and guide
    treatment selection.
  evidence:
  - reference: PMID:31894937
    reference_title: "Lymphoma: Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment."
    explanation: This review supports PET/CT-based Lugano staging as a standard part of lymphoma diagnosis and management.
differential_diagnoses:
- name: Nodular lymphocyte predominant Hodgkin lymphoma
  disease_term:
    preferred_term: nodular lymphocyte predominant Hodgkin lymphoma
    term:
      id: MONDO:0044778
      label: nodular lymphocyte predominant Hodgkin lymphoma
  description: >-
    NLPHL is a major pathologic differential because it can overlap morphologically
    with classic Hodgkin lymphoma while differing in immunophenotype and clinical
    behavior.
  distinguishing_features:
  - NLPHL retains a B-cell program with LP cells rather than classic Hodgkin/Reed-Sternberg cells.
  - NLPHL requires careful separation from classic Hodgkin lymphoma because management and biologic behavior differ.
  evidence:
  - reference: PMID:34208705
    reference_title: "Pitfalls in the Diagnosis of Nodular Lymphocyte Predominant Hodgkin Lymphoma: Variant Patterns, Borderlines and Mimics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NLPHL also shows overlap with other lymphomas, particularly, classic Hodgkin lymphoma and T-cell lymphomas."
    explanation: This review explicitly identifies classic Hodgkin lymphoma as a diagnostic overlap and differential consideration for NLPHL.
- name: Primary mediastinal large B-cell lymphoma
  disease_term:
    preferred_term: primary mediastinal large B-cell lymphoma
    term:
      id: MONDO:0020323
      label: primary mediastinal large B-cell lymphoma
  description: >-
    PMBCL is a relevant mediastinal differential because it shares B-cell
    lineage features and overlapping immune-evasion biology with classic
    Hodgkin lymphoma, especially in mediastinal presentations.
  distinguishing_features:
  - PMBCL typically presents as a rapidly enlarging anterior mediastinal mass with preserved B-cell surface marker expression.
  - Classic Hodgkin lymphoma is defined by Hodgkin/Reed-Sternberg cells in an inflammatory background rather than a diffuse large B-cell phenotype.
  evidence:
  - reference: PMID:34590432
    reference_title: Primary mediastinal large B cell lymphoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive large B cell lymphoma originating in the mediastinum, that mainly expresses B cell surface molecules, such as CD19, CD20, CD22, andCD79a."
    explanation: This supports PMBCL as a clinically and pathologically distinct mediastinal B-cell lymphoma that must be separated from classic Hodgkin lymphoma.
genetic:
- name: TNFAIP3
  association: Somatic Loss-of-Function Mutation
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  notes: >-
    TNFAIP3 encodes the NF-kappaB negative regulator A20. Destructive somatic
    lesions contribute to constitutive NF-kappaB activation in Hodgkin/Reed-Sternberg cells.
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-κB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)."
    explanation: This review directly identifies TNFAIP3 as a recurrently mutated negative regulator of NF-kappaB signaling in Hodgkin lymphoma.
- name: NFKBIA
  association: Somatic Loss-of-Function Mutation
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: NFKBIA
    term:
      id: hgnc:7797
      label: NFKBIA
  notes: >-
    NFKBIA encodes IkappaBalpha, a negative regulator of canonical NF-kappaB
    signaling. Its loss contributes to constitutive pathway activation.
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-κB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)."
    explanation: This review directly identifies NFKBIA as a recurrently mutated negative regulator of NF-kappaB signaling in Hodgkin lymphoma.
- name: B2M
  association: Somatic Mutation
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: B2M
    term:
      id: hgnc:914
      label: B2M
  notes: >-
    B2M mutations disrupt major histocompatibility complex class I antigen
    presentation and contribute to immune evasion by Hodgkin/Reed-Sternberg cells.
  evidence:
  - reference: PMID:31816062
    reference_title: "Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases."
    explanation: This genomic study identifies recurrent B2M mutations as one of the characteristic immune-evasion-associated lesions in classic Hodgkin lymphoma.
- name: CIITA
  association: Somatic Rearrangement/Fusion
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CIITA
    term:
      id: hgnc:7067
      label: CIITA
  notes: >-
    Recurrent CIITA breaks or fusions occur in a subset of classic Hodgkin
    lymphoma and can alter antigen-presentation and checkpoint-ligand programs.
  evidence:
  - reference: PMID:21368758
    reference_title: "MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%)."
    explanation: This study directly supports recurrent CIITA genomic breaks in a subset of classic Hodgkin lymphoma.
- name: CD274 (9p24.1 copy gain)
  gene_term:
    preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  association: Somatic Copy-Number Gain
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Recurrent copy gain of the 9p24.1 locus increases PD-1 ligand expression and
    is a hallmark of classic Hodgkin lymphoma immune evasion. The record is kept
    locus-named because the lesion is a copy-number gain of the whole amplicon
    rather than a variant in one gene, but CD274 (PD-L1) is bound here so the
    gene reaches the pathograph and the knowledge-graph export; PDCD1LG2 (PD-L2),
    the other gene in the same amplicon, has its own record below.
  evidence:
  - reference: PMID:31816062
    reference_title: "Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands."
    explanation: This directly supports recurrent 9p24.1 copy gain as a defining genetic immune-evasion lesion in classic Hodgkin lymphoma.
  - reference: PMID:27069084
    reference_title: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL"
    explanation: Names CD274 as one of the two 9p24.1 genes whose alterations were assayed in cHL biopsies.
- name: PDCD1LG2 (9p24.1 copy gain)
  gene_term:
    preferred_term: PDCD1LG2
    term:
      id: hgnc:18731
      label: PDCD1LG2
  association: Somatic Copy-Number Gain
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    The second PD-1 ligand gene in the 9p24.1 amplicon. It is altered together
    with CD274 in essentially every case rather than independently, so the two
    records describe one lesion seen through its two genes.
  evidence:
  - reference: PMID:27069084
    reference_title: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci"
    explanation: Establishes concordant alteration of the PD-L2 (PDCD1LG2) locus with PD-L1 across the cHL cohort.
- name: JAK2
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  association: Somatic alteration activating JAK/STAT signaling
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    JAK2 lies within the same 9p24.1 amplicon as CD274 and PDCD1LG2, and
    JAK2-STAT signalling further induces the PD-1 ligands encoded beside it, so
    one copy-number event both raises ligand dosage and amplifies the pathway that
    drives ligand transcription. This gene was already bound on the
    Mutation-Driven JAK/STAT Activation pathophysiology node but had no
    `genetic:` record, and only `genetic:` records reach the gene-to-disease
    export.
  evidence:
  - reference: PMID:27069084
    reference_title: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling."
    explanation: Places JAK2-STAT signalling as an amplifier of PD-1 ligand abundance in cHL alongside the copy-number gain.
  - reference: PMID:34075767
    reference_title: "Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Among the most fre -\nquent are amplifications of 9p24.1 locus, affecting \nJAK2, PD-L1 and PD-L2 genes"
    explanation: >-
      Places JAK2 inside the same 9p24.1 amplicon as the two PD-1 ligand genes,
      which is the claim this record's notes make about the shared locus.
- name: STAT6
  gene_term:
    preferred_term: STAT6
    term:
      id: hgnc:11368
      label: STAT6
  association: Somatic Mutation
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    STAT6 is among the recurrently mutated genes in flow-sorted HRS cells and is
    the transcription-factor end of the JAK/STAT arm. As with JAK2, it was bound
    on the pathophysiology node without a `genetic:` record.
  evidence:
  - reference: PMID:31816062
    reference_title: "Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1"
    explanation: Lists STAT6 among the recurrent somatic alterations identified in flow-sorted HRS cells.
- name: REL
  gene_term:
    preferred_term: REL
    term:
      id: hgnc:9954
      label: REL
  association: Somatic Copy-Number Gain
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    REL encodes c-Rel, an NF-kappaB subunit. In cHL the recurrent lesion is a copy
    gain of a positive regulator rather than a destructive mutation of a negative
    one, which is the mirror image of the TNFAIP3 and NFKBIA lesions in the same
    pathway.
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-\u03baB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)"
    explanation: Identifies REL copy-number gain as a recurrent NF-kappaB-activating lesion in Hodgkin lymphoma.
- name: MAP3K14
  gene_term:
    preferred_term: MAP3K14
    term:
      id: hgnc:6853
      label: MAP3K14
  association: Somatic Copy-Number Gain
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    MAP3K14 encodes NIK, the kinase that drives non-canonical NF-kappaB
    signalling; like REL it is recurrently gained rather than lost.
  evidence:
  - reference: PMID:27221964
    reference_title: "NF-\u03baB deregulation in Hodgkin lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14)"
    explanation: Identifies MAP3K14 copy-number gain as a recurrent NF-kappaB-activating lesion in Hodgkin lymphoma.
- name: KLHDC8B
  gene_term:
    preferred_term: KLHDC8B
    term:
      id: hgnc:28557
      label: KLHDC8B
  association: Germline predisposition in familial classic Hodgkin lymphoma
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The only germline record in this otherwise somatic entry, and the only one
    graded below SOMATIC_DRIVER. KLHDC8B is a midbody kelch protein required for
    cytokinesis, and its loss produces binucleate cells - the morphology that
    defines the Reed-Sternberg cell - so the mechanistic story is unusually
    specific for a predisposition gene. The human genetic evidence is a
    segregating translocation in one pedigree, a 5'-UTR variant associated with
    and segregating in further pedigrees, and LOH in sorted RS cells from one of
    three informative sporadic cases; a 2023 whole-genome study of 36 HL pedigrees
    independently recovered the same 5'-UTR variant among its top four recurrent
    risk variants.

    It is graded SUSCEPTIBILITY rather than CAUSATIVE on three grounds. The
    evidence is a familial risk allele of incomplete penetrance rather than a
    Mendelian lesion; a five-member nodular-sclerosis pedigree with linkage at
    3p21 was sequenced in 2018 and carried no KLHDC8B variant at all, with
    KLHDC8B expression indistinguishable between carriers and non-carriers; and
    the ClinGen gene-validity CSV committed in this repository has no KLHDC8B row
    (`grep '"KLHDC8B",' cache/clingen/gene_validity.csv` returns nothing), so
    there is no expert-panel classification to defer to. The refuting study is
    recorded below as its own evidence item rather than being left out.

    The grading is deliberate and is expected to be flattened by the current KGX
    exporter, which hardcodes `biolink:contributes_to` and never reads
    `relationship_type` (dismech#12320) - so this will export looking like the
    somatic drivers beside it until that is fixed.
  evidence:
  - reference: PMID:19706467
    reference_title: "Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We tested KLHDC8B as a candidate gene for cHL and found that a 5'-UTR polymorphism responsible for decreasing its translational expression is associated with cHL in probands from other families with cHL and segregates with disease in those pedigrees"
    explanation: >-
      The primary human genetic evidence: a KLHDC8B regulatory variant associated
      with and segregating in multiple classic Hodgkin lymphoma pedigrees.
  - reference: PMID:19706467
    reference_title: "Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its reduced expression in the formation of cHL's signature RS cell."
    explanation: >-
      Supplies the mechanistic link from reduced KLHDC8B to the binucleate
      Reed-Sternberg morphology.
  - reference: PMID:22988245
    reference_title: The kelch protein KLHDC8B guards against mitotic errors, centrosomal amplification, and chromosomal instability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We recapitulated the major pathologic features of the Reed-Sternberg cell and concluded that KLHDC8B is essential for mitotic integrity and maintenance of chromosomal stability."
    explanation: >-
      Independent functional replication across three cell types, and the reason
      the mechanistic story for this predisposition gene is unusually specific
      for the disease it predisposes to.
  - reference: PMID:35977101
    reference_title: Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5' untranslated region variant in KLHDC8B (rs387906223)"
    explanation: >-
      Independent whole-genome replication of the KLHDC8B 5'-UTR risk variant
      across 36 Hodgkin lymphoma pedigrees, and the basis for grading the
      relationship as a recurrent risk allele.
  - reference: PMID:29755658
    reference_title: Combined linkage and association analysis of classical Hodgkin lymphoma.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21."
    explanation: >-
      Counter-evidence in a five-member nodular-sclerosis cHL family with linkage
      at 3p21: no KLHDC8B variant was found, and the authors proposed FAM107A and
      SLC26A6 instead. This is why the record is graded SUSCEPTIBILITY and not
      CAUSATIVE.
treatments:
- name: ABVD-Based Chemotherapy
  description: >-
    Combination chemotherapy with ABVD remains a standard systemic treatment
    backbone for Hodgkin lymphoma.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
    - preferred_term: bleomycin
      term:
        id: CHEBI:22907
        label: bleomycin
    - preferred_term: vinblastine
      term:
        id: CHEBI:27375
        label: vincaleukoblastine
    - preferred_term: dacarbazine
      term:
        id: CHEBI:4305
        label: dacarbazine
  regimen_term:
    preferred_term: ABVD regimen
    term:
      id: NCIT:C9509
      label: ABVD Regimen
  evidence:
  - reference: NCIT:C411
    reference_title: "Dacarbazine (NCIT)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dacarbazine | Accepted_Therapeutic_Use_For | - | - | Carcinoid cancer; Hodgkins disease; Islet cell carcinoma; Melanoma; Neuroblastoma; Soft tissue sarcoma"
    explanation: >-
      NCI Thesaurus asserts accepted therapeutic use of dacarbazine for
      Hodgkin's disease; it is the dacarbazine component of the ABVD regimen.
  - reference: PMID:31894937
    reference_title: "Lymphoma: Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy."
    explanation: This treatment review identifies ABVD-containing combination chemotherapy as a standard treatment approach for Hodgkin lymphoma.
- name: Radiation Therapy
  description: >-
    Radiotherapy is used with chemotherapy in selected Hodgkin lymphoma
    treatment strategies.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:31894937
    reference_title: "Lymphoma: Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy."
    explanation: This review explicitly states that radiotherapy is used in combination treatment regimens for Hodgkin lymphoma.
- name: Brentuximab Vedotin
  description: >-
    CD30-directed antibody-drug conjugate therapy has activity in relapsed or
    refractory classic Hodgkin lymphoma and is commonly combined with chemotherapy.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: brentuximab vedotin
      term:
        id: NCIT:C66944
        label: Brentuximab Vedotin
  evidence:
  - reference: PMID:39039881
    reference_title: "[Analysis of 10 cases of brentuximab vedotin combined with chemotherapy in the treatment of children with refractory and or relapsed classic Hodgkin lymphoma]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin's lymphoma in children."
    explanation: >-
      Supports brentuximab vedotin as an active CD30-targeted therapy in relapsed or
      refractory disease. Marked INDIRECT because the cited series is 10 children, so
      it does not by itself establish the activity of the drug across the adult
      classic Hodgkin lymphoma population this entry describes.
- name: Pembrolizumab
  description: >-
    PD-1 blockade with pembrolizumab is active in relapsed or refractory classic
    Hodgkin lymphoma.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: PMID:28441111
    reference_title: "Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease."
    explanation: This phase II trial supports pembrolizumab as an effective PD-1-blocking therapy in relapsed or refractory classic Hodgkin lymphoma.
  target_mechanisms:
  - target: PD-1 Ligand-Mediated Immune Evasion
    treatment_effect: INHIBITS
    description: >-
      Pembrolizumab blocks PD-1 signaling and counteracts PD-1 ligand-mediated
      suppression of anti-tumor T-cell activity in classic Hodgkin lymphoma.
    evidence:
    - reference: PMID:28441111
      reference_title: "Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease."
      explanation: The clinical activity of pembrolizumab supports inhibition of PD-1 ligand-mediated immune evasion as a therapeutically relevant mechanism in relapsed or refractory classic Hodgkin lymphoma.
- name: Nivolumab
  description: >-
    PD-1 blockade with nivolumab, aligned to the disease's 9p24.1-driven checkpoint
    biology. The evidence carried in this entry is the CheckMate 205 registration
    record, which fixes the drug, disease and treated population; the efficacy of
    PD-1 blockade in relapsed or refractory classic Hodgkin lymphoma is evidenced
    here by the pembrolizumab phase II trial.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
  evidence:
  - reference: clinicaltrials:NCT02181738
    reference_title: "Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Classical Hodgkin Lymphoma (cHL) Subjects"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants.
    explanation: >-
      Establishes that nivolumab was tested in previously treated and newly diagnosed
      classical Hodgkin lymphoma. Marked INDIRECT because this is the registration
      record's statement of purpose: it fixes the drug, disease and population but
      reports no outcome, so it does not on its own establish efficacy.
  target_mechanisms:
  - target: PD-1 Ligand-Mediated Immune Evasion
    treatment_effect: INHIBITS
    description: >-
      Nivolumab blocks PD-1 signaling and counteracts checkpoint-mediated immune
      escape in classic Hodgkin lymphoma.
    evidence:
    - reference: clinicaltrials:NCT02181738
      reference_title: "Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Classical Hodgkin Lymphoma (cHL) Subjects"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants.
      explanation: >-
        Shows that a PD-1-blocking antibody was taken into trial in this disease.
        Marked INDIRECT because the registration record reports no result, so the
        claim that blockade reverses PD-1 ligand-mediated immune evasion rests on
        the pembrolizumab trial above rather than on this record.
clinical_trials:
- name: NCT02181738
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Multi-cohort phase II nivolumab study in previously treated or newly diagnosed
    classical Hodgkin lymphoma.
  evidence:
  - reference: clinicaltrials:NCT02181738
    reference_title: "Non-Comparative, Multi-Cohort, Single Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in Classical Hodgkin Lymphoma (cHL) Subjects"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this study is to evaluate the efficacy and safety of Nivolumab in previously treated (cohorts, A, B & C) or newly diagnosed (cohort D) classical Hodgkin Lymphoma participants.
    explanation: This directly supports active clinical development of nivolumab in classical Hodgkin lymphoma.
- name: NCT00265889
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase II tandem autologous stem-cell transplantation study for primary
    progressive or poor-risk recurrent Hodgkin lymphoma.
  evidence:
  - reference: clinicaltrials:NCT00265889
    reference_title: "Tandem Autologous Stem Cell Transplantation for Patients With Primary Progressive or Poor Risk Recurrent Hodgkin's Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Giving two autologous stem cell transplants (one after the other) may be an effective treatment for Hodgkin's lymphoma.
    explanation: This supports autologous transplantation as an actively studied salvage strategy in poor-risk recurrent Hodgkin lymphoma.
datasets:
- accession: geo:GSE301492
  title: Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Stenberg cells reveals escape from NK cell recognition and an unfolded protein response
  description: >-
    Bulk RNA-seq resource profiling flow-sorted primary Hodgkin/Reed-Sternberg
    cells, matched intratumoral non-neoplastic B cells, and cell lines to define
    malignant-cell transcriptional programs and immune-evasion biology in classic
    Hodgkin lymphoma.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 18
  conditions:
  - classic Hodgkin lymphoma Hodgkin/Reed-Sternberg cells
  - matched intratumoral non-neoplastic B cells
  evidence:
  - reference: GEO:GSE301492
    reference_title: "Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Stenberg cells reveals escape from NK cell recognition and an unfolded protein response"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To discover the molecular features that distinguish cHL, we deployed flow cytometric cell sorting and low-input RNA sequencing to generate full transcriptome data from viable, isolated Hodgkin and Red-Sternberg (HRS) cells from eighteen primary tumors, alongside matched intra-tumoral non-neoplastic B cells and four cell lines."
    explanation: This GEO series directly provides a patient-derived transcriptomic resource focused on malignant HRS cells and matched intratumoral B cells in classic Hodgkin lymphoma.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Classic Hodgkin Lymphoma. Core disease mechanisms, molecular and cellular...
Asta Scientific Corpus Retrieval 18 citations 2026-04-21T08:23:40.898797

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Classic Hodgkin Lymphoma. Core disease mechanisms, molecular and cellular...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] P-Glycoprotein as a Therapeutic Target in Hematological Malignancies: A Challenge to Overcome

  • Authors: Pablo Álvarez-Carrasco, Fernanda Morales-Villamil, C. Maldonado-Bernal
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/e5804b5ab8e1ed680a595670111915afd0be21fd
  • DOI: 10.3390/ijms26104701
  • PMID: 40429842
  • PMCID: 12112708
  • Citations: 6
  • Summary: Recent advances in combating P-gp-mediated resistance are examined, including the development of novel P-gp inhibitors, innovative drug delivery systems, and strategies to modulate P-gp expression or activity, including targeting relevant signaling pathways and exploring drug repurposing.
  • Evidence snippets:
  • Snippet 1 (score: 0.478) > Lymphomas, a diverse group of blood cancers originating in the lymphatic system, are primarily classified based on the lymphocyte type involved: B-cell, T-cell, or NK-cell. The World Health Organization (WHO) classification is the most widely accepted framework, considering morphology, immunophenotype, genetics, and clinical presentation. B-cell lymphomas, the most common type, include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma [83]. T-cell and NK-cell lymphomas, such as peripheral T-cell lymphomas and anaplastic large-cell lymphoma, are less common and often more aggressive. Hodgkin lymphoma, distinct from non-Hodgkin lymphomas, is characterized by the presence of Reed-Sternberg cells. Previous classification systems, such as the Revised European-American Lymphoma (REAL) classification and the Kiel classification, contributed to the development of the current WHO classification, emphasizing histological and immunophenotypic features [84,85]. > About 30% of diffuse large B-cell lymphoma patients display early relapse and 10% show therapy-refractory disease, often due to the development of multidrug resistance. The mechanisms underlying multidrug resistance in lymphomas are complex and include target gene mutations, metabolic reprogramming, overexpression of drug efflux transporters such as P-gp, upregulation of anti-apoptotic proteins, and enhanced DNA damage repair. P-gp increases resistance to chemotherapy, targeted therapy, and immunotherapy in lymphomas, clinically leading to poor treatment outcomes [86]. > Non-Hodgkin lymphoma (NHL) is a prevalent hematological malignancy arising from lymphoid tissue and lymph nodes throughout the body. Consequently, NHL can manifest in several anatomical locations. Chemotherapy constitutes the primary therapeutic modality for most NHL subtypes [87].

[2] CD20 role in pathophysiology of Hodgkin's disease.

  • Authors: Marcelo Antônio Oliveira Santos, M. M. Lima
  • Year: 2017
  • Venue: Revista da Associacao Medica Brasileira
  • URL: https://www.semanticscholar.org/paper/04e73161107ceb5fae03a0e118c8f7dd6c33543c
  • DOI: 10.1590/1806-9282.63.09.810
  • PMID: 29239464
  • Citations: 16
  • Summary: CD20 function in Hodgkin's lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients' prognostic are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.473) > Hodgkin's lymphoma (HL) is a tumor comprising non-malignant and malignant B-cells. Classical HL expresses CD15+ and CD30+ antigens, and 20 to 40% of patients are CD20+. This antigen is a ligand free protein present in B lymphocyte cells and its function is not well known. Some studies suggest that expression of CD20 may play a major role in Hodgkin's disease pathophysiology and may affect the patients' treatment prognosis, as well as relapse and refractory response. In the past few years, development of monoclonal anti-CD20 antibodies changed drastically the treatment for non-Hodgkin lymphomas in which CD20 is expressed. HL treatment is essentially composed of radiotherapy and chemotherapy; however, monoclonal anti-CD20 antibodies applicability is not well delimitated due to lack of information about clinical outcomes with anti-CD20 monotherapy or combined drug therapy using a classic regimen, as well as about CD20 pathophysiology mechanisms in B-cells tumors. The objective of our review is to discuss CD20 function in Hodgkin's lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients' prognostic.

[3] The Lymphoproliferative Disorders: Handbook of diagnosis, investigation and management

  • Authors: G. Morgan, A. Jack, J. Child
  • Year: 1998
  • Venue: British Journal of Cancer
  • URL: https://www.semanticscholar.org/paper/941780a301f63ddd89a00ed9c11aabdf76c2ed33
  • DOI: 10.1038/sj.bjc.6690402
  • PMCID: 2362316
  • Citations: 5
  • Summary: Part 1 Principles of diagnosis and treatment: the structure of the lymphoid system laboratory methods for the diagnosis and classification of lymphoproliferative disorders staging and imaging of lymphoarthritis diseases and the development of classifications of lymphanoplastic disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.450) > somewhat understated, particularly for Hodgkin's disease, in which, at present, assessment of mediastinal masses on chest X-ray remains a major factor in therapeutic decisions. The role of magnetic resonance imaging as a means of assessing disease viability in residual masses and staging the bone marrow is overstated since there have been conflicting reports of the value of this technique and, unfortunately, the chapter presents relatively little data on the use of Gallium scanning and none on the use of PET scanning, which is an emerging technique in lymphomas. > The chapter on principles of therapy begins with an excellent description of apoptopic pathways and the way in which currently available treatments can modify these. It is a welcome change from the standard account of the action of cytotoxic drugs and radiotherapy etc. > Section 2 of the book covers the specific lymphoproliferative disorders, divided up roughly along the lines of the REAL classification, although the authors acknowledge that it was not possible to adhere strictly to this. Nevertheless, this provides a novel approach to the accounts of these various lymphoma entities. > Each of these chapters take a roughly similar approach to the groups of diseases being discussed. Each provides a thorough description of the diagnosis, pathology and molecular pathology of the disorders followed by, in most cases, a concise but relatively brief account of treatment. This section of the book is particularly strong in its coverage of pathology, diagnosis and underlying molecular mechanisms, and is heavily biased in this direction. Accounts of management of the diseases are relatively brief and will be inadequate for those who wish to gain an insight into some of the complexities of clinical management. For example, the chapter on Hodgkin's disease provides an elegantly written account of the various sub-types of Hodgkin's disease, including lymphocyte predominant nodular Hodgkin's disease and then the various types of classical Hodgkin's with an extensive description of their pathology, the nature of the Reed-Sternberg cell, etc. However, treatment issues in Hodgkin's disease are condensed into only approximately three pages and fail to convey the complexity of the treatment decisions in this disease, the balance between disease control and long-term toxicity and the many ongoing clinical trials. Similarly, in this chapter and

[4] Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

  • Authors: E. Mata, A. Díaz-López, A. M. Martín-Moreno, M. Sánchez-Beato, I. Varela et al.
  • Year: 2017
  • Venue: Oncotarget
  • URL: https://www.semanticscholar.org/paper/024bfd902d2428c06820bdedab50ba27b3a5f313
  • DOI: 10.18632/oncotarget.22799
  • PMID: 29340061
  • PMCID: 5762329
  • Citations: 37
  • Influential citations: 3
  • Summary: The mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg cells, is described, confirming the presence of strong genomic heterogeneity and indicating new pathogenic mechanisms and therapeutic opportunities in this disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.446) > Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease.

[5] Recurrent Composite Lymphoma in an Elderly Man: A Case of Marginal Zone Lymphoma With Classic Hodgkin Features Treated With Brentuximab and Immunotherapy

  • Authors: Muhammad Daniyal, Anamm Polani, Amrat Kumar, Ahmad Raja, Marcy Canary
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/f0b4e77a96f22f5b65eb81cb5e0190f1d845dcfd
  • DOI: 10.7759/cureus.84943
  • PMID: 40585708
  • PMCID: 12203287
  • Summary: The case of an 82-year-old man with a history of low-grade B-cell lymphoma, now presenting with recurrent disease characterized by a composite histology of marginal zone lymphoma (MZL) and classic Hodgkin's lymphoma (CHL), illustrates key considerations in the diagnosis, staging, and treatment of CLs in geriatric patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Composite lymphoma (CL) is a rare hematologic condition characterized by the coexistence of two or more distinct lymphoma types within the same anatomical location or biopsy specimen. Although it comprises only 1%-4% of all lymphomas, its clinical importance lies in its diagnostic complexity and implications for treatment selection and prognosis [1]. The most frequently reported combination involves a B-cell non-Hodgkin's lymphoma (NHL), such as marginal zone lymphoma (MZL) or follicular lymphoma, paired with classic Hodgkin's lymphoma (CHL), as seen in this case [2]. > The etiology and pathogenesis of CL remain incompletely understood, though several theories have been proposed. These include the possibility of biclonal or divergent clonal evolution from a common progenitor, genetic instability, prior immunosuppressive therapy, and viral involvement, particularly Epstein-Barr virus (EBV) in the Hodgkin component [3,4]. EBV is known to contribute to lymphomagenesis by promoting B-cell proliferation and survival, especially in immunosenescent or immunocompromised hosts, a relevant consideration in elderly patients [5]. > From a diagnostic standpoint, CLs challenge conventional classification schemes. They often require extensive immunohistochemical analysis and molecular studies to distinguish and characterize each component. Immunophenotypic markers such as CD20, CD30, CD15, PAX5, Bcl-2, and CD3, in conjunction with EBV-encoded RNA (EBER) in situ hybridization, play a critical role in differentiating the B-cell and Hodgkin components [6]. Misdiagnosis or underdiagnosis can lead to suboptimal therapeutic strategies, particularly if only the indolent or aggressive component is identified. > Clinically, patients may present with B-symptoms, lymphadenopathy, or findings on surveillance imaging, as in our case. Management strategies for CL are not standardized due to its rarity and heterogeneity.
  • Snippet 2 (score: 0.424) > Composite lymphoma (CL) is a rare and diagnostically challenging condition where two or more distinct types of lymphoma coexist within the same anatomical site. We report the case of an 82-year-old man with a history of low-grade B-cell lymphoma, now presenting with recurrent disease characterized by a composite histology of marginal zone lymphoma (MZL) and classic Hodgkin's lymphoma (CHL). Management involved single-agent brentuximab due to comorbidities, followed by immune checkpoint inhibition upon relapse. This case illustrates key considerations in the diagnosis, staging, and treatment of CLs in geriatric patients. The clinical course further highlights the importance of personalized therapy selection based on age, comorbidities, and histological features. This case also contributes to the limited literature on real-world outcomes in patients with CL and underscores the need for future prospective studies and biomarker-driven treatment approaches in this rare entity.

[6] Current Progress in Investigating Mature T- and NK-Cell Lymphoma Gene Aberrations by Next-Generation Sequencing (NGS)

  • Authors: Lifen Zhu, Shufang Xie, Chen Yang, Nanni Hua, Yi Wu et al.
  • Year: 2021
  • Venue: Cancer Management and Research
  • URL: https://www.semanticscholar.org/paper/803d9d0d479883b6ac9fba1df46d9ee919821dd9
  • DOI: 10.2147/CMAR.S299505
  • PMID: 34239326
  • PMCID: 8259727
  • Citations: 3
  • Summary: Advances in NKTCL-related gene mutations are reviewed and next-generation sequencing is an increasingly developing gene detection technique, which has been widely used in lymphoma genetic research in recent years, making genetic mutation a new research hotspot in lymph cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.438) > Hodgkin's lymphoma is divided into nodular lymphocytes and classic Hodgkin's lymphoma, the former being the dominant type of the disease. 17 NK/T extranodal cell lymphoma is a major NK cell lymphoma with a ratio of 10.4% in mature T cell lymphoma and NK cell lymphoma. 18 Similar to other malignant proliferative diseases, lymphoma has genetic instability and chromosomal abnormalities, which together directly cause the development of malignancy. > NGS has been applied to accurate diagnosis of gene mutation, analysis of pathogenesis, prognosis monitoring and so on. 19 Recent developments in lymphoma genome sequencing have led to a preliminary appreciation of somatic mutation complexity in these tumors as well as a number of findings of significant functional and clinical significance, including studies on the prognostic impact of some genes on lymphoma or potential as drug targets. 20 ompared with cases of B cell lymphoma, there has been slower use of NGS for molecular studies in mature NK/ T-cell lymphoma. 21 This article reviews the application of NGS in scientific analysis and clinical detection of mature T-and NK-cell lymphoma (

[7] Editorial: Pathogenesis, immune escape, prognosis, and novel management of lymphoid proliferative disorders

  • Authors: W. Sang
  • Year: 2022
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/f34f83a45e0eca9c766112ae4fc2ef2775b0a177
  • DOI: 10.3389/fimmu.2022.1063418
  • PMID: 36479113
  • PMCID: 9720891
  • Summary: This Research Topic examines lymphoproliferative diseases (LPD), focusing on the pathological microenvironment, immune escape, prognosis, and the processes involved with seeking novel treatment methods. Including four editors who worked with invited reviewers, for this collection we invited potential contributors and accepted online contributions. Based on the comprehensive evaluation of the theme fi t and the quality of those manuscripts, 17 contributions were accepted. These manuscripts incl...
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > This Research Topic examines lymphoproliferative diseases (LPD), focusing on the pathological microenvironment, immune escape, prognosis, and the processes involved with seeking novel treatment methods. Including four editors who worked with invited reviewers, for this collection we invited potential contributors and accepted online contributions. Based on the comprehensive evaluation of the theme fi t and the quality of those manuscripts, 17 contributions were accepted. These manuscripts include different types of LPD, such as hemophagocytic lymphohistiocytosis (HLH), follicular cell lymphoma (FL), peripheral T cell lymphoma (PTCL), diffuse large B cell lymphoma (DLBCL), Castleman disease (CD), extranodal natural killer/T cell lymphoma (NK/ Hodgkin lymphoma (HL), and other subtypes of non-Hodgkin lymphoma (NHL). LPDs are often driven by different causes and have great differences in pathogenesis, pathology, and genetic characteristics. Clarifying these potential cloning and transformation mechanisms and regulatory mechanisms us better understand these kinds of diseases. The prognosis of DLBCL in the is et al. the elderly DLBCL is accompanied by undesirable clinical and molecular features, represented by the accumulation of oncogenic mutations and with the MYD88-like genetic subtype and immunosuppressive tumor microenvironment alterations. It is proposed that, in the elderly DLBCL patients need to explore new treatment methods based on these characteristics. Tumor protein 53 ( TP53 ) mutation predicts an

[8] Expression of Apoptosis Related and Proliferative Proteins in Malignant Lympho-Proliferative Disorders

  • Authors: Z. Jairajpuri, Rekha Ghai, S. Saluja, S. Kapur, K. Bhowmik
  • Year: 2017
  • Venue: Iranian Journal of Pathology
  • URL: https://www.semanticscholar.org/paper/0789eaebc75bc50bdeeab42c1e2171cd9832575d
  • DOI: 10.30699/IJP.2017.25051
  • PMID: 29531548
  • PMCID: 5835371
  • Citations: 3
  • Summary: An immunohistochemical analysis of patterns of apoptotic and cell proliferative related protein expression in different histological grades and immune phenotypes of malignant lymphomas and other lymphoproliferative disorders indicated the important role of Bcl-2 and Bax in biological behavior of lymphomas.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > The histological spectrum of benign and malignant lymphoproliferative disorders range from non-specific reactive hyperplasia to atypical lymphoid hyperplasia and lymphomas (Non-Hodgkin's Lymphoma (NHL) and Hodgkin's Disease (HD) (1). Molecular, biological and genetic discoveries have improved the primary diagnosis of lymphoproliferative processes permitting better assessment of prognosis within histologic groups (2). Furthermore, integration of clinical features with recent advances in lymphoma biology has contributed significantly to the understanding of tumor specific variables that have a direct impact on clinical behaviors. Integration of clinical features with morphology, cytochemistry and immune phenotype has clinical and prognostic value (3).A key issue regarding lymphoid neoplasm is to discriminate between disease entities and prognostic factors. Both apoptosis and mitosis serve as potential prognostic indicators and are firmly interrelated. The growth of both indolent and aggressive lymphomas depends on the proliferation and death rates of cancer cells. Cell proliferation, as determined by immunocytochemistry, using proliferation antigens Ki-67 and Proliferating Cell Nuclear Antigen (PCNA), is the principal determinant of tumor progression and prognosis. Apoptosis or programmed cell death on the other hand, occurs through a sequence of active mechanisms within the cell that are controlled by positive and negative regulators of the apoptotic pathway (4). A number of genes including c-myc, P53, Bcl-2 and Bax are known to regulate the apoptotic pathway with some preventing and others promoting cell death. The failure of apoptosis leads to the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein Bcl-2. Abnormally high levels of Bcl-2 help sustain tumors and can be used as a target in an approach to treat various hematologic malignancies (5).

[9] Role of CREB Protein Family Members in Human Haematological Malignancies

  • Authors: F. D'Auria, R. Pietro
  • Year: 2013
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/efe976ba9ae3c96fddd2df18a8ea4b90dd16aa8a
  • DOI: 10.5772/55368
  • Citations: 9
  • Influential citations: 1
  • Summary: The present chapter is aimed at revising literature focusing on the involvement of CREB/ATF family members in leukemogenesis and lymphomagenesis, in order to gain more insight into this matter that could result useful to the treatment of leukaemia and lymphoma diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.420) > Lymphomas are haematological malignancies of the lymphoid system. Deregulated gene expression is a hallmark of cancer and is well documented in B-cell lymphomas [98]. B cells are particularly susceptible to malignant transformation since the mechanisms involved in antibody diversification can cause chromosomal translocations and oncogenic mutations. Bcell lymphomas include Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (B-NHL). B-NHL consists of a heterogeneous group of diseases whose pathogenesis is associated with multiple genetic lesions affecting oncogenes and tumour-suppressor genes and whose treatment is related to the different grade of malignancy. The most common type of B-NHL is represented by the diffuse large B-cell lymphoma (DLBCL), which generally arises as a clinical evolution of the follicular lymphoma (FL). A number of papers have demonstrated the involvement of CREB family members in the pathogenesis of lymphoma. It has been previously found that CREB acts as a positive regulator of the translocated BCL-2 allele in FLs with the t(14;18) translocation [60] and that the high constitutive expression of ATF-3 is linked to the viability of Hodgkin/Reed-Sternberg cells and, thus, considered as a molecular hallmark of classical HL [99]. More recently, a number of studies have disclosed the implication of the HAT proteins CBP and p300 as tumour suppressors in B-cell neoplasms [100-102]. Nevertheless, the various mechanisms through which each of these cofactors specifically contributes to lymphomagenesis are still to be elucidated. As before mentioned, CBP and p300 function as co-activators of transcription factors and acetylate proteins relevant to lymphomagenesis such as p53, NF-κB, Bcl-6 and Hsp90 [100, 103,104].

[10] Identification of ATP1B1, a key copy number driver gene in diffuse large B-cell lymphoma and potential target for drugs

  • Authors: Shuo Zhang, Hongmin Wang, Aichun Liu
  • Year: 2022
  • Venue: Annals of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/a38e9a2ada49df4b57db652d8b663c64939bdde1
  • DOI: 10.21037/atm-22-4709
  • PMID: 36388804
  • PMCID: 9652577
  • Citations: 5
  • Summary: A Kyoto Encyclopedia of Genes and Genomes analysis found that ATP1B1 is a copy number driver gene that could potentially be adopted as a diagnostic biomarker and therapeutic target of DLBCL.
  • Evidence snippets:
  • Snippet 1 (score: 0.417) > Lymphoma is a malignant tumor that originates from the lymphoid hematopoietic system. Hodgkin's and non-Hodgkin's lymphomas are two common types. Existing data surveys have estimated that in 2020, there were 509,590 new cases as well as more than 248,724 lymphoma deaths worldwide (1). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for approximately 30% of all cases, which also includes specific subtypes or disease entities (2). Among the current clinical diagnostic and therapeutic strategies, R-CHOP (retuximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the preferred treatment choice and has an excellent ability to inhibit disease development (3). There are many patients who either relapse or experience primary refractory disease and eventually succumb to the illness (4,5). To provide new diagnostic and therapeutic ideas for the detection and treatments of DLBCL, DLBCL biomarker-related research and further exploration of the related molecular mechanisms are in demand. Thus, our research provides a new diagnostic and treatment strategy for the clinical treatment of DLBCL. > Genetic elements are key to DLBCL's etiology. Meanwhile, the development and progression of DLBCL are derived from a multistep pathway that involves genetic alteration accumulations at proto-oncogenes and carcinogenesis of tumor suppressive genes. The mechanisms of the above-mentioned process include chromosomal alterations, single nucleotide variants, copy number variations (CNVs), and epigenetic alterations (6,7). DLBCL carcinogenetic abnormality detection may act as a key indicator of prognosis, and could also act as a key contributing factor to the customized treatment of special markers. > CNVs are a recognized cancer hallmark that may result in the activation of oncogenes and the inactivation of genes that express tumor-suppressing attributes in several malignancies.

[11] Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers.

  • Authors: Anamarija M. Perry, Lauren B. Smith, A. Bagg
  • Year: 2021
  • Venue: Acta medica academica
  • URL: https://www.semanticscholar.org/paper/02e166d06164db4291a94b6778ec1c744614cc97
  • DOI: 10.5644/ama2006-124.329
  • PMID: 34075767
  • Citations: 7
  • Summary: The aim of this paper is to review morphologic, immunophenotypic, and molecular features of classic Hodgkin lymphoma, as well as different prognostic markers in this neoplasm. Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world. The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers. HRS cells are scattered within a dense inflammat...
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > The aim of this paper is to review morphologic, immunophenotypic, and molecular features of classic Hodgkin lymphoma, as well as different prognostic markers in this neoplasm. Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world. The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers. HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow. In the last two decades multiple prognostic markers related to HRS cells, the microenvironment or both, have been evaluated in patients with CHL. They include clinical, immunohistochemical, cytogenetic, and molecular markers that can predict survival and identify high-risk patients who will likely relapse after therapy. More recently, circulating tumor DNA analysis by next-generation sequencing has opened new avenues for diagnosis and disease monitoring after therapy. The increased understanding of molecular mechanisms underlying CHL pathogenesis has led to successful implementation of novel therapies, such as anti-PD-1 antibodies, which are becoming a mainstay of treatment in relapsed/refractory patients. CONCLUSION: Currently, pathologic prognostic markers are not routinely assessed at initial diagnosis of CHL. However, as more therapies become available, it will be important to identify patients with high-risk disease who may benefit from more intense or targeted therapy upfront.
  • Snippet 2 (score: 0.412) > Hodgkin lymphoma is a common lymphoma in the Western world accounting for 15-25% of all lymphomas. This group is comprised of two morphologically and immunophenotypically distinct entities -classic Hodgkin lymphoma (CHL) which accounts for over 90% of cases and nodular lymphocyte predominant Hodgkin lymphoma (1,2). Although "Hodgkin's disease" was first reported nearly 200 years ago and Hodgkin/Reed-Sternberg (HRS) cells were described at the turn of the 20 th century, the nature of this disease (i.e. neoplastic vs. infectious/inflammatory) remained a mystery for a long time (3,4). The B-cell origin of HRS cells was finally elucidated in the 1990s and the new terminology "Hodgkin lymphoma" was included in the Revised European American Lymphoma (REAL) Classification (5)(6)(7). Since then, CHL has been a focus of extensive research which paved the way for better risk stratification and novel therapies. > Classic Hodgkin lymphoma has a bimodal age distribution, with the first peak from 15 to 35 years of and the second after 55 years of age. In resourcepoor countries, however, the first peak occurs earlier in childhood. The overall male-to-female ratio is 1.5:1, but females have higher incidence of nodular sclerosis subtype of CHL (2,(8)(9)(10). Clini-Clinical Science cally, CHL mainly involves lymph nodes, most frequently above the diaphragm with cervical, mediastinal, axillary, and supraclavicular lymph node chains being most commonly affected. In a subset of patients, extranodal tissues are involved, such as spleen, lungs and liver (2,10). Bone marrow involvement is uncommon, occurring in approximately 5% of patients and is more common in the elderly and HIV positive patients (11).

[12] Impact of Nutritional Status on Survival and Development of Hodgkin’s Lymphoma: A Scoping Review

  • Authors: Sabina Krupa-Nurcek, Dominika Wiśniewska, Michał Klimas, Martyna Winiarska, Dominik Jucha et al.
  • Year: 2025
  • Venue: Nutrients
  • URL: https://www.semanticscholar.org/paper/358d0e6ac1fce5128bfe647a150a0c3fed5aedb8
  • DOI: 10.3390/nu17233777
  • PMID: 41374067
  • PMCID: 12694317
  • Summary: Available data suggest that a diet rich in vegetables, fruits, fiber, and omega-3 fatty acids may have a protective effect, reducing the risk of developing Hodgkin’s lymphoma and improving prognosis and survival through anti-inflammatory and immune-supporting effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > The review work indicates that nutrition plays a significant role in both the risk of development and the course and mortality of Hodgkin lymphoma. Excessive consumption of saturated fats, simple sugars and processed meat products can promote cancer transformation by inducing chronic inflammation, immune disorders and oxidative stress. On the other hand, a diet rich in vegetables, fruits, fiber and omega-3 fatty acids has antiinflammatory and immunomodulatory effects, supporting the body's defense mechanisms and improving treatment tolerance. The patient's nutritional status, both before diagnosis and during therapy, affects the prognosis, and malnutrition or obesity may increase the risk of complications and death. Further clinical studies are needed to precisely determine the relationship between diet quality and treatment outcomes in HL. > Nutrition plays a significant role in the course of cancer, including Hodgkin's lymphoma, influencing both disease progression, treatment efficacy, and patient mortality. The mechanisms linking nutritional factors to cancer are extremely complex and involve metabolic, immunological, and epigenetic interactions. Diet can modulate the risk of disease, the course of therapy, and prognosis, and its importance stems from its impact on the immune system, gut microbiota, cellular metabolism, and inflammatory processes. At the molecular level, dietary components influence the proliferation and apoptosis of lymphocytes, from which Hodgkin's lymphoma originates. Excessive intake of saturated fats and simple sugars promotes chronic inflammation and insulin resistance, which can stimulate signaling pathways associated with cancer development. In turn, a diet rich in antioxidants, fiber, and omega-3 fatty acids supports DNA repair mechanisms, reduces oxidative stress, and modulates the immune response, potentially reducing the risk of disease progression. The gut microbiota, shaped by diet, influences immunomodulatory metabolites, which can either support or weaken the effectiveness of chemotherapy. Diet is particularly important during Hodgkin lymphoma treatment. Chemotherapy and radiotherapy lead to taste disturbances, loss of appetite, nausea, and diarrhea, which increase the risk of malnutrition.

[13] Identifying a Novel BCL2L1-Targeting Peptide from Porcine Placenta for Lymphoma Therapy

  • Authors: Tassanee Ongtanasup, Nattawan Suwannakul, Komgrit Eawsakul
  • Year: 2025
  • Venue: ACS Omega
  • URL: https://www.semanticscholar.org/paper/bfea8ba76173cceedfd0cc34c31cf55906354dca
  • DOI: 10.1021/acsomega.5c09730
  • PMID: 41487244
  • PMCID: 12756794
  • Summary: By balancing high target efficacy with crucial drug-like properties, QPLLLDDR is identified not merely as a candidate but as the most pragmatically viable lead compound for future experimental validation as a parenteral therapeutic for lymphoma.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > In the United States, the lifetime risk of developing lymphoma is approximately 2.1%, with a slightly higher prevalence in males (5.0%) compared to females (1.5%). 9 At the molecular level, lymphoma's pathogenesis is characterized by profound genetic and molecular dysregulations involving critical genes such as BCL2L1, 10 CASP3, 11 NFKB1, 12 and Sphingosine-1-phosphate receptors. 13 These molecular players orchestrate intricate cellular processes of survival, proliferation, and apoptosis. The BCL2L1 gene, encoding the BCL-XL protein, serves as a pivotal antiapoptotic regulator, frequently overexpressed in lymphoid neoplasms. Epidemiological studies suggest that genetic alterations in this gene are present in approximately 30−40% of Non-Hodgkin Lymphoma cases, 14 significantly impacting disease progression and treatment outcomes. CASP3, a key executioner caspase, plays a fundamental role in the apoptotic cascade, with its dysregulation potentially contributing to lymphoma progression. Molecular epidemiology research indicates that mutations in this gene are associated with increased treatment resistance and poorer prognosis. 15 NFKB1, a critical transcription factor, emerges as a central mediator of inflammatory responses and cellular survival mechanisms. Epidemiological data suggest that its dysregulation is observed in up to 28−55% of lymphoma cases, 16 correlating with more aggressive disease phenotypes. Sphingosine-1-phosphate receptors facilitate complex signaling pathways that modulate lymphoma cell migration, proliferation, and metastatic potential. Recent studies have highlighted their role in approximately 54.2% of lymphoma cases, presenting potential therapeutic targets. 17 his study uses a systematic method to explore the molecular mechanisms of porcine peptides. Network pharmacology 18 and molecular docking, 19 two methods that can help bridge the gap in our knowledge, were applied. A system approach based on systems biology, network pharmacology can explore the complex interactions between peptides and various related proteins by revealing how peptides affect multiple targets within biological networks.

[14] Genomic landscape of mature B-cell non-Hodgkin lymphomas - an appraisal from lymphomagenesis to drug resistance.

  • Authors: D. Panda, N. Das, D. Thakral, Ritu Gupta
  • Year: 2022
  • Venue: Journal of the Egyptian National Cancer Institute
  • URL: https://www.semanticscholar.org/paper/8b2406b177783cfeed38c417e550521d4d2e6ef2
  • DOI: 10.1186/s43046-022-00154-z
  • PMID: 36504392
  • Citations: 4
  • Summary: The wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > BACKGROUND > Mature B-cell non-Hodgkin lymphomas are one of the most common hematological malignancies with a divergent clinical presentation, phenotype, and course of disease regulated by underlying genetic mechanism. > MAIN BODY > Genetic and molecular alterations are not only critical for lymphomagenesis but also largely responsible for differing therapeutic response in these neoplasms. In recent years, advanced molecular tools have provided a deeper understanding regarding these oncogenic drives for predicting progression as well as refractory behavior in these diseases. The prognostic models based on gene expression profiling have also been proved effective in various clinical scenarios. However, considerable overlap does exist between the genotypes of individual lymphomas and at the same time where additional molecular lesions may be associated with each entity apart from the key genetic event. Therefore, genomics is one of the cornerstones in the multimodality approach essential for classification and risk stratification of B-cell non-Hodgkin lymphomas. > CONCLUSION > We hereby in this review discuss the wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas.

[15] Predictive Modeling of Drug Response in Non-Hodgkin’s Lymphoma

  • Authors: H. Frieboes, B. Smith, Zhihui Wang, M. Kotsuma, Ken Ito et al.
  • Year: 2015
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/391dbd7ad2a4c83c60e034a2d6e0935f040c0e26
  • DOI: 10.1371/journal.pone.0129433
  • PMID: 26061425
  • PMCID: 4464754
  • Citations: 23
  • Summary: A proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions, and tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Lymphoma drug response has predominantly been studied at the subcellular-to-cellular scale (molecular cancer biology), or at the whole-organ and/or systemic scale (oncology and clinical applications) (e.g., see recent studies [1][2][3][4][5]). Despite a multitude of genetic, proteomic, and histological analyses to understand lymphoma progression and treatment, drug resistance remains a major challenge to chemotherapy [6]. It is well known that specific phenomena at various physical scales contribute to this resistance. At the molecular scale, genetic/proteomic make-up can lead to intrinsic cellular drug resistance [7]; at an intermediate scale, transport barriers in the tissue microenvironment due to diffusion gradients of oxygen, nutrients, and drug may impede optimal response to cell-cycle specific drugs through cell quiescence as well as insufficient drug levels to achieve cytotoxicity [8,9]; at the tissue scale, tumor morphological instability as a result of vascularization irregularities may lead to tumor tissue fragmentation and increased invasiveness [10]. > The relative contribution to drug resistance due to intrinsic cellular mechanisms vs. physiologic resistance originating from the 3D tumor microenvironment is unclear. Cellular-intrinsic drug resistance depends on molecular mechanisms that support individual cell survival, including increased repair pathways and detoxification, adaptations leading to failure of apoptosis, and alterations in transmembrane drug transport [11]. These mechanisms define the resistant phenotype at the molecular scale primarily based on the cells' molecular and genetic properties. Physiologic resistance that is not a direct result of the molecular phenotype can arise when a cell enters a quiescent proliferative state, thus becoming insensitive to the mode of action of cell-cycle specific drugs such as doxorubicin (Dox) and cyclophosphamide. An arrested proliferative state is a well-studied mechanism of physiological resistance to most chemotherapeutic agents currently in use. This resistance may depend on tumor and vascular geometry as well as distance to blood vessels and diffusion and pressure gradients.

[16] BEND4: a novel prognostic biomarker in diffuse large B-cell lymphoma

  • Authors: Yanfang Wang, Zhen-Hao Zhang, Lian-yong Xi, Hua Wang, Fei Dong
  • Year: 2025
  • Venue: Discover Oncology
  • URL: https://www.semanticscholar.org/paper/fc004bda08760e875c9fbf2cd0f7348dd3aeb9ae
  • DOI: 10.1007/s12672-025-02519-x
  • PMID: 40327257
  • PMCID: 12055718
  • Citations: 1
  • Summary: Elevated BEND4 levels were linked to poor prognosis and chemoresistance in DLBCL, potentially due to transcriptional regulation and immune suppression roles, and may represent a viable therapeutic target in DLBCL.
  • Evidence snippets:
  • Snippet 1 (score: 0.403) > Diffuse large B-cell lymphoma (DLBCL) is the most prevalent lymphocytic cancer in adults, comprising 30-40% of non-Hodgkin's lymphoma cases [1]. DLBCL shows substantial variability in clinical presentations, biological traits, and treatment responses [2]. While rituximab-based chemotherapy cures many patients, 40% experience relapse or initial drug resistance [3]. Advances in gene sequencing have classified DLBCL into seven genetic subtypes, each with distinct prognoses and potential targeted treatments [4]. However, the exact mechanisms of tumor recurrence or progression remain unclear, highlighting the need for identifying high-risk biomarkers to improve molecular understanding, enhance risk stratification, and support targeted drug development.

[17] Novel Approaches in Molecular Characterization of Classical Hodgkin Lymphoma

  • Authors: Diede A G van Bladel, W. Stevens, M. van den Brand, L. Kroeze, P. Groenen et al.
  • Year: 2022
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/83b26089091ab6fe6ca9ffe9413761b325018d53
  • DOI: 10.3390/cancers14133222
  • PMID: 35805000
  • PMCID: 9264882
  • Citations: 11
  • Summary: This review provides an overview of the recent advances in genotyping the clonal and mutational landscape of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings.
  • Evidence snippets:
  • Snippet 1 (score: 0.397) > Simple Summary The unique tumor composition of classical Hodgkin lymphoma (cHL), with only a small fraction of malignant Hodgkin and Reed–Sternberg cells within the tumor tissue, has created many challenges to characterize the genetic alterations that drive this lymphoid malignancy. Major advances in sequencing technologies and detailed analysis of circulating tumor DNA in blood samples of patients have provided important contributions to enhance our understanding of the pathogenesis of cHL. In this review, we provide an overview of the recent advances in genotyping the clonal and mutational landscape of cHL. In addition, we discuss different next-generation sequencing applications to characterize tumor tissue and cell-free DNA, which are now available to improve the diagnosis of cHL, and to monitor therapeutic response or disease progression during treatment and follow up of cHL patients. Abstract Classical Hodgkin lymphoma (cHL) represents a B-cell lymphoproliferative disease characterized by clonal immunoglobulin gene rearrangements and recurrent genomic aberrations in the Hodgkin Reed–Sternberg cells in a reactive inflammatory background. Several methods are available for the molecular analysis of cHL on both tissue and cell-free DNA isolated from blood, which can provide detailed information regarding the clonal composition and genetic alterations that drive lymphoma pathogenesis. Clonality testing involving the detection of immunoglobulin and T cell receptor gene rearrangements, together with mutation analysis, represent valuable tools for cHL diagnostics, especially for patients with an atypical histological or clinical presentation reminiscent of a reactive lesion or another lymphoma subtype. In addition, clonality assessment may establish the clonal relationship of composite or subsequent lymphoma presentations within one patient. During the last few decades, more insight has been obtained on the molecular mechanisms that drive cHL development, including recurrently affected signaling pathways (e.g., NF-κB and JAK/STAT) and immune evasion. We provide an overview of the different approaches to characterize the molecular composition of cHL, and the implementation of these next-generation sequencing-based techniques in research and diagnostic settings.

[18] In silico analyses reveal common cellular pathways affected by loss of heterozygosity (LOH) events in the lymphomagenesis of Non-Hodgkin’s lymphoma (NHL)

  • Authors: C. Aya-Bonilla, E. Camilleri, L. Haupt, R. Lea, M. Gandhi et al.
  • Year: 2014
  • Venue: BMC Genomics
  • URL: https://www.semanticscholar.org/paper/42b9cff292bb57fa69db22d2b49a7433821e8d4b
  • DOI: 10.1186/1471-2164-15-390
  • PMID: 24885312
  • PMCID: 4041994
  • Citations: 8
  • Influential citations: 1
  • Summary: The evidence obtained in this research supports findings suggesting that FL and DLBCL share common pathogenic mechanisms and suggests that activation of PTPRJ might be an interesting novel chemotherapeutic target for the treatment of these B-cell tumours.
  • Evidence snippets:
  • Snippet 1 (score: 0.395) > The identification of altered pathways in tumour cells has provided a more holistic understanding of the pathogenic mechanisms that underlie the genesis, progression and chemoresponse of cancer. As a consequence, malfunction of a gene or a group of genes must be analysed as part of a complex network of components that are highly related to each other. However, this analysis is limited by factors such as the lack of analytic tools to convert and integrate, in a feasible and reliable manner, large amounts of data derived from different high-throughput genomic approaches into outputs with more biological meaning. > Non-Hodgkin's lymphoma (NHL) represents a highly biological and clinical heterogeneous group of blood cancers [1,2]. Two of the most common NHL subtypes are Diffuse Large B-cell Lymphoma (DLBCL), an aggressive lymphoma, and Follicular lymphoma (FL), a slow-growing type of lymphoma, which account for around 50% of NHL cases [1,3]. The poor treatment outcomes obtained between 20-40% of cases with these NHL lymphomas has prompted studies aimed at the discovery of genes and pathways that could act as novel targets for a therapy that increase the survival rates of patients suffering from NHL [4][5][6]. However, the high genetic variability observed within NHL subtypes, has limited the understanding of the pathology of these NHL subtypes, as well as the discovery of new molecular targets for therapeutic development. > In a previous study, the integration of copy number (CNV) and gene expression profiling (GEP) data from DLBCL and FL cases, allowed us to identify common and disease-specific genetic alterations targeting known oncogenic pathways, such as the mitogen activated protein kinase (MAPK) and apoptosis signalling pathways, unmasking common pathogenic mechanisms underlying the malignant phenotype of these biologically and genetically distinct NHL subtypes [7].

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.