Large B-cell lymphoma with IRF4 rearrangement
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Large B-cell Lymphoma with IRF4 Rearrangement.
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
- Afia Hasnain, MBBS, PhD
Cancer Category / Type
Cancer Sub-Classification / Subtype
- Large B-cell Lymphoma (LBCL) with IRF4 Rearrangement
Definition / Description of Disease
- Rare LBCL harboring IRF4 gene rearrangement and involving head & neck lymphoid tissues typically in the pediatric age group[1][2][3]
Synonyms / Terminology
- None
Epidemiology / Prevalence
- Rare ~0.05% of LBCLs
- Median age 12 years
- Male ~ Female
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Clinical Features
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| Signs and Symptoms | EXAMPLE: Asymptomatic (incidental finding on complete blood counts)
EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE: Cytopenias
EXAMPLE: Lymphocytosis (low level) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.
- Lymphadenopathy
- Tonsillar hypertrophy
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Sites of Involvement
- Head and neck lymph nodes
- Waldeyer ring
- Gastrointestinal tract
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Morphologic Features
- Medium to large sized neoplastic cells
- Chromatin is more open than seen in centrocytes
- Small basophilic nucleoli
- Follicular type: large neoplastic follicles are seen with a back-to-back growth pattern and absent or attenuated mantle zones
- Follicles lack serpiginous configuration and starry-sky pattern
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Immunophenotype
| Finding | Marker |
|---|---|
| Positive (universal) | CD20, CD79a, PAX5, BCL6, MUM1 |
| Positive (subset) | CD10, BCL2 |
| Negative (universal) | PRDM1 |
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Chromosomal Rearrangements (Gene Fusions)
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| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: 3'ABL1 / 5'BCR | EXAMPLE: der(22) | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add reference) |
Yes | No | Yes | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.
IG/IRF4 translocations activate the transcription of the IRF4 gene resulting in increased expression of the IRF4/MUM1 protein. Translocations between IGH, IGL, and IGK with IRF4 have been described. Most common translocation partner is IGH with a cytogenetically cryptic t(6;14)(p25;q32) translocation, whereas, light chain variants are rare.
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(6;14)(p25;q32) IGH/IRF4 der(14) Most common t(6;22)(p25;q11) IGL/IRF4 der(22) Rare t(2;6)(p12;p25) IGK/IRF4 der(2) Rare editUnassigned ReferencesThe following referenees were placed in the header. Please place them into the appropriate locations in the text.
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
- Diagnostic: IG/IRF4 rearrangements are diagnostic and specific to this disease entity. Further studies on mutation profiling in these cases may help in defining parameters for risk stratification.
- Prognostic: Favorable outcome after treatment (combination immunochemotherapy with or without radiation)
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Individual Region Genomic Gain / Loss / LOH
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| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7:1- 159,335,973 [hg38] |
EXAMPLE:
chr7 |
Yes | Yes | No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8:1-145,138,636 [hg38] |
EXAMPLE:
chr8 |
No | No | No | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.
- One study using comparative genomic hybridization showed complex changes with gains of 7q32.1-qter, 11q22.3-qter, and Xq28 and losses of 6q13–16.1, 15q14–22.3, and 17p.
- TP53 point mutations were detected with a loss of 17p showing inactivation of TP53 in a subset of these cases.
- Further studies are needed to define the potential functional effect of these variants
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Characteristic Chromosomal Patterns
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| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.IRF4 Rearrangement[3]
Gene Mutations (SNV / INDEL)
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| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.
- These tumors have shown a distinct molecular profile characterized by frequent mutations in IRF4 and NF-κB-related genes (CARD11, CD79B, and MYD88) and overexpression of downstream target genes of the NF-κB pathway.
- SNV profile for LBCL-IRF4: Frequently mutated genes were IRF4 (76%), CARD11 (35%), and CCND3 (24%)
- CNV profile for LBCL-IRF4: Frequent 17p/TP53 deletions (25%), without gene mutations, and gains of chromosome 7 (45%) and 11q12.3-q25 (35%).
- Further studies are needed to define the potential functional effect of these variants.
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Epigenomic Alterations
- No recurrent epigenetic changes have been reported in literature.
- Further studies are needed to describe the role of epigenomics in this entity
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Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.
- IRF4 rearrangement with IGH locus detected in most cases
- Mutations in NF-κB-related genes, in particular the CARD11 gene are responsible for overexpression of the NF-κB pathway
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Genetic Diagnostic Testing Methods
- IG/IRF4 rearrangements
- Strong and diffuse MUM1 staining suggestive of this diagnosis
- Cryptic IRF4 translocation are not detectable by cytogenetic techniques
- IRF rearrangements can be detected by IHC and FISH analysis
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Familial Forms
- No familial form reported in literature.
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Additional Information
- None
Links
- None
References
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- ↑ Liu, Qingyan; et al. (2013-03). "Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma". The American Journal of Surgical Pathology. 37 (3): 333–343. doi:10.1097/PAS.0b013e31826b9b57. ISSN 1532-0979. PMC 3566339. PMID 23108024. Check date values in:
|date=(help) - ↑ Louissaint, Abner; et al. (2012-09-20). "Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement". Blood. 120 (12): 2395–2404. doi:10.1182/blood-2012-05-429514. ISSN 1528-0020. PMID 22855608.
- ↑ 3.0 3.1 3.2 3.3 Salaverria, Itziar; et al. (2011-07-07). "Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults". Blood. 118 (1): 139–147. doi:10.1182/blood-2011-01-330795. ISSN 0006-4971.
- ↑ 4.0 4.1 4.2 4.3 de Leval, L.; et al. (2012-12). "Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study". Annals of Oncology: Official Journal of the European Society for Medical Oncology. 23 (12): 3143–3151. doi:10.1093/annonc/mds150. ISSN 1569-8041. PMID 22700993. Check date values in:
|date=(help) - ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Chisholm, Karen M.; et al. (2019-08). "IRF4 translocation status in pediatric follicular and diffuse large B‐cell lymphoma patients enrolled in Children's Oncology Group trials". Pediatric Blood & Cancer. 66 (8). doi:10.1002/pbc.27770. ISSN 1545-5009. Check date values in:
|date=(help) - ↑ Sukswai, Narittee; et al. (2020-01). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52 (1): 53–67. doi:10.1016/j.pathol.2019.08.013. ISSN 1465-3931. PMID 31735345. Check date values in:
|date=(help) - ↑ Ramis-Zaldivar, Joan Enric; et al. (01 23, 2020). "Distinct molecular profile of IRF4-rearranged large B-cell lymphoma". Blood. 135 (4): 274–286. doi:10.1182/blood.2019002699. ISSN 1528-0020. PMC 6978155. PMID 31738823. Check date values in:
|date=(help) - ↑ Salaverria, Itziar; et al. (2013-02). "High resolution copy number analysis of IRF4 translocation-positive diffuse large B-cell and follicular lymphomas". Genes, Chromosomes & Cancer. 52 (2): 150–155. doi:10.1002/gcc.22014. ISSN 1098-2264. PMID 23073988. Check date values in:
|date=(help) - ↑ 9.0 9.1 9.2 Ramis-Zaldivar, Joan Enric; et al. (01 23, 2020). "Distinct molecular profile of IRF4-rearranged large B-cell lymphoma". Blood. 135 (4): 274–286. doi:10.1182/blood.2019002699. ISSN 1528-0020. PMC 6978155. PMID 31738823. Check date values in:
|date=(help) - ↑ Salaverria, Itziar; et al. (2013-02). "High resolution copy number analysis of IRF4 translocation-positive diffuse large B-cell and follicular lymphomas". Genes, Chromosomes & Cancer. 52 (2): 150–155. doi:10.1002/gcc.22014. ISSN 1098-2264. PMID 23073988. Check date values in:
|date=(help)
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “Large B-cell lymphoma with IRF4 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Large_B-cell_lymphoma_with_IRF4_rearrangement.