HAEM5:Large B-cell lymphoma with IRF4 rearrangement

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Large B-cell Lymphoma with IRF4 Rearrangement.

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Primary Author(s)*

• Afia Hasnain, MBBS, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	Large B-cell lymphomas
Subtype(s)	Large B-cell lymphoma 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

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 Features

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• 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)

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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

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• 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).

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• 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 / Patterns

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IRF4 Rearrangement

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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)

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• 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

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• 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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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 02/10/2025, https://ccga.io/index.php/HAEM5:Large_B-cell_lymphoma_with_IRF4_rearrangement.