Large B-cell Lymphoma with IRF4 Rearrangement

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editPREVIOUS EDITION
This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

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 [4][5]

  • Rare ~0.05% of LBCLs
  • Median age 12 years
  • Male ~ Female

Clinical Features [4][5]

  • Lymphadenopathy
  • Tonsillar hypertrophy

Sites of Involvement [4]

  • Head and neck lymph nodes
  • Waldeyer ring
  • Gastrointestinal tract

Morphologic Features [4]

  • 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

Immunophenotype [5][6]

Finding Marker
Positive (universal) CD20, CD79a, PAX5, BCL6, MUM1
Positive (subset) CD10, BCL2
Negative (universal) PRDM1

Chromosomal Rearrangements (Gene Fusions) [3][7]

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

Characteristic Chromosomal Aberrations / Patterns

IRF4 Rearrangement[3]

Genomic Gain/Loss/LOH[8]

  • 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

Gene Mutations (SNV/INDEL)[9]

  • 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.

Epigenomics (Methylation)[5][9]

  • No recurrent epigenetic changes have been reported in literature.
  • Further studies are needed to describe the role of epigenomics in this entity

Genes and Main Pathways Involved[9]

  • 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


Diagnostic Testing Methods[10]

  • 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


Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)[3][5]

  • 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)

Familial Forms[5]

  • No familial form reported in literature.

Other Information

  • None

Links

  • None

References

(use "Cite" icon at top of page)

  1. ↑ 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)
  2. ↑ 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. ↑ 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. ↑ 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. ↑ 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)
  6. ↑ 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)
  7. ↑ 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)
  8. ↑ 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. ↑ 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)
  10. ↑ 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)

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

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