IRF4/DUSP22 Gene Rearrangement by FISH

IRF4/DUSP22 (6p25) Gene Rearrangement by FISH 3001568
Method: Fluorescence in situ Hybridization

Test is useful in identifying ALK-negative anaplastic large cell lymphomas and large B-cell lymphoma with IRF4 rearrangement

The rearrangement is associated with an improved prognosis

The IRF4/DUSP22 locus is rearranged in a newly recognized subtype of non-Hodgkin lymphoma, large B-cell lymphoma with IRF4 rearrangement. These lymphomas are uncommon, but are clinically distinct from morphologically similar lymphomas, including diffuse large B-cell lymphoma, high-grade follicular lymphoma, and pediatric-type follicular lymphoma. The IRF4/DUSP22 locus is also rearranged in a subset of ALK-negative anaplastic large cell lymphomas (ALCL), where this rearrangement is associated with a significantly better prognosis.

Disease Overview

Incidence

  • Large B-cell lymphoma with IRF4 rearrangement accounts for <1% of all non-Hodgkin B-cell lymphomas overall
    • More common in younger patients, with an incidence of 5-6% under age 18
  • IRF4/DUSP22 rearrangement is found in 30% of ALK-negative ALCLs

Symptoms/Findings

Large B-cell lymphoma with IRF4 rearrangement typically presents with limited stage disease in the head and neck, while the presentation of ALK-negative ALCLs is variable.

Disease-Oriented Information

Patients with large B-cell lymphoma with IRF4 rearrangement typically have a favorable outcome after treatment. Rearrangement of the IRF4/DUSP22 locus in ALK-negative ALCL is associated with a better prognosis than ALK-negative ALCL without this rearrangement.

Test Interpretation

Analytical Sensitivity

The limit of detection (LOD) for the IRF4/DUSP22 probe was established by calculating the upper limit of the abnormal signal pattern in normal cells using the Microsoft Excel BETAINV function. The LOD of IRF4/DUSP22 fluorescence in situ hybridization (FISH) is 11% when 100 cells are enumerated. Using the LOD of 11% the analytical sensitivity was found to be 100% when testing two 6p25 rearranged samples.

Results

Positive

  • Depending on the context of the case, the presence of the 6p25 gene rearrangement supports a diagnosis of large B-cell lymphoma with IRF4 rearrangement or ALK-negative ALCL with IRF4/DUSP22 rearrangement.

Negative

  • Absence of the 6p25 gene rearrangement

Limitations

  • IRF4/DUSP22 FISH testing has not been validated for
    • Tissue fixed in alcohol-based or non-formalin fixatives
    • Decalcified tissue
  • Results should be analyzed in conjunction with morphology, immunohistochemistry, and immunophenotyping results.
References 
  1. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Harald S, Thiele J, Vardiman J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon, France: International Agency for Research on Cancer, 2008.
  2. Salaverria I, Philipp C, Oschlies I, Kohler CW, Kreuz M, Szczepanowski M, Burkhardt B, Trautmann H, Gesk S, Andrusiewicz M, Berger H, Fey M, Harder L, Hasenclever D, Hummel M, Loeffler M, Mahn F, Martin-Guerrero I, Pellissery S, Pott C, Pfreundschuh M, Reiter A, Richter J, Rosolowski M, Schwaenen C, Stein H, Trümper L, Wessendorf S, Spang R, Küppers R, Klapper W, Siebert R, Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe, German High-Grade Lymphoma Study Group, Berlin-Frankfurt-Münster-NHL trial group. Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood. 2011; 118(1): 139-47. PubMed
  3. Castellar ER, Jaffe ES, Said JW, Swerdlow SH, Ketterling RP, Knudson RA, Sidhu JS, Hsi ED, Karikehalli S, Jiang L, Vasmatzis G, Gibson SE, Ondrejka S, Nicolae A, Grogg KL, Allmer C, Ristow KM, Wilson WH, Macon WR, Law ME, Cerhan JR, Habermann TM, Ansell SM, Dogan A, Maurer MJ, Feldman AL. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014; 124(9): 1473-80. PubMed

Last Update: November 2019