Cutaneous Anaplastic Large Cell Lymphoma, 6p25.3 (IRF4) Rearrangement, FISH, Tissue
Providing potential prognostic information in patients with documented systemic anaplastic lymphoma kinase-negative anaplastic large cell lymphoma
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a systemic CD30-positive T-cell lymphoma that was included as a provisional entity in the 2008 World Health Organization (WHO) classification of hematopoietic neoplasms. By definition, ALK-negative ALCL resembles ALK-positive ALCL but lacks ALK protein or ALK gene rearrangements. It affects predominantly adults with a male to female ratio of about 1.5 to 1. ALK-negative ALCL typically involves lymph nodes and sometimes extranodal sites. ALK-negative ALCL must be distinguished clinically from primary cutaneous ALCL, which also is usually ALK-negative.
Recurrent rearrangements of the DUSP22(IRF4) (dual-specificity phosphatase-22,interferon regulatory factor-4) gene locus on 6p25.3 have been described in CD30-positive T-cell lymphomas and lymphoproliferative disorders, including systemic ALK-negative ALCL, primary cutaneous ALCL, and lymphomatoid papulosis. The presence of this rearrangement has potential prognostic significance in ALCL. Specifically, systemic ALK-negative ALCLs with rearrangements of DUSP22(IRF4) but without rearrangements of TP63 on 3q28 have been reported to be associated with favorable clinical outcomes similar to those in systemic ALK-positive ALCL. The frequency of these rearrangements in ALK-negative ALCL was reported to be 30% in 1 recent series; therefore, absence of a DUSP22(IRF4) rearrangement does not exclude ALK-negative ALCL. Because a similar frequency of this rearrangement has been reported in primary cutaneous ALCL (28% in 1 recent report), the presence of a DUSP22(IRF4) rearrangement does not distinguish between systemic ALK-negative ALCL and primary cutaneous ALCL, and does not eliminate the need for, or take precedence over, collecting a thorough clinical history and staging.
This test does not distinguish between rearrangements localized to the DUSP22 gene and those localized to the IRF4 gene. IRF4 rearrangements are seen in rare CD30-negative T-cell lymphomas, a subset of multiple myelomas, and occasional B-cell lymphomas of various subtypes. Clinical utility for demonstrating their presence in these other neoplasms has not been established.
For other FISH testing for T-cell disorders in tissues, see:
-70014 / Peripheral T-Cell Lymphoma (PTCL), TP63 (3q28) Rearrangement, FISH, Tissue
-89041 / T-Cell Lymphoma, FISH, Tissue
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretative report will be provided.
Systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) with rearrangements of DUSP22(IRF4) but without rearrangements of TP63 on 3q28 have been associated with favorable clinical outcomes. Therefore, presence or absence of a TP63 rearrangement needs to be determined to interpret this test accurately. The clinical significance of identifying this rearrangement in cutaneous CD30-positive T-cell lymphoproliferative disorders, including primary cutaneous ALCL and lymphomatoid papulosis, has not been established. Furthermore, other T- and B-lineage neoplasms can demonstrate this finding. Clinical and pathologic correlation is recommended.
A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff for the DUSP22(IRF4) probe set.
A negative result suggests that an DUSP22(IRF4) gene rearrangement is not present, but does not exclude the diagnosis of ALCL.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not approved by the FDA and it is best used as an adjunct to existing clinical and pathologic information.
Fixatives other than formalin (eg, Prefer, Bouin's) may not be successful for FISH assays. Although FISH testing will not be rejected due to nonformalin fixation, results may be compromised.
Paraffin-embedded tissues that have been decalcified are generally unsuccessful for FISH analysis. The pathologist reviewing the hematoxylin and eosin-stained slide may find it necessary to cancel testing.
FISH analysis was performed on 33 formalin-fixed, paraffin-embedded tissue samples; 8 cutaneous anaplastic large cell lymphoma (ALCL) tumors; and 25 noncancerous control specimens. The normal controls were used to generate a normal cutoff for this assay. Rearrangement of IRF4 was identified in 8 of 8 (100%) cutaneous ALCL specimens.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Feldman AL, Law M, Remstein ED, et al: Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas. Leukemia 2009;23:574-580
2. Feldman AL, Dogan A, Smith DI, et al: Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood 2011 Jan 20;117(3):915-919
3. Parilla Castellar ER, Jaffe ES, Said JW, et al: ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 2014:Epub ahead of print (June 3)