Cutaneous Anaplastic Large Cell Lymphoma, 6p25.3 (IRF4) Rearrangement, FISH, Tissue
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Primary cutaneous anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell lymphoproliferative disorder presenting in the skin and affecting predominantly adults with a male to female ratio of about 2:1 to 3:1. Most patients have solitary or localized tumor nodules, often with ulceration. About 20% of cases are multifocal. Regional lymph nodes may be secondarily involved.
The differential diagnosis in skin biopsies includes lymphomatoid papulosis (LyP), transformed mycosis fungoides (MF), and secondary skin involvement by systemic ALCL. All these disorders have overlapping morphologic and immunophenotypic features, making collection of a comprehensive clinical history and staging paramount. LyP typically demonstrates a chronic course with a history of waxing and waning papular skin lesions. Transformed MF requires an established diagnosis of MF. Diagnosis of systemic ALCL is based on presence of systemic disease, timing of skin versus nodal disease, with or without the presence of anaplastic lymphoma kinase (ALK) protein or ALK gene rearrangements, both of which are absent in cutaneous ALCL based on World Health Organization (WHO) criteria.
Recurrent translocations in or near the IRF4 (interferon regulatory factor 4) gene locus on 6p25.3 have been described in cutaneous ALCLs. IRF4 translocations occur in 20% to 57% of cutaneous ALCLs, and recent studies have shown high specificity for this disorder when present in skin biopsies involved by T-cell lymphoproliferative disorders. Most CD30-positive T-cell lymphoproliferative disorders are positive for the IRF4/MUM1 protein by immunohistochemistry, regardless of translocation status; thus, unlike ALK, IRF4/MUM1 immunohistochemistry is not a surrogate for testing for IRF4 translocations.
There currently are insufficient data to suggest presence of an IRF4 translocation has prognostic value in T-cell lymphoproliferative disorders. Absence of an IRF4 translocation does not exclude cutaneous ALCL. Rare instances of IRF4 translocations have been reported in LyP, transformed MF, systemic ALK-negative ALCL, and CD30-negative systemic T-cell lymphoma; therefore, testing for IRF4 translocations does not eliminate the need for, or take precedence over, collecting a thorough clinical history and staging.
IRF4 translocations are also seen in a subset of multiple myelomas and occasional B-cell lymphomas of various subtypes; however, clinical utility for demonstrating their presence in B-lineage neoplasms has not been established.
For testing for other T-cell disorders in tissues, see 89041 T-Cell Lymphoma, FISH, Tissue.
Supporting the diagnosis of cutaneous anaplastic large cell lymphoma when coordinated with a consultation by anatomic pathology
Among cutaneous CD30-positive T-cell lymphoproliferative disorders, rearrangement of the IRF4 (interferon regulatory factor 4) gene at 6p25.3 is most closely associated with a diagnosis of cutaneous anaplastic large cell lymphoma (ALCL). However, systemic ALCL, lymphomatoid papulosis, and transformed mycosis fungoides are not excluded by this result. 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 IRF4 probe set.
A positive result is consistent with the diagnosis of ALCL, but is not exclusive to this disorder. Among cutaneous CD30-positive T-cell lymphoproliferative disorders, rearrangement of the IRF4 gene at 6p25.3 is most closely associated with a diagnosis of cutaneous anaplastic large cell lymphoma (ALCL). However, systemic ALCL, lymphomatoid papulosis, and transformed mycosis fungoides are not excluded by this result. Furthermore, other T- and B-lineage neoplasms can demonstrate this finding. Clinical and pathologic correlation is recommended.
A negative result suggests that an 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 US Food and Drug Administration 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 slide may find it necessary to cancel testing.
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.
Clinical References 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. Pham-Ledard A, Prochazkova-Carlotti M, Laharanne E, et al: IRF4 gene rearrangements define a subgroup of CD30-positive cutaneous T-cell lymphoma: a study of 54 cases. J Invest Dermatol 2010;130:816-825
3. Wada D, Law M, de Souza A, et al: IRF4 Translocations are specific for cutaneous anaplastic large cell lymphoma in skin biopsies involved by T-cell lymphoproliferative disorders. Mod Pathol 2009;22(suppl 1):289A (abstract 1308)