Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies

Abstract

Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. Nine of forty-five (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, fluorescence in situ hybridization for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99% and 90%, respectively (p=0.00002, Fisher’s exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98% and 90%, respectively (p=0.005). Fluorescence in situ hybridization abnormalities other than translocations and IRF4 protein expression were seen in 13% and 65% of cases, respectively, but were non-specific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of fluorescence in situ hybridization for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all fluorescence in situ hybridization studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.

Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders

“…Rearrangements of 6p25.3 are recurrent in ALK-negative anaplastic large cell lymphomas and are most common in primary cutaneous anaplastic large cell lymphoma, where they are seen in about 28% of cases. 8,[23][24][25] This finding is an additional feature shared between patients with primary mucosal CD30-positive T-cell lymphoproliferations and primary cutaneous cases. A 6p25.3 rearrangement also was seen in a patient with orbital disease (case 15) but unfortunately staging data were not available.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…In contrast, the TCR gene loci, while involved in recurrent chromosomal translocations in precursor T-cell lymphoblastic leukemias/ lymphomas, are rarely involved in recurrent translocations in mature T-cell lymphoproliferative disorders [65,66]. With the exception of translocations involving the interferon regulatory factor 4 (IRF4) gene (also known as MUM1) in a subset of cutaneous anaplastic large cell lymphomas, recurrent chromosomal translocations are infrequently observed in CTCL [67][68][69][70][71]. Despite this, a number of signaling pathways regulating cell-cycle progression and survival have been implicated in CTCL pathogenesis.…”

Aspects moléculaires des lymphomes T périphériques (1)

“…Cette translocation affecte dans 1/3 des cas le gène IRF4 et dans 2/3 des cas le gène DUSP22 [50,56,57]. Le facteur de transcription IRF4/MUM1 est connu pour être un important régulateur de la différencia-tion lymphoïde normale, fortement exprimé dans les plasmocytes et les lymphocytes T activés [72].…”

“…En revanche, quand le gène affecté en 6p25 est DUSP22, son partenaire se situe dans plus de la moitié des cas en 7q32.3, à proximité du site D'autres partenaires d'ALK ont par la suite été rapportés [15,17,55] (Tableau III). Outre les translocations impliquant le gène ALK, les LAGC ALK + peuvent présenter d'autres anomalies cytogénétiques telles que des pertes en 4q13-q28, 6q13-q22, 11q14-q23, et 13q, et/ou des gains en 7p11-pter et du chromosome 17 [50,52,[56][57][58]. Les réarrangements de ALK entraînent une activation constitutive de la tyrosine kinase ALK [17], qui conduit à l'activation de multiples voies de signalisation telles que PI3K/AKT/mTOR, JAK/STAT3, ou encore RAS/ ERK [59], avec pour conséquences une diminution de l'apoptose et une prolifération accrue des cellules tumorales.…”