DUSP22-rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers

Abstract

DUSP22-rearranged anaplastic lymphomas are characterized by specific morphological features and a lack of cytotoxic and JAK/STAT surrogate markers ALK-negative anaplastic large cell lymphoma (ALKnegative ALCL) is a heterogeneous disease with very disparate outcomes. Molecular studies have identified chromosomal rearrangements involving the DUSP22-IRF4 locus on 6p25.3 (DUSP22 rearrangements) as a favorable prognostic factor, associated with complete remission after first treatment thereby suggesting that this subgroup of patients may not gain additional benefit from autologous stem cell transplantation in first remission. [1][2][3] Recognition of these cases is critical, and we therefore aimed to study in greater detail the histological and immunophenotypic features of DUSP22-rearranged ALK-negative ALCLs.After approval by the Institutional Review Board of the Hospital Universitario Marqués de Valdecilla and the Fundación Jiménez Díaz, Spain, we collected 91 cases with a diagnosis of systemic or primary cutaneous ALCL made at the participating institutions. Clinical data were retrieved and cases were reviewed by 3 independent pathologists (AO, SMRP, and MAP) using hematoxylin & eosin stains. Immunohistochemistry was performed using a panel of antibodies against ALK, CD3, CD4, CD8, granzyme B, MUM1, perforin, P-STAT3 (D3A7, 1/400 Cell Signaling), TIA1, P-STAT5, TCR-βF1, P63, STAT3 (Online Supplementary Appendix). Of 91 evaluated cases, 18 were primary cutaneous ALCLs (pcALCLs) and 73 cases were systemic ALCLs (19 were ALK-positive ALCLs). ALK-positive cases were not further considered for the study. Only 31 cases were eligible for further study due to tissue scarcity, including 22 ALK-negative ALCL and 9 pcALCLs. Fluorescence in situ hybridization (FISH) analyses were performed on these cases using an IRF4-DUSP22 (6p25.3) break-apart probe (KBI-10613; Kreatech, Leica, Spain) following standard procedures. 4,5 Cytotoxic markers, pSTAT3, p63 and MUM1 expression were evaluated as described in the Online Supplementary Appendix. Associations of genetic and immunohistochemical subgroups with overall survival (OS) and progression-free survival were assessed using Kaplan-Meier curves. Differences between genetic subgroups in patients' characteristics, tumor phenotype and other clinical factors were assessed using the χ 2 test and Wilcoxon rank-sum test, as appropriate.

Circulating JNK pathway-associated phosphatase level correlates with decreased risk, activity, inflammation level and reduced clinical response to tumor necrosis factor-α inhibitor in Crohn disease patients

“…The possible reason to our data might be that: JKAP might directly regulate the signal transducer and transcription activator signal transducer and activator of transcription 3 (STAT3), which attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727, and subsequently regulated the differentiation of Th17 cells, thereby reduced the CD risk, activity, and inflammation. [20,21] JKAP might also inhibit T-cell-mediated immune activity through other pathways such as mitogen-activated protein kinase / extracellular signal-regulated kinase pathway and stress-activated protein kinase/JNK pathway, or through inactivating Lck (a src-family tyrosine kinase) by dephosphorylating Tyr394 during T-cell receptor signaling, thus the declined JKAP expression was correlated with increased disease risk, activity, and inflammation. [9,13,22]…”

Freiburg Neuropathology Case Conference

“…Furthermore, a peripheral T cell lymphoma not otherwise specified (NOS) should be taken into account; however, according to the World Health Organization (WHO) recommendations both the morphology and phenotype of the current biopsy support the diagnosis of an ALK-negative, anaplastic large cell lymphoma [15]. The diagnosis is further supported by detection of the IRF4/DUSP22 translocation [16] and was confirmed independently by the institute of neuropathology Cologne, Germany.…”

Molecular profiling of Chinese systemic anaplastic large cell lymphoma patients: novel evidence of genetic heterogeneity

“…Approximately half of the patients diagnosed with ALCL have ALK-positive status and have high response to standard chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone (CHOP) (6). Contrastingly, due to inefficacy of standard regimens, patients with ALK-negative ALCL often undergo more intensive therapies than ALK-positive ALCL patients (7)(8)(9). A growing number of studies have reported that the 5-year survival of a subset of ALK-negative ALCL patients with dual specificity phosphatase 22 (DUSP22) rearrangement was comparable to that of ALK-positive ALCL patients who received the same treatment regimen (9)(10)(11).…”

“…Contrastingly, due to inefficacy of standard regimens, patients with ALK-negative ALCL often undergo more intensive therapies than ALK-positive ALCL patients (7)(8)(9). A growing number of studies have reported that the 5-year survival of a subset of ALK-negative ALCL patients with dual specificity phosphatase 22 (DUSP22) rearrangement was comparable to that of ALK-positive ALCL patients who received the same treatment regimen (9)(10)(11). Routine stem cell transplantation may lead to overtreatment for subsets of ALK-negative ALCL patients, such as those with DUSP22 rearrangement, resulting in unnecessary increases in costs and risks for those patients.…”