Lymphomatoid Papulosis With DUSP22 Rearrangement in a Patient With a Historical Diagnosis of Primary Cutaneous Anaplastic Large Cell Lymphoma.

Lymphomatoid papulosis (LyP) with DUSP22 rearrangement is an uncommon subtype of lymphomatoid papulosis featured histologically by two distinct patterns of epidermotropic cells, weakly CD30+ small- to medium-sized T-cells and a dermal infiltrate of strongly CD30+ medium- to large-sized T-cells. DUSP22 rearrangement is detected more frequently in anaplastic large cell lymphoma (ALCL) than in LyP. Primary cutaneous anaplastic large cell lymphoma (pcALCL) cases can also show a similar biphasic CD30 staining pattern. LyP with DUSP22 rearrangement has a more indolent clinical course than pcALCL and is more likely to regress without treatment. Herein, we report a unique case of LyP with DUSP22 rearrangement diagnosed in an 81-year-old female with a historical diagnosis of pcALCL, made 20 years prior.

Small cell pattern of ALK-negative anaplastic large cell lymphoma with double-hit rearrangements of DUSP22 and TP63.

In ALK-negative anaplastic large cell lymphoma (ALCL), gene rearrangements of DUSP22 and TP63 are considered mutually exclusive. The former predicts a favorable prognosis, while the latter is generally unfavorable. We report the first case of ALK-negative ALCL in a leukemic phase with small cell pattern transformation, harboring double-hit rearrangements of the DUSP22 gene by inv(6)(p25q21) and TP63 gene by TBL1XR1-TP63 inversion. Despite the resistance to chemotherapies, the patient remained in remission with allogeneic stem cell transplantation over 20 months. Recognizing this pathologically and genetically rare condition is needed for prompt diagnosis and therapeutic decision-making in ALK-negative ALCL.

DUSP22-rearranged primary cutaneous CD30-positive T-cell lymphoproliferative disorders and adult T-cell leukemia/lymphoma frequently share the LEF1+/TIA1- immunophenotype.

DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1- immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1- immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL.

DUSP22 suppresses tumor progression by directly dephosphorylating AKT in non-small cell lung cancer.

Protein kinase B (AKT) plays a pivotal in regulating cell migration, proliferation, apoptosis, and survival, making it a prominent target for anticancer therapy. While the kinase activity of AKT has been extensively explored, its dephosphorylation have largely remained uncharted. Herein, we aimed to unravel the molecular mechanisms governing AKT dephosphorylation, with a specific emphasis on dual-specificity phosphatases DUSP22. Our investigation sought to shed light on the potential of DUSP22 as a potential therapeutic target for non-small cell lung cancer (NSCLC). To determine the expression level of DUSP22 in NSCLC cell lines, the gene expression profiling interactive analysis (GEPIA) and Oncomine database were searched. Additionally, the effect of DUSP22 on patient survival was analyzed with Kaplan-Meier database. Antitumor effects of DUSP22 were tested in A549 and H1299 cell lines. Experiments are based on: (1) cell viability determined by the cell counting kit-8 assay and colony-formation assay; (2) cell migratory ability assessed through the scratch assay and the transwell migration assay; (3) the mechanism behind the antitumor effects of DUSP22 dissected with co-immunoprecipitation (Co-IP) and in vitro kinase assays. Our study revealed a significant downregulation of DUSP22 in both NSCLC cell lines and tissues. Meanwhile, survival rate analysis results demonstrated that reduced DUSP22 expression was correlated with poorer overall survival in lung cancer patients. Moreover, DUSP22 exhibited an inhibitory effect on the cell viability and migratory capacity of A549 and H1299 cells. This inhibition was accompanied by the decrease in the phosphorylation of AKT and p38. Mechanistically, the phosphatase domain of DUSP22 interacted with AKT, resulting in the inhibition of AKT phosphorylation. This inhibitory effect was contingent upon the phosphatase activity of DUSP22. These findings provide compelling evidence that DUSP22 directly interacted with AKT, leading to the dephosphorylation of AKT at S473 and T308 residues, ultimately curbing the proliferation and migration of lung cancer cells. Additionally, our results also highlight a preclinical rationale for utilizing DUSP22 as a prognostic marker in NSCLC.

Primary cutaneous CD30+ lymphoproliferative disorders with DUSP22 translocation.

Primary cutaneous CD30+ lymphoproliferative disorders (LPD) encompass a broad category of clonal T cell proliferations with varied clinical presentations. Classically, lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) have been recognized as distinct clinicopathological entities according to their differing clinical features. Recently, a subset of LyP and both cutaneous and systemic ALCL have been shown to carry a DUSP22 translocation [1-3], a defining molecular feature for the novel entity "LyP with DUSP22t" [1]. In cutaneous biopsies, both primary cutaneous DUSP22-translocated ALCL and LyP with DUSP22 rearrangements are characterized by a biphasic pattern with significant small cell epidermotropism. A distinct protein expression profile with preserved T Cell Receptor (TCR) expression, positivity for CD30, LEF1, HLA, and CD58, and negativity for cytotoxic marker expression as well as phospho-STAT3 protein is consistently found in these cases.

Constant small-cell changes and variable LEF1 expression in DUSP22-rearranged primary cutaneous anaplastic large-cell lymphoma: Analysis of the repeated biopsies of three patients.

DUSP22-rearranged primary cutaneous anaplastic large-cell lymphoma (pcALCL) has a biphasic histological pattern defined by large dermal atypical lymphocytes and epidermotropic small lymphocytes resembling pagetoid reticulosis, but the positivity rate of the biphasic pattern in DUSP22-rearranged pcALCL is unknown. Immunohistochemically, LEF1 expression in >75% of tumor cells is associated with DUSP22-rearrangement (DUSP22-R) in systemic ALCL. However, whether this association applies to pcALCL remains unclear. To analyze these pathological clues for screening DUSP22-R, we reviewed 11 skin biopsies from three patients with DUSP22-rearranged pcALCL. All specimens showed a biphasic pattern, of which three showed nonpagetoid infiltration of the epidermis. In all lesions, small-cell changes of tumor cells were observed not only within the epidermis but also under the epidermis. LEF1 positivity rates varied by lesion (range: 30%-90%, mean: 59.6%) with only three patients expressing LEF1 in more than 75% of tumor cells. In conclusion, the biphasic pattern was a constant finding in DUSP22-rearranged pcALCL, but it was not always pagetoid reticulosis-like. The recognition of small-cell change outside the epidermis may be helpful in diagnosing DUSP22-rearranged pcALCL. However, LEF1 expression was variable and its diagnostic usefulness may be limited.

Primary Cutaneous Anaplastic Large Cell Lymphoma-A Review of Clinical, Morphological, Immunohistochemical, and Molecular Features.

Primary cutaneous anaplastic large cell lymphoma (ALCL) is the second most common cutaneous T-cell lymphoma after mycosis fungoides and belongs to the spectrum of cutaneous CD30+ T-cell lymphoproliferative disorders. Although primary cutaneous ALCL usually presents as a localized nodule or papule with or without ulceration, multifocal lesions may occur in up to 20% of cases. Histologically, primary cutaneous ALCL consists of a diffuse dermal infiltrate of medium to large anaplastic/pleomorphic cells with abundant amphophilic-to-eosinophilic cytoplasm, horseshoe-shaped nuclei, strong and diffuse expression of CD30, and with focal or no epidermotropism. The neoplastic infiltrate may show angiocentric distribution and may extend to the subcutis. Patients with localized or multifocal disease have a similar prognosis with a 10-year overall survival rate of 90%. Approximately 30% of primary cutaneous ALCLs harbor a DUSP22 (6p25.3) gene rearrangement that results in decreased expression of this dual-specific phosphatase, decreased STAT3 activation, and decreased activity of immune and autoimmune-mediated mechanisms regulated by T-cells.

Anaplastic large cell lymphomas with equivocal DUSP22 FISH results: recommendations for clinical reporting and diagnostic evaluation.

Anaplastic large cell lymphoma (ALCL), one of the most common T-cell lymphomas, shows unifying pathological features but is clinically and genetically heterogeneous. One genetic subgroup, characterized by recurrent DUSP22 rearrangements (R), has distinct morphologic, immunophenotypic, and molecular features and can be identified in routine pathology practice using a breakapart (BAP) fluorescence in situ hybridization (FISH) probe. However, some cases show equivocal BAP-FISH findings (BAP-FISHEQ) and the features of these cases are poorly understood. Here, we sought to characterize DUSP22 BAP-FISHEQ ALCLs further. First, we applied an immunohistochemistry (IHC) algorithm using TIA1, pSTAT3Y705, and LEF1, which can predict DUSP22-R with high accuracy. Among 37 BAP-FISHEQ ALCLs, 18 (49%) were IHC-algorithm positive (IHCPOS), 8 (21%) were IHC-algorithm negative (IHCNEG), and 11 (30%) were IHCEQ. In 32 BAP-FISHEQ cases, we also applied a dual-color, dual-fusion (D-FISH) probe for t(6;7)(p25.3;q32.3), which accounts for 45% of DUSP22-R ALCLs. Among BAP-FISHEQ cases, D-FISH was positive in 10/18 IHCPOS cases (56%), 0/9 IHCEQ cases (0%), and 0/5 IHCNEG cases (0%). Median survival in BAP-FISHEQ ALCLs was 105 months, intermediate between BAP-FISHPOS ALCLs (median survival not reached) and BAP-FISHNEG ALCLs (19 months). Thus, DUSP22 BAP-FISHEQ ALCLs are clinicopathologically heterogeneous, likely due to an admixture of cases with an unbalanced DUSP22-R and cases with focal deletions without rearrangement. For clinical reporting, we recommend that DUSP22 BAP-FISHEQ ALCLs be reported as equivocal, and not be grouped with BAP-FISHPOS ALCLs. Clinical adoption of an IHC algorithm, possibly supplemented by t(6; 7) D-FISH, could facilitate genetic subtyping in about two-thirds of BAP-FISHEQ ALCLs.

Anaplastic large cell lymphomas with the 6p25.3 rearrangement are a heterogeneous group of tumours with a diverse molecular background.

ALK-negative anaplastic large cell lymphoma (ALCL) cases with 6p25.3 rearrangement are characterized by peculiar morphological and immunohistochemical features compare to 6p25.3-negative ALK-negative ALCL cases. A subgroup of 6p25.3-positive ALK-negative ALCL cases show the t(6,7) (p25.3;q32.3) rearrangement. Aims: To analyse the differences between 6p25.3-rearranged cases with and without t(6,7) (p25.3;q32.3). Using RNA-sequencing we studied a series of 17 samples showing 6p25.3-rearrangement, identified by FISH, consisting of seven systemic and eight primary cutaneous cases including two examples of secondary skin involvement by systemic ALCL. RNA-sequencing exclusively detected a translocation involving a gene in the 6p25.3 region (either IRF4 or DUSP22) in 7/14 cases (50%). In six of these seven cases the partner proved to be the LINC-PINT region in chromosome 7, while an EXOC2::DUSP22 rearrangement was found in one case. All cases but one were primary cutaneous ALCLs. They all were CD3 positive and BCL2 negative, while most of them expressed p-STAT3. On the contrary, cases without the t(6,7) (p25.3;q32.3) were mainly systemic (71%, 5/7) against just two pcALCL. In general, they lose CD3 (50% positive) and p-STAT3 (25% positive) expression, being all of them BCL2 positive. Moreover, in 60% of them other gene fusions were found. At the transcriptional level, they were characterized by the overexpression of TCF3 (TCF7L1/E2A), DLL3, CD58 and BCL2 genes 75%(6/8) of pcALCL with 6p25.3 rearrangement featured the so-called "biphasic morphologic pattern, which was not found in cutaneous involvement from systemic ALCL. 83% (5/6) of the pcALCL cases with the "biphasic morphologic pattern" showed the t(6,7) (p25.3;q32.3) rearrangement. ALK-negative ALCL cases with 6p25.3 rearrangement are a subgroup of tumours that are heterogeneous with respect to the presence or absence of the t(6,7) (p25.3;q32.3) translocation.

Lymphomatoid papulosis with DUSP22-IRF4 rearrangement: A case report and literature review.

Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement is a rare, recently described variant of LyP histopathologically characterized by a biphasic growth pattern, with epidermotropic small-to-medium-sized atypical T-cells and dermal large and transformed T-cells diffusely expressing CD30. LyP with DUSP22-IRF4 rearrangement can mimic other cutaneous lymphoproliferative disorders, particularly primary cutaneous anaplastic large cell lymphoma (PCALCL) or transformed mycosis fungoides (MF). Unlike PCALCL or transformed MF, LyP with DUSP22-IRF4 rearrangement shows an indolent clinical behavior, with frequent spontaneous regression of untreated lesions. Thus, it is important to recognize this rare variant of LyP to avoid misclassification, which may potentially lead to unnecessarily aggressive patient management. To our knowledge, only 13 cases of LyP with DUSP22-IRF4 rearrangement have been reported to date in the English literature. Herein, we describe an additional case of LyP with DUSP22-IRF4 rearrangement in a 63-year-old man and provide a comprehensive literature review with regards to the clinical, histopathologic, and molecular features of this novel entity.

Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis.

BACKGROUND: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). METHODS: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. RESULTS: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α+, interleukin-17A+, and interferon-γ+ CD3+ T cells. CONCLUSIONS: DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.

Primary effusion anaplastic large cell lymphoma with indolent clinical course and IRF4/DUSP22 rearrangement: a case report expanding the spectrum of effusion-based lymphoma.

Effusion-based lymphomas arising from pleural cavities are mostly B cell lymphomas. Non-B cell origins are very rare. These non-B cell lymphomas are usually disseminated and aggressive, and their underlying genetic changes are indeterminate. Here, we reported the first case of primary effusion anaplastic large cell lymphoma (ALCL) with exclusive involvement of a single body cavity, indolent initial presentation, and IRF4/DUSP22 rearrangement. This 73-year-old man had been in his usual health until he presented with exertional dyspnea for 1 month. Physical examination and whole-body imaging indicated isolated left pleural effusion without lymphadenopathies or tumors. Thoracentesis revealed anaplastic large lymphoid cells that were CD30 + , CD3 - , CD8 + , TIA1 + , CD138 - , Epstein-Barr virus-encoded small RNA - , human herpesvirus 8 - , and ALK - . Fluorescence in situ hybridization exhibited IRF4/DUSP22 rearrangement. A primary effusion ALK-negative ALCL was diagnosed. There was no evident progression without chemotherapeutics until 4 months after the diagnosis. Our findings expanded the spectrum of effusion-based lymphoma. Recognition of this disease could prevent misdiagnosis and guide treatment strategies for patients.

Analysis of Phosphatase Activity in a Droplet-Based Microfluidic Chip.

We report analysis of phosphatase activity and inhibition on droplet-based microfluidic chips. Phosphatases are such attractive potential drug targets because abnormal phosphatase activity has been implicated in a variety of diseases including cancer, neurological disorders, diabetes, osteoporosis, and obesity. So far, several methods for assessing phosphatase activity have been reported. However, they require a large sample volume and additional chemical modifications such as fluorescent dye conjugation and nanomaterial conjugation, and are not cost-effective. In this study, we used an artificial phosphatase substrate 3-O-methylfluorescein phosphate as a fluorescent reporter and dual specificity phosphatase 22. Using these materials, the phosphatase assay was performed from approximately 340.4 picoliter (pL) droplets generated at a frequency of ~40 hertz (Hz) in a droplet-based microfluidic chip. To evaluate the suitability of droplet-based platform for screening phosphatase inhibitors, a dose-response inhibition study was performed with ethyl-3,4-dephostatin and the half-maximal inhibitory concentration (IC50) was calculated as 5.79 ± 1.09 µM. The droplet-based results were compared to microplate-based experiments, which showed agreement. The droplet-based phosphatase assay proposed here is simple, reproducible, and generates enormous data sets within the limited sample and reagent volumes.

Systemic ALK-negative anaplastic large cell lymphoma with distinctive myxoid change and DUSP22 rearrangement.

Systemic anaplastic lymphoma kinase-negative (ALK-) anaplastic large cell lymphoma (ALCL) comprises a genomically heterogeneous disease that is considered a distinct entity by the 2016 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Other than lymph nodes, systemic ALK- ALCL may affect extranodal tissues, sites where the inflammatory background may be especially prominent. In this scenario, myxoid change is exceptional in systemic ALK- ALCL. We describe a rare case of systemic ALK- ALCL with distinctive myxoid changes, carrying specific chromosomal aberrations that affect the clinical outcome. Careful morphological, immunohistochemical, and molecular workup is mandatory because a myxoid background should not be a reason to ignore the possibility of a lymphoma. Finally, extensive correlation with staging and the detection of prognostic biomarkers such as DUSP22 and TP63 rearrangements are essential for the diagnosis and prediction of clinical outcome in ALK- ALCL.

Cutaneous presentation of enteropathy-associated T-cell lymphoma masquerading as a DUSP22-rearranged CD30+ lymphoproliferation.

DUSP22 gene rearrangements are recurrent in systemic and cutaneous ALK-negative anaplastic large cell lymphomas, rarely encountered in other cutaneous CD30+ lymphoproliferations, and typically absent in other peripheral T-cell lymphomas. We report the case of a 51-year-old woman, with longstanding celiac disease and a rapidly enlarging leg ulcer, due to a DUSP22-rearranged CD30+ T-cell lymphoproliferation. Subsequent history revealed an intestinal enteropathy-associated T-cell lymphoma (EATL). Identical monoclonal TR gene rearrangements and mutations in STAT3 and JAK1 typical of EATL were present in the cutaneous and intestinal lesions. No DUSP22 rearrangement was detected in the patient's intestinal tumour, nor in 15 additional EATLs tested. These findings indicate that DUSP22 rearrangements are not entirely specific of ALCLs, may rarely occur as a secondary aberration in EATL, and expand the differential diagnosis of DUSP22-rearranged cutaneous CD30+ lymphoproliferative disorders.

Measurement of synovium and serum dual specificity phosphatase 22 level: Their inter-correlation and potency as biomarkers in rheumatoid arthritis.

BACKGROUND: Dual specificity phosphatase 22 (DUSP22), also named as Jun N-terminal kinase pathway associated phosphatase recently, is reported to be closely engaged in immune and inflammation regulation. This study aimed to investigate the interaction between synovium DUSP22 and serum DUSP22 levels and to explore their correlation with rheumatoid arthritis (RA) risk, inflammation, and disease activity. METHODS: Synovium and serum samples from 42 RA patients with knee involvement underwent arthroscopy, and 20 knee trauma patients were collected. Besides, serum samples from 40 healthy controls were also obtained. Synovium DUSP22 expression was detected by reverse transcription quantitative polymerase chain reaction, while serum DUSP22 level was detected by enzyme-linked immunosorbent assay. RESULTS: Synovium DUSP22 level was greatly decreased in RA patients compared to trauma controls (p < 0.001), and it was negatively correlated with tender joint count (TJC) (r = -0.318, p = 0.040), C-reactive protein (CRP) (r = -0.330, p = 0.033), and Lysholm score (r = -0.423, p = 0.005) in RA patients. Serum DUSP22 level was lowest in RA patients, followed by trauma controls, then highest in healthy controls (p < 0.001). Serum DUSP22 level was negatively associated with TJC (r = -0.438, p = 0.004), swollen joint count (SJC) (r = -0.372, p = 0.015), CRP (r = -0.391, p = 0.011), and disease activity score in 28 joints (DAS28ESR ) score (r = -0.406, p = 0.008), and it increased after treatment (p = 0.001) in RA patients. In addition, serum DUSP22 level positively related to synovium DUSP22 level in RA patients (r = 0.394, p = 0.010). CONCLUSION: Synovium and serum DUSP22 are intercorrelated and insufficiently expressed in RA patients; meanwhile, their deficiency correlates with increased systemic inflammation, disease activity, and joint dysfunction.

Primary cutaneous anaplastic large-cell lymphoma with DUSP22-IRF4 rearrangement following insect bites.

Primary cutaneous anaplastic large-cell lymphoma (pC-ALCL) is distinguished from systemic anaplastic large-cell lymphoma (S-ALCL) with cutaneous involvement. Although pC-ALCL is a unique entity with different genetics, clinical characteristics, and prognosis, its causes are unknown. Herein, we report the case of a Chinese woman with a 4-month history of a gradually enlarged ulcerative mass in her right forearm following an unidentified insect bite. Biopsy revealed an extensive infiltrate with patches of large anaplastic lymphoid cells. These cells were immunohistochemically positive for CD45, CD30, and TIA-1 and negative for CD2, CD3, CD4, CD5, CD20, CD7, CD8, and ALK-1. DUSP22-IRF4 rearrangement was detected; on the other hand, TP63 rearrangement was not observed by fluorescence in situ hybridization (FISH). No Epstein-Barr virus-encoded small RNAs (EBERs) were detected by ISH. Rearrangement of monoclonal TCR gene was found using BIOMED-2 polymerase chain reaction. No abnormality was found on the subsequent positron emission tomography-computed tomography (PET-CT) scan. After five cycles of cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP) chemotherapy, the patient achieved complete remission. This is the first report of a unique pC-ALCL with DUSP22-IRF4 rearrangement following an insect bite other than S-ALCL involving the skin.

Central nervous system ALK-negative anaplastic large cell lymphoma with IRF4/DUSP22 rearrangement.

Anaplastic large cell lymphomas (ALCL) are mature T-cell neoplasms, approximately half of which harbor rearrangements of the ALK gene that confer a good prognosis. Recent studies have demonstrated that a significant proportion of ALK-negative ALCLs demonstrate rearrangements of the IRF4/DUSP22 locus that also are typically associated with a favorable prognosis. ALCL with primary involvement of the central nervous system (CNS) is extremely rare. We report what may be the first case of ALK-negative ALCL with IRF4/DUSP22 rearrangement involving the brain in a 55-year-old man. Magnetic resonance imaging demonstrated signal abnormalities in the periventricular region, corpus callosum and cingulate gyrus. Biopsy revealed a diffuse parenchymal and angiocentric infiltrate of CD30-positive cells that showed IRF4/DUSP22 rearrangement by fluorescence in situ hybridization. We also review the clinical and pathologic features of primary CNS ALK-negative ALCLs in the literature and highlight the need for awareness of this entity to optimize appropriate management.