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Introduction: The development of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) concurrently or sequentially in the same patient is a rare clinical scenario and can be labeled as a poly-lymphomatous syndrome (PLS)., Methods: We report clinico-pathologic characteristics and survival outcomes of 7 such cases from our institution. In concurrent PLS, HL is present with NHL in the same location (composite PLS) or in separate locations (discordant PLS). Sequential presentations were seen with HL following NHL or vice versa (sequential PLS)., Conclusions: It is essential to perform adequate biopsies in supposedly relapsed or refractory settings to diagnose PLS. We suggest that the incidence of PLS is likely underestimated due to the under-utilization of repeat biopsies. In patients with concurrent PLS, the treatment should ideally cover both types of lymphoma with an emphasis on tailoring the treatment towards the more aggressive lymphoma. In patients with sequential PLS, the treatment should target the new lymphoma. Consolidation treatments such as autologous hematopoietic cell transplant should be considered when there is a component of relapsed cHL or aggressive NHL. Based on our experience, PLS does not appear to be associated with a poor prognosis. Further research is necessary for better understanding of the biology and management of PLS., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting., Materials and Methods: Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings., Results: Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival., Conclusion: L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the role of miRNA-335 on the proliferation and apoptosis of placental trophoblast cells in preeclamptic rats and its potential mechanism., Methods: Placental trophoblast cells were isolated from preeclamptic model rats and normal ones. Trophoblast cells from the model group were divided into six groups for transfection: the blank (empty vector) group, the NC (negative control) group, the miRNA-335 mimic group, the miRNA-335 inhibitor group, the CRIM1 (overexpressed recombinant plasmid) group, and the miRNA-335 inhibitor + CRIM1 group. The miRNA-335 expressions after the transfection were determined using qRT-PCR. The mRNA and protein expressions of CRIM1, the transforming growth factor (TGF-β1), and the apoptosis-related factors (Bax and Bcl-2) in each group were determined using qRT-PCR and Western blotting. The cell proliferation and apoptosis were determined using MTT assays and flow cytometry, respectively., Results: Compared with normal rats, the systolic blood pressure, diastolic blood pressure, and urinary protein levels were increased in the model rats, which had increased miRNA-335 expressions, but a decreased CRIM1 expressions (all P<0.05). The inhibition of miRNA-335 promoted the expressions of CRIM1, TGF-β1, and Bcl-2 and inhibited the expression of Bax in trophoblast cells (all P<0.05). miRNA-335 inhibition or CRIM1 over-expression promoted the proliferation and reduced the apoptosis of trophoblast cells. The combined effect of miRNA-335 inhibition or CRIM1 over-expression had an even more significant effect on the changes in the above indicators (all P<0.05)., Conclusion: miRNA-335 inhibition can enhance the expression of CRIM1 to promote the proliferation and reduce the apoptosis of trophoblast cells in preeclamptic rats., Competing Interests: None., (AJTR Copyright © 2021.)

Novel high-risk groups have recently been identified in adult acute lymphoblastic leukemia (ALL), including Philadelphia-like, therapy-related, and measurable residual disease after induction therapy. Furthermore, modern targeted therapies have recently been incorporated into ALL management; rituximab for CD20-positive and blinatumomab for measurable residual disease after induction therapy or relapsed or refractory disease. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended as consolidation therapy for high-risk ALL; however, its relative benefit for these high-risk groups and after novel therapies is unclear. We performed an analysis of posttransplantation outcomes in a cohort of 261 consecutive patients who underwent allo-HCT for ALL at the 3-site Mayo Clinic Cancer Center (January 1, 2008-December 31, 2018). With a median (range) follow-up of 22.4 months (0.5-135.0), the 100-day and 5-year cumulative incidences of nonrelapse mortality rates were 6.5% and 26.7%, respectively. The 5-year cumulative incidences of relapse and death were 22.6% and 46.2%, respectively. The 1-year estimate of the composite endpoint of graft-versus-host disease/relapse-free survival was 39.3%. We observed no associations of novel high-risk groups or modern targeted therapies with overall survival, nonrelapse mortality, or relapse in multivariable analysis. An increased risk of relapse was observed with T-ALL (hazard ratio, 2.16; 95% confidence interval, 1.14-4.09; P = .02) and hypodiploidy/near-triploidy (hazard ratio, 2.84; 95% confidence interval, 1.06-7.62; P = .04). Our analysis suggests that novel high-risk groups derive a similar benefit from allo-HCT as traditional high-risk adult ALL and that novel targeted therapies do not seem to independently predict for posttransplantation outcomes. It also calls for further exploration of maintenance strategies after Allo-HCT to prevent relapse in high-risk subgroups., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

A 75-year-old male evaluated for pancytopenia. Abnormal lymphocytes with hairy projections noted on peripheral blood. Bone marrow examination showed diffuse proliferation of CD20+ B-lymphocytes. Flowcytometry revealed monoclonal lambda-restricted B-cells expressing CD19, CD20, CD11c, CD103, CD25 and CD123, negative for CD5 and CD10. Additional staining showed positivity for cyclin-D1, Annexin-A1 and TRAP. FISH identified t(11;14). PCR was positive for BRAF V600E. Given the above findings, nonspecificity of t(11;14) and the presence of BRAF V600E; the diagnosis of HCL was favored. Patient achieved CR with infusional cladribine. Herein, we report the co-occurrence of CCND1/IGH and BRAF V600E in HCL, a rare scenario that could characterize a new subtype of HCL., (© 2020 The Authors.)

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK) + or ALK - , based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSC E116K , exclusively in ALK - ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC E116K for ALK - ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSC E116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSC E116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSC E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs., (© 2019 by The American Society of Hematology.)

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22- rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22- rearranged ALCLs. DUSP22- rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22- rearranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors., (© 2018 by The American Society of Hematology.)

Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P=0.039), less likely to have pleomorphic cells (23% vs. 49%; P=0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P<0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.

B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (DLBCL/BL) is a new lymphoma entity which is recognized in the current World Health Organization (WHO) classification (2008). We report a case of a primary central nervous system lymphoma (PCNSL) with findings consistent with DLBCL/BL. It is characterized by a very aggressive clinical course, and a widespread multifocal involvement of the CNS. Our case shows that a DLBCL/BL can manifest in the CNS alone without any systemic involvement.

Primary Central nervous system lymphoma (PCNSL) is most frequently a diffuse large B cell lymphoma (DLBCL), which is confined to the Central nervous system (CNS). We performed an experiment in which lymphoma cells from a PCNSL patient were implanted subcutaneously in an athymic mouse. The lymphoma cells were shown to home to the CNS with histologic evaluations of the brain showing multiple large B cells in blood vessels consistent with intravascular large B cell lymphoma (IVL). We did not find any evidence of lymphoma at the site of implantation or other locations. The findings are consistent with highly selective tropism of PCNSLforthe CNS and its vasculature.

Hepatosplenic (gammadelta) T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma with an aggressive clinical course and poor prognosis. Bone marrow and peripheral blood are frequently involved, with central nervous system involvement less common. We describe a case of a 31-year old man diagnosed with a gammadelta HSTCL in 2003, successfully treated with chemotherapy and allogeneic stem cell transplantation, and followed from 2003 to present. Four-color flow cytometry (FC) was performed on a BD FACSCalibur and data analyzed with CellQuest Pro and FCS Express software. For cerebrospinal fluid (CSF), all cells were acquired due to limited material. Cytological correlation was available on all specimens. Molecular studies for T-cell gene rearrangement were non-contributory. By FC, the diagnostic HSTCL immunophenotype was CD3 (+), CD7 (+), CD2 (+), CD5 (-), CD4 (-), CD8 (-), TCR gammadelta (+). Subsequent CSF FC analysis revealed a distinct population of gammadelta T-cells in all specimens, ranging from <1% to 13% of lymphocytes. Consistently, the gammadelta T-cells exhibited a different immunophenotypic profile from the reported diagnostic immunophenotype; they expressed CD5, and exhibited a heterogeneous pattern of CD8 expression. Comparison to in-house cases from patients with hairy cell leukemia and concomitant increases in non-neoplastic gammadelta T-cells was performed. The persistent gammadelta T-cells from the CSF of the patient with HSTCL were immunophenotypically consistent with non-neoplastic gammadelta T-cells. We describe an unusual case of persistent gammadelta T-cells in the CSF of a patient during 6 years of flow cytometric follow-up after treatment for gammadelta HSTCL. By cytology, non-neoplastic and malignant gammadelta T-cells are often difficult to distinguish. FC analysis helps to make this distinction, even with a limited panel. By FC, the gammadelta-T cells in the CSF of this patient are immunophenotypically consistent with non-neoplastic gammadelta T-cells. Remarkably, this finding is underscored by the patient's unusual clinical picture; he remains well and disease free.