Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.

Cadherins are critically involved in tissue development and tissue homeostasis. We demonstrate here that neuronal cadherin (N-cadherin) is cleaved specifically by the disintegrin and metalloproteinase ADAM10 in its ectodomain. ADAM10 is not only responsible for the constitutive, but also for the regulated, shedding of this adhesion molecule in fibroblasts and neuronal cells directly regulating the overall levels of N-cadherin expression at the cell surface. The ADAM10-induced N-cadherin cleavage resulted in changes in the adhesive behaviour of cells and also in a dramatic redistribution of b-catenin from the cell surface to the cytoplasmic pool, thereby influencing the expression of b-catenin target genes. Our data therefore demonstrate a crucial role of ADAM10 in the regulation of cell-cell adhesion and on b-catenin signalling, leading to the conclusion that this protease constitutes a central switch in the signalling pathway from N-cadherin at the cell surface to b-catenin/LEF-1-regulated gene expression in the nucleus.

Plasmablastic lymphoma (PBL) is a rare B-cell non-Hodgkin lymphoma often associated with Epstein-Barr virus (EBV) infection. To gain insight in this aggressive lymphoma subtype, the clinicopathologic characteristics of 25 unpublished single-center PBLs (2 in acquired immunodeficiency syndrome patients, 11 in immunocompetent individuals [IC-PBL], 12 in transplant recipients [PT-PBL]) and of 277 reported PBLs were summarized. In the reported series, PBL patients were predominantly male (77%) with a median age at diagnosis of 46 years (range, 1.2 to 87 y). The majority of the biopsies (66%) was EBV positive. Extranodal presentation was most frequent (88%, of which 35% were oral, 18% gastrointestinal, 12% cutaneous). PBL was diagnosed in acquired immunodeficiency syndrome patients (50%), immunocompetent individuals (35%), and transplant recipients (14%). These subgroups differed in age at diagnosis (median: 41, 64, 47 y, respectively), primary localization (oral, oral, cutaneous, respectively), EBV positivity (75%, 50%, 67%, respectively), CD45 expression (31%, 33%, 70%, respectively), and C-MYC aberrations (78%, 44%, 38%, respectively). Ann Arbor stage I, EBV positivity, CD45 expression, and lack of C-MYC aberrations were associated with better outcome (P<0.05). Our series of IC-PBL and PT-PBL cases revealed differential expression of CD10 (0% vs. 42%, respectively), CD56 (22% vs. 42%, respectively), TP53 (67% vs. 8%, respectively), and BCL2 (88% vs. 25%, respectively). Gene expression analysis of 5 of our PT-PBLs revealed upregulation of DNMT3B, PTP4A3, and CD320 in EBV-positive PT-PBL and suggested a role for cancer/testis antigens. The results of this retrospective study suggest different pathogenic mechanisms of PBL in different immunologic settings and a potentially important impact of EBV and CD45 on prognosis.

Summary A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK− ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 155 ALK− ALCLs and demonstrated that 38% of systemic ALK− ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK− ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo.

We show that maternal plasma cell-free DNA sequencing for noninvasive prenatal testing also may enable accurate presymptomatic detection of maternal tumors and treatment during pregnancy.

BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and FindingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

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Key Points• JAK3 pseudokinase mutants require JAK1 for their transforming potential.• JAK3 mutants cause T-ALL in a mouse bone marrow transplant model and respond to tofacitinib, a JAK3-selective inhibitor.JAK3 is a tyrosine kinase that associates with the common g chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner.