Mature T‐cell and T/NK‐cell neoplasms are both uncommon and heterogeneous, among the broad category of non‐Hodgkin lymphomas. Owing to the lack of specific genetic alterations in the vast majority, ...most currently defined entities show overlapping morphological and immunophenotypic features, and therefore pose a challenge to the diagnostic pathologist. In the light of recent immunophenotypic, cytogenetic and molecular genetics advances in the field of T‐cell and T/NK‐cell lymphomas, the focus of the lymphoma workshop of the European Association for Haematopathology/Society for Hematopathology meeting in Lisbon, Portugal, in October 2012 was to refine existing diagnostic criteria and clarify the borders between overlapping entities. The panel reviewed over 200 submitted cases, which were grouped into five categories: (i) angioimmunoblastic T‐cell lymphoma and T‐follicular‐helper‐cell‐associated lymphomas; (ii) CD30‐positive T‐cell lymphomas/lymphoproliferative diseases; (iii) extranodal T‐cell and NK‐cell neoplasms; (iv) EBV‐associated T‐cell/NK‐cell lymphomas/lymphoproliferative diseases; and (v) peripheral T‐cell lymphoma, not otherwise specified, post‐transplant lymphoproliferative disorders, and mimics. This report summarizes the discussions and conclusions of the workshop, which question current diagnostic criteria and provide recommendations for refining existing classifications.
The role of cytopathology in malignant lymphoma is largely restricted to primary screening in patients with lymphadenopathy of unknown causes and evaluation of relapse and transformation during ...follow‐up of patients with known and fully classified malignant lymphoma. Few lymphoma diagnoses fully rely on cytology, although breast‐implant associated anaplastic large cell lymphoma is currently the centre of clinical attention. Due to the major attention both in the medical and lay media for the recently substantiated high lymphoma risk in women with breast implants, cytopathology departments now frequently receive seroma fluid aspirates with this specific differential diagnostic consideration. In this review, we discuss clinico‐pathological aspects of breast‐implant associated anaplastic large cell lymphoma from a cytological point of view and provide guidelines for the processing of aspirates in daily practice and strategies for diagnostic work‐up of seroma fluids.
Due to the major attention in medical publications and in the lay media for the recently substantiated high lymphoma risk in women with breast implants, cytopathology departments now frequently receive seroma fluid aspirates specifically indicating this diagnostic consideration. In this review, we discuss clinico‐pathological aspects of BIA‐ALCL from a cytological point of view and provide guidelines for the processing of aspirates in daily practice and strategies for diagnostic work‐up of seroma fluids.
Diffuse gastric cancers typically present as late‐stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; ...30–40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E‐cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α‐E‐catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α‐E‐catenin functions in the same complex as E‐cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.
Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome ...9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.
We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage AS III/IV) and progression-free survival (PFS).
Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% five of 108; copy gain, 56% 61 of 108; amplification, 36% 39 of 108). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.
PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.
Multi-arm multi-stage clinical trials in which more than two drugs are simultaneously investigated provide gains over separate single- or two-arm trials. In this paper we propose a generic Bayesian ...adaptive decision-theoretic design for multi-arm multi-stage clinical trials with K (
K
≥
2
) arms. The basic idea is that after each stage a decision about continuation of the trial and accrual of patients for an additional stage is made on the basis of the expected reduction in loss. For this purpose, we define a loss function that incorporates the patient accrual costs as well as costs associated with an incorrect decision at the end of the trial. An attractive feature of our loss function is that its estimation is computationally undemanding, also when K > 2. We evaluate the frequentist operating characteristics for settings with a binary outcome and multiple experimental arms. We consider both the situation with and without a control arm. In a simulation study, we show that our design increases the probability of making a correct decision at the end of the trial as compared to nonadaptive designs and adaptive two-stage designs.
Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20
tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary ...tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.
The purpose of this review is to give an overview on the conceptual framework and major developments of the upcoming 5th edition of the World Health Organization (WHO) Classification of ...Haematolymphoid tumours (WHO-HAEM5) and to highlight the most significant changes made in WHO-HAEM5 compared with the revised 4
edition (WHO-HAEM4R) of lymphoid and stromal neoplasms. The changes from the revised 4th edition include the reorganization of entities by means of a hierarchical system that is realized throughout the 5th edition of the WHO classification of tumors of all organ systems, a modification of nomenclature for some entities, the refinement of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. For the first time, tumor-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms are included in the classification.
Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in ...clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8–associated LPDs also include polyclonal and monoclonal proliferations. EBV− B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.
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