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Purpose of Review: Mature T/NK-cell neoplasms comprise a heterogeneous group of diseases with diverse clinical, histopathologic, immunophenotypic, and molecular features. A clinically relevant, comprehensive, and reproducible classification system for T/NK-cell neoplasms is essential for optimal management, risk stratification, and advancing understanding of these diseases. Two classification systems for lymphoid neoplasms were recently introduced: the 5th edition of World Health Organization classification (WHO-HAEM5) and the 2022 International Consensus Classification (ICC). In this review, we summarize the basic framework and updates in the classification of mature T/NK-cell neoplasms., Recent Findings: WHO-HAEM5 and ICC share basic concepts in classification of T/NK-cell neoplasms, emphasizing integration of clinical presentation, pathology, immunophenotype, and genetics. Major updates in both classifications include unifying nodal T-follicular helper-cell lymphomas into a single entity and establishing EBV-positive nodal T/NK-cell lymphoma as a distinct entity. However, some differences exist in taxonomy, terminology, and disease definitions. The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid malignancy associated with a poor clinical prognosis. The AITL tumor microenvironment (TME) is unique, featuring a minority population of malignant CD4+ T follicular helper (TFH) cells inter-mixed with a diverse infiltrate of multi-lineage immune cells. While much of the understanding of AITL biology to date has focused on characteristics of the malignant clone, less is known about the many non-malignant populations that comprise the TME. Recently, mutational consistencies have been identified between malignant cells and non-malignant B cells within the AITL TME. As a result, a significant role for non-malignant populations in AITL biology has been increasingly hypothesized. In this study, we have utilized mass cytometry and single-cell transcriptome analysis to identify several expanded populations within the AITL TME. Notably, we find that B cells within the AITL TME feature decreased expression of key markers including CD73 and CXCR5. Furthermore, we describe the expansion of distinct CD8+ T cell populations that feature an exhausted phenotype and an underlying expression profile indicative of dysfunction, impaired cytotoxicity, and upregulation of the chemokines XCL2 and XCL1., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The diagnosis of T-cell lymphomas is highly challenging and requires an integrated approach in which clinical, morphologic, immunophenotypic and molecular data are incorporated into the diagnosis. Under the auspices of the American Registry of Pathology, the authors met to discuss this topic with the goal to provide practical and useful recommendations for pathologists when evaluating T-cell lymphomas. In this review, we discuss the diagnostic findings and workup for the various types of nodal T-cell lymphoma including anaplastic large cell lymphoma, nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and PTCL with a T follicular helper (TFH) phenotype. We review clinicopathologic and immunophenotypic features (including flow cytometry panels) helpful in the differential diagnosis of mature T-cell lymphomas presenting in the peripheral blood and bone marrow, and we discuss some of the more common extranodal-based T-cell lymphomas including extranodal natural killer/T-cell lymphoma of nasal and non-nasal type, gamma delta T cell lymphomas, and aggressive and indolent T- and NK-lymphoproliferative disorders involving the gastrointestinal tract. Mycosis fungoides and most other cutaneous T-cell lymphomas are not the focus of this review, although the differential diagnosis of Sezary syndrome from mycosis fungoides is covered. We do not intend for these recommendations to be anything other than suggestions that will hopefully spur on additional discussion, and perhaps eventually evolve into a consensus approach for the workup of T-cell lymphomas., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction : T-cell lymphomas represent a broad group of malignant T-cell neoplasms with marked molecular, clinical, and biologic heterogeneity. Survival rates after conventional chemotherapy regimens are poor for most subtypes and new therapies are needed. Rapidly expanding knowledge in the field of epigenomics and the development of an increasing number of epigenetic-modifying agents have created new opportunities for epigenetic therapies for patients with this complex group of diseases. Areas covered : The present review summarizes current knowledge on epigenetic alterations in T-cell lymphomas, availability, and mechanisms of action of epigenetic-modifying agents, results of clinical trials of epigenetic therapies in T-cell lymphomas, status of FDA approval, and biomarker approaches to guide therapy. Promising future directions are discussed. Expert opinion : Mutations in epigenetic-modifying genes are among the most common genetic alterations in T-cell lymphomas, highlighting the potential for epigenetic therapies to improve management of this group of diseases. Single-agent efficacy is well documented, leading to FDA approval for several indications, but overall response rates and durability of responses remain modest. Critical next steps for the field include optimizing combination therapies that incorporate epigenetic-modifying agents and developing predictive biomarkers that help guide patient and drug selection.

Aims: The aims of this study were to review our 5-year experience with clinical FISH testing for TP63 rearrangements using both TP63 break-apart (BAP) and TBL1XR1/TP63 dual-fusion (D-FISH) probes to evaluate the frequency of TP63 rearrangements and the distribution of TBL1XR1 vs. alternate partner loci, and to assess whether both probe sets are necessary in all cases undergoing FISH testing., Methods and Results: A retrospective review of the Mayo Clinic cytogenetic database identified 470 patients evaluated by FISH testing for TP63 rearrangements in formalin-fixed paraffin-embedded (FFPE) tissue using both BAP and D-FISH probes. Of these, 25 (5.3%) had TP63 rearrangements. All samples were being investigated for anaplastic large-cell lymphoma or other T cell lymphoma subtypes. A TBL1XR1 partner was identified by D-FISH in 12 (48%) of 25 cases. All cases positive by TBL1XR1/TP63 D-FISH were also positive by TP63 BAP FISH., Conclusion: This is the largest series of TP63 rearrangements to date. The frequency of positive results among cases referred to a large reference laboratory for TP63 FISH testing was 5.3%. Approximately half of TP63 rearrangements have a TBL1XR1 partner. TP63 BAP FISH testing is sufficient for up-front testing of FFPE tissue samples. However, because of the genomic proximity of the TP63 and TBL1XR1 loci, we recommend reflex TBL1XR1/TP63 D-FISH testing in positive and equivocal cases., (© 2019 John Wiley & Sons Ltd.)

Introduction : The classification of lymphomas is based on the postulated normal counterparts of lymphoid neoplasms and currently constitutes over 100 definite or provisional entities. As this number of entities implies, lymphomas show marked pathological, genetic, and clinical heterogeneity. Recent molecular findings have significantly advanced our understanding of lymphomas. Areas covered : The World Health Organization (WHO) classification of lymphoid neoplasms was updated in 2017. The present review summarizes the new findings that have been gained in the areas of mature T-cell neoplasms, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms since the publication of the 2017 WHO classification. Expert opinion : Although formal revisions to the WHO classification are published only periodically, our understanding of the pathologic, genetic, and clinical features of lymphoid neoplasms is constantly evolving, particularly in the age of -omics technologies and targeted therapeutics. Even in the relatively short time since the publication of the 2017 WHO classification, many significant findings have been identified in the entities covered in this review.

Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with generally poor outcomes following standard therapy. Few candidate therapeutic targets have been identified to date. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to retinoids. While retinoids have been used to treat some cutaneous T-cell lymphomas (CTCLs), their mechanism of action and the role of RARA in CTCL and other mature T-cell lymphomas remain poorly understood. After identifying a PTCL with a RARAR394Q mutation, we sought to characterize the role of RARA in T-cell lymphoma cells. Overexpressing wild-type RARA or RARAR394Q significantly increased cell growth in RARAlow cell lines, while RARA knockdown induced G1 arrest and decreased expression of cyclin-dependent kinases CDK2/4/6 in RARAhigh cells. The retinoids, AM80 (tamibarotene) and all-trans retinoic acid, caused dose-dependent growth inhibition, G1 arrest, and CDK2/4/6 down-regulation. Genes down-regulated in transcriptome data were enriched for cell cycle and G1-S transition. Finally, RARA overexpression augmented chemosensitivity to retinoids. In conclusion, RARA drives cyclin-dependent kinase expression, G1-S transition, and cell growth in T-cell lymphoma. Synthetic retinoids inhibit these functions in a dose-dependent fashion and are most effective in cells with high RARA expression, indicating RARA may represent a therapeutic target in some PTCLs.

CD30-positive T-cell lymphoproliferative disorders are classified as cutaneous (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis) or systemic. As extent of disease dictates prognosis and treatment, patients with skin involvement need clinical staging to determine whether systemic lymphoma also is present. Similar processes may involve mucosal sites of the head and neck, constituting a spectrum that includes both neoplasms and reactive conditions (eg, traumatic ulcerative granuloma with stromal eosinophilia). However, no standard classification exists for mucosal CD30-positive T-cell lymphoproliferations. To improve our understanding of these processes, we identified 15 such patients and examined clinical presentation, treatment and outcome, morphology, phenotype using immunohistochemistry, and genetics using gene rearrangement studies and fluorescence in situ hybridization. The 15 patients (11 M, 4 F; mean age, 57 years) had disease involving the oral cavity/lip/tongue (9), orbit/conjunctiva (3) or nasal cavity/sinuses (3). Of 14 patients with staging data, 7 had mucosal disease only; 2 had mucocutaneous disease; and 5 had systemic anaplastic large cell lymphoma. Patients with mucosal or mucocutaneous disease only had a favorable prognosis and none developed systemic spread (follow-up, 4-93 months). Three of five patients with systemic disease died of lymphoma after 1-48 months. Morphologic and phenotypic features were similar regardless of extent of disease. One anaplastic lymphoma kinase-positive case was associated with systemic disease. Two cases had rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3, seen most frequently in primary cutaneous anaplastic large cell lymphoma. Our findings suggest mucosal CD30-positive T-cell lymphoproliferations share features with cutaneous CD30-positive T-cell lymphoproliferative disorders, and require clinical staging for stratification into primary and secondary types. Primary cases have clinicopathologic features closer to primary cutaneous disease than to systemic anaplastic large cell lymphoma, including indolent clinical behavior. Understanding the spectrum of mucosal CD30-positive T-cell lymphoproliferations is important to avoid possible overtreatment resulting from a diagnosis of overt T-cell lymphoma.

A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell-derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxorubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Monocytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously undescribed role for monocytes in T-cell lymphoproliferative disorders.