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![TBX21 and GATA3 subgroups of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). An immunohistochemical algorithm using antibodies to TBX21, CXCR3, GATA3, and CCR4 can replicate the gene expression-based stratification of PTCL, NOS into TBX21 and GATA3 subgroups and is an independent adverse predictor of overall survival [43]](publication/364294942/figure/fig6/AS:11431281114146686@1674269996121/TBX21-and-GATA3-subgroups-of-peripheral-T-cell-lymphoma-not-otherwise-specified-PTCL.png)
TBX21 and GATA3 subgroups of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). An immunohistochemical algorithm using antibodies to TBX21, CXCR3, GATA3, and CCR4 can replicate the gene expression-based stratification of PTCL, NOS into TBX21 and GATA3 subgroups and is an independent adverse predictor of overall survival [43]
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Nodal T- and NK-cell lymphomas are among the most frequent T-cell malignancies and most subtypes have aggressive clinical behavior. Evolving understanding of the biology and molecular characteristics of these lymphomas, as well as the development of new precision therapy approaches, underscores the importance of ongoing updates to the classificatio...
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Background
Although increasing evidence has reported an increased risk of atherosclerosis (AS) in rheumatoid arthritis (RA), the communal molecular mechanism of this phenomenon is still far from being fully elucidated. Hence, this article aimed to explore the pathogenesis of RA complicated with AS.
Methods
Based on the strict inclusion/exclusion c...
Citations
... 9,10 Indeed, molecular signatures increasingly inform diagnosis, classi cation and prognostication in several subtypes of mTCL. [11][12][13][14] Based on the improved understanding of the pathobiology of mTCLs, targeted therapeutic approaches including epigenetically modifying drugs and inhibitors of crucial oncogenic signaling pathways in mTCL show promise. [15][16][17] Still, identi cation of molecularly informed treatment strategies, prognostic biomarkers and rational combination strategies remain an ongoing challenge. ...
Mature T-cell lymphomas and leukemias (mTCL) comprise a clinically and genetically heterogeneous group of lymphoid malignancies. Most subtypes of peripheral T-cell lymphomas and leukemic T-cell malignancies show an aggressive clinical course and poor prognosis. Thus, these diseases urgently require novel therapeutic strategies. Taking advantage of recent progress deciphering the genetic basis of mTCL, we generated a comprehensive database of genetic alterations from >1 800 patients with mTCL and utilized bioinformatic methodology developed to support treatment decisions in molecular tumorboards to identify novel potential therapeutics. To assess the in vitro activity of potential therapeutics, broad drug screening was performed in molecularly characterized cell lines of mTCL. Notably, the cell cycle regulator WEE1 was identified as a novel therapeutic target in mTCL. Indeed, WEE1 kinase inhibitors potently induced replication stress, premature mitotic entry, accumulation of DNA damage and induction of apoptosis in mTCL cell lines. Exploring potential drug combination strategies through mechanistic studies, we identified strong synergistic effects of combined WEE1 and JAK inhibition in JAK/STAT driven preclinical models as well as in primary patient samples of T-cell prolymphocytic leukemia (T-PLL). In summary, our results identified combinatorial effects of WEE1 and JAK inhibition in genetically defined subtypes of mTCL.
... A few characteristic genetic alterations have been identified in a subset of ALK-negative ALCL cases, which can aid in diagnosis. These include chromosomal rearrangement involving DUSP22 in 20-30% cases, associated with overall favorable prognosis, and rearrangement of TP63 in 5-8% cases, associated with poor clinical outcomes [9]. Recently, cases with strong diffuse CD30 expression and anaplastic morphology resembling Hodgkin-like cells with expression of CD15 have been documented in PTCL [10]. ...
... As our understanding of the pathobiology of EBV+ mature T-cell lymphoma and ALK-negative ALCL advances, the classification of these two entities has been better defined [9]. In this report, we present a case of EBV+ NT/NKCL exhibiting morphologic and immunophenotypic features resembling ALK-negative ALCL. ...
EBV-positive nodal T- and NK-cell lymphoma (EBV+ NT/NKCL) is a recently recognized entity in the 5th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Notably, CD30 positivity is frequently observed in (EBV+ NT/NKCL), creating diagnostic challenges to distinguish it from ALK-negative anaplastic large cell lymphoma (ALCL). Furthermore, cases of EBV+ ALCL have been documented in the literature, predating the inclusion of EBV+ nodal cytotoxic T-cell lymphoma as a variant of peripheral T-cell lymphoma. We present a case of a 47-year-old male presenting with multiple lymphadenopathies. The histomorphologic and immunophenotypic features of the lymph node closely resemble ALK-negative ALCL, characterized by uniform CD30 expression and a subcapsular distribution of lymphoma cells. However, the lymphoma cells exhibit diffuse positivity for EBV, consistent with EBV+ NT/NKCL. A case of ALK-negative ALCL with an immunophenotype identical to the EBV-positive case is included for comparison. Given that EBV+ NT/NKCL represents an aggressive neoplasm requiring unique clinical management compared to ALK-negative ALCL, it is critical to accurately differentiate EBV+ NT/NKCL from ALK-negative ALCL with a cytotoxic T-cell immunophenotype.
... The ALK gene can activate cell signaling pathways, leading to abnormal cell proliferation and growth, which ultimately results in malignancy. The morphological features of ALK-negative ALCL and ALK-positive ALCL are nearly indistinguishable, with the only differentiation being the presence or absence of the ALK gene chromosomal rearrangements [11][12][13]. ...
Anaplastic large cell lymphomas (ALCL) are a group of sporadic malignancies that generally have an aggressive clinical course, especially the subtype of anaplastic lymphoma kinase (ALK)-negative ALCL. The appropriate diagnostic study modalities must be chosen to make an accurate diagnosis and promptly initiate specific treatment. We present the clinical case of a 72-year-old male patient with dyspnea on small efforts accompanied by diaphoresis and a weight loss of 10 kg in two months. Physical examination revealed adenopathy in the cervical region and bilateral pleural effusion. The pleural and lung biopsies revealed poorly differentiated metastatic adenocarcinomas. A multidisciplinary analysis was carried out; the typical clinical-radiographic presentation of adenocarcinoma was ruled out with immunohistochemistry, thus determining a diagnosis of ALK-negative anaplastic large cell non-Hodgkin's lymphoma. This case represented a diagnostic and therapeutic challenge since it is a rare entity with a poor prognosis, and there are only a few studies about the choice of appropriate chemotherapy in these patients.
... Therefore, the ICC considers one single disease entity, namely follicular helper T cell lymphoma, comprising three subtypes, angioimmunoblastic, follicular, and NOS (. Fig. 2b-d; [11]). This entity by definition excludes primary cutaneous CD4+ T cell lymphoproliferations which also feature a TFH phenotype. ...
In this review focus article, we highlight the main modifications introduced in the latest 2022 International Consensus Classification and World Health Organization classification (ICC and WHO-HAEM5) of mature T (and NK) cell neoplasms (PTCLs) and consequent implications for diagnostic practice. The changes result from recent advances in the genomic and molecular characterization of PTCLs and enhanced understanding of their pathobiology. Specifically, consideration is given to the following groups of diseases: Epstein–Barr virus (EBV)-associated neoplasms; follicular helper T cell lymphoma; anaplastic large cell lymphomas; primary intestinal T and NK cell lymphomas and lymphoproliferative disorders; and PTCL, not otherwise specified.
... 4,49 Therefore the ICC considers one single disease entity, namely follicular helper T-cell lymphoma, with three subtypes, angioimmunoblastic, follicular and NOS (Table 3). 50 This entity by definition applies to CD4 + PTCL, implies significant expression of TFH markers, and excludes primary cutaneous CD4 + T-cell lymphoproliferative disorders with a TFH phenotype. The WHO-HAEM5 proposal considers a family of three related entities of nodal T-follicular helper cell lymphomas, angioimmunoblastic-type, follicular-type and NOS types. ...
Predominantly nodal is the most common clinical presentation of peripheral T- (and NK-) cell lymphomas (PTCL), which comprise three main groups of diseases: (i) systemic anaplastic large cell lymphomas (ALCL), whether positive or negative for anaplastic lymphoma kinase (ALK); (ii) follicular helper T-cell lymphomas (TFHL); and (iii) PTCL, not otherwise specified (NOS). Recent advances in the genomic and molecular characterization of PTCL, with enhanced understanding of pathobiology, have translated into significant updates in the latest 2022 classifications of lymphomas. ALK-negative ALCL is now recognized to be genetically heterogeneous, with identification of DUSP22 rearrangements in approximately 20-30% of cases, correlated with distinctive pathological and biological features. The notion of cell-of-origin as an important determinant of the classification of nodal PTCL is best exemplified by TFHL, considered as one disease or a group of related entities, sharing oncogenic pathways with frequent recurrent epigenetic mutations as well as a relationship to clonal hematopoiesis. Data are emerging to support that a similar cell-of-origin concept might be relevant to characterize meaningful subgroups within PTCL, NOS, based on cytotoxic and/or Th1 versus Th2 signatures. The small group of primary nodal Epstein-Barr virus-positive lymphomas of T- or NK-cell derivation, formerly considered PTCL, NOS, is now classified separately, due to distinctive features, and notably an aggressive course. This review summarizes current knowledge of the pathology and biology of nodal-based PTCL entities, with an emphasis on recent findings and underlying oncogenic mechanisms.
... T/NK-cell lymphomas and lymphoproliferative disorders (LPDs) represent a highly heterogeneous group of lymphoid neoplasms of mature T-or NK-cell derivation [1••, 2••, [3][4][5]. T/NK-cell lymphomas are usually aggressive and involve various nodal and extranodal sites, with varying clinical presentation, histopathology, immunophenotype, and prognosis. In contrast, T/NK-cell LPDs represent neoplastic proliferations with a more indolent clinical course, which often do not require systemic chemotherapy [6]. ...
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.
Summary
The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features.
... A predominant genetic alteration has been identified in only a minority of nodal T-cell lymphomas, such as ALK or DUSP22 rearrangement (R) in anaplastic large T-cell lymphoma (ALCL). Although most nodal T-cell lymphomas have diverse molecular alterations, there are commonly affected cellular processes and signaling pathways [26]. In general, T-cell lymphomas are characterized by alterations in the TR and JAK/STAT signaling pathways, as well as mutations in epigenetic regulators [20]. ...
... ALKnegative ALCL with DUSP22-R (20-30%), has monomorphic cytology, absence of cytotoxic molecules and PD-L1 expression, lacks JAK-STAT pathway activation, has a characteristic gene expression signature and recurrent MSC mutations [55,56]. The 2022 ICC considers ALK-negative ALCL with DUSP22-R a genetic subtype of ALK-negative ALCL with usually favorable outcome [12,26]. FISH analysis for DUSP22 is recommended to identify this genetic subgroup (Fig. 5). ...
... TFH lymphoma has distinctive clinical, morphological, immunophenotypic, and genetic features. Angioimmunoblastic T-cell lymphoma (AITL) is the prototype and best-characterized subtype [26]. The mutational landscape of TFH lymphoma includes genes involved in epigenetic pathways such as TET2 (up to 90%), IDH2 (20-45%), and DNMT3A (20-30%), mutations in the small GTPase RHOA (50-70%) and mutations in the TR signaling pathway including PLCG1, CD28, FYN, and VAV1 [105]. ...
With the explosion in knowledge about the molecular landscape of lymphoid malignancies and the increasing availability of high throughput techniques, molecular diagnostics in hematopathology has moved from isolated marker studies to a more comprehensive approach, integrating results of multiple genes analyzed with a variety of techniques on the DNA and RNA level. Although diagnosis of lymphoma still relies on the careful integration of clinical, morphological, phenotypic, and, if necessary molecular features, and only few entities are defined strictly by genetic features, genetic profiling has contributed profoundly to our current understanding of lymphomas and shaped the two current lymphoma classifications, the International Consensus Classification and the fifth edition of the WHO classification of lymphoid malignancies. In this review, the current state of the art of molecular diagnostics in lymphoproliferations is summarized, including clonality analysis, mutational studies, and gene expression profiling, with a focus on practical applications for diagnosis and prognostication. With consideration for differences in accessibility of high throughput techniques and cost limitations, we tried to distinguish between diagnostically relevant and in part disease-defining molecular features and optional, more extensive genetic profiling, which is usually restricted to clinical studies, patients with relapsed or refractory disease or specific therapeutic decisions. Although molecular diagnostics in lymphomas currently is primarily done for diagnosis and subclassification, prognostic stratification and predictive markers will gain importance in the near future.
... Depending on the histological subtype, NHL-T debuts with a nodal or extranodal presentation [116,117]. The recent WHO and ICC classifications recognized the following subtypes as the primary nodal T and NK-derived neoplasias: follicular helper TCL (TFH); anaplastic large cell lymphoma (ALCL; ALK-positive and ALK-negative); peripheral TCL not otherwise specified (PTCL-NOS); and primary nodal EBV-positive T-/NK-cell lymphoma [1,2,118,119]. Regarding extranodal subtypes, the most common extranodal entities TCL subtypes are the cutaneous TCL (CTCL), extranodal NK/T-cell lymphomas nasal type (ENKL), breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), intestinal TCL (ITCL) and hepatosplenic TCL (HSTCL) [120] (Table 3 and Fig. 2). ...
... ICOS::CD28, ITK::SYK and fusions involving VAV1 are some of the recurrent fusions that have been described. In summary, TFH lymphomas share alterations in epigenetics and TCR signaling genes [118,121,122]. ...
... Anaplastic large cell lymphoma (ALCL) is characterized by pleomorphic tumor cells with uniform CD30 expression and includes four distinct subtypes [1,2]: two nodal and two extranodal subtypes. This section will focus on systemic ALK-positive (with the ALK rearrangement, with several different fusion partners) and ALK-negative ALCL [118,123,124], which is more frequent in children and young adults. The most frequent ALK rearrangement is the t(2;5) (p23;q35), which leads to the fusion of nucleophosmin (NPM1) to ALK, resulting in a chimeric protein. ...
The new lymphoma classifications (International Consensus Classification of Mature Lymphoid Neoplasms, and 5th World Health Organization Classification of Lymphoid Neoplasms) include genetics as an integral part of lymphoma diagnosis, allowing better lymphoma subclassification, patient risk stratification, and prediction of treatment response. Lymphomas are characterized by very few recurrent and disease-specific mutations, and most entities have a heterogenous genetic landscape with a long tail of recurrently mutated genes. Most of these occur at low frequencies, reflecting the clinical heterogeneity of lymphomas. Multiple studies have identified genetic markers that improve diagnostics and prognostication, and next-generation sequencing is becoming an essential tool in the clinical laboratory. This review provides a "next-generation sequencing" guide for lymphomas. It discusses the genetic alterations of the most frequent mature lymphoma entities with diagnostic, prognostic, and predictive potential and proposes targeted sequencing panels to detect mutations and copy-number alterations for Band NK/T-cell lymphomas.
... The most recent fifth edition of the world health organization (WHO) classification (2) and the international consensus classification of mature lymphoid neoplasms (ICC 2022) (12) now incorporates the recent advances in the understanding of T cell lymphomas. The mature T cell and NK-cell neoplasms are broadly grouped into 9 types, based on the cell of origin, cytomorphology, disease localization and clinical features (2). ...
... EBV positive T and NK cell lymphoma was previously classified under the PTCL-NOS. It is now recognized as a distinct entity in both the WHO classification and the 2022 ICC classification (12). It is seen more commonly among East Asians, with patients presenting with advanced lymphadenopathy with or without extra nodal involvement, B symptoms. ...
T cell lymphomas are a heterogenous group with varying biological and clinical features that tend to have poor outcomes with a few exceptions. They account for 10-15% of all non-Hodgkin lymphomas (NHL), and 20% of aggressive NHL. There has been little change in the overall prognosis of T cell lymphomas over the last 2 decades. Most subtypes carry an inferior prognosis when compared to the B cell lymphomas, with a 5-year OS of 30%. Gene expression profiling and other molecular techniques has enabled a deeper understanding of these differences in the various subtypes as reflected in the latest 5th WHO and ICC classification of T cell lymphomas. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of T cell lymphomas. This review will focus on nodal T cell lymphomas and describe novel treatments and their applicability to the various subtypes.
... The contrasting genetic landscape observed in "GATA-3 PTCL" and "T-bet PTCL" provides further evidence that these are truly distinct PTCL subtypes, and should be classified as such, although the current WHO and ICC classifications view the current evidence as insufficient for such a subclassification (4, 40,41). For example, copy number gains or amplifications involving c-Myc, STAT3, EZH2, and Rel, among others, were recurrent in (and specific for) the GATA-3 subgroup, whereas losses involving the tumor suppressors p53, PTEN, and CDKN2A/B were observed (42). ...
The peripheral T-cell lymphomas (PTCL) are relatively rare, heterogeneous, and therapeutically challenging. While significant therapeutic gains and improved understanding of disease pathogenesis have been realized for selected PTCL subtypes, the most common PTCL in North America remains “not otherwise specified (NOS)” and is an unmet need. However, improved understanding of the genetic landscape and ontogeny for the PTCL subtypes currently classified as PTCL, NOS have been realized, and have significant therapeutic implications, which will be reviewed here.
