Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Mature T-Cell, NK-Cell, and Stroma-Derived Neoplasms of Lymphoid Tissues.

This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice.

Co-occurrence of Epstein-Barr virus-positive nodal T/NK-cell lymphoma and nodal T-follicular helper cell lymphoma of different clonal origins: An autopsy case report.

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL.

Haemophagocytic lymphohistiocytosis and Epstein-Barr virus: a complex relationship with diverse origins, expression and outcomes.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.

Application of high-throughput gene sequencing in lymphoma.

As a malignant tumor originating from the lymphoid hematopoietic tissues, lymphoma has an increased incidence in recent years and has ranked among the top ten malignant tumors in the world. But until now, due to the multiple pathological subtypes and the unclear molecular mechanism, it's still difficult to make rapid diagnosis and accurate prognosis assessment for lymphoma patients. Recently, the development of high-throughput gene sequencing technology has provided the possibility to solve these clinical problems. This technology has realized large-scale screening of specific markers for lymphoma at the molecular biology level, followed by discovery of prognostic indicators and biological targets for new drug research. In this paper, we summarize the results of large-scale high-throughput gene sequencing research, and introduce the genetic changes associated with occurrence and prognosis of lymphomas with different pathological subtypes, hoping to further promote the application of this technology in clinical research of lymphoma.

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.

NK-Cell Lymphomas.

NK-cell malignancies are rare aggressive diseases associated with poor clinical outcome. There is a significant geographic variation in their incidence. At least a part of the reason for that is the fact that Epstein-Barr virus plays an important role in pathogenesis, and importantly, the plasma viral titer reflects disease burden and response to therapy. Extranodal NK/T-cell lymphoma, nasal type (ENKL), is the most common disease subtype in NK-cell malignancies. Conventional anthracycline-based chemotherapy was historically used for ENKL, only to produce dismal outcome. More recently, concurrent chemoradiation therapy for early-stage disease and non-anthracycline-based L-asparaginase containing chemotherapy have been studied, showing improved clinical response and survival, with long-term survival rates of 60-70% and 50-60%, respectively. Stem cell transplant can provide long-term disease control in recurrent or refractory disease settings, but the role of frontline use of such approach is yet to be determined. Several novel therapeutic approaches have shown promising results, and enrollment to clinical trials is the essential key to improve the treatment outcome in the future.

[Mature T- and NK-cell lymphomas].

Mature T- and NK-cell neoplasms are a heterogeneous hematological malignancy. The current treatment of mature T- and NK-cell lymphoma depends on combination chemotherapy with or without auto/allogeneic hematopoietic stem cell transplantation. Recent comprehensive, integrated genetic analyses have revealed distinct genetic and molecular subgroups, which are related to different therapeutic responses. Thus, the genetic landscape of mature T- and NK-cell neoplasms is essential for the development of novel treatment modalities and offers opportunities for individualized therapy. This review aims to discuss the recent progress regarding genetic and molecular analyses of mature T- and NK-cell neoplasms toward stratified therapy.

Expression of activating natural killer-cell receptors is a hallmark of the innate-like T-cell neoplasm in peripheral T-cell lymphomas.

Peripheral T- or natural killer (NK)-cell lymphomas are rare and difficult-to-recognize diseases. It remains arduous to distinguish between NK cell- and cytotoxic T-lymphocyte-derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK-cell receptors and examined the expression using immunohistochemistry in 22 cases with T- and NK-cell neoplasms comprising angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive and -negative anaplastic large-cell lymphomas, extranodal NK/T-cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, and other peripheral T-cell lymphomas. Inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK-cell receptors were expressed predominantly in TIA-1-positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK-cell neoplasms and cytotoxic T-lymphocyte-derived lymphomas including monomorphic epitheliotropic intestinal T-cell lymphoma. One Epstein-Barr virus-harboring cytotoxic T-lymphocyte-derived lymphoma mimicking extranodal NK/T-cell lymphoma, nasal type lacked these NK-cell receptors, indicating different cell origin from NK and innate-like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log-rank test, P = .024). We propose that the presence of activating NK-cell receptors may provide new insights into understanding peripheral T-cell lymphomas and characterizing them as innate-like T-cell neoplasm.

Breakthrough Candida guilliermondii (Meyerozyma guilliermondii) fungemia after cord blood transplantation for extranodal NK-cell lymphoma with azole prophylaxis.

Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non-albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long-term azole administration.

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL).

AIMS: Epstein-Barr virus-positive (EBV+ ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. METHODS AND RESULTS: We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. CONCLUSIONS: This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice.

Mature T- and NK-cell non-Hodgkin lymphoma in children and young adolescents.

Mature T/Natural killer (NK)-cell neoplasms of children and the young adolescent population exhibit higher prevalence in Central and South American and Asian populations and many are associated with Epstein-Barr virus (EBV). They are represented in large part by extranodal T/NK cell lymphomas- nasal-type or extra nasal-type, chronic lymphoproliferative disorders of T/NK cells or chronic active EBV disease, systemic EBV-positive lymphoproliferative disorders of childhood, hydroa vacciniforme-like lymphoma, hepatosplenic T-cell lymphoma and primary cutaneous gamma/delta T-cell lymphoma among others. Many T/NK cell neoplasms in this age group are derived from cells of the innate immune system, in contrast to adults where they are predominantly from the adaptive immune system. The genetic basis of T/NK cell lymphomas in children and young adolescents remains largely unknown. Anthracycline-based regimens and haematopoietic stem cell transplants (allogeneic and autologous) are current treatment modalities, however it is anticipated that novel targeted therapeutic agents will be available in the near future.

Risk factor analysis of non-Hodgkin lymphoma-associated haemophagocytic syndromes: a multicentre study.

Haemophagocytic syndrome is often associated with malignant lymphoma; however, few studies have examined lymphoma-associated haemophagocytic syndrome (LAHS). A total of 1239 patients with non-Hodgkin lymphoma were analysed at 12 institutions in Hokkaido prefecture between January 2007 and December 2011 to assess the incidence, prognosis and risk factors of LAHS. The cumulative incidence rate of LAHS was 2·8% (35/1239). Overall survival (OS) in patients with LAHS was significantly inferior to those without LAHS (3-year OS: 35·6 vs. 59·0% respectively, P < 0·0001). The cumulative incidence of LAHS was higher in patients with T/Natural Killer (NK)-cell lymphoma than in those with B-cell lymphoma (8·2 vs. 1·8% respectively, P < 0·0001). The characteristics of patients with and without early death (within the first 120 d after developing LAHS) were subsequently compared to evaluate the prognostic factor of LAHS. The results obtained showed that the rate of early death after developing LAHS was higher in patients with T/NK-cell lymphoma than in those with B-cell lymphoma (62·5 vs. 10·5%, P = 0·0033). In conclusion, the complication and mortality rates of LAHS were higher in patients with T/NK-cell lymphoma after they developed LAHS than in those with B-cell lymphoma.

SIE-SIES-GITMO guidelines for the management of adult peripheral T- and NK-cell lymphomas, excluding mature T-cell leukaemias.

BACKGROUND: In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. In this article, we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukaemias. DESIGN: By using the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) system, we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues. RESULTS: Six courses of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP) chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large-cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while l-asparaginase-containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong). CONCLUSION: In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.

EBV-Positive Nodal T- and NK-Cell Lymphoma Mimicking Anaplastic Large Cell Lymphoma: A Case Report.

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.

Classification and diagnostic evaluation of nodal T- and NK-cell lymphomas.

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 classification and diagnostic evaluation of this group of malignancies. Here, we discuss the classification of nodal T- and NK-cell lymphomas based on the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC). Lymphomas of T-follicular helper cell origin are now grouped into a single entity, follicular helper T-cell lymphoma (TFH lymphoma), with three subtypes (angioimmunoblastic-type, follicular-type, and not otherwise specified), reflecting their common cellular origin and shared molecular and clinical characteristics. Classification of anaplastic large cell lymphoma (ALCL) remains essentially unchanged; DUSP22-rearranged cases are now considered a genetic subtype of ALK-negative ALCL. Primary nodal EBV-positive T-/NK-cell lymphoma is introduced as a new provisional entity; these cases were previously considered a variant of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). PTCL, NOS remains a diagnosis of exclusion, with evolving molecular data indicating the presence of distinct subgroups, including PTCL-TBX21, PTCL-GATA3, and EBV-negative cytotoxic PTCLs. We also discuss diagnostic strategies to facilitate the 2022 ICC classification among nodal T- and NK-cell lymphomas and the distinction from nodal involvement by extranodal neoplasms.

Acquired Clotting Factor Deficits During Treatment with Asparaginase in an Institutional Cohort.

We invariably see prolongation of activated partial thromboplastin time in patients treated with asparaginase in our clinical practice, but have noted that, contrary to hypofibrinogenemia and low antithrombin, clotting times' prolongation by asparaginase is largely unreported in the literature and guidelines and is not widely known to clinicians. We report on aPTT prolongations in a small cohort of patients, and on their origin, as investigated by measurements of clotting factors, fibrinogen, and D-dimers before and after asparaginase administration. We observed significant reductions in FIX and FXI (median post-treatment values of 27 IU/dl and 52 IU/dl, respectively), confirming one previous observation. A decrease in FXII was less pronounced but contributed to the prolonged aPTTs (FXII has no effect on in vivo haemostasis). The factor deficits are not due to consumption, as evidenced by unchanged D-dimer levels, and are, therefore, probably caused by disturbed factor synthesis. Our observations and insights contribute to elucidation of the profile of clotting assays during asparaginase treatment, and thus, to optimally monitor for undesirable events or steer situations of therapeutic anticoagulation without the risk of suboptimal or excessive anticoagulation.

[Blastic plasmacytoid dendritic cell neoplasm (BPDCN) : A rare hematologic neoplasm with frequent cutaneous involvement]. / Blastische plasmazytoide dendritische Zellneoplasie (BPDCN) : Eine seltene hämatologische Neoplasie mit häufiger kutaner Beteiligung.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy that derives from precursors of plasmacytoid dendritic cells and is characterized by disseminated, erythematous or bluish-livid plaques or nodi. Because of the disease's rarity the diagnosis and treatment still pose a significant challenge. We present a case of a patient with BPDCN and show clinical and diagnostic characteristics as well as potential treatment regimes.

Mature T-cell and NK-cell lymphoma involvement of the central nervous system: a single center experience.

Mature T-cell and NK-cell lymphomas (MTNKL) are rare and heterogeneous lymphoproliferative disorders with poor clinical outcomes despite novel therapeutic advances. Although infrequent, central nervous system (CNS) involvement by MTNKL is associated with poor outcomes with a median overall survival (OS) of <12 months based on retrospective studies. We performed a retrospective analysis of patients who developed CNS involvement of MTNKL diagnosed at a single center from 1999 through 2020. Twenty-five patients were identified. Characteristics such as a diagnosis of adult T-cell leukemia/lymphoma, extranodal involvement, and poor performance status were associated with a higher risk of CNS involvement (p < 0.01). The median OS after diagnosis with CNS involvement was approximately 1 month (0.03-103.97 months). Patients exposed to novel therapeutics and/or clinical trial enrollment tolerated treatment without safety concerns and appeared to derive reasonable therapeutic benefit. Despite advances in the field, new therapeutic approaches are needed for patients with MTNKL with CNS involvement.

Contribution of the Epstein-Barr virus to the oncogenesis of mature T-cell lymphoproliferative neoplasms.

EBV is a lymphotropic virus, member of the Herpesviridae family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B cells. EBV exhibits complex survival and persistence dynamics, replicating its genome through the proliferation of infected B cells or production of the lytic virions. Many studies have documented the infection of T/NK cells by EBV in healthy individuals during and after primary infection. This feature has been confirmed in humanized mouse models. Together these results have challenged the hypothesis that the infection of T/NK cells per se by EBV could be a triggering event for lymphomagenesis. Extranodal NK/T-cell lymphoma (ENKTCL) and Epstein-Barr virus (EBV)-positive nodal T- and NK-cell lymphoma (NKTCL) are two EBV-associated lymphomas of T/NK cells. These two lymphomas display different clinical, histological and molecular features. However, they share two intriguing characteristics: the association with EBV and a geographical prevalence in East Asia and Latin America. In this review we will discuss the genetic characteristics of EBV in order to understand the possible role of this virus in the oncogenesis of ENKTCL and NKTCL. In addition, the main immunohistological, molecular, cytogenetic and epigenetic differences between ENKTCL and NKTCL will be discussed, as well as EBV differences in latency patterns and other viral molecular characteristics.

Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases: emerging concepts, recent advances, and the putative role of clonal hematopoiesis. A report of the 2022 EA4HP/SH lymphoma workshop.

Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases were discussed at the 2022 European Association for Haematopathology/Society for Hematopathology lymphoma workshop held in Florence, Italy. This session focused on (i) primary nodal EBV-positive T and NK-cell lymphomas (primary nodal-EBV-TNKL), (ii) extranodal EBV-positive T/NK lymphoproliferative diseases (LPD) in children and adults, (iii) cytotoxic peripheral T-cell lymphomas, NOS (cPTCL-NOS), EBV-negative, and (iv) miscellaneous cases. Primary nodal-EBV-TNKL is a newly recognized entity which is rare, aggressive, and associated with underlying immune deficiency/immune dysregulation. All cases presented with lymphadenopathy but some demonstrated involvement of tonsil/Waldeyer's ring and extranodal sites. The majority of tumors are of T-cell lineage, and the most frequent mutations involve the epigenetic modifier genes, such as TET2 and DNMT3A, and JAK-STAT genes. A spectrum of EBV-positive T/NK LPD involving extranodal sites were discussed and highlight the diagnostic challenge with primary nodal-EBV-TNKL when these extranodal EBV-positive T/NK LPD cases demonstrate predominant nodal disease either at presentation or during disease progression from chronic active EBV disease. The majority of cPTCL-NOS demonstrated the TBX21 phenotype. Some cases had a background of immunosuppression or immune dysregulation. Interestingly, an unexpected association of cPTCL-NOS, EBV-positive and negative, with TFH lymphomas/LPDs was observed in the workshop cases. Similar to a published literature, the genetic landscape of cPTCL-NOS from the workshop showed frequent mutations in epigenetic modifiers, including TET2 and DNMT3A, suggesting a role of clonal hematopoiesis in the disease pathogenesis.