• Epstein-Barr virus (EBV)
• JAK/STAT pathway
• angiocentricity
• extended-field radiotherapy (EF-RT)
• extranodal NK-/T-cell lymphoma
• multi-drug resistance (MDR)
• nasal type (ENKTCL-NT)
• prognosis

• acute lymphocytic leukaemia
• cancer genomics
• oncogenes

• Humans
• Forkhead Transcription Factors/metabolism
• Forkhead Box Protein O3/genetics
• Forkhead Box Protein O3/metabolism
• Chromosomes, Human, Pair 6/metabolism
• Gene Expression Regulation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
• Positive Regulatory Domain I-Binding Factor 1/genetics

• 27193 Cancer Research UK
• Newcastle Annual Fund
• Bloodwise
• The European Research Council (#249891)

Natural killer (NK)/T-cell lymphomas are aggressive extranodal Epstein–Barr virus (EBV)-positive malignancies. They can be divided into three subtypes: nasal (involving the nose and upper aerodigestive tract), non-nasal (involving skin, gastrointestinal tract, testis and other organs) and disseminated (involving multiple organs). Lymphoma cells are positive for CD3ε, CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asians. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial at diagnosis and follow-up. Stage I/II patients receive non-athracycline asparaginse-containing regimens, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients receive asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT). Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches include PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial.

Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.

• EBV
• NK/T-cell lymphomas
• PD1
• asparaginase
• haematopoietic stem cell transplantation
• radiotherapy

• extranodal NK/T-cell lymphoma
• genetics
• pathology
• review

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein–Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.

• EBV DNA
• EBV-encoded small nuclear early region (EBER)-1
• Epstein–Barr virus (EBV)
• MPVIC-P
• extranodal NK/T-cell lymphoma
• latent membrane protein (LMP) 1
• nasal type

The incidence of intestinal NK/T cell lymphoma (NKTCL) is extremely low, and the clinical symptoms are atypical, which makes it difficult to distinguish this disorder from Crohn's disease (CD), T lymphocyte proliferative disease, and other immune disorders. The misdiagnosis rate is high, and the patient's prognosis is poor.

In this case, the patient had repeated high fever, colonoscopy revealed multiple ulcers, and the initial diagnosis was CD. The patient’s condition did not improve after treatment with hormones and infliximab, and she eventually died. Positron emission tomographic-computed tomographic and B-ultrasound were performed in our hospital and showed that multiple lymph nodes were enlarged. Immunohistochemi-stry showed that CD3 and Epstein-Barr virus encoded RNA expression was positive. Colonoscopy, tissue biopsy, and histopathology showed intestinal focal mucosal infiltration of heterotypic lymphocytes with an abnormal immune phenotype. On the basis of the patient’s medical history, auxiliary examination, and pathological findings, digestive physicians and pathologists gave the diagnosis of NKTCL.

Clinicians need to improve their comprehensive knowledge of NKTCL, and combination of clinical symptoms, histological characteristics, as well as colonoscopy biopsies should be considered to improve the diagnosis and thereby reduce misdiagnosis.

• NK/T cell lymphoma
• Indolent T lymphocyte proliferative disease
• Crohn's disease
• Endoscopy
• Misdiagnosis
• Case report

• Adult
• Crohn Disease/diagnosis
• Diagnosis, Differential
• Enteropathy-Associated T-Cell Lymphoma
• Epstein-Barr Virus Infections/diagnosis
• Female
• Herpesvirus 4, Human
• Humans
• Intestines

• Asparaginase
• EBV
• Immunotherapy
• NK/T-cell lymphoma
• Nasal
• Non-nasal
• PD1
• PET/CT

• Extranodal NK/T cell lymphoma
• Hallmarks of cancer
• Molecular pathogenesis

• CCR4
• Epstein-Barr virus
• ICAM-1
• MPVIC-P
• PD-L1
• chemokine
• cytokine
• nasal natural killer /T-cell lymphoma

• EBV
• aggressive NK-cell leukemia
• chronic active EBV infection
• extranodal NK/T-cell lymphoma
• hemophagocytic lymphohistiocytosis
• lymphoproliferations
• primary EBV nodal T and NK-cell lymphoma
• systemic EBV positive T-cell lymphoma

• Biology
• Gene expression profiling
• Mutational landscape
• Mycosis fungoides
• Pathogenesis
• Peripheral T-cell lymphoma
• Sezary syndrome

• Gene Expression Profiling
• Genomics
• Humans
• Lymphoma, T-Cell, Peripheral/genetics

• Gene expression profiling (GEP)
• NK/T-cell lymphoma
• copy number
• epigenetics
• genomics
• immune checkpoint
• targeted therapy

• Animals
• DNA Copy Number Variations/genetics
• Epigenomics/methods
• Gene Expression Profiling/methods
• Genomics/methods
• Humans
• Lymphoma, Extranodal NK-T-Cell/genetics
• Lymphoma, Extranodal NK-T-Cell/metabolism
• Platelet-Derived Growth Factor/metabolism
• Protein Tyrosine Phosphatases/metabolism

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.

• Epstein-Barr virus
• clinical features
• epidemiology
• lymphoma
• lymphoproliferations
• morphology
• pathogenesis

Aggressive natural killer cell leukemia (ANKL) is extremely rare and habitually manifests as a systemic disease with multiorgan failure that rapidly evolves to death. The neoplastic natural killer (NK) cells usually harbor the Epstein-Barr virus (EBV) with a latent viral infection pattern type II; they often have a cytoplasmic CD3ε⁺ and surface CD3⁻, CD2⁺, and CD56⁺ immunophenotype, and they show complex genetic abnormalities affecting multiple tumor suppressor genes and oncogenes. We present a rare case of CD56-negative ANKL and review the clinical and laboratorial criteria for the diagnosis, as well as the available therapies.

A European 36-year-old male presented with acute onset fever, pallor, weakness, and jaundice. He had hepatosplenomegaly, severe pancytopenia, hepatic cytolysis, and very high serum lactic dehydrogenase levels. The bone marrow studies resulted in the diagnosis of an EBV-positive, CD56-negative ANKL. The patient failed to respond to gemcitabine and cisplatin-based polychemotherapy, dying three months later with leukemic meningitis and multiple cranial nerves palsies.

The diagnosis of ANKL is difficult and requires both clinical suspicion and an extensive laboratorial approach. Absence of CD56 expression on the neoplastic NK cells may impose difficulties in the diagnosis, which requires morphological, immunophenotypic, histopathological, immunohistochemical, cytogenetic, and molecular studies.

NKL homeobox gene MSX1 is physiologically expressed in lymphoid progenitors and subsequently downregulated in developing T- and B-cells. In contrast, elevated expression levels of MSX1 persist in mature natural killer (NK)-cells, indicating a functional role in this compartment. While T-cell acute lymphoblastic leukemia (T-ALL) subsets exhibit aberrant overexpression of MSX1, we show here that in malignant NK-cells the level of MSX1 transcripts is aberrantly downregulated. Chromosomal deletions at 4p16 hosting the MSX1 locus have been described in NK-cell leukemia patients. However, NK-cell lines analyzed here showed normal MSX1 gene configurations, indicating that this aberration might be uncommon. To identify alternative MSX1 regulatory mechanisms we compared expression profiling data of primary normal NK-cells and malignant NK-cell lines. This procedure revealed several deregulated genes including overexpressed IRF4, MIR155HG and MIR17HG and downregulated AUTS2, EP300, GATA3 and HHEX. As shown recently, chromatin-modulator AUTS2 is overexpressed in T-ALL subsets where it mediates aberrant transcriptional activation of MSX1. Here, our data demonstrate that in malignant NK-cell lines AUTS2 performed MSX1 activation as well, but in accordance with downregulated MSX1 transcription therein we detected reduced AUTS2 expression, a small genomic deletion at 7q11 removing exons 3 and 4, and truncating mutations in exon 1. Moreover, genomic profiling and chromosomal analyses of NK-cell lines demonstrated amplification of IRF4 at 6p25 and deletion of PRDM1 at 6q21, highlighting their potential oncogenic impact. Functional analyses performed via knockdown or forced expression of these genes revealed regulatory network disturbances effecting downregulation of MSX1 which may underlie malignant development in NK-cells.

• NKL-code
• T-ALL
• homeobox

• EBV DNA quantification
• Extranodal
• Immunotherapy
• L-asparaginase
• NK/T-cell lymphoma
• Nasal
• Non-nasal
• PD1
• Prognostication

• Asparaginase/therapeutic use
• Combined Modality Therapy/methods
• Hematopoietic Stem Cell Transplantation
• Humans
• Lymphoma, Extranodal NK-T-Cell/diagnosis
• Lymphoma, Extranodal NK-T-Cell/genetics
• Lymphoma, Extranodal NK-T-Cell/pathology
• Lymphoma, Extranodal NK-T-Cell/therapy
• Prognosis
• Programmed Cell Death 1 Receptor/antagonists & inhibitors
• Radiotherapy
• Salvage Therapy/methods

• Chromosomal translocation
• Classification
• Cytogenetics
• Diagnosis
• FISH
• Molecular targeted therapy
• Non-Hodgkin lymphoma
• PCR
• Personalized medicine
• Prognosis

• Epstein Barr virus
• Extranodal NK/T-cell lymphoma
• L-asparaginase
• hematopoietic stem cell transplantation
• natural killer cell

• T-cell lymphoma
• cell of origin
• mechanisms of transformation

• Epstein-Barr virus
• Korea
• T/natural killer cell
• lymphoma
• lymphoproliferative disease

Extranodal NK/T-cell lymphoma, nasal type, is an aggressive mature NK-cell/T-cell lymphoma. Using array-based comparative genomic hybridization (array CGH) assays, we screened genomic alterations and potential candidate genes implicated in pathogenesis, progression, and prognosis. Our array CGH analysis detected an average of 83 chromosomal aberrations in 13 cases, ranging from 0 to 387. There were 177 recurrent chromosomal gains and 35 recurrent losses. Eleven gains and 14 losses were detected in more than 30 % of the cases, including gains of 3q26.1, 7q34, and 8q24.3 and losses of 15q24.2, 19q13.32, 5p13.2, and 14q21.1. The most common losses were observed in the 15q24.2 and 19q13.32 regions (9 cases, 69.2 %, respectively). Loss of 8p11.23 was associated with significant poor survival (P = 0.024). Five out of six patients with the loss of 8p11.23 died within 8 months after initial diagnosis with a median survival of 6 months. Several candidate genes were identified in the regions with frequent chromosomal aberrations, including ADAM3A (8p11.23) and GSTT1 (22q11.23). In summary, our studies detected recurrent genetic alterations in NK/T-cell lymphoma, some of which are associated with adverse prognosis. Some candidate genes in these regions may be involved in the pathogenesis and disease progression.

• array comparative genomic hybridization
• clinicopathologic features
• cutaneous T-cell lymphoma
• extranodal natural killer–/T-cell lymphoma
• genomic aberrations
• nasal type
• prognosis

• nk-cell neoplasms
• nk/t-cell lymphoma
• nasal-type
• aggressive nk-cell leukemia
• cd56
• neoplasias de células nk
• linfomas de células nk
• tipo nasal
• leucemia agressiva de células nk

• Asia/epidemiology
• Herpesvirus 4, Human/isolation & purification
• Humans
• Killer Cells, Natural/metabolism
• Killer Cells, Natural/pathology
• Leukemia/diagnosis
• Leukemia/epidemiology
• Leukemia/pathology
• Leukemia/virology
• Lymphoma, Extranodal NK-T-Cell/diagnosis
• Lymphoma, Extranodal NK-T-Cell/epidemiology
• Lymphoma, Extranodal NK-T-Cell/pathology
• Lymphoma, Extranodal NK-T-Cell/virology
• Nose Neoplasms/diagnosis
• Nose Neoplasms/epidemiology
• Nose Neoplasms/pathology
• Nose Neoplasms/virology
• Prevalence
• South America

• Cell Transformation, Neoplastic/pathology
• Epstein-Barr Virus Infections/complications
• Epstein-Barr Virus Infections/pathology
• Humans
• Lymphoma, Extranodal NK-T-Cell/pathology
• Lymphoma, Extranodal NK-T-Cell/virology
• Lymphoma, T-Cell, Peripheral/pathology
• Lymphoma, T-Cell, Peripheral/virology

Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr virus infection. Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin's lymphomas. It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies.