ABSTRACT
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is strongly associated with Epstein-Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T-cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T-cell lymphomas include mutations of genes, involving in the Janus Kinase/signal transducer and activator of transcription pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen has been demonstrated. Radiotherapy plays a key role in the first-line treatment of early-stage. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are recommended. Although clinical remission after L-asparaginase-based combination therapy has been achieved in the majority of patients with advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma-nasal type, the long-term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Extranodal NK-T-Cell , Humans , Asparaginase , Epstein-Barr Virus Infections/pathology , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/therapy , Epigenesis, Genetic , Herpesvirus 4, Human/physiology , Killer Cells, Natural/pathologyABSTRACT
Aim: The emergence of antitumor immunotherapy has been beneficial for patients with tumors, but more attention should be paid to the toxic side effects of chemoimmunotherapy. Here we describe a patient with NK/T-cell lymphoma who developed toxic epidermal necrolysis (TEN) during treatment with a regimen consisting of sintilimab combined with pegaspargase, gemcitabine and oxaliplatin (P-GemOx). Case presentation: A patient received six cycles of P-GemOx chemotherapy as first-line treatment; 1 year later, he received the same dose of P-GemOx combined with sintilimab as chemoimmunotherapy due to recurrence of NK/T-cell lymphoma. He developed a massive rash that quickly developed into TEN after the fourth chemoimmunotherapy. Conclusion: Although rare, cases of fatal TEN caused by single-agent PD-1 inhibitor or gemcitabine have been reported. Careful attention to drug-related cutaneous toxicities is needed when these two agents are combined. This report highlights the significance of TEN as a rapid and serious adverse event induced by chemoimmunotherapy.
Immune checkpoint inhibitors that block the interaction of PD-1 with its ligand, PD-L1, have been increasingly used in cancer therapy. However, some rare side effects induced by these drugs, such as toxic epidermal necrolysis (TEN), can be extremely dangerous. Here we describe a patient with natural killer/T-cell lymphoma who developed TEN during treatment with a combination of sintilimab and pegaspargase/gemcitabine/oxaliplatin (P-GemOx). The patient received six cycles of P-GemOx chemotherapy as first-line treatment and showed no skin reactions during or after treatment. However, 1 year later, the patient received the same dose of P-GemOx combined with sintilimab as second-line treatment for recurrent natural killer/T-cell lymphoma and developed a massive rash that quickly developed into TEN after four cycles of chemoimmunotherapy. Cutaneous toxicities are some of the most prevalent immune-related adverse events, both with anti-PD-1 and anti-PD-L1 agents, which correspond to a class effect.
Subject(s)
Lymphoma, Extranodal NK-T-Cell , Stevens-Johnson Syndrome , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Humans , Immunotherapy/adverse effects , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Extranodal NK-T-Cell/etiology , Male , Oxaliplatin/therapeutic use , Stevens-Johnson Syndrome/diagnosis , Stevens-Johnson Syndrome/drug therapy , Stevens-Johnson Syndrome/etiology , Treatment OutcomeABSTRACT
Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.
Subject(s)
Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , Host-Pathogen Interactions/immunology , Immunity, Humoral , Lymphoma, Extranodal NK-T-Cell/etiology , Viral Proteins/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , Case-Control Studies , Disease Susceptibility , Enzyme-Linked Immunosorbent Assay , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Hong Kong , Humans , Immunoglobulin G/immunology , Lymphoma, Extranodal NK-T-Cell/pathology , Male , Middle Aged , Odds Ratio , Protein Array Analysis , Taiwan , Viral Proteins/metabolism , Young AdultABSTRACT
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is an aggressive malignancy associated with Epstein-Barr virus infection, with a geographic and racial predilection for some Asian and Latin American countries. ENKTCL-NT manifests as a necrotic process affecting nasal or upper aerodigestive structures and, rarely, extranasal sites such as skin, and the gastrointestinal tract. ENKTCL-NT was characterized by its poor prognosis irrespective of clinical stage and therapy. However, during the last two decades, advances in its clinicopathologic, genetic and molecular characterization have been achieved, as have changes in the chemotherapy regimens that, in combination with radiotherapy, are significantly improving the survival of these patients, especially in initial stages. For these reasons, we present an overview of the historical background of ENKTCL-NT along with an updated review of its potential etiological factors, clinicopathologic and molecular features, as well as its prognostic models, current treatment protocols, and future directions on potential promising therapeutic approaches.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Extranodal NK-T-Cell , Humans , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/epidemiology , Lymphoma, Extranodal NK-T-Cell/etiology , PrognosisABSTRACT
Increased incidence of lymphoproliferative disorders is reported in patients with autoimmune diseases, majority of which have a B-cell phenotype and are pathogenetically associated with the reactivation of Epstein-Barr virus (EBV). However, EBV-associated T/NK-cell lymphoma has hardly been reported. We present the case of a 68-year-old-woman, who had been diagnosed with systemic lupus erythematosus (SLE) 28 years back and was treated with various immunosuppressive agents including steroids, cyclophosphamide, and tacrolimus. She presented with a progressively worsening swelling of the right thigh for the last few months. Radiological examination revealed an intramuscular bulky tumor without any other lesions and the biopsy results led to a diagnosis of extranodal NK/T-cell lymphoma, nasal type (ENKL). Concurrent chemoradiotherapy resulted in a complete response, which has been sustained for more than 2 years without requiring additional therapy. After the initiation of chemotherapy, SLE did not worsen with the administration of low-dose corticosteroids. To the best of our knowledge, this is the first case report of a localized extranasal ENKL developing in a patient with SLE.
Subject(s)
Chemoradiotherapy , Lupus Erythematosus, Systemic/complications , Lymphoma, Extranodal NK-T-Cell/therapy , Muscle Neoplasms/therapy , Aged , Epstein-Barr Virus Infections/complications , Female , Humans , Immunocompromised Host , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/etiology , Muscle Neoplasms/diagnosis , Muscle Neoplasms/etiology , Thigh , Treatment OutcomeABSTRACT
Extranodal nasal-type natural killer/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma that progresses rapidly and relapses frequently. Advanced ENKTL is multidrug chemoresistant and has a poor prognosis. In this study, we aim to develop a novel hexokinase domain component 1 (HKDC1)-based antitumor target for ENKTL that is involved with the antimetabolic signaling pathway, EBV replication, and P-glycoprotein (P-gp) expression. We showed that HKDC1 is highly upregulated in ENKTL cells and HKDC1 knockdown significantly suppresses ENKTL tumor growth. In addition, HKDC1 is highly identical with four other hexokinase isoforms, with the only difference being in the last eight amino acids (aa) at the C-terminal. Further investigation showed that peptide delivery of the last eight aa of HKDC1 at the C-terminal (HKC8) with D-configuration using transferrin (Tf) receptor internalization sequence (Tf-D-HKC8) inhibits HKDC1 association with vascular endothelial growth factor 1 (VDAC1), resulting in mitochondrial dysfunction and reactive oxygen species (ROS) overgeneration and subsequently suppressing EBV replication and P-gp expression, making it very effective in killing EBV-positive ENKTL cells. Further in vivo experiments showed that local injection of Tf-D-HKC8 peptide significantly suppresses ENKTL tumor growth and EBV replication in ENKTL xenograft mouse models. We conclude that HKDC1 C-terminal-based peptides inhibit ENKTL by modulation of mitochondrial function and EBV suppression.
Subject(s)
Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/drug effects , Hexokinase/metabolism , Lymphoma, Extranodal NK-T-Cell/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Peptides/pharmacology , Amino Acid Sequence , Animals , Apoptosis/drug effects , DNA Damage , Disease Models, Animal , Dose-Response Relationship, Drug , Epstein-Barr Virus Infections/virology , Gene Expression Regulation, Neoplastic , Heterografts , Hexokinase/chemistry , Humans , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/pathology , Mice , Peptides/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare peripheral T-cell lymphoma associated with Epstein-Barr virus. It most often presents as limited-stage disease in patients of East Asian descent with a palatal deformity caused by erosion of the tumor through the hard palate. Limited-stage disease is often curable with the use of l-asparaginase-based chemotherapy and high-dose radiation therapy. Obtaining an accurate diagnosis is essential, because treatment with standard lymphoma regimens and omission of radiation severely compromise the likelihood of long-term survival. Conversely, patients with advanced disease have a poor prognosis and are recommended for asparaginase-based chemotherapy followed by consolidation with autologous transplantation as a potentially curative approach. Progress often has been hampered by the rarity of this disease. However, discovery of common genetic alterations in pathways that promote growth and inhibit apoptosis, and actionable markers such as CD30 (among others), have begun to broaden the availability of novel drugs (eg, targeted therapies). There is also cautious optimism about immunotherapies, such as checkpoint blockade and novel cellular therapies that target Epstein-Barr virus. Advances in treatment and understanding of the genetic landscape of this disease offer hope for improved treatment outcomes.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/therapy , Combined Modality Therapy , Disease Management , Humans , Lymphoma, Extranodal NK-T-Cell/epidemiology , Lymphoma, Extranodal NK-T-Cell/etiology , Neoplasm Staging , SEER Program , Treatment OutcomeABSTRACT
Natural-killer/T cell lymphoma (NKTCL) is the most common extranodal lymphoma with highly aggressive clinical outcome. System biology techniques provide novel insights into the pathogenesis, risk stratification, and clinical management in NKTCL. Comparative genomic hybridization analysis reveal most frequent deletion of chromosome 6q21. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Genome-wide association study reports strongest association of HLA-DPB1 rs9277378 with lymphomagenesis. Alterations of oncogenic signaling pathways as well as epigenetic dysregulation of microRNA and long non-coding RNAs are also observed in NKTCL. Epstein-Barr virus (EBV) is the major etiology of NKTCL and the pathogenic mechanism remains unclear. Different risk stratification models are proposed based on clinical parameters (IPI, PINK, and PINK-E, etc.) or biomarkers (Ki67, C-reactive protein level, and EBV DNA, etc.). Therapeutic strategies vary according to disease stage, including radiotherapy, asparaginase-based chemotherapy, hematopoietic stem-cell transplantation, targeted therapy (immune checkpoints inhibitors, and histone deacetylation inhibitors, etc.). Future investigations will be emphasized on EBV-related pathogenesis of NKTCL, prognostic and therapeutic biomarkers, as well as multi-center clinical trials, so as to optimize personalized treatment of NKTCL in the era of precision medicine.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/therapy , Biomarkers, Tumor , Combined Modality Therapy , Diagnostic Imaging/methods , Disease Management , Disease Susceptibility , Humans , Lymphoma, Extranodal NK-T-Cell/epidemiology , Lymphoma, Extranodal NK-T-Cell/etiology , Prognosis , Recurrence , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Natural Killer T-Cell Lymphoma (NKTCL) is a subtype of Non-Hodgkin's Lymphoma, and its morbidity is ranked the first of T-Cell Lymphoma. Hippo signaling pathway is involved in the pathogenesis of tumors. However, the role of Hippo signaling pathway in the oncogenesis of NKTCL still remains unclear. METHODS: The expressions of mammalian sterile 20-like kinase 1 (MST1) and Yes-associated protein (YAP) were investigated by RT-PCR and Western blotting. Cell viability was detected by MTT assays. Cell cycle and cell apoptosis were determined by flow cytometry. Cell proliferative capacity was detected by colony formation assay. Nude mice xenograft models were established and the tumor sections were analyzed by immunohistochemistry (IHC) staining. RESULTS: The expression of MST1 was significantly down-regulated in NKTCL tissues (n = 30) and cell lines, while the expression of YAP was significantly up-regulated, and the phosphorylation of YAP was inhibited. Overexpression of MST1, knockdown of YAP, or verteporfin (VP) treatment could inhibit cell proliferation, and promote cell cycle arrest and apoptosis in NKTCL cells, while knockdown of MST1 and overexpression of YAP promoted cell proliferation. Additionally, Bcl-2/Bax ratio and downstream effectors of Hippo signaling pathway (c-myc, survivin, cyclinD1, CTGF, and TEAD) were significantly decreased when MST1 was overexpressed and YAP was knocked down or after VP treatment. Furthermore, our mice model demonstrated that activation of Hippo signal pathway suppressed the tumorigenesis of NKTCL. CONCLUSION: The activation of Hippo signal pathway via overexpressing MST1 or down-regulating YAP can inhibit the tumorigenesis of NKTCL.
Subject(s)
Apoptosis , Lymphoma, Extranodal NK-T-Cell/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Animals , Biomarkers , Cell Cycle , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Gene Expression , Hippo Signaling Pathway , Humans , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/pathology , Male , Mice , Transcription Factors/genetics , Transcription Factors/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Paediatric non-Hodgkin lymphomas (pNHL) are a diverse group of malignancies characterised by nodal and/or extranodal involvement. Less common pNHL forms include those derived from mature T- and natural killer (NK) cells. Much of our current understanding of paediatric mature (non-anaplastic) T/NK-cell lymphomas with respect to pathogenesis, diagnosis and treatment is extrapolated from adult literature. At the Sixth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma, convened September 26-29, 2018 in Rotterdam, The Netherlands, some important aspects on diagnosis and outcomes of mature (non-anaplastic) T/NK-cell lymphoma in children and adolescents were discussed and will be reviewed in here.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/therapy , Adolescent , Child , Combined Modality Therapy , Diagnosis, Differential , Disease Management , Disease Susceptibility , Female , Humans , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/mortality , Male , Neoplasm Grading , Prognosis , Treatment Outcome , Young AdultABSTRACT
Circulating EBV-DNA is an accurate biomarker of tumor load in extranodal natural killer (NK)/T cell lymphoma (ENKTL); however, its role in patients treated with P-GEMOX has not been evaluated. In this study, we examined plasma EBV-DNA of 99 patients at different time points by real-time quantitative polymerase chain reaction. Multivariate analysis revealed that ECOG PS score, response rate, and post-treatment EBV-DNA level were independent predictors of progression-free survival (PFS) and overall survival (OS). Positive post-treatment plasma EBV-DNA was associated with poor OS in ENKTL patients. The 3-year OS for patients with positive pre-, interim-, post-treatment EBV-DNA was significantly lower than that for patients with negative EBV-DNA; the values were 70.2% vs. 93.9% (p = .022), 53.8% vs. 99.1% (p < .001), and 40.6% vs. 91.8% (p < .001), respectively. We conclude that monitoring dynamic changes in plasma EBV-DNA in ENKTL patients treated with P-GEMOX could predict important outcomes such as OS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Deoxycytidine/analogs & derivatives , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Extranodal NK-T-Cell/etiology , Polyethylene Glycols/administration & dosage , Viral Load , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , DNA, Viral , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Female , Humans , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/mortality , Male , Middle Aged , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/therapeutic use , Prognosis , Proportional Hazards Models , Treatment Outcome , Young AdultABSTRACT
Extranodal natural killer/T-cell lymphoma (ENKTL) is associated with Epstein-Barr virus (EBV) infection, a common cause of hemophagocytosis. As interleukin-18 (IL18) is related with hemophagocytosis, we measured serum IL18 and IL18-related cytokines of newly diagnosed patients with ENKTL (N = 114) to investigate the role as a biomarker for hemophagocytosis and determine the prognosis of ENKTL. The median value of serum IL18 was 20.5 pg/mL (1.23-2021.81 pg/mL). The high IL18 group (≥20.5 pg/mL) was associated with stage III/IV, the presence of hemophagocytosis and poor treatment outcome. Serum IL18 showed significant positive correlations with TNFα, IFNγ, and IP10. Overall survival was significantly different between the high and low IL18 groups (p < .001), and high serum IL18 was independently prognostic for survival in the multivariate analysis. In conclusion, serum IL18 levels may be associated with the hemophagocytosis and poor survival outcomes in patients with ENKTL.
Subject(s)
Biomarkers , Interleukin-18/blood , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/mortality , Lymphoma, Extranodal NK-T-Cell/blood , Lymphoma, Extranodal NK-T-Cell/mortality , Adolescent , Adult , Aged , Combined Modality Therapy , Cytokines/blood , Female , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/etiology , Male , Middle Aged , Neoplasm Staging , Prognosis , Survival Analysis , Young AdultSubject(s)
Liver Transplantation/adverse effects , Lymphoma, Extranodal NK-T-Cell/pathology , Lymphoproliferative Disorders/pathology , Skin Neoplasms/pathology , Aged , Humans , Immunosuppression Therapy/adverse effects , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , Male , Skin Neoplasms/diagnosis , Skin Neoplasms/etiologyABSTRACT
BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Biopsy , Cyclophosphamide/therapeutic use , DNA, Viral , Doxorubicin/therapeutic use , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/genetics , Humans , Immunophenotyping/methods , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/metabolism , Malawi , Male , Middle Aged , Prednisone/therapeutic use , Treatment Outcome , Vincristine/therapeutic useABSTRACT
A 74-year-old woman developed bilateral uveitis with high Epstein-Barr virus (EBV) DNA load in the vitreous fluid without lymphoma cells. Four years after the onset, T2-weighted contrast-enhanced MRI revealed hyperintense lesions in the right occipital and parietal lobe. A biopsy resulted in the diagnosis of extranodal NK/T-cell lymphoma nasal type (ENKL). The repeat region of LMP1, an EBV gene, detected in the brain lesion was identical to that detected in the vitreous fluid. ENKL of the central nervous system is quite rare, and the pathogenesis has not been determined. The lymphoma in this case might have been closely associated with the EBV-positive uveitis.
Subject(s)
Brain Neoplasms/etiology , Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/genetics , Lymphoma, Extranodal NK-T-Cell/etiology , Uveitis/complications , Uveitis/virology , Aged , Brain Neoplasms/diagnosis , Brain Neoplasms/virology , Cerebrum , Female , Humans , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/virologyABSTRACT
Extranodal NK/T-cell lymphoma (ENKTL) is a rare aggressive extranodal non-Hodgkin lymphoma (NHL) universally associated with Epstein-Barr virus (EBV). ENKTL most commonly occurs in non-elderly immune competent males in Asia and South America. A number of antecedent lymphoproliferative disorders (LPDs) have been described in Asian and South American patients, but the majority of Caucasian ENKTL patients have no known preceding LPD or underlying immunodeficiency. Other than EBV, no environmental or extrinsic factor has been implicated in oncogenesis. The precise mechanisms by which EBV infects NK or T cells and the virus' role in the pathogenesis of ENKTL have not been fully deciphered. However, a number of recent discoveries including disturbances in cell signaling and mutations in tumor suppressor genes have been identified, which are providing insights into the pathogenesis of ENKTL. In this review, we highlight the molecular, viral, and genetic underpinnings of ENKTL and discuss potential therapeutic implications.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/therapy , Epstein-Barr Virus Infections/complications , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genomics , Herpesvirus 4, Human/physiology , Humans , Lymphoma, Extranodal NK-T-Cell/genetics , Lymphoma, Extranodal NK-T-Cell/virologySubject(s)
Immunosuppressive Agents/adverse effects , Liver Transplantation , Lymphoma, Extranodal NK-T-Cell/etiology , Postoperative Complications/etiology , Allografts , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Dexamethasone/administration & dosage , Drug Substitution , Etoposide/administration & dosage , Humans , Ifosfamide/administration & dosage , Immunosuppressive Agents/therapeutic use , Liver Cirrhosis/etiology , Living Donors , Lymphoma, Extranodal NK-T-Cell/drug therapy , Methotrexate/administration & dosage , Methylprednisolone/therapeutic use , Mycophenolic Acid/therapeutic use , Postoperative Complications/drug therapy , Remission Induction , Tacrolimus/adverse effects , Tacrolimus/therapeutic use , Transplant RecipientsABSTRACT
RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation-quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.
Subject(s)
Cell Transformation, Neoplastic/genetics , Core Binding Factor Alpha 3 Subunit/physiology , Gene Expression Regulation, Neoplastic , Lymphoma, Extranodal NK-T-Cell/genetics , Nose Neoplasms/genetics , Proto-Oncogene Proteins c-myc/physiology , Transcription, Genetic/genetics , Apoptosis , Azepines/pharmacology , Binding Sites , Cell Division , Cell Line, Tumor , Core Binding Factor Alpha 3 Subunit/antagonists & inhibitors , Core Binding Factor Alpha 3 Subunit/genetics , Enhancer Elements, Genetic , Genes, Reporter , Genetic Vectors , Humans , Lymphoma, Extranodal NK-T-Cell/etiology , Lymphoma, Extranodal NK-T-Cell/metabolism , Lymphoma, Extranodal NK-T-Cell/pathology , Molecular Targeted Therapy , Nose Neoplasms/etiology , Nose Neoplasms/metabolism , Nose Neoplasms/pathology , Protein Interaction Mapping , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , RNA Interference , RNA, Small Interfering/genetics , Recombinant Fusion Proteins/metabolism , Triazoles/pharmacology , Up-RegulationABSTRACT
Nasal natural killer/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-associated malignancy and is characterized by local invasion and widespread dissemination, with a consequent poor prognosis. Micro-RNAs (miRNAs) play roles in the pathogenesis of several malignancies by regulating gene expression and have been recently identified as stable entities in serum. Here, we investigated the value of circulating EBV-miRNAs as biomarkers for NNKTL. Sera of patients with NNKTL were subjected to miRNA polymerase chain reaction (PCR)-array analysis, after which serum EBV-miRNA levels were verified using quantitative PCR. The latter analysis revealed high miR-BART2-5p, miR-BART7-3p, miR-BART13-3p, and miR-BART1-5p expression levels in sera of patients with NNKTL and indicated accurate values for discriminating patients with NNKTL from healthy controls. Levels of these 4 EBV-miRNAs, which were secreted from NNKTL cells, significantly decreased after treatment compared with those before treatment. Furthermore, a high circulating miR-BART2-5p level was associated with disease progression and poor prognosis in patients with NNKTL. Our findings demonstrate that circulating EBV-miRNAs, particularly miR-BART2-5p, may serve as potential diagnostic and prognostic biomarkers in patients with NNKTL.
Subject(s)
Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , Lymphoma, Extranodal NK-T-Cell/blood , Lymphoma, Extranodal NK-T-Cell/etiology , MicroRNAs/blood , RNA, Viral/blood , Adult , Aged , Biomarkers , Cell Line, Tumor , Combined Modality Therapy , Exosomes , Female , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Lymphoma, Extranodal NK-T-Cell/diagnosis , Lymphoma, Extranodal NK-T-Cell/therapy , Male , Middle Aged , Prognosis , ROC Curve , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Extranodal NK/T-cell lymphoma nasal type is a distinct clinicopathologic entity. The most common initial site of presentation is the nasopharyngeal area, but non-nasals sites including the skin and the gastrointestinal tract may be affected. AREAS COVERED: The diagnosis and management of NK/T-cell lymphoma is discussed, based on a literature search on PubMed. NK/T-cell lymphoma are typically positive for CD3 (cytoplasmic), CD56, cytotoxic markers (granzyme B, TIA1) and Epstein Barr virus (EBV). Plasma EBV DNA is an accurate surrogate biomarker for lymphoma load. For stage I/II nasal lymphoma, a combination of chemotherapy and radiotherapy yields the best results. Concomitant chemoradiotherapy and sequential chemotherapy and radiotherapy give similar response rates and survivals. For stage III/IV nasal lymphoma and non-nasal lymphomas, chemotherapy is the mainstay of treatment. Conventional anthracycline-based regimens are ineffective. Recommended chemotherapy protocols are based on the use of L-asparaginase combined with other effective drugs. Durable remission can be expected in at least 60% of patients irrespective of stage. Prognostically models based on clinicopathologic parameters and EBV DNA load are useful in stratification of patients for therapy. Expert commentary: Current treatment leads to long-term survival in a significant proportion of patients. For relapsed patients, novel strategies are needed.