Extranodal NK/T-cell lymphoma, nasal type

Extranodal NK/T-cell lymphoma, nasal type occurs primarily in Asians and South Americans; it is comparatively uncommon in other areas. Affected patients (median age 50–60 years old; males predominate) most often (~80% of cases) present with nasal bleeding, upper airway obstruction, perforation of the hard palate, and/or disfiguring, necrotic lesions of the nasal cavity, nasopharynx (including Waldeyer's tonsillar ring), paranasal sinuses, palate, and/or eye socket. Rarely, individuals present with evidence of involvement in the later sites without those involving the head/neck area. On further study these individuals may be found to have occult involvement in the head and neck or to develop such involvement. However, ~10 present of patients present with only skin lesions such as a solitary or multiple subcutaneous masses (which may be ulcerated) in the arms or legs Also in rare cases, patients evidence a widespread disease that includes malignant cell infiltrations in the liver, spleen, lymph nodes, bone marrow, and/or blood. These case are, or may soon progress to, a related but potentially fatal disease, aggressive NK-cell leukemia. or aggressive NK-cell leukemia (e.g. decreased circulating red blood cells, leukocytes, and/or platelets, increased circulating large, granule-containing malignant NK cells, and infiltrations of the latter cells in bone marrow and other tissues). == Pathogenesis ==

Disease location ENKTCL-NT is a disease of malignant NK or, very much less often, cytotoxic T cells. Unlike most other lymphomas, which typically develop in and involve lymphatic tissues (particularly lymph nodes and spleen), ENKTCL-NT commonly develops in non-lymphatic tissues. This difference in distribution probably reflects the occupancy of the T cell and B cell precursors to most lymphomas in lymphatic tissues versus the frequent occupancy of the NK and cytotoxic T cells precursors to ENTCL-NT in non-lymphatic tissues. Genes ENKTCL-NT is thought to arise from the expression of EBV genes in the infected NK or cytotoxic T cells and the ability of these genes to cause the cells they infect to overexpress and acquire mutations in key genes that regulate cell growth, immortalization, invasiveness, and ability to evade normal control mechanisms, particularly immune surveillance. Since these gene-related abnormalities are multiple and vary between patients, it is not clear which contribute to the development and/or progression of ENKTCL-NT. Clinical studies are therefore examining targeted therapy tactics to determine which gene abnormalities contribute to, and which drugs targeting these abnormalities are useful in treating, ENKTCL-NT. In consequence, the EBV latency II genes force infected cells to become immortal, proliferate excessively, invade tissues, and avoid attack by the hosts' immune system. Due at least in part to these imposed factors, the infected cells may acquire other genetic abnormalities that further promote their malignant behavior. Infected cell genes The rapidly proliferating and immortalized EBV-infected NK/T cells accumulate numerous changes in the expression or activity of their genes by acquisition of chromosome deletions, gene mutations, and changes in gene expression. Chromosomes Deletions in the long (i.e. "q") arm at position 21–25 (notated as 6q21–25) from one of the two chromosome 6's was an early finding in occasional cases of ENKTCL-NT. This deletion removes one of the two copies of several tumor suppressor genes (i.e. genes that protect cells from becoming malignant) such as HACE1, PRDM1, FOXO3, and PTPRK. Subsequent studies showed that the disease is also occasionally associated with losses in the short arm of chromosome 8 at position 11.23 (8p11.23) which for unclear reasons are associated with a poor prognosis, and occasional losses at position 11l.2 in the q arm of chromosome 14 (14q11.2) which correlates with the ENKTCL-NT malignancy being of cytotoxic T cell origin.) and MIR17HG ((see). which when up-regulated suppress programmed cell death to promote these cell's survival and resistance to attack by the host immune system; 3) multidrug resistance protein 1, a surface membrane protein that when up-regulated causes these cells to greatly increases the export of anthracyclines such as Adriamycin and Daunomycin thereby rendering them resistant to this class of chemotherapy drugs; 4) EZH2, a histone methyltransferase that when up-regulated indirectly promotes these cells' growth; 5) runt-related transcription factor 3 that when up-regulated indirectly promotes the survival and proliferation of these cells; Signaling pathways In consequence of, or addition to the cited genetic abnormalities, ENKTCL-NT malignant cells have overly active the; JAK-STAT signaling pathway that in the cancer setting promotes cell proliferation, survival, and other pro-malignant behaviors; platelet-derived growth factor signaling pathway that in the cancer setting promotes cell survival and proliferation; Notch signaling pathway that in the cancer setting promotes cellular differentiation and proliferation; and NF-κB signaling that in the cancer setting promotes cell survival and proliferation. Studies suggest that overactive VEGF receptor and Protein kinase B signaling pathways may also play a role in the pathogenesis of ENKTCL-NT.) Epigenetic abnormalities Studies on cultured malignant NK cells and/or patient tissue specimens find that numerous genes are hypermethylated at their promoter sites and therefore are silenced, i.e. make less or none of their protein products. This silencing has been detected in numerous proteins expressed by cultured NK cells (e.g. BCL2L11, DAPK1, PTPN6, TET2, SOCS6, PRDM1, AIM1, HACE, p15, p16, p73, MLH1, RARB, and ASNS) and the MIR146A gene for its miR-146a microRNA product. Studies conducted on the expression of microRNAs in cultured malignant NK cells have also revealed that many are either over- or under-expressed compared to non-malignant cultured NK cells. This dysregulation of these microRNA genes may reflect the action of products expressed by certain EBV genes and/or the overexpression of the infected cells' MYC gene. In all cases, the epigenetic dysregulation of these genes requires further study to determine its significance for the development and progression of ENKTCL-NT. == Histology ==

On microscopic examination, involved tissues show commonly show areas of necrosis and cellular infiltrates that are centered around and often injure or destroy small blood vessels. The infiltrates contain large granule-containing lymphocytes that express cell surface CD2, cytoplasmic CD3ε, and cell surface CD56 as well the cytoplasmic intracellular proteins, perforin, granzyme B, and T cell intracellular antigen-1 (TIA-1). These cells exhibit evidence of EBV infection as determined by in situ hybridization assays to detect one of the virus's latent products, typically EBER-1/2 micoRNAs. Identification of the genetic abnormalities cited above in the cells may be of help in establishing the diagnoses and be of use for selecting novel therapeutic approaches to individual patients. Non-malignant inflammatory white blood cells, including eosinophils, are also commonly found in these infiltrates. == Diagnosis ==

The diagnosis of ENKTCL-NT depends on histological findings that biopsied tissue infiltrates contain lymphocytes that express CD3ε, cytotoxic molecules (granzyme B, perforin, TIA1), and EBV. Another lymphoproliferative disorder of the GI tract, indolent T cell lymphoproliferative disorder of the gastrointestinal tract may also mimic ENKTCL-NT. This chronic disorder involves the proliferation of CD+4, CD8+, CD4-/CD8-, or CD4+/CD8+ T cells in the mucosal layers of the GI tract to give a variety of GI tract symptoms. While generally a persistent and benign disorder, a small but significant percentage of cases have progressed to aggressive lymphomas. The disease may be incidentally diagnosed upon histopathology os sinus contents removed from sinusitis surgery. == Course of ENKTCL-NT ==

The course of the untreated disease is heavily dependent on its clinical stage at diagnosis. Patients presenting with highly localized stage I nasal disease usually have nasal but no other symptoms; these individuals commonly show no progression of their disease over long periods of time. Other patients with limited (i.e. stage I or II) disease involving other sites in the head area are more likely to have a relatively slow progression of their disease while patients with stage III or IV disease have a more rapidly progressive disease with a poor prognosis. Patients presenting with ENKTCL-NT that does not involve the head area typically have a disseminated and aggressively progressive disease with a very poor prognosis. Patients with stage I or II localized disease that have been treated with the recently defined chemotherapeutic protocols have 5 year survivals of ~70–89% while those with advanced stage III or IV disseminated disease treated with these protocols have 5 year survivals of 50%. Patients who relapse or are resistant to these protocols have had overall survivals of just a few months. Three prognostic models, NK-PI, PINK (i.e. prognostic index of natural killer lymphomas), and PINK-E) for ENKTCL-NT have evolved over the past 12 years. The latest model, PINK-E, which applies to patients treated with recently defined regimens, lists 5 risk factors (age >60, state III or IV disease, no nasal involvement, distant lymph node involvement, and detectable blood levels of EBV DNA) to define patients as low, intermediate, and high risk based on their having 0–1, 2, or 3–5 risk factors, respectively. Overall 3 year survival in these 3 respective groups were 81, 55, and 28%. Patients, particularly those in the advanced poor risk groups may develop hemophagocytic lymphohistiocytosis or have their disease progress to aggressive NK-cell leukemia. Both conditions are life-threatening and far less responsive to treatment. == Treatment ==

The treatment of ENKTCL- NT employs chemotherapy plus, where indicated, radiotherapy. Early chemotherapies relied on CHOP (i.e. cyclophosphamide, an anthracycline (primarily adriamycin), vincristine, and prednisolone) or chop-like regimens. These were only marginally successful because, as it was later discovered, the malignant NK cells in ENKTCL-NT over-express multidrug resistance protein 1. This protein exports various molecules, including anthracyclines and vincristine, from its parent cells and thereby renders these cells resistant to adriamycin and therefore to CHOP and CHOP-like regimens. • Localized stage I and 2 diseases are treated with a combination of local radiation followed by DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin). Five-year progression-free and overall survival rates with this regimen are 70–72% and 61–63%, respectively. An alternative regimen, termed CCRT-VIDL, combines cisplatin plus radiation followed by etoposide, ifosfamide, cisplatin, and dexamethasone to give complete response and 5 overall survival rates of 87 and 73%, respectively. a phase I/II clinical study sponsored by the Abramson Cancer Center of the University of Pennsylvania in Philadelphia is recruiting individuals to examine the effects of Pembrolizumab in individuals with relapsed or refractory ENKTCL-NA; and a clinical phase 2 study sponsored by the University of Hong Kong is recruiting individuals to examine the effects of Pembrolizmab on ENKTCL-NT. • CD30: The malignant cells in ~40% of ENKTCL-NT cases express the surface membrane protein, CD30. Two case reports have indicated that the CD30-targeted monoclonal antibody, which is conjugated to the cytoxic/antineoplastic agent auristatin E, brentuximab vedotin, was helpful in treating relapsed ENKTCL-NT. • CD38: CD38 is almost always expressed in the malignant cells of ENkTCL-NT. One patient with this disease, after relapsing following each of two chemotherapy courses, had a complete remission when treated with a cytotoxic antibody directed at CD38, Daratumumab. • EBV antigens: EBV-infected cells express the viral LMP1 and LMP2 proteins on their surface membranes and therefore are potential targets for attack by cytotoxic T cells (CTL). Studies have used CTL that have been engineered to attack and kill LMP1 and/or LMP2 expressing cells. Eleven patients with refractory or relapsed ENKTCL-NT were treated with their own CTL that had been engineered to kill LMP1/2-expressing cells. Nine patients had durable (>4 years) remissions, 1 patient had a complete remission which lasted only 9 months, and 2 patients show no response to the treatment. In a second study, 8 patients with localized and two with advanced disease who were in complete remission after chemotherapy (with or without radiation treatment) were given their own CTL that had been engineered to kill LMP1/2-bearing cells. One patient relapsed after 32 months while the remaining 7 patients had progression-free and overall survivals of 100 and 90%, respectively. A phase 2 clinical study sponsored by ViGenCell Inc. is being conducted at the Catholic University of Korea to test the effects of CTL engineered to kill EBV-infected cells on patients that are in complete remission following chemotherapy (±radiation treatment) but at high risk for recurrent disease. Patients will receive the CTL or placebo (i.e. peripheral blood mononuclear cells). The study, which begins recruitment in late Feb., 2019, seeks to determine if the CTL treatment prolongs remissions. • Bcl-2 proteins: Bcl-2 proteins are a family of proteins that regulate cellular apoptosis. Venetoclax (also termed ABT-199) is a small-molecule drug that indirectly promotes the activation of two apoptosis-inducing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer thereby promoting cell death. It is approved for the treatment of chronic lymphocytic leukemia. Small molecule inhibitors of JAK3 (e.g. tofacitinib), JAK1/JAK2 (e.g. AZD1480), STAT3 (e.g. WP1066), and DDX3X (e.g. RK-33) are being study in pre-clinical in vitro experiments as potential inhibitors of malignant NK/T cell proliferation and survival. They are in further studies to test them as potential therapeutic agents in ENKTCL-NT patients that have activating mutations or overexpression of the cited targets. == See also ==