Extranodal NK/T-cell lymphoma, nasal type

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) (also termed angiocentric lymphoma, nasal-type NK lymphoma, NK/T-cell lymphoma, polymorphic/malignant midline reticulosis, and lethal midline granuloma) is a rare type of lymphoma that commonly involves midline areas of the nasal cavity, oral cavity, and/or pharynx At these sites, the disease often takes the form of massive, necrotic, and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, larynx, lung, gastrointestinal tract, skin, and various other tissues. ENKTCL-NT mainly afflicts adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America. In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous lymphoma after mycosis fungoides.aggressive: Sézary disease Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) (also termed angiocentric lymphoma, nasal-type NK lymphoma, NK/T-cell lymphoma, polymorphic/malignant midline reticulosis, and lethal midline granuloma) is a rare type of lymphoma that commonly involves midline areas of the nasal cavity, oral cavity, and/or pharynx At these sites, the disease often takes the form of massive, necrotic, and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, larynx, lung, gastrointestinal tract, skin, and various other tissues. ENKTCL-NT mainly afflicts adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America. In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous lymphoma after mycosis fungoides. ENKTCL-NT is classified as an Epstein-Barr virus-associated lymphoproliferative disease. It is due to the malignant transformation of either one of two types of lymphocytes, NK cells or a T cell variant termed cytotoxic T cells, that are infected with the Epstein-Barr virus (EBV). Typically, the viral infection, which afflicts >90% of the world population, occurs years before evidence of ENKTCL-NT, is carried in cells in a latent, asymptomatic form, and for unclear reasons becomes active in causing the disease. Following the virus's activation, the infected cells acquire numerous genetic abnormalities which may play an important role in the development and/or progression of ENKTCL-NT. Epstein-Barr virus-positive nodal NK/T cell lymphoma (EBV+ nodal NKTCL) was considered to be one form of ENKTCL-NT since it is a malignancy of EBV-infected NK or T cells. However, EBV+ nodal NKTCL is manifested primarily by its involvement in lymph nodes; it also has clinical, pathological, pathophysiological, and genetic features that differ significantly from those of ENKTCL-NT. The World Health Organization, 2016, therefore reclassified this lymphoma as a variant of a disease to which its features more closely resemble, peripheral T-cell lymphoma not otherwise specified. While a rare disease, particularly in North America, ENKTCL-NT has recently gained much interest. Clinical studies have found that newer chemotherapeutic regimens greatly improved survival in cases of early disease. While, survival in advanced cases is still extremely poor, generally being only a few months, recent studies suggest that new regimens directed at gene mutation and expression abnormalities may improve survival. Further study of these new regimens has important implications not only for ENKTCL-NT but also for other NK/T cell malignancies. Extranodal NK/T-cell lymphoma, nasal type occurs primarily in Asians and South Americans; it is comparatively uncommon in other areas. Afflicted 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. Less often, patients present with these findings plus signs and symptoms involving extranasal sites such as the skin, upper respiratory tract, gastrointestinal tract, uterus, testes, and/or elsewhere. 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 while another ~10% present with masses in the lower gastrointestinal tract (which may be accompanied by bleeding or obstruction), salivary glands, testes, muscles, or other organs without evidence of lesions in the head/neck areas. In these cases, there is relatively little involvement of lymph nodes except as a result of direct invasiosn from non-nodal sites. Thirty-five to forty-five percent of patients present with a history of malaise, fever, night sweats, and/or weight loss. Most (70-75%) patients are diagnosed with early stage I or II disease while the rest have far more serious stage III or IV disease. Rarely, patients with stage III or IV disease have evidence of a life threatening complication, hemophagocytic lymphohistiocytosis. 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. About 45% of patients present with elevated levels of serum lactate dehydrogenase; elevation in this serum enzyme is a poor prognostic indicator. Patients with ENKTCL-NT also have elevated levels of plasma EBV DNA. Quantification of these levels at diagnosis correlates with the extent of their tumor load while serially assaying these levels during treatment gives evidence of the tumors response to treatment and residual disease. Rarely, patients show laboratory evidence of hemophagocytic lymphohistiocytosis such as: decreased circulating red blood cells, leukocytes, and/or platelets; increased serum levels of liver-derived enzymes, ferritin, and/or triglycerides; decreased serum levels of fibrinogen; and/or hemophagocytosis, i.e engulfment of blood cells by tissue histiocytes in the liver, spleen, bone morrow, and/or other tissues. 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). 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. 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 ENKTLC-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. Infected cells carry ~10 cytosolic EBV episomes, i.e. gene-bearing viral DNA particles. In the premalignant precursor NK and cytotoxic T cells of ENKTCL-NT, these episomes express only some of their many latency genes, i.e. genes which promote the virus's latency rather than lytic phase of infectivity. EBV has three different latency phases, I, II, and III, in each of which different sets of latency genes are expressed to establish different controls on the cells which they infect. In the premalignant cells of ENKTCL-NT, EBV express latency II genes such as EBNA-1, LMP-1, LMP-2A, and LMP-2B protein-producing genes; EBER-1 and EBER-2 non-coding RNA-producing genes (see EBV non-coding RNAs); and certain BART microRNA-producing genes (see EBV microRNAs). LMP1 protein induces infected cells to overexpress genes that produce cMyc, NF-κB, and BCL2 proteins which when overexpressed block these cells' apoptosis (i.e. cell death) response to injury or the host's immune system and promote their survival and proliferation; LMP2A and LMP2B proteins induce infected cells to overexpress the genes that make AKT and B cell receptor proteins and to activate the NF-κ pathway which when over-activated blocks these cells' apoptosis response and promotes their survival and proliferation; EBER 1 and 2 non-coding RNAs induce infected cells to overexpress the gene that makes the interleukin 10 protein which when overexpressed may promote its parent cells to proliferate and avoid the host's immune system; and certain BART microRNAs may help infected cells avoid attack by the hosts immune system and modify their notch signaling pathway thereby promoting their proliferation. 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 lease in part to these imposed factors, the infected cells may acquire other genetic abnormalities that further promote their malignant behavior.