also present with arthralgias, arthritis, pleural effusions, ascites, lung lesions, and neurological and gastrointestinal disturbances. laboratory tests commonly reveal the presence of immune-mediated hemolytic anemia; elevated blood levels of eosinophils, gamma globulins, and lactic dehydrogenase; high erythrocyte sedimentation rates; and positive blood tests for autoantibodies such as rheumatoid factor, anti-nuclear antibody, and anti-smooth muscle antibody. several of these clinical and laboratory features suggest that the affected individuals have an underlining abnormality in their immune system. involved tissues exhibit vascular proliferation, small lymphoid cells clustered around venules in a background containing tfh cells, activated lymphocytes, follicular dendritic cells, epithelioid cells, plasma cells, and eosinophils. only the tfh cells are malignant. the latter cells represent 5–30% of all cells in the disease's lesions, express tfh cell marker proteins (e.g. cd3, cd4, cd10, programmed cell death protein 1 (pd-1), and also express the b lymphocyte chemoattractant, chemokine (c-x-c motif) ligand 13 (i.e. cxcl13). virtually all cases exhibit a scattering of ebv+ b cells with the virus possibly being in a restricted latency ii phase. the other cell types in these lesions, including the malignant tfh cells are ebv negative. the ebv+ b cells have numerous non-malignant crippling mutations, often proliferate excessively, and in some cases transform into ebv+ b cell lymphomas. ebv may be involved in the development and/or transformation of these ebv+ b cells to lymphoma but the virus's role in this as well as atil is uncertain. the diagnosis of aitl depends on demonstrating tfh cells expressing the appropriated markers, particularly cxcl13; the presence of ebv+ cells supports the diagnosis. the malignant tfh cells in aitl have mutations in their tet2, idh2, and rhoa genes in 30–83% of cases whereas the malignant cells in ptcl, nos exhibit these mutations in 17%, 0%, and 0% of cases, respectively. mutations in tet2 are the most prevalent (48% to 83% of cases) in aitl and generally occur in advanced-stage disease. further study may add the presence of these mutations, particularly tet2, to aitl's diagnostic criteria. the prognosis of atil has been poor. as rated by the international prognostic index (more severe disease with increasing score), 14% of aitl patients presented with an ipi score of 0–1, 59% with a score of 2–3, and 28% with a score of 4–5. the five-year overall survival for patients with scores of 0–1 andr 4–5 are 56% and 25%, respectively, when treated with a recommended chop or a chop-like chemotherapy regimen. the addition of etoposide or the proteasome inhibitor, bortezomib, to chop regimens has modestly increased overall and complete response rates. autologous hematopoietic stem cell transplantation likewise appears to improve the results of chop regimens. small studies have found that patients with refractory or relapsed aitl have positive responses to pralatrexate, romidepsin, belinostat, brentuximab vedotin, lenalidomide, alisertib, and mogamulizumab. these drugs are being further studied for their usefulness for refractory and relapsed as well as initially untreated aitl. follicular t cell lymphoma follicular t cell lymphoma (ftcl), previously considered a variant of peripheral t cell lymphomas, was reclassified by the world health organization (2016) as a type of lymphoma in the category of angioimmunoblastic t cell lymphoma (aitl) and other nodal tfh cell lymphomas. this rare disorder is similar to aitl in that it is a lymph node-based malignancy or tfh cells; it differs from aitl in that it may be diagnosed at an early, limited, and comparatively less aggressive stage and that its tissue lesions lack characteristic features of aitl, e.g. the do not show vascular proliferation. ftcl develops mostly in elderly individuals but has been reported in those as young as 27 years. individuals commonly (~73% of cases) present with advanced stage iii or iv disease characterized by lymphadenopathy involving neck, armpit, and/or groin areas (~86%); enlarged liver (~25%) and/or spleen (25%); and malignant cell infiltrations in the bone marrow (~25%) or, rarely, tonsils, salivary glands, and/or hard palate. b symptoms of fever, night sweats, and weight loss occur in <33% of cases. laboratory abnormalities include a positive coombs test with or without accompanying autoimmune hemolytic anemia (~50%) and elevated blood levels of lactic acid dehydrogenase (45%) and gamma globulins (19%). two histologic patterns of pathology in involved lymphoid tissues are described, 1) a follicular lymphoma-like pattern in which malignant tfh cells form nodules and 2) a progressive transformation of germinal centers-like pattern in which malignant tfh cells from irregularly-shaped nodules surrounded by immunoglobulin d positive mantle cells (a type of b cell). large b cell immunoblasts and occasional reed-sternberg cell-like b cells may also occupy these lesions. in 50–60% of ftcl, one or more of these b cell types, but not the malignant tfh cells, are infected with ebv, apparently in a latency ii stage. diagnosis of ftcll depends on clinical and laboratory findings, the pathology of the lesions, and identification in lymph nodes, skin, or other lesions of tfh cells as defined by their expression of appropriate marker proteins (e.g. pd-1, icos, cxcl13, cxcr5, and tox). no controlled studies on the treatment of the disease have been reported. stage i and ii localized ftcl has been treated with surgery, x-ray therapy, puva therapy, topical steroids, chlormethine, and/or carmustine. more extensive stage iii and iv disease has been treated with single chemotherapy drugs (e.g. methotrexate); multiple chemotherapy drug regimens (e.g. chop, r-cvp (i.e. rituximab, cytoxin, vincristine, prednisone); with rituximab, bortezomib, thalidomide, interferon-alpha, interferon-gamma, bexarotene, gemcitabine; and with hematopoietic stem cell transplantation. responses to these treatments were variable and often disappointing. most recently, however, bendamustine combined with rituximab or rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone have achieved partial response rates of >90% even in patients with advanced stage disease. while complete remission rates are substantially lower than 90% and treated patients have inevitably relapsed, these regiments are recommended front-line treatments for symptomatic advanced stage follicular lymphoma. systemic epstein–barr virus-positive t cell lymphoma of childhood systemic ebv-positive t cell lymphoma of childhood (tclc) is an extremely rare and aggressive t cell lymphoma that occurs almost exclusively in children, adolescents, and young adults. it occurs more frequently in asians and latin americans. the disease develops as a complication or progression of either epstein–barr virus-positive infectious mononucleosis (epv+ im) or chronic active epstein–barr virus infection (caebv)., that is, as a worsening of the signs/symptoms some three weeks after the onset of an ebv+ im-like disease or an any time during the course of caebv. it presents in these diseases as the onset of progressive enlargements of the liver and spleen, worsening liver dysfunction, new skin rashes, pancytopenia (i.e. falls in the blood levels of leukocytes, red blood cells, and platelets), hemophagocytosis (i.e. ingestion of blood cells by histiocytes) in bone marrow and spleen), a coagulopathy (poor blood clotting), sepsis, and/or one or multiple organ failures. unlike the findings in im, patients with tclc show low or undetectable levels of circulating igm antibody but detectable levels of igg antibody directed against ebv capsular antigens. involved tissues contain rapidly proliferating small or, less commonly, somewhat larger lymphoid cells. these cells are ebv+ cytotoxic t cells and express cd8, cd3, cd2, tai1, and granzyme but not cd56. rarely and mostly in the setting of caebv disease, these cells are cd4+ t cells or a mixture of cd4+ and cd8+ t cells. the disease is usually fatal within weeks of diagnosis. a few cases have responded to the hlh-2004 chemotherapy protocol (etoposide, dexamethasone, cyclosporine a or, in selected cases, corticosteroids and intrathecal methotrexate, which may or many not be followed by hematopoietic stem cell transplantation. epstein–barr virus–associated aggressive nk cell leukemia main article: aggressive nk cell leukemia epstein–barr virus–associated aggressive nk cell leukemia (ebv+ ankl) is a rare nk cell malignancy that occurs most often in asians and young to middle-aged adults. it sometimes evolves directly from other nk cell proliferative disorders such as, particularly in younger individuals, chronic active ebv infection (caebv). a study conducted in china found that all or almost all patients presented with b symptoms (weight loss, fever, night sweats) and an enlarged liver and/or spleen but not lymph nodes. laboratory studies revealed pancytopenia (i.e. reduced numbers of circulating white blood cells, platelets, and red blood cells) in almost all cases; small increases in the levels of circulating large granular lymphocytes shown or suspected of being malignant nk cells in 50% of cases; increased numbers of nk cells in the bone marrow in all cases; greatly increased blood levels of lactic acid dehydrogenase and β2 microglobulin in all cases; liver damage as defined by increased blood levels of enzymes, total bilirubin, and indirect total bilirubin plus increased blood clotting time in ≥30% of cases; and ct scans showing non-specific interstitial pneumonia in 90% of cases. all cases had epv+ lymphocytes in bone marrow and tissue infiltrates; occasional cases had also has circulating ebv+ lymphocytes. in other studies, ebv+ nk cells have been reported in 85–100% of cases. histological analysis of involved tissues generally reveals infiltrates of large granular ebv+ nk cells mixed with benign inflammatory cells that are often focused around small blood vessels; these findings are usually accompanied by tissue necrosis. the ebv+ nk cells express cd56 antigen and are malignant with ebv in its latency ii phase. the nk cells expression relatively high levels of the lmp1 viral protein; this protein may activate the nf-κb cell signaling pathway and thereby stimulate ebv-infected cells to proliferate. these findings occur in ~84% of individuals with what is termed "classic ankl". some 16% of individuals present with "sub-acute ankl". the latter individuals exhibit signs and symptoms resembling infectious mononucleosis that endures for 3–15 months and then takes the fulminant course characteristic of classic ankl. classic and sub-acute ankl rapidly progress to life-threatening hemophagocytosis, disseminated intravascular coagulation, liver failure, renal failure, respiratory failure, and/or multiple organ failures. median survival times in studies that did not distinguish between classic and sub-acute disease were ~60 days. a study of chinese patients reported medium survival times of 49 days for classic and 215 days for sub-acute ankl. treatments for ankl have typically used intensive chemotherapy regimens, either chop plus l-asparaginase or, alternatively, smile (i.e. dexamethasone, methotrexate, leucovorin, ifosfamide, l-asparaginase, and etoposide. however, results with these regimens have been poor with little improvement in survival times. more recently, addition of autologous autologous hematopoietic stem cell transplantation to these chemotherapy regiments has modestly improved medium survival times in both classic and sub-acute disease. further studies to find more effective treatment regimens for ankl are needed. one regimen under such consideration uses aspametdex (l-asparagenase, methotrexate, dexamethasone) for induction therapy and smile for consolidation therapy followed by autologous hemotopoietic stem cell transplantation. intravascular nk/t-cell lymphomas main article: intravascular lymphomas two extremely rare types of the intravascular lymphomas, intravascular nk-cell lymphoma and intravascular t- cell lymphoma, are associated with, and appear driven by, ebv infection of nk- and cytotoxic t-cells, respectively. at presentation, affected individuals (age range 23–81 years) exhibit skin lesions; less commonly, signs and symptoms of central nervous system involvement; and, in a minority of cases, signs and symptoms of bone marrow, liver, kidneys, ovaries, and/or cervix involvement. at that time or shortly thereafter, they show clear signs of having a disseminated disease such as fever, weight loss, night sweats, arthralgias, jaundice, decreased numbers of circulating red blood cells, white blood cells, and/or platelets, and the involvement of multiple organs. the two intravascular lymphomas are, in general, aggressive and rapidly progressive diseases with patients usually responding poorly to treatment and having short (often less than 12 months) survival times. ebv-associated immunodeficiency-related lymphoproliferative disorders ebv infection is associated with various lymphoproliferative disorders that have a high frequency of occurring in individuals with any one of several different types of immunodeficiency. this category of ebv+ lpd is heterogeneous, involving ebv-infected b cells, t cells, and/or histiocytic/dendritic cells. these lpd also occur in immunocompetent individuals and are detailed in the above section entitled "ebv+ b cell lymphoproliferative diseases". ebv-related and hiv-related lpd individuals carrying the human immunodeficiency virus (hiv, the cause of aids) have an increased incidence of developing a lpd ranging from polyclonal lymphocyte proliferation (i.e. the abnormal proliferation of two or more clones of benign lymphocytes) to overtly malignant lpd. the ebv-related and hiv-related malignant lpd are: diffuse large b cell lymphomas with plasmablastic features (dlbl); a distinctive subtype of dlbl termed primary central nervous system lymphoma (pcnsl); burkitt lymphoma (bl); hodgkin lymphoma (hl);