therapy and, in rare cases, remits spontaneously. grade ii and severe grade i disease is treated with immune regimens that include various interferons and/or rituximab, a monoclonal antibody against the b cell protein, cd20. grade iii and severe grade ii disease are treated with either high dose glucocorticoids; chemotherapy regimens such as chop, ice, or hyper-cvad; or combinations of these treatments. however, the efficacy of interferon-α and rituximab in ebv+g is disputed.) while ebv+ lg often responds to these treatments, there are no controlled clinical trials proving their long-term therapeutic value. medium survival times for all cases of the disease are ~4 years with many cases progressing to other lymphoid malignancies that shorten survival times. epstein–barr virus-positive hodgkin lymphoma main article: hodgkin lymphoma hodgkin lymphoma (hl) falls into two histologic forms, nodular lymphocyte predominant hodgkin lymphoma (nlphl) and classical hodgkin lymphoma (chl) with chl being divided into nodular sclerosis (nshd), mixed cellularity (mchd), lymphocyte rich (lrhd), and lymphocyte depleted (ldhd) subtypes. ebv is found in 30% to 50% of hl cases, but occurs in ~90% of nshd and mchd but ≤10% of lrhd, lphd, or nlphd cases. hl involves the infiltration of t cells, b cells, macrophages, eosinophils, fibroblasts, and reed–sternberg cells (hrs cells, also termed hodgkin reed-sternberg cells) into lymphoid and other tissues. hrs cells are large mono- or poly-nuclear cells which: 1) derive from lymph node and/or spleen germinal center b cells; 2) may contain ebv and viral products indicative of stage ii latency; and 3) are the only malignant cells in, and the mediators of, hd. ebv in hrs cells are thought to play a role in the pathogenesis (i.e. development) of ebv+ hl. these cells express uniquely high levels of the virus's lmp1 gene. this gene product protein, lmp1, mimics activated human tnf receptors (e.g. cd40, cd40, and rank) in continuously stimulating the nf-κb, pi3k and jak-stat signaling pathways which promote cell proliferation, survival, and production of cytokines that may suppress the ebv's lytic cycle to maintain the hrs cells viability. hrs cells also express the virus's lmp2a gene protein product which mimics the human bcr gene product) in promoting the survival of its parent cells. and, ebv, by undefined mechanisms, causes crippling mutations in the hrs cell's rearranged immunoglobulin g genes to prevent them from expressing immunoglobulins and inducing them to secrete cytokines which recruit the other cited cell types into the ebv+hl's pathological infiltrates. this helps create a local environment conducive for hrs cells to evade the immune system and proliferate. ebv+ hl is more prevalent in young children and young adults but can occur in those over 80 years old, perhaps because of old age-related deterioration in immune system function, infectious diseases, or malnutrition. the incidence of ebv+ hd's in individuals with hiv/aids is also high, ~10-fold greater than the general population, but the causes for this is unclear. the presentation of ebv+ hl is similar to that of ebv-hl, e.g. fever, night sweats, weight loss in the setting of swollen lymph nodes, and/or evidence of tumor invasion of other tissues. treatment of the ebv+ hd is also similar to ebv- hd and offers cure rates approaching 90%, although some population based studies have found a higher incidence of relatively adverse outcomes in older individuals with ebv+ hl. epstein–barr virus-positive diffuse large b cell lymphoma, not otherwise specified main article: diffuse large b-cell lymphoma diffuse large b-cell lymphoma (dlbcl) is the second most common type of lymphoma. it occurs primarily in elderly adults, far less frequency in younger adults, and rarely in children. elderly adults present with b symptoms (i.e. fever, night sweats, and weight loss), swollen lymph nodes, and symptoms due to malignant cell infiltrations into the upper gastrointestinal tract, lungs, upper airways, and/or other organs. younger individuals present with swollen lymph nodes but frequently do not have class b symptoms or involvement of extra-nodal tissues. it is a more aggressive disease in the elderly. histologic features of dlbcl can be divided into three patterns based on the cell types in tissue infiltrates; the anplastic variant (~3% of cases) exhibits prominent reed–sternberg-like cells embedded in a background of histiocytes and lymphocytes; the immunoblastic variant (8–10% of cases) has 90% immunoblasts; and the centroblastic variant (80% of cases) is dominated by centroblasts. these histological features are typically accompanied by the invasion and destruction (i.e. necrosis) of small blood vessels. an alternative classification is based on the disease's cell of origin: germinal center b cell dlbcl (gcb-dlbcl) and activated b cell dlbcl (abc-dlbcl). uncommonly, dlbcl occurs by what is known as a richter transformation of chronic lymphocytic leukemia (cll) to an extremely aggressive form of dlbcl. many of these transformations develop in ebv-associated cll cases (~10–15% of all cll cases are ebv-associated). about 10–15% of dlbcl cases are ebv+. these cases, termed epstein–barr virus-positive (ebv+) diffuse large b cell lymphoma, not otherwise specified (ebv+ dlbcl), occur predominantly in east asia and mexico and less commonly in europe and the usa. ebv+ dlbcl is distinguished from dlbcl (often termed diffuse large b-cell lymphoma, not otherwise specified, i.e. dlbcl, nos) in that virtually all the large b cells in the tissue infiltrates of the ebv+ disease type express ebv genes characteristic of the virus's latency iii (common in the elderly) or ii (common in younger patients) phase. these large b cells in ebv+ dlbcl are centroblastic (i.e. activated) b-cells that express ebers, lmp1, ebna1, ebna2, and other viral proteins; in >50% of cases, they also express classic b cell antigenic proteins such as cd20, bcl6, and cd15. the viral proteins may be responsible for activating their infected cells' nf-κb, stat/jak, nod-like receptor, and toll-like receptor cell signaling pathways which may act to promote the proliferation and survival of the infected cells. ebv+ dlbcl commonly occurs in immune-deficient individuals. it is thought to arise in the elderly because of their immunosenescence as manifested by an age-related decline in the specific types of cd4+ and cd8+ lymphocytes that function to suppress the growth of ebv+ cells. ebv+ dlbcl also occurs in individuals who are overtly immunosuppressed due to hiv/aids (~33% of hiv/aids cases are ebv+) or anti-rejection drug therapy following solid organ transplantation (30% to 70% or these cases are ebv+). similarly, the richter transformation of ebv+ cll to ebv+ dlbcl occurs primarily in cll cases treated with immunosuppressant drugs and therefore appears due in part to immunosuppression-related reactivation of the latent ebv infecting these cll cells. currant treatments for ebv+ and ebv- dlbcl use either r-chop (rituximab, chimeric anti-cd20 monoclonal antibody, cyclophosphamide, doxorubicin, vincristine, and prednisone or r-epoch rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (r-epoch). responses to these regimens are poor in ebv+ dlbcl (median survival two years), particularly in cll-transformed ebv+ dlbcl (median survival four months). epstein–barr virus–associated diffuse large b cell lymphoma associated with chronic inflammation main article: diffuse large b-cell lymphoma associated with chronic inflammation diffuse large cell lymphoma associated with chronic inflammation (dlbcl-ci) is an extremely rare ebv-positive dlbcl that arises as a mass in areas of longstanding inflammation, usually body cavities or narrow spaces. almost all of the reported cases of dlbcl involve pyothorax-associated lymphoma (pal). pal occurs years after a pneumothorax is medically induced in order to collapse a lobe or entire lung around a cavity or to treat pleurisy (inflammation of the pleural cavity) caused by an otherwise uncontrollable condition, almost always pulmonary tuberculosis. reports on it are primarily in japanese elderly males. far less commonly, dlbcl-ci occurs in association with other chronic inflammation conditions such as osteomyelitis, medical insertion of a foreign body (intrauterine contraceptive devices, metallic implants, surgical mesh), skin ulcers, and venous ulcers. signs and symptoms of dlbcl-ci reflect the destructive effects of the malignancy in the affected areas. the infiltrative lesions consist of diffuse large ebv+ b cells in latency iii amidst a variety of benign, ebv-negative chronic inflammatory white blood cells. the ebv+ large b cells in these lesions often have reduced expression of the cd20 antigen and contain genetic abnormalities such as mutations in p53, overexpression of myc, and deletion of tnfaip3. these abnormalities differ form those in the ebv+ large b cells of ordinary dlbcl. studies suggest that the disease arises as the result of the ebv-driven proliferation of large b cells in a confined anatomical space that segregates them from immune surveillance. and/or of ebv-driven release of cytokines with anti-inflammatory activity (e.g. interleukin 6 and interleukin 10) that may also help the infected cells escape this surveillance. while dlbcl-ci is an aggressive malignancy, its treatment, particularly in localized disease, should include efforts to remove its underlying inflammatory causes. for example, pal is a particularly aggressive form of dlbcl-ci. nonetheless, surgical removal of the pleural tumor effectively treats the few cases in which it is localized and of low-grade. more severe cases of pal have been treated with chemotherapy regimens such as chop but overall five-year survival rates with these regiments have been poor (~21%). there are too few reports on the treatment of non-paf forms of dlbcl-ci to make recommendations. fibrin-associated diffuse large b cell lymphoma main article: fibrin-associated diffuse large b-cell lymphoma fibrin-associated diffuse large b cell lymphoma (fa-dlbcl) is included as a provisional entry as a type of dlbcl-ci by the world health organization, 2016. it is an extremely rare disease that occurs in immunologically competent individuals. it is due to the infiltration of large b cells into long-standing, avascular fibrin-based masses that develop in, on, or around long-standing hamartomas, pseudocysts, cardiac myxommas, prosthetic heart valves, thrombus-laden in endovascular grafts, hematomas, hydroceles, and prosthetic implants of the hip. the infiltrations consist of sheets, ribbons, or clusters of proliferating large b cells within avascular tissue that are coated with or contain abundant fibrin plus a paucity or absence of other types of inflammatory cells. the large b cells are infected with ebv in latency iii and express this virus's eber, ebna2, and lmp-1 genes. the infiltrations typically do not spread beyond these initial sites and there is no evidence of lymph node, spleen, or other tissue involvement: fa-dlbcl appears to be a non-malignant proliferation of ebv+ large b cells. similar to dlbcl-ci, the development of fa-dldcl may be due to localized immune suppression at its sites of origin. unlike dlbcl-ci, however, the large b cells in fa-dlbcl appear unable to proliferate and survive long-term outside of the sequestered sites; consequently, the ebv+ cells tend to spread beyond these sequestered sits and fa-dkbcl does not appear to be a truly malignant disease. the two disorders also have other differences: the histology of the involved tissues in fa-dlbcl and dlbcl-ci are dissimilar and the large ebv+ b cells in fa-dlbcl, unlike those in dlbcl-ci, do not overexpress the myc gene and have relatively few karyotype chromosomal abnormalities. patients with fa-dlbcl present with signs and symptoms reflecting the location of the infiltrative lesion. when these lesions occupy the heart (e.g. on myxommas or prosthetic valves) or vasculature (e.g. on thrombus-laden vascular grafts) the disease may present as a life-threatening cardiovascular symptoms, particularly strokes. outside of these cardiovascular complications, the disease typically takes an indolent course without spreading beyond its site of origin. removal of the tissues along with any associated foreign implant is usually curative. refractory or recurrent disease has been treated with the chop (± rituximab) with only limited success. epstein–barr virus-positive human herpes virus 8-associated b cell lymphoproliferative disorders human herpes virus 8 (hhv8) is associated with four rare lymphoproliferative disorders: 1) a subset of diffuse large b cell lymphoma (dlbcl), b) large b-cell lymphoma arising in hhv8-associated multicentric castleman's disease, c) primary effusion lymphoma, and 4) germinotropic lymphoproliferative disorder. the latter two forms of hhv8+ lymphoproliferatvive disorders have been associated in rare case reports with ebv infection. primary effusion lymphoma main article: primary effusion lymphoma primary effusion lymphoma (pel) is a hhv8+ b cell lymphoma presenting as an effusion (i.e. excess fluid) in the pleural cavity (see pleural effusion), peritoneal cavity (see peritoneal effusion), or pericardium (see pericardial effusion). these effusions are due to the infiltration of hhv8-infected b cells into the membrane tissues that line these spaces. tumor masses are infrequent and generally occur late in the disease. pel is an aggressive, rapidly proliferating lymphoma that commonly spreads to multiple organs adjacent to the involved membrane tissues. diagnosis of the diseases requires evidence of hhv8 virus involvement