by detecting the hhv8 viral protein, lana-1, in the malignant b cells. pel occurs primarily in individuals who are immunodeficient due to hiv/aids infection or solid organ transplantation. ebv is found in the malignant hhv8+ b cells of ~70% of pel patients. however, a role for ebv in the development of pel is not supported since hhv8 appears to drive the development and progression of the disease. treatment of pel with surgery, radiation, chemotherapy (e.g. chop or epoch drug regimens), antiviral agents, and/or experimental drugs (e.g. rituximab, bortezomib) have not given results that are sufficiently beneficial to make clear recommendations. pel reportedly has a median overall survival time of 4.8 months and one-, three-, and five-year overall survival rates of 30%, 18%, and 17%, respectively. epstein–barr virus-positive, human herpes virus-positive germinotropic lymphoproliferative disorder human herpes virus-positive germinotropic lymphoproliferative disorder (hhv+ glpd) is an extremely rare disorder characterized by the localized swelling of lymph nodes due to the infiltration by plasmablasts (i.e. immature plasma cells). the disorder generally occurs in immune-competent individuals although it has been reported to occur in hiv-positive individuals. in most cases, the involved lymph nodes have a normal architecture with clusters of plasmablasts that are not only hhv8+ but also ebv+ with ebv likely being in its latency i phase. in the few cases reported, the disorder has shown good to excellent responses to chemotherapy. however, too few cases have been reported to make therapy recommendations or to define the role, if any, of ebv in the disorder. epstein–barr virus-positive plasmablastic lymphoma main article: plasmablastic lymphoma plasmablastic lymphoma (pbl) is an uncommon lymphoma that occurs mostly in immune-deficient individuals, primarily those with hiv/aids. indeed, it is an aids-defining clinical condition. the disease can also occur in those who have had an organ transplantation or chemotherapy treatment or are presumed to have age-related immune senescence. chronic autoimmune or inflammatory diseases (e.g. rheumatoid arthritis, graves' disease, giant-cell arteritis, sarcoidosis, or severe psoriasis) may also underlie development of pbl. the disease occurs in individuals (male:female ratio 4:1) of all ages. it presents as a tumor of the head, neck, oral cavity, sinuses or, less commonly, gastrointestinal tact, skin, or other tissues. histologically, the tumors are classified as monomorphic pbl (consisting predominantly of immunoblastic cells) or plasmacytic pbl (consisting predominantly of cells with features of plasma cells at varying stages of development). while originating from b cells, these cells express plasma cell markers such as cd79a, ir4, blimp1, cd38, and cd138. about 70% of pbl cases are ebv+, with most of the lymphoma cells expressing ebv genes indicating that this virus is in latency phase 0 or i. the disease appears to develop and progress as a result of the actions of both the epv and human immunodeficiency virus (i.e.hiv) and, particularly in ebv+ disease, to be associated with overexpression of the myc gene in ebv+ cells. overexpressed myc protein is thought to drive the disease but the role of epv in myc gene overexpression as well as the development and/or progression of ebv+ pbl is not clear. the prognosis of patients with advanced stage pbl, which is a common presentation of the disease in patients with hiv/aids, is poor (media survival 6–7 months). however, pbl patients with early stages of the disease and/or ebv+ disease have a much better survival rate. overall, patients with hiv+ pbl respond to chop or epoch chemotherapy regimens with early results for the epoch regimen achieving medium survival rates that extend beyond one year. epstein–barr virus–associated plasma cell myeloma main article: multiple myeloma § epstein-barr virus plasma cell myeloma (pcm, also termed multiple myeloma), is a common cancer in which malignant plasma cells infiltrate the bone marrow or form soft tissue masses termed plasmacytomas. rarely, ebv may be associated with this disease, particularly in individuals with an immunodeficiency (e.g. hiv/aids, history of organ transplantation) or chronic inflammation (e.g. rheumatoid arthritis). ebv positivity is more common in the plasmacytoma rather than bone marrow infiltration form of pcm. tissues involved in ebv+ pcm typically show foci of ebv+ cells with the appearance of rapidly proliferating (e.g. high mitotic index) immature or poorly differentiated anplastic plasma cells. the cells express products of ebv genes such as eber which suggest that ebv is in a restricted latency ii phase. although derived from b cells, these cells express plasma cell rather than b cell markers. the role of ebv in the development and progression of ebv+ pcm is unknown. eber-positive patients with the localized plasmacytoma form of pcm are more likely to progress to the infiltrative (i.e. systemic) form of pcm compared to individuals with ebv- disease. the disorder has been treated with surgical removal in cases with one or two isolated plasmacytoma masses, radiation to isolated plasmacytoma tumor masses, and systemic chemotherapy (e.g. a doxorubicin, dexamethasone, and thalidomide regimen). however, post-therapeutic recurrence of the disease is common. ebv+ nk/t cell lymphoproliferative diseases while ebv preferentially infects b cells, it may also infect other lymphocyte types viz., cd4+ t cells (i.e. t helper cells), cd8+ cells (i.e. cytotoxic t cells), nk cells (i.e. natural killer cells). the mechanism by which ebv infects these other cell types is unknown but may be their direct movement from b cells that are infected with the virus. peripheral t-cell lymphomas peripheral t cell lymphomas (ptcl) are a group of nk-cell or t-cell malignancies that include extranodal nk/t cell lymphoma, nasal type, peripheral t cell lymphoma, not otherwise specified (ptl, nos), angioimmunoblastic t-cell lymphoma (aitl), and anaplastic lymphoma kinase positive or negative anaplastic large-cell lymphoma (akl+/− alcl). akl+/− alcl is rarely if ever associated with ebv and therefore not considered here. extranodal nk/t cell lymphoma, nasal type main article: extranodal nk/t cell lymphoma, nasal type extranodal nk/t cell lymphoma, nasal type (enktl), is a malignancy of nk or, less commonly, t cells that affects primarily asians and the indigenous populations of mexico, central america, and south america. it is less common in western countries of the northern hemisphere. the disease usually consists of malignant tumors in the nasal cavities, paranasal sinuses, palate, tonsils, nasopharynx, hypopharynx, and/or larynx or, in ~20% of cases, tumors in the skin, soft tissues, gastrointestinal tract, testes, and/or central nervous system. affected individuals are usually middle aged and present with obvious tumors, hemoptysis, ulcerating skin nodules, obstructions in the upper airways, and/or obstructions/bleeding in the lower gastrointestinal tract, particularly the colon. involvement of lymph nodes is uncommon and generally due to the tumors' spread from their primary sites. about 70% of enltl cases are diagnosed as having cancer stage i or ii disease (tumors localized to a single site or region of the body ) with the remainder having disseminated stage iii or iv disease. all stages of enktl involve destructive, ulcerating, and necrotic lesions. histologically, these tumors are composed of small, medium-sized, or large malignant lymphoid cells often accompanied by a mixture of benign inflammatory cells. the malignant cells express markers characteristic of nk and/or t cells (e.g. cd2, cd56, cd38), granzyme b, perforin, tia1, and, with respect to t cells which are commonly gamma delta t cells in type, t-cell receptor gamma and delta chains). in nearly all cases, the lymphoma cells are eber+, show a latency ii pattern of ebv infection, have several somatic gene mutations among a group of >35 mutations know to be recurrent in the disease, and overexpress other genes (e.g. p53, and/or pd-l1). the genes most often mutated are gak (25.9% of cases), beta-catenin (22.9%), tp53 (22.7%), and ecsit (19.3%). these genes regulate cell growth and survival. other genes (e.g. jak3, stat3, and stat5b ) that are mutated in far lower percentages of cases also regulate these potentially pro-malignant cell functions. however, the relationship of ebv infection to these gene changes and the relationship of these changes to the development of enktl are unclear. the diagnosis of enktl depends upon finding ebv and granzyme b in the disease's lymphoid tumor cells. treatment varies with grade. for cancer grade i and ii localized diseases, the recommended treatment is radiation directed at the tumor lesions plus a chemotherapy regimen such as devic (dexamethasone, etoposide, ifosfamide, and carboplatin). reported overall long-term survival and progression-free survival rates in japan for individuals treated with this regimen are 72% and 61%, respectively. for stage iii and iv disease, a more aggressive treatment regimen is used, smile (dexamethasone, methotrexate, leucovorin, ifosamide, l-asparaginase, and etoposide followed, in patients with ≥2 risk factors, by allogeneic bone marrow stem cell transplantation); this regimen reportedly achieves complete response and five-year survival rates of 87% and 73%, respectively. reported complete response and five-year survival rates for relapsed or refractory enktl treated with the smile regimen are 45% and 47%, respectively. pd-l1 (programmed death-ligand 1) functions to suppress the proliferation of antigen-specific t cells and promote the survival of inflammation-suppressing t cells; it is over-expressed in >80% of enktl cases. preparations of the monoclonal antibody directed against pd-l1 have given encouraging results in small clinical trials on patients with relapsed/refractory enktl. for example, pembrolizumab achieved clinical response in 8 of 15 patients and nivolumab in 2 of 3 patients with recurrent/refractory enktl. pembrolizumab is now included as a treatment option for recurrent/refractory enktl by the national comprehensive cancer network. epstein–barr virus–associated peripheral t cell lymphoma, not otherwise specified main article: t cell lymphoma peripheral t cell lymphoma, not otherwise specified (ptcl, nos), is an aggressive, heterogeneous group of t cell malignancies with features that do not fit the diagnostic criteria for other types of ptcl. about 30–40% of all ptcl cases are classified as ptcl, nos. this lymphoma commonly occurs in men (median age ~60 years) who present with advanced stage iii or iv disease (~70% of cases) characterized by t cell infiltrations that cause prevalent lymph node swelling often accompanied by evidence of bone marrow, liver, spleen, and/or skin involvement. these individuals usually have b symptoms (i.e. fever, night sweats, weight loss). involved tissues exhibit mature-appearing t cells that express cd4. however, attempts to define diagnostic criteria for ptcl, nos by histology and immunophenotyping have not translated into clinical practice. gene expression profiling has proven more useful for diagnosing the disease: gene abnormalities commonly associated with ptlc, nos include various fusion rearrangements of the vav1 or tbx21 genes and fusion rearrangements of the itk gene with the syk, fer, or erbb4 genes. two distinct profiles of gene overexpression have emerged from these studies: the malignant cells may overexpress gata3, myc, mtor, and β-catenin genes or, alternatively, the tbx21, interferon-γ, and nf-κb genes. individuals whose malignant cells express the gata3 gene group have a poorer overall five-year survival than those whose malignant cells express the tbx2 gene group. as defined by the expression of eber, ~30% of ptcl, nos cases exhibit malignant t cells that are infected with ebv; in these cases, the virus is in its latency ii phase. however, few of these cases evidence strong eber expression in the malignant t cells. more often, eber expression in this disease is limited to the small and large benign b cells the populate the background of the disease's lesions. thus, the relationship of ebv to the development and progression of ptcl, nos is unclear. there are no controlled studies on the treatment of this disease. recommended treatments for advanced stage ptcl, nos (regardless of ebv status) include intensive chemotherapy regimens, e.g. chop, as induction therapy possibly followed by autologous hematopoietic stem cell transplantation. these regimens have shown only limited results with five-year overall survival rates <50% for chemotherapy alone. these survival rates may be improved in patients able to withstand follow-up bone marrow transplantation. newer drug approaches using pralatrexate, romidepsin, brentuximab vedotin, belinostat, bendamustine, lenalidomide, and alisertib have shown activity against ctcl, nos and are being further studied in randomized trials for use in treating refractory and relapsed as well as initial disease. angioimmunoblastic t cell lymphoma main article: angioimmunoblastic t-cell lymphoma angioimmunoblastic t cell lymphoma (atil) is a systemic malignancy of mature follicular b helper t cells (tfh cells). atil is often manifested soon after individuals ingest antibiotics or have an infection or allergic reaction. the disease presents with generalized swelling of lymph nodes, enlarged liver and spleen, skin lesions (rash, or, less commonly, nodules, plaques, purpura, and urticarial), bone marrow involvement, and b symptoms of fever, weight loss, and night sweats. individuals may