children, follow a waxing and waning course, and resolve in early adulthood. however, the disorder can occur in adults. furthermore, the disease in children or adults may progress to cause severe, extensive, and disfiguring skin lesions unrelated to sunlight exposure, facial edema, and systemic manifestations such as fever, weight loss, and enlargements of lymph nodes, liver, and/or spleen. these cases may progress to an ebv+ lpd such as t cell lymphoma, t cell leukemia, b cell lymphoma, or b cell leukemia. the milder and more aggressive forms of hydroa vacciniforme were initially termed classic hydroa vacciniforme and hydroa vacciniforme-like lymphoma, respectively, but extensive overlap between the two disease types lead the 2016 world health organization to reclassify them into a single disorder termed hydroa vacciniforme-like lymphoproliferative disease and to be a subcategory of caebv. histological examination of the skin lesions reveals infiltrating lymphocytes most of which are t cells and a minority of which are nk- or b- cells. in the skin lesions, ebv occurs primarily in the t cells and to a lesser extent nk cells. marker studies indicate that the ebv in these cells is in latency phase ii. treatment of the non-aggressive cases of hydroa vaccinforme-like lymphoproliferative disease follow standard dermatological practices for non-malignant diseases. for malignant cases of the disease, immunotherapeutic drugs prednisone, interferon-α, chloroquine, and thalidomide) have given temporary remissions and improvements; standard chemotherapy and radiotherapy regimens used to treat lymphoma and leukemia have produced only transient benefits while often causing unacceptable toxicities. cases of ebv+ hydroa vacciniforme-like lymphoproliferative disease associated with clear evidence of concurrent caebv have been treated with relative success by the three-step regimen used to treat caebv. epstein–barr virus-positive mucocutaneous ulcer main article: mouth ulcer § epstein-barr virus-positive mucocutaneous ulcer ebv+ mucocutaneous ulcer is a rare lymphoproliferative disorder in which infiltrating b cells cause solitary, well-circumscribed ulcers in mucous membranes and skin. the disorder affects individuals who have poor immune function because of old age, immunosuppressant diseases (e.g. hiv/aids), immunosuppressive drug therapy, or allogenic hematopoietic stem cell transplantation. immunosuppressive drugs associated with the development of these ulcers include methotrexate (the most often cited drug causing the disease), cyclosporin a, azathioprine, mycophenolate, tnf inhibitors, tacrolimus, and topical steroids. it is thought that the reduce efficacy of immune surveillance associated with these predisposing conditions or treatments maintain ebv in a dormant state systemically but not where ebv+ b cells are prevalent, i.e. in afflicted mucous membranes and skin. consequently, the ebv+ cells at these sites proliferate and destroy tissue to create ulcerating lesions. persons developing these ulcers are usually elderly. their ulcers are typically isolated, occur in the oral mucosa and less commonly in skin or gastrointestinal tract mucosa. besides pain at the ulcer site and local tissue destruction (which may be severe), individuals with ebv+ mucocutaneous ulcer are symptomless and lack lymphadenopathy (i.e. enlarged and painful lymph nodes), involvement in other tissues, or b symptoms. however, ulcers in the gastrointestinal tract may present with a variety of abdominal symptoms including acute emergency perforations. unlike most other forms of ebv+lpd, ebv-associated mucocutantious ulcers are generally not associated with detectable blood levels of ebv. microscopically, the ulcers consist of lymphocytes, including ebv+ b cells, sometimes a scattering of other ebv+ lymphoid cell types, and histiocytes, plasma cells, eosinophils, and scattered large immunoblasts which may closely resemble but are not the reed–sternberg cells seen in hodgkin lymphoma. these reed-sternberg–like cells are ebv+ b cells that express the tumor marker cell surface membrane protein, cd30, the b cell surface membrane marker, cd20, and the proteins typical of the ebv replication cycle latency ii or iii phase. in elderly individuals with no other cause for immunosuppression, ebv+ mucocutaneous disease may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously. persistent and/or severely symptomatic cases have had excellent responses to rituximab, a commercial monoclonal antibody directed against the cd20 protein present on b cells. individuals developing these ulcers as a consequence of immunosuppressive therapy for other diseases generally have a remission after the dosages of the drugs used in their immunosuppressive treatment regimens are reduced. most of these patients do not experience a relapse. ebv+ b cell lymphoproliferative diseases after its initial entry into b cells, the epstein–barr virus infects other b cells and in doing so may or may not cause a symptomatic disease viz., infectious mononucleosis. in either case, the virus soon switches to its dormant, viral latency 0 phase within memory b cells and the infected individual becomes an asymptomatic, lifelong ebv carrier. at any time thereafter, however, the virus may reactivate, enter either its lytic cycle, latency phase ii, or latency phase iii; spread to other lymphoid cells, and drive its infected cells to proliferate excessively, survive abnormally, and establish an ebv+ lpd. epstein–barr virus-positive burkitt lymphoma main article: burkitt's lymphoma burkitt lymphoma occurs in three forms. epidemic burkitt lymphoma (ebl) is common in africa, the middle east, brazil, papua new guinea, and other areas where malaria is endemic. it usually presents in children 4–7 years old and in almost all cases is associated with ebv infection. sporadic burkitt lymphoma (sbl) is rare. it occurs in children and, less commonly, older (>60 years) adults. it is found primarily in northern and eastern europe, east asia, and north america. there are ~1,200 cases/year in the usa. only 10–15% of sbl cases are associated with ebv infection. the immunodeficiency-related form of burkitt lymphoma (ibl) strikes 30–40% of individuals with hiv-induced aids and rare cases of patients who received a bone marrow or other organ transplant; in the latter cases, individuals have almost always received intensive chemotherapy and therefore are immunodeficient. about 30% of ibl cases are infected with ebv. ebl commonly presents with a jaw mass; periorbital swelling due to an orbital tumor; or an abdominal mass caused by a tumor in the retroperitoneum, kidney, or ovary. less commonly, it present as a sudden onset of paraplegia or urinary incontinence due to tumor infiltration into neural tissue. sbl commonly presents with abdominal pain, nausea, vomiting, and/or gastrointestinal bleeding caused by the growth of an abdominal tumor; a head or neck tumor in lymph nodes, tonsils, nose, sinuses, and/or oropharynx); or extensive bone marrow infiltrations by malignant tumor cells. ibl commonly presents with fever, other constitutional symptoms, and tumors in the gastrointestinal tract, bone marrow, liver, lung, and central nervous system. histologic examination of bl-involved tissues shows infiltrations by a uniform population of rapidly proliferating (i.e. mitotic index approaching 100%) and rapidly turning over (i.e. cells not only rapidly proliferate but also rapidly die due to apoptosis) lymphocytes punctuated by intermittent clear spaces where macrophagess containing ingested dead cells give the tissues the impression of a "starry sky" pattern. the lymphocytes are primarily b cells (e.g., express cd20 and cd10 markers) with rare t cells evident only in the background. the b cells are derived mostly from germinal center b cells, contain ebv in latency i phase, and express high levels of ebna1 and eber viral products. some cases also express other ebna and the lmp2a products. ebna1 and eber proteins may contribute to the development and/or progression of bl by inhibiting the death by apoptosis of the cells they infect while the product of lmp2a may activate the infected cell's pi3k cell signaling pathway thereby stimulating this cell's proliferation. the malignant b cells in all three forms of bl commonly have acquired chromosomal translocations involving their myc gene. myc is a proto-oncogene (i.e. a cancer-causing gene if appropriately mutated or overexpressed) located on the long ("q") arm of human chromosome 8 at position 24 (i.e. at 8q24). in ~90% of bl cases, myc is translocated to the igh (i.e. immunoglobulin heavy chain) gene locus at position 14q32, the igk (i.e. immunoglobulin kappa light chain) gene at position 2p12 ("p" stands for short chromosome arm), or the igl (i.e. immunoglobulin lambda light chain) gene at position 22q11. these translocations bring myc under the transcriptional control of these antibody-forming loci and thereby cause the myc product, myc to be overexpressed and continuously driving the infected cell to proliferate. mutations in other genes of the infected cell may promote its malignancy, e.g. ~30% of bl cases harbor b cell p53 gene mutations which may promote cell survival. these alternate, potentially ebv-independent routes to malignancy and the fact that some bl cases do not involve ebv allow that many cases of ebv+ bl are not caused and/or promoted by ebv: the ubiquitous virus is the likely cause of almost all cases of ebl but be an innocent passenger virus in many cases of sbl and ibl. patients with any of the three forms of bl (with or without an association with ebv) are treated with multiple drug chemotherapy regimens. while past studies found much better results in children than adults using this approach, recent studies report that more aggressive chemotherapy regimens that include the intrathecal administration of drugs give better results. the cocox-m-ivac regimen (systemic cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine plus intrathecal methotrexate and cytarabine) give event-free two-year response rates of >90% in both children and adults. addition of rituximab, a monoclonal antibody against the cd20 antigen expressed on b cells, may be added to this or other multiple drug regimens. autologous stem cell bone marrow transplantation has not improved the results of these regiments. treatment of hiv-associated ibl is similar to, and has success rates comparable, to non-hiv bl, particularly when coupled with treatment directed at hiv although adults >40 years old have had poorer responses to these regiments. cases refractory to these regimens have a poor prognosis with average overall three-year survival rates of ~7%. epstein–barr virus-positive lymphomatoid granulomatosis main article: lymphomatoid granulomatosis ebv+ lymphomatoid granulomatosis (ebv+ lg, also termed lymphomatoid granulomatosis ) is a rare disease that involves malignant b cells and reactive, non-malignant t cells; it is almost always ebv+. this lpd occurs primarily in middle aged males (male:female ratio 2:1). ebv+ lg usually (~90% of cases) presents as a lung disorder with coughing, hemoptysis, shortness of breath, and chest x-rays showing multiple nodular lesions at the base of both lungs. it may also evidence signs and symptoms caused by nodular or infiltrative lesions in the skin, central nervous system, kidney, liver, and/or peripheral nervous system, at presentation the disease usually does not involve lymph nodes. in rare cases it may not even involve the lung. the lesions in ebv+ lg consist of occasional large, atypical b cells located in a background of numerous reactive cd4+ helper t cells, plasma cells, macrophages, and variable numbers of large atypical lymphoid cells which resemble immunoblasts, plasmablasts, or reed–sternberg cells. the lesions often center around and evidence destruction of small blood vessels but, paradoxically, do not contain well‑formed granulomas. only the lymphoid b cells in the lesions are ebv+; these cells express lmp1 and ebna2 viral proteins and therefore carry ebv in its latency iii phase. individuals with the disease may be immune deficient due to subtle reductions in their immune function or, based on individual case reports, immunodeficiency diseases such as hiv/aids, common variable immunodeficiency, x-linked agammaglobulinemia, hypogammaglobulinemia, sarcoidosis, methotrexate-treated rheumatoid arthritis, or the wiskott–aldrich syndrome. they may also have, again based on case reports, a history of inflammatory/autoimmune diseases such as chronic hepatitis, ulcerative colitis, retroperitoneal fibrosis, or primary biliary cholangitis. ebv+ lg may progress to or become complicated by the non-malignant skin disease, lymphomatoid papulosis, or a second lymphoid malignancy such as hodgkin lymphoma, mycosis fungoides, cd30+ anaplastic large cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, or diffuse large b cell lymphoma. ebv+ lg appears in part due to the virus causing its infected b cell to release chemokines which attract, and thereby stimulate t cells to injure tissues, particularly blood vessels. impaired host immune function and failure of infected cells to express viral proteins recognized by cytotoxic t cells allows ebv+ b cells to evade the immune system and proliferate. lg presents as one of three grades based on the histology of biopsied tissues: grade i (<5 ebv+ cells per high power microscopic field (hpf), no atypical cells/hpf, and minimal necrosis); grade ii (5–20 ebv+ cells/hpf, occasional atypical cells/hpf, and moderate necrosis); and grade iii (>20 ebv+ cells/hpf, predominance of atypical cells/hpf, and extensive necrosis). grade i disease may not need