Epstein–Barr virus–associated lymphoproliferative diseases

Lymphoid cells involved in EBV+ LPD In the "germinal center model" for the normal maturation of B cells, naive B cells enter the germinal centers of lymph nodes and other lymphoid tissues and in the process of becoming competent for producing functional antibodies, mature into lymphoblasts, centroblasts, centrocytes, memory B cells, and ultimately plasma cells. During this maturation, the B cells rearrange their immunoglobulin genes at multiple sites. The T cells that may become infected by EBV are natural killer T cells (NK cells), Gamma delta T cells (γδ T cells), cytotoxic T cells (CTL), helper T cells (Th cells), and follicular B helper T cells (TFH cells). The means by which EBV establishes a dendritic-histiocytic cell (i.e. follicular dendritic cell) infection are unclear. Follicular dendritic cells are connective tissue rather than lymphoid cells. They do, however, have a surface membrane receptor, CD21 (also known as complement receptor type 2), which EBV uses to enter B cells. EBV may escape their infected B cell to invade follicular dendritic cells through this CD21 entry pathway. However, it is also thought possible that the EBV may direct its infected lymphoid cell to mature into an apparent follicular dendritic cell. Epstein–Barr virus infection The Epstein–Barr virus (also termed human herpesvirus 4) belongs to the Herpes family of Group I double-stranded DNA viruses. It is spread by transfer from the oral/nasal secretions of an infected individual to the oral cavity of an uninfected individual. Once in the oral cavity, the virus invades, reproduces in, establishes its lytic phase in, and lyses (i.e. bursts open) epithelial cells that line the oral mucosa of the newly infected individual. The freed virus then invades naïve B cells located in submucosal lymphoid tissue e.g. tonsils or adenoids. Here, it establishes either a lytic phase that allows it to infect other lymphoid cells or expresses genes that suppress the lytic cycle and impose one of four latency phases. Initially, the virus establishes latency III by expressing nuclear proteins encoded by its EBNA-1, -2, -3A, -3B, -3C, LP, LMP-1, -2A, and -2B and BART genes; cell surface membrane proteins encoded by its LMP-1, -2A, and 3A genes; and microRNAs encoded by its EBER-1 and EBER-2 genes. The products of these genes immortalize, promote the growth and survival, and regulate the maturation of the infected B cell. However, products of some latency III genes (particularly the viral cell surface proteins) make the infected cell susceptible to attack by the host's immune system. The virus avoids this by limiting expression of its latency genes to EBNA-1, LMP-1, -2A, -2B, some BARTs, and the two EBERs. This Latency II pattern of gene expression continues the infected cells' immortalization and proliferation, helps the cells escape the immune surveillance, and forces them to differentiate (i.e. mature) into memory B cells. EBV may establish and maintain a Latency I state in its infected memory B cells by expressing only EBNA1 and the two EBER genes. The products of the latter genes keep the virus in a mostly dormant state. Finally, EBV may establish and maintain a Latency 0 phase by expressing only EBER genes. In latency 0, EBV is in memory B cells as fully dormant, non-reproductive viruses but in this, as in all of the other latency phases, it can revert to its lytic phase. The following table gives more information on the actions of the EBV latency genes. == EBV-associated reactive lymphoid proliferations ==

EBV-associated reactive lymphoid proliferations are a set of disorders in which B cells or NK/T cells proliferate as an apparent reaction to EBV infection. They are usually self-limiting, non-malignant disorders but have a variable possibility of progressing to a malignant lymphoproliferative disease. Epstein–Barr virus-positive infectious mononucleosis Infectious mononucleosis (IM) is caused by EBV in ~90% of cases; the remaining cases are caused by human cytomegalovirus, adenovirus, or toxoplasma. HIV, rubella, and Hepatitis viruses A, B, and C can produce an illness resembling IM. The acute EBV infection is usually asymptomatic or mild in children 3 months; 2) high blood levels of EBV DNA (i.e. >25 viral copies per mg of total DNA); 3) histologic evidence of organ disease; 4) presence of EBV RNA (e.g. an EBER) in an affected organ or tissue; and 5) occurrence of these findings in individuals who do not have a known immunodeficiency, malignancy, or autoimmune disorder. Other symptoms of CAEBV include persistent or intermittent fever, enlargement of lymph nodes, spleen, and/or liver, severe mosquito bite allergy, rashes, herpes virus-like skin blistering, diarrhea, and uveitis. The disorder may take a protracted course without progression over several years or a fulminant course with life-threatening complications such as Hemophagocytosis (i.e. ingestion of blood cells by histiocytes), myocarditis, liver failure, interstitial pneumonia, or rupture of the intestines. The disorder may involve EBV+ T, NK, or, rarely, B cells. In EBV+ T and NK cell-associated disease, the tissues affected by CAEBV usually exhibit an histology that is not suggestive of a malignancy: lymph nodes have areas of hyperplasia, focal necrosis, and small granulomas; spleen shows atrophy of white pulp with congested red pulp; liver contains infiltrations of small lymphocytes around portal vasculature and sinuses; and lung and heart have findings typical of interstitial pneumonitis and viral myocarditis, respectively. Erythrophagocytosis (i.e. ingestion of red blood cells by histiocytes) often occurs in the bone marrow, spleen, and/or liver. The principal EBV+ cells in these tissues are T cells in ~59%, both T- and NK cells in ~40%, Severe mosquito bite allergy Severe mosquito bite allergy (SMBA) is a rare disorder which occurs mainly in young East Asians (median age 6.7 years). In most cases, it is a manifestation of CAEBV infection of the EBV+ NK cell type: ~33% of all individuals with CAEBV develop this allergy. SMBA has also been reported to occur in rare cases of EBV positive Hodgkin disease, hydroa vacciniforme, aggressive NK‐cell leukemia (also termed aggressive NK-cell leukemia/lymphoma), and extranodal NK/T-cell lymphoma, nasal type, as well as in EBV negative LPD such as chronic lymphocytic leukemia and mantle cell lymphoma. However, cases with evidence of significant complications of CAEFV such as the development of hemophagocytosis, NK/T cell lymphoma, or aggressive NK cell lymphoma, support the use of the chemotherapeutic regimens directed at these complications. Cases of EBV+ SMBA associated with clear evidence of concurrent aggressive CAEBV have been treated with relative success by the three-step regimen used to treat CAEBV. Rare cases of SMBA have been reported to occur in individuals who have no apparent predisposing disease but later develop CAEBV. Such cases require careful evaluation and follow-up for development of a predisposing disorder. Hydroa vacciniforme-like lymphoproliferative disease Hydroa vacciniforme is a rare photodermatitis reaction in which sunlight causes itchy skin papules and vesicles that develop crusts and eventually become scarred tissue. The lesions occur primarily on the sun-exposed skin of the face and back of the hand. It is an EBV+ disorder in which most cases develop in 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 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 mucocutanious 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. Sporadic Burkitt lymphoma (sBL) is rare. It occurs in children and, less commonly, older (>60 years) adults. There are ~1,200 cases/year in the USA. The immunodeficiency-related form of Burkitt lymphoma (iBL) strikes 30–40% of individuals with HIV-induced AIDS 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. 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 macrophages 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. kidney, liver, At presentation the disease usually does not involve lymph nodes. The lesions in EBV+ LG consist of occasional large, atypical B cells methotrexate-treated rheumatoid arthritis, or the Wiskott–Aldrich syndrome. 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. 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. embedded in a background of histiocytes and lymphocytes; 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. particularly in CLL-transformed EBV+ DLBCL (median survival four months). Epstein–Barr virus–associated 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 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 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 from 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. For example, PAL is a particularly aggressive form of DLBCL-CI. 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 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. 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. 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 by detecting the HHV8 viral protein, LANA-1, in the malignant B cells. 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. The disease occurs in individuals (male:female ratio 4:1) of all ages, typically presenting as a tumor of the head, neck, oral cavity or sinuses; less common sites include the gastrointestinal tract, skin, and 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. Epstein–Barr virus–associated plasma cell myeloma 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. 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. AKL+/− ALCL is rarely if ever associated with EBV and therefore not considered here. 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. 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). Epstein–Barr virus–associated peripheral T cell lymphoma, not otherwise specified 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. 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. Virtually all cases exhibit a scattering of EBV+ B cells, where the virus has likely entered into a restricted latency II phase, while other cell types in these lesions - including 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. The prognosis for ATIL is historically poor; on an increasing scale of disease severity, 14% of AITL patients present with an International Prognostic Index (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 rate of patients receiving CHOP or CHOP-like chemotherapy, and with IPI scores of 0–1 and 4–5 are 56% and 25%, respectively. The addition of etoposide or proteasome inhibitor, bortezomib, to CHOP regimes has modestly increased overall and complete response rates, likewise, autologous hematopoietic stem cell transplantation has shown improved results of CHOP. Existing small studies have evidenced that patients with refractory or relapsed AITL show positive responses to pralatrexate, romidepsin, belinostat, brentuximab vedotin, lenalidomide, alisertib, and mogamulizumab; these drugs are currently being investigated for their utility in both refractory/relapsed and initially untreated AITL. 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. 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)., In other studies, EBV+ NK cells have been reported in 85–100% of cases. 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. 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. 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); plasmablastic lymphoma (PBL); and primary effusion lymphoma (PEL) (also termed pleural effusion lymphoma). (PEL cases are infected not only with HIV and in most cases EBV but also Kaposi's sarcoma-associated herpesvirus (HHV8) in all cases.) These LPD are B cell diseases which the World Health Organization (2016) divides into those occurring in: 1) immune-competent, HIV-negative individuals; 2) HIV+ individuals; and 3) individuals with other immunodeficiency disorders. The LPD occurring in immune-competent, HIV-negative individuals are detailed in the above section entitled EBV+ B cell lymphoproliferative diseases. The LPD occurring predominantly in HIV-positive individuals are detailed in the following Table which gives the percentage of the LPD that are EBV+, the latency phase of the virus in each LPD, and some factors expressed by the hosts malignant cells which promote the development, growth, and/or survival of the malignant cells in each LPD. Further findings and the treatment of EBV-related and HIV-related LPD are given in the "EBV+ B cell lymphoproliferative diseases" section. Except for the possible exclusion of PEL, these treatments should include continuance or, in individuals who have not yet been treated for AIDS, the institution of anti-HIV combination drug regimens. In the category of EBV+ LPD occurring in individuals who are immunodeficient due to other causes than HIV infection, the other causes for immune-incompetency include: 1) Immune deficiency diseases such as common variable immunodeficiency, X-linked agammaglobulinemia, hypogammaglobulinemia, the Wiskott–Aldrich syndrome, ataxia telangiectasia, the radiosensitive forms of severe combined immunodeficiency disease (SCID), the autoimmune lymphoproliferative syndrome, and the WHIM syndrome. 2) Immunosuppressive drug therapy, particularly methotrexate and regimens including methotrexate. 3) Genetic defects in the expression of genes for XIAP encoding the X-linked inhibitor of apoptosis protein, IAK encoding interleukin-2 inducible T cell kinase, CD27 encoding a receptor in the tumor necrosis factor receptor superfamily, STK4 encoding serine/threonine-protein kinase 4, 1CTPS1 encoding CTP sythetase, CORO1A encoding coronin 1A, APDS encoding activated phosphatidylinositide 3-kinase, CD16 encoding FcγRIII, GATA2 encoding GATA-binding factor 2 (a transcription factor), and MCM4 encoding the DNA replication licensing factor, MCM4. 4) Inflammatory/autoimmune diseases such as chronic hepatitis, ulcerative colitis, retroperitoneal fibrosis, and primary biliary cholangitis. 5) Chronic autoimmune and inflammatory diseases such as rheumatoid arthritis, Graves' disease, Giant-cell arteritis, sarcoidosis, and severe psoriasis), particularly in individuals receiving immunosuppressive drugs for these diseases. Treatment of these diseases generally follows that for the LPD occurring in immune-competent individuals but include discontinuing or reducing the dosages of immunosuppressive drugs and addressing the underlying disease causing immunodeficiency. Post-transplant lymphoproliferative disorders Post-transplant lymphoproliferative disorders (PTLD) are a group of LPD that occur following solid organ or hematopoietic stem cell transplantation. It is due to the immunosuppressive drug regimens that accompany these transplantations. EBV-positivity occurs in 60–80% of these cases and, unlike EBV-negative cases, EBV+ cases develop more often within the first year after transplantation. The 2026 WHO classification divides these disorders into: 1) Non-destructive PTLD: this disorder is characterized by hyperplasia of plasma cells, florid hyperplasia of lymph node follicles, and infectious mononucleosis. All three of these are non-malignant disorders that involve lesions admixed with non-destructive proliferations of plasma which are usually EBV-negative, EBV-negative B cells, and rare EBV-positive T cells. 2) Monomorphic PTLD: this disorder is a B- or T cell lymphoma. It includes only aggressive lymphomas while excluding all indolent forms of LPD except for the inclusion of EBV-positive mucocutaneous ulcer The EBV+ positivity of cells involved in these PTLD are similar to those occurring in immune-competent individuals. In EBV-positive mucocutaneous ulcer, lesions commonly include EBV-positive plasma cells. 3) Classic Hodgkin lymphoma: This HD malignancy is characterized by have EBV+ cells its lesions. These lesions are otherwise similar to those occurring in immune competent individuals. The virus in the three PTLD are in latency phase III and express most if not all of their latency genes including, in particular, LMP1 and LMP2A. The latter two EBV latency proteins are thought to promote the development and progression these PTLD by activating the NFkB pathway in and thereby stimulating the proliferation and survival of the infected host cells. == EBV-associated histiocytic-dendritic disorders ==

Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma is a variant of follicular dendritic cell sarcoma (FDCS). FDCS is a rare malignancy of follicular dendritic cells (FD cells). These myofibroblast-like cells are derived from the stroma (i.e. connective tissue) of lymph nodes and other lymphatic tissue and therefore are not lymphocytes. FD cells express several markers expressed by lymphocytes; occupy the germinal centers of lymphoid tissues; and attract, stimulate the differentiation and proliferation of, and present foreign antigens to B-cells. There are two histopathological forms of FDCS, conventional and inflammatory. Conventional FDCS exhibits spindle-shaped FD cells in a background of small lymphocytes; inflammatory FDCS exhibits relatively rare spindle-shaped cells in a background of plasma cells, middle- to large-sized lymphocytes, and Reed–Sternberg-like cells. EBV is associated only with the inflammatory form of FDCS. In these cases, the FD cells express FD-cell markers (e.g. CD21, CD23, CD35, clusterin, podoplanin, gamma-synuclein) and in >90% of cases products of the virus's EBER and LMLP1 genes. These cells are infected with EBV in latency II or III phases while the background cells are EBV-negative and not malignant. In one study, two of five individuals with EBV+ FDCS had an activating mutation in BRAF. While a role for EBV in FDCS remains unproven, LMP1 is able to transform rat fibroblasts into malignant-like behavior in vitro. The expression of LMP1 by FD cells might contribute to the malignancy of these cells in FDCS. Overall, patients with FDCS have local recurrence rates of 40–50 and a long term mortality rates due to the disease of ~20%. However, FDSC, particularly in cases with only lymph node involvement, usually has an indolent course with a low rate (~10%) of metastasis. In these cases, surgical removal appears to be the treatment of choice; the role of radiation and chemotherapy here is not well-defined. Cases with extranodal involvement, especially those with abdominal tumors, have a higher metastatic rate (~20%). Chemotherapy regimens remain the mainstay for treating disseminated FDCS. However, these regimens (e.g. CHOP, ICE, and ABVD) have produced variable results. Too few individuals have been treated with allogeneic hematopoietic stem cell transplantation to determine its role in treating FDSC. Further studies on the usefulness of radiation, chemotherapy, bone marrow transplantation, and newer non-chemotherapy drugs such as the BRAF oncogene inhibitor, vemurafenib, (for individuals with the BRAF oncogene), are needed. == Treatment ==

Tabelecleucel (trade name Ebvallo) was granted marketing authorization under ‘exceptional circumstances’ on 16 December 2022 as monotherapy for the treatment of patients who are: at least 2 years of age; had received a hematopoietic stem cell transplantation; and then developed an EBV+ LPD which was either refractory to or relapsed after receiving at least one therapy for their EBV+ LPD. == References ==