Epstein–Barr virus–associated lymphoproliferative diseases

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Epstein–Barr virus–associated lymphoproliferative diseases
Other namesEBV-associated lymphoproliferative diseases
infectious disease, virology
CausesEpstein–Barr virus

Epstein–Barr virus–associated lymphoproliferative diseases (also abbreviated EBV-associated lymphoproliferative diseases or EBV+ LPD) are a group of disorders in which one or more types of

lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.[1]

EBV-associated LPDs are a subcategory of

nasopharyngeal cancer;[5] the childhood disorders of Alice in Wonderland syndrome;[6] and acute cerebellar ataxia.[7]

About 95% of the world's population is infected with EBV. During the initial infection, the virus may cause infectious mononucleosis, only minor

non-specific symptoms, or no symptoms. Regardless of this, the virus enters a latency phase in its host and the infected individual becomes a lifetime asymptomatic carrier of EBV. Weeks, months, years, or decades thereafter, a small percentage of these carriers, particularly those with an immunodeficiency, develop an EBV+ LPD. Worldwide, EBV infection is associated with 1%[8] to 1.5%[9] of all cancers.[1] The vast majority of these EBV-associated cancers are LPD. The non-malignant, premalignant, and malignant forms of EBV+ LPD have a huge impact on world health.[1]

The classification and nomenclature of the LPD reported here follow the revisions made by the World Health Organization in 2016. This classification divides EBV+ LPD into five categories: EBV-associated reactive lymphoid proliferations, EBV-associated B cell lymphoproliferative disorders, EBV-associated NK/T cell lymphoproliferative disorders, EBV-associated immunodeficiency-related lymphoproliferative disorders, and EBV-associated histiocytic-dendritic disorders.[10]

Pathophysiology

Lymphoid cells involved in EBV+ LPD

In the "germinal center model" for the normal maturation of B cells,

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.[13]

Epstein–Barr virus infection

Main article: Epstein–Barr virus § Replication cycle

The Epstein–Barr virus (also termed human herpesvirus 4) belongs to the

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.[9]
The following table gives more information on the actions of the EBV latency genes.

EBV product Latency Function
EBNA-1 III, II, I Promote replication of the viral genome;[9] controls the infected cell's expression of nuclear and surface membrane proteins that regulate the virus's latency phases.[1]
EBNA-2 III Induces expression of the virus's LMP gene and ~300 genes of the infected cell (e.g. the
proto-oncogene) which promote this cell's proliferation, survival, and malignancy;[9] required for the malignant transformation of this cell.[1]
EBNA-3A III Represses expression of the infected cell's p16INK4a protein thereby promoting its proliferation; represses expression the infected cell's BCL2L11 protein thereby inhibiting apoptosis to promote this cell's survival.[9]
EBNA-3B III Inhibits the infected cell's proliferation; attracts lymphoid cells to its infected cell; inactivates promoters of its infected cell's genes possibly thereby causing this cell more able to evade the host's immune system and to become malignant.[1]
EBNA-3C III Required for the malignant transformation of infected cells; along with EBNA-3A, represses the infected cell's p16INK4a and BCL2L11 proteins thereby promoting, respectively, this cell's proliferation and repressing its apoptosis;[9] disturbs cell cycle checkpoints in the infected cell to promote its proliferation or locking it in the non-reproductive cell cycle state of G1.[1]
EBNA-LP III Overcomes the
innate immune responses of infected cells to promote the virus's survival;[9] acts with EBNA-2 to promote the malignant transformation of its infected cells.[1]
LMP-1 III, II Induces the expression of the infected cell's
BCL2 proteins thereby blocking this cells apoptosis and stimulating its proliferation; regulates the infected cell's maturation.[9]
LMP-2A III, II Prevents the establishment of EBV's lytic cycle;
B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation.[9]
LMP-2B III, II Inhibits the ability of the virus's LMP-2A protein to establish EBV's lytic cycle; stimulates the infected host cell's
AKT and B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation.[1]
BART microRNAs III, II, I While abundantly expressed, the functions of BART microRNAs are unclear;[14] may help evade the infected cell avoid attack by uninfected T- and NK-cells[9] or modify the infected cell's notch signaling pathway to promote its proliferation; not required for EBV-induced B cell immortalization or malignant transformation.[1]
EBER1/2 nucelar RNAs III, II, I, 0 Abundantly expressed by EBV-infected cells in all latency stages; causes infected cell to produce interleukin 10 which may promote this cell to proliferate and avoid attack by host cytotoxic T cells;[1] may block apoptosis in the infected cell.[15]

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.[1]

Epstein–Barr virus-positive reactive lymphoid hyperplasia

EBV-positive reactive lymphoid hyperplasia (or EBV-positive reactive lymphoid proliferation) is a benign form of

histologic findings that occur in the lymphoid tissue of mainly older individuals who were infected with EBV many years earlier. Immunodeficient individuals of any age may also have the disorder. In immunologically normal individuals, histologic findings include the presence of small B cells located in the extrafollicular or, rarely, the follicular area of normal or minimally hyperplastic lymph nodes. These cells are commonly EBV+, express EBER viral genes, and carry the virus in its latency I or II phase. These cells may also occur in the bone marrow. Individuals who are immunodeficient because of disease, immunosuppressive drugs, or old age immunosenescence may exhibit a more pronounced hyperplasia of affected nodes, higher numbers of EBV+ cells, and a more disseminated disorder termed polymorphic lymphoproliferative disorder.[1] These disorders almost always resolve spontaneously but in very rare cases progress over months or years to EBV+ Hodgkin lymphoma or EBV+ diffuse large B-cell lymphoma of the elderly.[16]

Epstein–Barr virus-positive infectious mononucleosis

Main article: Infectious mononucleosis

Infectious mononucleosis (IM) is caused by EBV in ~90% of cases; the remaining cases are caused by

toxoplasma.[17] 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 <5 years old whereas 25–75% of adolescents and adults develop overt IM after infection.[11] The signs and symptoms of IM occur within weeks of EBV infection. Most cases involve a self-limiting flu-like illness or a mild to moderate illness of fever, sore throat, enlarged, painful lymph nodes in the head and neck, and/or an enlarged spleen. These manifestations usually abate within six weeks. More severe cases persist beyond six weeks and may be accompanied by uncommon but serious complications such as hepatitis, anemia, thrombocytopenia, hemophagocytosis, meningoencephalitis, myocarditis, pericarditis, pneumonitis, parotitis, pancreatitis[17] and, in rare but extremely severe cases, life-threatening complications such as rupture of the spleen or disease-transitions to other LPD such as hemophagocytic lymphohisiocytosis (HLH), chronic active EBV (CAEBV), or lymphoma.[18]

During the infection's acute phase, individuals generally have high levels of infective EBV in their oral/nasal secretions plus high blood levels of EBV, atypical lymphocytes,

autoimmune anemia or thrombocytopenia), or other complications of the disease.[18] Treatment of these and the severest IM cases generally use regimens directed at the specific features of each type of complication.[11]

Epstein–Barr virus-related hemophagocytic lymphohistiocytosis

Main article: Hemophagocytic lymphohistiocytosis
Main article: Macrophage activation syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder characterized by a

MAGT1 genes that encode proteins required for the development, survival, and/or other cell-killing functions of ctyotoxic T and/or NK cells.[19]

Secondary HLH is associated with and thought to be promoted by malignant and non-malignant diseases that, like primary HLH, also weaken the

interferon-γ, Interleukin 1 beta, interleukin 18, and CXCL9) causes a systemic and often overwhelming inflammatory condition.[22]

Primary HLH is most often seen in Asians <4 years of age while secondary HLH is most often seen in older children and adults of various races.

interleukin-2 receptor, and, in EBV+ HLH cases, circulating EBV. In the latter cases, histological examination of lymphatic, bone marrow, liver, neuronal, and other involved tissues show infiltrations of small EBV+ T cells, scattered small bystander EBV+ B cells, reactive histiocytes, reactive macrophages, and, in ~70% of cases, hemophagocytosis, i.e. ingestion of erythrocytes, leukocytes, platelets, and/or their precursor cells by histiocytes and macrophages. (Evidence of hemophagocytosis is not critical for the diagnosis of HLH.) The EBV in infected lymphocytes is in its lytic cycle rather than any latent phase.[1] Criteria consistent with the diagnosis of HLH, as developed by the Histiocytic Society (2004), include finding five of the eight following signs or symptoms: fever ≥38.5 °C; splenomegaly; low blood levels of any two of the following, hemoglobin (<10 mg/L), platelets (<100,000/μL), or neutrophils <1,000/μl; either one or both of the following, blood fasting triglyceride levels >265 mg/dL or fibrinogen levels <150 mg/dL; hemophagocytosis in lymphoid tissue; low or absent NK cell activity as tested in vitro on blood cell isolates; elevated blood levels of ferritin; and elevated blood levels or the soluble IL-2 receptor.[22] The finding of EBV in T cells of blood or involved tissues is required to diagnose the EBV-associatec disease.[1]

Prior to 1994, the treatments used for HLH were generally unsuccessful with average response rates to therapeutic interventions of ~10% and median survival times of ~12 month. In 1994, the Histiocytic Society established a drug regimen of

antithymocyte globulin, the DEP regimen (i.e. liposomal doxorubicin, etoposide, methylprednisolone), an anti-interferon gamma monoclonal antibody,[23] and, particularly in patients with EBV+-HLH, rituximab.[11]

Chronic active Epstein–Barr virus infection

Main article: Chronic active EBV infection

Chronic active Epstein–Barr virus infection (CAEBV) (also termed chronic active EBV infection of T and NK cells, systemic form) is a rare LPD

interstitial pneumonia, or rupture of the intestines.[15] CAEBV can progress to a malignant type of EBV+ T-cell LPD such as aggressive NK cell leukemia, NK/T cell leukemia, or peripheral T cell lymphoma.[25]

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

IFNγ) seen in hemophagocytic lymphohystiocytosis. Furthermore, the disease has a strong racial preferences for Eastern Asians. These associations suggest that there are strong genetic predispositions involved in the disease's development and that this development is driven by T- and/or NK cell production of inflammatory cytokines.[15]

Initially, CAEBV may assume a relatively indolent course with exacerbations and recoveries. However, the disease almost invariably develops lethal complications such as single or multiple organ failures. Current recommendations based on studies in Japan suggest that patients diagnosed with CAEBV be treated early in their disease with an intensive three-step sequential regimen: 1) immunotherapy (

cytosine arabinoside followed by fludarabine, melphalan, anti-thymocyte globulin, methylprednisolone, and etoposide). Patients receiving this regimen obtained unusually high three-year event-free and overall survival rates of >87%. Further studies are required to determine how long these event-free and overall survival rates endure.[26]

Severe mosquito bite allergy

Main article:
Mosquito bite allergies

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,

aggressive NK cell leukemia.[15] Diagnostically, the skin lesions show infiltrating NK cells in the epidermis and subcutaneous tissue with a small fraction of these cells being EBV+ with the virus in its latency II phase. A very high density of EBV+ NK cells in these lesions suggests the disorder has progressed to NK/T cell lymphoma or NK cell leukemia.[1] While the disorder's etiology is unclear, it is thought that the mosquito salivary gland allergenic proteins trigger reactivation of EBV in latently infected NK cells. Upon reactivation, EBV genes such as LMP1 express products that induce immortalization, proliferation, and in some cases malignancy of the EBV reactivated NK cells.[27] The best treatment for SMBA remains unclear. Mild and clearly uncomplicated cases can be treated conservatively focusing on obtaining relief of symptoms such as skin irritation, fever, and malaise.[29] 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.[26] Rare cases of SMBA have been reported to occur in individuals who have no apparent predisposing disease but later develop CAEBV.[28][29] Such cases require careful evaluation and follow-up for development of a predisposing disorder.[29]

Hydroa vacciniforme-like lymphoproliferative disease

Main article: Hydroa vacciniforme

Hydroa vacciniforme is a rare

B cell leukemia.[24] 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.[24] In the skin lesions, EBV occurs primarily in the T cells[1] and to a lesser extent NK cells.[15] Marker studies indicate that the EBV in these cells is in latency phase II.[1]

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,

radiotherapy regimens used to treat lymphoma and leukemia have produced only transient benefits while often causing unacceptable toxicities.[24] 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.[26]

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

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.[24]

Persons developing these ulcers are usually elderly. Their ulcers are typically isolated, occur in the oral

eosinophils, and scattered large immunoblasts which may closely resemble but are not the Reed–Sternberg cells seen in Hodgkin lymphoma.[15] 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,[24] and the proteins typical of the EBV replication cycle latency II or III phase.[1]

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.[24] 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.[15] 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.[24]

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.[1]

Epstein–Barr virus-positive Burkitt lymphoma

Main article:
Burkitt's lymphoma

organ transplant; in the latter cases, individuals have almost always received intensive chemotherapy and therefore are immunodeficient.[31] About 30% of iBL cases are infected with EBV.[33]

eBL commonly presents with a jaw mass;

PI3K cell signaling pathway thereby stimulating this cell's proliferation.[citation needed
]

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.[15] 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.[1]

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%.[30]

Epstein–Barr virus-positive lymphomatoid granulomatosis

Main article: Lymphomatoid granulomatosis

EBV+ lymphomatoid granulomatosis (EBV+ LG, also termed

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.[37] 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.[1]

Individuals with the disease may be immune deficient due to subtle reductions in their immune function

cytotoxic T cells allows EBV+ B cells to evade the immune system and proliferate.[37]

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 therapy and, in rare cases, remits spontaneously.[37] Grade II and severe grade I disease is treated with immune regimens that include various interferons[37] and/or rituximab, a monoclonal antibody against the B cell protein, CD20.[35] 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.[35]) While EBV+ LG often responds to these treatments, there are no controlled clinical trials proving their long-term therapeutic value.[37] Medium survival times for all cases of the disease are ~4 years with many cases progressing to other lymphoid malignancies that shorten survival times.[37]

Epstein–Barr virus-positive Hodgkin lymphoma

Main article: Hodgkin lymphoma

cytokines that may suppress the EBV's lytic cycle to maintain the HRS cells viability.[40] 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.[1] 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.[40]

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.[1] 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.[40] 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%,[15] although some population based studies have found a higher incidence of relatively adverse outcomes in older individuals with EBV+ HL.[1]

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

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).[42]

About 10–15% of DLBCL cases are EBV+. These cases, termed

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.[1]

EBV+ DLBCL commonly occurs in immune-deficient individuals. It is thought to arise in the elderly because of their

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.[42] 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),[43] particularly in CLL-transformed EBV+ DLBCL (median survival four months).[44]

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

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.[15] 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.[1]

While DLBCL-CI is an aggressive malignancy, its treatment, particularly in localized disease, should include efforts to remove its underlying inflammatory causes.[47] For example, PAL is a particularly aggressive form of DLBCL-CI.[45] Nonetheless, surgical removal of the pleural tumor effectively treats the few cases in which it is localized and of low-grade.[15] 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%).[48] There are too few reports on the treatment of non-PAF forms of DLBCL-CI to make recommendations.[citation needed]

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.

prosthetic implants of the hip.[49] 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.[49] The large B cells are infected with EBV in latency III and express this virus's EBER, EBNA2, and LMP-1 genes.[15] 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.[15] 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.[49]

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.[49]

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.[50]

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

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.[50] 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.[1] 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.[51]

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[52] 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.[1]

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

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).[50] However, PBL patients with early stages of the disease and/or EBV+ disease have a much better survival rate.[15] 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.[54]

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).[55] EBV positivity is more common in the plasmacytoma rather than bone marrow infiltration form of PCM.[1] 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.[1] The cells express products of EBV genes such as EBER[56] which suggest that EBV is in a restricted latency II phase.[1] 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.[15] 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.[56] 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.[56]

EBV+ NK/T cell lymphoproliferative diseases

While EBV preferentially infects B cells, it may also infect other lymphocyte types viz.,

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.[1]

Peripheral T-cell lymphomas

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).[57] AKL+/− ALCL is rarely if ever associated with EBV and therefore not considered here.[58]

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

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.[15]

The diagnosis of ENKTL depends upon finding EBV and granzyme B in the disease's lymphoid tumor cells.

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.[59] 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.[60]

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.

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.[61] 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.[1]

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.

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.[61]

Angioimmunoblastic T cell lymphoma

Main article: angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T cell lymphoma (ATIL) is a systemic malignancy of mature

chemoattractant, chemokine (C-X-C motif) ligand 13 (i.e. CXCL13).[65] 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.[1] 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.[citation needed
]

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

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.[66] 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 and 4–5 are 56% and 25%, respectively, when treated with a recommended CHOP or a CHOP-like chemotherapy regimen.[67] The addition of etoposide or the proteasome inhibitor, bortezomib, to CHOP regimens has modestly increased overall and complete response rates.[68] 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.[67]

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.

ICOS, CXCL13, CXCR5, and TOX).[citation needed
]

No controlled studies on the treatment of the disease have been reported.

interferon-gamma, bexarotene, gemcitabine; and with hematopoietic stem cell transplantation. Responses to these treatments were variable and often disappointing.[70] 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.[71]

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).,

intrathecal methotrexate, which may or many not be followed by hematopoietic stem cell transplantation.[15]

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).

CD56 antigen and are malignant[73] 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.[1] 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.[74]

Classic and sub-acute ANKL rapidly progress to life-threatening

consolidation therapy followed by autologous hemotopoietic stem cell transplantation.[74]

Intravascular NK/T-cell lymphomas

Main article: Intravascular lymphomas

Two extremely rare types of the intravascular lymphomas,

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.[75] 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.[76] 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.[77][78][79][80]

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".[citation needed]

EBV-related and HIV-related LPD

Individuals carrying the

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.[1] 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.[citation needed
]

LPD type Percent EBV+ Latency phase[1] Latent EBV genes expressed[1] Factors promoting the development, growth and/or survival of malignant cells
DLBL 30–40% III all Mutations or changes in the expression of TNFAIP3, MYC, and/or BCL6 genes.[13]
PCNSL 90–100% III all Mutations in MYD88 and CD79B genes and copy number gains at the programmed death ligand 1 and programmed death ligand 2 gene loci on chromosome 9.[81]
BL 30–40% I EBERs Translocations and/or mutations in the
TP53 genes.[1]
HL 100% II LMP1, LMP2, LMP2A, EBNA1, EBERs The products proteins of some of these viral genes stimulate the NFkB cell signaling pathway.[1]
PBL 70–80% possible I/II EBERs, rarely LMP1 Translocations, amplifications, and other causes (e.g. mutations in the PRDM1 gene) lead to the overexpression of the MYC gene.[50]
PEL 90% possible I/II EBNA1, LMP2A, EBERs Concurrent infection with HHV8 and this virus's expression of its transforming proteins (e.g. LANA1) appears responsible for the disorder.[50]

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,[51] these treatments should include continuance or, in individuals who have not yet been treated for AIDS, the institution of anti-HIV combination drug regimens.[1] 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

severe combined immunodeficiency disease (SCID), the autoimmune lymphoproliferative syndrome, and the WHIM syndrome.[11]

2) Immunosuppressive drug therapy, particularly methotrexate and regimens including methotrexate.[38]

3) Genetic defects in the expression of genes for

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.[11]

4) Inflammatory/autoimmune diseases such as

chronic hepatitis, ulcerative colitis, retroperitoneal fibrosis, and primary biliary cholangitis.[38]

5) Chronic

Giant-cell arteritis, sarcoidosis, and severe psoriasis), particularly in individuals receiving immunosuppressive drugs for these diseases.[53]

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.[50]

Post-transplant lymphoproliferative disorders

Main article: Post-transplant lymphoproliferative disorder

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:[50]

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.[50]

EBV-associated histiocytic-dendritic disorders

Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma

Main article: Follicular 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

podoplanin, gamma-synuclein)[82] and in >90% of cases products of the virus's EBER[83] and LMLP1 genes.[1] 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.[1]

Overall, patients with FDCS have local recurrence rates of 40–50 and a long term mortality rates due to the disease of ~20%.[82] 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.[13] 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.[82]

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.[84]

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