Primary effusion lymphoma

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Primary effusion lymphoma
3 PEL 1 680x512px.tif
Specialty Hematology, oncology, virology
CausesChronic viral infection with KSHV/HHV8 or HIV
Prognosis Guarded

Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus (i.e. KSHV/HHV8). Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. [1] In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions (i.e. accumulations of fluid), primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. [2] In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule (i.e. tightly woven collagen fibers) which forms around breast implants. [1] Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. [3] The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. [1] As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions. [4]

Contents

PEL typically occurs in individuals who are immunocompromised, i.e., individuals whose immune system is weakened and therefore less able to fight infectious agents and cancers. This weakening is ascribed to KSHV/HHV8 infection that is commonly further promoted by concurrent human immunodeficiency virus (i.e. HIV) infection, prior organ transplantation, [4] the decline in immunity that develops with aging, [1] and/or cirrhosis of the liver due to hepatitis B or C virus. [5] The plasmacytoid cells in PEL are also commonly infected with the Epstein-Barr virus (i.e. EBV). EBV is a known cause of various Epstein-Barr virus-associated lymphoproliferative diseases including various B-cell lymphomas. However, the role of this virus in the development of PEL is not clear, [4] although some studies suggest that EBV infection cooperates with KSHV/HHV8 infection to promote the development and/or progression of this disease. [3]

Formally, PEL is defined by the World Health Organization, 2016 as a KSHV/HHV8-positive [6] and KSHV/HHV8-driven large B-cell lymphoma. This lymphoma also belongs to a group of lymphoid neoplasms with plasmablastic differentiation that involve malignant plasmablasts but differ from PEL in the types of tissues where they accumulate, the gene abnormalities they carry, and/or the predisposing conditions involved in their development. [1] More than 50, 30, and 60% of all PEL cases, respectively, develop in individuals who already have KSHV/HHV8-positive Kaposi's sarcoma, human herpesvirus 8-associated multicentric Castleman disease, [7] and/or (especially in HIV-positive individuals) evidence of bearing EBV-infected plasmablasts. [2]

Primary effussion lymphoma is an extremely aggressive cancer that is highly resistant to various chemotherapy treatments. It has carried a median survival time of ~5 months, [8] with overall survival rates at 1, 3, and 5 year of only 30, 18, and 17%, respectively. In many cases, however, this high mortality reflects, at least in part, the lethality of its underlying predisposing diseases, particularly HIV/AIDS in HIV-infected individuals. New treatment strategies, including those directed at its underlying predisposing diseases, may improve the prognosis of PEL. [9]

Presentation

Individuals diagnosed with PEL most commonly (>33% of all cases) present with advanced Stage III or IV disease. [5] They are predominately males with a median age of 42 years if they are infected with HIV and 73 years if they are not so infected. Some one-third to one-half of these individuals have a history of Kaposi's sarcoma, less commonly of multicentric Castleman disease, and/or rarely of immune deficiency due to organ transplantation, hepatitis complicated by cirrhosis caused by hepatitis B or C viral infection, or of old age. PEL occurring in the elderly generally occurs in EBV-negative individuals residing in the Mediterranean region. Individuals with the cavitary form of PEL present with symptoms due to effusions in the pleural cavity (e.g. shortness of breath), pericardium (e.g. chest pain/discomfort, hypotension, shortness of breath), peritoneal cavity (e.g. abdominal swelling), or, much less often, joints (e.g. swelling), the epidural space (e.g. central nervous system symptoms), or breast implants (e.g. breast swelling/pain/malformation). While most cases of classical PEL involve one cavitary site, some individuals present with two or more sites of cavitary involvement. [4] Individuals with extracavitary PEL present with lesions in the lung, central nervous system, gastrointestinal tract, [4] and/or lymph nodes. [5] Gastrointestinal track lesions often occur as multiple lymphoid polyps in the large intestine. [1] At diagnosis, more than 50% of individuals afflicted with either cavitary or extracavitary PEL have or report a history of B symptoms (i.e. fever, weight loss, night sweat). [7] Laboratory examination in all PEL cases often show anemia, low blood levels of platelets, high serum levels of IL6, and high levels of circulating KSHV/HHV8. [8]

Pathophysiology

PEL develops in patients that have predisposing diseases that reduce the immune systems ability to attack precancerous and cancerous cells. Initially, KSHV/HHV8 viruses infect plasmablasts to establish a latency state in which the viruses express malignancy-promoting genes (see KSHV/HHV8 genes). Products of these viral genes include: 1) LANA-1, which inhibits host cells' p53 protein thereby reducing these cells' apoptosis (i.e. programmed cell death) response to injury, and also inhibits the activity of host cells' retinoblastoma protein thereby increasing these cells' proliferation; 2) vcylin, an analog of host cell cyclin, which binds RB to increase these cells' proliferation; 3) vFLIP, which inhibits host cell's apoptosis and activates these cells' NF-κB signaling pathway to prolong their survival; 4) various protein isoforms of kaposin which stimulate host cells to release cytokines (e.g., GM-CSF and IL-6) that act back on these cells to stimulate their growth; [4] 5) vIL6, a viral analog of host cells' IL-6 which, while not often expressed, [8] induces these cells to produce VEGF, a cytokine that feeds back on these cells to inhibit their apoptosis and to increase the permeability of nearby blood vessels thereby promoting the formation of effusions; [10] 6) K1 protein which promotes the malignancy of host cells; 7) G-protein coupled receptor protein which promotes host cells' proliferation and survival; and 8) several viral microRNAs that promote host cells to proliferate, inhibit these cells' apoptosis, and stimulate the vascularization of nearby small blood vessel to promote effusions. [9] While HIV/AIDS is associated with a wide range of cancers, including those involving B-cells such as plasmablastic lymphoma, the development of these cancers is commonly attributed to co-infection with oncogenic viruses (e.g. KSHV/HHV8, EBV): the direct role of HIV/AIDS in promoting PEL is unclear. [11] Finally, some studies suggest that EBV cooperates with KSHV/HHV8 to cause PEL, perhaps by enhancing the ability of KSHV/HHV8 to establish their pro-malignant latency phase in infected cells. [3]

As a probable result of their excessive proliferation, prolonged survival, and ability to avoid attack by a weakened immune system, the malignant cells in PEL exhibit a high degree of genomic instability, i.e. alterations in the structure and/or expression of their genetic material which are associated with the development and/or progression of PEL. These alterations include mutations (i.e. changes in nucleic acid sequences), chromosomal rearrangements (i.e. deletions, duplications, inversions, translocations), aneuploidy (i.e. increases or decreases in the number of chromosomes), and the abnormal expression of genes that may or may not be a result of the preceding structural gene changes. Potentially important examples include: 1) overexpression of the APOBEC3B gene whose protein product (termed "probable DNA dC->dU-editing enzyme APOBEC-3B") contributes to the regulation of cell growth; 2) missense mutations in the IRAK1 gene which causes overactivation of its product protein, interleukin-1 receptor-associated kinase 1, and thereby overactivation of the NF-κB signaling pathway that regulates cell proliferation and survival; [4] 3) overexpression of the AQP3 gene whose protein product, aquaporin 3, is a water channel that when overexpressed is thought to promote the progression and spread of various types of cancers; [12] 4) overexpression of the P-selectin glycoprotein ligand-1 gene whose protein product promotes cell attachment to vascular endothelium; 5) overexpression of the MUC1 gene whose product, the Mucin 1, cell surface associated protein, binds with P53 to inhibit cell death and interacts with beta-catenin to promote the tissue-invasiveness of cancer cells; and 6) overexpression of the MYC gene, whose product, c-Myc, is the cancer-causing MYC proto-oncogene although this overexpression, unlike the c-Myc overexpression occurring in other B-cell lymphomas, is usually not associated with structural abnormalities in its gene [4] but rather is often overexpressed due to the action of the LANA-1 protein made by KSHV/HHV8. [2] The identification of these changes in tissue samples can assist in making the diagnosis of PEL. [4]

Diagnosis

In classical cavitary cases, the diagnosis of PEL may be suspected based on its presentation as effusions in one or more bodily cavities in individuals with a history of the immunodeficiencies cited above. The diagnosis is supported by microscopic examination of cytologic smears taken from these effusions. These smears typically show plasmablasts and, in some cases, other malignant cells that have the morphology of anaplastic cells (i.e., large pleomorphic cells) or the Reed-Sternberg cells associated with Hodgkin disease. [1] As detected by immunostaining methods, the malignant cells typically express molecular marker proteins such as CD45 (which is not expressed on mature plasma cells) as well as activation and plasma cell marker proteins such as CD30, MUC1, CD38, syndecan 1, and IRF4/MUM1; they do not express B-cell molecular marker proteins such as PAX5, CD19, CD29, or CD79a. The cells may also express many of the structural and non-structural gene abnormalities cited in the Pathophysiology section. [1] By definition, individuals with PEL are infected by Kaposi's sarcoma-associated herpesvirus (HHV-8 or KSHV/HHV8) [13] [14] and therefore evidence malignant cells that express products of this virus such as LANA1. [1] In most cases, these individuals are also infected with EBV [15] and therefore evidence malignant cells that express products of this virus such as EBER1/2 nuclear RNA's. [1] Cases associated with HIV/AIDS test positive for antibodies directed against this virus. [1] (PEL occurs in the absence of HHV-8 and HIV, although this is rare. [16] ) Individuals with PEL that is associated with cirrosis due to hepatitis evidence positive serum tests for the hepatitis virus B antigen (HBsAg) or one of the various tests for hepatitis C antigen. [5] Extracavitary PEL is diagnosed based on findings that their mass lesions contain the same or very similar types of malignant cells and the same set of blood and serum findings as those that are found in cavitary PEL. [3]

KSHV/HHV8-negative primary effusion lymphoma

Effusion-based lymphoma, KSHV/HHV8-negative (also termed Type II PEL) has been described by some researchers. These cases closely resemble KSHV/HHV8-positive (also termed Type I PEL) but have yet to be defined by the World Health Organization (2017). Compared to Type I PEL, Type II PEL occurs more often in older individuals, is less often associated with EBV, and more often afflicts individuals who lack evidence of being immunocompromised. [1] That is, the majority of HHV-8-negative EBL cases do not evidence a potentially PEL causative agent, such as HIV, EBV, HCV, or iatrogenic immunodeficiency, except for old age and, in 20% to 40% of cases, the presence of hepatitis C virus infection. [17] Type II PEL also tends to involve malignant plasmablasts, anaplastic cells, and/or Reed-Sternberg-like cells that have somewhat different expression patters of protein markers (e.g. the malignant cells in Type II PEL frequently express CD20 but often do not express CD30) and gene abnormalities (e.g. the malignant cells in Type II PEL more commonly evidence rearrangements in their Myc, BCL2, and BCL6 genes) than the malignant cells in Type I PEL. The response to treatment and prognosis of Type II PEL is poor [1] but may be somewhat better than the treatment-responsiveness and prognosis of Type I PEL. [17] One factor that appears to improve the treatment of Type II PEL is the addition of rituximab (a monoclonal antibody directed against and killing CD20-bearing cell) to the intensive chemotherapy regimens used to treat Type I PEL: the malignant cells in Type II PEL commonly express CD20 whereas the malignant cells in Type I PEL rarely express this cell surface marker. However, there are several cases of KSHV/HHV8-negative EBL that presented with pericardial effusions without evidence of more extensive disease that have experienced complete responses and favorable prognoses without chemotherapy or other cancer treatment (including rituximab) after simple drainage of the effusion. These cases suggest that, in addition to the presence of rituximab-sensitive CD20-bearing malignant cells, Type II PEL may be a less severe disease than Type I PEL, at least in certain cases. [17]

Treatment

PEL is generally resistant to cancer chemotherapy drugs that are active against other B-cell lymphomas and therefore carries a poor prognosis. [18] Overall median and 1 year survival rates in a series of 28 patients treated with chemotherapy for PEL were 6.2 months and 39.3%, respectively. In this study, the complete response rate (presumed to be temporary) to a standard CHOP chemotherapeutic regimen (i.e. cyclophosphamide doxorubicin, vincristine, and prednisone) was only 10% whereas a more intensive CHO chemotherapy regimen which included high dose methotrexate and bleomycin achieved a compete response rate (presumed temporary) of 70%. A second study using CHOP-like regimens or one of these regimens plus methotrexate also produced better results with the latter regimens: 5 year survival rates for the CHOP-like and CHOP-like plus methotrexate regimens were 34.4% and 45.7%, respectively. [4] A review of 105 PEL cases reported median survival times, 1 year, 3 year, and 5 year survival rates of 4.8 months, 30%, 18%, and 17%, respectively. In this study, patients with advanced Ann Arbor Stage III or IV disease had a particularly poor survival rate at 1 year of 25%; this compared to a rate of 42% for patients with stage I or II disease. [5]

Anti-viral drugs directed against Cytomegalovirus (i.e. cidofovir, ganciclovir, and valganciclovir) have been reported to produce complete presumed temporary responses in individual cases of PEL while drugs directed against HIV in patients with HIV+ PEL have achieved presumed temporary median response and 5 year survival rates of 0.7 months and 28%, respectively. The National Comprehensive Cancer Network (NCCN) guideline recommends treating HIV/AIDS-related PEL with antiviral therapy in combination with aggressive chemotherapy regimens such as DA-EPOCH, cyclophosphamide, doxorubicin, and etoposide, or CHOP. Rituximab, a monoclonal antibody directed against and killing CD20-expressing cells, appears to improve the efficacy of chemotherapy regimens in treating cases of PEL that evidence CD20-positive malignant cells such as Type II PEL. It has been suggested that regimens that include rituximab might improve the treatment of not only CD+ Type II PEL but also the uncommon cases of CD20+ Type I PEL and all cases of CD- PEL. The efficacy of rituximab in CD- PEL may be due to the ability of this antibody to kill non-malignant CD+ 20 lymphocytes and thereby their potential to promote the disease. [8] [19] [20] A National Cancer Institute-sponsored clinical study is in its recruiting phase to study the efficacy of DA-EPOCH (which includes rituximab) plus lenalidomide in treating PEL. [21] Current studies are also examining the effects of drug-based inhibition of the signaling pathways that are overactive in the malignant plasmablasts in PEL (see Pathophysiology section) for their therapeutic effectiveness. [4]

History

PEL was first described in 1989 as a malignant B cell-derived non-Hodgkin lymphoma that developed in three individuals afflicted with HIV/AIDS. [22] In 1995, a group of researchers found DNA sequences that identified KSHV/HHV8 sequences in 8 lymphomas in the malignant cells of patients infected with the HIV; all 8 patients had effusions containing malignant cells in their pleural, pericardial, or peritoneal spaces and had malignant cells in their effusions that evidenced the Epstein-Barr viral genome. [23] Nadir and colleagues termed this syndrome of findings pulmonary effusion lymphoma in 1996. [24] During the years following these initial reports, several cases of PEL were found to be KSHV/HHV8-negative, i.e. occurring in individuals with no evidence of being infected with KSHV/HHV8, or to be manifested by solid tumors that were not associated with effusions, i.e. cases of extracavitary PEL. [17]

See also

Related Research Articles

<span class="mw-page-title-main">Epstein–Barr virus</span> Virus of the herpes family

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.

<span class="mw-page-title-main">Burkitt lymphoma</span> Cancer of the lymphatic system

Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. The overall cure rate for Burkitt lymphoma in developed countries is about 90%, and it is worse in low-income countries. Burkitt lymphoma is uncommon in adults, in whom it has a worse prognosis.

<span class="mw-page-title-main">Kaposi's sarcoma-associated herpesvirus</span> Species of virus

Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.

<span class="mw-page-title-main">Follicular lymphoma</span> Medical condition

Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer.

<span class="mw-page-title-main">Yuan Chang</span> American virologist and pathologist

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<span class="mw-page-title-main">Intravascular lymphomas</span> Medical condition

Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other types of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, other parts of the lymphatic system, and various non-lymphatic organs but not in blood vessels.

<span class="mw-page-title-main">Diffuse large B-cell lymphoma</span> Type of blood cancer

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.

<i>Gammaherpesvirinae</i> Subfamily of viruses

Gammaherpesvirinae is a subfamily of viruses in the order Herpesvirales and in the family Herpesviridae. Viruses in Gammaherpesvirinae are distinguished by reproducing at a more variable rate than other subfamilies of Herpesviridae. Mammals serve as natural hosts. There are 43 species in this subfamily, divided among 7 genera with three species unassigned to a genus. Diseases associated with this subfamily include: HHV-4: infectious mononucleosis. HHV-8: Kaposi's sarcoma.

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The latency-associated nuclear antigen (LANA-1) or latent nuclear antigen is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein initially found by Moore and colleagues as a speckled nuclear antigen present in primary effusion lymphoma cells that reacts with antibodies from patients with KS. It is the most immunodominant KSHV protein identified by Western-blotting as 222–234 kDa double bands migrate slower than the predicted molecular weight. LANA has been suspected of playing a crucial role in modulating viral and cellular gene expression. It is commonly used as an antigen in blood tests to detect antibodies in persons that have been exposed to KSHV.

<span class="mw-page-title-main">Extranodal NK/T-cell lymphoma, nasal type</span> Medical condition

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is a rare type of lymphoma that commonly involves midline areas of the nasal cavity, oral cavity, and/or pharynx At these sites, the disease often takes the form of massive, necrotic, and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, larynx, lung, gastrointestinal tract, skin, and various other tissues. ENKTCL-NT mainly affects adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America. In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous lymphoma after mycosis fungoides.

<span class="mw-page-title-main">Signs and symptoms of HIV/AIDS</span>

The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.

<span class="mw-page-title-main">Plasmablastic lymphoma</span> Type of large B-cell lymphoma

Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma ; primary effusion lymphoma that is Kaposi's sarcoma-associated herpesvirus positive or Kaposi's sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.

Large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease is a type of large B-cell lymphoma, recognized in the WHO 2008 classification. It is sometimes called the plasmablastic form of multicentric Castleman disease. It has sometimes been confused with plasmablastic lymphoma in the literature, although that is a dissimilar specific entity. It has variable CD20 expression and unmutated immunoglobulin variable region genes.

<span class="mw-page-title-main">Epigenetics of human herpesvirus latency</span>

Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.

<span class="mw-page-title-main">HHV-8-associated MCD</span> Disease subtype

Human herpesvirus 8 associated multicentric Castleman disease is a subtype of Castleman disease, a group of rare lymphoproliferative disorders characterized by lymph node enlargement, characteristic features on microscopic analysis of enlarged lymph node tissue, and a range of symptoms and clinical findings.

Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous 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.

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.

Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is an extremely rare form of the diffuse large B-cell lymphomas (DLBCL). DLBCL are lymphomas in which a particular type of lymphocyte, the B-cell, proliferates excessively, invades multiple tissues, and often causes life-threatening tissue damage. DLBCL have various forms as exemplified by one of its subtypes, diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). DLBCL-CI is an aggressive malignancy that develops in sites of chronic inflammation that are walled off from the immune system. In this protected environment, the B-cells proliferate excessively, acquire malignant gene changes, form tumor masses, and often spread outside of the protected environment. In 2016, the World Health Organization provisionally classified FA-DLBCL as a DLBCL-CI. Similar to DLBCL-CI, FA-DLBCL involves the proliferation of EBV-infected large B-cells in restricted anatomical spaces that afford protection from an individual's immune system. However, FA-DLBCL differs from DLBCL-CI in many other ways, including, most importantly, its comparatively benign nature. Some researchers have suggested that this disease should be regarded as a non-malignant or pre-malignant lymphoproliferative disorder rather than a malignant DLBCL-CI.

<span class="mw-page-title-main">Lymphoid neoplasms with plasmablastic differentiation</span>

Lymphoid neoplasms with plasmablastic differentiation were classified by the World Health Organization, 2017 as a sub-grouping of several distinct but rare lymphomas in which the malignant cells are B-cell lymphocytes that have become plasmablasts, i.e. immature plasma cells. Normally, B-cells take up foreign antigens, move to the germinal centers of secondary lymphoid organs such the spleen and lymph nodes, and at these sites are stimulated by T-cell lymphocytes to differentiate into plasmablasts and thereafter mature plasma cells. Plasmablasts, and to a greater extent, plasma cells make and secrete antibodies that bind the antigens to which their predecessor B-cells were previously exposed. Antibodies function, in part, to neutralize harmful bacteria and viruses by binding antigens that are exposed on their surfaces. Due to their malignant nature, however, the plasmablasts in lymphoid neoplasms with plasmablastic differentiation do not mature into plasma cells or form antibodies but rather uncontrollably proliferate in and damage various tissues and organs. The individual lymphomas in this sub-group of malignancies have heterogeneous clinical, morphological, and gene findings that often overlap with other members of the sub-group. In consequence, correctly diagnosing these lymphomas has been challenging. Nonetheless, it is particularly important to diagnose them correctly because they often have very different prognoses and treatments. The lymphoid neoplasms with plasmacytic differentiation are:

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  9. 1 2 Arora N, Gupta A, Sadeghi N (July 2017). "Primary effusion lymphoma: current concepts and management". Current Opinion in Pulmonary Medicine. 23 (4): 365–370. doi:10.1097/MCP.0000000000000384. PMID   28399009. S2CID   4514140.
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  14. ↑ Staudt MR, Kanan Y, Jeong JH, Papin JF, Hines-Boykin R, Dittmer DP (July 2004). "The tumor microenvironment controls primary effusion lymphoma growth in vivo". Cancer Res. 64 (14): 4790–9. doi: 10.1158/0008-5472.CAN-03-3835 . PMID   15256448.
  15. ↑ Fan W, Bubman D, Chadburn A, Harrington WJ, Cesarman E, Knowles DM (January 2005). "Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association". J. Virol. 79 (2): 1244–51. doi:10.1128/JVI.79.2.1244-1251.2005. PMC   538532 . PMID   15613351.
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  17. 1 2 3 4 Kubota T, Sasaki Y, Shiozawa E, Takimoto M, Hishima T, Chong JM (December 2018). "Age and CD20 Expression Are Significant Prognostic Factors in Human Herpes Virus-8-negative Effusion-based Lymphoma". The American Journal of Surgical Pathology. 42 (12): 1607–1616. doi:10.1097/PAS.0000000000001168. PMID   30273194. S2CID   52900937.
  18. ↑ Chen YB, Rahemtullah A, Hochberg E (May 2007). "Primary effusion lymphoma". Oncologist. 12 (5): 569–76. doi:10.1634/theoncologist.12-5-569. PMID   17522245.
  19. ↑ Shin J, Lee JO, Choe JY, Bang SM, Lee JS (January 2017). "Human Herpesvirus 8-Unrelated Primary Effusion Lymphoma-Like Lymphoma in an Elderly Korean Patient with a Good Response to Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone". Cancer Research and Treatment. 49 (1): 274–278. doi:10.4143/crt.2016.076. PMC   5266403 . PMID   27283030.
  20. ↑ Horiuchi M, Nakao T, Tsutsumi M, Nakaya Y, Fuseya H, Yoshida M, Yoshimura T, Hayashi Y, Fukushima H, Inoue T, Yamane T (2019). "[Human herpes virus 8-negative primary effusion lymphoma-like lymphoma recurring as a tumor adjacent to the left atrium]". [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology (in Japanese). 60 (3): 218–222. doi:10.11406/rinketsu.60.218. PMID   31068519.
  21. ↑ "Phase I/II Study of Lenalidomide Combined with Modified DA-EPOCH and Rituximab (EPOCH-R(2)) in Primary Effusion Lymphoma or KSHV-Associated Large Cell Lymphoma". 23 December 2020.
  22. ↑ Knowles DM, Inghirami G, Ubriaco A, Dalla-Favera R (February 1989). "Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus". Blood. 73 (3): 792–9. doi:10.1182/blood.V73.3.792.bloodjournal733792. PMID   2537119.
  23. ↑ Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (May 1995). "Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas". The New England Journal of Medicine. 332 (18): 1186–91. doi:10.1056/NEJM199505043321802. PMID   7700311.
  24. ↑ Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J, Knowles DM (July 1996). "Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus". Blood. 88 (2): 645–56. doi:10.1182/blood.V88.2.645.bloodjournal882645. PMID   8695812.
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