Primary effusion lymphoma

Individuals diagnosed with PEL most commonly (>33% of all cases) present with advanced Stage III or IV disease. 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. Individuals with extracavitary PEL present with lesions in the lung, central nervous system, gastrointestinal tract, and/or lymph nodes. Gastrointestinal track lesions often occur as multiple lymphoid polyps in the large intestine. 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). 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. == 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; 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. 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. 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 but rather is often overexpressed due to the action of the LANA-1 protein made by KSHV/HHV8. The identification of these changes in tissue samples can assist in making the diagnosis of PEL. == 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. and therefore evidence malignant cells that express products of this virus such as LANA1. and therefore evidence malignant cells that express products of this virus such as EBER1/2 nuclear RNA's.) Individuals with PEL that is associated with cirrhosis due to hepatitis evidence positive serum tests for the hepatitis virus B antigen (HBsAg) or one of the various tests for hepatitis C antigen. 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. == 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. 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. 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 but may be somewhat better than the treatment-responsiveness and prognosis of Type I PEL. 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. ==Treatment==

PEL is generally resistant to cancer chemotherapy drugs that are active against other B-cell lymphomas and therefore carries a poor prognosis. 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. 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. 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. == 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. 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. Nadir and colleagues termed this syndrome of findings pulmonary effusion lymphoma in 1996. 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. ==See also==