INTRODUCTION — Infection with the human immunodeficiency virus (HIV) predisposes to the development of neoplasms, including lymphoma. HIV-related lymphoma is generally divided into three types: systemic non-Hodgkin lymphoma (NHL), primary central nervous system lymphoma, and the primary effusion ("body cavity") lymphomas (PEL) [1-3]. Systemic NHL accounts for the great majority of HIV-related lymphomas .
Issues related to PEL will be reviewed here. The epidemiology of and risk factors of HIV-related lymphomas are discussed separately.
EPIDEMIOLOGY — PEL is one of the least common of the HIV-related lymphomas, accounting for less than 1 to 4 percent of cases [4-6]. The overwhelming majority of cases of PEL occur in people living with HIV. However, this lesion can occur in the absence of HIV infection [7-10] and rarely has been seen following solid organ transplantation [11-13] and in chronic hepatitis C virus infection [14,15].
There appears to be a strong male predominance with men accounting for all 15 cases in one of the original descriptions, and for 10 of 11 cases in a separate single-institution study [4,7]. This may reflect the increased prevalence of HIV infection among men. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)
Although earlier studies of this rare condition had reported low CD4 counts in patients with PEL , larger and more recent series do not support this observation [4,5,17]. Among people living with HIV, patients with PEL are similar to those with other non-Hodgkin lymphomas in age, race, and HIV transmission category .
As described below, human herpesvirus 8 (HHV-8) plays a role in the pathogenesis of PEL. Those individuals with other disorders related to HHV-8 infection have an increased risk for developing PEL, and vice-versa. These disorders include Kaposi's sarcoma and multicentric Castleman disease. (See "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Etiology and pathogenesis' and "Human herpesvirus-8 infection".)
PATHOGENESIS — The malignant cells of PEL are monoclonal B cells (as defined by rearrangement of the immunoglobulin gene) that express cell surface CD38 and contain genomic material from human herpesvirus 8 (HHV-8, also called Kaposi's sarcoma-associated herpesvirus or KSHV) [7,18-20] and, in many cases, Epstein-Barr virus (EBV) [7,21,22]. The importance of EBV in lymphomatous transformation in this setting is uncertain, as opposed to its primary role in primary central nervous system lymphoma [21,23]. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
Cell of origin — The precise B cell subset from which these cells are derived and the biological mechanisms responsible for its unusual growth pattern (ie, limited to body cavities) are uncertain. It has been suggested that the cells represent a preterminal stage of B cell differentiation . However, others suggest that the development of PEL is not restricted to one stage of B cell differentiation and may represent transformation of B cells at different stages of ontogeny .
PELs express a common gene profile that is distinct from that of other HIV-related non-Hodgkin lymphomas (NHLs) or lymphomas in the immunocompetent population [26,27]. This profile suggests that the tumor cells are not of germinal center or memory cell origin. Rather, they more likely correspond to a stage of B cell development intermediate between that of immunoblasts and plasma cells [26,28].
Viral infection — All patients with PEL have HHV-8 infection and many patients also demonstrate evidence of EBV infection. While HHV-8 infection is required for the development of PEL, the mechanisms by which HHV-8 infection might promote tumor growth are uncertain. Loss of the HHV-8 genome results in the death of PEL cells, demonstrating that genes of this virus play a vital role in PEL cell survival .
The following latent gene products of HHV-8 appear to play significant roles in the development of PEL by promoting proliferation and impairing apoptosis [29-33]:
●Latency-associated nuclear antigen (LANA-1)
●Viral cyclin (v-cyclin)
●Viral FLICE inhibitory protein (v-FLIP)
●Viral interleukin (IL)-6
●Viral IL-8 receptor homolog (vIL8R), also known as viral G-protein coupled receptor homolog (vGPCR)
●The transmembrane protein K1
Proposed pathogenic roles for LANA-1 in PEL development include tethering HHV-8 DNA to chromosomes during mitosis to permit segregation of HHV-8 episomes to the progeny cells , activation of EBV promoter regions in co-infected cells [35,36], and inhibition of tumor suppressor genes [37-40].
V-cyclin binds and phosphorylates the cell cycle inhibitor p27Kip1 (KIP1), thereby inhibiting the negative cell cycle control function of p27Kip1 and promoting the rapid proliferation of PEL cells [41,42]. Further, v-cyclin forms a complex with the CDK6 cyclin-dependent kinase to form an active kinase inhibitor that also promotes cell proliferation .
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 gene is expressed in PEL cells and is up-regulated when these cells enter the lytic phase of the virus life cycle . The product of this gene promotes the survival of infected cells and further dissemination of HHV-8. This occurs through the activation of nuclear factor-kappa B (NF-kB), by disrupting cytokine regulation, and by its ability to bind and disrupt other proteins.
HHV-8 infection results in the constitutive activation of NF-kB in endothelial cells perhaps through the latent protein v-FLIP [35,43-45]. Much like in other virally-mediated lymphomas, the survival of PEL cells depends on the unregulated production of NF-kB . Inhibition of NF-kB has been shown to induce apoptosis in PEL cells [47-49]. In addition, PEL cells contain a unique form of the molecular chaperone Hsp90, known as tumor-enriched Hsp90 (teHsp90), which forms a complex with KSHV viral proteins (oncoproteins) and co-chaperones. Inhibition of tumor-enriched Hsp90 with the teHsp90-specific inhibitor PU-H71 leads to the degradation of v-FLIP, downregulation of NF-kB, and apoptosis of PEL cells . In vitro antitumor activity was found to be synergistic with a BCL2 family inhibitor. Treatment with these inhibitors induced anti-tumor responses in mouse PEL-xenograft models.
IL-6 and IL-10 may act as autocrine growth factors to promote lymphomagenesis and the growth of PEL cells [51,52]. The HHV-8 genome encodes viral IL-6, a cytokine that promotes plasmacytosis and angiogenesis .
Additional studies suggest that constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the cells of PELs occurs secondary to IL-10 and viral IL-6. Phosphorylation of STAT3 directly contributes to the malignant progression of PEL cells by activating the prosurvival (anti-apoptotic) protein survivin .
Expression of PDL1 (programmed death ligand 1) by some cells suggests that immune escape may contribute to in the development of PEL .
CLINICAL MANIFESTATIONS — The clinical manifestations of PEL depend upon the extent and distribution of disease. In the "classic" presentation, PEL originates on serosal surfaces, including the pleura (60 to 90 percent), pericardium (up to 30 percent), peritoneum (30 to 60 percent), joint spaces, and, rarely, the meninges [4,7,17,56]. Patients usually present with symptoms related to fluid accumulation, such as dyspnea (from pleural or pericardial effusions), abdominal distension (from ascites), or joint swelling. Radiographic imaging may reveal pleural and/or pericardial effusion, slight serosal (pleural, pericardial) thickening, and the absence of parenchymal abnormalities, solid masses, or mediastinal enlargement [7,18,57].
Extracavitary PEL is a clinical variant of PEL that presents with solid tumor lesions without malignant serous fluid, predominantly in the gastrointestinal tract [58-60]. Extracavitary PEL accounts for approximately one-third of all cases of PEL but is similar to classic PEL with regard to epidemiology, morphology, immunophenotype, viral associations, clinical course, and overall survival [59,61].
EVALUATION AND DIAGNOSIS — The evaluation of the patient suspected of having PEL involves imaging techniques to detect the effusion followed by fluid examination. While the morphology and immunophenotype can vary, the key diagnostic criterion for PEL is the presence of human herpesvirus 8 (HHV-8) in the nuclei of the malignant cells.
Fluid examination — Samples of the effusion are almost always positive for malignant cells due to the unique liquid-phase of growth of these tumors [7,57]. The effusions are exudative and often bloody .
Morphology — The malignant cells exhibit a range of appearances, from large immunoblastic or plasmablastic cells to those with more anaplastic characteristics; some cells can resemble Reed-Sternberg cells (picture 1) . A perinuclear hof consistent with plasmacytoid differentiation may be seen. The cytoplasm is deeply basophilic with vacuoles in occasional cells.
Immunophenotype — The immunophenotype of the malignant cells in PEL often reflect that of a mature B cell shifting towards terminal plasma cell differentiation. Over 90 percent of cases demonstrate expression of CD45. Other B cell (ie, CD19, CD20, CD79a) and T cell-associated antigens are typically negative but can be seen in a fraction of cases [16,22,64]. Activation and plasma cell-related markers such as CD30, CD38, CD71, CD138, and epithelial membrane antigen are usually present [30,63].
Genotype — No characteristic genetic abnormalities have been identified in PEL, but complex and recurrent cytogenetic abnormalities in the tumor cells have been reported . Immunoglobulin genes are clonally rearranged and hypermutated ; some cases also have rearranged T cell receptor genes (so-called "genotypic infidelity") .
Viral testing — The key diagnostic criterion for PEL is the presence of HHV-8 in the nuclei of the malignant cells. The most common method for detecting HHV-8 positivity is immunohistochemical staining for the latent viral gene product known as latency-associated nuclear antigen (LANA-1). Despite the usual co-infection with Epstein-Barr virus, staining for latent membrane protein (LMP1) is negative .
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for patients who present with an effusion that is subsequently found to contain lymphoma cells includes systemic lymphomas with secondary involvement of the body fluid (ie, secondary effusion), extranodal variants of various subtypes of lymphoma (eg, extranodal large cell lymphoma), and lymphomas that develop as a result of chronic pyothorax (ie, pyothorax-associated lymphoma). PEL is characteristically distinguished from all of these other types of lymphoma by its HHV-8 positivity [30,31].
In addition, there is a broad differential diagnosis for pleural effusions in people living with HIV, which includes both infectious and non-infectious causes. These are discussed in detail separately. (See "Pleural effusions in HIV-infected patients".)
Extranodal Burkitt lymphoma — Patients with Burkitt lymphoma can sometimes present with an effusion as the sole marker of disease, most frequently in the context of HIV infection. The defining biological feature of Burkitt lymphoma is MYC deregulation, which is not found in PEL. Ninety percent of the time the malignant cells of Burkitt lymphoma display a translocation between the long arm of chromosome 8 (the site of the MYC oncogene) and one of three other chromosomes resulting in t(8;14), t(2;8), or t(8;22). The principal feature that distinguishes Burkitt lymphoma from PEL is its HHV-8 negativity. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)
Pyothorax-associated lymphoma — Pyothorax-associated lymphoma, reported mostly from Japan, is a rare complication of long-standing pyothorax, most often in association with tuberculosis in the context of Epstein-Barr virus infection . In contrast to PEL, these lymphomas have no association with immunosuppression and are HHV-8 negative. They also typically present with a tumor mass within the body cavity .
STAGING — The staging systems used for other types of non-Hodgkin lymphoma are not useful in PEL since all patients have stage IV disease by definition (table 1) . In addition, the International Prognostic Index used in most other types of non-Hodgkin lymphoma has not been validated in patients with PEL. However, a pretreatment evaluation can help determine the extent of disease. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)
Computed tomography (CT) of the chest, abdomen, and pelvis is recommended for all patients with consideration given to nuclear imaging with positron emission tomography (PET) . The use of other imaging modalities, bone marrow biopsy, lumbar puncture, and/or endoscopy is driven by the clinical manifestations.
Evaluation of the newly diagnosed patient should also include a complete blood count with differential, chemistries with liver and renal function and electrolytes, serum lactate dehydrogenase (LDH) level, and HIV serologies.
MANAGEMENT — Although they have little propensity to disseminate, PELs cause local destruction and have a uniformly poor prognosis without treatment . The median overall survival (OS) after diagnosis without treatment is approximately two to three months [22,70]. While many cases demonstrate a response to chemotherapy treatment, remissions are often of short duration. Even with aggressive chemotherapy, historically the median OS extended on average to only six months [7,18,22,56,70].
There is a paucity of data to guide the treatment of patients with PEL. Since the disease is so uncommon, there are very few retrospective series and no prospective trials in this patient group. In addition, the unique clinical manifestations make trials of other non-Hodgkin lymphoma (NHL) subtypes largely inapplicable.
Treatment approaches that have been used for PEL include antiretroviral therapy (ART), cytotoxic chemotherapy, radiation therapy, antiviral therapy, and combinations of these.
People living with HIV — The optimal treatment of PEL in people living with HIV is unknown. All patients should be encouraged to enroll on a clinical trial. Outside of a trial, most clinicians advocate the administration of both ART and combination chemotherapy as initial therapy.
ART — A key component of the treatment of all people living with HIV with an HIV-related NHL is the administration of an effective ART regimen. This is supported by retrospective studies in other HIV-related NHL subtypes that have reported a survival benefit with ART plus chemotherapy compared with chemotherapy alone. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Effect of ART'.)
Retrospective studies evaluating the use of chemotherapy in patients with HIV-associated PEL have included patients who did or did not receive ART. Although data are limited, patients treated with ART alone appear to have similar outcomes as those administered ART plus chemotherapy and superior survival compared with those given chemotherapy alone.
The following is a survey of these retrospective analyses:
●A retrospective single-institution study reported outcomes of 10 people living with HIV with PEL, five of whom had received prior ART therapy . Five patients were treated with CHOP-like chemotherapy plus ART, which resulted in two complete remissions (CR) and mean OS of 16 months. One received ART alone resulting in a CR and was alive at 14 months of follow-up. Three were treated with chemotherapy but no ART which resulted in a three month OS. One patient received neither chemotherapy nor ART and was dead in two weeks.
●A multi-center retrospective study evaluated the outcomes of 17 people with HIV-related PEL treated with combination chemotherapy plus ART . Only two patients were ART-naive at the time of diagnosis. There were eight CRs. Median OS was six months and the one-year survival rate was 40 percent. This series also reported on two patients who received CHOP chemotherapy without ART, neither of whom achieved a CR and both died within six weeks. By multivariate analysis, predictors of worse survival were shown to be Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 and lack of ART treatment prior to PEL diagnosis.
●Another retrospective series of seven people living with HIV reported on the use of standard doses of CHOP chemotherapy plus high dose methotrexate with leucovorin rescue . Five patients received chemotherapy plus ART. Three had a CR and were alive at an average follow-up of 40 months. A fourth died from plasmablastic NHL with PEL in CR at the time of his death. Two patients were treated with chemotherapy without ART; one had a CR and started ART one month after chemotherapy and was alive 78 months after diagnosis while the other patient was dead 22 days after the diagnosis.
●In a single institution, retrospective series, 28 patients with PEL received treatment with either the intensive doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen followed by high dose methotrexate (n = 2) or high dose methotrexate (2.5 to 3 grams/m2) combined with CHOP (n = 10) . Five patients received interferon alfa with or without cidofovir and others received standard or reduced dose anthracycline- and/or cyclophosphamide-based regimens (CHOP, mini-CHOP, CDE [cyclophosphamide, doxorubicin, etoposide], or ABVP [doxorubicin, bleomycin, etoposide]). Although the median OS for the 28 patients was only 6.2 months, it is notable that one year disease-free survival (DFS) was 79 percent and median DFS was 94.8 months for the 14 patients who achieved CR. However, not surprisingly, high dose methotrexate was associated with substantial hematologic, hepatic, and renal toxicity.
Case reports have demonstrated that some patients with PEL can obtain CR with ART alone [4,30,71-73]. However, we reserve this approach for patients with poor performance status or other comorbidities that would preclude the use of combination chemotherapy. For patients with newly diagnosed HIV-related PEL, we suggest the use of chemotherapy in addition to the institution of ART or modification of an existing ART regimen rather than administering ART alone. As with all antiviral therapy in people living with HIV, the goal is to achieve an undetectable viral load. Chemotherapy options are discussed in the following section.
When choosing among ART regimens, it is important to take into consideration overlapping toxicities or interference of anti-retrovirals with chemotherapeutic agents that may be used in the future. As an example, anti-retroviral drugs with excessive myelotoxicity, such as zidovudine, should be avoided in patients who are receiving or may soon receive myelotoxic chemotherapy. The choice of initial ART regimens in patients with HIV is discussed in more detail separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
Chemotherapy — The effectiveness of combination chemotherapy with or without ART in patients with PEL has been evaluated in uncontrolled retrospective analyses, some of which are described in the section above. For patients with newly diagnosed HIV-related PEL, we suggest the use of chemotherapy in addition to the institution of ART or modification of an existing ART regimen rather than administering ART alone. We reserve the use of ART without chemotherapy for patients with poor performance status or other comorbidities that would preclude the use of combination chemotherapy. Patients should be enrolled on clinical trials, if available.
The following options are offered based upon our clinical experience and limited case reports:
●Dose-adjusted EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) (table 2) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (table 3) with ART results in response rates of 40 to 50 percent and appears to extend median survival from two to three months in those not receiving therapy to a median survival of five to six months [6,30]. Those achieving a CR may have an improved prognosis . Our preference is for the more aggressive daEPOCH regimen in those patients likely to tolerate it as most of these are high-proliferative fraction tumors.
●CHOP-related chemotherapy (including high dose methotrexate in >60 percent) achieved CR in 21 of 34 patients (62 percent) with classic PEL and 7 of 17 (41 percent) with extracavitary variant . Nevertheless, the median OS with median follow-up of 10 years was 10.2 months. The most common cause of death was PEL and there was no plateau in the survival curve with fewer than 25 percent alive at 10 years. The addition of high dose methotrexate did not appear to improve outcomes and there was no discussion of related toxicities.
●CODOX-M/IVAC (the Magrath regimen) has been used for tumors with a very high growth fraction. However, we do not favor this regimen in most patients with PEL because it includes high dose methotrexate, which has a significant risk of delayed drug clearance and associated toxicity in patients with pleural effusions. Since this regimen has greater toxicity, it is reserved for patients with a very good performance status and few comorbidities. (See "Treatment of Burkitt leukemia/lymphoma in adults", section on 'CODOX-M plus IVAC ("Magrath regimen")'.)
●Bortezomib has demonstrated in vitro activity against PEL with efficacy varying depending upon the timing of administration and combination with other agents [30,47-49,74]. Bortezomib may sensitize PEL cells to chemotherapy-induced apoptosis [43,75]. The only published reports on its efficacy are mixed: one series of three patients demonstrating no responses  and a case report of an HIV-negative PEL showing a significant response to a combination of bortezomib with pegylated doxorubicin and rituximab .
It is standard practice to use granulocyte stimulating growth factors to limit the period of neutropenia in patients with HIV-related lymphoma receiving chemotherapy [6,30]. We also routinely administer Pneumocystis jirovecii pneumonia (PCP) prophylaxis, ideally with oral trimethoprim-sulfamethoxazole (TMP-SMX). TMP/SMX can be myelosuppressive and may synergize with chemotherapy to result in a more profound and longer nadir. As such, blood counts must be monitored during therapy. PCP prophylaxis is continued for several months after completion of chemotherapy and until the CD4 counts are stable above 200/mm3. Fungal prophylaxis and screening for cytomegalovirus reactivation while on therapy may be considered in patients with a CD4 count <50 . (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Preventing initial infection'.)
Consolidation — The efficacy of consolidation with hematopoietic cell transplantation (HCT) for PEL is uncertain. From the limited reports, it is not clear if transplantation improves clinical outcomes.
In one study, two-year progression-free survival was 50 percent and OS was 75 percent in four patients who underwent autologous HCT after achieving a complete response with anthracycline-based combination chemotherapy . Two case reports of autologous HCT showed success and another showed no response [79-81]. Reduced-intensity allogeneic transplant in second remission was successful in a single patient with HIV-PEL .
Radiation therapy — When systemic chemotherapy is not possible or a patient has failed other treatment regimens, local palliative radiation therapy to the body cavity of origin may provide symptomatic relief for up to 12 months .
HIV-negative patients — There is even less evidence to guide the treatment of HIV-negative patients with PEL. This is an extremely rare patient population and the majority are being administered chronic immunosuppressant agents to prevent rejection of a solid organ transplantation. Therapy is based upon extrapolation of the data from people living with HIV discussed in the sections above. ART therapy is not indicated in the absence of HIV infection so initial therapy is with chemotherapy. Radiation therapy can also be given to patients who are unable to tolerate or have failed other treatments.
Based upon clinical experience that people living with HIV with PEL treated with ART have better outcomes than those who do not receive ART therapy, we would expect that patients without HIV infection on immunosuppressive therapy would do better if their immunosuppressive therapy were decreased .
For patients with HIV-negative PEL, we suggest dose-adjusted EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), or R-CHOP (rituximab plus CHOP) in cases that express CD20. If the patient is receiving immunosuppressive therapy, we decrease this immunosuppression, if possible. (See 'People living with HIV' above.)
FOLLOW-UP — For patients initiating antiretroviral therapy (ART) or changing an ART regimen, we reevaluate their HIV status four weeks after starting the regimen with a measurement of viral load. We expect to see a drop in the viral load by at least one log(10) at this time. By 12 weeks the viral load should become undetectable. If it is still detectable at 12 weeks, a change in regimen should be considered. (See "Patient monitoring during HIV antiretroviral therapy".)
Response of the PEL to therapy is evaluated six to eight weeks after attainment of an undetectable viral load or completion of chemotherapy with a history, physical examination, laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile), and a PET/CT scan, which provides information on the size and activity of residual masses and allows for the distinction between active disease and fibrosis (table 4) .
While many patients will demonstrate a response to treatment, these remissions are often short-lived. Following documentation of a complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician.
We generally follow our patients every three months. At these visits, we perform a history and physical examination, complete blood count, chemistries, lactate dehydrogenase, and imaging studies if indicated based on signs and symptoms. A biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy.
Causes of death include not only progression of lymphoma, but also opportunistic infections and other HIV-related complications . It is critical for these patients to be closely followed by their HIV specialist in order to control their HIV infection and prevent opportunistic infections.
INVESTIGATIONAL AGENTS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
PEL cell lines and primary PEL tumor cells express CD30 and the anti-CD30 drug conjugate brentuximab vedotin has been shown to induce apoptosis of PEL cell lines and prolong survival of PEL xenograft animals . Brentuximab vedotin has activity against both classic and extracavitary variants of PEL [85,86]. Additionally, a combination of brentuximab vedotin with the HDAC inhibitor vorinostat was shown to potently reactivate HHV-8 lytic replication, inducing PEL cell death and prolonging survival in an animal model . Clinical use of these treatment approaches has yet to be reported.
Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PDL-1) are highly expressed in the tumor cells and the tumor-infiltrating immune cells in PEL [55,88]. The anti PD-1 monoclonal antibody, pembrolizumab has demonstrated activity against PEL .
SUMMARY AND RECOMMENDATIONS
●Primary effusion lymphoma (PEL) is one of the least common of the human immunodeficiency virus (HIV)-related lymphomas. Although most cases occur in people living with HIV, this lesion can occur in the absence of HIV infection most often in patients with other causes of immunocompromise (eg, solid organ transplantation recipients). Latent gene products of human herpesvirus 8 (HHV-8) appear to play a role in the pathogenesis. (See 'Epidemiology' above and 'Pathogenesis' above.)
●PEL originates on serosal surfaces and most affected patients present with a symptomatic serous effusion containing high-grade, malignant lymphocytes, but with no detectable mass lesion. Approximately one-third of patients have a variant presentation with solid tumors, generally involving the gastrointestinal tract, with serous effusion. (See 'Clinical manifestations' above.)
●The diagnosis of PEL is usually made based upon a cytologic examination of the effusion which almost always contains malignant cells. The key diagnostic criterion is the presence of HHV-8 in the nuclei of the malignant cells. (See 'Evaluation and diagnosis' above and 'Differential diagnosis' above.)
●Patients with PEL have a poor prognosis. Mean overall survival is less than three months without treatment and approximately six months with chemotherapy and antiretroviral therapy (ART).
●We suggest enrollment on a clinical trial, if available. There are limited data to guide the treatment of patients with PEL and recommendations are based on expert opinion, case reports, and small retrospective case series. Treatment is modified based on whether the patient is HIV-infected. (See 'Management' above.)
●For patients with newly diagnosed HIV-related PEL, we suggest the institution of ART or modification of an existing ART regimen plus the administration of combination chemotherapy (Grade 2C).
Care must be taken to choose an ART regimen with minimal overlap of chemotherapy-related toxicities. We generally favor integrase inhibitor-based regimens as they have fewer associated drug-drug interactions. (See 'ART' above and 'Chemotherapy' above.)
●The selection of combination chemotherapy to administer in conjunction with ART is largely dependent upon patient and tumor characteristics (see 'Chemotherapy' above):
•For most patients, we prefer dose-adjusted EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) (table 2) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (table 3). Rituximab is added if the tumor expresses CD20.
•Other clinicians have offered more aggressive regimens (eg, CODOX-M/IVAC) to patients with a very good performance status and few medical comorbidities. However, there are no clinical data that would favor this regimen over others and caution must be used with this regimen in PEL given the significant risk of delayed drug clearance and associated toxicity when high dose methotrexate is administered to patients with pleural effusions.
•For those with a poor performance status or significant medical comorbidities, a liposomal anthracycline alone or a liposomal anthracycline plus bortezomib and prednisone (or an equivalent steroid) may be considered. These agents are administered in combination with continued ART.
●Patients who are unable to tolerate or who have failed combination chemotherapy may be treated with ART with or without local radiation therapy to the body cavity of origin. (See 'Radiation therapy' above.)
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