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Primary effusion lymphoma

Primary effusion lymphoma
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — Infection with the human immunodeficiency virus (HIV) predisposes to the development of neoplasms, including lymphomas. 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 [4].

PEL is a large B cell lymphoma that usually presents as serous effusions, without lymphadenopathy, organomegaly, or other detectable tumor masses in people living with HIV (PLWH) or other immunosuppressed individuals.

Evaluation, diagnosis, and management of PEL is discussed in this topic.

Epidemiology and risk factors for HIV-related lymphomas are discussed separately:

(See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

(See "HIV-related lymphomas: Clinical manifestations and diagnosis".)

(See "HIV-related lymphomas: Treatment of systemic lymphoma".)

(See "HIV-related lymphomas: Primary central nervous system lymphoma".)

EPIDEMIOLOGY — Primary effusion lymphoma (PEL) is an uncommon HIV-related lymphoma, 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 [16], 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 [5].

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 biologic 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 [24]. 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 [25].

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 [29].

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 [34], 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 [42].

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 [29]. 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 [46]. 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 [50]. 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 [53].

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 [54].

Expression of PDL1 (programmed death ligand 1) by some cells suggests that immune escape may contribute to in the development of PEL [55].

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 — 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 [62].

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) [63]. 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 [27]. Immunoglobulin genes are clonally rearranged and hypermutated [25]; some cases also have rearranged T cell receptor genes (so-called "genotypic infidelity") [65].

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 (LANA1). Despite the usual co-infection with Epstein-Barr virus, staining for latent membrane protein (LMP1) is negative [63].

DIAGNOSIS — PEL should be suspected in people living with HIV and in other immunosuppressed individuals who have unexplained effusions involving pleura, pericardium, abdomen, or other sites without lymphadenopathy or organomegaly.

Diagnosis of PEL requires demonstration of large blastic or anaplastic monoclonal B lymphocytes with nuclei that are positive for HHV-8 latent protein LANA1 in an immunosuppressed individual.

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 after 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 biologic 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 [66]. 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 [67].

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) [68]. 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) [69]. 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 [7]. 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.

Treatment

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 [4]. 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 [17]. Only two patients were ART-naive at the time of diagnosis. There were eight CRs. The 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 [56]. 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) [17]. 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 [17]. 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 [61]. 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")'.)

Rare cases of PEL are composed of CD20-positive cells. In such cases, we incorporate rituximab into the treatment regimen [30].

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 [76] and a case report of an HIV-negative PEL showing a significant response to a combination of bortezomib with pegylated doxorubicin and rituximab [77].

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 [6]. (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 [78]. 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 [81].

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 [82].

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 [83].

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) [69].

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 [6]. 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 [84]. 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 [87]. 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 [89].

SUMMARY AND RECOMMENDATIONS

Description – Primary effusion lymphoma (PEL; sometimes called body cavity lymphoma) is a B cell lymphoma that is usually seen in association with HIV infection.

Epidemiology – Nearly all cases of PEL arise in people living with HIV (PLWH), although some cases occur in solid organ transplantation recipients and other immunosuppressed individuals. There is a strong male predominance. (See 'Epidemiology' above.)

Pathogenesis – The malignant cells of PEL are monoclonal B cells. Latent gene products of human herpesvirus 8 (HHV-8) appear to play a role in the pathogenesis. (See 'Pathogenesis' above.)

Presentation – Clinical manifestations vary with the extent and distribution of disease. Most cases originate on serosal surfaces, predominantly pleura, pericardium, and peritoneum; extracavitary, joint spaces, and meninges are less often involved. (See 'Clinical manifestations' above.)

Evaluation – Imaging is used to detect effusions and obtain involved fluid or tissue.

Effusions are almost always positive for malignant cells. Specimens should be examined by microscopy, immunophenotype, and for evidence of HHV-8 in nuclei of malignant cells.

Diagnosis – PEL should be suspected in PLWH and other immunosuppressed individuals who have unexplained effusions involving pleura, pericardium, abdomen, or other sites, without lymphadenopathy or organomegaly.

Diagnosis requires demonstration of large blastic or anaplastic monoclonal B lymphocytes with nuclei that are positive for HHV-8 latent protein LANA1 in an immunosuppressed individual. (See 'Diagnosis' above.)

Differential diagnosis – PEL must be distinguished from other causes of effusions. For patients with malignant B cells in an effusion, PEL should be distinguished from extranodal Burkitt lymphoma and pyothorax-associated lymphoma. (See 'Differential diagnosis' above.)

Staging – Sites of involvement are identified by CT of the chest, abdomen, and pelvis, with or without positron emission tomography. (See 'Staging' above.)

By definition, all cases of PEL are considered stage IV disease (table 1).

Management – Prognosis of PEL is poor, and optimal management is not well-defined. We encourage enrollment in a clinical trial, when possible.

Antiretroviral therapy (ART) – For newly diagnosed HIV-related PEL, we suggest the institution of ART or modification of an existing ART regimen (Grade 2C). (See 'ART' above.)

Care should be taken to choose an ART regimen with minimal overlap of chemotherapy-related toxicities (eg, integrase inhibitor-based regimens).

Systemic therapy – For patients who are medically fit for systemic therapy, we suggest dose-adjusted EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) (table 2) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (table 3) (Grade 2C). Rituximab can be added for rare cases that express CD20. (See 'Chemotherapy' above.)

Regimens that include methotrexate can be especially toxic because of delayed drug clearance due to effusions. Patients with significant comorbidities can be treated with liposomal anthracycline alone or with bortezomib and prednisone.

Consolidation – There is no evidence that consolidation with hematopoietic cell transplantation improves outcomes with PEL. (See 'Consolidation' above.)

Radiation – Radiation therapy can provide palliation for selected patients. (See 'Radiation therapy' above.)

HIV-negative PEL – Management is like that for HIV-associated PEL, except ART is not used. We decrease immunosuppressive therapy, if possible. (See 'HIV-negative patients' above.)

Monitoring – Response to treatment is monitored by clinical evaluation and imaging. The response to ART in PLWH is monitored. (See 'Follow-up' above.)

  1. Sandler AS, Kaplan LD. Diagnosis and management of systemic non-Hodgkin's lymphoma in HIV disease. Hematol Oncol Clin North Am 1996; 10:1111.
  2. Coté TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 1997; 73:645.
  3. Wang CC, Kaplan LD. Clinical management of HIV-associated hematologic malignancies. Expert Rev Hematol 2016; 9:361.
  4. Simonelli C, Spina M, Cinelli R, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003; 21:3948.
  5. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Pleural and peritoneal lymphoma among people with AIDS in the United States. J Acquir Immune Defic Syndr 2002; 29:418.
  6. Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist 2007; 12:569.
  7. Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88:645.
  8. Said JW, Tasaka T, Takeuchi S, et al. Primary effusion lymphoma in women: report of two cases of Kaposi's sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women. Blood 1996; 88:3124.
  9. Gandhi SA, Mufti G, Devereux S, Ireland R. Primary effusion lymphoma in an HIV-negative man. Br J Haematol 2011; 155:411.
  10. Ganzel C, Rowe JM, Ruchlemer R. Primary effusion lymphoma in a HIV-negative patient associated with hypogammaglobulinemia. Am J Hematol 2011; 86:777.
  11. Jones D, Ballestas ME, Kaye KM, et al. Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient. N Engl J Med 1998; 339:444.
  12. Dotti G, Fiocchi R, Motta T, et al. Primary effusion lymphoma after heart transplantation: a new entity associated with human herpesvirus-8. Leukemia 1999; 13:664.
  13. Melo NC, Sales MM, Santana AN, et al. Pleural primary effusion lymphoma in a renal transplant recipient. Am J Transplant 2008; 8:906.
  14. Makis W, Stern J. Hepatitis C-related primary effusion lymphoma of the pleura and peritoneum, imaged with F-18 FDG PET/CT. Clin Nucl Med 2010; 35:797.
  15. Nakayama-Ichiyama S, Yokote T, Kobayashi K, et al. Primary effusion lymphoma of T-cell origin with t(7;8)(q32;q13) in an HIV-negative patient with HCV-related liver cirrhosis and hepatocellular carcinoma positive for HHV6 and HHV8. Ann Hematol 2011; 90:1229.
  16. Lynch JW Jr. AIDS-related non-Hodgkin's lymphoma. Useful techniques for diagnosis. Chest 1996; 110:585.
  17. Boulanger E, Gérard L, Gabarre J, et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol 2005; 23:4372.
  18. Karcher DS, Alkan S. Human herpesvirus-8-associated body cavity-based lymphoma in human immunodeficiency virus-infected patients: a unique B-cell neoplasm. Hum Pathol 1997; 28:801.
  19. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332:1186.
  20. Cesarman E, Nador RG, Bai F, et al. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J Virol 1996; 70:8218.
  21. Horenstein MG, Nador RG, Chadburn A, et al. Epstein-Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8. Blood 1997; 90:1186.
  22. Komanduri KV, Luce JA, McGrath MS, et al. The natural history and molecular heterogeneity of HIV-associated primary malignant lymphomatous effusions. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13:215.
  23. Arvanitakis L, Mesri EA, Nador RG, et al. Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus. Blood 1996; 88:2648.
  24. Gaidano G, Gloghini A, Gattei V, et al. Association of Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma with expression of the CD138/syndecan-1 antigen. Blood 1997; 90:4894.
  25. Matolcsy A, Nádor RG, Cesarman E, Knowles DM. Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation. Am J Pathol 1998; 153:1609.
  26. Klein U, Gloghini A, Gaidano G, et al. Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts. Blood 2003; 101:4115.
  27. Wilson KS, McKenna RW, Kroft SH, et al. Primary effusion lymphomas exhibit complex and recurrent cytogenetic abnormalities. Br J Haematol 2002; 116:113.
  28. Jenner RG, Maillard K, Cattini N, et al. Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile. Proc Natl Acad Sci U S A 2003; 100:10399.
  29. Wies E, Mori Y, Hahn A, et al. The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells. Blood 2008; 111:320.
  30. Carbone A, Gloghini A. KSHV/HHV8-associated lymphomas. Br J Haematol 2008; 140:13.
  31. Du MQ, Bacon CM, Isaacson PG. Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and lymphoproliferative disorders. J Clin Pathol 2007; 60:1350.
  32. Wang S, Wang S, Maeng H, et al. K1 protein of human herpesvirus 8 suppresses lymphoma cell Fas-mediated apoptosis. Blood 2007; 109:2174.
  33. Ballon G, Chen K, Perez R, et al. Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 2011; 121:1141.
  34. Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 1999; 284:641.
  35. Inoue Y, Tsukasaki K, Nagai K, et al. Durable remission by sobuzoxane in an HIV-seronegative patient with human herpesvirus 8-negative primary effusion lymphoma. Int J Hematol 2004; 79:271.
  36. Groves AK, Cotter MA, Subramanian C, Robertson ES. The latency-associated nuclear antigen encoded by Kaposi's sarcoma-associated herpesvirus activates two major essential Epstein-Barr virus latent promoters. J Virol 2001; 75:9446.
  37. Katano H, Sato Y, Sata T. Expression of p53 and human herpesvirus-8 (HHV-8)-encoded latency-associated nuclear antigen with inhibition of apoptosis in HHV-8-associated malignancies. Cancer 2001; 92:3076.
  38. Friborg J Jr, Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 1999; 402:889.
  39. Radkov SA, Kellam P, Boshoff C. The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med 2000; 6:1121.
  40. Di Bartolo DL, Cannon M, Liu YF, et al. KSHV LANA inhibits TGF-beta signaling through epigenetic silencing of the TGF-beta type II receptor. Blood 2008; 111:4731.
  41. Sarek G, Järviluoma A, Ojala PM. KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 2006; 107:725.
  42. Järviluoma A, Koopal S, Räsänen S, et al. KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas. Blood 2004; 104:3349.
  43. An J, Sun Y, Fisher M, Rettig MB. Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 2004; 18:1699.
  44. Caselli E, Fiorentini S, Amici C, et al. Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway. Blood 2007; 109:2718.
  45. Matta H, Chaudhary PM. Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci U S A 2004; 101:9399.
  46. Ghosh SK, Wood C, Boise LH, et al. Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-kappa B. Blood 2003; 101:2321.
  47. Thome M, Schneider P, Hofmann K, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997; 386:517.
  48. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999; 11:255.
  49. Keller SA, Schattner EJ, Cesarman E. Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 2000; 96:2537.
  50. Nayar U, Lu P, Goldstein RL, et al. Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 2013; 122:2837.
  51. Jones KD, Aoki Y, Chang Y, et al. Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi's sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood 1999; 94:2871.
  52. Sin SH, Roy D, Wang L, et al. Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 2007; 109:2165.
  53. Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 1996; 274:1739.
  54. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 2003; 101:1535.
  55. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19:3462.
  56. Boulanger E, Daniel MT, Agbalika F, Oksenhendler E. Combined chemotherapy including high-dose methotrexate in KSHV/HHV8-associated primary effusion lymphoma. Am J Hematol 2003; 73:143.
  57. Morassut S, Vaccher E, Balestreri L, et al. HIV-associated human herpesvirus 8-positive primary lymphomatous effusions: radiologic findings in six patients. Radiology 1997; 205:459.
  58. Mate JL, Navarro JT, Ariza A, et al. Oral solid form of primary effusion lymphoma mimicking plasmablastic lymphoma. Hum Pathol 2004; 35:632.
  59. Chadburn A, Hyjek E, Mathew S, et al. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol 2004; 28:1401.
  60. Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol 2007; 60:1365.
  61. Guillet S, Gérard L, Meignin V, et al. Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution. Am J Hematol 2016; 91:233.
  62. Boulanger E, Agbalika F, Maarek O, et al. A clinical, molecular and cytogenetic study of 12 cases of human herpesvirus 8 associated primary effusion lymphoma in HIV-infected patients. Hematol J 2001; 2:172.
  63. Banks PM, Warnke, RA. Primary effusion lymphoma. In: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds), IARC Press, Lyon 2001. p.179.
  64. Ascoli V, Mastroianni CM, Galati V, et al. Primary effusion lymphoma containing human herpesvirus 8 DNA in two AIDS patients with Kaposi's sarcoma. Haematologica 1998; 83:8.
  65. Hollingsworth HC, Stetler-Stevenson M, Gagneten D, et al. Immunodeficiency-associated malignant lymphoma. Three cases showing genotypic evidence of both T- and B-cell lineages. Am J Surg Pathol 1994; 18:1092.
  66. Nakatsuka S, Yao M, Hoshida Y, et al. Pyothorax-associated lymphoma: a review of 106 cases. J Clin Oncol 2002; 20:4255.
  67. Iuchi K, Aozasa K, Yamamoto S, et al. Non-Hodgkin's lymphoma of the pleural cavity developing from long-standing pyothorax. Summary of clinical and pathological findings in thirty-seven cases. Jpn J Clin Oncol 1989; 19:249.
  68. Rosenberg SA. Validity of the Ann Arbor staging classification for the non-Hodgkin's lymphomas. Cancer Treat Rep 1977; 61:1023.
  69. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25:571.
  70. Valencia Ortega ME, Martínez Santos P, Gómez Aguado F, et al. [Primary cavity-based lymphoma and HIV infection]. Rev Clin Esp 1999; 199:73.
  71. Oksenhendler E, Clauvel JP, Jouveshomme S, et al. Complete remission of a primary effusion lymphoma with antiretroviral therapy. Am J Hematol 1998; 57:266.
  72. Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 2001; 15:280.
  73. Ripamonti D, Marini B, Rambaldi A, Suter F. Treatment of primary effusion lymphoma with highly active antiviral therapy in the setting of HIV infection. AIDS 2008; 22:1236.
  74. Sarosiek KA, Cavallin LE, Bhatt S, et al. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A 2010; 107:13069.
  75. Yu D, Carroll M, Thomas-Tikhonenko A. p53 status dictates responses of B lymphomas to monotherapy with proteasome inhibitors. Blood 2007; 109:4936.
  76. Boulanger E, Meignin V, Oksenhendler E. Bortezomib (PS-341) in patients with human herpesvirus 8-associated primary effusion lymphoma. Br J Haematol 2008; 141:559.
  77. Siddiqi T, Joyce RM. A case of HIV-negative primary effusion lymphoma treated with bortezomib, pegylated liposomal doxorubicin, and rituximab. Clin Lymphoma Myeloma 2008; 8:300.
  78. Mirza AS, Dholaria BR, Hussaini M, et al. High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma. Clin Lymphoma Myeloma Leuk 2019; 19:e513.
  79. Waddington TW, Aboulafia DM. Failure to eradicate AIDS-associated primary effusion lymphoma with high-dose chemotherapy and autologous stem cell reinfusion: case report and literature review. AIDS Patient Care STDS 2004; 18:67.
  80. Won JH, Han SH, Bae SB, et al. Successful eradication of relapsed primary effusion lymphoma with high-dose chemotherapy and autologous stem cell transplantation in a patient seronegative for human immunodeficiency virus. Int J Hematol 2006; 83:328.
  81. Bryant A, Milliken S. Successful reduced-intensity conditioning allogeneic HSCT for HIV-related primary effusion lymphoma. Biol Blood Marrow Transplant 2008; 14:601.
  82. Cassoni A, Ali U, Cave J, et al. Remission after radiotherapy for a patient with chemotherapy-refractory HIV-associated primary effusion lymphoma. J Clin Oncol 2008; 26:5297.
  83. Riva G, Luppi M, Barozzi P, et al. How I treat HHV8/KSHV-related diseases in posttransplant patients. Blood 2012; 120:4150.
  84. Bhatt S, Ashlock BM, Natkunam Y, et al. CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma. Blood 2013; 122:1233.
  85. Chang VA, Wang HY, Reid EG. Activity of brentuximab vedotin in AIDS-related primary effusion lymphoma. Blood Adv 2019; 3:766.
  86. Sandoval-Sus JD, Brahim A, Khan A, et al. Brentuximab vedotin as frontline treatment for HIV-related extracavitary primary effusion lymphoma. Int J Hematol 2019; 109:622.
  87. Bhatt S, Ashlock BM, Toomey NL, et al. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 2013; 123:2616.
  88. Calvani J, Gérard L, Fadlallah J, et al. A Comprehensive Clinicopathologic and Molecular Study of 19 Primary Effusion Lymphomas in HIV-infected Patients. Am J Surg Pathol 2022; 46:353.
  89. Lurain K, Ramaswami R, Mangusan R, et al. Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin's lymphoma. J Immunother Cancer 2021; 9.
Topic 4752 Version 30.0

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