Primary Effusion Lymphoma

Primary effusion lymphoma is a rare large B-cell lymphoma caused by human herpesvirus 8 (HHV-8, Kaposi sarcoma herpesvirus) that presents as lymphomatous effusions in serous cavities (pleural, pericardial, peritoneal) without a tumour mass. It occurs mainly in people with HIV and other immunodeficiency, has an aggressive course, and responds poorly to conventional dose lymphoma regimens, so treatment combines antiretroviral therapy with intensive chemotherapy.

It accounts for under 1% of HIV-associated lymphomas and under 0.1% of all lymphomas. Median age at diagnosis is 40 to 50 in HIV, with male predominance. Cases in older adults with no HIV (HHV-8-positive, often from endemic Mediterranean regions or after transplantation) are described, and a minority with hepatitis C or cirrhosis (HHV-8-negative variants).

Most patients are co-infected with Epstein-Barr virus (60% to 90%). Associated conditions are Kaposi sarcoma and multicentric Castleman disease (in 30% to 60%).

Pathophysiology. HHV-8 infects B cells at a post-germinal-centre stage and drives proliferation through viral cyclin, FLIP and interleukin-6 homologues, with NF-kB activation. The cells lack B-cell markers (CD19, CD20, CD79a), and carry clonal immunoglobulin gene rearrangements.

Prognosis. Median survival is 6 to 14 months, with 1-year survival of about 30% to 40%, and 5-year survival of 20% to 40% in better responding patients treated with intensive regimens. Poor prognostic factors are poor performance status, multiple effusions, and absence of antiretroviral therapy.

• Dyspnoea and chest discomfort (pleural effusion), abdominal distension (ascites), or tamponade features (pericardial effusion).
• B symptoms (fever, weight loss, night sweats) in about half.
• Little or no lymphadenopathy or organ mass (extracavitary variant has solid masses).
• Features of HIV, Kaposi sarcoma or Castleman disease.

Red flags.

• Cardiac tamponade (hypotension, raised jugular venous pressure, pulsus paradoxus).
• Respiratory failure from a large effusion, or tumour lysis.

• Effusion fluid cytology with cell block: large pleomorphic immunoblastic or anaplastic cells. Flow cytometry and immunohistochemistry: CD45 positive, CD30, CD138, MUM1, EMA, HHV-8 LANA-1 positive; CD19, CD20, CD79a and surface immunoglobulin usually negative; EBER in situ hybridisation positive in most.
• HIV testing with CD4 count and viral load; HHV-8 viral load; hepatitis B and C serology.
• Immunoglobulin heavy chain gene rearrangement studies (clonality).
• CT or PET-CT to exclude solid lymphoma, and echocardiography for pericardial effusion.
• FBC, creatinine, LDH, urate and electrolytes (tumour lysis risk), and marrow biopsy if staging is needed.

Differential diagnosis.

• Malignant effusion from carcinoma or mesothelioma, and plasmablastic lymphoma
• Pyothorax associated lymphoma and effusions in cardiac or liver disease
• Large B-cell lymphoma with effusion, Kaposi sarcoma with effusion
• Tuberculous or infective effusion

Management involves haematology, HIV medicine, and, for effusions, cardiothoracic or interventional teams.

Antiretroviral therapy (start or optimise at once, with chemotherapy).

• Dolutegravir based regimen: dolutegravir 50 mg orally once daily with tenofovir alafenamide 25 mg and emtricitabine 200 mg once daily (dolutegravir 50 mg twice daily with rifampicin); maximum dolutegravir 100 mg daily; monitoring: HIV viral load at 4 weeks, 3 months and then every 3 to 6 months, CD4 count, creatinine and phosphate, weight, hepatitis B status (tenofovir and emtricitabine also treat hepatitis B); adjustment: avoid tenofovir alafenamide with emtricitabine when creatinine clearance is under 30 mL/min, separate dolutegravir from antacids, iron and calcium by 2 hours before or 6 hours after, prefer integrase inhibitors to boosted protease inhibitors and efavirenz to limit interactions with etoposide, doxorubicin and vincristine

Chemotherapy (curative intent combination).

• Dose adjusted etoposide, vincristine, cyclophosphamide, doxorubicin and prednisolone (rituximab is not used because the cells lack CD20): etoposide 50 mg/m2, doxorubicin 10 mg/m2 and vincristine 0.4 mg/m2 (no dose cap) each given daily as a continuous infusion over 96 hours on days 1 to 4, cyclophosphamide 750 mg/m2 IV on day 5 and prednisolone 60 mg/m2 orally daily on days 1 to 5, every 21 days for 6 cycles, with pegfilgrastim 6 mg subcutaneously 24 hours after the end of the infusion; maximum cyclophosphamide 1200 mg/m2 after escalation and cumulative doxorubicin 450 mg/m2; monitoring: FBC twice weekly (the nadir neutrophil and platelet counts decide the next dose), echocardiography at baseline, creatinine, liver tests, urate, neuropathy; adjustment: escalate etoposide, doxorubicin and cyclophosphamide by 20% when the nadir neutrophil count stays over 0.5 x 10^9/L, reduce by 20% when it falls under 0.5 x 10^9/L on 1 or more measurements or platelets fall under 25 x 10^9/L, reduce for bilirubin over 26 micromol/L, use central venous access
• Opportunistic infection prophylaxis during chemotherapy: co-trimoxazole 480 mg orally once daily (or 960 mg orally three times weekly), continued while prednisolone 20 mg daily or more is used for over 4 weeks, during immunosuppressive chemotherapy and until the lymphocyte count has recovered; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use atovaquone 1500 mg orally once daily with food or inhaled pentamidine 300 mg every 4 weeks, avoid with methotrexate
• Tumour lysis prophylaxis in high tumour burden: rasburicase 0.2 mg/kg IV over 30 minutes once daily for 1 to 5 days, for high risk tumour lysis (high tumour burden, raised LDH or urate); maximum 7 days of treatment; monitoring: G6PD status before the first dose, urate (samples on ice), potassium, phosphate, calcium, creatinine, haemolysis, methaemoglobinaemia; adjustment: contraindicated in G6PD deficiency (use allopurinol 300 mg orally daily with hydration), hydrate with 3 L/m2 each day, no renal adjustment, stop when urate is controlled and risk has fallen

Effusion management. Therapeutic drainage (pericardiocentesis or pericardial window for tamponade, thoracentesis or indwelling pleural catheter, paracentesis) with chemotherapy. Chemical pleurodesis if recurrent.

Relapsed or refractory disease. Salvage chemotherapy at a specialist centre, lenalidomide, bortezomib based therapy, brentuximab vedotin for CD30-positive disease, and autologous stem cell transplant for fit responders (individualised).

Monitoring. FBC, creatinine, LDH and electrolytes during chemotherapy, repeat imaging and effusion assessment after 2 to 3 cycles, and HIV viral load. CD4 count and HHV-8 viral load during follow up.

Referral and escalation.

• Urgent referral to haematology and HIV services on cytological suspicion.
• Emergency drainage for tamponade or respiratory compromise.

Special groups.

• HHV-8-positive older adults without HIV: reduced intensity regimens and supportive care.
• Transplant recipients: reduce immunosuppression and discuss with the transplant team.
• Pregnancy: antiretroviral therapy continues, with individualised chemotherapy planning.