Primary Cardiac Lymphoma

Primary cardiac lymphoma is an extranodal lymphoma that involves only the heart or pericardium at presentation, or that is dominated by cardiac masses. It is rare but treatable, and prompt chemotherapy can produce long remissions.

It accounts for about 1% of primary cardiac tumours and under 0.5% of extranodal lymphomas. It occurs mostly in people aged 60 to 70, with men affected more than women, and in younger immunosuppressed patients (HIV infection, organ transplant recipients, in whom EBV is often present).

Diffuse large B-cell lymphoma accounts for 80 to 90% of cases. Others are Burkitt, T-cell, follicular and primary effusion lymphoma. The right atrium, right ventricle and pericardium are the commonest sites, and the masses are often multiple.

Without treatment survival is weeks to months. With anthracycline based chemotherapy, remission rates are high, and median survival of 2 to 4 years or more is reported in case series, with long term survival in a good share of patients.

Pathophysiology.

Malignant lymphocytes infiltrate the myocardium and pericardium, forming bulky infiltrating masses that thicken the walls and may protrude into chambers. They invade the conduction system, causing atrioventricular block, bradycardia and atrial arrhythmia, and the pericardium, causing effusion and tamponade.

Infiltration and the mass effect cause right heart failure, caval obstruction and valve obstruction. Chemotherapy can cause rapid tumour necrosis, with a risk of wall rupture, tamponade, arrhythmia and tumour lysis syndrome, particularly in bulky disease.

In immunosuppressed patients, EBV-driven proliferation and loss of immune surveillance contribute, and the disease may respond to reduction of immunosuppression.

Dyspnoea, chest pain, fatigue, oedema, palpitations, syncope and heart failure. Arrhythmia, particularly heart block, and pericardial effusion with tamponade are common. Superior vena cava syndrome, pulmonary or systemic emboli and constitutional symptoms (fever, night sweats, weight loss) occur. Presentation is usually subacute, over weeks. Lymphadenopathy and hepatosplenomegaly are absent by definition at the onset in primary disease, but should be sought.

• ECG: atrioventricular block (first degree to complete), bundle branch block, atrial arrhythmia, low voltage with effusion.
• Echocardiography: right sided masses (often right atrium and ventricle), wall thickening, pericardial effusion, tamponade physiology.
• Cardiac MRI: infiltrative mass, isointense to hypointense on T1 and hyperintense on T2, with heterogeneous enhancement. CT of chest, abdomen and pelvis for staging. PET-CT shows intense FDG uptake and identifies other sites and a biopsy target.
• Tissue diagnosis is essential: percutaneous or transvenous biopsy, or surgical biopsy by thoracoscopy or sternotomy. Pericardial fluid cytology with flow cytometry is positive in a majority of cases with effusion, and spares biopsy when positive. Immunohistochemistry: CD20, CD79a, CD10, BCL6, MUM1, Ki-67, and EBER for EBV. Fluorescence in situ hybridisation for MYC, BCL2 and BCL6 rearrangements.
• Staging and baseline: bone marrow biopsy, lumbar puncture when CNS risk is high, LDH, urate, creatinine, liver tests, full blood count, HIV test, and hepatitis B (HBsAg and anti-HBc) and hepatitis C serology before rituximab.
• Cardiac baseline before anthracycline: echocardiography for ejection fraction, ECG, troponin and NT-proBNP.

Differential diagnosis.

• Cardiac angiosarcoma and other primary or metastatic cardiac sarcoma.
• Myxoma, thrombus and vegetation.
• Secondary cardiac involvement by systemic lymphoma, and mesothelioma.
• Amyloidosis, sarcoidosis and infiltrative cardiomyopathy.

Start treatment urgently once the diagnosis is made (often within days), in a unit with cardiology and intensive care support. Do not delay for complete staging in a deteriorating patient.

Emergencies and supportive measures before and during chemotherapy.

• Tamponade: echocardiography directed pericardiocentesis with pigtail catheter, and send fluid for cytology and flow cytometry.
• Heart block: temporary transvenous pacing for symptomatic or high grade block, and later permanent pacing if it persists after remission.
• Heart failure and caval obstruction: furosemide 20 to 80 mg intravenously or orally with careful volume control, and early chemotherapy as definitive relief. Low dose steroid pre-phase: prednisolone 100 mg orally daily (or equivalent) for 5 to 7 days before the first cycle in bulky or unstable disease, under haematology direction, to reduce tumour bulk gradually.
• Tumour lysis prevention: hydration (crystalloid 2 to 3 litres daily if tolerated), allopurinol 300 mg orally once daily starting 1 to 2 days before treatment (100 mg daily when eGFR is under 30 mL/min/1.73 m2), or rasburicase 0.2 mg/kg intravenously once daily for up to 5 days in high risk disease (contraindicated in G6PD deficiency; check G6PD before use). Check potassium, phosphate, calcium, urate and creatinine every 6 to 12 hours for the first 48 to 72 hours.
• Hepatitis B: entecavir 0.5 mg orally once daily (reduce at eGFR under 50 mL/min/1.73 m2) for HBsAg-positive patients and for anti-HBc-positive patients receiving rituximab, started before treatment and continued for at least 12 months afterwards.
• Cardiac monitoring in an intensive care or cardiac care setting for the first cycle, since rapid tumour necrosis can cause wall rupture, tamponade or arrhythmia.

First line chemotherapy: R-CHOP every 21 days for 6 cycles.

• Rituximab 375 mg/m2 intravenously on day 1 (first infusion started at 50 mg/h and increased by 50 mg/h every 30 minutes to a maximum of 400 mg/h, with premedication of paracetamol 1 g, chlorphenamine 10 mg and hydrocortisone 100 mg).
• Cyclophosphamide 750 mg/m2 intravenously on day 1.
• Doxorubicin 50 mg/m2 intravenously on day 1 (cumulative ceiling 450 to 550 mg/m2; echocardiography before each cycle; stop or substitute for a fall in ejection fraction to under 50% or a fall of 10 percentage points or more). Use dexrazoxane at 10 times the doxorubicin dose for patients with reduced ejection fraction or high cardiac risk, or liposomal doxorubicin as a substitute.
• Vincristine 1.4 mg/m2 intravenously on day 1 (maximum 2 mg).
• Prednisolone 100 mg orally daily on days 1 to 5.
• Antiemetics (5-HT3 antagonist and dexamethasone), pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy when febrile neutropenia risk is 20% or more, and co-trimoxazole 960 mg orally three times each week for pneumocystis prophylaxis in high risk patients.
• Monitor full blood count before each cycle (proceed with neutrophils 1.0 x 10^9/L or more and platelets 75 x 10^9/L or more), creatinine, liver tests, neuropathy and constipation (vincristine), and haemorrhagic cystitis.

HIV-associated or Burkitt type disease. Dose adjusted EPOCH-R (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) with antiretroviral therapy, chosen for drug interactions, under haematology and HIV specialist direction.

CNS prophylaxis. For high CNS risk (cardiac involvement with other high risk features such as multiple extranodal sites or elevated LDH), consider high dose methotrexate 3 to 3.5 g/m2 intravenously with leucovorin rescue and urinary alkalinisation, by specialist decision (not if eGFR is under 60 mL/min/1.73 m2 or with ascites or large effusion), or intrathecal methotrexate 12 mg.

Radiotherapy and surgery. Consolidation radiotherapy for residual disease after chemotherapy, with careful cardiac dose limits. Surgery is limited to biopsy and relief of obstruction and is not curative.

Relapsed or refractory disease. Salvage chemotherapy (R-ICE or R-DHAP) followed by autologous stem cell transplantation in fit patients, with CAR T-cell therapy or other novel agents in specialist centres.

Response assessment. PET-CT after 3 to 4 cycles and at the end of treatment.

Monitoring. Echocardiography and ECG before each cycle and at the end of treatment, then at 3, 6 and 12 months and annually (anthracycline cardiotoxicity). Full blood count, creatinine, potassium, phosphate, calcium and urate every 6 to 12 hours for the first 48 to 72 hours of each cycle, then before each cycle. Imaging for relapse every 3 to 6 months for 2 years.

Referral and escalation. Refer urgently the same day to a haematology and cardiac centre. Emergency escalation for tamponade, heart block, caval obstruction, shock or tumour lysis (potassium over 6.0 mmol/L or rising creatinine).

Special groups.

• Pregnancy: avoid chemotherapy in the first trimester; rituximab crosses the placenta; plan treatment with haematology and obstetrics, possibly with early delivery.
• Immunosuppressed patients: reduce immunosuppression where possible (transplant recipients), and treat HIV with antiretroviral therapy.
• Older adults: use R-miniCHOP with dose reduced doxorubicin (25 mg/m2), cyclophosphamide 400 mg/m2 and vincristine 1 mg, with rituximab 375 mg/m2 and prednisolone 40 mg/m2 for 5 days, every 21 days for 6 cycles, in frail patients.
• Kidney or liver impairment: adjust cyclophosphamide, doxorubicin, vincristine and methotrexate with haematology pharmacy support.
• Region specific: HIV-associated and EBV-driven lymphomas are more frequent where HIV is prevalent, so test every patient for HIV.