A previously well 55-year-old man was referred to the cardiology service with a three-month history of vague chest tightness and progressive exertional dyspnea. He was in New York Heart Association (NYHA) functional class III on presentation. However, this was not associated with orthopnea, paroxysmal nocturnal dyspnea, or lower-limb swelling. He underwent an exercise stress electrocardiogram test six weeks prior to presentation, which was normal up to stage 4 of the Bruce protocol. He had no significant past medical illness. Two months prior to his presentation, he was being investigated for pyrexia of unknown origin. It was later attributed to glandular fever with presence of positive anti-Epstein-Barr virus (EBV) Ea-IgM.
Physical examination in the clinic revealed an anxious man with blood pressure of 110/70mmHg with no pulsus paradoxus and a heart rate of 120bpm. The jugular veins were not distended. Cardiovascular examination showed normal heart sound, which was not muffled and without friction rub. Systemic examination was otherwise unremarkable and there was no peripheral lymphadenopathy or hepatosplenomegaly. The resting 12-lead electrocardiogram showed small voltages of the QRS complexes without electrical alternans. Chest X-ray revealed a significantly enlarged cardiac silhouette with a globular appearance. Transthoracic echocardiogram showed a large circumferential pericardial effusion with marked respiratory variation in tricuspid and mitral inflow, as well as a hepatic venous Doppler signal consistent with cardiac tamponade. There was also late diastolic collapse of the right atrium, and the inferior vena cava was plethoric. In addition, there was a large mass in the superior part of the right atrium involving the atrial septum and the roof of the left atrium (see Figure 1).
The patient was promptly admitted into the intensive care unit for ultrasound-guided pericardiocentesis, which yielded 600ml of hemorrhagic fluid. Fluid analysis showed a nucleated cell count of 12,370/μl, of which 43% were lymphocytes. Fluid biochemistry showed a glucose level of <1.1mmol/l, specific gravity of 1.034, and an exudative picture with protein 57g/l and lactate dehydrogenase (LDH) >11,000U/l. However, cytology of the pericardial fluid was negative for malignant cells. No acid-fast bacillus was detected on smear or on culture. The erythrocyte sedimentation rate, β2 microglobulin, and lactate dehydrogenase were all elevated. Complete blood counts were normal. Tumor markers including α-fetal protein, chorioembryonic antigen, β-human chorionic globulin, and CA-125 were within normal limits. HIV antibody was negative.
A subsequent computed tomography (CT) scan of the thorax, abdomen, and pelvis demonstrated a large infiltrative cardiac tumor involving mainly the right atrium (see Figure 2A) with mediastinal (see Figure 2B) and upper abdominal lymphadenopathy, as well as bilateral moderate-size pleural effusions. Cardiovascular magnetic resonance (CMR) imaging revealed a large tumor mass encompassing the atrial septum and both atria with right hilar and extensive mediastinal lymphadenopathy (see Figure 3A). The mass surrounded the right pulmonary vein and right pulmonary artery, but did not obliterate these vessels. Following gadolinium administration, there was heterogeneous uptake of gadolinium within the tumor mass, giving a variegated appearance (see Figure 3B). Normal biventricular systolic function was noted, with no evidence of ventricular myocardial late gadolinium enhancement.
Mediastinoscopic biopsy of the mediastinal lymph nodes revealed the histology of a diffused large B-cell lymphoma (DLBCL) (see Figure 4). The tumor cells expressed CD79a and CD20 and were non-reactive for CD3, CD30, and AE1/3. The proliferation index Ki67 was approximately 80%. In situ hybridization with an oligonucleotide probe specific for EBV-encoded small RNA was negative in the lymphoma cell. Bilateral bone marrow trephine biopsy showed no lymphomatous infiltrate. Chemotherapy using rituximab, cyclophosphomide, doxorubicin, vincristine, and prednisolone (R-CHOP) was commenced promptly. A follow-up CT scan of the thorax and abdomen after one month of chemotherapy showed regression of the right atrial mass and mediastinal lymphadenopathy and resolution of the abdominal lymphadenopathy. A repeat transthoracic echocardiogram after the third cycle of R-CHOP showed complete resolution of the cardiac mass and pericardial effusion.
Discussion
Primary cardiac lymphoma (PCL) in an immunocompetent patient is rare. It occurs more frequently in immunocompromised persons.1 The incidence of primary cardiac tumors is approximately 0.02% in autopsy series. PCL accounts for fewer than 2% of cardiac tumors.2 PCL is initially defined as an extranodal lymphoma involving only the heart and/or pericardium.2 Lymphoma with the bulk of the tumors originating in the heart with minimal extracardiac or locoregional infiltration is considered as PCL with early dissemination.3 Our case was compatible with this broader definition of PCL. The median age at presentation of PCL in immunocompetent patients is 64 years, with a male-to-female ratio of 3:1.3
The clinical manifestations of PCL are often non-specific. Patients may present with symptoms that mimic other cardiac diseases, including dyspnea, edema, heart failure, precordial pain, constitutional symptoms, arrhythmias, cardiac tamponade, and superior vena cava obstruction syndrome.1–3 Our patient initially presented with vague chest pain and dyspnea, which led to the evaluation for ischemic heart disease with exercise stress testing by the unsuspecting physician. Interestingly, this patient was also being evaluated for pyrexia of unknown origin, which was later attributed to EBV glandular fever. However, an EBV nucleic acid sequence was not found in the malignant cells by in situ hybridization in this case. By using immunostaining for EBV and EBV-encoded RNA-1 in situ hybridization in two autopsied cases of PCL in immunocompetent patients, Ito et al. demonstrated no association of PCL with EBV infection.4
Due to its non-specific presentation, as well as its rarity, it is a challenge to consider this cardiac tumor as a differential diagnosis. A high index of suspicion is usually needed to make a diagnosis, especially in an immunocompetent patient. The presence of the tumor mass can be detected by transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), CT, CMR, nuclear medicine techniques, or positron emission tomography.5 TTE remains a valuable non-invasive tool for initial evaluation. It is widely available, and convenient due to its portability. In our patient, TTE was the initial investigation, and identified the presence of the intracardiac tumor mass and pericardial effusion. The right atrium is most commonly involved in PCL.1 TEE is superior to TTE in detecting intracardiac masses and has a sensitivity of more than 90%.3 CT findings for PCL often showed poorly enhanced mass, as occurred in our case.6 CT is a better imaging modality for tumor staging in the lung parenchyma compared with echocardiogram and CMR. On the other hand, CMR is superior in defining the extent of intracardiac and paracardiac involvement, as well as the characterization of the tumor tissue. The appearance of the tumor on CMR is variable. Compared with the myocardial signal intensity, PCL mass may be iso-intense or hypo-intense on T1-weighted images and iso-intense or mildly hyper-intense on T2-weighted images. Post-contrast enhancement may be homogeneous or heterogeneous.6,7
In our patient, the tumor mass was iso-intense on T1-weighted spin echo images and hyper-intense on T2-weighted images, and showed heterogeneous enhancement in post-gadolinium contrast imaging. Positron emission tomography is useful in evaluating the metabolic activity of the lymphoma.5 Nuclear medicine techniques have also been reported to be helpful as an additional assessment tool, but the findings are not specific.3
The diagnosis of cardiac lymphoma can be confirmed by either cytological or histological means. The cytology of pericardial fluid in our patient was negative. In PCL patients with pericardial effusion, only 67% of the cytology was diagnostic.3 In our patient, the diagnosis of PCL was obtained by biopsy of the lymph nodes using mediastinoscopy. DLBCL is the most common histological subtype of PCL, which has been found in 80% of cases involving immunocompetent patients.1,6
Chemotherapy is the main treatment strategy in PCL. Complete remission was reported in 38% in a literature review of 40 cases.1 However, the overall prognosis remains poor.
Conclusions
PCL is a truly rare tumor that may present with non-specific symptoms and signs. However, it is a highly chemo-sensitive tumor, and early diagnosis coupled with appropriate chemotherapy can result in remission. Non-invasive multimodality imaging techniques including CT, CMR, and echocardiography are indispensable for diagnosis and for the overall management of the patient with PCL.