Primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma

Abstract

Cardiac and pericardial involvement by malignant lymphoma is a rare condition. The present case report describes a case of primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma in the pericardium, and highlights the importance of a prompt diagnosis and aggressive pharmacologic treatment of this disease. In a symptomatic patient, a minimally invasive 3 cm sub-xiphoidal incision was performed under deep sedation with spontaneous ventilation to perform a pericardial biopsy. A 5 cm × 3 cm portion of pericardium was removed from above the right ventricle, thus ameliorating the extrinsic compression on the right chambers. The patient received 6 cycles of immuno-chemotherapy (rituximab plus cyclophosphamide, vincristine, and methylprednisolone), with no complications, achieving complete remission with no symptoms. Malignancies must be excluded in every case of acute pericardial disease with imaging techniques, and lymphomas should be always considered in the differential diagnosis of cardiac tumors. Complete surgical removal of the tumor is not necessary to achieve complete remission, and minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow a precise histologic characterization.

<Learning objective: Primary MYC/BCL6 double hit non-Hodgkin lymphoma is a rare tumor of the pericardium, which requires prompt diagnosis and treatment. Minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow a precise histologic characterization. Pericardial tumors should always be considered in the differential diagnosis of acute pericardial disease presenting with pericardial effusion. Double hit diffuse large B cell-lymphoma has a poor prognosis with standard chemotherapy and the treatment should be tailored according to the patient’s comorbidities and performance status.>

Introduction

Cardiac and pericardial involvement by malignant lymphoma is a rare condition, representing approximately 1% of cardiac tumors and 0.5% of extra-nodal non-Hodgkin lymphoma, with diffuse large B cell lymphoma being the most common type [1]. Early symptoms are cardiac failure, syncope, arrhythmia, and pericardial effusion [2], but diagnosis is suspected with cardiac imaging and confirmed histologically. In addition to having a difficult diagnosis, prognosis is poor since patients usually die within a few months after diagnosis due to systemic involvement [3]. The present case report describes a case of primary cardiac MYC/BCL6 double hit non-Hodgkin lymphoma in the pericardium, and highlights the importance of a prompt diagnosis and aggressive pharmacologic treatment of this disease.

Case report

An 80-year-old man with a 3-month history of dyspnea was hospitalized because of chest pain and dyspnea with mild effort (New York Heart Association class III). Blood tests were unremarkable except for high levels of lactate dehydrogenase (1608 U/L) and C-reactive protein (193 mg/L). Electrocardiogram showed atrial fibrillation with high ventricular response, incomplete left bundle branch block, and Q wave alterations. Physical examination showed irregular pulse with distant heart sounds. Echocardiography demonstrated a 12-mm pericardial effusion with slight compression on right chambers, with slightly reduced ejection fraction (45%). Previous medical history was unremarkable, except for well-controlled mild hypertension and smoking habit. Hemoglobin was 12.1 g/dL with no abnormalities in white blood cells count and platelet count. Subcutaneous enoxaparin (100 UI/kg b.i.d.) was started and 5 mg metoprolol were administered to slow ventricular response. Considering the clinical presentation and instrumental findings, the patient was referred for a computed tomography (CT) scan of the heart with angiographic reconstructions.

Heart CT scan showed no signs of coronary heart disease. However, pericardium was thickened with minimal infiltration of right atrium and greater infiltration of the right ventricle from the right atrioventricular region until the ascending aorta (10 cm × 4 cm × 12 cm), and determining compression of the right ventricle. With a primary diagnosis of pericardial tumor, a whole-body CT scan was performed and no other site of disease was found. Magnetic resonance imaging (MRI) of the heart confirmed a huge soft tissue mass (12 cm × 4.4 cm × 1.2 cm) infiltrating the myocardium in the right chambers. The mass was extending around the anterior surface of the ascending aorta (Fig. 1). The exact histological diagnosis was considered mandatory and therefore an open biopsy was planned.

Fig. 1.

Magnetic resonance imaging of the pericardial lymphoma.

(A) T2-weighted 4 chambers image demonstrates right atrio-ventricular pericardial thickening (arrow). (B) Steady state short-axis image confirms thickening of the right pericardium extending from the level of the pulmonary artery to the diaphragmatic surface of the right ventricle. (C, D) T1-weighted short-axis images delineate the extension of the pericardial mass to the right ventricular myocardium. Panel C is more apical than Panel D. (E, F) Post-contrast T1-weighted short-axis images show homogeneous enhancement of both pericardial layers and right ventricular wall. Panel E is more apical than Panel F. (G, H) T1-weighted (G) and T2-weighted (H) sagittal plane images show the compression on the right ventricle. Panel G is more apical than Panel H. (I, J) coronary plane images indicating the anatomical relationships between the tumor and the great vessels. Panel J is more external than Panel I.

RV, right ventricle; LV, left ventricle; PA, pulmonary artery.

A 3 cm sub-xiphoidal incision was performed under deep sedation with spontaneous ventilation to perform a pericardial biopsy. After accurate lysis of adherences, a 5 cm × 3 cm portion of pericardium was removed from above the right ventricle, thus ameliorating the extrinsic compression on the chamber. Overall duration of the surgical procedure was about 15 min, with no complications. After surgery, a chest tube was placed in the pericardium and was removed two days after procedure. Postoperative course was uneventful, and the patient was discharged on the 3rd postoperative day in good clinical condition, asymptomatic, with no transfusional requirements.

Histological examination demonstrated the presence of fibro-adipose tissue infiltrated by a population of loosely attached cells with big nuclei, prominent nucleoli, and numerous mitoses (Fig. 2A). Immunohistochemistry showed in these cells expression of CD20 (Fig. 2B), CD79a (Fig. 2C), Ki67 expression was 95% (Fig. 2D); MUM1 (Fig. 1E) and Bcl-6 (Fig. 2F) were also expressed. Moreover, CD5 and Bcl-2 were also positive, while CD10, CD3, CD30, CD138, and HHV-8 were negative. The result of Epstein–Barr encoding region in situ hybridization analysis was negative. Fluorescent in situ hybridization analysis revealed MYC and BCL6 gene rearrangement (Fig. 2G), and no rearrangement for BCL-2.

Fig. 2.

Histological features of the pericardial lymphoma.

(A) Hematoxylin and eosin staining (400×) of pericardial fat tissue infiltration of polymorphic lymphoid cells with large nuclei containing one or more nucleoli and numerous mitoses. (B) Immunohistochemical assay for B-cell markers CD20. (C) Immunohistochemical assay for B-cell markers CD79a. (D) Ki67 expression. (E) MUM-1 expression. (F) Bcl-6 expression. (G) Fluorescence interphase in situ hybridization analysis shows C-MYC and BCL6 genes rearrangements (one non-rearranged red/green fusion probe, one red, and one separate green probe indicating the translocation with Dual Color Break Apart Probe).

The case was diagnosed as having diffuse large B cell non-Hodgkin lymphoma, NOS [4], activated B cell (ABC) type according to Hans’ classification, MYC/BCL6 double hit [5]. The patient received 6 cycles of immuno-chemotherapy (rituximab plus cyclophosphamide, vincristine, and methylprednisolone), with no complications, obtaining a complete remission diagnosed by CT scan and an improvement in ejection fraction (60%). After 8 months, the patient had a sudden loss of consciousness and cerebral CT scan revealed a devastating central nervous system relapse, with cerebral edema and median shift; after palliative treatments, the patient died after a few days.

Discussion

Pharmacologic treatment of primary cardiac lymphomas results in a complete remission in more than 60% of patients, while surgical eradication of the tumor is associated with poorer prognosis [6], [7]. However, early surgery should be considered if the tumor impairs hemodynamics, as described in this case. A sub-xiphoidal approach can be easily performed without general anesthesia and allows the removal of an adequate portion of the pericardium, in order to confirm the diagnosis and decrease the extrinsic compression of the right ventricle. If the tumor is localized in the right ventricular outflow tract with partial or complete occlusion, the prognosis is worse [8]. As stated by the literature, in most cases surgery is not the definitive treatment, and the main goal of the surgical procedure is to give time for immuno-chemotherapy to have its therapeutic effect and allow an exact characterization of the tumor [9].

However, double hit diffuse large B cell-lymphoma has a poor prognosis with standard chemotherapy and the treatment should be tailored according to the patient’s comorbidities.

Considering the central nervous system relapse observed in our patient, the role of intrathecal methotrexate prophylaxis should be considered even in older patients with good performance status.

Considering cardiac non-Hodgkin lymphoma, diffuse large B-cell lymphoma is the most common histologic subtype (58%), followed by T-cell lymphoma (16%), Burkitt’s lymphoma (9%), and small lymphocytic lymphoma (6%) [10]. Symptomatic heart failure is the most common clinical presentation, as in our case report, but some patients may experience no cardiac symptoms. In our case, the patient’s symptoms can be related to multiple conditions, since both atrial fibrillation with high ventricular response and the compression on right chambers by the tumor played a significant role. However, after surgery the patient was asymptomatic at discharge, while he was still experiencing atrial fibrillation; therefore, the effect of the tumor on clinical presentation seems greater compared to the effect of the arrhythmia.

Overall survival is generally poor, with a median survival of about 3 months, but immuno-chemotherapy strongly enhances survival (hazard ratio for overall mortality: 0.16, p < 0.001). This might pose relevant questions if patients with primary cardiac tumor may be incidentally diagnosed with other cardiac problems, such as coronary artery disease (CAD). Considering the cardiotoxic effect of many chemotherapeutic compounds, which might worsen an underlying ischemic condition, percutaneous or surgical treatment of CAD should be carefully evaluated with a patient-based approach.

Many of the symptoms of cardiac lymphoma are non-specific, and cardiac manifestations such as chest pain, arrhythmia, and heart failure may be explained by underlying conditions. In case of echocardiographic evidence of pericardial disease with atrial or ventricular compression, however, lymphomatous involvement should be suspected, and other imaging techniques, such as CT scan, can be performed to rule-out primary pericardial diseases. Also, considering the low risk associated with biopsy, in case of inconclusive results at the CT scan or MRI, the case can be discussed with the cardiac surgeon to plan an open biopsy.

Conclusion

Malignancies must be excluded in every case of acute pericardial disease with imaging techniques, and non-Hodgkin lymphoma should be always considered in the differential diagnosis of cardiac tumors. Complete surgical removal of the tumor is not necessary to achieve complete remission, and minimally invasive surgical approaches are an effective tool to confirm diagnosis and allow histologic characterization.

Conflict of interest

None.

Funding support

None.