Primary cardiac lymphoma: The unusual suspect and the importance of a multimodality approach

Abstract

Primary cardiac lymphomas are rare tumors with heterogeneous presentation, often difficult to diagnose, requiring a high level of clinical suspicion. An attempted diagnosis is fundamental for effective treatment. We report a very rare case of a primary cardiac lymphoma in a middle-age female patient that presented with atrial flutter, atrioventricular conduction disorder, and a secondary autoimmune hemolytic anemia with cold agglutinin syndrome. The investigation was challenging and a definite diagnosis was achieved by histopathological study and corroborated by regression after chemotherapy.

Learning objectives

Primary cardiac tumors are rare, often difficult to diagnose, and a multimodality imaging approach is essential for diagnosis. Although complete atrioventricular (AV) block is often an indication for permanent pacemaker, reversible causes should be considered. AV blocks caused by infiltration of lymphoma can resolve after effective treatment and so it may be reasonable to delay pacemaker implantation until after treatment. A multidisciplinary approach is fundamental in complex cases.

Introduction

Primary cardiac tumors are extremely rare entities, with incidence ranging from 0.001 % to 0.03 % and among these primary cardiac lymphoma (PCL) accounts for only 1.3 % [1]. They are typically non-Hodgkin lymphoma with diffuse large B-cell lymphoma (DLBCL) being the most frequent, and are often associated with immunodeficiency states and very rarely affect immunocompetent patients [2]. They can occur as intracardiac or pericardiac masses or more rarely, infiltrate the myocardium. Clinical presentation is heterogeneous, often with non-specific symptoms, which contributes to late diagnosis and often comprises heart failure, pericardial effusion, and more rarely atrioventricular (AV) conduction disorders [3]. Other systemic manifestations as autoimmune hemolytic anemia (AIHA) are rarely described. According to autoantibodies cold type AIHA is the rarest form and cold agglutinin syndrome (CAS) secondary to DLBCL has been reported [4]. Clinical awareness and suspicion is crucial and a multimodal imaging approach is often necessary for a complete and precise diagnosis.

Case report

We report the case of a middle-age female patient that presented with dyspnea, cough and fatigue for one week. An electrocardiogram (ECG) confirmed atrial flutter (AFL) with variable AV conduction and slow ventricular rate alternating with second degree Mobitz I and small periods of complete AV block (Fig. 1). A pacemaker DDDR was implanted and one day later the patient was discharged with anticoagulation.

Fig. 1.

Electrocardiogram (ECG). (A) 12‑lead ECG at presentation with atrial flutter with variable atrioventricular conduction and slow ventricular rate; (B) 12‑lead ECG at presentation with second degree Mobitz type I atrioventricular block; (C) rhythm strip with complete atrioventricular block; (D) 12‑lead ECG after treatment: sinus rhythm.

One week later the patient was readmitted with similar complaints. On examination the patient was afebrile, heart rate 56 bpm, blood pressure 110/67 mmHg, SpO2 98 % in room air. Cardiac auscultation was rhythmic without murmurs and pulmonary auscultation revealed bilateral basal crackles and no lymphadenopathy or peripheral edema was noted.

The patient had history of breast ductal carcinoma 28 years previously that was treated with mastectomy, adjuvant chemotherapy, and hormonal therapy with regular follow-up and no other relevant past medical or family history. She was medicated with apixaban since the previous week.

Laboratory tests revealed aggravated normocytic normochromic anemia [Hb 8.4 g/dL (normal range 13.0–18.0 g/dL), Htc 23.3 % (normal range 40–52 %)], previous values from one week earlier were Hb 10.2 g/dL, Htc 30.9 %), mild leukocytosis [11.090/uL (normal range 3.800–10.600/uL)] and elevated N-terminal brain natriuretic peptide (NT-proBNP) 5001 pg/mL (normal range < 125 pg/mL). ECG revealed AFL with pacemaker ventricular pacing at 70 bpm. Transthoracic echocardiography (TTE) showed normal biventricular function, a small circumferential pericardial effusion (15 mm) without hemodynamic compromise (Video 1). Posteriorly after reviewing the TTE images an increased thickness of the basal portion of the right ventricle and basal portion of the interventricular septum was noted. Chest radiography was normal. Pacemaker interrogation showed periods of AFL and atrial fibrillation (AF) with normal parameters. A diagnosis of congestive heart failure was assumed and she was hospitalized for further investigation and therapy optimization. One day later she had clinical deterioration with lower blood pressure and abdominal diffuse pain. TTE excluded cardiac tamponade. Laboratory results revealed leukocytosis (21.400/uL) and elevated C-reactive protein (11 mg/L, normal range 0–5 mg/L). Considering the hypothesis of a systemic infection, blood cultures were collected and antibiotic was initiated. A thoracoabdominal computed tomography (TACT) showed a pseudonodular mass in the basal right ventricle, extending to the interventricular sulcus and left ventricle, pericardial effusion, and right paratracheal and subcarinal enlarged mediastinal lymph nodes (Fig. 2). Considering the recent pacemaker implantation, the hypothesis of a lead complication was contemplated and the pacemaker was removed. The patient remained in AFL and AF with preserved AV conduction. Later she continued to deteriorate with jaundice and increasing abdominal pain and anemia was worse despite transfusion of two red blood cell units (Hb 6.8 g/dL) with increased lactate dehydrogenase (914 U/L, normal range 135–225 U/L) and bilirubin [total 4.8 mg/dL, (normal range 0.1–1.1 mg/dL), direct 1.5 mg/dL (normal range 0–0.3 mg/dL)]. AIHA was suspected and a direct antiglobulin test was positive for IgM (3+), C3c (4+), and C3d (4+) confirming the diagnosis of a CAS. Treatment with prednisolone (1.0 mg/kg/daily initially and then titrated to 1.5 mg/kg/daily) and rituximab (375 mg/m²) was initiated with clinical improvement.

Fig. 2.

Multimodality imaging. (A) Thoracoabdominal computed tomography showing two pacemaker leads in the right ventricle and right atrium, right paratracheal and subcarinal enlarged mediastinal lymph nodes (yellow arrows), and a moderate circumferential pericardial effusion (13 mm) contiguous to an irregular pseudonodular infiltrative mass in the basal portion of the right ventricle, extending to the interventricular sulcus and left ventricle (red arrows); (B-F) Cardiac magnetic resonance (CMR) imaging. CMR short-axis shows an infiltrative mass in the basal interventricular sulcus (red circle) with conserved peripheral perfusion and mild hypoperfusion in its center. Mild hyperintense on T1-weighted images (B and C, without and with fat suppression) and T2-weighted images (D and E, without and with fat suppression). Short-axis late gadolinium enhancement image shows diffuse heterogeneous late enhancement in the interventricular sulcus with extension to the basal right and left ventricle and interventricular sulcus (purple arrows) (F).

LV, left ventricle; RV, right ventricle; RVOT, right ventricular outflow tract.

Three days after the treatment was initiated, a cardiac magnetic resonance (CMR) confirmed the diagnosis of an infiltration in the basal interventricular sulcus with extension to the basal right and left ventricle with diffuse heterogeneous late enhancement (Fig. 2) and peripheral enhancement with central hypoperfusion (Video 2). Left and right ventricular systolic function were preserved with hypokinesia of the inferior wall of the right ventricle and basal and medial segments of the inferior and inferoseptal walls of the left ventricle.

18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan showed a conglomerate of lymph nodes in the aortopulmonary region [standardized uptake value (SUV)] of 11.4 and in the basal inferior wall of the left ventricle and basal interventricular septum (SUV 8.3) (Fig. 3).

Fig. 3.

18F-fluorodeoxyglucose positron emission tomography-computed tomography scan showing a conglomerate of lymph nodes in the aortopulmonary region [standardized uptake value (SUV)] of 11.4 (A) and in the basal inferior wall of the left ventricle and basal interventricular septum (SUV 8.3) (B).

After discussion in a multidisciplinary team with cardiologists, hematologists, and cardiac surgeons a surgical biopsy through sternotomy was performed. On surgical inspection an infiltrative mass on the interventricular sulcus was identified and five biopsies were obtained. Microscopic analysis revealed fragments with marked lymphoid infiltration composed of large immunoblast-like and centroblastic-like cells. Immunohistochemical findings revealed CD45+, CD20+, BCL2+, BCL6+, MUM1+, CD3-, CD5-, MYC-, AE1/AE3-, S100- and a proliferative index of Ki67 95 %, confirming the diagnosis of a DLBCL non germinal center type.

The patient was transferred to an oncology center and chemotherapy was initiated according to established protocols with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Six cycles of R-CHOP were administrated with complete regression in a CMR (3 months after the initiation of the treatment). Clinically the patient improved with resolution of the dyspnea and is now in New York Heart Association Functional Classification class I and NT-proBNP decreased to 321 pg/mL and remained in AF with preserved AV conduction alternating with sinus rhythm (Fig. 1) and did not require a pacemaker. Seventeen months since the initiation of the treatment the patient is still in remission.

Discussion

Our patient had PCL with a very uncommon presentation with pericardial effusion, slow AFL, and variable AV conduction disorder including periods of complete AV block and AIHA with CAS.

Complete AV block often requires permanent pacing, unless a reversible cause can be identified.

Our patient alternated between AFL with variable AV conduction and slow ventricular rate, second degree Mobitz I, and small periods of complete AV block, most of the time with an adequate ventricular rate (>50 bpm), which may explain why the patient did not have symptoms related to rhythm disturbance. Considering the short time after pacemaker implantation, the pericardial effusion and the elevated inflammatory parameters were assumed to be a complication of its implantation and the pacemaker was removed and antibiotic therapy initiated. Since then the patient remained in slow AF alternating with AFL with close monitoring and did not have symptoms related to rhythm disturbance. When chemotherapy is started early most reports show an improvement or resolution of AV conduction disorder related to PCL, as happened in this case [3], [5], [6], [7]. And so, if the patient is clinically stable, it may be reasonable to prefer a conservative strategy with close monitoring and delay pacemaker implantation.

PCL in immunocompetent patients is rare [5] and in this case the patient had no obvious risk factors for lymphoproliferative disease except for chemotherapy treatment in the past.

Cold type AIHA is the rarest form of AIHA and CAS can be secondary to infections, autoimmune or lymphoproliferative disorders. CAS secondary to DLBCL is rare [4]. In our case AIHA was initially thought to be secondary to a systemic infection, to recurrence of breast cancer or, as it turned out to be, secondary to a lymphoproliferative disorder.

The diagnosis was challenging and clinician awareness was essential. After suspicion of a cardiac mass, diagnostic work-up involved multimodality noninvasive imaging. TTE is widely available and is the first imaging modality used in clinical practice, it is essential for the diagnosis of pericardial effusion and a cardiac mass may be suspected but, as it happened in this case, mass images may be missed or difficult to characterize and so TACT and CMR are the next steps [3], [8]. TACT is useful in visualizing the heart and adjacent structures and allowed the identification of the mass and lymphadenopathies. CMR was essential to assess the characteristics of the mass and its relationship to surrounding structures and plays a role in monitoring treatment response. PET/CT helped to evaluate the nature of the mass and exclude dissemination. Histopathological study is the gold standard and allowed definite diagnosis and the determination of the adequate treatment. Many reports describe a poor prognosis, frequently related to late diagnosis [9], [10]. In this case the prognosis was surprisingly good due to an attempted diagnosis and prompt initiation of treatment.

The following are the supplementary data related to this article.

Video 1

Transthoracic echocardiogram video showing a small concentric pericardial effusion, increased thickness of the basal portion of the right ventricle and basal portion of the interventricular septum.

Video 2

Cardiac magnetic resonance (CMR) perfusion video. CMR short-axis of the infiltrative mass showing peripheral enhancement with central hypoperfusion.

Funding

Self-finance.

Declaration of competing interest

The authors declare that there is no conflict of interest.