Cardiac Malignant Lymphoma with Diffuse Extension to the Left Ventricle

Abstract

Malignant cardiac lymphoma is rare and commonly involves nodules on the right side of the heart. We herein report a case of malignant cardiac lymphoma with diffuse extension into the left ventricle. The patient was a woman in her 60s who complained of dyspnea and malaise. Echocardiography revealed left ventricular hypertrophy (LVH), and magnetic resonance imaging revealed diffuse contrast enhancement on delayed contrast. Cardiac catheterization and a myocardial biopsy suggested heart failure due to cardiac malignant lymphoma, and diastolic dysfunction was mild despite LVH. The patient underwent chemotherapy, and her cardiac function improved and was maintained.

Introduction

Cardiac malignant lymphoma is rare and commonly involves the nodules on the right side of the heart (1,2). We herein report a case of malignant cardiac lymphoma with diffuse extension into the left ventricle.

Case Report

We encountered a woman in her 60s who complained of dyspnea and malaise for the past 6 months. Two days before hospital admission, she complained of anterior chest pain. She then presented to hospital A with hypotension and worsening dyspnea. Owing to hypoxemia, she was referred to our hospital with suspected pulmonary thromboembolism.

Upon arrival, her pulse rate was 87 beats/min, blood pressure was 114/61 mmHg, and SpO₂ was 97% on room air. Electrocardiogram (ECG) findings revealed left-axis deviation and inverted T waves in I, aVL, and V3-6 (Fig. 1A). Chest radiography revealed an increased cardiothoracic ratio and decreased permeability of the bilateral lower lungs (Fig. 2). Contrast-enhanced computed tomography (CECT) showed enlarged celiac lymph nodes, bilateral pleural effusion, and a soft-tissue shadow around the left ureter, but no thrombus in either pulmonary artery (Fig. 3A, B). Furthermore, the blood samples showed mild liver dysfunction and elevated lactate dehydrogenase, brain natriuretic peptide (BNP), and soluble interleukin-2 receptor levels (Table). Echocardiography revealed a global circumferential left ventricular hypertrophy (LVH) and partial myocardial opacification. The intraventricular septal thickness in diastole and posterior wall thickness in diastole were 16 and 20 mm, respectively. The left ventricular ejection fraction (LVEF) was reduced to 54%. The E/A was 1.1, deceleration time (DcT) was 164 ms, and E/e' was 16.9, indicating a mild decline in the diastolic function (Fig. 4A, B). Magnetic resonance imaging (MRI) showed decreased left ventricular wall motion on the cine sequence, high intensity on the T2 sequence, and diffuse contrast enhancement on the delayed contrast (Fig. 5A-C).

Figure 1.

An electrocardiogram on admission (A) and after six courses of Pola-R-CHP (B). Pola-R-CHP: polatuzumab vedotin (pola) plus rituximab, cyclophosphamide, doxorubicin, and prednisolone

Figure 2.

Chest radiograph on admission.

Figure 3.

CECT showed enlarged celiac lymph nodes (A, arrowheads) and a soft-tissue shadow around the left ureter (B, arrow). CECT: contrast-enhanced computed tomography

Table.

Laboratory Data.

WBC	8,510	/μL
RBC	4,310,000	/μL
Hb	12.1	g/dL
Plt	232,000	/μL
AST	66	U/L
ALT	48	U/L
LDH	458	U/L
Na	141	mEq/L
K	3.68	mEq/L
Cl	107.8	mEq/L
BUN	15.0	mg/dL
Cre	0.5	mg/dL
Alb	3.7	g/dL
TP	6.7	g/dL
CRP	0.94	mg/dL
BNP	503.4	pg/mL
IgG	1,110	mg/dL
IgA	242	mg/dL
IgM	196	mg/dL
IgG4	84.3	mg/dL
RF	<3.9	IU/mL
ANA	40	times
Anti-SS-A antibody	<1.0	U/mL
Anti-SS-B antibody	<1.0	U/mL
Anti-RNP antibody	<1.0	U/mL
Anti-Sm antibody	<1.0	U/mL
Anti-dsDNA antibody	<10	IU/mL
Anti-Scl-70 antibody	<1.0	U/mL
Anti-Jo-1 antibody	<1.0	U/mL
APTT	34.2	s
PT-INR	1.02
Fibrinogen	372	mg/dL
D-Dimer	1.8	μg/dL
CEA	1.2	ng/mL
CA19-9	87.2	U/mL
CA125	83.2	U/mL
SCC	0.3	ng/mL
sIL-2R	1,920	U/mL

Alb: albumin, ALT: alanine aminotransferase, ANA: antinuclear antibody, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BNP: brain natriuretic peptide, BUN: blood urea nitrogen, CA125: carbohydrate antigen 125, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, Cl: chloride, Cre: creatinine, CRP: C-reactive protein, dsDNA: double-stranded deoxyribonucleic acid, Hb: hemoglobin, IgA: immunoglobulin A, IgG: immunoglobulin G, IgG4: immunoglobulin G4, IgM: immunoglobulin M, K: potassium, LDH: lactate dehydrogenase, Na: sodium, Plt: platelet, PT-INR: prothrombin time-international normalized ratio, RBC: red blood cell, RF: rheumatoid factor, RNP: ribonucleoprotein, SCC: squamous cell carcinoma antigen, Scl-70: scleroderma-70, sIL-2R: interleuken-2 receptor, Sm: Smith, SS-A: Sjögren syndrome-A, SS-B: Sjögren syndrome-B, TP: total protein, WBC: white blood cell

Figure 4.

Echocardiography on admission. A parasternal long-axis view (A) and parasternal short-axis view at the mid-ventricular level (B) showed the entire circumferential left ventricular hypertrophy and partially blacked out the myocardium (arrowhead). After six courses of Pola-R-CHP, these findings were improved (C, D). Pola-R-CHP: polatuzumab vedotin (pola) plus rituximab, cyclophosphamide, doxorubicin, and prednisolone

Figure 5.

MRI on cine sequencing (A), T2 sequencing (B), and delayed contrast (C) on admission. T2 sequencing showed a slightly high-intensity area, whereas delayed contrast showed a slightly high-intensity area. MRI on cine sequencing (D), T2 sequencing (E), and delayed contrast (F) after six courses of Pola-R-CHP. T2 sequencing showed a reduced degree of high intensity. On delayed contrast, the diffuse contrast effects of the left ventricle were reduced but partially remained in the anterior wall. Pola-R-CHP: polatuzumab vedotin (pola) plus rituximab, cyclophosphamide, doxorubicin, and prednisolone, MRI: magnetic resonance imaging

Based on cardiac catheterization after the initial treatment with diuretics, the pulmonary artery wedge pressure was 8 mmHg, and the cardiac index measured by the Fick method was 1.7 L/min/m². The left and right ventricular end-diastolic pressures were 12 and 3 mmHg, respectively, and no significant coronary artery stenosis was observed. Left ventricularulography showed diffuse reduction in wall motion, with an LVEF of 45%. A myocardial biopsy revealed large atypical lymphocytes infiltrating the endocardium and partial infiltration of the myocardium (CD20+, CD79a+, CD3-, CD5-, and CD10-) (Fig. 6A). A biopsy of the gastric lesion incidentally revealed atypical lymphocytes (CD20+, CD79a+, CD3-, CD5-, CD10-, bcl-6+, and MUM-1+) (Fig. 6B). Therefore, a diagnosis of diffuse large B-cell lymphoma [DLBCL; non-germinal center B-cell (non-GCB)] with the heart, stomach, and abdominal lymph nodes was made [clinical stage IV, high International Prognostic Index (IPI)]. She was diagnosed with heart failure (HF) due to the cardiac involvement of malignant lymphoma.

Figure 6.

The myocardial biopsy revealed large, atypical lymphocytes infiltrating the endocardium and partially infiltrating the myocardium [Hematoxylin and Eosin (H&E) staining ×40] (A). The biopsy of a gastric lesion incidentally revealed atypical lymphocytes (H&E staining ×40) (B).

The HF treatment was initiated with spironolactone and enalapril. From Day 52, six courses of polatuzumab vedotin (pola) plus rituximab, cyclophosphamide, doxorubicin, and prednisolone (Pola-R-CHP) were administered, and the BNP levels decreased over time. ECG findings revealed the disappearance of the axis division and inverted T waves in I and V3-6 (Fig. 1B). Echocardiography showed an improvement in LVH. Furthermore, the ejection fraction was 61%. E/A was 0.72, DcT was 211 ms, and E/e' was 7.8, indicating an improvement in the systolic and diastolic function (Fig. 4C, D). On Day 199, ¹⁸F-fluorodeoxyglucose positron emission tomography revealed no obvious lesions, and complete remission (CR) was achieved. On Day 277, relapse in the right cervical lymph node was detected, but no obvious cardiac lesions were found based on echocardiography and CT findings. On Day 373, follow-up MRI showed an improvement in the left ventricular wall motion on the cine sequence and a reduced degree of high intensity on the T2 sequence. On delayed contrast, diffuse contrast enhancement of the left ventricle was reduced (Fig. 5D-F). One year after the disease onset, no deterioration in the cardiac function was observed.

Discussion

Impact on the hemodynamics of cardiac malignant lymphoma

There is a trend toward an increase in the number of HF patients with a preserved ejection fraction (HFpEF) in Japan (3). In the present case, echocardiography revealed significant LVH and a preserved EF. Furthermore, the patient had a score of 6 on the HFA-PEFF diagnostic algorithm, thus suggesting HFpEF (4). Because HFpEF is treatable, such as in the case of amyloidosis and Fabry disease, it is important to investigate the underlying disease of HFpEF. Generally, increased LV wall thickness eventually leads to impaired systolic and diastolic functions, increased mechanical stress, microvascular dysfunction, and decreased coronary flow reserve, resulting in irreversible tissue damage (5). However, in the present case, mild diastolic dysfunction was observed based on echocardiography findings. Furthermore, cardiac catheterization showed no marked increase in the end-diastolic pressure of either ventricle after the initial treatment with diuretics. Malignant lymphomas are soft and easily disintegrated. Tumor softness may be associated with mild diastolic dysfunction, despite the severity of LVH. Furthermore, the high intensity on the T2 sequence on cardiac MRI was suggestive of edema associated with tumor invasion of the myocardium, which may not have caused severe diastolic dysfunction. Cardiac malignant lymphoma should be considered in patients with severe LVH and without severe diastolic dysfunction. Imaging studies such as cardiac MRI and cardiac catheterization are important, especially in HFpEF patients with malignant lymphoma.

Definition of cardiac malignant lymphoma

In oncology, cardiac malignant lymphoma is classified as primary or secondary, based on extracardiac involvement. However, the definition of primary cardiac lymphoma (PCL) has not yet been determined. PCL was previously defined as an extranodal lymphoma involving only the heart or pericardium (6). However, it is currently defined as lymphoma in which the bulk of the disease is found in the heart or pericardium, regardless of the presence of extracardiac involvement, as it is impossible to accurately determine the exact origin (1). Therefore, the present case is considered to be PCL, based on the current definition. Conversely, in hematology, there is no particular problem associated with the origin of cardiac lymphoma, due to the fact that lymphoma is a systemic disease. Lymphoma is usually classified according to genetic mutations and cytomorphological features, although some of the criteria are based on the distribution and clinical course of the disease (7). Therefore, the present case was hematologically classified as DLBCL or not otherwise specified, with cardiac involvement.

Epidemiology, the prognosis, and treatment of cardiac malignant lymphoma

It was reported that 24% of malignant lymphoma autopsies revealed macroscopic or histological involvement of the heart or pericardium, of which 10% had clinical symptoms before death (8). The lack of clinical symptoms is due to the fact that cardiac malignant lymphoma is often nodal and unlikely to affect the cardiac function (1,2). Therefore, cardiac malignant lymphoma may be more common than previously reported, with DLBCL being the most common subtype (1). Symptoms reflect the location and form of the lesion in the heart. The most common symptoms are dyspnea, followed by malaise and chest pain, and the most common physiological findings are arrhythmias and congestive HF (1). Right heart involvement is more common than left heart involvement (1). Extension is often seen as localized nodules (1,2), and cases with diffuse extension, as in the present case, are rare (9-12). In a report of 128 patients from 1949 to 2009, the median overall survival of cardiac malignant lymphoma was 12 months, whereas the median overall survival of patients with LV involvement, as in the present case, was 1 month (1). This is because LV involvement may significantly affect hemodynamics (1).

Regarding the treatment of cardiac malignant lymphoma, Petrich et al. reported that only chemotherapy showed a statistically significant difference in the overall survival, whereas surgery and radiation did not (1). However, there are some case reports of patients with rapidly worsening right HF due to tumor compression who underwent partial surgical resection, and after achieving a temporary improvement, chemotherapy was administered (13,14). Generally, radiotherapy is considered based on the same criteria as that used for lymphoma. In the present case, owing to the diffuse extension of the disease and other regions, neither surgery nor radiotherapy was performed.

Because the present case had a non-GCB type and high IPI, Pola-R-CHP, which has been shown to prolong the progression-free survival compared with rituximab, cyclophosphamide, doxorubicin, and prednisolone (R-CHOP), was administered, and CR was achieved (15). Although relapse in the right cervical lymph node was detected, no deterioration in the cardiac function was noted for 12 months.

Cardiac MRI of cardiac malignant lymphoma

Cardiac MRI is an effective imaging modality for the early detection of cardiac malignant lymphoma and assessment of the treatment response. Malignant lymphoma lesions appear isointense to low in intensity on T1 sequencing. On T2 sequencing, the lesions with edema appeared as diffuse high-intensity areas, and necrotic tissue was shown as scattered low-intensity areas (16), whereas on delayed contrast, the lesions showed heterogeneous contrast effects, indicating lymphoma invasion or tumor-induced myocardial inflammation and scar tissue. Furthermore, contrast enhancement indicates myocardial fibrosis at the post-treatment follow-up (17). In the present case, the lesions showed high intensity on T2 sequencing and diffuse contrast effects on delayed contrast, indicating tumor invasion of the myocardium. In this case, the diffuse contrast enhancement decreased but partially persisted after Pola-R-CHP, which indicated recovery of the myocardial tissue. Although echocardiography also showed recovery of the cardiac function, cardiac MRI is superior to echocardiography for evaluating the treatment response, especially in cardiac malignant lymphoma.

Form of infiltration into the heart in malignant lymphoma

The lymphatic system in the heart has a drainage function. The cardiac lymphatic networks comprise three structures: subepicardial, myocardial, and subendocardial networks. The direction of lymphatic flow is from the endocardium to the epicardium. After the subepicardial lymphatic vessels unite, they flow along the right and left coronary arteries and unite at the level of the aortic root. They then flow into the right lymphatic duct via the pretracheal and cardiac lymph nodes (18). The types of infiltration into the heart in malignant lymphoma occur via the bloodstream, direct extension, and retrograde lymphatic spread (19). Furthermore, lymphatic infiltration into the heart is considered a retrograde lymphatic spread, with tumor cells moving against this physiological flow. With increasing lymphatic obstruction by the tumor, lymphatic flow may be reversed, and the tumor may spread to distant and sometimes abnormal sites (20). At the initial visit, the lesions were located in the LV, gastric, and abdominal lymph nodes. Bloodstream infiltration is unlikely, as the tumor may be trapped in the pulmonary circulation. Direct extension was excluded because CECT did not reveal any mediastinal involvement. Thus, the form of infiltration into the heart is considered to be retrograde lymphatic infiltration from abdominal lymph nodes. Alternatively, the heart may have been the initial lesion and may have progressed to other lesions.

The authors state that they have no Conflict of Interest (COI).