Echocardiographic Findings of Malignant Lymphoma with Cardiac Involvement: A Single-center Retrospective Observational Study

Abstract

Objective

Although malignant lymphoma (ML) can occur in every organ, diagnosing cardiac involvement without cardiac manifestations is difficult. We therefore investigated the incidence of cardiac involvement in ML in our hospital and clarified the transthoracic echocardiography (TTE) findings of cardiac involvement.

Methods

Patients with ML referred to our hospital between January 2013 and December 2019 were retrospectively reviewed.

Patients

During the study period, 453 patients were identified. The mean age was 64.9 years old, and 54% of the patients were men.

Results

Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma, followed by follicular lymphoma. Of the 453 patients, 394 (87.0%) underwent TTE at the initial diagnosis or during the clinical course. The performance rates of TTE in DLBCL, Hodgkin lymphoma, and mantle cell lymphoma were above 90%. Cardiac involvement was detected in 6 (five with DLBCL and one with B-cell lymphoma) (1.5%) of the 394 patients who underwent TTE. The involved lesions of the heart varied, and five patients had pericardial effusion. Five patients had a preserved left ventricular ejection fraction. All patients were treated with chemotherapy, and some were treated with radiation and surgery.

Conclusion

Cardiac involvement was observed in six (1.5%) of the patients with ML who underwent TTE. B-cell lymphoma, especially DLBCL, is a common ML with cardiac involvement. Although five patients had pericardial effusion, the involved lesions of the heart were not uniform. TTE is a useful imaging modality to noninvasively and repeatedly evaluate the tumor characteristics, response to ML treatment, and cardiac function.

Introduction

Malignant lymphoma (ML) is the most common hematological malignant tumor, occurring in every body organ. While primary cardiac lymphomas are rare (1-4), the frequency of cardiac involvement in ML originating from other organs is reported to be 10-25% in the autopsy of ML cases (2,5-7). However, diagnosing cardiac involvement in ML is difficult in the absence of symptoms or signs of heart failure, arrhythmia, or cardiac tamponade (5,7).

Evaluating the extent of ML and the cardiac function is important for choosing the treatment strategy and estimating the prognosis (8-10). Transthoracic echocardiography (TTE) is a noninvasive and useful imaging modality for evaluating the cardiac involvement of ML and the cardiac function when deciding the treatment strategy for ML.

The present study investigated the incidence of cardiac involvement in ML at our hospital and clarified the echocardiographic findings of cardiac involvement in ML.

Materials and Methods

Patients with ML who were referred to the Department of Hematology at Yokohama City University Medical Center (Yokohama, Japan) between January 2013 and December 2019 were reviewed retrospectively. We analyzed the clinical course and laboratory, imaging, and pathological data from the medical records of patients with ML. Patients with methotrexate-associated lymphoproliferative disorder were excluded because of the spontaneous regression of the tumor after discontinuation of methotrexate at the stage of ML suspicion.

This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Yokohama City University (approval number B200500013).

Results

During the study period, 453 patients with ML were identified. The mean age±standard deviation was 64.9±13.0 years old, and 54% of the patients were men. ML was classified as B-cell lymphoma in 391 (86.3%) cases, T/NK-cell lymphoma in 38 (8.4%), and Hodgkin lymphoma (HL) in 24 (5.3%) (Fig. 1). Among B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL) was the most common, with 198 (43.7%) cases, followed by follicular lymphoma (FL) in 81 (17.9%) cases and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) in 61 (13.5%) cases.

Figure 1.

Classification of malignant lymphoma.

TTE was performed in 394 (87.0%) of the 453 ML patients during their clinical course. The performance rates of TTE were 86.2%, 92.1%, and 91.7% for B-cell lymphoma, T/NK-cell lymphoma, and HL, respectively. From the perspective of disease, the performance rates of TTE in DLBCL, HL, and mantle cell lymphoma (MCL) were above 90%, and that of MALT was 67.2% (Table 1).

Table 1.

Performance Rate of Echocardiography by the Classification of Malignant Lymphoma.

Classification		No. of cases		TTE-performed cases		Performing rate of TTE (%)
Non-Hodgkin lymphoma		429		372		86.7
B-cell lymphoma		391		337		86.2
DLBCL		198		184		92.9
FL		81		65		80.2
MALT		61		41		67.2
MCL		15		15		100.0
Others		36		32		88.9
T/NK-cell lymphoma		38		35		92.1
PTCL		9		8		88.9
ALCL		6		6		100.0
ENKL		6		6		100.0
AITL		5		5		100.0
ATLL		5		5		100.0
Others		7		5		71.4
Hodgkin lymphoma		24		22		91.7
Total		453		394		87.0

TTE: transthoracic echocardiography, DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, MALT: extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, MCL: mantle cell lymphoma, PTCL: peripheral T-cell lymphoma, ALCL: anaplastic large cell lymphoma, ENKL: extranodal NK/T-cell lymphoma, AITL: angioimmunoblastic T-cell lymphoma, ATLL: adult T-cell leukemia/lymphoma

Cardiac involvement of ML was detected in six (1.5%) of the 394 ML patients who underwent TTE. Most of the patients with ML in whom TTE was performed were examined using computed tomography (CT), Ga scintigraphy, and/or positron emission tomography (PET) for the evaluation of the clinical stage. Table 2 shows a summary of the six cases with cardiac involvement. Five of the six cases had DLBCL, and one had B-cell lymphoma. The left ventricular wall was involved in three cases (Cases 2, 4, and 5). Case 1 initially involved the right atrium (RA) and right ventricular wall, but these tumors resolved after chemotherapy. ML then relapsed and involved the left atrium (LA) and left ventricular wall. Case 3 was a B-cell lymphoma, and the tumor appeared in the RA. Case 6 was thought to be primary cardiac lymphoma, and the tumor was found in the LA. Except for Case 2, five patients had a preserved left ventricular ejection fraction (LVEF). Five patients with DLBCL had pericardial effusion without cardiac tamponade. Regarding the revised International Prognostic Index (R-IPI) (11), three cases (Cases 1, 5, and 6) were good, while the other three cases (Cases 2, 3, and 4) were poor. All cases except Case 2 were initially treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Case 2, conversely, was initially treated with rituximab plus cyclophosphamide, vincristine, and prednisolone because the LVEF was reduced before chemotherapy. Although cardiac involvement regressed or resolved after the initial chemotherapy in four cases of stage IV [Cases 1-4; central nervous system International Prognostic Index (CNS-IPI) (12) high-risk in all], ML finally invaded the central nervous system and caused death. In Cases 5 and 6, treatment was successful. Five cases (Cases 1-5) were diagnosed with cardiac tumors as cardiac involvement of ML because lymphoma was detected in multiple organs or remote lymph nodes as well as cardiac tumors, and the cardiac tumors regressed or resolved after chemotherapy. In Case 6, we diagnosed the cardiac tumor as DLBCL by pathological examination of the resected tissue.

Table 2.

Cases with Cardiac Involvement on Echocardiography.

Case	Age	Gender	Disease	Stage	R-IPI	Chief complaints	Involved location of the heart	PE	LVEF (%)	Arrhythmia	CNS-IPI	Other involved organs at cardiac involvement found	Treatment	Prognosis after cardiac involvement found
1	58	Male	DLBCL	IV	Good	Dyspnea, chest pain	RA・RV (resolved after treatment), LA・LV (relapse)	++	64	PAF	High-risk	Kidney	R-CHOP, ESHAP, DeVIC	18 months, died
2	67	Female	DLBCL	IV	Poor	Fatigue	LV wall	+	30	PAF	High-risk	Mediastinal LN (initially, tonsil, adrenal gland, bonem, etc.)	R-COP, R-GDP, R-ESHAP, R-MA, radiation (brain)	11 months, died
3	77	Male	BCL	IV	Poor	Cough, dyspnea	RA	-	82	None	High-risk	Thorax	R-CHOP	19 months, died
4	58	Male	DLBCL	IV	Poor	Lumbago, lower leg pain	LV wall	+	70	None	High-risk	Liver, kidney, stomach, bone	R-CHOP	2 months, died
5	65	Male	DLBCL	IV	Good	No (ECG abnormality)	LV wall	+	75	None	Intermediate-risk	Cervical LN	R-CHOP	50 months, alive
6	62	Female	DLBCL	I	Good	Palpitation, dyspnea	LA	+	72	PAF	Intermediate-risk	No	Surgery, R-CHOP, radiation (chest)	39 months, alive

R-IPI: revised International Prognostic Index, PE: pericardial effusion, LVEF: left ventricular ejection fraction, CNS-IPI: central nervous system International Prognostic Index, LN: lymph node, DLBCL: diffuse large B-cell lymphoma, BCL: B-cell lymphoma, RA: right atrium, RV: right ventricle, LA: left atrium, LV: left ventricle, ECG: electrocardiography, PAF: paroxysmal atrial fibrillation, R: rituximab, CHOP: cyclophosphamide+doxorubicin+vincristine+prednisolone, ESHAP: etoposide+methylprednisolone+cytarabine+cisplatin, DeVIC: dexamethasone+etoposide+ifosfamide+carboplatin, COP: cyclophosphamide+vincristine+prednisolone, GDP: gemcitabine+dexamethasone+cisplatin, MA: methotrexate+cytarabine

We herein report a representative case (Case 4). TTE before treatment (Fig. 2) demonstrated a low-echoic tumor at the posterolateral wall of the left ventricle (LV) and LA. The tumor extended to the posterior mitral leaflet. There was pericardial effusion behind the LV, but no signs of cardiac tamponade were observed. The LVEF was preserved. CT revealed tumor-like wall thickening of the LA and LV near the mitral valve (Fig. 3). The tumor size decreased without impairment of the LVEF after two courses of R-CHOP therapy (Fig. 4).

Figure 2.

Transthoracic echocardiography of Case 4 before chemotherapy. (A) Parasternal long-axis view; (B) parasternal short-axis view at the level of the mitral valve; (C) apical three-chamber view; (D) apical four-chamber view. A hypoechoic tumor was revealed at the posterolateral wall of the left ventricle and left atrium. The tumor extended to the posterior mitral leaflet. There was pericardial effusion behind the left ventricle. Arrows indicate the tumor.

Figure 3.

Computed tomography image of Case 4. Tumor-like wall thickening of the left atrium and left ventricle near the mitral valve were revealed (arrow).

Figure 4.

Transthoracic echocardiography of Case 4 after two courses of R-CHOP therapy. (A) Parasternal long-axis view; (B) parasternal short-axis view at the level of the mitral valve; (C) apical three-chamber view; (D) apical four-chamber view. A hypoechoic tumor was revealed at the posterolateral wall of the left ventricle and left atrium. However, the tumor size decreased to below that at the pretreatment examination, and the tumor extending to the posterior mitral leaflet disappeared. Arrows show the tumor.

Discussion

We retrospectively reviewed patients with ML at our hospital. TTE was performed in 394 (87.0%) of 453 patients with ML. Cardiac involvement was detected in six (1.5%) of the 394 patients who underwent TTE.

TTE is a useful imaging modality for evaluating the relationship between the tumor and cardiovascular system; it can noninvasively and repeatedly evaluate tumor size changes after ML treatment (13,14). Furthermore, it is important to examine the cardiac function by TTE before chemotherapy and after a series of chemotherapies in some cases because some anticancer drugs exert cardiotoxicity (8-10,15,16).

The majority of ML cases in our study population were B-cell lymphoma (86.3%). DLBCL is the most common B-cell lymphoma, followed by FL and MALT. These results are similar to those of a previous Japanese study (17). Patients with ML who may be treated with chemotherapy, including anthracyclines, are generally required to undergo TTE in our hospital. However, TTE is not necessarily performed when urgent chemotherapy is required or when chemotherapy is thought to be difficult because of comorbidities or an advanced disease stage, even at the initial examination. Doxorubicin (DOX) is a common anticancer drug used for ML chemotherapy. As DOX is cardiotoxic, it is important to monitor the cardiac function when using the drug. Thus, the performance rate of TTE was relatively high in patients with DLBCL, HL, and MCL. However, the performance rate of TTE was relatively low in MALT patients, as those with gastrointestinal lesions alone did not undergo chemotherapy as the treatment strategy.

The incidence of cardiac involvement in ML detected using TTE was 1.5% in our study. However, in previous autopsy studies, the incidence of cardiac involvement in ML was 10-25% (2,5-7). The discrepancy in the incidence was due to the different backgrounds of the study populations. Lymphoma might be disseminated throughout the body in autopsy cases, whereas the cases in our study included ML in the early stage and with complete remission. Another reason for the discrepancy may be that cardiac involvement by TTE was not necessarily investigated in end-stage ML patients. Rosenberg et al. analyzed 1,269 patients with lymphoma when the imaging findings were not sufficient to diagnose cardiac involvement before the autopsy. Only 13 patients (1.1%) out of 1,269 had strong evidence of cardiac involvement with lymphoma during the clinical course of the disease (18). Zhao et al. analyzed the clinical characteristics and pathological features of 37 patients with cardiac lymphoma (19). Among these 37 patients, 36 had secondary cardiac lymphoma. Imaging revealed 3 cases of solid occupying masses in the heart, and all 37 patients had pericardial effusion. However, they did not show the prevalence of secondary cardiac lymphoma.

Chinen et al. reported cardiac involvement in the autopsy of 25 ML cases (5). Fourteen (56%) patients had B-cell lymphoma (12 DLBCL and 2 FL), and 11 (44%) had T/NK-cell lymphoma. DLBCL was the most common lymphoma with cardiac involvement. Gordon et al. performed a retrospective analysis of 94 non-Hodgkin lymphoma cases with cardiac involvement published between 1990 and 2015 (20). Among the cases with cardiac involvement, DLBCL was the most common (58%), followed by T-cell lymphoma (16%) and Burkitt's lymphoma (9%). Similar to previous reports, DLBCL was common in our study, although a small number of cases were investigated.

We encountered six cases of ML with cardiac involvement. Four cases involved the left-sided heart, and one involved the right-sided heart. The remaining patient had an unusual course: cardiac involvement initially appeared on the right side of the heart, but the tumors resolved after chemotherapy, and the ML then relapsed in the left-sided heart. Pericardial effusion was detected in five of six cases. Meng et al. investigated ML patients with cardiac involvement who underwent TTE before death and an autopsy (21). In this retrospective analysis of 29 patients with disseminated lymphoma, TTE had 60% sensitivity for detecting cardiac involvement. The most common site of involvement was the pericardium (41%), followed by the myocardium (35%). The valves were the least involved (7%). In a study of 40 cases of primary cardiac lymphoma, Ikeda et al. showed that RA was the most common location (67%), followed by the pericardium (37%) and right ventricle (25%) (22). Jeudy et al. reviewed cardiac lymphoma (23). Cardiac lymphomas are commonly of B-cell origin and manifest as ill-defined infiltrative masses. The atrium is a typically involved site, and pericardial thickening and effusion are common.

Most patients with ML undergo TTE regardless of the presence or absence of cardiac involvement in order to evaluate the cardiac function. However, the frequency of cardiac involvement in ML is low at less-advanced stages. A careful examination of TTE is thus needed, especially in cases of B-cell lymphoma, as some have cardiac involvement.

Study limitations

Several limitations associated with the present study warrant mention. First, this was a single-center retrospective observational study. Therefore, the number of patients with ML was relatively small. Second, the patients with ML enrolled in this study did not necessarily undergo TTE before ML treatment. Despite these limitations, we identified six ML cases with cardiac involvement and described their characteristics in detail.

Conclusion

Cardiac involvement was recognized in six (1.5%) of the patients with ML who underwent TTE. We summarized six ML cases with cardiac involvement focusing on TTE findings. B-cell lymphoma, especially DLBCL, is a common ML with cardiac involvement. Although five patients had pericardial effusion, the involved lesions of the heart were not uniform. A careful examination of the TTE findings is needed, especially in cases of B-cell lymphoma, because some cases have cardiac involvement. TTE is a useful imaging modality to noninvasively and repeatedly evaluate the tumor characteristics, tumor size changes after ML treatment, and cardiac function.

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