Comprehensive understanding of a rare disease: Cardiac metastatic tumor, a double-center 10-year case review

Abstract

BACKGROUND

Cardiac metastatic tumors (CMTs) are rare yet pose significant medical concerns. Clinical studies on CMT are limited, particularly those involving multicenter data analysis.

AIM

To systematically analyze the etiology, sources, classification, treatment, and prognosis of CMT.

METHODS

A total of 226 CMT patients from two centers (2013 to 2023) were reviewed, and 153 tumor patients from China Health and Retirement Longitudinal Study were used as controls. The survival rates of 96 CMT patients were tracked through medical records and telephone follow-ups. Logistic regression and survival analyses were conducted to characterize CMT.

RESULTS

CMTs were predominantly male (67.26% vs 39.47%, P < 0.001). Intracardiac metastasis patients had worse heart and coagulation function than pericardial metastasis patients (prothrombin time: 13.90 vs 13.30, P = 0.002), D-dimer levels (2.16 vs 0.85, P = 0.001), B-type natriuretic peptide (BNP) levels (324.00 vs 136.50, P = 0.004), and troponin levels (5.35 vs 0.03, P < 0.001)). Lung and liver cancers were the predominant primary tumor types in CMT. Patients with lung cancer (76.40% vs 30.77%) and thymoma (7.45% vs 1.54%) exhibited a higher prevalence of pericardial metastasis, while those with liver cancer (35.38% vs 0.62%) showed a higher prevalence of intracardiac metastasis. Overall survival was better for pericardial metastasis than for intracardiac metastasis patients (median survival: 419 days vs 129 days, log-rank test P = 0.0029). Cox proportional hazards model revealed that advanced age [hazard ratio (HR) = 1.034, 95% confidence interval (95%CI): 1.011-1.057] and higher BNP and troponin levels (HR = 1.011, 95%CI: 1.004-1.018) were associated with worse survival. Surgery significantly improved the survival rate of patients. The median survival time was 275 days for patients who did not undergo surgery and 708 days for those who had surgery (log-rank test P = 0.0128)

CONCLUSION

Clinicians should consider CMT in the male lung or liver cancer patients with cardiac symptoms. Abnormal coagulation, impaired heart function, tumor location, and age are key prognostic factors for CMT. Surgical intervention is the preferred treatment option, as it significantly prolongs median survival.

Key Words: Cardiac metastatic tumor; Subtype; Prognosis; Coagulation; Primary tumor

Core Tip: Cardiac metastatic tumor (CMT) is a rare disease often accompanied by a poor prognosis. Currently, there is a dearth of clinical studies with sufficient cases to provide comprehensive insights. The present research has thoroughly characterized CMT, including its etiology, sources, classification, treatment options, and prognosis. It was found that CMT is predominant in male patients with liver cancer (often as intracardiac metastasis) and lung cancer (primarily involving the pericardium). Moreover, abnormal coagulation, heart function, tumor location, and age are key prognostic factors for CMT.

INTRODUCTION

Cardiac metastatic tumor (CMT) is a rare disease with a poor prognosis and an incidence rate of 0.7%-3.5%[1]. Theoretically, malignant neoplasms can metastasize to the heart, but the routes vary among different tumors[2]. Malignant tumors can spread to the heart via three primary pathways: Direct infiltration, as seen with mediastinal and intrathoracic tumors that result in pericardial metastasis; hematogenous dissemination, which typically leads to myocardial metastasis; and lymphatic spread[3]. The rarity and poor prognosis of cardiac metastases lead to a predominance of case reports in the literature, with a significant lack of clinical research, especially multi-center studies[4-6]. Consequently, our understanding of CMT remains limited.

The China Health and Retirement Longitudinal Study (CHARLS) encompasses 17708 participants drawn from 10257 households across 150 counties or districts and 450 villages in 28 provinces throughout China. It collects a high-quality nationally representative sample of Chinese residents ages 45 and older to assess the social, economic, and health circumstances of community residents[7].

Given the existing gaps in the literature and the growing elderly population, it is essential to develop a thorough and systematic comprehension of cardiac metastases. These conditions are more prevalent among older individuals and frequently result in significantly adverse clinical outcomes. Therefore, the current study aimed to identify factors contributing to cardiac metastases and potential clinical predictors in patients with CMT and the CHARLS cohort. We also examined two main types of cardiac metastases: intracardiac and pericardial metastasis, analyzing baseline data, clinical indicators and manifestations, primary tumor type, and prognosis.

MATERIALS AND METHODS

Data source

From 2013 to 2023, the clinical data of patients with CMT were obtained from Tongji Hospital Affiliated to Huazhong University of Science and Technology and The Third Affiliated Hospital of Chongqing Medical University. Data were extracted from an electronic clinical management system and normalized. Ethical approval was obtained from the respective hospitals, and participants provided informed consent.

The control participants were sourced from 2015 CHARLS Wave 3 and 2018 CHARLS Wave 4[7].

Inclusion criteria

A thorough search was conducted in the medical record systems of the two hospitals to identify eligible patients. A total of 397 patients with cardiac metastases were initially identified. After excluding patients with medical records predating 2013, those lacking imaging or pathological biopsy data, and those without sufficient clinical indicators, 226 patients (161 cases of pericardial metastasis and 65 cases of intracardiac metastasis) were included in the final analysis. Imaging and pathological biopsy data are presented in Supplementary Figures 1-4.

A control group of 19752 participants from the 2018 CHARLS Wave 4 was established, supplemented by 259 tumor patients. After excluding 36 patients with cardiac metastases and 70 without physical exam data, the final control group included 153 individuals (Figure 1).

Figure 1 The inclusion criteria of research individuals. CHARLS: China Health and Retirement Longitudinal Study.

Statistical analysis

Data normality was tested using the Kolmogorov-Smirnov test or the Shapiro-Wilk test. Normally distributed data were analyzed utilizing an independent sample t-test, whereas non-normally distributed data were analyzed using the Mann-Whitney U test. Categorical variables were compared using χ² tests. Data were analyzed using Stata (version 18.0), IBM SPSS Statistics 27, and R studio (version 4.3.2). P < 0.05 was considered statistically significant.

Survival analysis, also known as time-to-event analysis, is a statistical method for assessing the time until a predefined endpoint of interest occurs[8]. Herein, the date of confirmed CMT served as the starting point and the date of death as the endpoint. The Kaplan-Meier estimator, log-rank test, and Cox proportional hazards (PH) model were employed to evaluate patient survival.

Data were analyzed using Stata (version 18.0), IBM SPSS Statistics 27, and R studio (version 4.3.2).

RESULTS

Baseline characteristics

A total of 153 control individuals and 226 CMT cases were included in the final analysis. The baseline characteristics of patients in the three groups are summarized in Table 1. Patients with CMT were predominantly male compared with those with primary tumors (67.26% vs 39.47%, P < 0.001)

Table 1 Baseline characteristics of Primary tumors and cardiac metastasis.

	All (n = 379)	Primary tumors (n = 153)	Cardiac metastasis (n = 226)	P value
Age (year)	64.0 (55.0, 71.0)	69.0 (61.0, 74.0)	59.5 (50.0, 68)	< 0.001
Male	212 (55.94%)	60 (39.47%)	152 (67.26%)	< 0.001
BMI, kg/m2	23.32 (21.20, 25.66)	23.96 (21.63, 26.59)	22.74 (20.57, 24.88)	< 0.001
Basic vital signs
HR	80.00 (73.00, 88.00)	73.00 (67.00, 81.00)	80.50 (78.00, 96.00)	< 0.001
SBP (mmHg)	122.00 (111.00, 132.00)	122.00 (111.50, 135.50)	120.00 (110.00, 130.00)	0.151
DBP (mmHg)	75.00 (69.00, 82.00)	74.00 (68.00, 81.00)	76.00 (70.00, 82.00)	0.061
Past history
Smoking	155 (40.90)	67 (43.79)	88 (38.94)	0.346
Drinking	102 (26.91)	51 (33.33)	51 (22.57)	0.020
Diabetes	28 (7.71)	15 (10.95)	13 (5.75)	0.072
Hyperlipidemia	25 (6.96)	15 (11.28)	10 (4.42)	0.014
Hypertension	63 (18.98)	17 (16.04)	46 (20.35)	0.350

Data are presented as median (interquartile range) or n (%). BMI: Body mass index; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

Baseline characteristics of different types of CMT

A total of 226 CMT patients with detailed imaging and laboratory examination data were recruited. Patients were divided into two groups based on metastatic sites: the pericardial and intracardiac metastasis groups. The baseline characteristics of patients in the three groups are presented in Table 2.

Table 2 Baseline characteristics of pericardial and intracardiac metastasis groups.

	All (n = 226)	Pericardial metastasis (n = 161)	Intracardiac metastasis (n = 65)	P value
Age (year)	58.89 ± 12.86	60.01 ± 12.51	56.14 ± 13.40	0.040
Male	152 (67.26)	107 (66.46)	45 (69.23)	0.687
BMI (kg/m2)	22.56 ± 3.00	22.45 ± 2.97	22.96 ± 3.14	0.380
Basic vital signs
RR	20.00 (20.00, 20.00)	20.00 (20.00, 20.00)	20.00 (19.50, 20.00)	0.038
HR	80.50 (78.00, 96.00)	81.00 (78.00, 96.00)	80.00 (78.00, 95.00)	0.683
SBP (mmHg)	120.00 (110.00, 130.00)	120.00 (110.00, 130.00)	120.00 (112.00, 126.00)	0.775
DBP (mmHg)	76.00 (70.00, 82.00)	76.00 (69.00, 81.00)	78.00 (70.00, 85.00)	0.175
Temperature (°C)	36.50 (36.40, 36.60)	36.50 (36.40, 36.60)	36.50 (36.40, 36.60)	0.981
SpO2	99.00 (99.00, 99.00)	99.00 (99.00, 99.00)	99.00 (99.00, 99.00)	0.975
Past history
Smoking	88 (38.94%)	71 (44.10%)	17 (26.15%)	0.010
Drinking	51 (22.57%)	45 (27.95%)	6 (9.23%)	0.001
Diabetes	13 (5.75%)	11 (6.83%)	2 (3.08%)	0.245
Hyperlipidemia	10 (4.42%)	9 (5.59%)	1 (1.54%)	0.140
Hypertension	46 (20.35%)	33 (20.55%)	13 (20.00%)	0.933
Clinical indicators
EF (%)	66.00 (63.00, 69.00)	66.00 (62.00, 69.00)	67.00 (63.00, 71.00)	0.183
D-Dimer (mg/L)	1.06 (0.40, 2.95)	0.84 (0.31, 2.36)	2.16 (1.00, 3.67)	< 0.001
PT (second)	13.30 (12.20, 14.30)	13.00 (12.00, 14.00)	13.90 (12.95, 15.10)	< 0.001
Fibrinogen (g/L)	3.79 (2.65, 4.98)	3.70 (1.83, 4.83)	4.15 (3.23, 5.53)	0.003
INR	1.11 (1.03, 1.35)	1.11 (1.04, 2.20)	1.10 (1.03, 1.22)	0.203
BNP (pg/mL)	137.50 (56.00, 456.00)	120.00 (54.00, 292.00)	324.00 (110.00, 903.00)	0.001
Troponin (ug/L)	1.00 (0.010, 7.75)	0.022 (0.0060, 4.40)	5.35 (2.43, 36.08)	< 0.001
Treatment
Operation	104 (46.02%)	73 (45.34%)	31 (47.69%)	< 0.001

For pericardial metastasis, the main operations are pericardiocentesis drainage and affected pericardium resection. For cardiac metastasis, it is the resection of affected parts. BMI: Body mass index; RR: Respiratory rate; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; SpO₂: Percutaneous arterial oxygen saturation; EF: Ejection fraction; PT: Prothrombin time; INR: International standardized ratio; BNP: Brain natriuretic peptide.

Significant differences in several key parameters were observed between the intracardiac and pericardial metastasis groups. Specifically, prothrombin time [13.90 (12.95, 15.10) vs 13.30 (12.15, 14.05), P = 0.002], D-dimer levels [2.16 (1.00, 3.67) vs 0.85 (0.30, 3.02), P = 0.001], B-type natriuretic peptide (BNP) levels [324.00 (110.00, 903.00) vs 136.50 (53.5, 289.00), P = 0.004], and troponin levels [5.35 (2.43, 36.08) vs 0.03 (0.00, 2.70), P < 0.001] were significantly higher in the intracardiac, indicating worse coagulation and cardiac function than the pericardial metastasis group. Approximately 46.02% of patients underwent surgical treatment, with pericardial metastasis at 45.34% and intracardiac metastasis at 47.69%.

Analysis of primary tumor types in CMT

The primary tumor types linked to CMT are depicted in Figure 2. Lung and liver cancers were the most common primary tumor types in CMT, collectively accounting for 73.89%. Other cancer types included breast cancer, cervical carcinoma, chest wall tumor, colon cancer, esophageal cancer, lymphoma, mediastinal tumor, ovarian cancer, pleural mesothelioma, renal carcinoma, sarcoma, skin cancer, thymoma, thyroid cancer, and tongue cancer. Intriguingly, after excluding primary tumor types with < 5 cases, further χ² tests showed a significant difference in primary tumor types between pericardial and intracardiac metastasis (P < 0.0001). Notably, patients with lung cancer (76.40% vs 30.77%) and thymoma (7.45% vs 1.54%) exhibited a higher prevalence of pericardial metastasis, while those with liver cancer (35.38% vs 0.62%) showed a higher prevalence of intracardiac metastasis.

Figure 2 The primary tumor type of cardiac metastasis. A: Statistics of primary cancer types of cardiac metastatic tumor; B: The proportions of pericardial metastasis and cardiac metastasis to primary tumors.

Factors associated with CMT location

Binary logistic regression showed that drinking [odds ratio (OR) = 9.177, 95% confidence interval (95%CI): 1.881-44.759, P = 0.006], fibrinogen (OR = 1.273, 95%CI: 1.043-1.555, P = 0.018), and BNP (OR = 1.001, 95%CI: 1.000-1.001, P = 0.013) were associated with the CMT location (Figure 3). This suggests that CMT patients with a history of drinking and higher levels of fibrinogen and BNP are more likely to experience intracardiac metastasis rather than pericardium metastasis.

Figure 3 Factors related to the location of cardiac metastasis. 95%CI: 95% confidence interval; OR: Odds ratio.

Survival analyses of CMT patients

Survival analyses were conducted using age stratification and types of CMT as comparative factors (Figure 4). The results showed that the type of CMT significantly influenced survival outcomes. Patients in the pericardial metastasis group exhibited better overall survival than those in the intracardiac metastasis group (median survival time: 419 vs 129 days, log-rank test P = 0.0029). Surgery significantly improved the survival rate of patients. The median survival time was 275 days for patients who did not undergo surgery and 708 days for those who had surgery (log-rank test P = 0.0128). The survival curve with age stratification showed an inverse relationship between age and survival time. The Cox PH model revealed that advanced age and higher levels of BNP and troponin were associated with adverse survival periods (Table 3).

Figure 4 Kaplan-Meier survival estimator of cardiac metastasis. A: Survival curves of patients with intracardiac metastatic tumors and pericardial metastatic tumors; B: Survival curves of patients with cardiac metastatic tumor (CMT) undergoing surgery and those not undergoing surgery; C: Survival curves of CMT patients at different ages. 95%CI: 95% confidence interval.

Table 3 Cox proportional hazards model of cardiac metastasis tumor.

Variable	Hazard ratio	Standard error	z	P > |z|	95% confidence interval
Metastasis	2.046	0.775	1.89	0.059	0.975	4.297
Age	1.034	0.012	2.89	0.004	1.011	1.057
BNP (pg/mL)	1	0	2.3	0.022	1	1.001
Troponin (ug/L)	1.011	0.004	2.98	0.003	1.004	1.018

BNP: Brain natriuretic peptide.

DISCUSSION

The present study analyzed patients with CMT from two medical centers, alongside control individuals from the CHARLS cohort, yielding the following key findings: (1) Male cancer patients were highly susceptible to CMT; (2) Among CMT patients, those with intracardiac metastases displayed worse coagulation function than those with pericardial metastases; (3) Lung and liver cancers were the predominant primary tumor types that resulted in cardiac metastases. Lung cancer predominantly metastasized to the pericardium, while liver cancer was more frequently associated with intracardiac metastasis; (4) Poor cardiac function, intracardiac metastasis, and advanced age were the main predictors for poor prognosis of CMT; and (5) Surgical treatment significantly prolonged patient survival. Overall, these findings highlight the intricate dynamics and prognostic indicators underlying cardiac metastases, potentially paving the way for the creation of more targeted and effective management strategies for affected patients.

Most published autopsy series have reported that tumors with the highest rate of cardiac metastasis are pleural mesothelioma and melanoma, followed by lung adenocarcinoma[9,10]. However, our research has demonstrated that lung cancer is the predominant primary tumor for cardiac metastases. A 27-year single-center study also corroborated this finding, showing that lung carcinomas accounted for the highest proportion of cardiac metastases (38%)[1]. This discrepancy may be because patients with pericardial metastasis often exhibit milder symptoms and have a better prognosis, while autopsies typically concentrate on intracardiac metastases, which have a worse prognosis.

Regarding the underlying mechanisms that lead to the frequent metastasis of lung cancer to the pericardium and liver cancer to the myocardium, we propose that liver cancer spreads to the heart through the bloodstream, whereas lung cancer directly infiltrates the pericardium. The “seed and soil” hypothesis may help explain cardiac metastases, suggesting that some tumors (the seeds) thrive better in the cardiac microenvironment (the soil). Additionally, factors like epithelial-mesenchymal transition, extracellular matrix remodeling, and cancer stem cells may also play key roles in the development of cardiac metastases[11].

Patients with intracardiac metastasis often have a worse prognosis and higher mortality risk during tumor resection surgery[12]. Overall, the predominant treatment strategy focuses on targeting the primary tumor in patients with advanced tumors that have metastasized to the heart. Palliative surgical intervention may be considered when a cardiac tumor is large and poses a risk of sudden death, or when the patient's overall health is stable. Generally, surgery does not lead to adverse clinical outcomes[13,14]. Our study indicates that surgical intervention can significantly extend median survival, offering new treatment options. Additionally, clinical practitioners should closely monitor cardiac function and age, as they significantly impact the prognosis of CMT.

To improve the diagnosis of pericardial and intracardiac metastases for better intervention and treatment, we recommend the following essential examinations: Echocardiography for identifying cardiac masses and assessing their size, cardiac magnetic resonance imaging for its diagnostic value, and routine blood biochemical tests.

CONCLUSION

In summary, clinicians should be vigilant for the potential of CMT in male patients with lung or liver cancer who exhibit cardiac symptoms. Negative prognostic factors for CMT include abnormal coagulation, impaired cardiac function, tumor invasion site, and advanced age. Surgical intervention is recommended as the primary treatment.