Cardiac Masses: The Role of Cardiovascular Imaging in the Differential Diagnosis

Cardiac masses are space occupying lesions within the cardiac cavities or adjacent to the pericardium. They include frequently diagnosed clinical entities such as clots and vegetations, common benign tumors such as myxomas and papillary fibroelastomas and uncommon benign or malignant primary or metastatic tumors. Given their diversity, there are no guidelines or consensus statements regarding the best diagnostic or therapeutic approach. In the past, diagnosis used to be made by the histological specimens after surgery or during the post-mortem examination. Nevertheless, evolution and increased availability of cardiovascular imaging modalities has enabled better characterization of the masses and the surrounding tissue. Transthoracic echocardiography using contrast agents can evaluate the location, the morphology and the perfusion of the mass as well as its hemodynamic effect. Transesophageal echocardiography has increased spatial and temporal resolution; hence it is superior in depicting small highly mobile masses. Cardiac magnetic resonance and cardiac computed tomography are complementary providing tissue characterization. The scope of this review is to present the role of cardiovascular imaging in the differential diagnosis of cardiac masses and to propose a step-wise diagnostic algorithm, taking into account the epidemiology and clinical presentation of the cardiac masses, as well as the availability and the incremental value of each imaging modality.


Introduction
The diagnosis of space occupying lesions or masses in the heart can be done either in the context of investigation of a specific clinical symptomatology or incidentally, usually in the context of a cardiac imaging study performed for another reason. Cardiac masses can be classified as lesions that resemble tumors (clots, vegetations, calcifications or other rare lesions) and as benign or malignant, primary or metastatic, intracardial, or pericardial tumors [1][2][3]. Primary tumors are usually benign, with more than 50% chance of being a myxoma. Primary malignant tumors are rare, accounting for less than a quarter of primary heart tumors, in the majority of cases being sarcomas [4,5]. However, in autopsy studies a cardiac tumor most commonly represents a metastatic malignant tumor. The prevalence of primary cardiac tumors is 1:2000, while of metastatic 1:100 autopsies, reflecting a ratio of secondary   Knowledge of epidemiological data regarding frequency of each tumor, in the various age groups or between sexes and identification of accompanying symptoms and signs improves diagnostic accuracy of imaging tools.
The most frequent masses in the heart are clots or vegetations frequently accompanying a relevant clinical scenario such as mitral stenosis, atrial fibrillation, myocardial infarction, myocarditis with a very low ejection fraction, or infective endocarditis, respectively (Figures 1 and 2).
On the other hand, secondary cancer metastases in myocardium and pericardium are more common. Secondary metastases can occur due to direct invasion of the primary tumor to the adjacent heart tissue (i.e., in case of breast or lung cancer) or hematogenous (arterial/venous) and lymphoid dispersion [12][13][14]. In certain tumor types, a genetic predisposition has been identified [15].
In infants and children, rhabdomyoma is the most frequent tumor type, followed by myxoma and fibroma [16,17]. Primary malignant tumors (usually rhabdomyosarcoma and teratoma) are very rare.      Clinical symptoms and signs usually depend on the location of the tumor rather than its histological type [18,19]. Primary benign tumors as well as secondary malignant tumors may cause myocardial or valve dysfunction and could be accompanied by heart failure symptoms (most commonly dyspnea), angina, syncope and electrical disturbances of the heart or even fatal arrhythmias [20,21]. Pericardial effusion with or without tamponade is characteristic of malignant tumors ( Figure 3). Embolism due to tumor particles is a relatively frequent complication, occurring in a quarter of all cardiac tumor patients, and it is related to anatomical and histological characteristics of each tumor. Constitutional manifestations such as weight loss, malaise, and fatigue have also been described. However, most cardiac masses remain asymptomatic or present with mild and atypical symptoms [1][2][3]. Hence, they are usually recognized during outpatient care.

Information Extracted by the Use of the Imaging Modalities
Certain cardiac tumors tend to appear in specific locations and structures [22]. Myxomas usually develop within the left atrium [23] (Figure 4). Most sarcomas also develop within the left

Information Extracted by the Use of the Imaging Modalities
Certain cardiac tumors tend to appear in specific locations and structures [22]. Myxomas usually develop within the left atrium [23] (Figure 4). Most sarcomas also develop within the left atrium and can be mistakenly confused pre-operatively with myxomas. Angiosarcomas, on the other hand, are more often found within the right atrium [24]. Rhabdomyomas and fibromas are located in the ventricles, while papillary fibroelastomas are located on the valves [25] (Figure 5). Finally, metastatic tumors can be located anywhere in the heart, depending on the way cancer has spread [26]. In most cases masses spread through inferior vena cava to the right atrium ( Figure 6).

Information Extracted by the Use of the Imaging Modalities
Certain cardiac tumors tend to appear in specific locations and structures [22]. Myxomas usually develop within the left atrium [23] (Figure 4). Most sarcomas also develop within the left atrium and can be mistakenly confused pre-operatively with myxomas. Angiosarcomas, on the other hand, are more often found within the right atrium [24]. Rhabdomyomas and fibromas are located in the ventricles, while papillary fibroelastomas are located on the valves [25] (Figure 5). Finally, metastatic tumors can be located anywhere in the heart, depending on the way cancer has spread [26]. In most cases masses spread through inferior vena cava to the right atrium ( Figure 6).

Transthoracic Echocardiography
Echocardiography is simple to perform, non-invasive, widely-available, and affordable [3]. It provides accurate information on the morphology, localization, and mobility of the tumor and finally can evaluate its hemodynamic impact [27][28][29]. Transthoracic echocardiography (TTE) provides information about the echodensity and degree of calcification of the mass. Continuous Doppler velocities as well as Color Doppler can provide information on the hemodynamic effect of the mass. Furthermore, echo contrast agents (LVO or perfusion modalities) can provide significant information on morphological characteristics and tumor vascularity-perfusion [30][31][32] (Figure 7). Speckle tracking imaging can also highlight the non-contractible nature of non-mobile masses such as fibromas [31,33].

Transesophageal Echocardiography
Transesophageal echocardiography, especially when performed utilizing three-dimensional imaging techniques, can provide a detailed anatomical study of the mass and its surrounding tissues [34,35]. TEE is superior compared to TTE and can accurately highlight the relationship between the mass and the surrounding tissue especially for atrial tumors. It is also superior to CMR when imaging small and highly mobile masses such as vegetations, papillary fibroelastomas or other masses adjacent to the cardiac valves. It is worth to point out that for tumors in the atria, TEE is of high diagnostic utility contributing to the early differential diagnosis. Furthermore, TEE may provide information for the presence of infective endocarditis' complications such as abscess and infective infiltration of the surroundings tissues ( Figure 8).

Computed Tomography
CT and CMR are complementary and useful especially if surgical resection of the tumor is planned [36][37][38][39]. For both techniques acquisition protocols may vary and should be guided by clinical scenario and echocardiography data. CT can provide information about tumor vascularity (using contrast enhancement), the extent of tumor calcification, the presence of fat tissue, as well as the staging of the patient [39][40][41]. CT is the modality of choice in masses adjacent to the prosthetic valves and is superior to CMR for calcified masses (Figure 9). Compared to CMR, CT has superior spatial resolution facilitating 3D reconstruction [40,42]. Recent advances using spectral CT have also improved tissue characterization with decrease of radiation dose at the same time. Analysis of myocardial strain provides incremental value in the context of complex cardiac structures including cardiac masses.
CT can evaluate the extracellular volume to identify infiltration and fibrosis [43]. CT or coronary angiography can be performed to diagnose coronary aneurysms (Figure 10).

Cardiac Magnetic Resonance
CMR has adequate spatial and temporal resolution, and enables multi-planar reconstruction. It has tissue characterization capabilities due to inherent soft-tissue contrast, which can be brought out by using different tissue-weighted sequences and augmented by the administration of gadolinium-based contrast agents [44]. CMR differentiates benign from malignant cardiac masses, with tumor size, heterogeneity of signal intensity, local infiltration, and enhanced initial perfusion being the most reliable indicators of malignancy [38,[45][46][47]. 3D-MRA is a new sequence that diagnoses cardiac tumors and can also disclose vascular involvement. Tumor vascularization can also be assessed by other perfusion techniques (contrast echo, angiography) [30,39,45]. Hence, concerning patients with malignant tumors, CMR offers complementary information and helps in diagnosis and patient's management.
On the other hand, it may not recognize effectively some small and highly mobile benign masses previously depicted with echocardiography [48]. CMR, when compared to CT, is superior for tissue characterization and reveals presence of fat tissue, degree of tissue edema and iron content of the cells [36,39,49]. CMR does not expose patients to ionizing radiation, but has lower spatial

Cardiac Magnetic Resonance
CMR has adequate spatial and temporal resolution, and enables multi-planar reconstruction. It has tissue characterization capabilities due to inherent soft-tissue contrast, which can be brought out by using different tissue-weighted sequences and augmented by the administration of gadolinium-based contrast agents [44]. CMR differentiates benign from malignant cardiac masses, with tumor size, heterogeneity of signal intensity, local infiltration, and enhanced initial perfusion being the most reliable indicators of malignancy [38,[45][46][47]. 3D-MRA is a new sequence that diagnoses cardiac tumors and can also disclose vascular involvement. Tumor vascularization can also be assessed by other perfusion techniques (contrast echo, angiography) [30,39,45]. Hence, concerning patients with malignant tumors, CMR offers complementary information and helps in diagnosis and patient's management.
On the other hand, it may not recognize effectively some small and highly mobile benign masses previously depicted with echocardiography [48]. CMR, when compared to CT, is superior for tissue characterization and reveals presence of fat tissue, degree of tissue edema and iron content of the cells [36,39,49]. CMR does not expose patients to ionizing radiation, but has lower spatial

Cardiac Magnetic Resonance
CMR has adequate spatial and temporal resolution, and enables multi-planar reconstruction. It has tissue characterization capabilities due to inherent soft-tissue contrast, which can be brought out by using different tissue-weighted sequences and augmented by the administration of gadolinium-based contrast agents [44]. CMR differentiates benign from malignant cardiac masses, with tumor size, heterogeneity of signal intensity, local infiltration, and enhanced initial perfusion being the most reliable indicators of malignancy [38,[45][46][47]. 3D-MRA is a new sequence that diagnoses cardiac tumors and can also disclose vascular involvement. Tumor vascularization can also be assessed by other perfusion techniques (contrast echo, angiography) [30,39,45]. Hence, concerning patients with malignant tumors, CMR offers complementary information and helps in diagnosis and patient's management.
On the other hand, it may not recognize effectively some small and highly mobile benign masses previously depicted with echocardiography [48]. CMR, when compared to CT, is superior for tissue characterization and reveals presence of fat tissue, degree of tissue edema and iron content of the cells [36,39,49]. CMR does not expose patients to ionizing radiation, but has lower spatial resolution and is inferior in detecting mass calcification. Performing a CMR study is more time consuming and need more coordinative patients. 3D reconstruction is available for both techniques and can be used for preoperative planning [42]. In infants and children, echocardiography is even more frequently used because of the limitations of CMR and cardiac CT [50]. However, when available, CMR can in most cases predict the tumor type in pediatric patients [51,52].
Specific considerations related to CMR imaging include: 1.
Tissue characterization on T1-T2 weighted images: • Imaging characteristic of hemorrhagic pericardial effusion and clots depends on the age of the effusion.

•
Contrast enhancement during the first pass T1 weighted imaging is indicative of increased vasculature. • T1 hypo/isointensity with high T2 weighted signal intensity characterizes the majority of benign or malignant cardiac tumors • Apical and hypertrophic cardiomyopathy may mimic cardiac tumors such as fibromas.
In such cases fibromas appear hypointense in T2 weighted images while hypertrophic cardiomyopathy hyperintense. Moreover, CMR tagging can highlight the contractile nature of hypertrophic cardiomyopathy [53,54]. High T1 and low T2 weighted signal intensity is indicative of metastatic malignant melanoma.

•
High T1 signal intensity is also seen in lipomas. These masses and other lipomatoses can be recognized with fat suppression techniques ( Figure 11).

2.
Early gadolinium enhancement (EGE) which identifies thrombus from the adjacent hypokinetic cardiac wall.

3.
Late gadolinium enhancement (LGE) that is ideal for fibrosis and necrosis identification.
Diagnostics 2020, 10, 1088 13 of 17 resolution and is inferior in detecting mass calcification. Performing a CMR study is more time consuming and need more coordinative patients. 3D reconstruction is available for both techniques and can be used for preoperative planning [42]. In infants and children, echocardiography is even more frequently used because of the limitations of CMR and cardiac CT [50]. However, when available, CMR can in most cases predict the tumor type in pediatric patients [51,52]. Specific considerations related to CMR imaging include: 1. Tissue characterization on T1-T2 weighted images: • Imaging characteristic of hemorrhagic pericardial effusion and clots depends on the age of the effusion.

•
Contrast enhancement during the first pass T1 weighted imaging is indicative of increased vasculature. • T1 hypo/isointensity with high T2 weighted signal intensity characterizes the majority of benign or malignant cardiac tumors • Apical and hypertrophic cardiomyopathy may mimic cardiac tumors such as fibromas. In such cases fibromas appear hypointense in T2 weighted images while hypertrophic cardiomyopathy hyperintense. Moreover, CMR tagging can highlight the contractile nature of hypertrophic cardiomyopathy [53,54]. High T1 and low T2 weighted signal intensity is indicative of metastatic malignant melanoma.

•
High T1 signal intensity is also seen in lipomas. These masses and other lipomatoses can be recognized with fat suppression techniques ( Figure 11).
2. Early gadolinium enhancement (EGE) which identifies thrombus from the adjacent hypokinetic cardiac wall. 3. Late gadolinium enhancement (LGE) that is ideal for fibrosis and necrosis identification.

Positron Emission Tomography
Furthermore, 18 F FDG-PET provides valuable information on the metabolic activity of cardiac tumors, differentiates benign from malignant cardiac tumors and predicts survival [7,55,56]. When there is no 18 F-FDG uptake in a lesion, malignancy can be excluded in most cases. False-positive 18 F-FDG uptake can be seen in inadequate patient preparation, inflammatory conditions (e.g., sarcoidosis), infections, abscesses, surgical changes, radiation changes, and brown fat. Other hybrid modalities (PET/MRI) have further incremental value [56,57]. Hence, in cases that the malignant nature of the cardiac mass is still under question, PET/CT or PET/MRI can be used to increase the diagnostic accuracy and/or to define the staging of the patient with malignancy, so that oncology team can propose and initiate further medical care.

Conclusions
The differential diagnosis of the cardiac masses is critical for the clinical management of the patient. Patient history and clinical examination are evaluated in combination with cardiovascular imaging data. Experience when performing TTE or TEE and application of newer echocardiographic techniques such as contrast echocardiography, usually set the initial diagnosis and guide further work-up with the use of CT, CMR, and 18 F FDG PET-CT. The latter offer additional incremental information regarding diagnosis, therapeutic management and prognosis ( Figure 12).

Positron Emission Tomography
Furthermore, 18 F FDG-PET provides valuable information on the metabolic activity of cardiac tumors, differentiates benign from malignant cardiac tumors and predicts survival [7,55,56]. When there is no 18 F-FDG uptake in a lesion, malignancy can be excluded in most cases. False-positive 18 F-FDG uptake can be seen in inadequate patient preparation, inflammatory conditions (e.g., sarcoidosis), infections, abscesses, surgical changes, radiation changes, and brown fat. Other hybrid modalities (PET/MRI) have further incremental value [56,57]. Hence, in cases that the malignant nature of the cardiac mass is still under question, PET/CT or PET/MRI can be used to increase the diagnostic accuracy and/or to define the staging of the patient with malignancy, so that oncology team can propose and initiate further medical care.

Conclusions
The differential diagnosis of the cardiac masses is critical for the clinical management of the patient. Patient history and clinical examination are evaluated in combination with cardiovascular imaging data. Experience when performing TTE or TEE and application of newer echocardiographic techniques such as contrast echocardiography, usually set the initial diagnosis and guide further work-up with the use of CT, CMR, and 18 F FDG PET-CT. The latter offer additional incremental information regarding diagnosis, therapeutic management and prognosis ( Figure 12).

Figure 12.
Step-by-step diagnostic algorithm for cardiac masses using cardiovascular imaging. Patient's history, clinical data and ECG should be acquired and evaluated before extensive imaging work-up. With data extracted by the clinical evaluation and the TTE, a physician may initiate differential diagnosis and plan further work-up approach. When the mass is proved to be a thrombus (consider using ultrasound enhancing agents) no further work-up is needed. When thrombus is found on a prosthetic valve, TEE and/or CT can also be used. The next step is TEE especially for atrial masses. When the mass is vegetation or abscess then usually no-further work up is needed (consider PET scan as next best step when diagnosis is still under question). For other masses CMR is the next best step and guides further work-up which could include CT, or 18 F FDG * For ventricular masses which are not adjacent to the cardiac valves and are not highly mobile, CMR can be alternatively used after the transthoracic echocardiogram without the need of TEE.

Figure 12.
Step-by-step diagnostic algorithm for cardiac masses using cardiovascular imaging. Patient's history, clinical data and ECG should be acquired and evaluated before extensive imaging work-up. With data extracted by the clinical evaluation and the TTE, a physician may initiate differential diagnosis and plan further work-up approach. When the mass is proved to be a thrombus (consider using ultrasound enhancing agents) no further work-up is needed. When thrombus is found on a prosthetic valve, TEE and/or CT can also be used. The next step is TEE especially for atrial masses. When the mass is vegetation or abscess then usually no-further work up is needed (consider PET scan as next best step when diagnosis is still under question). For other masses CMR is the next best step and guides further work-up which could include CT, or 18 F FDG * For ventricular masses which are not adjacent to the cardiac valves and are not highly mobile, CMR can be alternatively used after the transthoracic echocardiogram without the need of TEE.