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Cardiac Tumors

IntRoductIon Cardiac tumors (CTs) are exceedingly rare. With an incidence of approximately 0.02% in autopsy series, primary tumors of the heart are far less common than metastatic tumors. Myxoma is the most common benign tumor (50%–70%); angiosarcoma is the most common malignant one (30%), followed by rhabdomyosarcoma (20%).[1,2] About 10% of all tumor patients develop cardiac metastases, but these are only rarely clinically manifest.[3] Nonetheless, they may cause a wide variety of clinical signs and symptoms that often masquerade as many other more common cardiovascular and systemic diseases. Echocardiography remains the first diagnostic approach when suspecting a CT which, on the other side, frequently appears unexpectedly during an echocardiographic examination. Yet, computed tomography (CT) and especially magnetic resonance imaging (MRI) offer several adjunctive advantages that make these technologies the most sophisticated among the imaging techniques available today. An early and correct diagnosis may change the patient’s clinical management and prognosis.

block (this is particularly common for fibromas); in some cases, the first manifestation of a CT is sudden cardiac death. CTs are often diagnosed after the patient has suffered a stroke, an embolism of the peripheral vasculature, or a pulmonary artery embolism, caused by detached tumor tissue or mobilization of thrombotic deposits. The possibility of paradoxical embolisms should also be kept in mind. Therefore, all fragments of embolic material retrieved during diagnostic investigations should be subjected to histological analysis. In particular, myxomas tend to cause embolisms because of their gelatinous structure. [6][7][8][9] Papillary fibroleastomas also have systemic embolism as the most common nical presentation. [7,8] classIfIcatIon CTs are divided into benign, malignant, and intermediate tumors of uncertain behavior, with separate sections on germ cell tumors and tumors of the pericardium [Tables 1 and 2]. [10] Most primary CTs are benign in nature. Of these benign CTs, cardiac myxomas by far are the most common entities in adults and rhabdomyomas in the pediatric population.

Cardiac myxoma
Cardiac myxoma typically presenting between the ages of 30 and 60 years and more commonly in women. [7][8][9] Approximately, 75% of myxomas occur in the left atrium where the site of attachment is almost always in the region of the limbus of the fossa ovalis. Myxomas may occasionally be found on the posterior left atrial wall, but tumors presenting in

Papillary fibroelastoma [Figure 2]
Papillary fibroelastoma (PFE) is the most common tumor of the cardiac valves; it is a benign papilloma of the endocardium with a highly mobile stalk and is more often singular than multiple [ Figure 2]. PFEs are most commonly localized on the valves, primarily the aortic valve followed by the mitral valve, mainly in the downstream side, with dimensions between 2 and 40 mm. Larger PFEs are seen when they occur on the right-sided valves, and they have the potential to embolize to vital structures. Embolization may occur from the fragile papillary fronds of the mass itself or from thrombotic material formed on the tumor. Accordingly to recent guidelines, intravenous alteplase is not contraindicated and may be reasonable for patients with major acute ischemic stroke likely to produce severe disability and cardiac myxoma or PFE. [12] These tumors may mimic infective endocarditis.

Lipomatous hypertrophy and lipomas
Lipomatous hypertrophy (LHAS) and lipomas arise from benign neoplastic proliferation of nature adipocytes. True lipomas are rare and can occur at any age and with equal frequency in both sexes. They range in diameter from 1 to 15 cm. Most tumors are sessile or polypoid and occur in the subendocardium or subepicardium and are usually enclosed in a capsule. LHIS classically involves the anterior or superior portion of the interatrial septum and spares the fossa ovalis. On average, the septum is thickened up to 2.5 cm. Clinically, LHIS is associated with a higher incidence of atrial arrhythmias, that is, correlated with the degree of hypertrophy. Massive lipomatous hypertrophy can cause obstruction of the SVC.

Rhabdomyomas
Rhabdomyomas are the most common CTs of children and infants. Evidence suggests that rhabdomyomas correspond to a focal hamartomatous accumulation of the striated cardiomyocytes, and it is not actually a neoplasm. Rhabdomyomas occur most frequently in the myocardium of the left ventricle or in the interventricular septum, and they are strongly associated with tuberous sclerosis and appear usually as small and lobulated intramural nodules, with diameters in the range of 2 mm to 2 cm. Typically, rhabdomyomas tend to regress spontaneously, and this occurs in 50% of patients. [13,14] Fibromas Fibromas are benign connective tissue tumors derived from fibroblast that occurs predominantly in children and constitute the second most frequent type of primary CT occurring in the pediatric age group. Typically are large tumors ranging from 3 to 10 cm in diameter. They usually occur within the ventricular myocardium and much more frequently within the anterior free wall of the left ventricle or the interventricular septum than in the posterior let ventricular wall or right ventricle. Approximately 70% of fibromas are symptomatic, causing mechanical interference with intracardiac flow, ventricular systolic function, or conduction disturbances.

Hemangiomas
Hemangiomas are extremely rare accounting for 5%-10% of benign tumors. They may occur in any part of the heart but more commonly are found in the lateral wall of the left ventricle, the anterior wall of the right ventricle, or the interventricular septum. Most often, they are incidentally, detected during examinations done for other reasons.

Teratomas
Teratomas are generally observed in children and occur in the pericardium. They are often attached to the base of the great vessels (root of the aorta or the pulmonary trunk). About 90% are located in the anterior mediastinum; the rest, mainly in the posterior mediastinum. [15]

Malignant primary tumors include sarcomas, pericardial mesothelioma, and primary lymphomas Sarcoma
Sarcoma is a rare type of cancer that occurs in adults, children, and teens. Sarcomas may occur at any age but are most common between the third and fifth decade. Almost 40% are angiosarcomas, have a striking predilection for the right atrium/right ventricle and pericardium, causing right ventricular inflow tract obstruction, pericardial tamponade, and lung metastasis. Other types include undifferentiated sarcoma (25%), malignant fibrous histiocytoma (11%-24%), leiomyosarcoma (8%-9%), fibrosarcoma, rhabdomyosarcoma, liposarcoma, and osteosarcoma; these types are more likely to originate in the left atrium, causing mitral valve obstruction and heart failure.

Primary lymphoma
Primary lymphoma is extremely rare. It occurs more frequently in patients with acquired immunodeficiency syndrome (AIDS) or other people with immunodeficiency. These tumors may infiltrate the cardiac walls and grow within the atrial and/or ventricular cavities; they usually grow rapidly and may cause heart failure, arrhythmias, tamponade, and superior vena cava (SVC) syndrome [ Figure 3]. [16][17][18][19]

Metastatic tumors
Metastases can reach the heart via the lymphatic way or through the arterial or venous circulation. Lymphatic spread is common for lung and breast cancers and for some sarcomas and lymphomas; it frequently causes pericardial effusion and may cause the so-called "tumor encasement of the heart," with constriction pattern. [20][21][22] It is important to Figure 4: Echocardiogram of cardiac lymphoma infiltrating the left ventricular wall and protruding into the left ventricular lumen, after contrast injection. The apical septum is partially spared from neoplastic infiltration and appears darker. The small residual left ventricular cavity appears brighter (contrast effect bear in mind the possibility of a tumor encasement (with or without effusion) in the patients presenting with suspected cardiac tamponade because pericardial drainage will be not effective to relieve symptoms. Intracoronary dissemination is common for leukemia, melanoma, and some lymphomas; the metastases are usually intramural, and cases of acute coronary syndrome have been described. Genitourinary tumors often invade the inferior vena cava, grow quickly in a symbiotic way with superimposed thrombus (the so-called "tumor thrombosis) and reach the right atrium. [23,24] Melanoma is a tumor with a high propensity for cardiac involvement; lung and breast carcinoma, soft-tissue sarcoma, and renal cancer are also common sources of metastases to the heart. [25,26] Leukemia and lymphoma often metastasize to the heart. Considering both the prevalence of the primary tumor and the propensity to metastasize, the most common secondary tumor of the heart observed in the clinical practice is lung carcinoma (35%-40%), followed by hematologic malignancies (10%-20%) and breast cancer (10%). [27] dIagnosIs Echocardiography Echocardiography is usually the first diagnostic procedure. When a cardiac mass is detected on echocardiography, the differential diagnosis includes thrombi, benignant tumors, and malignant tumors. The following characteristics must be considered: site, implant, involvement of other structures, and echogenicity. A broad-based mass located in an enlarged left atrium in a patient with atrial fibrillation and/or severe mitral stenosis is likely to be a thrombus. Thrombi in the right chambers are usually an extension or embolus from a deep venous thrombosis; usually, they are serpentine-like and highly mobile. [28] The most common benign tumors (myxomas and PFEs) are pedunculated, and the insertion is in the majority of cases on the left side of the interatrial septum (myxomas) or a cardiac valve (fibroelastomas). Malignant tumors are often broad-based and may have multiple sites; the extension of an intracardiac or pericardial mass in a cardiac wall is usually a marker of malignancy. However, also rhabdomyomas and fibromas may grow within a ventricular wall. Echo contrast agents are useful to confirm the presence of an intracardiac mass and to characterize it further by virtue of the extent of contrast enhancement, which is a marker of vascularity and to assess the myocardial infiltration [ Figure 4]. Accordingly, malignant and highly vascular tumors demonstrate hyperenhancement with contrast, whereas thrombi do not appear to enhance at all; myxomas tend to be partially  [39][40] enhanced. [29][30][31] Of note, the uptake of the contrast agent by a CT is usually delayed (several minutes after the injection) and persistent; the use of qualitative and quantitative analysis of the reperfusion time has been proven useful in the differential diagnosis. [32,33] Low mechanical index contrast echocardiography is an easy, noninvasive cardiac imaging tool to assess cardiac mass vascularization. The degree of contrast enhancement and time to opacification are highly variable among cardiac masses and correspond to different extent of vascularization. [34] The identification of tumor thrombosis is of utmost importance in planning the therapies and is better achieved, implementing the echocardiographic examination with sonography. [35] Transesophageal echocardiography Transesophageal echocardiography appears to be superior to transthoracic echocardiography when the cardiac mass is located in the atria. The potential advantages of transesophageal echocardiography include improved resolution of the tumor and its attachment, the ability to detect some masses not visualized by transthoracic echocardiography, and to examine the pulmonary veins, venae cavae, the infiltration of the pulmonary veins for the left atrial masses. It should be considered when the transthoracic study is suboptimal, and it is frequently used for intraoperative (transvenous biopsy or cardiac surgery) monitoring [ Figures 5 and 6]. [36][37][38] Three-dimensional echocardiography Three-dimensional (3D) echocardiography, both transthoracic and transesophageal, allows for a more accurate analysis of the mass (site, dimensions) and of its relationship with the neighboring structures. An additional advantage of 3D echo is the possibility of obtaining new section planes on the recorded images, and -using the cropping capability -to identify necrotic areas within the mass. [39,40] If a CT cannot be confirmed by echocardiography, further imaging procedures such as CT or MRI are employed. [41] Gated cardiac CT can act in a complimentary role to the other modalities in the evaluation of a cardiac mass. CT can provide information, functional assessment, and tissue characterization. With ECG gating to minimize motion-related artifacts, high-speed multistrate equipment provides high-quality images with superior resolution (<1 mm) and the possibility of obtaining multiplanar and tridimensional reconstructions. CT provides a high degree of soft-tissue discrimination, which is helpful in defining the degree of myocardial infiltration. CT can also be used to assess for the presence of calcification, which may be useful in the diagnosis of fibromas, teratomas, rhabdomyomas, hemangiomae, and osteosarcomas. The administration of a contrast agent may clarify further the degree of intramural invasion and can differentiate a vascular tumor from an avascular thrombus. CT provides additional information when the echocardiographic data are equivocal and allows a more accurate evaluation of changes in the follow-up. The main limits of this technique are the use of ionizing radiation. [42] Cardiovascular magnetic resonance Cardiovascular magnetic resonance (CMR) will probably become a staple imaging technique for CTs for several reasons, including its excellent spatial and contrast resolution (with no radiation exposure) and its ability to obtain a wide field of view and to perform multiplanar imaging. CMR can identify, with high specificity, cardiac masses that do not require excision: pseudotumors, thrombi, lipomas, lipomatous hypertrophy, and PFEs. Most other CTs will require tissue diagnosis to aid in the establishment of a treatment plan. [43][44][45] T1-weighted and T2-weighted dual-inversion recovery fast spin-echo sequences offer detailed morphological information, with T1-weighted images providing excellent soft-tissue characterization and T2-weighted images providing superior tissue contrast and demonstration of fluid components. For Heterogeneous tumors such as myxomas and teratomas, studies have demonstrated an excellent correlation between MRI and pathological findings. Short inversion recovery sequence permits the suppression of fat signals, and therefore, is useful in detecting lipid-containing masses such as lipoma. Contrast enhancement with gadolinium provides information on the vascularity of the mass; it often allows for better delineation of tumor infiltration within the myocardium and assists in the differentiation of thrombus from tumor. Steady-state free precession sequences cine acquisitions provide excellent 3D visualization of cardiac function, valve motion, and structure, size, attachment to adjacent structures and mobility of cardiac masses. CMR is emerging as the imaging modality of choice for complex cardiac masses [ . [46][47][48] Positron-emission tomography and positron-emission tomography/computed tomography Positron-emission tomography (PET) and PET/CT give additional information on the metabolic activity of the mass. As tumors are typically in a relatively hypermetabolic state, PET imaging using a metabolic tracer such as 2-fluorine 18 fluoro-2-deoxy-D-glucose ( 18 FDG) has proven useful in detecting malignant tumors. Glucose metabolism is quantified by the maximum standardized uptake value (SUV). Malignant tumors usually have a high SUV, proportional to their proliferative index; a maximum SUV <3.5 suggests a benign lesion, while a value >10 is highly suggestive of malignancy. [49,50] Using FDG-PET/CT, a sensitivity of over 90% in differentiating benign and malignant processes was achieved. [51] A major problem with 18 FDG is the variable uptake by the myocardium, which might reduce the diagnostic accuracy in ventricular tumors. [52] A low-carbohydrate, fat-rich meal followed by a prolonged fasting period reduces the myocardial uptake of glucose and make possible to highlight CTs. [53] The intravenous injection of 50 Units/Kg of body weight of unfractioned heparin shortly before the injection of 18 FDG further reduces the physiological myocardial uptake of glucose. [54] tReatment The treatment of benign primary tumors (myxoma, PFEs, and lipoma) is surgical excision followed by serial echocardiography over 5-6 years to monitor for recurrence. [55] In about 1%-5% of cases, a recurrence or second cardiac myxoma has been reported after resection of the initial one. Rhabdomyomas regress spontaneously after infancy. The prognosis after surgery is usually excellent in the case of benign tumors.
Treatment of malignant primary tumors is surgery, with the goal of a complete resection without infiltrated margins; this is more difficult in large tumors infiltrating the ventricular walls and in angiosarcomas (only in 30% of cases a complete resection is possible). [56] A neoadjuvant (preoperatory) chemotherapy may improve the resectability of large tumors; for left atrial tumors, autotransplantation may be necessary to achieve a complete resection. [57] Chemotherapy and -in selected cases -local radiotherapy may be used after surgery; it is mandatory in all the cases of incomplete resection because the rate of recurrence is usually high and may prolong the time-to-relapse and the overall survival in the other patients. [58,59] An accurate evaluation of the characteristic of malignant tumors (type, size, site, presence of metastases, and rese ctability) before planning any intervention is a mainstay of treatment. [60] Lymphomas are treated by steroids, systemic chemotherapy (and antiretroviral therapy in case of AIDS-related lymphomas). [61][62][63][64]  Treatment of metastatic CTs depends on tumor origin. It is usually based on systemic chemotherapy. For solid tumors, mostly those from lung cancer, with pericardial metastases, intrapericardial chemotherapy increases the rate of complete cure and event-free survival. [65,66] Tumor thrombosis may be treated with an association of chemotherapy and anticoagulants (low molecular weight heparin), but other options (insertion of a vena cava filter, thrombectomy, and closure of the IVC at the time of surgery) may be considered according to the clinical presentation. [67,68] conclusIons Primary CTs are mostly benign and have a good prognosis, whereas malignant primary CTs are most commonly sarcomas and have a poor prognosis. CTs may be misdiagnosed as other conditions (including rheumatic valvular disease, endocarditis, myocarditis, pericarditis, cardiomyopathies, and congenital heart disease), pulmonary conditions (including pulmonary emboli, pulmonary hypertension, and interstitial lung disease), cerebrovascular disease and vasculitis. Advances in noninvasive cardiovascular imaging techniques, especially echocardiography, CT and MRI have greatly facilitated the diagnostic evaluation and permit the rapid identification of intracardiac masses. A multidisciplinary approach is of paramount importance in defining the diagnosis and in planning therapies.

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