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From Future Cardiology

Tumors of the Heart

Mary N Sheppard; Raad Mohiaddin Posted: 04/22/2010; Future Cardiology. 2010;6(2):181-193. 2010 Future Medicine Ltd.

Abstract and Introduction

Abstract

Cardiac Tumors are very rare but have devastating consequences given that they involve such an important organ. The majority of tumors are benign myxomas, which can present in very subtle ways causing a subsequent delay in diagnosis. Routine echocardiography is advised for anybody who is feeling generally unwell, since myxomas can cause pyrexia of unknown origin. The use of cardiac imaging has increased the early diagnosis of these tumors. A total of 25% of cardiac tumors are malignant sarcomas and these have a highly aggressive behavior. Early detection of these tumors while they are resectable offers a possibility for cure in the future.
Introduction

Primary tumors of the heart are rare. Metastatic tumors to, or that are directly invasive into, the heart are far more common. Approximately 75% of primary tumors are benign and 5075% of these are atrial myxomas. The benign tumors include rhabdomyomas, fibromas, papillary fibroelastomas, hemangiomas, pericardial cysts, lipomas, hamartomas, teratomas and paragangliomas/pheochromocytomas. The malignant tumors consist of various sarcomas: myxosarcoma, liposarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma, lymphoma, neurofibrosarcoma and malignant fibrous histiocytoma. Primary tumors of the heart and pericardium have an incidence of between 0.0017 and 0.028% in collective series.[1] In the USA, based on data from 22 large autopsy series, the prevalence of primary cardiac tumors is approximately 0.02% (200 tumors per million autopsies). Approximately 75% of primary tumors are benign and 50% of benign tumors are myxomas, resulting in 75 cases of myxoma per million autopsies.[2] In a Chinese study, 39 (95.1%) tumors were benign and included myxoma, fibroma and rhabdomyoma, while two (4.9%) tumors were malignant and included neurofibrosarcoma and malignant mesothelioma.[3] In an Italian series of 125 cases, 113 tumors were benign; myxoma was the most frequent tumor (87 cases) followed by pericardial cyst, [4] endocardial papilloma,[5] fibroma,[3] rhabdomyoma,[3] hematic cyst,[2] teratoma,[2] hemangioma,[1] celothelioma[1] and lipoma.[1] Malignancy was diagnosed in 12 cases, and consisted of pericardial mesothelioma, [3] myxosarcoma,[3] angiosarcoma,[2] fibrosarcoma[2] and leiomyosarcoma.[4] At the Royal Brompton Hospital, London, UK, over the last 20 years, a total of 94 patients with a histological diagnosis of primary cardiac and pericardial tumors were identified. As observed in other series, the majority (n = 67; 71.3%) of cases were benign, with myxoma being the most common histologic type accounting for 27 cases. Primary malignant tumors (n = 27; 28.7%) included

unclassified sarcoma (n = 11), leiomyosarcoma (n = 5) and lymphoma (n = 4) as the most common histologic types.[5] Thus, there is a large spectrum of cardiac tumors with myxomas predominating among benign tumors while sarcomas predominate among malignant tumors.

Clinical
Cardiac tumors produce a large variety of symptoms through many mechanisms:

The mass can obstruct intracardiac blood flow or interfere with valve function leading to hemodynamic disturbances; Local invasion can lead to arrhythmias or cardiac failure; Pericardial effusions may occur with tamponade; Tumors can embolize causing systemic/pulmonary infarcts; Tumors may cause systemic or constitutional symptoms with pyrexia and weight loss; Mechanical hemolysis can occur; Biochemical effects are observed with an elevated erythrocyte sedimentation rate.

Some tumors produce no symptoms and become evident by incidental findings, especially today with the increased use of noninvasive imaging techniques. Most patients present with symptoms of congestive heart failure or superior vena caval obstruction. [6] The second most common presenting symptom is embolization. [7] In a recent series of 29 patients, six presented with thromboembolism, eight with congestive heart failure symptoms and three with chest discomfort. Five patients were asymptomatic or the neoplasm was an incidental finding. [8] According to the anatomic location of the tumor, some special symptoms and physical findings can be grouped together with regard to pericardial, myocardial and endocardial involvement. Owing to the nonspecific presentation, a high index of suspicion is needed and pyrexia, elevated sedimentation rate, anemia and thrombocytopenia may hint at cardiac involvement in neoplastic disease, and echocardiography should be carried out in such patients when other causes are eliminated.

Imaging
An increase in the incidence of primary cardiac tumors has been reported since the development of noninvasive imaging modalities. Earlier studies showed that most tumors were detected at autopsy. The introduction of imaging techniques has highlighted larger surgical series in the past 40 years. Among 27,640 patients assessed for cardiac disease, the incidence of tumors was 0.06% in 1980 1984, 0.22% in 19851989 and 0.32% in 19901995, [9] highlighting increasing detection. A number of imaging modalities are available for the assessment of cardiac tumors and each has advantages and limitations. Cardiac tumors rarely exhibit cardiomegaly at chest radiography. 2D echocardiography has become the most important method for noninvasive detection. This establishes the presence of a mass in the majority of patients. While echocardiography is the first-line imaging technique for cardiac tumors, computed tomography (CT) and MRI are useful for further characterization and differential diagnosis. Transthoracic echocardiography is usually adequate for providing diagnostic information when the lesion is large and confined to the pericardium or a specific cardiac chamber. However, the technique has a limited acoustic viewing window in some patients that is, ultrasound is blocked by bone and lung tissue, limiting access to the heart. In addition, lesions that are confined to the atrial

appendages and those with extracardiac extension are difficult to image. Transesophageal echocardiography is excellent for imaging the left atrium, small cardiac lesions and extracardiac involvement, but this technique is more invasive. Imaging of anterior structures, the aortic arch and the left pulmonary artery are more difficult. A common reason for referral for MRI is determination of the presence of intracardiac filling defects. Tumors of the heart and surrounding structures are demonstrated well by MRI owing to the inherent natural contrast between the cardiac structures and intravascular lumen. The wide field of view of MRI, together with its ability to acquire images in multiple planes, makes this method highly effective in demonstrating both intra- and extracardiac tumor extension. These advantages are particularly important in staging primary malignant cardiac neoplasms, such as sarcomas, which are frequently extensive in size and inoperable at initial diagnosis. Differentiation between benign and malignant cardiac tumors by their magnetic resonance signal characteristics is usually disappointing, since most tumors have a low-to-intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The exceptions are lipomas and fibromas. Lipomas produce a high-intensity signal on both T1- and T2-weighted images and a very low signal on fat-suppression images, while fibromas have a characteristic delayed enhancement with the use of the MRI contrast agent gadolinium diethylenetriamine penta-acetic acid (DTPA). The morphological appearances are usually relied upon to give clues. Malignant primary tumors can be differentiated from benign primary tumors owing to their large size, they have wide points of attachment, involve more than one cardiac chamber or great vessel and demonstrate pericardial or extracardiac extension. Angiosarcomas and hemangiomas exhibit signal enhancement after administration of a magnetic resonance contrast agent. Electron beam and multidetector CT are alternative fast imaging methods. Imaging is valuable for the diagnosis, characterization, presurgical evaluation and follow-up.[10] Benign cardiac tumors typically manifest as intracavitary, mural or epicardial focal masses; myxoma is usually is pedunculated and sometimes calcified. Malignant tumors are large in size and occupy almost the entire cardiac chamber. They demonstrate invasive features, show sessile infiltrative tumor characteristics and may involve the heart diffusely. [10] Lymphomas and metastases are usually recognized by the presence of a known tumor elsewhere, or by characteristic direct contiguous involvement. MRI is particularly useful for the depiction of contours and relationships to other cardiac structures, determining the location and border of the tumor and detecting pericardial invasion. MRI with gadolinium enhancement provides useful information for tissue characterization.[11] Pericardial or extracardiac extension is often noted and tumor necrosis can be seen. Thus, primary malignant cardiac tumors have distinctive magnetic resonance features that can be used to differentiate them from primary benign cardiac tumors. [12] As with all cardiac tumors, echocardiographic findings usually suggest the initial diagnosis, but crosssectional imaging with CT and MRI can help resolve diagnostically challenging cases. With its direct multiplanar capability, excellent contrast resolution and large field of view, MRI permits a detailed examination of the entire mediastinum, helping to rule out an equivocal mass observed on echocardiography. CT provides superior resolution for detecting calcification or fat, while MRI, with its direct multiplanar ability, more completely characterizes the heart, pericardium, mediastinum and lungs. MRI also helps elucidate the pathophysiological effects of these tumors on cardiac function through gated cine-loop sequences. Beyond tumor characterization, both modalities can help to confirm diagnoses through the addition of a contrast agent, which helps to distinguish a tumor from the myocardium, thrombus and a blood flow artifact. Ultimately, MRI is best for facilitating surgical planning and post-treatment follow-up, mainly owing to its unparalleled ability to locate and delimit these tumors.
[13]

As better diagnostic techniques and new operative approaches are developed, pathologists will be called upon more often for intraoperative consultations in order to render a pathologic diagnosis and assess the adequacy of resection during surgery. Percutaneous endomyocardial biopsy prior to surgery is now commonly used with a low complication rate. Intracavity right-sided masses can be approached using a transvenous catheter-directed technique and left-sided masses can be tackled with trans-septal atrial approaches. Presurgical diagnosis is valuable, allowing a more appropriate surgical or oncological approach to the individual case. The widespread use of new imaging techniques has contributed significantly to earlier diagnoses, earlier treatment and thus, improved survival.

Metastatic Tumors
It must be remembered that metastatic tumors are more frequent than primary cardiac tumors. Up to 3% of patients with carcinoma have metastases identified in their heart at autopsy. Although there are exceptions, epithelial malignancies typically spread to the heart by lymphatics. Melanomas, sarcomas, leukemia and renal cell carcinoma metastasize to the heart. Lymphomas may involve the heart by virtually any path, including direct extension, hematogenous seeding or lymphatic spread. Thymoma and esophageal carcinoma involve the heart by direct extension. Melanomas, renal tumors including Wilms' tumor and renal cell carcinoma, adrenal tumors, liver tumors and uterine tumors are the most frequent intracavitary tumors, often spreading directly up the inferior vena cava (Figure 1). In a recent study of cardiac metastases, lung, breast, gastric, urinary bladder and adrenal cortex cancer, malignant melanoma, hepatocarcinoma, malignant lymphoma, angiosarcoma, fibrosarcoma, leiomyosarcoma and unknown primaries were all reported. Metastatic tumors in the right cardiac chambers come through the inferior vena cava and tumors in the left atrium, left ventricle and pericardium develop from direct extension of the primary lesions. The average survival period after the diagnosis of cardiac metastases has been reported to be 5.5 months. [14]

Figure 1. Right renal cell carcinoma. Coronal steady state free precession image showing a large right-sided mass invading the inferior vena cava and extending into the right atrium (arrows). lv: Left ventricle; ra: Right atrium.

Secondary cardiac involvement with malignancy usually occurs at the terminal phase of a prolonged disease course, and palliative chemotherapy, radiotherapy and surgery can provide temporary symptomatic relief. In the specific instance in which secondary cardiac involvement leads to the initial diagnosis of malignancy, or provides the first evidence of small-volume metastatic recurrence, aggressive surgical management may result in long-term survival, provided that all of the gross tumor can be excised.[15]

Myxoma
Myxoma is the most common primary tumor of the heart and arises from the endocardium as a polypoid and often pedunculated mass extending into the chamber. Symptoms are frequently nonspecific, which poses a challenge in early diagnosis. The symptoms may vary from signs of congestive heart failure with murmurs and atrial arrhythmias to systemic findings such as an elevated erythrocyte sedimentation rate and an increase in -globulin levels. The second most common clinical presentation is embolic phenomena, which can occur in both the pulmonary and systemic circulations. The majority of patients are usually in the 3060-year age group. There is an equal sex distribution in most series but a female predominance has been reported. Most cases are sporadic but 2.7% are familial and associated with syndromes. Familial patients are more likely to be young and to have multiple right-sided lesions. Family studies suggest an autosomal dominant pattern of inheritance with a variable phenotype. The acronyms for lentiginosis, atrial myxoma, mucocutaneous myxomas and blue nevi (LAMB), and nevi, atrial myxoma, myxoid neurofibroma and ephelides (NAME) have been used to describe other physical associations with multiple myxomas. Carney described their association with cutaneous lentiginosis, fibroadenomas of the breast and pituitary, and cortical adenomas, testicular Sertoli-cell tumors and psammomatous melanotic schwannoma. [16] Recently, a specific mutation in the gene encoding the R1- regulatory subunit of cyclic AMP-dependent protein kinase A (PRKAR1) was discovered and was found to be associated with a high risk of developing cardiac myxomas.[16]
Macroscopic Findings

Myxomas are mainly located in the atria (75% in the left and 1520% in the right) and are attached to the atrial septum, usually in the region of the rim of the fossa ovalis (Figures 2 & 3). However, 10% of atrial myxomas originate from sites other than the septum, the most common being the posterior atrial wall, followed by the anterior wall and the atrial appendage. Myxomas do not usually arise from a cardiac valve and any tumor arising from such a location must be investigated thoroughly to rule out other tumors such as fibroelastoma or myxoid fibrosarcomas. Macroscopical myxomas are usually polypoid, friable and pedunculated. Most have a short, broad attachment, while flat, sessile myxomas are rare and usually result from embolization, leaving only the broad base of the polypoid tumor attached to the endocardium. Myxomas are soft and gelatinous in consistency, often with areas of hemorrhage or thrombus. Their size varies enormously from 1 to 15 cm, although the majority are in the 56 cm range. Polypoid myxomas are usually compact and demonstrate little tendency to embolize, but the villous or papillary type with multiple friable polypoid fronds embolize frequently. Myxomas can be so large that they fill the atria and project through the valve into the ventricular cavity, producing a distinctive groove at the distal end. The tumors can calcify, which can be seen radiographically (the so-called litomyxoma). Up to 7% of myxomas arise in the ventricular cavities and are equally divided between the right and left ventricles, and unlike the atria, they are not usually attached to the ventricular septum.

Figure 2. Atrial myxoma. (A) A spin echo image and (B) the corresponding late gadolinium image acquired in a tilted left ventricular horizontal long axis plane. A solid mass attached to the interatrial septum is clearly seen (arrow in A) with central enhancement (arrow in B) representing the area of scar of necrosis. la: Left atrium; lv: Left ventricle; ra: Right atrium; rv: Right ventricle.

Figure 3. Large polypoid mass with atrial septum attached, highlighted by the arrow. Note the focal hemorrhage. This is a typical myxoma.
Microscopic Appearance

Myxomas have an extensive myxoid stroma composed of acid mucopolysaccharides within which polygonal cells are embedded with a scanty eosinophilic cytoplasm (Figure 4). These cells have round nuclei with an open chromatin pattern and a small nucleoli. The cytoplasm is abundant and eosinophilic with indistinct cell borders, and they are often single with a stellate shape but small clusters also occur. Pleomorphism and multinucleated cells can be seen. They are considered neoplasms, arising from multipotential mesenchymal cells, which are found in the normal heart, predominantly in the subendocardial region and especially in the atria and atrial septum. Emboli from cardiac myxomas are a frequent occurrence in the brain, spleen, kidney and legs. Therefore, it is essential that all surgically removed emboli are sent for pathological examination. Most atrial myxomas are benign and can be removed by surgical resection. However, if they are not completely excised, they will recur and the incidence is reported to be at approximately 2%.

Figure 4. Atrial myxoma. Clusters and single polygonal cells with an irregular cytoplasm and dark nuclei can be seen. Note the background of the myxoid material.

Papillary Fibroelastoma
Papillary fibroelastoma is the third most common primary tumor of the heart and is most likely to involve the cardiac valves. Like myxomas, they arise from the endocardium in most patients and since these tumors are often incidental findings at echocardiography or autopsy, the true incidence is difficult to estimate. Most patients are older than 60 years, which also contrasts with myxomas. Papillary fibroelastomas can embolize, leading to severe neurological complications and therefore, surgical

removal is advised, although there is controversy regarding small incidental lesions and the need for surgery. The echocardiographic findings demonstrate a very mobile mass, usually on the valves, and the clinical differential diagnosis includes myxoma, vegetation, thrombi and lipoma.
Macroscopic Features

Papillary fibroelastoma tumors resemble what has been accurately described as 'a sea anemone', with multiple papillary fronds attached to the endocardium by a short pedicle (Figure 5). They are generally smaller than myxomas, usually 1 cm or less in diameter, and the fronds are longer, thinner and more delicate than those seen in papillary myxomas. They may arise anywhere in the heart but occur most frequently on the aortic valve, either on the ventricular or arterial aspect. On the atrioventricular valves, they are seen on the atrial aspect along the lines of closure or on the mid portion. Occasionally they are multiple, being located on the mitral, aortic, pulmonary and tricuspid valves.

Figure 5. Papillary fibroelastoma removed from the aortic valve. Note the thin multiple fronds that resemble a sea anenome.
Microscopic Appearance

Papillary fibroelastomas consist of papillary fronds containing fibrous tissue, elastic fibers and smooth muscle cells set in a mucopolysaccharide matrix covered with hyperplastic endocardial cells. Histologically, the papillary fronds consist of a central core of dense connective tissue surrounded by a layer of loose connective tissue and this is covered by endocardial cells. Papillary fibroelastoma is not considered to be a true tumor but is most likely secondary to mechanical wear and tear, similar to Lambl's excrescences, which are small filiform tags that especially occur along the contact surfaces of the heart valves of elderly patients and are most likely related to trauma with minute thrombus formation. Papillary fibroelastoma has been called 'giant Lambl's excrescence' because of this resemblance in appearance and location.

Fibromas
In children and infants, the most common cardiac tumor after the rhabdomyoma is a fibroma. [17] In surgical series involving all age groups, fibroma is the second most common benign primary cardiac tumor after myxoma. Fibromas are associated with Gorlin's syndrome in which patients develop odontogenic cysts, epidermal cysts, multiple naevi and basal cell carcinomas of the skin. Fibromas of the heart are connective tissue tumors derived from fibroblasts and are very similar to soft tissue fibromas. These tumors occur at all ages and in both sexes, although they are more frequent in childhood. The symptoms depend on the location of the tumor and include either sudden death or the development of cardiac failure. The majority of tumors that cause sudden death extend into the ventricular conduction system.
Macroscopic Description

Fibromas are almost always single and are located in the ventricular myocardium, frequently in the ventricular septum (Figure 6). The tumors are firm, gray/white with a whorled appearance and they often become very large, sometimes exceeding 10 cm in diameter. Central calcification is frequent and may even be seen on radiography. By contrast, rhabdomyomas rarely calcify.

Figure 6. Fibroma. (A) Diastolic frame from cine acquisition in the left ventricle horizontal long axis showing a mass involving the basal interventricular septum. The delayed contrast-enhanced image is in a similar plane to (B), showing homogenous uptake of the contrast agent gadolinium, indicating fibrous tissue. la: Left atrium; lv: Left ventricle; ra: Right atrium; rv: Right ventricle.
Microscopic Features

Fibromas are nonencapsulated tumors and extend into the surrounding myocardium. Central portions of the tumor are composed of hyalinized fibrous tissue, often with multiple calcification foci and myxoid cystic degeneration. Rhabdomyomas are the most common primary benign tumors of the heart in the pediatric age group of less than 15 years. These tumors are present in the myocardium and are often multiple. They are considered to represent fetal hamartomas. In approximately 50% of patients, these tumors are associated with tuberous sclerosis. Clinically, patients with rhabdomyomas can be divided into three groups:

Neonatal: approximately a third of patients may be either stillborn or die within the first few days of life. A total of 75% of these patients have large intracavity tumors with obstruction of at least one cardiac valve. Tuberous sclerosis is difficult to diagnose at this stage. Recent series have shown regression of these tumors with increasing age in those who survive into childhood. Rhabdomyomas can also be seen in children with congenital heart disease, such as hypoplastic left heart, transposition of the great vessels, Ebstein's anomaly, tricuspid and pulmonary atresia. Asymptomatic cases: in the second group, again representing approximately a third of patients, the majority exhibit clinical evidence of tuberous sclerosis. The rhabdomyomas are incidental findings at autopsy, being small and embedded in the myocardium. Juvenile cases: the third group of patients present with cardiac symptoms of congestive cardiac failure, cardiac murmurs, arrhythmias and cardiomegaly. The majority of these patients have single, large intracavity tumors with marked obstructions of blood flow in at least one cardiac chamber, and clinically, and there is no evidence of tuberous sclerosis. The patients are usually under 15 years of age.

Macroscopic Findings

Cardiac rhabdomyomas are multiple in most cases and occur throughout the heart although never on a cardiac valve. Most frequently, they are located in the myocardium of the left and right ventricles, including the septum, and protrude into the cardiac chamber. These tumors are usually white yellow/tan in color and can vary in size from 1 mm to 9 cm. On imaging, these tumors are usually more well defined and echodense than fibromas.
Microscopic Features

Cardiac rhabdomyomas are usually well defined and circumscribed but are not encapsulated, and they are easily distinguished from the surrounding myocardium as nodules of highly cellular tissue. The appearance of the cells is unique to this tumor they are 'spider cells', which are pathgnomonic of the rhabdomyoma. The typical rhabdomyoma cells are large, up to 18 m in diameter, and appear to be vacuolated since they are filled with glycogen. The spider cells have centrally placed nuclei with elongated cytoplasmic projections of slender myofibrils extending to the periphery of the cell. The cells are immunopositive for myoglobin, desmin, actin and vimentin. Fibromas and rhabdomyomas can both regress with age, so they may not require resection unless they are causing obstruction or severe symptoms.

Lipoma

Lipomas can occur in the heart, including in the visceral and parietal pericardium. Parietal pericardial lipomas are often clinically mistaken for pericardial cysts. Multiple myocardial lipomas have been described in tuberous sclerosis. Most lipomas occur in the epicardium, but in cases of multiple tumors, they can occur anywhere and have been reported on cardiac valves and obstructing coronary ostia causing sudden death.[18] They are a well-defined mass of mature fat, are well encapsulated and contain few myocytes in contrast to lipomatous hypertrophy, which is always found in the interatrial septum and is not encapsulated. Usually, lipomas are an incidental finding and rarely cause symptoms such as arrhythmias or obstruction, depending on their size and location.
Lipomatous Hypertrophy of the Atrial Septum & Lipoma

The interatrial septum largely consists of an invagination of the atrial roof and contains epicardial fat. This fat is the source of the entity known as lipomatous hypertrophy of the atrial septum, which is in fact characterized by excess accumulations of mature adipose tissue and brown fat admixed with residual myocytes, forming a recognizable mass that exceeds 2 cm in diameter (Figures 7 & 8). These masses are usually asymptomatic but may rarely present with arrhythmias or obstruction. They are commonly detected by routine echocardiography and are associated with older age, female sex, obesity and steroid use.

Figure 7. Lipomatous hypertrophy of the interatrial septum. (A) Steady state free precession image in the horizontal long axis of the left ventricle and (B) with fat-suppressed short tau inversion recovery image. The lesion () and the pericardial/epicardial fat appear bright in (A) and dark (suppressed signal) in (B). lv: Left ventricle; ra: Right atrium; rv: Right ventricle.

Figure 8. Lipomatous hypertrophy of the interatrial septum. Note the ill-defined area of fat expansion in the interatrial septum. Cardiac lipomas may occur anywhere in the heart and are well-defined masses of mature fat that are well encapsulated and contain few myocytes in contrast to lipomatous hypertrophy, which is always in the interatrial septum and is not encapsulated. Cardiac lipomas most frequently occur on the epicardial surface of younger patients. They are usually an incidental finding and rarely cause symptoms such as arrhythmias or obstruction, depending on their size and location.

Hemangiomas
Hemangiomas consist of benign proliferations of endothelial cells, usually forming channels containing blood. They rarely occur in the heart but may occur at any site in the ventricles, atria, on the epicardial surface of the heart and in the pericardium. The affect a wide age group from individuals of 7-months to 80 years old, and these tumors are often an incidental finding at necropsy. Other rare tumors of the heart include leiomyomas and neurofibromas. Endodermal heterotopia of the atrioventricular node is one of the smallest tumors that causes sudden death owing to involvement of the conduction system. These are considered congenital rests of endodermal origin. [19] In infants of less than 1 year, more than 75% of tumors and cysts of the heart are rhabdomyomas or teratomas. A teratoma by definition must contain elements derived from all three germ layers. They are often intrapericardial and attached to the root of the pulmonary artery or aorta. They affect young children with a female predominance. The tumors may be up to 15 cm in diameter and usually contain numerous multiloculated cysts with intervening solid areas.

Malignant Tumors of the Heart

A total of 25% of all tumors and cysts of the heart and pericardium are malignant 33% are angiosarcomas, 20% are rhabdomyosarcomas, 15% are mesotheliomas and 10% are fibrosarcomas or other sarcomas. Primary sarcomas of the heart are extremely rare, whereas secondary cardiac involvement owing to malignancy is relatively common, especially in the setting of widespread metastatic disease. Patients may present acutely with catastrophic hemodynamic instability, but presentation is more commonly nonspecific. The symptoms of primary cardiac sarcomas are often misattributed to more common conditions, and secondary cardiac involvement may be overlooked in the constellation of symptoms associated with widespread metastases. Initial diagnosis of cardiac malignancy is best made with echocardiography, but a more complete assessment of the extent of local and regional disease using CT and MRI is required when curative management is contemplated.
Angiosarcoma

Angiosarcomas are malignant tumors that originate from the vascular endothelium. They are rare, but are the most frequently occurring primary malignant cardiac tumor. Angiosarcomas are found more frequently in men than in women and occur in the right side of the heart. The majority of patients exhibit evidence of cardiac failure or pericardial disease. In many patients, the tumor is large and infiltrating with increased vascularity upon gadolinium injection (Figure 9).

Figure 9. Angiosarcoma. (A) Steady state free precession image and (B) the corresponding inversion recovery gradient echocardiography image acquired 5 min after intravenous injection of gadolinium diethylenetriamine penta-acetic acid. The steady state free precession image depicts the anatomical details of the right atrial mass (arrows) and its relation to the surrounding structures. Late enhancement (B) indicates necrosis/scarring. Pericardial effusion is highlighted by . lv: Left ventricle; ra: Right atrium; rv: Right ventricle. Microscopic Features Microscopically, there is great variation in the appearance of angiosarcomas, both between and within the same tumors. Basically, angiosarcomas are composed of proliferations of malignant cells forming vascular channels (Figure 10). There may also be solid areas of spindle cells as well as sheets of anaplastic rounds of spindle cells. The vascular channels vary greatly in size and shape, frequently forming multiple anastomosing channels. These are lined with swollen, multilayered endothelial cells. Nuclear pleomorphism and anaplasia are marked and mitoses are frequent.

Figure 10. Angiosarcoma of the right atrium. (A) Initial echocardiogram apical four-chamber view demonstrating pericardial tamponade and a suspected right atrial mass. (B) Operative photograph showing a tumor in the free wall of the right atrium. (C) High-power section showing a malignant spindle cell tumour with spaces filled with red blood cells, typical of angiosarcoma. RA: Right atrium; RV: Right ventricle; TAMP: Tamponade. The tumors are usually unresectable owing to extensive pericardial involvement. Radiotherapy and chemotherapy may offer temporary relief. Distant metastasis does occur, particularly to the central nervous system, but local spread is extensive.

Rhabdomyosarcoma

Rhabdomyosarcoma is a neoplasm of malignant cells with striated muscle features. It is the second most common primary sarcoma of the heart. The patients range in age from 3 months to 80 years old and a majority of patients have nonspecific symptoms. There appears to be no propensity of rhabdomyosarcomas to arise in any one of the cardiac chambers. The pericardium is usually involved by direct extension of the tumor from the myocardium. Diffuse pericardial involvement, which can typically be seen in mesothelioma or angiosarcoma, is not a feature of rhabdomyosarcomas. Microscopically, embryonal or alveolar and adult forms occur, with the adult form being much more common. Diagnosis is made by finding a typical rhabdomyoblast.
Sarcoma

Sarcomas can be undifferentiated tumors or can produce osteoid and cartilage in a sarcomatous stroma. Macroscopically, the tumors are similar to any other type of sarcoma and consist of spindle cells or pleomorphic cells with mitoses, necrosis and hemorrhage, and can contain malignant osteoids or chondroids in association with sarcomatous multinucleated giant cells. Patients develop metastasis early to the lungs, adjacent soft tissues or liver. In our series, most of the malignant tumors were undifferentiated sarcomas.[5]
Lymphoma

Primary cardiac lymphoma is a very rare malignancy, which is typically of a non-Hodgkin's type and involves only the heart and pericardium with no, or minimal, evidence of extracardiac involvement. Primary cardiac lymphomas account for approximately 1% of the primary cardiac tumors and 0.5% of the extranodal lymphomas. The patients range from 18 to 77 years of age with an equal male to female ratio. Both B- and T-cell lymphomas have been reported. They have been increasingly linked to AIDS, immunosuppression and cardiac transplantation. Lymphomas can be difficult to diagnose, as illustrated by a recent case in which the patient initially presented with an inflammatory 'pseudotumor', which after further development of skin metastases turned out to be an angiocentric T-cell lymphoma causing infarction and inflammation in the myocardium (Figure 11). [20] We reported two unique presentations of primary cardiac lymphomas, one within an atrial myxoma and other involving a valvular homograft.[21]

Figure 11. Cardiac lymphoma. (A) T1-weighted, (B) T2-weighted and (C) gadolinium-enhanced images. Multiple regional myocardial hypertrophy can be seen with abnormal signal intensity on the T2-weighted and the gadolinium-enhanced images. The hypertrophy is very localized (arrows) around the inferior interventricular groove, involving the right ventricle, septum and inferior wall of the left ventricle. Late gadolinium imaging demonstrates hyperenhancement due to interstitial expansion that is likely to be fibrosis or odema. (D) Hematoxylin- and eosin-stained section showing admixed histiocytes, blood vessels, lymphocytes and plasma cells. This tissue was infiltrating and destroying the myocardium and overlying pericardium. Magnification is 400. The diagnosis of lymphoma is suspected when patients present with a cardiac mass or an unexplained refractory pericardial effusion. Some T-cell lymphomas in children may present with large pericardial effusion and widespread disease.[22] Many cases are diagnosed at autopsy, but nowadays, with modern imaging technologies, early diagnosis and treatment is possible. A combination of chemotherapy and radiation therapy is considered the treatment of choice. [23]

Surgery in Cardiac Tumors

Early diagnosis and radical excision are essential for long-term survival for primary cardiac sarcoma patients, although this is rarely accomplished and overall, results are very disappointing. Neoadjuvant chemotherapy and radiotherapy have a limited role in primary management but can be beneficial and should be considered in selected cases. Orthotopic cardiac transplantation is a controversial treatment for primary cardiac sarcoma, but it has been associated with prolonged survival in selected cases. Improvement in noninvasive diagnostic technology has increased the number of patients identified with a primary cardiac tumor and has also increased the number referred for surgical resection. The results of surgical treatment of intracardiac benign tumors are good, regardless of their origins and multiplicity, both in the short and long term. The prognosis for patients with primary cardiac sarcoma is poor. Median survival is less than 10 months, especially when complete surgical excision is not feasible.[24]

Transplantation
Removal of all cardiopulmonary structures involved by the tumor followed by orthotopic allotransplantation has been proposed to improve long-term survival for malignant tumor patients. In one study, the median survival after transplantation was 31 months (range: 549 months). All patients had tumor recurrence. Combined heart and lung transplantation is a technically feasible treatment for highly selected patients with localized advanced primary cardiac sarcomas, but the high incidence of metastatic disease limits its utility.[25] Generally, heart transplantation is not justified, since prognosis is no better and donor organs are too rare.

Summary
Primary cardiac tumors are rare and experience with them in any one center is limited. We are becoming more aware of cardiac tumors owing to increased imaging modalities and earlier detection. [26] Imaging plays a vital role in delineating the location of a tumor, whether it is benign or malignant, and its overall characteristics and content of fat, fibrous tissue and vascularity can be identified with gadolinium enhancement. Thus, the surgeon will be well prepared when he enters the heart for resection of these largely benign tumors. Malignant tumors have a poorer prognosis but earlier detection may improve the outlook. Presentation may range from cardiac arrhythmias, sudden death and cardiac failure to valve obstruction or embolization. Systemic effects may also predominate as in myxomas, resulting in a delay in diagnosis. Imaging has improved detection, with echocardiography being the mainstay of diagnosis. CT provides superior resolution for detecting calcification or fat, while MRI with its direct multiplanar ability more completely characterizes the heart, pericardium, mediastinum and lungs. MRI also helps elucidate the pathophysiological effects of these tumors on cardiac function through gated cine-loop sequences. Beyond tumor characterization, both modalities can help to confirm diagnosis through the addition of contrast, which helps to distinguish tumors from the myocardium, thrombus and blood flow artifacts. Ultimately, MRI best facilitates surgical planning and post-treatment follow-up, in large part, because of its unparalleled ability to locate and delimit these tumors. Improvements in imaging are matched by histology, where morphology combined with immunohistochemistry will result in a specific diagnosis in most cases. [27]

Future Perspective
We believe that in the next 510 years, imaging will improve to enable earlier detection of these tumors to prevent morbidity and mortality, particularly with the malignant tumors in which earlier

surgery is feasible as a cure. In addition, the use of imaging with perfusion studies may lead to the application of antineoplastic or antivascular agents to aid resection or to cure.

Sidebar
Executive Summary

Primary cardiac tumors are rare. Metastatic tumors are more common than primary cardiac tumors. A total of 75% of cardiac tumors are benign, the majority being myxomas. A total of 25% of cardiac tumors are malignant, the majority are sarcomas with highly aggressive behaviors. Other rare tumors can occur in the heart as a primary entity, such as lymphomas, synovial sarcoma or malignant mesothelioma.

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Authors and Disclosures

Mary N Sheppard, MD, FRCPATH Department of Histopathology, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Tel.: +44 207 351 8424, Fax: +44 207 351 8293, m.sheppard@rbht.nhs.uk Raad Mohiaddin, MD, FRCP Magnetic Resonance Unit, Department of Imaging, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Tel.: +44 207 351 8813, Fax: +44 207 351 8293, m.mohiaddin@rbht.nhs.uk Author for correspondence Department of Histopathology, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Tel.: +44 207 351 8424, Fax: +44 207 351 8293, m.sheppard@rbht.nhs.uk

Financial & competing interests disclosure Mary N Sheppard is the recipient of a research grant from Charity Cardiac Risk in the Young (CRY). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial

conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Future Cardiology. 2010;6(2):181-193. 2010 Future Medicine Ltd.