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Reardon MJ, Smythe WR. Cardiac Neoplasms.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:13731400.

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Chapter 58

Cardiac Neoplasms

Michael J. Reardon/ W. Roy Smythe

HISTORICAL BACKGROUND
CLASSIFICATION
PRIMARY BENIGN TUMORS
????Myxoma
????????PATHOLOGY
????????CLINICAL PRESENTATION
????????DIAGNOSIS
????????SURGICAL MANAGEMENT
????????RESULTS
????Other Benign Cardiac Tumors
????????LIPOMA
????????LIPOMATOUS HYPERTROPHY OF THE INTERATRIAL SEPTUM
????????PAPILLARY FIBROELASTOMA OF THE HEART VALVES
????????RHABDOMYOMA
????????FIBROMA
????????MESOTHELIOMA OF THE AV NODE
????????PHEOCHROMOCYTOMA
????????HEMANGIOMA
????????TERATOMA
PRIMARY MALIGNANT TUMORS
????Angiosarcoma
????Malignant Fibrous Histiocytoma
????Rhabdomyosarcoma
????Other Sarcomas and Mesenchymal Origin Tumors
????Lymphomas
????Heart Transplantation
SECONDARY METASTATIC TUMORS
RIGHT ATRIAL EXTENSION OF SUBDIAPHRAGMATIC TUMORS
MOLECULAR AND BIOLOGIC-BASED DIAGNOSIS AND THERAPY FOR CARDIAC TUMORS
REFERENCES

?? INTRODUCTION
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Neoplasms of the heart can be divided into primary cardiac tumors arising in the heart and secondary cardiac tumors that have metastasized to the heart. Primary cardiac tumors can be further stratified into benign and malignant tumors. Secondary involvement of the heart is relatively uncommon; 10% to 20% of patients dying of disseminated cancer have metastatic involvement of the heart or pericardium.1,2 Surgical resection is seldom possible or advisable for these tumors, and surgical intervention is usually limited to drainage of malignant pericardial effusions and/or diagnostic biopsies.

Primary tumors of the heart are uncommon but not rare. The incidence of primary cardiac neoplasm ranges between 0.17% and 0.19% in unselected autopsy series.38 Approximately 75% of primary cardiac tumors are benign and 25% are malignant.2,9 Approximately 50% of the benign tumors are myxomas, and about 75% of the malignant tumors are sarcomas.2,9 The clinical incidence of these tumors is approximately 1 in 500 cardiac surgical cases and, with the exception of myxomas, most surgeons will encounter primary cardiac tumors rarely. The purpose of this chapter is to summarize useful information for the evaluation and management of patients with primary and secondary cardiac tumors and to provide a reference for additional study on these subjects.


?? HISTORICAL BACKGROUND
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A primary cardiac neoplasm was first described by Realdo Colombo in 1559.10,11 Alden Allen Burns of Edinburgh described cardiac neoplasm and suggested valvular obstruction by an atrial tumor in 1809.12 A series of six atrial tumors, with characteristics we now recognize as myxoma, was published in 1845 by King.13 In 1931, Yates reported nine cases of primary cardiac tumor and established a classification system similar to what we use today.14 The first antemortem diagnosis of a cardiac tumor was made in 1934 when Barnes diagnosed a cardiac sarcoma using electrocardiography and biopsy of a metastatic lymph node.15 In 1936 Beck successfully resected a teratoma external to the right ventricle16 and Mauer removed a left ventricular lipoma in 1951.17 Treatment of cardiac tumors was profoundly influenced by two events: the introduction of cardiopulmonary bypass in 1953 by John Gibbon, which allowed a safe and reproducible approach to the cardiac chambers, and the introduction of cardiac echocardiography, which allowed safe and noninvasive diagnosis of an intracardiac mass. The first echocardiographic diagnosis of an intracardiac tumor was made in 1959.18 An intracardiac myxoma was diagnosed by angiography in 1952 by Goldberg, but attempts at surgical removal were unsuccessful.13 A large right atrial myxoma was removed by Bhanson in 1952 using caval inflow occlusion but the patient expired 24 days later.19 Crafoord in Sweden first successfully removed a left atrial myxoma in 1954 using cardiopulmonary bypass,20 and Kay in Los Angeles first removed a left ventricular myxoma in 1959.21 By 1964, 60 atrial myxomas had been removed successfully, with a steady increase due to increasing safety of cardiopulmonary bypass and increased use of echocardiography for detection.22 Operations are currently routinely performed on the vast majority of patients with atrial myxoma with minimal mortality.9,2333 Primary malignant tumors, however, continue to represent a challenge.


?? CLASSIFICATION
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Surgeons generally classify cardiac tumors as primary or secondary, as previously noted, and divide primary tumors into benign and malignant categories. However, the tissue of origin may influence clinical behavior, and an understanding of the pathologic classification of cardiac tumors is important. Pathologic classification is listed in Table 58-1.


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TABLE 58-1 Types of cardiac tumors by pathology

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Mural thrombus is listed as a pseudotumor. Although not really a cardiac tumor, its presentation may clinically and pathologically mimic myxoma. Most mural thrombi are associated with underlying valvular disease, myocardial infarction or dysfunction, or atrial fibrillation.32 Mural thrombi have also been noted in hypercoagulable syndromes, particularly antiphospolipid syndrome.33 With increasing use of long-term central catheters, we have seen several right atrial masses that were difficult to tell from myxoma; these masses turned out to be mural thrombi on removal. Simple removal must be combined with addressing the underlying cause, and long-term anticoagulation is often needed.

Heterotopias and tumors of ectopic tissue include cystic tumors of the atrioventricular node consisting of multiple benign cysts in the region of the atrioventricular node, which can cause heart block or sudden death. Most are diagnosed at autopsy but biopsy diagnosis of atrioventricular nodal tumor has been reported.34 Germ cell tumors of the heart are usually teratomas, occurring within the pericardial sac, but yolk sac tumors have been described in infants and children.3536 Ectopic thyroid tissue may occur within the myocardium and is referred to as "struma cordis." Right ventricular outflow track obstruction may be present, but most patients are asymptomatic.3738

The majority of the remaining tumors arise in the mesenchymal, fat, fibrous, neural, or vascular cells of the heart, with myxoma representing a tumor of undetermined histogenesis. Primary cardiac lymphoma and mesothelioma and metastatic tumors to the heart represent the remaining pathologic categories that comprise the greater part of this chapter.


?? PRIMARY BENIGN TUMORS
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Myxoma

Myxoma comprises 50% of all benign cardiac tumors in adults but only 15% of such tumors in children. Occurrence during infancy is rare (Tables 58-2 and 58-3). A vast majority of myxomas occur sporadically and tend to be more common in women than men.4,31 The peak incidence is between the third and sixth decades of life and 94% of tumors are solitary.39 Approximately 75% occur in the left atrium.31 The deoxyribonucleic acid (DNA) genotype of sporadic myxomas is normal in 80% of patients.40 Tumors are unlikely to be associated with other abnormal conditions and have a low recurrence rate.4,39


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TABLE 58-2 Benign cardiac neoplasms in adults

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TABLE 58-3 Benign cardiac neoplasms in children

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About 5% of myxoma patients show a familial pattern of tumor development based on autosomal dominance inheritance.4142 These patients and 20% of those with sporadic myxoma have an abnormal DNA genotype chromosomal pattern.40 In contrast to the "typical" sporadic myxoma profile of a middle-aged, frequently female, patient with a single left atrial myxoma, familial myxoma patients are more likely to be younger, equally likely to be male and female, and more often (22%) have multicentric tumors originating from either the atrium or ventricle.4348 Although familial myxomas have the same histology as sporadic tumors, familial myxoma has a higher recurrence rate after surgical resection (21%67%).44,4950 Approximately 20% of familial patients have associated conditions such as adrenocortical nodule hyperplasia, Sertoli cell tumors of the testes, pituitary tumors, multiple myxoid breastfibroadenoma, cutaneous myomas, and facial or labial pigmented spots.39,49 These conditions are often described as "complex myxomas" within the group of familial myxoma.40 A familial syndrome with autosomal X-linked inheritance characterized by primary pigmented nodular adrenocortical disease with hypercortisolism, cutaneous pigmentous lentigines, and cardiac myxoma is referred to as Carney's complex.39,49

PATHOLOGY

Myxomas occur in any chamber of the heart but have a special predilection for the left atrium, from which approximately 75% originate.32 The next most frequent site is the right atrium, where 10%20% are found. The remaining 6% to 8% are equally distributed between the left and right ventricle.2 Both biatrial and multicentric tumors are more common in familial disease. Biatrial tumors probably arise from bidirectional growth of a tumor originating within the atrial septum.51 Atrial myxomas generally arise from the interatrial septum at the border of the fossa ovalis but can originate anywhere within the atrium including the appendage (Figs. 58-1 and 58-2).4 In addition, isolated reports confirm that myxomas arise from the cardiac valves, pulmonary artery and vein, and vena cava.5253 Right atrial myxomas are more likely to have broad-based attachments than left atrial tumors; they also are more likely to be calcified4546 and thus visible on chest radiographs (Fig. 58-3). Ventricular myxomas occur more often in women and children and may be multicentric.2,54 Right ventricular tumors typically arise from the free wall and left ventricular tumors tend to originate in the proximity of the posterior papillary muscle.



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FIGURE 58-1 Left atrial myxoma obstructing the mitral orifice. (Reproduced with permission from Hurst JW, et al: Atlas of the Heart. New York, McGraw-Hill, 1988.)

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FIGURE 58-2 Left atrial myxoma arising from the posterior papillary muscle. (Reproduced with permission from Hurst JW, et al: Atlas of the Heart. New York, McGraw-Hill, 1988.)

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FIGURE 58-3 Calcified right atrial myxoma. (Reproduced with permission from Hurst JW, et al: Atlas of the Heart. New York, McGraw-Hill, 1988.)

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Grossly, about two thirds of myxomas are round or oval tumors with a smooth or slightly lobulated surface.31 Most are polypoid, relatively compact, pedunculated, mobile, and not likely to fragment spontaneously.2,4 Mobility depends on the length of the stalk, the extent of attachment to the heart, and the amount of collagen in the tumor.4 Most tumors are pedunculated with a short broad base and although sessile forms occur they are unusual.2,55 Less common villous or papillary myxomas are gelatinous and fragile and prone to fragmentation and embolization, occurring about one third of the time.31,56 Myxomas are white, yellowish or brownish color, frequently covered with thrombus.2 Focal areas of hemorrhage, cyst formation, or necrosis may be seen in cut section. The average size is about 5 cm in diameter but growth to 15 cm in diameter and larger has been reported.4 Most myxoma tumors appear to grow rapidly, but growth rates vary and occasionally tumor growth arrests spontaneously.4 Weights range from 8 to 175 g with a mean between 50 and 60 g.8

Histologically, myxomas are composed of polygonal shaped cells and capillary channels within an acid mucopolysaccharide matrix (Fig. 58-4).4



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FIGURE 58-4 Typical microscopic appearance of atrial myxoma with nests of small stellate cells and blood vessels immersed in abundant accellular matrix rich in proteoglycams. These tumors often contain smooth muscle, areas of hemorrhage and calcification, hemosiderin-laden macrophages, and chronic inflammatory cells. Hematoxylin eosin X 200. (Courtesy of Dr. G. G. Pietra.)

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The cells appear singularly or in small clusters throughout the matrix, and mitoses are rare.57 The matrix also contains a smattering of smooth muscle cells, reticulocytes, collagen, elastin fibers, and a few blood cells. Cyst, areas of hemorrhage, and foci of extramedullary hematopoesis are present throughout the matrix.49,56,58 Ten percent of the tumors have microscopic deposits of calcium and metastatic bone deposits, and sometimes glandular-like structures.49,56 The base of the tumor contains a large artery and veins that connect with the subendocardium but do not extend deeply beyond the subendocardium in most cases.49 We have recently seen a myxoma that on coronary angiography had a large feeding vessel and was originally suspected of being a angiosarcoma, but on histology proved to be a typical benign myxoma. Myxomas tend to grow into the overlying cardiac cavity rather than into the surrounding myocardium. The tumor surface is covered by monolayer of polygonal cells with interspersed primitive blood vessels.

Myxomas arise from the endocardium and are considered derivative of the subendocardial multipotential mesenchymal cell,5960 although origin from endocardial nervous tissue has also been suggested.61 The multipotential mesenchymal cells are thought to be embryonic cells left behind during septation of the heart, and are capable of differentiating into endothelial cells, smooth muscle cells, angioblasts, fibroblasts, myoblasts, and cartilage. This accounts for the occasional presence of hematopoietic tissue and bone in these tumors. There is no evidence that these tumors are of thrombotic origin as was formerly speculated.62

Interestingly, myxomas have developed after cardiac trauma including repair of atrial septal defects and transseptal puncture for paracutaneous dilatation of the mitral valve.

CLINICAL PRESENTATION

The classic triad of myxoma clinical presentation is intracardiac obstruction with congestive heart failure (67%), signs of embolization (29%), systemic or constitutional symptoms of fever (19%) and weight loss or fatigue (17%), and immunologic manifestations of myalgia, weakness, and arthralgia (5%), with almost all patients presenting with one or more of these symptoms.31 Cardiac rhythm disturbances and infection occur less frequently.

Constitutional symptoms Nearly all myxoma patients on careful questioning admit to a variety of constitutional symptoms that may include weight loss, fever, and lethargy. These complaints may be accompanied by laboratory abnormalities including leukocytosis, elevated erythrocyte levels and sedimentation rate, hemolytic anemia, thrombocytopenia, and elevated C-reactive protein. Immunoelectrophoresis may reveal abnormal immunoglobulin levels with increased circulating IgG.63 These symptoms often suggest an inflammatory autoimmune disease and are unrelated to the location and size of the tumor.4

The recent discovery of elevated levels of interleukin-6 in patients with myxoma has been linked to a variety of associated conditions including lymphadenopathy, tumor metastasis, ventricular hypertrophy, and development of constitutional symptoms.54,6466 Other less frequent complaints include Raynaud's phenomenon, arthralgias, myalgias, erythematous rash, and clubbing of the digits.4,6768

Possible etiologies of such varied complaints and symptoms include tumor embolization with secondary myalgias and arthralgias and elevated immunoglobulin response.69 Circulating antibody tumor antigen complexes with complement activation may also play a role in the constitutional symptom complex.70 More important, such symptom complexes tend to resolve following surgical resection of tumor.58,7172

Obstruction Obstruction of blood flow in the heart is the most common cause of acute presenting symptoms. The nature of these symptoms is determined by which of the chambers is involved and the size of the tumor.

Myxomas in the left atrium tend to mimic mitral valvular heart disease. They produce dyspnea, which may be positional,73 and other signs and symptoms of heart failure associated with elevated left atrial and pulmonary venous pressures. Clinically, mitral stenosis is often suspected and leads to echocardiography and diagnosis of myxoma. On occasion, large myxomas may interfere with mitral leaflet closure and produce mitral regurgitation, but this is uncommon.4 Syncopal episodes occur in some patients and are thought to result from temporary occlusion of the mitral orifice.46,7375 Right atrial myxomas can produce a clinical picture of right heart failure with signs and symptoms of venous hypertension including hepatomegaly, ascites, and dependent edema. The tumor simulates tricuspid valve stenosis by partially obstructing the valve orifice.46,7375 If a patent foramen ovale is present, right to left atrial shunting may occur with central cyanosis, and paradoxal embolization has been reported.74,7677

Large ventricular myxomas may mimic ventricular outflow obstruction. The left ventricular myxoma may produce the equivalent of subaortic or aortic valvular stenosis,7779 whereas right ventricular myxomas can simulate right ventricular outflow track or pulmonic valve obstruction.

Embolization Systemic embolization is the second most common mode of presentation for patients with myxoma. It occurs in 30% to 40% of patients.2,4,46,7374 Because the majority of myxomas are left-sided, approximately 50% of embolic episodes affect the central nervous system owing to both intracranial and extracranial vascular obstruction. The neurologic deficits following embolization range from transient to permanent but a high portion do not resolve.80 Specific central nervous system consequences include intracranial aneurysms, seizures, hemiparesis, and brain necrosis.8184 Retinal artery embolization with visual loss has occurred in some patients.8586

Embolic material for cardiac myxoma has been found in iliac and femoral arteries, causing acute lower extremity ischemia.8789 Other sites of tumor embolization include abdominal viscera and the renal and coronary arteries.90 Histologic examination of surgically removed peripheral myxoma that has embolized provides the diagnosis of an otherwise unsuspected tumor.46,91,92

Right-sided myxomatous emboli usually do not cause clinical manifestations but do obstruct pulmonary arteries and cause pulmonary hypertension and even death from acute obstruction.4,77

Infection Infection arising in a myxoma is a rare complication and produces a clinical picture of infectious endocarditis,9195 and a variety of bacterial pathogens as well as fungus forms93 have been isolated.96 Infection increases the likelihood of systemic embolization4 and infected myxoma warrants urgent surgical resection.

DIAGNOSIS

Clinical examination Findings at the time of clinical assessment of a patient with cardiac myxoma vary according to the size, location, and mobility of the tumor. Left atrial myxomas may produce auscultatory findings similar to mitral stenosis just as these tumors may mimic the symptoms of mitral disease. The well-described "tumor plop" is an early diagnostic sound heard and sometimes confused with a third heart sound. The diagnostic tumor plop occurs just after the opening snap of the mitral valve and is believed to be secondary to contact between the tumor and endocardial wall.9798 Of note, the murmur of cardiac myxoma may depend on its position and this may aid in the auscultatory diagnosis. Left atrial myxomas that cause partial obstruction of left ventricular filling may result in elevated pulmonary vascular pressures with augmentation of the pulmonary component of the second heart sound.99

Right atrial myxomas may produce the same auscultatory findings as left atrial myxomas with the exception that they are best heard along the lower right sternal border rather than the cardiac apex. These include both systolic and diastolic murmurs and a tumor plop. In addition, right atrial hypertension may produce a large A wave in the jugular venous pulse and when severe may mimic superior vena caval syndrome. Similarly, elevated right atrial pressure can lead to right-to-left shunting across the patent foramen ovale. This may produce polycythemia, cyanosis, and clubbing of the digits. Lower body manifestations of venous hypertension are hepatomegaly, ascites, and peripheral edema.

Chest radiograph and electrocardiogram The findings on chest roentgenogram, although not specific, may include generalized cardiomegaly, individual cardiac chamber enlargement, and pulmonary venous congestion. More specific occasional findings are density within the cardiac silhouette caused by calcification within the tumor (see Fig. 58-3). This finding occurs more often with right-sided myxomas;4 however, the majority of our myxoma patients have normal chest roentgenograms.

Electrocardiographic findings Similar to plain film imaging, nonspecific abnormalities are noted, including chamber enlargements, cardiomegaly, bundle branch blocks, and axis deviation.100 Fewer than 20% of patients have atrial fibrillation.48 Evaluation of nonspecific electrocardiographic abnormalities occasionally leads to an incidental diagnosis of myxoma but, as with chest x-rays, most electrocardiograms are not helpful in establishing a diagnosis.

Echocardiography Cross-sectional echocardiography is the most useful test employed for the diagnosis and evaluation of myxoma. The sensitivity of 2-D echocardiography for myxoma is 100% and this imaging technique has largely supplanted angiocardiography.101 However, coronary angiography usually is performed in patients over 40 years of age to rule out significant coronary arterial disease in a patient who has another indication for cardiac surgery. A transthoracic echocardiogram usually provides all the information for surgical resection, but transesophageal echocardiography (TEE) provides the best information concerning tumor size, location, mobility, and attachment.102103 Transesophageal echocardiograms detect tumors as small as 13 mm in diameter.104 Our practice is to obtain a transesophageal echocardiogram in the operating room before commencing the operation (Fig. 58-5). We particularly evaluate the posterior left atrial wall, atrial septum, and right atrium, which often are not well displayed on transthoracic examination, to exclude the possibility of biatrial multiple tumors. Additionally, operative TEE assures a normal echocardiogram prior to leaving the operating room.



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FIGURE 58-5 Transesophageal echocardiogram of large left atrial myxoma in patient presenting with symptoms of mitral valve disease. The tumor is attached to the interatrial septum above the normal mitral valve. (Reproduced with permission from Hall RA, Anderson RP: Cardiac neoplasms, in Edmunds LH Jr: Cardiac Surgery in the Adult. New York, McGraw-Hill, 1997; p. 1350.)

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Computed tomography and magnetic resonance imaging Although myxomas have been identified using computed tomography (CT),100,105 this modality is most useful in malignant tumors of the heart because of its ability to demonstrate myocardial invasion and tumor involvement of adjacent structures.100 Similarly magnetic resonance imaging (MRI) has been employed in the diagnosis of myxomas and may yield a clear picture of tumor size, shape, and surface characteristics.100,103,105106 MRI is particularly useful in detecting intracardiac and pericardial extension and invasion of malignant secondary tumors, and is also useful in the evaluation of ventricular masses that occasionally turn out to be myxoma. Both CT and MRI detect tumors as small as 0.5 to 1.0 cm and provide information regarding the composition of the tumor.4 Neither CT nor MRI is needed for atrial myxomas if an adequate echocardiogram is available because the information from these studies is not likely to alter surgical approach. The exception is the occasional right atrial myxoma that extends into one or both caval or tricuspid orifice. CT or MRI should be reserved for the situation in which the diagnosis or characterization of the tumor is unclear after complete echocardiographic evaluation.

SURGICAL MANAGEMENT

Surgical resection is the only effective therapeutic option for patients with cardiac myxoma and should not be delayed because death from obstruction to flow within the heart or embolization may occur in as many as 8% of patients awaiting operation.107108 Mediasternotomy approach with ascending aortic and bicaval cannulation is usually employed. Manipulation of the heart before initiation of cardiopulmonary bypass is minimized in deference to the known friability and embolic tendency of myxomas. For left atrial myxomas the vena cava are cannulated through the right atrial wall with the inferior cannula placed close and laterally to the inferior vena cava right atrial junction (Fig. 58-6). Caval snares are always used to allow opening of the right atrium, if necessary. If extensive exposure of the left atrium is needed, or a malignant left atrial tumor is suspected, we mobilize and directly cannulate the superior vena cava, which allows it to be transected if necessary for additional exposure (Fig. 58-7). Body temperature is allowed to drift down but there is no attempt to induce systemic hypothermia unless the need for reduced perfusion flow is anticipated. Modern cardioplegic techniques yield a quiet operative field and protect the myocardium from ischemic injury during aortic cross-clamping. Cardiopulmonary bypass is started and the aorta is clamped prior to manipulation of the heart.



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FIGURE 58-6 Standard venous cannulation for atrial myxomas and left arteriotomy site for left atrial myxoma.

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FIGURE 58-7 Superior vena cava cannula to allow increased right atrial exposure or division of superior vena cava for additional left atrial exposure.

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Exposure of left atrial myxomas is maximized by using several principles from mitral valve repair surgery. The surgeon desires the right side of the heart to rotate up and the left side of the heart to rotate down. Therefore, stay sutures are placed low on the pericardium on the right side and no pericardial stay sutures on the left prior to placing the chest retractor. This rotates the heart for optimal exposure of both the right and, particularly, the left atrium (Fig. 58-8). For left atrial tumors the superior vena cava is extensively mobilized as is the inferior vena cavalright atrial junction, allowing increased mobility and exposing the left atrial cavity. Left atrial myxomas can be approached by an incision through the anterior wall of the left atrium anterior to the right pulmonary veins (Fig. 58-9). This incision can be extended behind both cava for greater exposure (Figs. 58-10 and 58-11).



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FIGURE 58-8 Rotation of the heart with pericardial stay sutures for left atrial exposure.

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FIGURE 58-9 Left atriotomy and exposure of myxoma.

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FIGURE 58-10 Repair of left atrial wall after removal of myxomas.

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FIGURE 58-11 Photographs of left atrial mysoma removal and repair.

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Exposure of large tumors attached to the interatrial septum and removal may be aided by a second incision parallel to the first in the right atrium going posterior to the superior vena caval cannula and anterior to the inferior vena caval cannula. This biatrial incision allows easy removal of tumor attached to the fossa ovalis with full thickness excision at the site of attachment and easy patch closure of the atrial septum if necessary.

Right atrial myxomas pose special venous cannulation problems and intraoperative echocardiography may be of benefit in allowing safe cannulation. Both vena cava may be cannulated directly. When low- or high-lying tumor pedicles preclude safe transatrial cannulation, cannulation of the jugular or femoral vein can provide venous drainage of the upper or lower body. In general, we can always cannulate the superior vena cava distal enough from the right atrium to allow adequate tumor resection, but occasionally femoral venous cannula drainage has been necessary for low-lying right atrial tumors encroaching on the inferior vena cava orifice. If the tumor is large or attached near both caval orifices, peripheral cannulation of both jugular and femoral vein may be used to initiate cardiopulmonary bypass and deep hypothermia. After the aorta is cross-clamped and the heart is arrested with antegrade cardioplegia, the right atrium may be opened widely for resection of the tumor and reconstruction of the atrium using pericardium or polyflorotetraethylene during a period of circulatory arrest if this is needed for a dry field. Resection of large or critically placed right atrial myxomas often requires careful preoperative planning, intraoperative transesophageal echocardiography, and special extracorporeal perfusion techniques to ensure complete removal of the tumor, protection of right atrial structures, and reconstruction of the atrium. Because myxomas rarely extend deep in the endocardium, it is not necessary to resect deeply around the conduction tissue. The tricuspid valve and the right atrium as well as the left atrium ventricle should be inspected carefully for multicentric tumors in patients with right atrial myxoma, with or without familial myxoma. However, in the age of pre- and intraoperative TEE, it is unusual to find additional tumors not seen on echocardiography.

Regardless of the surgical approach, the ideal resection encompasses the tumor and a portion of the cardiac wall or interatrial septum to which it is attached. Whether excision of full thickness wall is necessary or excision of only an endocardial attachment is sufficient to prevent recurrence is controversial. Our policy is to resect full thickness whenever possible. However, only partial thickness resection of the area of tumor attachment has been performed when anatomically necessary without a noted increase in recurrence rate.109110

Ventricular myxomas usually are approached through the AV valve111 or by detaching the anterior portion of the AV valve for exposure and resection and reattachment after resection (Fig. 58-12). Occasional small tumors in either outflow tract can be removed through the outflow valve.111112 If necessary, the tumor is excised through a direct incision into the ventricle, but this is unusual. It is not necessary to remove full thickness of the ventricular wall since no recurrences have been reported with partial thickness excisions. As with right atrial myxoma, the presence of ventricular myxoma prompts inspection for other tumors because of the high incidence of multiple tumors.



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FIGURE 58-12 (A) Takedown of atrial ventricular valve for ventricular exposure. (B) Tumor exposure after valve takedown.

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Every care should be taken to remove the tumor without fragmentation. Following tumor removal from the field, the area should be liberally irrigated, suctioned, and inspected for loose fragments. Whether blood removed from the field during tumor manipulation should be discarded or returned to the pump circuit is also controversial. There are rare instances of distant metastases from myxoma many years after tumor resection, and these reports raise the issue of potential intraoperative dissemination of tumor.113114 We use the cardiotomy suction during operation but use the wall suction during the brief time that the tumor is actually excised.

We reason that macro tumor emboli entering the profusion circuit will be filtered out in the cardiotomy reservoir. Considering the growth of the tumor within the bloodstream, its friable character would seem to pose no greater threat for distant metastases during tumor removal than it did during tumor development. The low malignant potential of the vast majority of myxomas and the rarity of metastasis further support this policy of retaining rather than discarding blood and we believe most cases of metastatic implantation of myxoma represent a preoperative embolic event.

Minimally invasive approaches to surgical removal Minimally invasive approaches are being applied with increasing frequency in all areas of cardiac surgery and cardiac tumors are no exception. Experience is confined to benign tumors and is quite limited. Approaches have included right parasternal or partial sternotomy exposure with standard cardioplegic techniques,115 right submammary incision with femoral-femoral bypass and non-clamped ventricular fibrillation,116 and right submammary port-access method with antegrade cardioplegia and ascending aortic balloon occlusion.117 Results in this limited number of selected patients have been good but more experience and longer follow-up are needed before this can be recommended as a standard approach.

RESULTS

Removal of atrial myxomas carries an operative mortality rate of 5% or less.31 A review of 202 resections indicates that operative mortality is related to advanced age or disability and comorbid conditions.113 Excision of ventricular myxomas carries a higher risk (approximately 10%) but the experience is small. Our experience over the last 15 years with 85 myxomas shows no operative or hospital mortality.

Recurrence of nonfamilial sporadic myxoma is approximately 1% to 4%.4,109110 It probably is even lower in patients with a normal DNA genotype. Many large series report no recurrent tumors.109,118121 The 20% of patients with sporadic myxoma and abnormal DNA have a recurrence rate estimated between 12% and 40%.4,62 The recurrence rate is highest in patients with familial complex myxomas, all of whom exhibit DNA mutation, and this is estimated to be about 22%.4 Overall, recurrences are more common in younger patients. The disease-free interval averages about 4 years and can be as brief as 6 months.109 Most recurrent myxomas occur within the heart, in the same or different cardiac chambers, and may be multiple.29,46,122123 Relationship of local recurrence to the adequacy of the original resection remains unsettled because sporadic tumors rarely recur even if full-thickness excision of the base is not done and because recurrent tumors often do not recur at the site of the original tumor.109,124 Extracardiac recurrence after resection of tumor, presumably from embolization and subsequent tumor growth and local invasion, has been observed.29,122124 The biology of the tumor, dictated by gene expression rather than histology, may be the only reliable factor predicting recurrence. DNA testing of all patients with cardiac myxoma may prove to be the best predictor of the likelihood of recurrence.125

Uncertainty concerning the true malignant potential of myxomas has increased as reports that myxomas generally classified as "malignant" are found on subsequent review to be sarcomas with myxoid degeneration.126 However, this issue also remains unsettled because of reports of metastatic growth of embolic myxoma fragments in the brain, arteries, soft tissue, and bones.80,124,127133 Symptomatic lesions of possible metastatic myxoma should be excised if possible.80,127

The extent to which patients should be subjected to long-term echocardiographic surveillance after myxoma resection is not standardized. It would seem prudent to closely follow patients who are treated initially for multicentric tumors, those whose tumors are removed from unusual locations in the heart, all tumors believed to have been incompletely resected, and tumors found to have an abnormal DNA genotype. Patients undergoing resection of tumors thought to be myxoma but with malignant characteristics at pathologic examination should have long-term, careful follow-up.

Other Benign Cardiac Tumors

As shown in Table 58-2, myxomas comprise approximately 41% of benign cardiac tumors, with three other tumors (lipoma, papillary fibroelastoma, and rhabdomyoma) together contributing a similar proportion. A variety of rarely encountered tumors accounts for the remainder.

LIPOMA

Lipomas are well-encapsulated tumors consisting of mature fat cells that may occur anywhere in the heart but also are found in the pericardium, subendocardium, subepicardium, or intra-atrial septum.2 They may occur at any age and have no sex predilection. Lipomas are slow growing and may attain considerable size before producing obstructive or arrhythmic symptoms. Many are asymptomatic and are discovered incidentally on routine chest roentgenogram, echocardiogram, or at surgery or autopsy.134,135 Subepicardial and parietal lipomas tend to compress the heart and may be associated with pericardial effusion. Subendocardial tumors may produce chamber obstruction. The right atrium and left ventricle are sites most often affected. Lipomas lying within the myocardium or septum can produce arrhythmias or conduction abnormalities.136,137 Large tumors that produce severe symptoms should be resected. Smaller, asymptomatic tumors encountered unexpectedly during cardiac operation should be removed if excision can be performed without adding risk to the primary procedure. These tumors are not known to recur.

LIPOMATOUS HYPERTROPHY OF THE INTERATRIAL SEPTUM

Nonencapsulated hypertrophy of the fat within the atrial septum is known as lipomatous hypertrophy.2 This abnormality is more common than cardiac lipoma and is usually encountered in elderly, obese, or female patients as an incidental finding during a variety of cardiac imaging procedures.119 Various arrhythmias and conduction disturbances have been attributed to its presence.120,137,138 The main problem is differentiation from a cardiac neoplasm when the lesion is discovered on echocardiography.139 After the demonstration of a mass by echocardiography, the typical T1 and T2 signal intensity of fat on MRI can usually establish a diagnosis.140,141 Arrhythmias or heart block are considered by some as an indication for resection, but data is lacking as to the long-term benefits from resection.142

PAPILLARY FIBROELASTOMA OF THE HEART VALVES

Papillary fibroelastomas are tumors that arise characteristically from the cardiac valves or adjacent endocardium.143 Grossly, these tumors are described as resembling sea anemones with frond-like projections (Fig. 58-13). The AV and semilunar valves are affected with equal frequency. Papillary fibroelastomas were formerly thought to be innocuous because they were incidental findings at autopsy. It is now known that they are capable of producing obstruction of flow, particularly coronary ostial flow, and may embolize to the brain and produce stroke.144157 They are usually asymptomatic until a critical event occurs but now are found more often because of the more frequent use of echocardiography. Papillary fibroelastomas of the cardiac valve should be resected whenever diagnosed because of their known tendency to produce life-threatening complications. Valve repair rather than replacement should follow the resection of these benign tumors whenever technically feasible, using conservative margins of resection. Cytomegalovirus has been recovered in these tumors suggesting the possibility of viral induction of the tumor and chronic viral endocarditis.152



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FIGURE 58-13 Papillary fibroelastoma of the tricuspid valve demonstrating delicate fronds.

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RHABDOMYOMA

Rhabdomyoma is the most frequently occurring cardiac tumor in children. It usually presents during the first few days after birth. It is thought to be a myocardial hamartoma rather than a true neoplasm.158 Although rhabdomyoma appears sporadically, it is associated strongly with tuberous sclerosis, a hereditary disorder characterized by hamartomas in various organs, epilepsy, mental deficiency, and sebaceous adenomas. Fifty percent of patients with tuberous sclerosis have rhabdomyoma but more than 50% of patients with rhabdomyoma have or will develop tuberous sclerosis.159,160 The exceptional patient is one with a solitary, single rhabdomyoma who does not have or develop tuberous sclerosis.

Over 90% of rhabdomyomas are multiple and occur with approximate equal frequency in both ventricles.161 The atrium is involved in fewer than 30% of patients. Pathologically, these tumors are firm, gray, and nodular and tend to project into the ventricular cavity. Micrographs show myocytes of twice normal size filled with glycogen and containing hyperchromatic nuclei and eosinophilic staining cytoplasmic granules.2,162 Scattered bundles of myofibrils can be seen within cells by electron microscopy.161

The most common presentation is heart failure caused by tumor obstruction of cardiac chambers or valvular orifice flow. Clinical findings may mimic valvular or subvalvular stenosis. Arrhythmias, particularly ventricular tachycardia and sudden death, may be a presenting symptom.162 Atrial tumors may produce atrial arrhythmias.162 The diagnosis is suggested by clinical features of tuberous sclerosis and is made by echocardiography. Rarely, no intramyocardial tumor is found in a patient with ventricular arrhythmias and the site of rhabdomyoma is located by electrophysiologic study.162

Early operation is recommended in patients who do not have tuberous sclerosis before 1 year of age.121 The tumor is usually removed easily in early infancy, and some can be enucleated.121 Unfortunately, symptomatic tumors often are both multiple and extensive, particularly in patients with tuberous sclerosis who unfortunately have a dismal long-term outlook. In such circumstances, surgery offers little benefit.

FIBROMA

Fibromas are the second most common benign cardiac tumor, with over 83% occurring in children. These tumors are solitary, occur exclusively within the ventricle and the ventricular septum, and affect the sexes equally. Fewer than 100 tumors have been reported and most are diagnosed by age 2 years. These tumors are not associated with other disease, nor are they inherited. Fibromas are nonencapsulated, firm, nodular, gray-white tumors that can become bulky. They are composed of elongated fibroblasts in broad spiral bands and whirls mixed with collagen and elastin fibers. Calcium deposits or bone may occur within the tumor and occasionally are seen in roentgenography.

The majority of fibromas produce symptoms through chamber obstruction, interference with contraction, or arrhythmias. Depending on size and location, such a tumor may interfere with valve function, obstruct flow paths, or cause sudden death from conduction disturbances in up to 25% of patients.121 Intracardiac calcification on chest roentgenograms suggests the diagnosis, which is confirmed by echocardiogram.

Surgical excision is successful in some patients, particularly if the tumor is localized, does not involve vital structures, and can be enucleated.121,163165 However, it is not always possible to completely remove the tumor and partial removal is only palliative although some patients have survived many years.121,164 Operative mortality may be high in infants. Most cases are in adolescents and adults.121,163,164 Successful, complete excision is curative.163,164 Children with extensive fibromas have been treated by cardiac transplantation.165,166

MESOTHELIOMA OF THE AV NODE

Mesothelioma of the atrial ventricular node, also termed polycystic tumor, Purkinje tumor, or conduction tumor, was mentioned in the pathologic classification of tumors. It is a relatively small, multicystic tumor that arises in proximity to the atrial ventricular node and may extend upward into the interventricular septum and downward along the bundle of His.2 Mesothelioma is associated with heart block, ventricular fibrillation,167 and sudden death. Cardiac pacing alone does not prevent subsequent ventricular fibrillation. Surgical excision has been reported.34

PHEOCHROMOCYTOMA

Cardiac pheochromocytomas arise from chromaffin cells of the sympathetic nervous system and produce excess amounts of catecholamines, particularly norepinephrine. Approximately 90% of pheochromocytomas are in the adrenal glands. Fewer than 2% arise in the chest. Only 32 cardiac pheochromocytomas had been reported by 1991.168 The tumor predominantly affects young and middle-aged adults with an equal distribution between the sexes. Approximately 60% occur in the roof of the left atrium. The remainder involve the interatrial septum or anterior surface of the heart. The tumor is reddish-brown, soft, lobular, and consists of nests of chromatin cells.

The patients usually present with symptoms of uncontrolled hypertension or are found to have elevated urinary catecholamines. The tumor is usually located by scintigraphy using 131-I-metaiodobenzylguanidine169,170 and CT or MRI.169,170 Cardiac catheterization with differential blood chamber sampling is sometimes necessary.168 Because these tumors are vascular and may be near major coronary arteries, coronary arteriograms are advisable.

After the tumor is located, it should be removed, using cardiopulmonary bypass with cardioplegic arrest. Patients require preanesthetic alpha and beta blockade, and careful intraoperative and immediate postoperative monitoring. Most tumors are extremely vascular and uncontrollable operative hemorrhage has occurred.170 Resection may require removal of the atrial and/or ventricular wall or a segment of a major coronary artery.168 Explantation of the heart to allow resection of a large left atrial pheochromocytoma has been attempted (Fig. 58-14).171



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FIGURE 58-14 Excised left atrial pheochomocytoma and explanted heart prior to reimplantation.

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Transplantation has been performed for nonresectable tumor. Complete excision produces cure.168170

HEMANGIOMA

Hemangiomas of the heart are rare tumors (24 clinical cases reported), affect all ages, and may occur anywhere within the heart.172,173 These are vascular tumors composed of capillaries or cavernous vascular channels. Patients usually develop dyspnea, occasional arrhythmias, or signs of right heart failure.174 Diagnosis is difficult and chest roentgenography may be abnormal but is not specific. Echocardiography or cardiac catheterization usually but not always establishes a diagnosis of cardiac tumor by showing an intracavity filling defect.175 CT and MRI should be done. Axial T2-weighted MRI should show a high signal mass due to vascularity (Fig. 58-15).176 Coronary angiography typically shows a tumor blush and maps the blood supply to the tumor.



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FIGURE 58-15 Axial T2-weighted magnetic resonance image showing high signal mass of left atrial hemangioma. (Reproduced with permission from Lo JJ, Ramsay CN, Allen JW, et al: Left atrial cardiac hemangioma associated with shortness of breath and palpitations. Ann Thorac Surg 2002; 73:979.)

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The tumors can be resected in asymptomatic patients, and cardiopulmonary bypass is recommended. Meticulous ligation of feeding vessels is required to prevent postoperative residual arteriovenous fistulas or intracavity communications. Partial resections have produced long-term benefits.172 Tumors rarely resolve spontaneously.177

TERATOMA

Cardiac teratoma is a rare tumor that usually presents in infants and young children but has occurred in adults.178 About 80% of the tumors are benign and the remainder have microscopic or clinically malignant cells.179 These tumors are discovered by echocardiography after a variety of symptoms lead to cardiac or mediastinal evaluation. There is little experience with surgical removal, which should be possible with modern imaging and surgical technology.


?? PRIMARY MALIGNANT TUMORS
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Primary cardiac malignancy is very uncommon, with only 21 surgically treated cases noted in a 25-year surgical experience from 196469, combining the experience of two large institutions, the Texas Heart Institute and the M.D. Anderson Cancer Center in Houston.180 Even in busy centers, primary cardiac malignancy continues to challenge the diagnostic ability and surgical skills of thoracic surgeons. Approximately 25% of primary cardiac tumors are malignant and of these about 75% are sarcomas. McAllister's survey of cardiac tumors found the most common to be angiosarcomas (31%), rhabdomyosarcomas (21%), malignant mesotheliomas (15%), and fibrosarcomas (11%) (Table 58-4).2


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TABLE 58-4 Primary malignant cardiac neoplasms in adults

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Primary malignant cardiac tumors arise sporadically, showing no inherited linkage. Although they may span the entire age spectrum, they usually occur in adults over 40 years of age. The patients usually present with symptoms of congestive heart failure, pleuritic chest pain, malaise, anorexia, and weight loss.178,181 The most common symptom has been dyspnea (Table 58-5). 180 Some develop refractory arrhythmias, syncope, pericardial effusion, and tamponade.180 The chest x-ray may be abnormal and even show a mass lesion, but the definite diagnosis is usually made with cardiac echocardiography.182,183 We have seen angiosarcoma of the right heart that presented as multiple nodules on chest x-ray, and at thoracoscopy it was found to present multiple reddish lesions of the lung consistent with angiosarcoma. Subsequent cardiac echocardiography was used to confirm the diagnosis of a cardiac primary tumor. Right atrial lesions are more frequently malignant (usually angiosarcoma) than left-sided lesions (usually myxoma, but when malignant are often malignant fibrous histiocytoma). If malignancy is suspected, chest CT or MRI may suggest histology and provide detailed anatomy and help in staging and assessing resectability. The current status of positron emission tomography (PET) scans in evaluating these patients remains controversial. We perform cardiac catheterization on all patients over 40 years of age presenting with intracardiac masses, and on all patients with large right atrial masses. Malignancy may be suggested and coronary involvement suspected by tumor blush (Fig. 58-16). This is not pathognomonic as we have seen large feeding vessel and tumor blush in a histologically confirmed myxoma.


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TABLE 58-5 Symptoms of primary malignant cardiac tumors

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FIGURE 58-16 Tumor blush in right atrial sarcoma.

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Unfortunately, primary cardiac malignancy may grow to a large size prior to detection and involve portions of the heart not amenable to resection. Some of these cases have been considered for transplantation and will be discussed later. Otherwise palliative medical therapy can be attempted with radiation therapy, although success in both symptom relief and longevity has been somewhat limited. Whether the tumor is primary or secondary, the decision to resect is based on tumor size and location and an absence of metastatic spread seen on complete evaluation. Unfortunately, the majority of primary cardiac malignancies that have been referred to our center were initially considered to be benign and incompletely resected at presentation. If malignancy is suspected or confirmed, and if the lesion appears anatomically resectable and there is no metastatic disease, then resection should be considered. If complete resection is possible, surgery provides better palliation and can possibly double survival.183 After resection, we recommend adjuvant chemotherapy and believe this will slightly improve survival179,183,184 and add to our ability to treat this desperate disease. Complete resection will depend on the location of the tumor, extent of involvement of the myocardium and/or fibrous skeleton of the heart, and histology.

Angiosarcoma

Angiosarcomas are two to three times more common in men than women and have a predilection for the right heart. Eighty percent arise in the right atrium.181,185,186 These tumors tend to be bulky and aggressively invade adjacent structures, including the great veins, tricuspid valve, right ventricular free wall, interventricular septum, and right coronary artery (Fig. 58-17).185 Obstruction and right heart failure are not uncommon. Pathologic examination of resected specimens demonstrates anastomosing vascular channels lined with typical anaplastic epithelial cells. Unfortunately, most of these tumors have spread by the time of presentation, usually to the lung, liver, and brain.181 Without resection 90% of the patients are dead within 9 to 12 months after diagnosis despite radiation or chemotherapy.32,187 We have found carefully selected patients without evidence of spread on metastatic evaluation who have undergone complete surgical resection with subsequent chemotherapy (Fig. 58-18). We have had no hospital mortality in this small group and the main problem remains metastasis rather than recurrence at the local site.



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FIGURE 58-17 Angiosarcoma with extensive involvement of mediastinum.

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FIGURE 58-18 (A) Right atrial angiosarcoma involving right coronary artery and tricuspid valve. (B) Excision of tumor with right coronary artery and tricuspid valve. (C) Tricuspid valve replaced. (D) Completed repair using bovine pericardium. (Copyright 2002, Baylor College of Medicine.)

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Malignant Fibrous Histiocytoma

Malignant fibrous histiocytoma (MFH) is the most common soft-tissue sarcoma in adults. Its occurrence as a cardiac primary malignancy has been relatively recently accepted as a specific entity. It is characterized histologically by a mixture of spindle cells in a storiform pattern, polygonal cells resembling histiocytes, and malignant giant cells. The cell of origin is the fibroblast or histioblast.182,188 It usually occurs in the left atrium and often mimics myxoma. In fact, every left atrial MFH referred to our institution has been previously incompletely resected when thought to represent a myxoma. The tendency to metastasize early is not as prominent as with angiosarcoma. Several reports exist with rapid symptomatic recurrence after incomplete resection despite chemotherapy. These patients often die of local cardiac disease prior to development of metastasis. We believe that if complete resection can be obtained (particularly if the malignant nature is recognized and complete resection can be done at the original operation) and adequate chemotherapy provided, we may improve the survival in this otherwise dismal disease. Our group believes incomplete resection is usually due to inadequate exposure of these broad-based tumors, which often extend to the anterior wall of the left atrium. Difficulty in exposing this posterior portion of the heart leads to inhibition of aggressive resection for clear margins, and makes reconstruction difficult. We believe that these difficulties can be overcome by excising the heart and inverting it so that the posterior left atrium is now an anterior structure. This allows excellent visualization for aggressive resection and reconstruction done ex vivo, after which the heart is reimplanted (Fig. 58-19).



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FIGURE 58-19 Ex vivo heart showing large sarcoma arising from the anterior left atrial wall.

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This was first attempted by Cooley in 1984 for a pheochromocytoma and, although technically accomplished, it was unsuccessful because of severe hemorrhage due to the vascular nature of the tumor.178 Our program first attempted this approach for MFH in 1998 (Fig. 58-20).188



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FIGURE 58-20 (A) Explanation of the heart for exposure of extensive left atrial sarcoma. (B) Resection of left atrial sarcoma. (C) Reconstruction of the heart with bovine pericardium after tumor resection. (D) Reimplantation of the heart using a 20-mm polytetrafluoroethylene graft between the inferior vena cava and right atrium.

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We have performed six of these autotransplant procedures with no operative or hospital mortality. Three patients have died of metastatic disease without local recurrence and three are alive and disease-free 4 months to 3 years postoperatively. All were given adjuvant chemotherapy. This has proven to be an efficacious technique at local control with a low mortality in our hands, but metastasis is still common and strongly suggests that further improvements in survival will require more effective, biologically based systemic therapy.

Rhabdomyosarcoma

Rhabdomyosarcomas do not evolve from rhabdomyoma and occur equally in the sexes. The tumors are multicentric in 60% of patients and arise from either ventricle. These tumors frequently invade cardiac valves or interfere with valve function because of their intracavitary bulk. Microscopically, tumors cells demonstrate pleomorphic nuclei and spidery, wispy, streaming eosinophilic cytoplasm, usually in a muscle-like pattern (Fig. 58-21).



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FIGURE 58-21 Representative microphotograph of rhabdomyosarcoma showing loosely elongated rhabdomyoblasts with distinct angulation of the muscle fibers and undifferentiated tumor cells with plump nuclei and prominent nucleoli. Masson's trichome X 800. (Courtesy of Dr. G. G. Pietra.)

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The tumors are aggressive and may invade pericardium. Surgical excision of small tumors may be rational but local and distant metastasis and poor response to radiation or chemotherapy limit survival to less than 12 months in the majority of these patients.163,178,179,183,189,190

Other Sarcomas and Mesenchymal Origin Tumors

McAllister and Fenoglio found that malignant mesotheliomas arising from the heart or pericardium and not from the surrounding pleura were the third most common malignant cardiac tumors and that fibrosarcomas were fourth.2 However, in the two decades since their work, clinicians have rarely encountered these tumors. This apparent decrease in incidence may be related to changes in histological criteria for classifying primary malignant neoplasm since their study.5,172,179184,190192

The histology of these tumors can be ambiguous and difficult. These neoplasms can resemble other sarcomas, and some might be deemed fibrous histiocytomas today. The behavior of these tumors is more important and, as with other cardiac sarcomas, resection of small tumors in the absence of known metastasis perhaps is justified but data is scarce.32,180,183,190 This being said, it is important to rule out more diffuse thoracic involvement with mesothelioma before considering resection of an isolated cardiac or pericardial mesothelioma. A PET scan may be considered, and any suspicious pleural thickening or effusion should be carefully evaluated both radiographically and histologically.

Myosarcoma, liposarcoma, osteosarcoma, chondromyxosarcoma, plasmacytoma, and carcinosarcoma arising from the heart have all been reported,121,192195 but by the time diagnosis is made, only palliative therapy can usually be offered and surgery is only occasionally indicated. Regardless of therapy, it is unusual for patients with these diagnoses to survive more than a year.

Lymphomas

Lymphomas may arise from the heart although it is rare.196 Most of these tumors respond to radiation and chemotherapy. Even when complete resection is not possible, and incomplete resection is performed to relieve acute obstructive systems, radiation and chemotherapy have allowed for up to 3-year survival in selected patients.

Heart Transplantation

Malignant primary cardiac tumors may grow to a large size prior to detection. Additionally, extensive myocardial involvement or location affecting the fibrous skeleton of the heart may make complete resection impossible. Because complete resection yields better results than incomplete resection,183 orthotopic cardiac transplantation has been considered as a treatment option in some cases. Reports of transplantation for a number of cardiac tumors including sarcoma,197199 pheochromocytoma,200 lymphoma,201 fibroma,166 and myxoma202 have appeared. However, the long-term results are uncertain because some patients die from recurrent metastatic disease despite transplantation.200,201,203 As of 2000, 28 patients had been reported who had undergone orthotopic transplantation for primary cardiac tumors and, of these, 21 had malignant tumors.203 The mean survival for patients with primary cardiac malignancy was 12 months. Although technically feasible in some cases, orthotopic transplantation is hindered by a scarcity of donor organs coupled with an extensive recipient list of patients without cancer. In addition, the large size of the tumor when diagnosed often necessitates rapid intervention for progressive congestive heart failure. Finally, the morbidity and mortality involved with immunosuppression as well as the unknown effect of immunosuppression on any remaining malignancy should be considered. For these reasons, orthotopic cardiac transplantation for primary cardiac tumor remains controversial and should be considered carefully on a case-by-case basis by experienced transplant and tumor boards. In most cases, orthotopic transplantation should be reserved for unresectable benign tumors, such as cardiac fibroma.


?? SECONDARY METASTATIC TUMORS
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Approximately 10% of metastatic tumors eventually reach the heart or pericardium, and almost every type of malignant tumor has been known to do so.2,5,9,204 Secondary neoplasms are 20 to 40 times more common than primary cardiac malignancies.4,205 Up to 50% of patients with leukemia develop cardiac lesions.5 Other cancers that commonly involve the heart include breast, lung, lymphoma, melanoma, and various sarcomas.2,206,207 Metastasis involving the pericardium, epicardium, myocardium, and endocardium roughly follow that order of frequency2,9 as well (Table 58-6).


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TABLE 58-6 Metastatic cardiac disease

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The most common means of spread, particularly for melanoma, sarcoma, and bronchogenic carcinoma, is hematogenous, and ultimately via coronary arteries. In addition, metastasis can reach the heart through lymphatic channels, though direct extension from adjacent lung, breast, esophageal, and thymic tumors, and from the subdiaphragmatic vena cava. The pericardium most often is involved by direct extension of thoracic cancer; the heart is the target of hematologous and/or retrograde lymphatic metastasis.5 Cardiac metastases rarely are solitary and nearly always produce multiple microscopic nests and discrete nodules of tumor cells (Fig. 58-22).2,5,9 Cardiac metastases produce clinical symptoms in only about 10% of afflicted patients.5,208,209 The most common symptom is pericardial effusion or cardiac tamponade. Occasionally patients develop refractory arrhythmias or congestive heart failure. Chest radiographs and electrocardiograms tend to show nonspecific changes but echocardiography is particularly useful for diagnosis of pericardial effusion, irregular pericardial thickening, or intracavity masses interfering with blood flow.



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FIGURE 58-22 Hematogenous metastases within the myocardium of a patient with renal cell cancer. (Reproduced with permission from Hurst JW, et al: Atlas of the Heart. New York, McGraw-Hill, 1988.)

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Surgical therapy is limited to relief of recurrent pericardial effusions or, occasionally, cardiac tamponade. In most instances, these patients have widespread disease with limited life expectancies. Surgical therapy is directed at providing symptomatic palliation with minimal patient discomfort and hospital stay. This is most readily accomplished via subxiphoid pericardiotomy, which can be accomplished under local anesthesia if necessary with reliable relief of symptoms, a recurrence rate of about 3%, and little mortality.207 Alternatively, a large pericardial window in the left pleural space can be created using thoracoscopy, but we would recommend this only under unusual circumstances.210 This can be accomplished with minimal patient discomfort, but does require general anesthesia with single-lung ventilation and may be poorly tolerated by patients with hemodynamic deterioration secondary to large effusions.


?? RIGHT ATRIAL EXTENSION OF SUBDIAPHRAGMATIC TUMORS
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Abdominal and pelvic tumors on occasion may grow in a cephalad direction via the inferior vena cava to reach the right atrium. Subdiaphragmatic tumors are frequently renal carcinomas, although hepatic, adrenal, and uterine tumors have occasionally exhibited this behavior. Up to 10% of renal cell carcinomas invade the inferior vena cava, and nearly 40% of these reach the right atrium.211 Radiation and chemotherapy are not effective in relieving the obstruction of blood flow. If the kidney can be fully removed as well as the tail of tumor thrombus, survival can approach 75% at 5 years.121,213

Renal cell tumors with atrial extension typically are resected with abdominal dissection to ensure resectability of the renal tumor. Initially we performed a concomitant median sternotomy and often used cardiopulmonary bypass with hypothermic circulatory arrest when treating these patients. However, we have changed our approach and now work closely with our liver transplant surgeons who have extensive experience in the area of the retrohepatic vena cava. We have found we can expose the vena cava up to the right atrium through an abdominal incision. With ligation of the arterial inflow, the tumor tail often shrinks below the diaphragm and, in almost all circumstances, this can be removed without the use of cardiopulmonary bypass. Occasionally veno-veno bypass as used in hepatic transplantation is necessary to occlude inflow through the inferior vena cava, but this is unusual. If the tumor is too extensive for that maneuver, then median sternotomy is performed and cardiopulmonary bypass with hypothermic circulatory arrest can be used to remove the tumor from the cardiac chambers down into the inferior vena cava. Perfusion can be restarted followed by removal of the rest of the tumor. Although it leads to adequate exposure, significant problems with coagulopathy are often apparent after cardiopulmonary bypass and profound hypothermia. A 5-year survival rate of 75% has been achieved following nephrectomy with resection of right atrial tumor extension.212,213 Other subdiaphragmatic tumors with atrial extension that have been resected successfully include hepatic and adrenal carcinoma as well gynecologic tumors.214218


?? MOLECULAR AND BIOLOGIC-BASED DIAGNOSIS AND THERAPY FOR CARDIAC TUMORS
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This is an exciting time for investigators involved in the search for novel therapies for tumors such as many of those discussed in this chapter. A "new biology" is being developed in laboratories around the world working in these areas, and this is supplanted by the knowledge that is being obtained from the concerted Human Genome Project and the subsequent development of proteomics.219 It is incumbent upon the thoracic surgeon involved in the care of patients with cardiac tumors to have some degree of familiarity with the terms and promise of these advances because significant additional improvement in survival of many of these patients is unlikely to result from further advances in surgical technique.

Interestingly, many sarcomas demonstrate reproducible translocations that allow for the production of novel chimeric genes, which may code for a variety of fusion proteins. Many of these proteins have been found to engender cellular phenotypic malignant changes, resistance to apoptosis, and unfettered growth.220 Although not associated with cardiac involvement, the fusion proteins EWS-FL11 and EWS-ERG are noted in Ewing's sarcoma. When full-length antisense oligonucleotide constructs are utilized to target the mRNA of these proteins, protein expression is downregulated, and an 8-fold increase in apoptosis sensitivity is noted.211 These fusion proteins have been noted in some forms of rhabdomyosarcoma, and the most common is PAX3-FKHR. This oncoprotein combines components of two strong transcriptional activators, and may increase the production of the downstream anti-apoptotic protein bcl-xl. Antisense oligonucleotides directed at this oncoprotein mRNA have led to apoptosis in rhabdomyosarcoma cells.221,222 Similarly, in our laboratory we have demonstrated that antisense oligonucleotides directed at the mRNA of the downstream anti-apoptotic protein bcl-xl in mesothelioma can induce apoptotic cellular death and engender chemosensitivity.223 A similar translocation and fusion protein has been noted in fibrosarcoma. This translocation (t(12;15)(p13q25)) brings together genes from chromosomes 12 and 15, which combines a transcription factor with a tyrosine kinase receptor. The resultant fusion protein is a tyrosine kinase that has oncogenic potential.224 Reproducible translocations and fusion proteins with downstream effectors of malignant behavior have not been described for angiosarcoma, but they are actively being sought. Antisense treatment has been maligned in the past due to problems with both delivery and stability of therapeutic constructs. However, sophisticated biochemical alteration of these molecules has improved stability, and two recent solid tumor trials utilizing antisense therapy for salvage have demonstrated positive results.225,226 Additional methods of delivering antisense to tumor cells, including viral vector delivery, have been developed. Finally, in addition to antisense methods, small molecule inhibition of many of these fusion proteins should be possible.

Angiosarcoma is an obvious target for therapies based on antiangiogenesis. The weak antiangiogenic properties of interferon alpha are presumed to be the mechanism that accounts for responses to this agent in this tumor.227 Multiple new antiangiogenic agents are being evaluated currently in phase I and II trials, and a number of noncardiac angiosarcoma patients have been treated at our institution on this basis. We have noted several to develop stabilized disease, but there are no definitive data yet published. Certainly, the use of these agents in these vascular origin tumors is theoretically attractive.

Viral vector-mediated gene therapy has been evaluated for various sarcomas in the preclinical setting. A number of potential targets exist for these sorts of therapies. Although p53 is not commonly mutated or absent, mdm-2 is often overexpressed in many sarcomas, including angiosarcoma. This gene is a known oncogene that is able to directly induce cellular transformation. Importantly, when overexpressed, it binds to and inhibits p53 activity, even though expression of p53 may appear normal. Overexpression of mdm-2 has also been associated with VEGF overproduction and angiogenesis.227,228 Preclinical studies of adenoviral vector p53 transduction of sarcoma in SCID mice have demonstrated growth delay, tumor regression, and decreases in VEGF expression.229 Many other targets for this approach, including the inhibition of Nf-kB expression utilizing an adenoviral dominant negative Ik-B{alpha} construct and prodrugmediated gene therapy utilizing a doxorubicin prodrug and adenoviral transfer of a metabolizing enzyme in sarcoma cells, have been shown to be effective.230,231 Unfortunately, the application of viral-mediated gene therapy paradigms to this tumor suffer the same problems of targeting, transgene expression durability, and immune response that are problematic for the field in general.

In regard to molecular diagnosis, there are no reproducible familial patterns for development of most malignant tumors. However, familial cardiac myxoma, rhabdomyoma, and fibroma may exhibit reproducible genetic abnormalities that lend themselves to the development of genetic testing to identify individuals at risk. Familial myxoma syndrome, or Carney complex, has been associated with mutations in the 17q24 gene PRKAR1{alpha} that codes for the R1{alpha} regulatory subunit of cAMP-dependent protein kinase A (PKA).232 Although not widely available, genetic diagnosis of this syndrome is now technically achievable.233 Reproducible mutations in the TSC-1 and TSC-2 genes in patients with tuberous sclerosis and cardiac rhabdomyoma, as well as mutations in the PTC gene of patients with the Gorlin syndrome and cardiac fibroma have been noted.234236 It is hoped that in the near future we will be able to predict who is at particular risk for these and other cardiac tumors. This could allow for more intense surveillance, earlier detection, and a higher rate of surgical or multimodality cure for these patients.


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