Definitions

Primary cardiac tumors are classified as neoplastic, hamartomatous, or hyperplastic. Typically, cardiac tumors originate from one of the following cell lines: mesenchymal, endothelial, neuroconduction system, autonomic nerve tissues, lymphatic tissues, or any other cell types normally found in the heart. Only tumors arising from cells within the myocardium and endocardium will be discussed in this chapter; masses arising from the pericardium will not be addressed.

History

The first known documentation of a cardiac tumor was by Realdo Colombo in his studies of anatomy in 1559.¹ By 1865, both benign and malignant cardiac tumors had been described, including fibromas, rhabdomyomas, and sarcomas. It was not until 1952, however, that the first report of a premortem diagnosis of atrial myxoma was published. The first successful surgical resection of a myxoma followed in 1954.² Currently, echocardiography and other imaging modalities allow for the rapid and accurate diagnosis of cardiac tumors. Furthermore, sophisticated operative techniques for resection and subsequent reconstruction are well established.

Overview

Cardiac neoplasms represent a rare disorder of the heart. Based on autopsy studies, the incidence of primary cardiac tumors is estimated to be 0.02 percent (ranging from 0.0017 to 0.25 percent).³ Metastatic tumors to cardiac structures are more common than primary tumors with an estimated incidence of 1.23 percent in a large autopsy study. Common metastatic lesions include carcinoma of the lung, esophagus, breast, liver, melanoma, and lymphoma.^4,5 Regarding primary cardiac tumors, it is generally accepted that three-quarters are benign and one-quarter are malignant.³ Among the benign tumors, atrial myxomas are by far the most common, accounting for one-half of all benign cardiac tumors, with other less common tumors being papillary fibroelastomas, lipomas, and rhabdomyomas. The most common malignant cardiac tumors are sarcomas.

Due to their relative infrequency, the diagnosis of cardiac neoplasms can be challenging. Clinical manifestations are independent of the pathologic subtype and are usually a function of the location of the tumor, propensity for systemic embolization, or nonspecific constitutional symptoms caused by elaboration of cytokines by the tumor. For example, patients may present with symptoms of either right- or left-sided heart failure secondary to the location and point of obstruction caused by the mass. Valvular masses can cause insufficiency or relative stenosis of the affected valve, and mechanical obstruction can occur due to the shape of the mass and its ability to occlude the valvular orifices, the vena cavae, or inflow from the pulmonary veins. Furthermore, left-sided masses can embolize to the systemic circulation, causing cerebrovascular events, myocardial infarction, and end-organ or limb malperfusion. Echocardiography is the initial diagnostic test of choice; however, EKG-gated computed tomography (CT) and magnetic resonance imaging (MRI) can provide useful additional information in terms of tumor diagnosis, extent, and involvement.

Treatment involves complete excision for curative therapy for benign tumors and even for malignant tumors when possible. The prognosis is generally excellent with benign resectable neoplasms; it remains dismal with malignant neoplasm, with survival generally around 1 to 2 years. Regardless, resection is recommended for cardiac sarcomas when feasible with adjuvant chemoradiation being protocol driven. Primary cardiac lymphomas are treated mainly with chemoradiation; surgical debulking can be performed for palliation.

Cardiac tumors often present as an incidental finding on echocardiography or as a new finding during operations for other indications. Symptoms of cardiac tumors can be broken down into three general categories: cardiac manifestations, embolic phenomena, and systemic manifestations. As will be discussed in more detail, these symptoms are dependent on the location and mobility of the tumor within the heart, the propensity for systemic thrombus and/or tumor emboli, and the production of cytokines causing generalized symptoms.

Cardiac Manifestations

Cardiac manifestations are the most common symptoms of cardiac neoplasms. The typical presentation can resemble congestive heart failure with dyspnea on exertion, peripheral edema, pulmonary edema, and orthopnea.⁵ Congestive heart failure caused by cardiac tumors is usually due to mechanical obstruction related to pedunculated tumors that can obstruct the mitral valve or, less commonly, the tricuspid valve orifices. Masses that arise directly from cardiac valve tissue usually cause valvular insufficiency by preventing proper leaflet coaptation of the involved valve but may, in rare circumstances, cause valvular stenosis.

Cardiac tumors, most commonly rhabdomyomas and fibromas, can be the etiology of significant arrhythmias. The arrhythmias are usually due to involvement of the myocardium and conduction system. Tumors involving the atrial septum near the atrioventricular node can cause heart block, while masses in the ventricles can result in lethal ventricular tachycardias or fibrillation. Clinical manifestations of these arrhythmias can be anywhere along the range from palpitations, syncope, to sudden death.

Other cardiac manifestations are much less common. Angina pectoris and myocardial infarction can be a manifestation of tumor emboli. Rarely, left ventricular tumors can grow and compress any portion of the left coronary artery, causing an ischemic event as well. Pericardial effusions or tamponade may occur with hemangiomas, angiosarcomas, or lymphomas.

Embolic Phenomena

Systemic embolization is a frequent clinical manifestation of friable tumors. The emboli can consist of fragmented tumor and/or thrombus formed on the surface of the mass. The clinical result of the embolization is a function of the vessels involved and the size of the emboli. Left-sided emboli may travel anywhere in the systemic circulation and can present as an ischemic stroke, myocardial infarction, mesenteric ischemia, or limb malperfusion. Large tumor fragments can cause occlusion of larger arteries, including the abdominal aorta. Right-sided tumors can lead to pulmonary emboli and, if the embolic burden is large enough, pulmonary hypertension may develop. Importantly, right- or left-sided embolic events in patients with no known risk factors are cardiac in origin until proven otherwise.

One recent study found the overall rate of embolization due to primary cardiac tumors to be 25 percent. This same study found that papillary fibroelastomas, which are typically found on the mitral and aortic valves, are the most likely histological tumor type to embolize. Tumors in the left atrium or on the aortic valve have the highest embolic potential.⁶ Given the relatively high risk of embolization, excision of all resectable cardiac tumors should be performed expeditiously.

Systemic Manifestations

Constitutional symptoms such as fever, anorexia, malaise, myalgias, arthralgias, and diffuse erythematous rash can be associated with cardiac tumor. This constellation of symptoms is usually associated with myxomas and is believed to be secondary to interleukin 6 production.⁷ Further, patients may be anemic or present with an increased erythrocyte sedimentation rate, C-reactive protein, and globulin levels. Notably, both the systemic manifestations and laboratory abnormalities usually resolve with resection of the mass.

Physical Exam

The physical exam is usually nonspecific in patients with cardiac tumors. Evidence of congestive heart failure (peripheral edema, hepatomegaly, jugular venous distention, and rales) may be present. Signs of systemic emboli—pulseless extremity, neurologic deficits, abdominal pain out of proportion to exam—should be assessed in all patients presenting with a cardiac tumor. Furthermore, the diagnosis of a cardiac tumor should prompt one to consider the possibility of a distant primary with metastatic lesion to the heart. For example, malignant melanoma is one of the most common cancers metastasizing to the heart, so inspection of the skin should be carried out to locate any possible lesions.

Cardiac auscultation can reveal evidence of pulmonary edema, such as a split S₁ or loud S₄. Also, a holosystolic murmur at the apex can signify mitral insufficiency, while a new-onset diastolic rumble can be heard in the case of a tumor partially occluding the mitral valve orifice during ventricular filling. These murmurs can be heard in up to 50 percent of patients with cardiac tumors.⁷ The specificity of the exam is increased when the intensity of the murmur changes with patient positioning. In addition, when a left atrial tumor prolapses through the mitral valve, a loud split S₁ can be heard due to delayed closure of the valve. A “tumor plop” can be also be heard, which is a small murmur heard early in diastole.⁵

Echocardiography is the gold standard in the diagnosis of cardiac tumors. Transthoracic echocardiography should be the initial imaging modality and usually provides all necessary information. Transesophageal echocardiography, however, is utilized if questions remain after the transthoracic echo, is especially useful with smaller tumors, and can provide greater detail regarding the size, location and even the likely point of origin of the tumor. CT and MRI are especially useful with malignant and metastatic tumors and can be used to further characterize the nature and location of cardiac masses. Other adjunctive tests, such as plain chest radiography and electrocardiography, are used in the workup of cardiac tumors to assess associated pathology and conduction abnormalities, respectively.

Electrocardiography

Electrocardiograms should be obtained in the workup of cardiac masses to assess for rhythm disturbances. Tumors involving the conduction system or atrioventricular node can cause atrioventricular block or supraventricular tachycardias. Masses found in the ventricles, such as fibromas, can cause lethal ventricular fibrillation or tachycardia as well. Despite these concerns, most patients with cardiac tumors maintain a normal sinus rhythm.

Chest X-Ray

A plain chest film, while not specific for cardiac tumor, is an important part of the initial workup. Significant findings on chest x-ray are cardiomegaly due to either heart failure or the mass itself, compensatory hypertrophy/dilation secondary to valvular dysfunction, or enlargement of one of the cardiac chambers from a large mass. Additional notable findings include pulmonary edema secondary to congestive heart failure and additional lesions in the lungs or bone that suggest additional metastatic disease.

Echocardiogram

Echocardiography, either transthoracic or transesophageal, is the mainstay of the diagnosis and evaluation of cardiac tumors. Transthoracic echocardiography is easy to perform, widely available, and can be used for screening in high-risk patients, such as those with a history of previous cardiac mass or the Carney complex (described later). While transthoracic echocardiography is excellent for determining the presence of a mass, transesophageal echocardiography can give more information regarding the location of the mass, the presence and morphology of a stalk, and the precise origin of the tumor. One advantage of echocardiography is the ability to give temporal as well as spatial resolution, thus evaluating the motion of a pedunculated tumor in the cardiac chamber and its effect on normal contraction, valvular function, and blood flow during the cardiac cycle.

Computed Tomography

With the advent of ECG-gated CT, this modality is being used more frequently to further characterize cardiac tumors. CT can detect areas of heterogeneity, calcification, or enhancement with contrast (important in the diagnosis of hemangiomas) and can yield information with regards to the amount of myocardial involvement. This is especially important in differentiating benign from malignant disease and aids in preoperative planning.

Magnetic Resonance Imaging

MRI can provide information regarding the anatomic location of the mass as well as the extent of invasion of the cardiac wall or septum. MRI can give better resolution of the soft tissues, thus making it more effective at determining the extent of involvement of the cardiac walls. This can be invaluable in the evaluation of masses and the differentiation between benign and malignant lesions, thus obviating the need for open biopsies. Images taken real time can also give an impression of the functional disturbances caused by the mass.⁵

Cardiac and Coronary Angiography

In the past, angiography was used to diagnose intracardiac tumors, but the use of angiography has declined dramatically with the widespread use of echocardiography and the recognized risk of tumor fragmentation due to the angiography catheter (Fig. 48-1). Coronary angiography should be considered in all patients undergoing cardiac mass resection to determine the presence of coronary artery disease and the need for simultaneous coronary bypass. Coronary angiography can also show if a tumor derives its vascular supply from a main coronary artery, which could suggest that a bypass of that artery may be necessary.

Myxoma

Atrial myxomas comprise one-half of all benign primary cardiac tumors, far outnumbering any other tumor type. Approximately 75 percent arise from the left atrium, with the majority originating at the edge of the fossa ovalis. An additional 15 to 20 percent arise from right atrium, again largely at the edge of the fossa ovalis. Biatrial myxomas have been described; they likely represent tumor extension from one atrium to another through the foramen ovale. The final 3 to 4 percent of myxomas arise from the ventricles with bilateral ventricular involvement being extremely rare.⁷ Most myxomas arise as solitary lesions but multifocal disease has been reported. When they do arise, the majority of cases of multiple myxomas are associated with a familial myxoma syndrome, such as the Carney complex of cardiac myxoma, adrenocortical tumors, and skin hyperpigmentation. Myxomas have little to no malignant or metastatic potential, although some rare cases of metastatic myxomas have been reported.⁸

Epidemiology

Although myxomas have been reported in people of any age ranging from infancy to 95 years, the median age at diagnosis is 50, with the majority of cases being discovered in the third through sixth decades of life.^7,9 There is a clear female preponderance, with women making up about two-thirds of diagnosed patients.⁹

The vast majority of myxomas are sporadic, but 5 to 10 percent of cases demonstrate familial patterns of inheritance. These patients are more likely to have multicentric disease, recur after excision, occur in younger patients (mean age of 23.9), and are more likely to affect males with a male-to-female ratio of 2:1.^10,11 Originally described as the NAME (nevi, atrial myxoma, myxoid neurofibromata, ephelides) and then the LAMB (lentigines, atrial myxoma, mucocutaneous, and blue nevi) syndromes, the Carney complex describes the close association of cardiac myxoma, Cushing syndrome secondary to pigmented nodular adrenocortical dysplasia, cutaneous myxoma, myxoid mammary fibroadenoma, and pigmented spots on the skin. Genetic studies have determined that the Carney complex is due to a mutation at the chromosome 17q24 locus. This locus contains the PRKAR1A gene, which codes for the R1-α regulatory subunit of the cAMP-dependent protein kinase A. Nonsense or frameshift mutations of this gene result in decreased R1-α protein; how this contributes to tumorigenesis has not yet been elucidated. Of note, it was initially thought that a mutation on chromosome 2p was the source of the symptoms in one family studied, but further analysis demonstrated that this kindred had a mutation at the 17q24 locus as well.¹¹ This disease is inherited with an autosomal dominant pattern.

Given that patients with familial myxoma have an elevated recurrence rate of 12 to 22 percent, close follow-up with echocardiography is recommended.⁷ First degree relatives of patients with the Carney complex should be screened for cardiac myxomas.

Pathology

Macroscopically, myxomas fit into two categories based on their gross appearance: solid and gelatinous (Fig. 48-2A and B). Solid tumors appear firm and are usually pedunculated and located on the edge of the fossa ovalis. Gelatinous tumors appear softer and more friable with clear pink or green coloration. Gelatinous tumors also have a villous or lobed appearance with thrombus development between the villi. These differences are not absolute, as some myxomas have characteristics of both types.¹² The clinical presentations can differ between the two, as solid tumors are more likely to present with symptoms of congestive heart failure and gelatinous tumors are more likely to embolize. These morphological differences can be seen on echocardiography.¹³

Histology

Microscopically, myxoma cells are spindle-shaped with round or oval nuclei, prominent nucleoli, and extremely rare mitotic figures. Some cells are noted to have two nuclei. They are arranged in groups around capillaries within a myxoid stroma and can resemble endothelial cells. Also present are chronic inflammatory cells and hemosiderin-laden macrophages.¹² Areas of hemorrhage are common in both types of myxoma, but they are more common in solid tumors.¹⁴ Necrosis and calcifications can be seen as well, up to 8.7 and 16 percent, respectively, in a study of 80 atrial myxoma resections performed at the Mayo Clinic. Other uncommon findings include bone and cartilage formation and glandular formations, including goblet cells and groups of cuboidal and columnar cells.¹⁵

The histogenesis of myxomas remains controversial. Initial hypotheses held that the myxomas actually arose from clot and represented highly organized thrombi. This view has largely been abandoned in favor of a neoplastic theory, although no definite progenitor cell has been implicated. Some studies have suggested that the tumors are endothelial in origin, supported by the fact that some cells will test positive for Factor VIII; it has been shown that only the cells lining vessels within the tumors have such staining properties. Presumably, these cells represent normal endothelium within the tumor and not neoplastic cells. The myxoma cells all stain strongly for vimentin, which suggests a mesenchymal origin. Also of note, many of the cells stained for S-100, a protein found in malignant melanoma as well as cells with chondromatous differentiation. Elements of smooth muscle have also been seen in myxomas; these are also located around vessels within the tumors and not dispersed within the myxomatous matrix. This has led investigators to conclude that myxomas likely arise from multipotent mesenchymal cells that may be embryological remnants.¹⁶ An alternative hypothesis is that myxomas are actually hamartomatous in nature, rather than neoplastic (Fig. 48-3A and B).

Treatment