Tumores cardíacos

General considerations and epidemiology

Cardiac masses range from non-neoplastic lesions to high grade malignancies and occur over a wide range of ages.   These tumours can be divided in non-neoplastic masses, which can mimic neoplasms on imaging; primary neoplasms, either benign or malignant; and metastatic tumours. The true incidence of primary cardiac tumours remains largely unknown, since a great number of cases are still undiagnosed antemortem, but it has been estimated based on population and autopsy studies from 0.0017-0.33 % [1]. Primary tumours may arise in adults most frequently from the endocardium, followed by the cardiac muscle, and, most infrequently, the pericardium.  Approximately 90% of adult heart tumours are either cardiac myxomas or sarcomas and the other 10% comprise a quite varied group of lesions. In children, the specific tumour types differ in their prevalence. Rhabdomyomas and fibromas comprise a large majority of pediatric heart tumours, which are generally benign.  Whereas myxoma is the most common adult heart tumour, pediatric tumours are comprised primarily of non-neoplastic hamartomatous lesions. These include two lesions of myocyte derivation, namely rhabdomyoma and histiocytoid cardiomyopathy (also called Purkinje cell hamartoma), and cardiac fibroma.  These hamartomatous lesions are best considered separately, as many do not occur in adults and have no extracardiac counterparts, and are not treated in this chapter.

Clinical features and radiological assessment

Cardiac tumours present with a variety of symptoms, including those related to obstruction, embolism, and elaboration of substances resulting in constitutional symptoms. The presentation of cardiac tumours depends not only upon the size of the tumour, but upon its anatomic location. Growth rate, friability, and invasiveness are also important factors that determine clinical features[2]. Large tumours may be relatively silent, whereas small tumours in a critical location may give rise to devastating clinic consequences. Left atrial tumours, especially those that are mobile or pedunculated, may lead to systemic embolism involving the coronary, cerebral and peripheral circulations. Intramural left ventricular tumours may be asymptomatic or present with a mass effect. With protrusion into the cavity, hemodynamic compromise may result. Right atrial or right ventricular tumours may result in right heart failure from atrioventricular or pulmonary outflow obstruction, resulting in peripheral edema, hepatomegaly, ascites, shortness of breath, syncope and sometimes, sudden death [3]. If the tumours interfere with valve function they may result in regurgitation or stenosis.

Primary tumours of the heart and pericardium may be detected as an abnormal finding on a chest radiogram or another imaging test obtained for an unrelated reason. The main imaging modalities for evaluating primary cardiac tumours are echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT). Echocardiography has the best spatial and temporal resolution of the cardiac imaging modalities, providing excellent anatomic and functional information  [4]. Echocardiography can image velocities with Doppler, which allows for assessment of presence, degree, and location of obstructions to blood flow or valve regurgitation. Disadvantages of echocardiography include suboptimal image quality in patients with poor acoustic windows, inability to image extent of disease outside of the mediastinum, and relatively low soft tissue contrast, which limits detection of tumour infiltration.  MRI has the highest soft tissue contrast of the imaging modalities, which makes it the most sensitive modality for detection of tumour infiltration [5].  MRI should be considered when the tissue type, exact location, or the relationships of the tumour with neighboring structures are not completely defined by echocardiography or when surgical resection of the tumour is considered. The advantages and disadvantages of CT are intermediate between those of echocardiography and MRI [6]. CT scanners have spatial resolution, better than that of MRI, but not as high echocardiography.  CT has better soft tissue contrast than echocardiography, and can be used to definitively characterize fatty content and calcifications; however, the overall soft tissue contrast and ability to characterize tumour infiltration and tumour type is less than that of MRI.

Benign tumour-like conditions

Mural thrombi

The majority of mural thrombi occur in association with underlying heart disease[7] or after cardiac surgery.  Left atrial thrombi are frequently associated with mitral valvular disease, especially mitral stenosis, and thrombi occur in either atrium in patients with atrial fibrillation[7]. Mural thrombi are occasionally removed surgically, and may be clinically and pathologically misdiagnosed as myxomas[8,9]. Mural thrombi in the absence of heart disease occur in any chamber, but are most common in the right atrium[7].  In the majority of patients, a coagulation defect is either suspected or documented[7-9].

Grossly, cardiac thrombi are relatively homogenous, firm, whitish tan masses, without gelatinous and hemorrhagic areas characteristic of myxoma. Mural thrombi typically occur in the atrial appendages or posterior walls of the atrium, often near the venae cava, whereas myxomas almost exclusively occur at the fossa ovalis.  Histologically, organized thrombi are characterized by layers of degenerated blood cells with a margin of granulation tissue, and eventually fibrosis.

 

Ectopias

Two main types of ectopias are uncommonly identified in the heart tissue. Cystic tumour of the atrioventricular node was once considered of mesothelial or endothelial origin, but nowadays there is some evidence that they represent a form of ultimobranchial heterotopia[10].  The majority of patients have congenital heart block, with a striking female predominance [11].  Death is usually sudden and unexpected.  Pathologically, there are multiple cysts, which occur in the area of the AV node and the nearby atrial tissues, without involvement of the central fibrous body or penetrating bundle.  The cysts are lined by cuboidal, transitional, or squamous epithelium, and there is often a combination of epithelial elements with endocrine cells [12].  Ectopic thyroid generally involves the right ventricular outflow tract, although left ventricular outflow obstruction has been reported[13]. Radio-iodide imaging is diagnostic[14].  Histologically, there are follicular structures containing colloid; if there is any difficulty in diagnosis, immunohistochemical stains for thyroglobulin may be performed.  The differential diagnosis includes metastatic carcinoma of various origins, and metastatic thyroid carcinoma.  The latter distinction may be difficult purely on histologic grounds, and is made clinically by exclusion of a dominant mass in the thyroid.  A case of thyroid carcinoma of the heart, possibly arising in ectopic thyroid, has been reported[3].

Papillary fibroelastoma

This is an unusual lesion that occurs exclusively on endocardial surfaces, most commonly on valve leaflets. There is no gender predominance, and there is a wide range of age at presentation, with a mean age of approximately 60 years. The most common symptoms are transient neurological defects and myocardial ischemia, and rarely sudden death.

Papillary fibroelastoma is probably an exaggerated form of Lambl’s excrescence, which is a small (<5mm) reactive filiform growth that occurs at the sites of greatest hemodynamic stress, usually at the nodules of Aranti of the semilunar valves. The most common location is the aortic valve, followed by the mitral and tricuspid valves, pulmonary valve, and endocardial surfaces.  Histologically, they are avascular papillary structures lined by endothelial cells (Figure 1A-B). The papillary cores contain a proteoglycan rich stroma, and layers of elastic fibers and collagen are prominent near the base of the lesion.  The cells covering the surface express vimentin, factor VIII-related antigen, and CD34, and the stroma is rich in collagen type IV [15]. Papillary fibroelastoma is cured by surgery, whether there are pre-existing embolic symptoms, or if a lesion is incidentally discovered. Asymptomatic patients could be treated surgically if the tumour is mobile, as the tumour mobility is the independent predictor of death or nonfatal embolization.

Lipomatous hypertrophy of the atrial septum

This lesion is an exaggeration of the normal accumulation of brown fat within the atrial septum. It was initially considered an incidental finding at autopsy, although there was found an increased incidence arrhythmias, particularly atrial, supraventricular tachycardias and sudden death[16].  The indications for surgery are somewhat controversial, as the detection of incidental masses may lead to unnecessary surgery for a benign lesion that may simply be an exaggeration of normal[17]. A deposit of fat in the atrial septum resulting in a thickness greater than 2 cm has been termed lipomatous hypertrophy.  Grossly, the tumour is not encapsulated and is bright yellow.  Histologically, there is a mixture of mature and brown fat, which ultrastructurally contains abundant mitochondria [16].  Entrapped, enlarged myocytes are common and may lead to the false diagnosis of sarcoma, or the brown fat clusters may be mistaken for lipoblasts.

Benign Neoplasms

Cardiac myxoma

Cardiac myxomas account for almost 80% of heart tumours [18-20]. Patient age ranges from 2-97 years. Mean age at presentation is 50 years [21]. Ninety percent of individuals are between the ages of 30-60 years[22,23]. Myxomas occur more often in women than men.  The clinical presentation is diverse, and includes obstructive cardiac symptoms, embolic phenomena and constitutional symptoms [22,23].  Most myxomas are sporadic, although syndromic and familial cases (Carney or myxoma complex) are well recognized. In familial cases, the patients present at a younger age, and the myxomas occur in unusual locations and have a higher recurrence rate than in non-familial cases [24,25]  At imaging cardiac myxomas typically appear as a mobile mass attached to the endocardial surface by a stalk, usually arising from the fossa ovalis[6].  Myxomas with this appearance can be confidently diagnosed by echocardiography and further imaging is not necessary.

The neoplastic nature of cardiac myxomas, once a matter of debate,  is supported by the presence of chromosomal abnormalities, somatic mutations,  and the presence of microsatellite instability[26,27], in addition to characteristic histologic features which clearly separate them from thrombi.

Cardiac myxomas arise from the endocardium of the left atrial septum near the fossa ovalis in 85-90% of cases. Most of the remainder is located in the right atrium. Rarely, they arise in the ventricles. The external appearance, consistency, size and weight are extremely variable. Myxomas are either sessile or pedunculated, but the site of attachment is always discrete and usually in the region of the fossa ovalis. Histologically, cardiac myxoma is defined by the presence of myxoma cells, which are be arranged singly, in cords, or in vasoformative ring structures[22]. (Figure 1A-1C) The stroma, which gives the tumour its name, contains variable amounts of proteoglycans, collagen and elastin. In approximately 2% of cardiac myxomas, heterologous elements, in the form of glandular structures, are identified. [22] Myxomas with invasion into adjacent cardiac tissue are rare, and the clinical significance of this histologic finding is unknown (Figure 3A-B).

Myxomas are usually sporadic, and less than 5% form a component of the myxoma complex [21]. This syndrome includes cardiac myxomas and extracardiac manifestations: abnormal skin pigmentation (lentigines and blue nevi), calcifying Sertoli-Leydig testicular tumours, cutaneous myxomas, myxoid breast fibroadenomas, pigmented adrenal cortical hyperplasia, pituitary hyperactivity, psammomatous melanotic schwannoma and thyroid tumours. Familial myxomas are more often multiple, recurrent and right sided, as compared to sporadic myxomas. The affected patients are also younger, most presenting at 20-30 years of age [22,24].The recurrence rate differs markedly between sporadic and familial myxomas [22,24,28]. Patients with sporadic tumours have a good prognosis, with 1 % recurrence rate. However, about 10 % of patients with familial myxomas either have recurrent tumours or develop another tumour in a different location.

Hemangioma

Hemangiomas occur infrequently in the heart.  Clinically, they may be incidental lesions discovered at chest radiogram or surgery for other purposes, or they may cause arrhythmias, pericardial effusions, congestive heart failure, or outflow tract obstruction, and rarely sudden death[29,30].  An interesting association with neurologic symptoms has been described. [31] They tend to occur in adults, but may be found at any age.  Most cardiac hemangiomas are circumscribed lesions that are histologically uniform and composed of cavernous vascular spaces, often with a myxoid background.  The lesions are occasionally misdiagnosed pathologically as myxomas, because of their vascularity and myxoid stroma.  Cardiac hemangiomas that arise intermingled with cardiac muscle and share a resemblance with intramuscular hemangiomas of other sites are more likely to cause symptoms than circumscribed hemangiomas, and often result in cardiac arrhythmias because of their intramural location[32].

Paraganglioma

Paraganglial cells and are normally found within the atrial walls, and neoplasms arising from them are rare.  The majority develop within the atria (most often at the right side), are benign, and are functional, resulting in systemic hypertension[33,34].  Most patients are young or middle aged adults.   Rare malignant cardiac paragangliomas have been reported.[35].Complete surgical excision is recommended for all cardiac paragangliomas, often with an atrial graft repairing the portion of atrium or atrial septum removed.  Pathologically, paragangliomas are poorly circumscribed masses measuring up to 15 cm.  Paragangliomas of the heart are similar histologically and immunohistochemically to extracardiac paragangliomas (Figure 4).

Neurofibromas and schwannomas.

Nerve sheath tumours of the heart are extremely rare, generally occur on the epicardial surfaces, may be benign or malignant, and rarely cause outflow obstruction [36,37].  They have been described in patients with neurofibromatosis and after radiation therapy.  Histologically, they resemble nerve sheath tumours of extracardiac soft tissue.

Lipoma

Cardiac lipomas may occur anywhere in the heart. There is a predilection for the pericardium and epicardial surfaces[38].  When they involve the valves, the designation  “fibrolipoma” has been used. As is the case with other heart tumours, the presentation is varied, and depends on location. Many cardiac lipomas are incidental findings, or cause a variety of arrhythmias, syncope and electrocardiographic abnormalities [38,39]. Surgical excision is generally curative[40].  Recurrences are rare.  Large size may preclude complete excision; in such instances, incomplete resection or follow-up may be indicated.

Malignant neoplasms

The vast majority of primary malignant cardiac tumours are sarcomas; rarely, other tumours such lymphoma or mesothelioma (usually in association with a pleural primary) may present as a cardiac mass. Cardiac sarcomas are pathologically classified by histologic type [41]. According to the current World Health Organization Classification of Soft Tissue tumours,  cardiac sarcomas are classified as undifferentiated pleomorphic sarcomas , angiosarcomas, fibrosarcomas, synovial sarcomas, leiomyosarcomas, and rhabdomyosarcomas. However, several tumours are difficult to classify with grays areas in the diagnosis. Tumours with more than one morphology are common, such as in cases of undifferentiated sarcomas showing chondro- and/or rhabdomyosarcomatous differentiation. Tumours with myofibroblastic differentiation range from inflammatory myofibroblastic tumours, now generally accepted as low-grade sarcomas, at least in other extra-cardiac sites, to sarcomas with “myofibroblastic” features and differentiation intermediate between MFH-like tumours and better-differentiated fibrosarcoma.  In the heart, these have been termed variously termed myxoid malignant fibrous histiocytoma and myxofibrosarcoma, and often show a range of features from dedifferentiated to fibrosarcoma-like areas.

Angiosarcoma

Cardiac angiosarcomas account for 36% of excised heart sarcomas[42]. Angiosarcomas are the most common malignant cardiac neoplasms with specific cell type differentiation[41]. They occur over a wide age range (36 months to 80 years)with a peak incidence in the fourth decade and no sex predilection. It most often arises in the right atrium (80%), but has been reported in the other three chambers as well as in the pericardium.  

Angiosarcomas demonstrate endothelial cell differentiation with similar morphology to angiosarcomas of other extra-cardiac sites, either by formation of endothelial-lined vascular channels (present to some degree in the majority of lesions) or evidence of expression of endothelial antigens, specifically factor VIII—related antigen, CD34, or CD31 by tumour cells. Angiosarcomas usually form lobulated variegated masses in the right atrial wall, protruding into the chamber (Figures 5A-B). They range from 2.0 cm to several centimeters. The pericardium is frequently involved and hence a hemorrhagic pericardial effusion is a frequent accompaniment. Cardiac angiosarcomas have an especially poor prognosis because they typically present with metastasis, with survival typically measured in months. Metastases occur most frequently to the lung, then liver. Angiosarcoma is generally treated by a combination of surgery and radiation with or without sarcoma-type chemotherapy; heart transplantation is a consideration if metastatic disease is not identified.

Epithelioid hemangioendothelioma

Epithelioid hemangioendothelioma is a low-grade malignancy with vascular differentiation.  It can be mistaken for an epithelial tumour, but the histologic appearance is quite characteristic (Figure 6), and the tumour cells express both epithelial and endothelial markers.  Only a few recent cases have been reported primary in the heart, where they have been reported mostly frequently in the left atrium  [43]. Long-term survival is possible unlike higher-grade angiosarcomas.  Epithelioid hemangioendothelioma should not be confused with epithelioid hemangioma, which is histologically distinct,  and is even more rarely found in an intracardiac location.

Undifferentiated Pleomorphic Sarcoma/ Malignant Fibrous Histiocytoma (MFH)

By far the most common cardiac sarcoma of intimal, and hence endocardial origin, is an undifferentiated sarcoma composed of cells with variable expression of fibroblasts and smooth muscle cells, which normally inhabit the intima.  There are several terms for pleomorphic sarcomas of myofibroblastic differentiation, with most common being malignant fibrous histiocytoma. The majority of these lesions arises in the left atrium, and is presumed derived from intimal precursor cells residing in the endocardium.  The term “intimal sarcoma” is sometimes used for these lesions, as sarcomas of similar morphology arise in the pulmonary artery and aortic lumen[44], and occasionally atypical “dysplastic” appearing intimal foci are identified adjacent to the sarcoma, which typically projects into the lumen.  If there is relatively little pleomorphism, the term fibrosarcoma or myxofibrosarcoma is generally used, although the distinction is not clear-cut, and there is often a range in the degree of pleomorphism in a given tumour (Figures 7A-B).  The difficulty in classification has led to a wide range in the frequency of undifferentiated pleomorphic sarcomas of the heart, but if similar lesions are combined into one group, they account for approximately 40% of heart sarcomas, about the frequency of angiosarcoma. The unifying characteristics of these cardiac lesions are typical location in the left atrium, and prominent luminal growth, which invariably occurs before extensive infiltration into the myocardium and pericardium. There is no gender predilection and the mean age is around 45 years. Although the majority occur in the left atrium, where they most often present like cardiac myxomas, they more commonly arise along the posterior wall in comparison to the septum.

The histologic appearance of undifferentiated pleomorphic sarcoma ranges from typical features of MFH, with a “storiform” appearance, to epithelioid undifferentiated areas (Figures 8A-B).  By definition, there is cellular pleomorphism, which separates these tumour from (myxo)fibrosarcoma.  Necrosis is variable, as is the degree of collagenization.  Areas indistinguishable from fibrosarcoma and myxosarcoma may be present. Occasionally, there is a prominent vascular background that has been associated with myxoid MFH.  The surface of the tumour projecting into the atrial lumen is often denuded and covered by fibrin.

Osteosarcoma and chondrosarcoma

Osteosarcomatous or chondrosarcomatous differentiation occurs in approximately 15% of undifferentiated cardiac sarcomas. (Figure 9) Virtually all osteosarcomas of the heart arise in the left atrium, and almost half of these have areas of chondrosarcoma. In contrast, pure cardiac chondrosarcoma has been described in various cardiac locations. Like skeletal osteosarcoma, areas of malignant giant cell tumour (giant cell malignant fibrous histiocytoma), chondroid differentiation, and osseous differentiation may coexist in variable amounts in a single lesion.

Leiomyosarcoma

Cardiac leiomyosarcoma represents less than 10% of cardiac sarcomas. Most cardiac leiomyosarcomas are located in the left atrium (posterior wall) and involve pulmonary veins or mitral valve. Because most originate from the left atrium, it is possible that some arise from pulmonary veins. There is no sex predilection, and most occur in patients between 40 and 50 years of age.  Histologically, leiomyosarcoma has recognizable features of smooth muscle cells (fascicular growth with characteristic features of smooth muscle bundles or definite expression of desmin).  Because they are relatively well differentiated, prognosis may be slightly better than for malignant fibrous histiocytoma or undifferentiated pleomorphic sarcoma.  Epithelioid features and myxoid background may occur .

Rhabdomyosarcoma

Cardiac embryonal rhabdomyosarcomas constitute 5% of primary cardiac sarcomas, and, unlike other sarcomas, do not have a predilection for the left atrium. Rhabdomyosarcoma is more likely than other primary cardiac sarcomas to involve the valves. The mean age at presentation is approximately 20 years, compared to 40-50 years of age for other subtypes of cardiac sarcoma. The clinical presentation, as with other cardiac tumours, depends on the cardiac location.   In adults, cardiac transplantation has been performed for primary cardiac rhabdomyosarcoma.    Histologically, cardiac rhabdomyosarcoma resemble embryonal rhabdomyosarcoma of soft tissue.  The alveolar variant has been described in the heart only as a metastatic lesion. Rarely, pleomorphic rhabdomyosarcoma occurs as a primary cardiac tumour.

Synovial sarcoma

Synovial sarcoma is a biphasic tumour composed of spindled and epithelioid areas, characterized by X;18 chromosomal translocations. Synovial sarcomas account for less than 5% of cardiac sarcomas.  The true incidence has probably been underestimated, as molecular studies can now confirm the diagnosis in the monophasic variant, which is the most common form in the heart. In addition to left atrial endocardium, there is a predilection for the pericardial surfaces. Histologically, the classic lesion is biphasic, but the monomorphic variant is especially common in the heart.  Synovial sarcoma should be considered for any densely cellular spindle cell sarcoma of the heart, regardless of presence of cytokeratin-positive epithelioid areas.  Molecular studies to identify the (x;18) translocation are diagnostic and can be performed on paraffin embedded tissue.

Lymphoma

Cardiac lymphomas are usually part of disseminated disease; up to 20% of patients with disseminated non-Hodgkin lymphoma will have evidence of cardiac involvement at autopsy [45].  Primary cardiac lymphoma implies initial symptoms and major tumour bulk confined to the heart.  Because of the rise in immunocompromised patients, due both to HIV-AIDS and allograft recipients, an increasing proportion, although still a small minority, of patients with cardiac lymphoma are in this category. In surgical series, lymphomas account for only 1% of primary cardiac tumours . Histologically, cardiac lymphomas span the spectrum of B cell proliferations, and include follicular lymphomas, immunoblastic lymphomas, diffuse large cell lymphomas, and Burkitt lymphoma. Diffuse large B-cell lymphoma is the subtype most frequently observed, accounting for nearly in 80 % of published cases.

Metastatic tumours

Secondary cardiac tumors, either metastatic or by direct invasion outnumber primary cardiac tumors [46]. Pericardial based metastases are typical of metastatic carcinomas, whereas sarcomas and lymphomas tend to be more myocardial-based.  Luminal tumors are typical of metastases that grow up through the inferior vena cava, especially renal cell carcinomas and hepatocellular carcinomas in the right atrium, and metastases that grow into the left atrium from the lung.  Metastatic cardiac tumors affect the right side of the heart in 20-30% of cases, the left side in 10 to 33% of cases, and show bilateral or diffuse involvement in approximately 30 to 35% of cases.   The endocardium or chamber cavities are involved in 5% of cases [47].  The valves and endocardium are usually spared. [48].  Generally, the heart is not the only organ involved, and metastatic deposits are usually present in extracardiac sites.  The myocardium is involved in virtually 100% of cases of metastatic melanoma (Figure 11), and there is less frequent infiltration of epi- and endocardium.   Leukemic and lymphomatous infiltrates are typically widespread, involving the epicardium (61%), and myocardium diffusely.  The left ventricle is involved in 55%, and right atrium in 54% of cases.  Sarcomatous deposits are found within the myocardium (50%), pericardium (33%), or both myocardium and pericardium (17% of cases).  Histologically, the tumours are classified as in the primary sites.

Practice points

  • Calretinin staining may distinguish the most common endocardial based lesions of the left atrium:  myxoma (generally positive); mural thrombi (negative); and myxoid sarcoma (negative).
  • The most malignant appearing areas of intimal sarcomas of the left atrium are often at the surface, and may overlie fibrin thrombus.
  • Endocardial based angiomas differ from myxomas in the absence of diffuse inflammation and presence of smooth muscle cell actin positive supporting pericytes.