Cardiac Myxoma Pathology

The World Health Organization (WHO) defines a cardiac myxoma as a neoplasm composed of stellate to plump, cytologically bland mesenchymal cells set in a myxoid stroma. ^[1]

From an epidemiologic perspective, cardiac myxomas are best divided into the following 2 categories: those that arise in isolation and those that arise in the setting of a syndrome (so-called Carney complex). The former account for about 90-95% of cases, while the latter account for a minority of cases.

Nonsyndromic cardiac myxomas have been described prenatally and in individuals as old as 97 years. ^{[2, 3]} Although they can be found anywhere within this very wide age range, these isolated cardiac myxomas are clearly more common among adults, who present at an average age of 50 years; furthermore, nonsyndromic cardiac myxomas occur more commonly in women than in men. ^{[3, 4]}

Syndromic cardiac myxomas typically arise as part of the Carney complex (see Molecular/Genetics). Cardiac myxomas occurring in this setting usually develop in combination with 1 or more of the following lesions:

• Myxomas in other sites (eg, cutaneous, mucosal, breast)

• Cutaneous lentiginosis

• Acromegaly

• Cushing syndrome (primary pigmented nodular adrenocortical disease)

• Large-cell calcifying Sertoli-cell tumors of the testis

• Psammomatous melanotic schwannoma

There are important demographic differences between syndromic and nonsyndromic cardiac myxomas. The syndromic variety, unlike their isolated counterpart of cardiac myxomas, do not exhibit a clear-cut sex predilection and typically present in the third decade rather than the fifth decade. ^[5]

Although numerous theories have been posited regarding the etiology of cardiac myxomas, the precise histogenesis of these tumors remains to be determined. For a time, cardiac myxomas were believed to arise from mural thrombi. ^[6] However, the differences between myxomas and thrombi are substantial. Although mural thrombi tend to occur in individuals with underlying heart disease and in many locations within the heart (eg, atrial appendages, atria, and ventricles), myxomas arise with astonishing consistency in 1 location: primarily adjacent to the fossa ovalis.

Furthermore, histologically, myxomas do not organize into fibrous tissue or show stratification, a classic feature of mural thrombi. Cardiac myxomas also behave differently from thrombi in tissue culture studies. ^[7] This body of evidence in support of the neoplastic nature of myxomas has led to the consensus that cardiac myxomas are not of thrombotic origin and are, indeed, neoplastic. ^[8]

The impetus for this neoplastic transformation is equally unclear. Although genetic factors (see Molecular/Genetics) clearly play a role in myxoma syndromes, they do not appear to offer a consistent explanation in sporadic cases. A study by Li et al reported finding evidence for HSV-1 infection in 70% of a relatively small cohort (n=17) of surgically resected sporadic cardiac myxomas. ^[9]

Regardless of the precise etiology of cardiac myxomas, the morphologic, ultrastructural, and immunoperoxidase studies done to date suggest that the neoplastic cells are of primitive multipotential mesenchymal origin. ^{[10, 8, 7]}

Most myxomas (75%) are located in the left atrium. Most of the remainder (18%) are found in the right atrium, ^[11] a smaller number (6%) are equally split between the left and right ventricles (3% each), ^[12] and only a very small fraction (< 1%) involve the valves. ^{[13, 14, 15, 16]}

These tumors are typically found in the region of the fossa ovalis. For a time, myxomas were thought to arise from minute endocardial endothelial structures known as Prichard structures, located primarily in the fossa ovalis. ^[17] However, this theory has now been largely discredited by studies that show no relation between the seemingly age-related Prichard structures and myxomas. ^[18]

Cardiac myxomas arising as part of the Carney complex occur somewhat less commonly in the left atrium (62%) and are often multicentric, occasionally involving multiple chambers. ^[5]

Cardiac myxomas elicit a wide variety of symptoms in patients, largely depending on the size and location of the tumor. Individuals with cardiac myxomas can present at any point along the clinical continuum, ranging from complete absence of symptoms (particularly with tumors less than 40 mm in size) to sudden death, usually owing to acute obstruction or embolization. ^{[19, 20]}

Although the clinical spectrum can be wide, most affected individuals present with 1 or more of a triad of symptoms (the so-called myxoma triad), which includes embolic phenomena, intracardiac flow obstruction, and constitutional symptoms. ^{[21, 22, 23, 24, 25]} These symptoms, however, are rather nonspecific, and myxomas (and cardiac tumors in general) are relatively rare in most clinicians' practices; consequently, cardiac myxomas are often misdiagnosed. ^[26]

Symptoms of intracardiac flow obstruction are the most commonly described manifestation, occurring in more than 50% of persons with cardiac myxomas. ^{[1, 27]} Typically, patients show symptoms of left-side heart failure (eg, dyspnea, orthopnea, or fatigue) or syncope. Right atrial myxomas can manifest with symptoms of right-side heart failure (eg, systemic edema or hepatomegaly). Occasionally, a systolic or diastolic murmur can be auscultated. In some cases, a characteristic “tumor plop” is audible in early diastole. ^[27]

About 30-40% of individuals with cardiac myxomas experience embolic phenomena. Sites of embolization include the central nervous system (CNS), kidneys, extremities, and coronary arteries. The clinical manifestations of embolization are broad and depend on the tissues downstream of the embolus. Note that paradoxical embolism may occur in individuals with an anatomically patent foramen ovale. ^[28] In rare cases, myxomas can also serve as a nidus for infection. ^[29] When this occurs, symptoms parallel those of infective endocarditis.

Nonspecific constitutional symptoms have been reported in 20-60% of individuals with cardiac myxomas. ^{[1, 11, 27]} Such symptoms may include fever, arthralgia, myalgia, and weight loss. ^[23] Laboratory findings may include elevated erythrocyte sedimentation rate (33%), normochromic anemia (15%), and thrombocytopenia (5%).

These findings are probably due to the tumor’s constitutive ability to elaborate interleukin (IL)-6, a cytokine that induces the acute-phase response. Individuals who experience these constitutional symptoms have been found to have higher serum levels of IL-6, with these levels dropping precipitously after removal of the tumor. ^[30]

Transthoracic echocardiography (TTE) is the diagnostic imaging modality of choice for cardiac myxomas, but transesophageal echocardiography (TEE) is better at defining the tumor's location and characteristics. ^[31] Both TTE and 2-dimensional (2D) TEE are highly sensitive for identifying cardiac myxomas; however, anatomic and morphologic information is often incomplete. Real-time 3-dimensional (3D) TEE may help surgeons gain a better understanding of the nature and location of the tumor. ^[32]

The differential diagnosis of cardiac myxoma is briefly summarized in Table 1 below.

Table 1. Differential Diagnosis of Cardiac Myxoma (Open Table in a new window)

The vast majority of cardiac myxomas manifest as cavitary gelatinous masses that arise adjacent to the fossa ovalis in the left atrium. ^[21] They are typically pedunculated but can also arise in a sessile fashion, ranging in size from as small as a few millimeters to upward of 15 cm (see the image below). ^{[33, 27]} Cardiac myxomas have been reported to weigh as much as 250 g. ^[1]

Cardiac myxomas may have a smooth or papillary surface and may have thrombus adherent. Both the papillary excrescences and the surface thrombi can be friable in nature and undergo embolization. On cut section, they often have a variegated appearance, with areas of pearly white, pale-gray, and yellow tissue punctuated by patchy dark-red hemorrhage, gritty necrosis, or calcification (see the image below).

The diagnosis of cardiac myxoma is primarily dependent on the presence of the myxoma or lepidic cells described in the World Health Organization (WHO) definition cited earlier (see Definition). Myxoma cells are frequently stellate with eosinophilic cytoplasm and indistinct cell borders (see the image below). Their ovoid nuclei are typically pale with open chromatin. Nucleoli may be prominent.

Architecturally, myxoma cells form rings, cords, and nests that are often closely associated with capillaries (see the images below). The cells can also exist singly as stellate cells in a myxoid stroma that is composed of variable amounts of proteoglycans, collagen, and elastin and that often contains lymphocytes, plasma cells, and histiocytes.

Extravasated erythrocytes and hemosiderin deposition are invariably present (see the first and second images below). Thin-walled blood vessels (occasionally large and cavernous) can be seen throughout the lesion (see the third image below), with thick-walled blood vessels typically present near the pedicle or attachment (see the fourth image below). Myxomas have been shown to elaborate vascular endothelial growth factor (VEGF), which may contribute to the high vascularity frequently encountered in these tumors. ^[34]

Secondarily, fibrosis, necrosis, thrombosis, calcification, or Gamna-Gandy body formation (calcific/siderotic elastic fiber degeneration) can be identified (see the images below). These secondary, degenerative changes are often attributed to a long clinical course and are more frequently encountered in right atrial myxomas. To prevent misdiagnosis, it is important for the surgical pathologist to keep in mind that myxomas frequently have adherent thrombus on their surface.

In addition to the more common histopathologic features of cardiac myxomas described above, heterologous elements, such as columnar epithelium (sometimes forming glands), ^{[11, 35]} bone formation (see the images below), ^[36] extramedullary hematopoiesis, ^[11] and thymic rests ^[11] have been described. However, these elements are quite uncommon and have been found in fewer than 2% of cardiac myxomas. ^[1]

To date, no study has been able to document consistently reproducible differences between sporadic and familial myxomas at the gross or the microscopic level.

Most studies that set forth to define myxomas on the basis of immunohistochemistry (IHC) have yielded somewhat conflicting results; accordingly, IHC is not particularly helpful in the diagnosis of cardiac myxomas. Myxoma cells exhibit immunoreactivity to calretinin (75-100%), vimentin (> 50%), and alpha-1 antichymotrypsin. ^{[37, 21, 38]} Calretinin, in particular, has been proved quite useful in discriminating cardiac myxomas from mural thrombi and papillary fibroelastomas, both of which lack immunoreactivity to this substance.

Cardiac myxomas have shown to be variably immunoreactive to S-100, smooth muscle actin, desmin, alpha-1 antitrypsin, synaptophysin, neuron-specific enolase (NSE), factor VII, CD34, and CD31. ^{[37, 1, 21, 39]} Although myxoma (lepidic) cells are not themselves immunoreactive to cytokeratins, myxomas can exhibit reactivity within heterologous glandular elements, when present. ^[35]

Hemminger et al studied the usefulness of NY-ESO-1 as a marker for myxoid and round cell liposarcoma among mesenchymal myxoid neoplasms. They concluded that this can be a less expensive, faster, and more accessible test for confirming the diagnosis. ^[40]

Between 5% and 10% of cardiac myxomas are associated with a heritable disorder that also includes spotty pigmentation of the skin and endocrinopathy, a set of conditions collectively referred to as the Carney complex. ^[11] Before Carney’s description of this form of multiple endocrine neoplasia, individuals with familial myxoma were described as having either the nevi, atrial myxoma, myxoid neurofibroma, and ephelides (NAME) syndrome ^[41] or the lentigines, atrial myxoma, and blue nevi (LAMB) syndrome. ^[42]

Two genetic loci have been ascribed to the Carney complex through linkage studies: 2p16 and 17q22-24. ^[43] The cellular mechanism of cardiac myxoma development has yet to be elucidated. The gene PRKAR1A does appear to play a role in the development of cardiac myxomas in the context of Carney complex, but its role in nonsyndromic myxoma genesis is much less clear.

The clinical manifestations of the Carney complex are as follows:

• Spotty skin pigmentation with a typical distribution (lips, conjunctiva, and inner or outer canthi, vaginal, and penile mucosa)

• Myxoma (cutaneous and mucosal)

• Cardiac myxoma

• Breast myxomatosis or fat-suppressed magnetic resonance imaging (MRI) findings suggestive of this diagnosis

• Primary pigmented nodular adrenocortical disease (PPNAD) or paradoxical positive response of urinary glucocorticosteroids to dexamethasone

• Administration during Liddle test

• Acromegaly due to growth hormone (GH)-producing adenoma

• Large-cell calcifying Sertoli cell tumor

• Thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasonography in a young patient

• Psammomatous melanotic schwannoma

• Blue nevus, epithelioid blue nevus (multiple)

• Breast ductal adenoma (multiple)

• Osteochondromyxoma

Supplemental criteria are as follows:

• Affected first-degree relative

• Inactivating mutation of the PRKAR1A gene

Diagnostic criteria for the Carney complex include having 2 recognized clinical manifestations or 1 clinical manifestation plus evidence of genetic transmission, which is usually autosomal dominant. ^[44]

Although the clinical course of cardiac myxomas is considered by most to be entirely benign, isolated cases of cardiac myxomas undergoing so-called malignant change have been reported. ^{[45, 46, 47]} Reports typically cite areas of hypercellularity, necrosis, and atypia as a rationale for this designation; however, in many instances, follow-up has been incomplete, leaving little objective evidence of a true malignant process. In addition, it is likely that many of these examples represent misdiagnosed myxoid sarcomas, a distinct and separate entity.

Myxomas can recur locally (usually with incomplete resection) and spread to distant sites through embolization. Embolization appears to be much more likely in myxomas that are friable with a broad-based attachment than they are in tumors that are fibrotic or calcified. ^[11] One study suggests that the expression of the mucin gene MUC5AC within sporadic cardiac myxomas may correlate with a lower risk of embolization. ^[43]

After embolization, myxomas are capable of infiltrating into the arterial wall and producing histologically identical tumors at the embolization site. Such lesions have been described in the skin, the central nervous system (CNS), the lungs, and bone. ^{[48, 49, 50, 51]}

Because of the benign nature of cardiac myxomas, no official staging system has been developed for them.

The factor that appears most predictive of a recurrence of myxoma is whether the tumor arose in the setting of a familial myxoma syndrome. The recurrence rate is 1-3% in patients with sporadic myxomas but 10-20% in patients with familial myxomas. ^{[52, 23]} The likelihood of developing a recurrence has been associated with abnormal DNA ploidy patterns, mostly in these familial myxomas. ^[53]

In patients with sporadic myxomas, incomplete excision is thought to be the most likely reason for tumor recurrence. Cellularity and mitotic index do not seem to correlate consistently with recurrence. Close clinical follow-up is recommended for individuals diagnosed with familial cardiac myxomas.