Myxoma pathophysiology

Cardiac myxoma is a benign intracavitary endocardial mass that represents the most common primary tumor of the heart. Myxoma cells are characterized by undifferentiated mesenchymal cells, which potentially differentiate into many tissues such as blood vessels, glandular structures, and bones. The primary distribution of cardiac myxoma is the left atrium (75%) of the heart; regularly, they tend to be located in the fossa ovalis and endocardium of the atrial septum.

• Cardiac myxoma arises from remnants of subendocardial vasoformative reserve cells, which are primitive mesenchymal cells that are normally involved in the supportive structure of the endocardium.^{[1][2][3][4][5]}
• The exact pathogenesis of cardiac myxoma is not fully understood.^[5]
• It is thought that cardiac myxoma is produced by the neoplastic theory, dysembryoplastic theory, histopathogenesis of glandular cells in myxoma or the thrombotic theory.^[6][7]
• The site of tumor attachment, normally the foramen ovale, is considered to be consistent with an origin from multipotent mesenchymal cells or from embryonic rests.^[8]

• Sporadic cardiac myxomas and familial forms are related with several chromosome and gene alterations which involve cardiac development.^[9]
• Inherited myxomas are usually present in Carney complex.^[9]
• The development of Carney complex is a result of PRKAR1A gene inactivation mutation that is associated with chromosome 17q24.2-q24.3.^[9]
• The gene 17q24.2-q24.3 plays an important role in cardiac development and myxomagenesis. The expression of PRKAR1A causes myxomatous changes in the endocardium.^[9]
• The encoded protein of PRKAR1A is a type 1A regulatory subunit of protein kinase A.Inactivating germline mutations of this gene are found in 70% of people with Carney complex.^[10]
• Less commonly, the molecular pathogenesis of Carney complex is a variety of genetic changes at chromosome 2p16.^[11]
• Both types of Carney complex are autosomal dominant.
• Despite dissimilar genetics, there appears to be no phenotypic difference between PRKAR1A and chromosome 2p16 mutations.^[12]

• The Carney complex is characterized by myxomatous neoplasms (cardiac, endocrine, cutaneous, and neural), and a host of pigmented lesions of the skin and mucosae, including the rarely occurring epitheloid blue nevus.^[13][14][15]
• Approximately 7% of all cardiac myxomas are associated with Carney complex.^[16]

• On gross pathology, external appearance, consistency size, and weight are extremely variable findings of cardiac myxoma.^[17]
• Tumor consistency depends on the quantity and distribution of fibrous tissue and calcification (it can be smooth, lobulated, friable or gelatinous).
• Myxomas are usually described as having a gelatinous, irregular surface.
• Myxomas that have an irregular consistency are more likely to form surface thrombi and embolize.^[18]
• Morphologically, these lesions tend to be attached to the endocardium by a broad-based pedunculated stalk.^[8]
• In some cases, the attachment to the endocardium can also be without a clear stalk, or sessile.^[8]
• Cardiac myxomas are non-invasive tumors, thus there is no infiltration to underlying tissues.^[19]
• Cardiac myxomas are intracavitary tumors.
• The distribution is normally within the interatrial septum or adjacent to foramen ovale (75%).
• However, they can also be found in other cardiac chambers, such as right atrium (15%), ventricles (2%) or cardiac valves (rare).
• Large cardiac myxomas are usually located in fossa ovalis.^[5]
• The size of the tumor varies from 0.6 to 12 cm, with a mean weight of 40 g.
• Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

• On microscopic histopathological analysis, myxoma cells have an ovoid nucleus with large nucleoli, abundant eosinophilic cytoplasm, and indistinct cell borders.^[20]

• They are usually arranged in perivascular ring structures (typically, infiltrated by lymphocytes and macrophages).^[17]

• The Gamna-Bodies which consist of fibrosis and deposition of iron pigments are a characteristic finding of myxoma tumors.^[17]

• Other frequent histological findings, are hemosiderin within the histiocytes, thrombosis, fibrosis and calcifications.^[17]

• In some cases, extramedullary hematopoiesis is present and mucin-producing glands can be also seen in the base of the tumor.^[17]

• The extracellular matrix forms an alcian blue-positive myxoid stroma, composed of variable amounts of proteoglycans, elastin and collagen.^[17]

• Cardiac myxoma cells exhibit immuno-reactivity mainly for calretinin (75–100%) followed by vimentin (>50%), NOTCH1, alpha-1 antichymotrypsin and plakophilin- 2.^[21]

• Calretinin plays an important role in the discrimination of mural thrombi and papillary fibroelastoma.^[21]

• Another immunohistochemical marker, survivin (an apoptosis inhibitor) has been detected to play an important role in the development and growth of cardiac myxomas.^[22]

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