The clinical presentation of primary cardiac tumors depends on their site, size, mobility and infiltration of adjacent structures. Up to 12% of primary cardiac tumors are completely asymptomatic and are diagnosed at incidental investigation (most commonly an echocardiogram) or at postmortem examination [7]. Others present with one or more signs and symptoms of the classical triad of hemodynamic changes caused by a mobile intracardiac mass, with obstruction, pulmonary or systemic embolism and nonspecific constitutional symptoms [7,8]. Malignant primary cardiac tumors may cause symptoms relatable to metastases to different organs such as the lungs, brain and bones.

CM are benign neoplasms whose cell of origin is still not fully established, though they are believed to develop from multipotent mesenchymal stem cells present in the fossa ovalis and surrounding the endocardium [3,14].

Sakamoto et al. supported the hypothesis that CM arise from the primitive mesenchymal cells which are capable of undergoing cardiogenic, neuroendocrine and endothelial cell differentiation by demonstrating increased expression of endothelin-1 (ET-1), interleukin-6 (IL-6), interleukin-8 (IL8), chemokine ligand 1 (CXCL1) and growth related oncogenes, and absence of stem cell factor, hepatocyte growth factor and granulocyte colony stimulating factor in CM [26]. In addition, some CM also express genes specific for chondrocyte development (sex determining region-box9 (SOX9), melanocyte inhibitory activity (MIA) and secreted phosphoprotein1 (SPP1)), which further support this hypothesis [27].

CM express transcription factors for primitive cardiomyocyte phenotype (Nkx2.5/Csx, GATA-4, MEF2 and eHAND), stem cell markers for endothelial cell precursors (Flt-1 and FlK-1), markers of primitive endothelial cells (CD34), and markers of early cardiogenic differentiation CALB2, MMP2, TIMP-1, Sox9, Notch1 and MMP-1 [28–30]. They also express α-smooth muscle actin (α-SMA), which is expressed in cardiac muscles in the early period of fetal development. They are negative for myosin light chain kinase v2 (MLC-2v) and α-skeletal actin (α-SKA) and focally express α-cardiac actin (α-CA), all of which are markers of terminally differentiated cardiac myocytes, suggesting that CM develop from multipotent mesenchymal progenitors that show cardiomyogenic differentiation [28,30–32]. In addition, coexpression of CD34 and α-actin by some CM further supports their origin from a common cardiac early precursor cell [30].

Pucci et al. [33] detected the expression of neuroendocrine markers such as protein gene product 5.5/PP9.5, S100 and neuron-specific enolase (NSE) in 94%, 89% and 57% cases, respectively of CM. In addition, 57% of cases of CM were positive for all these markers, while the chondroid looking areas were positive for S100 and NSE [33]. Teraccianno et al. also detected strong and diffuse cytoplasmic and nuclear expression of calretinin (CALB2) in CM, suggesting neuroendocrine differentiation [34].

CM express markers of endothelial cell differentiation such as the von Willebrand factor vWF/FVIII, CD31, CD34 and Ulex europeus agglutinins (UEA-1) in vascular endothelium cells, vascular like aggregates and in stromal cells, suggesting endothelial differentiation [33].

The glandular epithelial structures sometimes seen in CM express epithelial cell markers CK9p and CEA (Carcinoembryonic antigen) and suggest epithelial differentiation [33].

About 10%–15% of patients with CM are asymptomatic at the time of diagnosis [35]. Non-specific constitutional symptoms such as fever, lethargy, physical weakness, fatigue, anorexia, painful erythema, loss of weight and appetite, are seen in up to 90% of cases due to autocrine cytokine production such as IL-6 and IL-8 [8,36]. Non-specific laboratory findings such as chronic hemolytic anemia and thrombocytopenia (due to cellular destruction caused by abnormal blood flow across the tumor surface), polycythemia, erythrocytosis and leukocytosis, raised erythrocyte sedimentation rate, serum C-reactive proteins and immunoglobulins may also be seen in some CM [37,38]. These can lead to misdiagnosis of infective endocarditis, rheumatic heart disease, vasculitis, rheumatoid arthritis, and collagen vascular diseases and often resolve after tumor resection [7,39–42].

About 70% of CM can present with signs and symptoms of intracardiac obstruction such as left and right sided heart failure, with dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, hepatomegaly and peripheral edema [43,44]. Large atrial myxomas can cause episodic mitral or tricuspid valvular stenosis and the patient can present with intermittent syncope, dizziness, or sudden death [45]. Left atrial myxomas can produce valvular insufficiency due to the “wrecking ball effect” produced by the back and forth motion of the mass which interferes with valvular closure and can damage the chordae tendinea [46]. Right atrial myxomas can embolize to pulmonary vessels and produce signs of pulmonary hypertension [47]. Large ventricular myxomas can produce signs and symptoms of pulmonary and aortic valvular stenosis [48].

Embolic manifestations are seen in 30%–50% cases of CM, and these are due to fragmentation, detachment and dissemination of parts of the tumor, overlying thrombi or vegetation [38]. The emboli most commonly involve cerebral and retinal arteries (>50%) producing signs and symptoms such as vision disorders, cerebral infarcts, seizures, hemiparesis, aphasia, and progressive dementia [49,50]. Other arteries involved are those of the lower extremities producing claudication, visceral, renal and pulmonary arteries producing pulmonary hypertension and nonspecific symptoms such as myalgia, arthralgia, hyperhidrosis, facial edema and nocturnal hemoptysis [38,51,52]. Very rarely CM may embolize to coronary arteries and can produce myocardial infarction [53,54].

In extremely rare cases, infected CM can present as systemic bacteremia, mycotic embolism, disseminated intravascular coagulation, pulsatile tinnitus, back-ache and hair loss [55,56].

Approximately two-thirds of CM are round to oval, sessile, polyploid masses of varying sizes (average 5–6 cm), with a short broad base and smooth or slightly bosselated, glistening surface covered with thrombus and are attached to the interatrial septum (Figure 1). The cut surface is usually bosselated and has a variegated appearance composed of fibrous, gelatinous, myxoid and hemorrhagic areas. One-third of CM are soft, gelatinous, fragile, with papillary or finger-like villous extensions, and prone to fragmentation, embolization and erosion [8,53] Figure 2a–c. The polyploid myxomas usually cause obstructive symptoms while papillary myxomas are usually associated with embolic and neurologic manifestations [53,57].

CM arise from the endocardium, do not invade the interatrial septum or underlying myocardium and are covered by a single layer of flat endothelial cells [8,42,58] (Figure 3). They are characterized by the presence of stellate, polygonal (lepidic) cells in an amorphous, basophilic, afibrillar myxoid stroma containing mucopolysaccharides [6,14] (Figure 4a,b). The cells have indistinct cell membranes, a small amount of eosinophilic cytoplasm, round, oval or elongated nucleus and dispersed chromatin. At the surface of the lesion, the cells are arranged in the form of single cells, parallel clusters, syncytial cords, tubular structures or perivascular cuffing [30,59]. Inflammatory cells may be present throughout the lesion. The base of the lesion usually contains prominent chronic inflammatory cells (lymphocytes, plasma cells, and macrophages), areas of old and recent hemorrhage with hemosiderin-laden macrophages, and thick walled vessels, which are likely related to the solid phenotype and chronicity of the lesion [13,57,60] (Figures 5a–c, 6a,b). Occasionally, multinucleated tumor giant cells, blood cells, histiocytes, fibroblasts, smooth muscle cells, mucin-forming glands, ring structures (single or multiple concentric layers of myxoma cells surrounding the capillaries), artery-like vessels, superficial thrombi, calcification, chondrocytes, osteoblasts, metaplastic bone, cysts, Gamna-Gandy bodies (degenerated collagen encrusted with iron or calcium), thymic rests and foci of extramedullary hematopoiesis are also seen (Figures 7a,b, 8a,b). Very rarely, mitotic figures can also be seen [6,8,14,61–63].

About 80%–90% of CM express vimentin, Notch1, α smooth muscle actin (α-SMA), calretinin, caldesmon and tenascin C. CD34 positivity is seen in 66.7% cases of CM which stains multinucleated cells in superficial tumor area and lacunae, ring structures, and endothelial cells in arterial-like structures. α-SMA positivity is seen in interstitial and perivascular multinucleated cells and in parietal cells in vascular and ring structures. Other occasionally positive immunohistochemical stains in CM are MMP1, MMP2, TIMP-1 (36.7%), factor VIII, (36.7% in vascular structures), cytokeratin (6.7% in gland like structures), Flt-1 (26.7%), S100 (13.3%) and α-cardiac actin (10%) [30]. Some cases of CM show positive staining for: PGP9.5, NSE, synaptophysin, endothelin-1 in lepidic cells; for CD8, CD45 and CD68 in lymphocytes and hemosiderin-laden macrophages; for UEA and CD31 in vascular structures; and EMA, CEA, NSE, S100 and chromogranin in glandular structures [26,33,62,64] Figure 9a–d.

Electron microscopy of CM shows lepidic cells with single, round, elongated nuclei, with or without nucleolus. The cytoplasm of these cells shows abundant rough and smooth endoplasmic reticulum, polyribosomes, lysosomes, varying shapes and sizes of mitochondria, pinocytic vesicles, numerous filaments and iron deposits [65,66].

The differential diagnosis of CM includes organizing thrombus, and primary or metastatic sarcomas such as low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid liposarcoma, and inflammatory myofibroblastic tumor [58,67,68]. Rare case reports of myxoid leiomyosarcoma and angiosarcoma mimicking clinically, radiologically and grossly as myxoma are present in the literature [69–71]. However, histological features such as presence of “ring structure”, absence of cytologic atypia, mitotic activity, myocardial invasion, metastasis and recurrence (except in Carney complex), slow growth rate and immunohistochemistry in CM helps to differentiate it from primary or metastatic sarcomas (Table 1) [3,67,72–74].

Sporadic CM shows a 10-fold greater expression of MIA (melanoma inhibitory activity) and altered expression of S100 protein, both of which are markers of poor prognosis in malignant melanoma, and correlate with malignant transformation [27,107]. However their exact role in sporadic CM as a marker of malignant transformation needs further evaluation [38]. CM also coexpress CXCL1 (angiogenic factor) and growth related oncogenes, which promote their malignant potential. Overexpression of IL-6, VEGF, PCNA, FGFβ, FGFR1, VEGF, VEGFR1 and VEGFR2 is seen in highly proliferative, angiogenic and malignant myxomas [14].

The main disease pathways in CM include (CCR2, FMOD-TGFβ, S100-FGFR, NKX2.5-GATA4-SOX9-FGFR, HAND1-GATA4 and MUC1), through which other disease pathways work. The potential drug targets in CM were identified to be the key-nodes (CCR2, TGFβ, MUC1, FGFR, EGFR, GATA4 and HAND1) along with their upstream and downstream regulators (MYC, FOS and MMP9). Blocking the key nodes and their regulators can block the pathways involved in CM development [14,38].

DNA analysis has detected that CM have a diploid or aneuploid DNA pattern and exhibit heterogenicity in karyotype [8,35]. Cytogenetic analysis has revealed two major loci of susceptibility genes in CNC [108,109].

The CNC1 susceptibility gene is the PPKAR1A gene, which acts as a tumor suppressor gene. It is found in 80% of cases of familial CNC, is located at 17q22–24, and encodes for R1α subunit of cAMP dependent protein kinase A (PKA), involved in the G protein receptor signalling pathway [13,23]. There can be 80 different mutations in the PRKAR1A gene of which the most common leads to a premature stop codon (short premature transcripts) and subsequently nonsense mediated mRNA decay (NMD), which leads to R1α haploinsufficiency (absence or reduction in the mutant protein level) and increased PKA enzyme activity [110,111]. However, occasionally when PRKAR1A mutations are not associated with NMD, the outcome of the disease is aggressive [20]. Bertherat et al. have identified a hot spot c.491–492del TG mutation which was more significantly associated with CM. They also suggested a role of environmental factors in the pathogenesis of CM considering earlier and frequent occurrence of PPNAD disease in female carriers having PRKAR1A mutation [112].

Recently, missense mutation (Arg674Gln) in another CNC gene, perinatal isoform of the myosin heavy chain gene MYH8, located at 17p12–31, has been identified. Although the exact mechanism of CM development is not known, it is proposed that mutation in MYH8 promotes the survival of multipotent progenitor cells in the mature heart and provides a substrate for secondary tumorigenic events [112].

A small subset of families with CNC syndrome shows amplification in the CNC2 gene, located on 2p16, without PRKAR1A mutation. These subjects have negative family history, present later in life and usually do not develop myxomas, PMS, thyroid tumors and LCCSCT [108,110].

In contrast, no single gene mutation has been identified for sporadic CM. However, structural rearrangement in PRKAR1A has been identified in one-third of cases of sporadic CM [113].

Experimental models have suggested that various epigenetic factors such as DNA methylation, posttranslational modifications of proteins and miRNA molecules may play a role in the histogenesis of CM by causing reactivation and ectopic expression of early embryonic heart genes such as NKX2.5/CSX, GATA4, HOX, HAND, MYOD, SOX4-6, S100 and TGFβ [14].

It is predicted that the combination of microRNA (let-7, miR-125, miR205, miR-214, miR217 and miR-296) can help in the treatment of CM by targeting the key nodes and their potential upstream and downstream regulators. However, the exact role of these microRNA molecules in the treatment of CM is yet to be established [14].