Review articleCardiac myxoma induced paraneoplastic syndromes: A review of the literature
Introduction
Primary cardiac tumors are very rare with an incidence ranging from 0.0017% to 0.19% in one autopsy series [1]. Atrial myxomas are the most common cardiac tumors and comprise 50% of all benign cardiac tumors [2], [3]. In this review, we will review all aspects of myxomas including location and nature of myxomas, pathogenesis, diagnosis, and treatment. Further discussion will include the metastatic potential and paraneoplastic manifestations that complicate myxomas.
The name myxoma is derived from its appearance as a cell-poor, myxoid neoplasm with a mucopolysaccharide-rich extracellular matrix. Myxomas range in size from 1 to 15 cm and are typically round, oval, or lobulated with a smooth surface and a narrow pedicle attaching to the cardiac tissue [4]. Broad-based features and a frond-like appearance have also been reported [4].
The most common locations for myxomas are the left atrium (60–75%), the right atrium (20–28%) and, rarely in both atria and ventricles. Typically, myxomas arise close to the fossa ovalis of the interatrial septum, although a few arise from free walls of the atria or from atrioventricular valve leaflets [5]. There is a 2:1 female predominance and diagnosis is typically between 50 and 70 years of age [6].
Although atrial myxomas occur sporadically, at least 10% of the cases are familial, the most common of which is the Carney syndrome [7]. This autosomal dominant syndrome consists of multiple cardiac myxomas, a variety of pigmented skin lesions, extra-cardiac tumors and melanotic schwannomas. Patients with Carney's triad are usually younger and more likely to have myxomas outside the left atrium. Carney syndrome is also associated with increased risk of myxoma recurrence, approaching 25%, after tumor resection [8]. Mutations in the tumor suppressor gene, protein kinase A (PKA) type-1 regulatory subunit (R1A) PRKAR1A, occur in > 50% of cases while linkage to chromosome 2p16 occurs in other families [9], [10], [11], [12].
The mechanisms by which atrial myxomas produce symptoms include constitutional symptoms, systemic embolization, and mitral valve obstruction. Although 10% of patients may be asymptomatic, most patients present with constitutional symptoms such as fever, weight loss, weakness or myalgias [6]. Cardiac symptoms usually manifest as dyspnea, palpitations or syncope. These symptoms are related to obstruction to left ventricular inflow or elevated left atrial pressures. Neurological manifestations are frequent and have been reported in 25–45% of cases [13]. The neurological signs and symptoms are usually a result of embolization. Tumor mobility, not size, appears to be related to embolic potential. Rarely, neurological complications may be due to embolized tumor fragments instead of surface thrombi [14], [15].
Section snippets
Pathogenesis
There are two main gross anatomical types of atrial myxomas, a solid type that is firm and smooth and a gelatinous type that is soft and friable [16]. Shimono et al. found that clinical presentation correlated with the gross tumor appearance [17]. Patients with solid tumors were more likely to present with congestive heart failure symptoms while patients with gelatinous tumors were more likely to present with cerebral and peripheral embolization [17]. Solid myxomas are highly vascular tumors
Diagnosis and treatment
Until 1977 when echocardiography became readily available, a means of noninvasive diagnosis was unavailable. Previously atrial myxomas had been described postmortem, as was the case with the first atrial myxoma described in the literature by Goldberg et al. in 1952 [29]. Even today, the diagnosis of atrial myxoma can be challenging given the variety of nonspecific symptoms patients may have. Echocardiography remains the most frequently used imaging modality to detect atrial myxomas.
Metastatic myxomas
The metastatic potential of cardiac myxomas and its true existence is still a matter of debate. Traditionally, myxomas are considered to be a benign neoplasm with spread to extracardiac sites considered to be a result of embolic phenomena. There are, however, a number of cases in the literature which reflect possible true metastatic potential and this should be considered a rare complication of myxomas.
Metastatic myxomas have been documented in the lungs, bones, soft tissues and even
Paraneoplastic manifestations
Paraneoplastic syndromes have been speculated to be associated with myxomas in several case reports (Table 2). A wide range of cutaneous manifestations appears to be related to cardiac myxomas including Raynaud's phenomenon, livedo reticularis, splinter hemorrhages, non-blanching lesions of fingertips, violaceous eruptions with peripheral cyanosis and toe necrosis [55], [56], [57], [58], [59]. More severe manifestations have also been reported including vasculitis, demyelinating neuropathy, and
Conclusion
Atrial myxomas are a diverse cardiac tumor with a wide spectrum of symptoms that often leads to significant delays in diagnosis. Traditionally many of the symptoms could be attributed to systemic embolization of either surface emboli or tumor fragments. Furthermore, many cardiovascular symptoms are secondary to alterations in the hemodynamics produced by these tumors. Although these remain viable explanations for many of the symptoms produced by atrial myxoma, there also appears to be other
Learning points
- •
Cardiac myxomas present with a wide variety of cardiac, neurological, and systemic symptoms.
- •
Neurological manifestations are the most common sign of myxomas and often result from embolization of surface thrombi.
- •
Cardiac myxomas may metastasize by tumor fragment embolization and can be found in remote locations including bone, brain, and muscle.
- •
Cardiac myxomas may present with paraneoplastic syndromes likely related to abnormal cytokine production from the tumor.
Conflict of interest statement
None of the authors have any actual or potential conflict of interest financial, personal, or otherwise that could influence or be perceived to influence their work.
References (78)
Pathology of cardiac tumors
Am J Cardiol
(1968)- et al.
Left atrial myxomas. Using gross anatomic tumor types to determine clinical features and coronary angiographic findings
Chest
(1995) - et al.
Interleukin-6 production and recurrent cardiac myxoma
J Thorac Cardiovasc Surg
(2001) - et al.
Expression of vascular endothelial growth factor and angiogenesis in cardiac myxoma: a study of fifteen patients
J Thorac Cardiovasc Surg
(2000) - et al.
The significance of multiple, recurrent, and “complex” cardiac myxomas
J Thorac Cardiovasc Surg
(1986) Surgical considerations in the treatment of cardiac myxoma
J Thorac Cardiovasc Surg
(1984)- et al.
Long-term remission after resection, chemotherapy, and irradiation of a metastatic myxoma
Ann Thorac Surg
(1998) - et al.
Metastatic atrial myxoma to the skin at 15 years after surgical resection
Ann Thorac Surg
(2000) - et al.
Cardiac myxoma: 40 years' experience in 63 patients
Ann Thorac Surg
(1997) - et al.
Livedo reticularis developing simultaneously with a syncopal attack in a patient with atrial myxoma
J Am Acad Dermatol
(1991)
Masquerading myxoma
Am J Med Sci
An interleukin-6 secreting myxoma in a hypertrophic left ventricle
Chest
Bilateral atrial myxomas with multiple arterial aneurysms—a syndrome mimicking polyarteritis nodosa
Am J Med
Infected biatrial myxoma: transesophageal echocardiography-guided surgical resection
Ann Thorac Surg
Cardiac tumors: a current clinical and pathological perspective
Crit Rev Oncog
Primary cardiac tumors
Ann Surg
Atrial myxoma: national incidence, diagnosis and surgical management
Ir J Med Sci
Cardiac myxoma. A clinicopathologic study
Am J Clin Pathol
Cardiac myxoma: imaging features in 83 patients
Radiographics
Cardiac myxomas
N Engl J Med
Carney complex
Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex
Hum Mol Genet
Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex
Nat Genet
Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit (PRKAR1A) in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas” (Carney complex)
Ann N Y Acad Sci
Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2
J Clin Invest
Central nervous system manifestations of cardiac myxoma
Arch Neurol
Left hemiparesis from atrial myxoma emboli
Cardiol Rev
Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases
Medicine (Baltimore)
Histopathologic and clinical characterization of atrial myxoma: a review of 19 cases
Lab Med
Cardiac myxoma: its origin and tumor characteristics
Ann Thorac Cardiovasc Surg
Cardiac myxoma metastasized to the brain: potential role of endogenous interleukin-6
Cardiology
Proinflammatory cytokines in cardiac myxomas
J Intern Med
The role of interleukin-6 in cases of cardiac myxoma. Clinical features, immunologic abnormalities, and a possible role in recurrence
Tex Heart Inst J
Vascular endothelial growth factor is an autocrine growth factor for cardiac myxoma cells
Circ J
Expression of basic fibroblast growth factor and its receptor-1 in cardiac myxoma
J Cardiovasc Surg (Torino)
Significance of monocyte chemotactic protein-1 and thymidine phosphorylase in angiogenesis of human cardiac myxoma
Circ J
Myxoma of the left atrium; diagnosis made during life with operative and post-mortem findings
Circulation
Cited by (25)
Cardiac myxoma with atypical cell population mimicking malignancy – a diagnostic pitfall
2023, Cardiovascular PathologyCitation Excerpt :Myxomas can cause cardiac symptoms due to mass effect and break off with consequent embolism. Systemic symptoms such as fever, malaise, weight loss, arthralgia and others are explained by myxoma cells' secretion of inflammatory cytokines (IL-4, IL-6, IL-12, interferon-γ, and TNF) and other substances [4]. Grossly, they can be rounded (solid) or papillary (filiform), sessile or pedunculated (with a stalk).
Autophagy in cardiac myxoma: An important puzzle piece in understanding its inflammatory environment
2021, Pathology Research and PracticeSenescence, immune microenvironment, and vascularization in cardiac myxomas
2021, Cardiovascular PathologyCitation Excerpt :Interestingly, it has long been noted that patients with cardiac myxomas show systematic symptoms, such as fever, weakness, and arthralgias/myalgias, and clinical signs, such as leukocytosis, anemia, and an elevated erythrocyte sedimentation rate, attributed to cytokine production within the tumors [3]. It has been suggested that one of the principal mediators being elevated in myxomas, probably directly secreted by the tumors and explaining the systematic symptomatology, is interleukin 6 (IL-6) [3]. IL-6 can induce cellular senescence; senescence is characterized by cell cycle arrest, secretion of cytokines, and recruitment of inflammatory cells, inducing the so-called senescence-associated secretory phenotype (SASP) [4,5].
Cerebrovascular manifestations of tumors of the heart
2021, Handbook of Clinical NeurologyCitation Excerpt :Patients may have elevations in erythrocyte sedimentation rate (ESR) or C-reactive protein. Increased antiphospholipid antibodies or decreased factor VII levels also may be found (Smith et al., 2012). Because of the variety of findings, including some response to treatment with steroids, that suggest a vasculitis, the delay in diagnosis may be months in duration (Moreno-Arino et al., 2016).
Left atrial myxoma as a cause of a transient ischaemic stroke and acute myocardial infarction with ST elevation
2020, Revista Colombiana de CardiologiaCommentary: Cutaneous presentation of cardiac myxoma
2020, JTCVS Techniques