No significant association could be found between myxoma size (< or > 5 cm) and diagnosis circumstances (asymptomatic or symptomatic cases); villous surface; or presence of embolic, neurologic, systemic, or serologic symptoms or signs (Table 6). However, a myxoma size >5 cm was significantly associated with cardiac symptoms, auscultatory signs, and ECG and chest X-ray abnormalities. Diagnosis of larger myxomas paradoxically appeared to be more difficult, and the delay to diagnosis was shorter for small tumors than for large tumors (see Table 6).
Villosity was associated significantly with neurologic symptoms, embolic complications, and cardiac auscultation abnormalities. However, there was no significant association between villosity and cardiac, systemic, serologic, ECG, or X-ray signs or symptoms; serendipitous discovery; or delay in diagnosis (Table 7).
All patients had surgery. Four patients (3.5%) died during the perioperative period: 1 patient died in 1967 during a second surgical intervention for a recurrence of myxoma 6 years after the first surgical removal; a 66-year-old woman, operated on in 1965 with severe cardiac insufficiency and instable hemodynamic function, died on the second postoperative day from acute renal insufficiency; a 5-year-old boy died in 1978 from acute mitral insufficiency by a mitral annulus rupture; and a 73-year-old man died in 1996 from bacterial meningitis concomitant with the myxoma, whereas the incidental tumor had been removed successfully.
Only 1 patient needed a prosthetic mitral valve replacement: bacterial endocarditis was associated with the myxoma. The most frequent postoperative complication was transient arrhythmias (supraventricular arrhythmia or atrial fibrillation) in 29 patients (26%). A permanent cardiac pacemaker implantation for persistent bradycardia was necessary for only 2 patients.
During the postoperative course, 13 patients (11.5%) were lost to follow-up: foreign patients who returned alive to their native country and did not answer our questionnaire. Among the other 99 patients, 4 died and 95 (96%) were alive during the follow-up period. Patients who presented with peripheral arterial embolization fully recovered. The longest follow-up for patients alive with multiple cerebral aneurysms is 14 years (a woman suffering a stable cerebellum syndrome). In the present series, survivors were followed for a median of 3 years (range, 1 mo-17 yr).
Six patients (5%) had a recurrence of myxoma. Three patients with sporadic myxoma relapsed in the left atrium, (2.5, 8, and 17 years later, respectively). Three other patients had Carney complex. One of them suffered 2 recurrences in the left atrium, 16 and 26 months later, respectively. The other 2 patients with Carney complex had an initial myxoma in the right atrium; for 1 of them the recurrence was localized in the left atrium 3 years later, and for the other the recurrences were multiple in the left atrium (0.5 and 3.5 years later, respectively) and then in the right atrium 6.5 years later.
We report here the largest series of patients with left atrial myxoma consecutively diagnosed in a single institution, to our knowledge. The patients presented over a 40-year period.
Our 2:1 female-to-male ratio is consistent with other studies, in which this ratio varies from 2:1 to 3:1 (35,47,55). Myxomas can occur in all age-groups but are most frequent between the third and sixth decades of life (13,30,44,47). They occur predominantly in adult women (70%), although currently there is no explanation for this female predominance (perhaps due in part to hormonal influence). In our series, younger age is significantly associated with neurologic signs or cardiac auscultation abnormalities, and gender is associated with neurologic or embolic symptoms in men and systemic symptoms in women.
The clinical features of these tumors are determined by their location, size, and mobility; there are no pathognomonic signs and symptoms that suggest the presence of a myxoma (35,47,55). In a minority of cases, there are no symptoms at all (47) (10% in our series). However, there is no significant association between the size of the tumor (< or > 5 cm) and the circumstances of discovery (symptomatic or asymptomatic). Left atrial myxomas become symptomatic when they obstruct the mitral valve, embolize peripherally, or cause systemic effects:
1) Obstructive symptoms (valvular ball-valve obstruction) occur in 54%–95% of patients (35,55), 67% in our series. Many cases masquerade as mitral valve disease, but, conversely in mitral stenosis, atrial fibrillation and history of rheumatic fever are uncommon (47); only 9% of patients had arrhythmias in our study. Cardiac obstruction can be revealed by unusual, rapidly progressive congestive cardiac failure (dyspnea on exertion or orthopnea), or by malaise, syncope, or sudden death (due to complete mitral valve obstruction by the myxoma or coronary arteries embolism). The extent of valvular obstruction may vary with body position, and these symptoms’ postural changes are particularly suggestive of myxoma (35,47). Cardiac failure remains the most frequent manifestation (43% in our series). In our study, the presence of cardiac signs paradoxically increased the diagnosis delay, probably because one tends to believe that clinical symptoms are explained by another more common disease (myocardiopathy due to hypertension, ischemic processes, etc.).
2) Systemic emboli are the second arm of the classic triad, occurring in 10%–45% of myxoma patients (4,35,55), 29% in our study. More than two-thirds of myxomatous emboli migrate to the central nervous system (28,50) (24/33 in our series), but any arterial bed may be affected, leading to a great variety of symptoms and signs. Recorded cases document emboli in the upper and lower extremities, aortic saddle, coronary arteries, kidneys, liver, spleen, eye, skin, and more (47). Cerebral emboli may lead to numerous fusiform aneurysms, described as typical of cardiac myxomas (48), as in 3 patients in our study, whose long-term outcome was good (follow-up: 14, 12, 8 yr, respectively). We demonstrate that the presence of an irregular or friable (villous) surface is significantly associated with cerebral and peripheral embolisms.
3) Constitutional signs are the third arm of the classic triad (8,47,55). While these symptoms are rarely prominent, they may occur in up to 90% of cases (35). The prevalence is lower in our series (34%), perhaps because we studied a population at a cardiovascular institute. These signs and symptoms include myalgia, muscle weakness, arthralgia, fever, weight loss, and fatigue. They are obviously nonspecific and may occur in a variety of infectious (endocarditis or rheumatic fever), malignant, or immunologic diseases (rheumatoid arthritis, vasculitis, connective tissue diseases). Nonspecific cutaneous manifestations have also been reported in myxoma patients (18,31).
Cardiac auscultatory findings may vary between examinations, and may depend on body position. Apical presystolic or diastolic murmurs, suggesting significant mitral stenosis, may be heard in more than half of the patients (47,55), 54% in our series. The specific auscultatory finding of myxoma is called “tumor plop”: it is a protodiastolic heart sound of low frequency heard 0.08–0.15 seconds after the second heart sound (21,35). It may be confused with a third heart sound or a mitral opening snap. The tumor plop is uncommon, found in only 15% of patients in our series. We established a significant association between cardiac auscultation abnormalities and cardiac or systemic symptoms.
Serologic and hematologic tests are abnormal in only one-third of the patients (47,55), usually those presenting with systemic symptoms (a significant association was found in our study). The main but nonspecific laboratory abnormalities are anemia and elevated ESR, serum C-reactive protein, or globulin level. Anemia is generally normochromic or hypo-chromic; hemolytic anemia may occur by erythrocytes mechanical destruction on the tumor; polycythemia has also been reported. Less common findings are leukocytosis and thrombocythemia. Recent findings suggest that the production and release of a cytokine by the tumor itself may be responsible for systemic inflammatory and autoimmune manifestations (27). Interleukin-6 (IL6) has been implicated, with high serum levels of IL6 in patients with myxoma that return to normal after surgical removal (51). A correlation between the size of the tumor and the serum level of IL6 has also been suggested (54). Increased IL6 mRNA levels have also been found in myxoma tissue (52), probably explaining myxoma tissue infiltration in some cases by lymphocytes and plasma cells.
ECG findings are nonspecific (35,47,55) but frequently observed (62% in our series). Left atrial hypertrophy occurs in one-third of patients, reflecting the hemodynamic alterations caused by the tumor. Atrial fibrillation is uncommon (less than 10% of cases) in contrast to the findings in mitral valve disease. We observed a significant association between ECG signs and the presence of cardiac or systemic symptoms.
Chest X-rays also reveal nonspecific features in half the patients (35,47,55) and are not helpful for diagnosis, except when the tumor is heavily calcified (9% in our study). Otherwise, a left atrium enlargement and signs of pulmonary congestion may be revealed. In our series, chest X-ray abnormalities were significantly associated with cardiac or systemic symptoms, but there were fewer radiologic signs when the myxoma was revealed by embolic or neurologic manifestations. In fact, cardiac signs or symptoms are more prevalent with large tumors, and one may hypothesize that friable, embolic tumors becoming symptomatic are diagnosed before the reach the size (about 5 cm) that leads to cardiac and radiologic signs. Our data suggest a positive association between small tumor size and embolic frequency (see Table 6).
Echocardiography is the screening and diagnostic method of choice (36,47,55). It is accurate, reliable, noninvasive, and it does not entail any risk of tumor fragmentation and embolization (unlike angiography and cardiac catheterization). Transthoracic examination may be extended by the transesophageal approach (17,59). Transthoracic echocardiography is less invasive, with an excellent sensitivity, up to 95%(41,42), but transesophageal echocardiography sensitivity reaches 100%(17,39). Currently, the decision for surgery is generally based only on echocardiographic evidence of the disease; in our series angiocardiography has not been used since 1977. However, coronary arteriography in patients over 40 years old is usually required in order to rule out concomitant coronary artery disease (47). Other potential diagnostic methods include CT (40) and MRI (20,45). The advantage of CT and MRI over echocardiography is that they provide sectional views of mediastinal, pulmonary, and thoracic structures. They are also more accurate in assessing tumor attachment, endocardial site localization, and tumor stalk presence and size (45).
Anatomic data indicate that most left atrial myxomas arise from the atrial septum, usually near or around the fossa ovalis margin (14,19,55). Tumor mobility depends on the extent of attachment and on the stalk length. Gross appearance is generally white, gray-white, yellowish, or brownish with a polypoid, round or oval tumor, pedunculated or sessile. Tumor consistency is gelatinous (7), and the surface is either smooth or villous (66% and 34%, respectively, in our study). Smooth-surfaced myxomas usually appear with constitutional symptoms, while friable, irregular, or villous tumors usually embolize (30). In the literature (7,30), histologic findings such as fibrosis, calcification, and smooth surface are seen in older people, suggesting that they represent degenerative phenomena. In our series, there was no significant association between villosity and age. The size and weight of myxomas vary, but in our study, the mean duration of symptoms was paradoxically longer in patients with larger tumors.
When, based on histologic appearance, we could distinguish active or inactive myxomas and normally or poorly differentiated myxomas according to the aspect of the cell infiltrate (33), we found that all recurrences actually occurred in patients with “active and poorly differentiated” myxomas.
Many hypotheses regarding the origin of cardiac myxomas have been proposed (5,14,19). The current opinion of most authors is that myxomas are benign neoplasms of endocardial origin (24,32). It is no longer believed that myxomas are organized thrombi. Some myxomas may have a complex of pleomorphic cells that at first view may be considered malignant. However, the rare presence of multiple surface cell layers or mitotic activity is not associated with recurrence or any particular mode of presentation, and it is important not to predict an aggressive behavior on the basis of these atypical cells (7). Conversely, “myxoid imitators,” which are true cardiac sarcomas, must not be confused with myxomas (2).
The cells giving rise to the tumor are considered to be multipotential mesenchymal cells, and immunohistochemical analysis (5,7) has shown that myxoma cells express endothelial markers (60) as tumor vessel cells (QBEnd = CD34 and factor VIII-related antigen). Tumor cells are vimentin-positive, and some may be smooth-muscle-actin positive. Positivity for S-100 protein and cytokeratin (scarce cases with glandular structures) is rarely observed, as is the histocytic marker KP-1 (7,24). Burke (7) showed that endothelial differentiation was best demonstrated by CD34 positivity, which is also a sensitive endothelial marker for Kaposi sarcoma. This corroborates the concept that myxomas arise from primitive stromal cells having the capacity to differentiate along endothelial lines. A recent study (29) confirms that myxomas produce vascular endothelial growth factor, with a correlation between tumor size and the expression of this factor (suggesting a role in angiogenesis).
Myxomas may “metastasize”(6,49), commonly to the brain, but these “metastases” do not have any malignant potential (32). The myxoma tissue emboli may remain intraluminal; may penetrate the vessel wall and may cause stroke; or may remain asymptomatic, but without any cerebral tissue invasion. However, years later, the vessel walls myxomatous invasion may lead to formations resembling mycotic aneurysms (2). Three patients in our series had embolic implants that grew into the surrounding arterial walls, with development of multiple intracranial aneurysms, without any detectable recurrences or malignant behavior elsewhere during long-term follow-up.
Treatment and follow-up
The treatment of choice for myxomas is surgical removal (3,12,15,37,38,57). Once the diagnosis is made, urgent excision of the tumor is essential. Embolic complications or sudden death are always possible, even in asymptomatic patients: 8% of patients in some studies (1,34,58). During the time of our series, we did not observe sudden death due to cardiac myxoma, but 2 patients had cardiac arrest in the hospital before surgery with successful resuscitation. With current operative techniques, surgery is generally a safe procedure, and, as most tumors are usually pedunculated, they can be removed easily (57). The operative procedure may differ according to surgeons’ habits (15,25,34,38). In our series, mortality was low. Only 3 patients died during the postoperative period before 1978, and another patient died in 1996 of meningitis not imputable to myxoma. The most frequent postoperative complication was early transient arrhythmias or atrioventricular disorders, with an incidence of 26%.
Cardiac myxomas usually occur sporadically, but recurrent or familial cases have been described. The reported recurrence rate ranges from 5% to 14% in the literature (4,15,23,35,38,39), 5% in our series. Recurrences are reported from as soon as a few months to as long as 8 years after excision of the myxoma (0.5–6.5 yr in our series). The cause of recurrence is not clear, but probable risk factors include inadequate or incomplete resection, intracardiac implantation, intraoperative displacement of tumor material, embolization, multicentricity of the tumor, and/or a reserve of tumor precursor cells in the subendocardium. In most cases of sporadic myxoma, incomplete resection of the attachment area seems to be the cause of recurrence (30,34). Patients with genetic abnormalities (11,56) are at high risk of recurrence and multifocal tumors. They usually suffer from 2 or more of the following conditions: cardiac and skin myxomas (single or multiple), spotty pigmentation, cutaneous lentiginosis, myxoid fibroadenomas of the breast, endocrine overactivity (pituitary adenomas, primary adrenal hyperplasia with Cushing syndrome) and testicular tumors (9,10). They are described as having “Carney complex” or “myxoma syndrome.” The overall risk of recurrence for familial and Carney complex myxomas is about 12% and 22%, respectively (56), whereas it is only 1%–3% for sporadic tumors (47). In our series, 3 cases fulfilled the cardiac myxoma “Carney complex” criteria. At the time of diagnosis, familial myxoma patients are usually considerably younger than nonfamilial myxoma patients. Histologically, myxomas of the 2 patient groups are not different. A gene linked to Carney complex has been identified recently (26).
The long-term prognosis is excellent. In the literature (25,34,38,57), the operative mortality rate is low (0–3%), and hospital mortality after excision of intracardiac myxomas ranges from 0 to 12% (3.5% in our study). Transient supraventricular arrhythmias may follow surgical removal (26% in our series). A few patients may require permanent cardiac pacing for atrioventricular conduction disturbances (only 2 patients in our series). In spite of the presence of a tumor that interferes with mitral valve function enough to result in heart failure, the mitral valve is rarely damaged (wrecking ball effect). In our study, only 1 patient required mitral valve replacement, for bacterial endocarditis associated with left atrial myxoma. However, despite the low recurrence rate, myxoma patients need to be followed carefully, especially familial, younger, and Carney complex cases. An annual echocardiogram is recommended over the 3-to 6-year period following surgery, at least.
The differential diagnosis, besides mitral valve disease, encompasses other benign and malignant primary heart tumors (lipomas, papillary fibroelastomas, fibromas, sarcomas, etc.), metastatic tumors (20–40 times more common than primary tumors) and thrombi, which occur in patients with myocardial infarction or dilated cardiomyopathy (47). When systemic symptoms are present (fever, weight loss, fatigue), the differential diagnosis should consider rheumatic heart disease, subacute bacterial endocarditis, and connective tissue disease or vasculitis (8,35). The combination of embolic events and constitutional symptoms is due more commonly to infective endocarditis, but may also reveal myxoma. The presence of splenomegaly or septic syndrome helps to differentiate the 2 diseases, as these are extremely rare in myxoma. However, myxomas are occasionally infected, making the clinical differentiation of myxoma and endocarditis even more difficult (47). An exhaustive review of infected cardiac myxomas (46) reported 40 cases with a presentation often similar to subacute bacterial endocarditis. There is no clear clinical distinction between infected and noninfected myxoma (for cardiac symptoms and the rate of systemic or cerebral emboli); however, constitutional symptoms increase significantly in patients with infected myxoma (fever, elevated ESR), and men are more often affected than women.
Our series of 112 cases of left atrial myxoma allows some useful clinical remarks. It illustrates that this benign tumor may cause a wide range of clinical symptoms not only such as cardiac disease, but also infective, immunologic, or neurologic diseases. Diagnosis is rarely made only on clinical grounds, because there are no specific physical signs or symptoms. Myxoma usually occurs sporadically, but familial or recurrent cases have been reported. Recent findings suggest that production and release of the IL6 cytokine by the tumor may be responsible for inflammatory or autoimmune manifestations. Two-dimensional echocardiography, including the transesophageal approach, is the technique of choice for diagnosis and follow-up of this tumor. Although myxomas are rare, they should be considered in the differential diagnosis of mitral valve disease and congestive heart failure, especially in patients with sinus rhythm. Echocardiography is also indicated for any patient with embolic phenomena. An embolic event in young adults, in the absence of signs or symptoms of endocarditis or arrhythmia, must lead to a primary consideration of myxoma as the embolic source. The material obtained by embolectomy should always be examined histologically. Further biologic studies are needed to understand better the clinical features of myxoma; in particular, adhesion protein in myxoma cells or matrix should be studied for embolic myxomas (villous surface). Immunohistostaining with detection of potential estrogen receptors could be performed to attempt explanation for the high female-to-male ratio and age distribution.
We analyzed a series of 112 consecutive cases of left atrial myxoma diagnosed in a single French hospital (72 women and 40 men; age range, 5–84 yr) over 40 years, from 1959 to 1998. Symptoms of mitral valve obstruction, the first arm of the classic triad of myxoma presentation, were present in 75 patients (67%), with mostly cardiac failure or malaise. Symptoms of embolism, the second frequent presentation in the classic triad, were observed in 33 cases (29%) with 1 or several locations, essentially cerebral emboli with stroke. Males are statistically at greater risk than females of developing embolic complications. The third arm of the classic triad consists of constitutional symptoms (34%) with fever, weight loss, or symptoms resembling connective tissue disease, due to cytokine (interleukin-6) secretion. Younger and male patients have more neurologic symptoms, and female patients have more systemic symptoms. Seventy-two patients (64%) had cardiac auscultation abnormalities, essentially pseudo-mitral valve disease (53.5%) and more rarely the suggestive tumor plop (15%). The most frequent electrocardiographic sign was left atrial hypertrophy (35%), whereas arrhythmias were uncommon. The greater number of myxoma patients (98) diagnosed preoperatively after 1977 reflects the introduction of echocardiography as a noninvasive diagnostic procedure. However, there was no significant reduction in the average time from onset of symptoms to operation between patients seen in the periods before and after 1977. The tumor diameter ranged from 1 to 15 cm with a weight of between 15 and 180 g (mean, 37 g). The myxoma surface was friable or villous in 35% of the cases, and smooth in the other 65% cases. Myxomas in patients presenting with embolism have a friable surface; those in patients with cardiac symptoms, pseudo-mitral auscultation signs, tumor plop, and electrocardiogram or radiologic signs of left atrium hypertrophy and dilatation are significantly the larger tumors. The long-term prognosis is excellent, and only 4 deaths occurred among our 112 cases over a median follow-up of 3 years. The recurrence rate is low (5%), but long-term follow-up and serial echocardiography are advisable especially for young patients.
The surgical removals were performed during the 40-year period by Drs Barral, Champsaur, Chassignolle, Dureau, Frieh, Jegaden, Maret, Marion, Michaud, Mikaeloff, Ninet, Termet, Villard.
We are indebted to Dr Alison Foote for editing the manuscript.
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