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Ann Thorac Surg 1999;68:1236-1241
© 1999 The Society of Thoracic Surgeons

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Original Articles

Primary cardiac tumors: early and late results of surgical treatment in 91 patients

^a Department of Cardiovascular Surgery, University of Turin, Turin, Italy

Address reprint requests to Dr Centofanti, Division of Cardiac Surgery, University of Turin, C.so Bramante, 10126 Turin, Italy

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Between March 1980 and September 1997, 91 patients underwent evaluation and treatment for primary cardiac neoplasms.

Methods. Tumors were grouped into three categories: atrial myxomas, benign nonmyxomas, and malignant tumors. Survivors were contacted; no one was lost to follow-up. The mean follow-up for this series is 7 ± 5 years.

Results. Eighty-three patients were diagnosed with atrial myxomas (Male/Female: 29/54), average age 55 ± 13 years. The hospital mortality was 3.6% (3/83), the late mortality was 6.5% (5/80). No recurrent myxomas have been identified clinically or by echocardiography in any patient. Three patients were diagnosed with benign nonmyxoma tumors. (Male/Female: 2/1), average age 64 ± 8 years. There were no perioperative deaths and 1 patient died 4 years postoperatively from fibroma, with no linked causes. No recurrent tumors have been identified. Five patients were diagnosed with malignant tumors. (M/F: 1/4), average age 53 ± 16 years. The hospital mortality was 20% (1/5); in 3 patients a redo-operation was necessary after 8, 11, and 12 months because of tumor recurrence. All patients died within 3 years of the first operation (mean 13 ± 14 months).

Conclusions. Surgical resection, when possible, is the treatment of choice for all primary cardiac tumors. Patients with benign tumors are probably cured by resection and in our experience there was no known tumor recurrence. Effective palliation is possible with resection of malignant tumors, but more effective adjuvant therapy will be necessary to improve long-term prognosis.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Primary cardiac neoplasms are rare entities, with an autopsy incidence ranging from 0.001% to 0.03%. Three-quarters of the tumors are benign; nearly half the benign heart tumors are myxomas; and the majority of the rest are lipomas, papillary fibroelastomas, and rhabdomyomas [1].

The advent of modern diagnostic procedures and cardiac operations has transformed primary cardiac neoplasm from a condition rarely diagnosed before autopsy to a potentially curable form of heart disease.

A first surgical excision was performed in 1952 by Bahnson and Newman. In 1954, Crafoord successfully removed an atrial myxoma by using cardiopulmonary bypass [2]. During the past 3 decades, multiple centers have shown excellent surgical therapy results with a decreasing mortality. Generally, operation quickly relieves symptoms and the recurrence of tumors is uncommon.

In this report we review the clinical and surgical experience and late results with cardiac tumors (other than classical benign myxomas) at the Division of Cardiac Surgery of the University of Turin, over the past 17 years. It is hoped that the analysis of a large hospital series, such as this, will help clarify the clinical presentation, anatomic findings, and long-term results of surgical therapy.

A review of 91 patients with primary cardiac neoplasms treated between 1980 and 1997 was conducted. Survivors were contacted by telephone. None was lost to follow-up. The mean follow-up for this series is 7 ± 5 years (range: 10 months to 17 years).

For reporting purposes, neoplasms were grouped into three categories: myxomas, benign nonmyxomas, and malignant tumors.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Myxomas
Myxomas represent 91% of the heart tumors we resected in our division. Of the 83 patients 54 were female and 29 male. The patients were adults, ranging in age from 19 to 79 years (mean age 55 ± 13 years). Seventy-seven myxomas occurred in the left atrium and six in the right atrium (Table 1).

A clinical picture of congestive heart failure was found in 43 patients (52%), 20 of who were in New York Heart Association (NYHA) class III or IV. Thromboembolic episodes in the central nervous system, usually resembling transient ischemic attacks, occurred in 17 patients and thromboembolic episodes in the lower extremity occurred in 2 patients.

Chest pain was reported in 17 patients (20%) and was frequently atypical, unrelated to exercise and described as substernal heaviness or burning. Symptoms related to exercise angina were found in only 3 patients, 2 of who were later found to have significant coronary artery disease. One patient was asymptomatic.

The average time from onset of symptoms to diagnosis was 3.3 months (ranging from as little as 1 day to as long as 32 months) and in 52.5% of patients was much shorter (less than 1 month).

The presence of a tumor was strongly suggested or established by echocardiogram. Coronary angiography was performed in 7 patients (8.4%). Three patients were catheterized for suspected coronary artery disease and not for tumors. One of these three patients had a normal coronary angiogram.

Operative findings and surgical techniques
The treatment of choice for myxomas is surgical removal; it is usually curative. All patients underwent surgical exploration soon after the diagnosis of myxoma had been made, because of the possibility of embolic complications or sudden death.

After a median sternotomy has been performed, the tumor is excised with the use of cardiopulmonary bypass with moderate systemic hypothermia, deep topical hypothermia, and cardioplegic cardiac arrest.

A right and left atriotomy was employed for resection of tumor in 40 patients (48.2%); a right atriotomy in 31 patients (37.7%), and a left atriotomy in 12 patients (14.4%).

Of 77 left atrial myxomas, 59 (76.6%) arose from the interatrial septum, 10 (12.9%) from the posterior left atrial wall, 5 (6.5%) from the superior left atrial wall, 2 (2.6%) from lateral left atrial wall, and 1 (1.3%) near the anulus of the posterior leaflet of the mitral valve. Of six right atrial myxomas, three (50%) arose from the interatrial septum, two (33.3%) from the lateral right atrial wall, and one (16.6%) from the posterior atrial wall.

Tumor size varied from approximately 2 x 1 x 1.5 cm to 12 x 7 x 7 cm. Tumors were excised without an associated endocardial resection in 69 cases. In 14 cases they were excised with a cuff of full-thickness, normal atrial tissue (interatrial septum: 12 cases, atrial wall 2 cases) with pericardial or Dacron (C.R. Bard, Haverhill, PA) patch closure of the defect.

Associated procedures included: coronary artery bypass grafting in 3 patients, mitral valve replacement in 2 patients, conservative mitral valve surgery in 1 patient, aortic valve replacement in 1 patient, pulmonary valve annuloplasty in 1 patient, and right pulmonary lobectomy in 1 patient.

Two patients came to surgery with a documented embolic obstruction of right and left femoral artery respectively: in these cases a femoral embolectomy with a Fogarty catheter (Baxter, Irvine, CA) was successfully performed.

Pathology
The diagnosis of myxoma was histologically confirmed in all cases. Formalin-fixed samples were routinely processed for light microscopy and stained with hematoxylin-eosin. Special stains (Masson’s trichrome for collagen, Van Gieson for elastic fibers and PAS staining) and immunohistochemistry were performed when required for diagnosis by using avidin-biotin complex technique; we investigated myxomatous cell immunoreactivity for -smooth muscle, vimentin, desmin, myosin, and D factor VIII-related antigen.

Benign nonmyxoma tumors
Benign non-myxoma tumors represent only the 3.2% of heart tumors we resected in our institute, including 3 patients (1 female and 2 male). The average age was 64 ± 8 years (Table 2).

The symptoms were present in 1 patient with dyspnea and palpitation. The time from onset of symptoms to diagnosis was 9 days.

Operative findings and surgical techniques
The technique of cardiopulmonary by-pass and myocardial preservation was the same as for the patients with myxomas. Two tumors occurred in the right ventricle and one in the right atrium.

Right atriotomy was performed on 2 patients, and right ventriculotomy on 1 patient. Associated procedures included tricuspid valve annuloplasty in 1 patient and coronary artery bypass grafting in another. The lesions included a fibroma of the interventricular septum, a fibroma of the right ventricle lateral wall and a fibroelastoma of the tricuspid valve.

Malignant tumors
Malignant tumors represent only 5.5% of the heart tumors we resected in our institute (5 patients: 4 females and 1 male). The average age was 53 ± 16 years (Table 3).

Operative findings and surgical techniques
All operations were performed with the aid of cardiopulmonary bypass and myocardial preservation by moderate systemic hypothermia, deep topical hypothermia, and cardioplegic cardiac arrest. Three tumors occurred in the left ventricle, one on the mitral valve, and one in the right ventricle.

Right atriotomy was performed on 4 patients and right ventriculotomy on 1 patient. A left pulmonary lobectomy was performed on 1 patient with pulmonary neoplasm (Table 3; case 4).

The lesions included three sarcomas (unclassified), one on the mitral valve, one on the left atrial lateral wall, and one on the left atrial posterior wall included the mitral valve. The rhabdomyosarcoma arose from the left atria on the interatrial septum. The leiomyosarcoma arose from the right ventricle.

We have pursued a policy of wide resection with adequate margins and replacement of cardiac valves as needed.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Myxomas
Among the 83 patients who underwent operation at our institution, there were 3 hospital deaths (3.6%). Early morbidity included atrial arrhythmias in 31 of 83 patients (37.3%), AV heart block in 3 patients (3.6%), and pericardial effusion in 1 patient.

Late follow-up is complete for the 80 patients discharged from the hospital. The late mortality was 6.5% (5/80). Late morbidity included arrhythmias and palpitation in 3 patients. One patient had AV heart block and required insertion of a pacemaker 2 years after operation.

No recurrent myxomas have been identified clinically or by echocardiography.

Benign nonmyxoma tumors
There were no perioperative deaths. There was 1 late death. A patient with severe coronary artery disease and poor left ventricular function died of fibroma with no linked causes, 4 years after coronary artery bypass grafting and resection of right ventricular tumor with a large patch repair.

The remaining 2 survivors were followed up for an average of 7 years and were in functional NYHA class I. No recurrent tumors have been identified clinically or by echocardiography in either patient.

Malignant tumors
All 5 patients survived their operations, but 1 died within 30 days of postoperative complications. One patient died suddenly 2 months after operation. In 3 patients, a redo-operation was necessary after 8, 11, and 12 months because of tumor recurrence. In the case of leiomyosarcoma of the right ventricle, the reoperation was performed after 11 months and the patient died after 7 months; in the case of the rhabdomyosarcoma of the left atria redo was necessary 12 months later and death occurred after 25 months. At last the sarcoma of the left atrial posterior wall included the mitral valve after 8 months and also underwent a mitral valve replacement. The patient died after 15 days after redo operation of multi-organ failure (MOF).

All patients died within 3 years of the first operation (mean 13 ± 14 months).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
Tumors of the heart remain a rare occurrence. Approximately 75% of such tumors are benign and 25% are malignant. Nearly half of the benign heart tumors are myxomas and 75% of malignant tumors are sarcomas [3]. Eighty-six of 91 (94.5%) tumors in this series were benign lesions. A higher than usual incidence of myxomas (91.2%; 83/91 was observed. The location, size, and mobility of tumors determine their clinical features.

Most patients present with one or more of the triad of embolism, intracardiac obstruction, and constitutional symptoms. Of our patients with myxomas, 59 of 83 (71%) had congestive heart failure or palpitation or both, 19 patients (23%) had embolic disease, 17 patients (20%) had neurologic findings or symptoms.

Others have reported similar findings, with approximately 88% of patients having congestive heart failure or palpitation, 22% having neurologic symptoms, and 11% having constitutional symptoms [4]. However, other series report a higher frequency of embolization (40%) [1, 5].

In the literature, approximately half of the embolic problems involve the central nervous system [6]. In our patients, however, 89.4% of recognized emboli involved the central nervous system.

Symptoms in patients with nonmyxoma benign lesions were generally absent, as one tumor was an incidental finding at cardiac operation for coronary artery disease and one patient had symptoms due to congestive heart failure from obstruction.

Malignant lesions, like benign tumors, mainly caused symptoms of congestive heart failure resulting from obstruction of cardiac output. In this series, the symptoms occurred in one patient having palpitation. One patient had embolic disease before the redo operation because of tumor recurrence.

The use of echocardiography has greatly facilitated the diagnosis of both benign and malignant tumors. Transthoracic echocardiography can generally be used to determine the location, size, shape, attachment, and mobility of a tumor. The transesophageal approach is particularly helpful in detecting the site of insertion and morphologic features of atrial and ventricular myxomas [7].

The excellent results obtained with echocardiography in this series and by others [8, 9] have made it the most important diagnostic modality available today for documenting the presence of these tumors. However, if the patient’s age is greater than 50 years, or coronary artery disease is suspected, coronary arteriography is advised to evaluate the coronary arteries.

Complete resection is best performed through a median sternotomy with total cardiopulmonary bypass and cardiac standstill.

Jones and associates believe that a surgical approach to atrial myxomas should allow minimal manipulation of the tumor, provide adequate exposure for complete resection of tumor, allow inspection of all four heart chambers, minimize recurrence, and be safe and efficacious. They use a biatrial approach to myxoma [10].

Others consider the exposure of the left atriotomy approach to be adequate and have demonstrated the low recurrence rates and safety of this technique [11, 12]. The transseptal approach to atrial myxomas is a technique in which the interatrial septum is incised vertically through a right atriotomy. Proposed advantages of this technique include only one atrial incision, adequate exposure to evaluate the mitral valve, low recurrence rates, and long-term efficaciousness [13].

Clearly, the optimal operative approach to the atrial myxoma lacks uniformity. In this series, a right and left atriotomy was employed for resection of tumor in 48.2% of the patients. A right atriotomy was employed in 37.7% of the patients and a left atriotomy in 14.4%. However, all surgeons described an adequate exposure in their reports.

There is still considerable controversy concerning the extent of resection necessary to prevent recurrences. Some authors have stressed the need to examine all four cardiac chambers [14]. In our experience, after the advent of transesophageal echocardiography, we believe visual inspection of all four cardiac chambers is unnecessary.

Some authors have recommended wide excision and patch repair [15]. Others have recommended simple excision as being satisfactory, and have observed patients for periods of 4.5 to 10 years with no evidence of recurrence [16, 17].

In this series, myxomas were excised in 69 cases without an associated endocardial resection (83%), and were excised in 14 cases with a cuff of full-thickness normal atrial tissue and patch repair with autologous pericardium or Dacron (Sauvage, CR Bard Inc, Billerica, MA).

Recurrence of cardiac myxomas is 4% to 5% in some series [13, 18]. In the follow-up period of this series (mean 7 ± 5 years, range 10 months to 17 years) no recurrent myxomas have been identified clinically or by echocardiography.

Therefore, one must conclude that complete resection of the septum or the atrial wall is not always necessary, and practically speaking, is not always possible.

The prognosis of nonmyxoma benign lesions is closely related to resectability. A poor prognosis has been documented for unresectable fibromas and hamartomas, and lipomatous hypertrophy of the interatrial septum [1, 19].

Of note is the good long-term survival in the 2 patients undergoing incomplete resection: one with a fibroma of the interventricular septum and the other with fibroelastoma of the tricuspid valve. Both are alive and well postoperatively, at 12 years and 3 years, respectively. These two patients show no evidence of recurrence by clinical status and echocardiography.

Sarcomas are the most common malignant tumors of the heart, with only isolated reports of melanomas [20], plasmacytomas [21], and lymphomas [22]. Although the histologic classification of sarcomas of the heart is confusing, this series demonstrates three malignant histologic variants. These are sarcomas "unclassified," three cases; rhabdomyosarcoma, one case; and leiomyosarcoma, one case. The prognosis of patients with primary malignant cardiac disease is guarded, with death occurring within 6 months postoperatively on average, regardless of the particular histologic diagnosis [3, 23].

We have pursued a policy of wide resection of primary malignant cardiac tumors, even though a redo operation was necessary in three patients because of tumor recurrence, and all patients died within 3 years from the first operation. We have three reasons for our policy:

1. To allow secure and definitive histologic diagnosis.
   
2. Mechanical obstruction of cardiac output in three (one first operation, two redo) of eight tumors was judged to be severe. A palliative procedure then might be expected to prolong life and allow time for effective adjuvant therapy.
   
3. Finally, there are reports of survival of up to 3 years, after resection, chemotherapy, radiation therapy, or combinations of these treatments [24, 25].
   

In conclusion, the early and late results of operation are more specifically predicted in our series by histologic tumor type. In general, survival chances are excellent for patients with myxomas, fair for those with nonmyxomatous benign tumors, and dismal for patients with malignant tumors.

Surgical resection, when possible, is the treatment of choice for all patients with cardiac neoplasms. It is curative in benign tumors. It may prolong life in malignant tumors, although improvement in adjuvant therapy is clearly needed before any real hope of a cure can be offered to these individuals.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Reynen K. Cardiac myxomas. N Engl J Med 1995;33:1610-1617.
2. Kirklin J.W., Barratt-Boyes B.G. Cardiac surgery, 2nd ed. New York: Churchill Livingstone, 1993:1636-1646.
3. McAllister H.A., Fenoglio J.J. Tumors of cardiovascular system. Atlas of tumor pathology. 2nd series. Fascicle 15. Washington, DC: Armed Forces Institute of Pathology, 1978:1-20.
4. Dein J.R., Frist W.H., Stinson E.B., et al. Primary Cardiac Neoplasms. J Thorac Cardiovasc Surg 1987;93:502-511.[Abstract]
5. Larrieu A.J., Jamieson W.R.E., Tyers G.F.O., et al. Primary cardiac tumors. J Thorac Cardiovasc Surg 1982;83:339-348.[Abstract]
6. Firor W.B., Aldridge H.E., Bigelow W.G. A follow-up study of three patients after removal of left atrial myxoma five to ten years previously. J Thorac Cardiovasc Surg 1966;51:515-520.[Medline]
7. Obeid A.I., Marvasti M., Parker F., Rosenberg J. Comparison of transthoracic and transesophageal echocardiography in diagnosis of left atrial myxomas. Am J Cardiol 1989;63:1006-1008.[Medline]
8. Cohen M.V. Left atrial myxoma. J Med Soc NJ 1979;76:213-215.
9. Berning J., Egeblad H., Lauridsen P., Wennevold A. The diagnostic challenge of left atrial myxoma. Acta Med Scand 1979;206:115-121.[Medline]
10. Jones D.R., Warden H.E., Murray G.F., et al. Biatrial approach to cardiac myxomas. Ann Thorac Surg 1995;59:851-856.[Abstract/Free Full Text]
11. Meyns B., Vanclemmput J., Flameng W., Daenen W. Surgery for cardiac myxoma. Eur J Cardiothorac Surg 1993;7:437-440.[Abstract]
12. Actis Dato G.M., de Benedictis M., Actis Dato A., Jr, Ricci A., Sommariva L., De Paulis R. Long-term follow-up of cardiac myxomas (7–31 years). J Cardiovasc Surg 1993;34:141-143.[Medline]
13. Sellke F.W., Lemmer J.H., Jr, Vandenberg B.F., Ehrenhaft J.L. Surgical treatment of cardiac myxomas. Ann Thorac Surg 1990;50:557-561.[Abstract]
14. Marvasti M.A., Obeid A.I., Potts J.L., Parker F.B. Approach in the management of atrial myxoma with long-term follow-up. Ann Thorac Surg 1984;38:53-58.[Abstract]
15. Gerbode F., Kerth W.J., Hill J.D. Surgical management of tumors of the heart. Surgery 1967;61:94-101.[Medline]
16. Attar S., Lee Y., Singleton R., Scherlis L., David R., McLaughlin J.S. Cardiac myxoma. Ann Thorac Surg 1980;29:397-405.[Abstract]
17. Melo J., Ahmad A., Chapman R., Wood J., Starr A. Primary tumors of the heart. Am Surg 1979;45:681-683.[Medline]
18. Kabbani S.S., Jokhader M., Meada R., et al. Atrial myxoma. Ann Thorac Surg 1994;58:483-488.[Abstract]
19. Reyes C.V., Jablokow V.R. Lipomatous hypertrophy of the cardiac interatrial septum. Am J Clin Pathol 1979;72:785-788.[Medline]
20. Gelfand E.T., Taylor R.F., Rao S., Hendin D., Akabutu J., Callaghan J.C. Melanotic malignant schwannoma of the right atrium. J Thorac Cardiovasc Surg 1977;74:808-812.[Abstract]
21. Torstveit J.R., Bennett W.A., Hinchcliffe W.A., Cornell W.P. Primary plasmacytoma of the atrium. J Thorac Cardiovasc Surg 1977;74:563-566.[Abstract]
22. Pastakia B. Malignant atrial myxoma presenting as intracranial mass. Chest 1979;79:531-532.
23. Poole G.V., Meredith J.W., Breyer R.H., Mills S.A. Surgical implications in malignant cardiac disease. Ann Thorac Surg 1983;36:484-491.[Abstract]
24. Sorlie D., Myhre E.S.P., Stalsberg H. Angiosarcoma of the heart. Br Heart J 1984;51:94-97.[Abstract/Free Full Text]
25. Rossi N.P., Kioschos J.M., Aschenbrener C.A., Ehrenhaft J.L. Primary angiosarcoma of the heart. Cancer 1976;37:891-894.[Medline]

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