Clinical Recognition and Management of Cardiac Metastatic Disease Observations in a Unique Case of Alveolar Soft-Part Sarcoma
ROBERT M. STARK, M.D.’ JOSEPH K. PERLOFF. M.D. JOHN H. GLICK, M.D. JOHN W. HIRSHFELD, Jr., M.D. RICHARD B. DEVEREUX. M.D. Philadelphia, Pennsylvania
From the Hospital of the University of Pennsylvania, and the Cardiovascular and HematologyOncology Sections, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Dr. Joseph K. Perloff, Cardiovascular Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104. Manuscript accepted September 29, 1976.
* Present address: National Heart and Lung Institute, Building 10, Room 7B 15, National Institutes of Health, Bethesda, Maryland 20014.
A 22 year old woman presented with a three month history of progressive dyspnea, orthopnea and pedal edema. She had previously been in excellent health with the exception of surgery five years before for a tumor of her left thigh. The histopathologic diagnosis was alveolar soft-part sarcoma, a slow-growing granular cell sarcoma not previously known to metastasize to the heart. Her clinical course was characterized by increasingly severe dyspnea, edema, and ascites unresponsive to digitalis and diuretic therapy. Echocardiography during the most acute phase of the illness showed right ventricular dilitation, paradoxic septal motion and a normal left ventricle. Cardiac catheterization and angiography revealed a severely-obstructing filling defect moving with systole and diastole from the pulmonary trunk to the right ventricular outflow tract. At surgery, a mass of friable tumor tissue was removed from the right ventricular cavity, outflow tract, and pulmonary trunk with dramatic postoperative relief of symptoms and virtual abolition of the major hemodynamic abnormalities. Histopathologic examination showed the resected cardiac tumor to be alveolar soft-part sarcoma. To our knowledge, cardiac metastasis from alveolar soft-part sarcoma is thus far unique to the patient described in this report. Her unusual presentation and course, which extend the known clinical spectrum of this tumor, are discussed in the broader context of clinical recognition and management of cardiac metastatic disease. Metastatic cancer to the heart is not rare, occurring in 1.5 to 18.3 per cent of the patients who die from malignancies and who are examined at autopsy [ 11. Even though the first clinical observations were made as early as 1924 [2] and 1930[3,4], metastatic cardiac tumor is still infrequently diagnosed during life despite the availability of refined noninvasive and angiocardiographic technics. The difficulty in clinical recognition lies in the protean clinical manifestations of cardiac metastaies which may mimic far more common types of acquired pericardial, myocardial or valvular heart disease. The irnproved survival afforded by aggressive treatment of many malignancies has increased
October 1977
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1. Electrocardiogram obtained on admission shows a vertical axis, a bizarre right ventricular conduction defect, tall right precordial R waves, and widespread nonspecific ST-T abnormalities in limb and precordial leads. Figure
the potential frequency with which late and seemingly-unrelated metastatic disease is encountered in clinical practice. Concurrent advances in chemotherapy, radiotherapy and open heart surgery improve the prognosis for patients with symptomatic or life-threatening cardiac metastases, and underscore the need for heightened clinical suspicion in cases of unexplained cardiovascular disease in the setting of a history of malignancy, recent or remote. Alveolar soft-part sarcoma, a granular-cell tumor histologically similar to chemodectoma, is a slow-
growing malignancy arising from skeletal muscle and metastasizing widely to lung, brain, bone, lymph nodes and other organs [6]. This neoplasm exhibits a number of unusual features among which are a striking tendency to originate from muscles on the right side of the body, to pursue an indolent course and to metastasize both very early and very late [5]. Considering its origin in contractile tissue and its propensity to infiltrate surrounding blood vessels [6], it is curious that soft-part sarcoma has not been observed to metastasize to or originate in the heart.
A, normal chest roentgenogram taken three months prior to admission. B, chest roentgenogram mission shows marked cardiomegaly and a right pleural effusion.
Figure 2.
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CASE REPORT A 22 year old housewife presented with a history of rapidly progressive dyspnea and orthopnea. She had been entirely well until three months prior to admission when effort dyspnea and intermittent or-thopnea began. She became increasingly symptomatic over the next two months until she was bedridden and able to sleep only when sitting upright in a chair. One month prior to admission, edema of both lower extremities developed and she had a progressive weight gain of 20 to 30 pounds. She was admitted to another hospital where chest films revealed massive cardiomegaly and a right pleural effusion. An echocardiogram was reported to show minimal pericardial effusion. Treatment with furosemide and digoxin afforded no improvement, and she was transferred to the Hospital of the University of Pennsylvania with a provisional diagnosis of congestive cardiomyopathy. fhere was no past history of heart disease. A tumor (tissue diagnosis, alveolar soft-part sarcoma) had been resected from her left thigh five years prior to admission with no subsequent symptoms or signs of recurrence on careful yearly follow-up. Physical examination on admission revealed a pale, anxious white woman, dyspneic at rest. Blood pressure was 105/88 mm Hg with 15 mm Hg paradox, heart rate 1 lG/min and respirations 36/min. There was slight cyanosis of the lips and nail beds. The jugular venous pressure was 12 cm HP0 with a markedly increased V wave. There was dullness to percussion and decreased. breath sounds over the right hemithorax up to the scapula. A left ventricular impulse was barely palpable in the fifth intercostal space just beyond the mid-clavicular line. There was a right ventricular impulse at the lower left sternal edge. The first heart sound was normal and the second sound single. The pulmonic component of the second sound was not heard. A long, grade 316 slightly crescendo-decrescendo systolic murmur was heard at the lower left sternal border. The murmur did not radiate or change with respiration. There were prominent third and fourth heart sounds which increased with inspiration. Peripheral arterial pulses were of low amplitude but normal contour. The liver edge was palpable 4 cm below the right costal margin. There was moderate ascites and pitting edema of both legs up to the knees; a well-healed surgical scar was present on the lateral aspect of the left thigh. The remainder of the physical examination was unrevealing. Laboratory values on admission included a hematocrit of 45 per cent and a white cell count of 8,000/mm3 with a normal differential. Electrolytes were normal, but arterial blood gases showed a respiratory alkalosis with hypoxemia (pH 7.49, oxygen tension (~0~) 58 mm Hg, carbon dioxide tension (pCOz) 30 mm Hg and bicarbonate (HCOs) 23 mm Hg. Blood urea nitrogen was 23 mg/dl, creatinine 2.0 mg/dl, total bilirubin 1.4 mg/dl, lactic dehydrogenase 897 IWliter (normal 140 to 270 Ill/liter), cu-hydroxybutyrate dehydrogenase (HBD) 689 Ill/liter (normal 110 to 230 IWliter), creatine phosphokinase 17 Ill/liter (normal 14 to 60 Ill/liter) and serum aspartate transaminase 32 IWliter (normal 9 to 22 Ill/liter). The electrocardiogram (Figure 1) showed sinus tachycardia, a vertical axis, a bizarre right ventricular conduction defect, tall R waves in the right precordial leads, and widespread nonspecific ST-T abnormalities in limb and precordial leads.
Figure 3, Echocardiograms taken while the patient was acutely ill (recording quality limited by severe dyspnea and orthopnea). A mass of echoes (arrow, tumor) is shown, particularly in systole, anterior to the tricuspid valve (TV). The right ventricle (RV) is dilated and the motion of the interventricular septum (IVS) is reversed. L V = left ventricle.
Vectorcardiogram (Frank lead system) recorded a bizarre intraventricular conduction~defect of uncertain type, abnormal TsE loop consistent with conduction abnormality, and anterior displacement of the QRS SE loop suggesting right ventricular enlargement. A chest film showed massive cardiomegaly and a large right pleural effusion (Figure 2B). In contrast, a chest film obtained three months prior to the illness was entirely within normal limits (Figure 2A). Thoracentesis resulted in considerable symptomatic improvement and yielded 900 cc of straw-colored, sterile transudate which was negative for acid-fast and bacterial organisms. There was class I cytology on cell block. The echocardiogram is shown in Figure 3 and described in detail in the legend. Cardiac catheterization demonstrated right ventricular outflow obstruction with data shown in Table I. Using the Gorlin formula, the zone of obstruction ‘to right ventricular outflow was estimated at 0.5 cm*. Right ventriculography (in both oblique projections) demonstrated a mobile filling defect that protruded into the pulmonary trunk during systole and descended into the right ventricular outflow tract during diastole (Figure 4). The right ventricular outflow tract, itself, was deformed and relatively immobile, with persistent filling defects. Tricuspid regurgitation was seen in the right anterior oblique projection.
October 1977
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Volume 63
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CARDIAC
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TABLE I
DISEASE-STARK
ET AL.
Cardiac Catheterization Findings Before and After Resection of Intracardiac Metastasis Intracardiac Site
Pressures (mm Hg)
Preop
Postop 118/66 -
Aorta Left ventricle
95/68 9515
Pulmonary artery Right ventricle Right atrium
1617 (10) 65/15
20/10 24112
(16)
(9)
(78)
(82)
increased septal thickness.
(13)
COMMENTS
NOTE: Mean values are given in parentheses.
Open heart surgery (Dr. L. Henry Edmund@ was performed through a midline sternotomy. The right atrium was markedly enlarged and tense. A large tumor mass infiltrated the entire wall of the right ventricle and septum, presenting on the epicardial surface (Figure 5A). The right atrium was free of tumor except for two nodules on the tricuspid valve. Tumor projected through the pulmonary valve into the proximal pulmonary trunk, but the valve, itself, was not involved. The right ventricle was almost entirely filled with spongy tumor, including the infundibular cavity (Figure 5B). lntracavity tumor was excised between the tricuspid valve and pulmonic trunk; a large mass was also excised from the papillary muscles and crista supraventricularis to improve the outflow tract. The apex of the right ventricle, however, was filled with solid, infiltrating tumor which could not be removed. On microscopic examination, the cardiac tumor demonstrated characteristic villous structures lined with malignant ceils which showed crystalline inclusion bodies on periodic acid-Schiff stain (Figure 6B). This was similar to the findings on the
Cineangiogram (right anterior oblique projection) shows outline (dashed line) of right ventricle (RV) and pulmonary artery (PA). Arrows denote two large filling defects in the right ventricular cavity and a smaller defect in the pulmonary outflow tract. Figure 4.
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original slides of tumor from the thigh (Figure 6A) and was diagnostic of alveolar soft-part sarcoma metastatic to myocardium. Postoperatively, there was dramatic symptomatic relief and an uncomplicated convalescence. Cardiac catheterization 11 days after surgery recorded the results shown in Table I. Postoperative echocardiograms showed an appreciable decrease in right ventricular size but persistence of
The American Journal of Mediclne
Tumor Characteristics. Alveolar soft-part sarcoma is a malignant granular cell tumor of obscure histogenesis characteristically originating in skeletal muscle [6]. Although it is histologically very similar to granular cell myoblastoma and nonchromaffin paraganglioma, it fails, on detailed examination by light and electron microscopy, to demonstrate any of the characteristic structures associated with muscle or nerve [7]. Its name derives from the characteristic histologic pattern of granular tumor cells arranged in alveolar nests surrounded by thin-walled vascular sinusoids. The cellular granules are actually intracytoplasmic protein-carbohydrate crystals which are unique to this tumor [a]. Clinical Features. There are a number of clinical features which serve to distinguish alveolar soft-part sarcoma from other tumors. Peak incidence is in the second and third decades with a female:male predominance of 2:l. The tumor has a striking anatomic predisposition to originate in skeletal muscles on the right side of the body (over two thirds of the cases) [5]. This tendency toward laterality remains unexplained and has not been observed in other malignancies. The tumor is slow growing with a five year survival of 59 per cent and a 10 year survival of 47 per cent [5], but its tendency toward early and widespread metastasis is suggested from the histology which frequently reveals budding of the granular tumor cells into the surrounding vascular sinusoids with invasion of the local vessels [6]. The most frequent sites for this presumably hematogenous dissemination are lung 42 per cent, bone 19 per cent, brain 15 per cent and lymph nodes 7 per cent [5]. Considering the unusual vascular affinity of this tumor, and its origin in contractile tissue, the conspicuous absence of cardiac metastasis is peculiar and unexplained. In the patient under discussion, the initial presentation at age 17 with a slowly enlarging tumor of the left thigh was in accord with many of the features of alveolar soft-part sarcoma. Although we were aware of this diagnosis at the time of admission five years later for fulminant congestive heart failure, we did not initially connect the two events owing to complete absence of previously reported cardiac metastases. The diagnosis
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Figure 5. A, tumor mass (arrows) infiltrating the right ventricular wall and presenting on the epicardial surface. B, tumor tissue filling the right ventricular cavity (viewed through right ventriculotomy}.
on admission of idiopathic congestive cardiomyopathy appeared reasonable. However, since congestive cardiomyopathy is virtually always a disease involving the left ventricle, echocardiographic evidence of a small left ventricular cavity with very good posterior wall motion warned against this diagnosis (and explained why the left ventricular impulse was clinically so inconspicuous). A mass of echoes anterior to the tricuspid valve together with marked dilatation of the right ventricle and paradoxic motion of the septum directed attention to the right side of the heart. The long systolic murmur at the lower left sternal edge proved to be the
sum of tricuspid regurgitation and ob:struction to right ventricular outflow. The pulmonic component of the second heart sound was absent because tumor straddled the valve. It was regretably impossible to record echoes from the pulmonary leaflets because of technical limitations in an acutely ill patient and because tumor mass projected from right ventricle through the valve into the pulmonary trunk. The third and fourth heart sounds were clearly right-sided events, even at the bedside. Clinical suspicion therefore shifted to rightsided cardiac tumor, dramatically outlined in the cineangiogram and confirmed at surgery.
Figure 6. A, photomicrograph of the original tumor from the thigh. On the left, is shown the typical appearance of an alveolar soft-part sarcoma with coarsely granular cells lining the septums of alveolar subunits. On the right, the tumor has invaded a vein and the alveolar subunits are growing freely in papillary fashion in the blood stream. Periodic acid-Schiff stain; original magnification X 120, reduced by 22 per cent. B, representative area from the intracardiac metastasis showing numerous papillary fronds composed of the basic alveolar subunits. The cells are granular and contain the periodic acid-SchiffCpositive crystalline inclfsion bodies characteristic of alveolar soft-part sarcoma. Periodic acid-Schiff stain; original magnification X 80, reduced by 22 per cent.
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Cardiac Metastasis. Metastatic tumors of the heart are 16 times more common than primary cardiac tumors [ 91, and are found in up to 20 per cent of the patients who die from malignancies [ 11. There is a consistent trend toward higher incidence figures in more recent series [l] due, possibly, to the increasingly aggressive Combined-modality treatment of both primary and metastatic disease, improving long-term survival of patients with cancer. Approximately 13 per cent of cardiac metastases are symptomatic or lifethreatening [lo]. A significant number of these patients might benefit from early diagnosis and appropriate palliative treatment, but antemortem diagnosis of cardiac metastases remains difficult, owing, in great measure, to their protean clinical manifestations. Clinical Manifestations. The clinical manifestations of cardiac metastases can be grouped on the basis of predominance of pericardial, myocardial or endocardial involvement [ 111. Patients with pericardial metastases often present with signs of effusion, constriction, tamponade or pericardial inflammation. Associated electrocardiographic findings are persistent S-T segment elevation, low voltage and/or electrical alternans in some cases of malignant effusion. Patients with myocardial involvement present most commonly with ectopic electrical activity, tachyarrhythmias or conduction defects, but more extensive infiltration can result in intractable congestive heart failure. The electrocardiogram, in addition to recording arrhythmias and conduction defects, may also exhibit “infarct” patterns due to transmural replacement of myocardium by solid tumor. Further, tumor emboli to the coronary arterial bed (especially the intramural portion of the left anterior descending coronary artery) can produce myocardial infarction. Endocardial or intracavitary involvement is characterized by ventricular inflow/outflow obstruction due to encroachment on valve orifices. In addition, valvular regurgitation can develop due to the constant traumatic impact inflicted on the valve by mobile or pedunculated tumors. lntracavitary tumor can also give rise to recurrent, unexplained systemic or pulmonary emboli. Diagnosis. Although each of these manifestations can occur with cardiac metastases, none is distinctive. A high index of suspicion is therefore necessary when evaluating a patient with a history of malignancy and new, unexplained or bizarre cardiovascular abnormalities. The diagnosis, once suspected, can be pointedly investigated with noninvasive modalities of considerable potential value. Echocardiography, already employed in detecting left atrial myxomas as well as other primary tumors of the heart, has been useful in the investigation of cardiac me&stases. Echocardiographic demonstration of hypokinesis and increased thickness
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of the interventricular septum preceded the discovery of unsuspected intracardiac metastases in another patient of ours with primary carcinoma of the lung [ 121. In the patient presently described, the first important laboratory information was the echocardiogram which effectively ruled out congestive (dilated) cardiomyopathy by recording normal left ventricular and left atrial dimensions, and directing attention to the paradoxically moving septum and dilated right ventricle. Radionuclide imaging has also been useful in the antemortem diagnosis of both primary [ 131 and metastatic [ 141 tumors of the heart, and promises to be of even greater utility with the advent of new radiopharmaceuticals and improved imaging synchronization for electrocardiographic-gated radionuclide scinticardiography [ 151. Treatment. The goal of therapy in cases of symptomatic or life-threatening cardiac metastases is relief of symptoms and arrest or regression of tumor growth. The degree of potential palliation, and the aggressiveness justified in achieving it, depend to a large extent on the biology and natural history of the tumor. In both aggressive and slow-growing tumors, radiation delivered by external beam to cardiac metastases has resulted in clinical improvement in 60 per cent of the patients so treated [ 161. In radioresistant tumors, particularly those indolent malignancies in which rapid progression of the primary or metastases is not expected to be a limiting factor, surgery may be successful in ameliorating symptoms and significantly prolonging survival [ 171. Since radioresistance [ 181 and indolent growth are both characteristics of alveolar soft-part sarcoma, surgical intervention was selected for treating the cardiac metastasis in the patient under discussion. Chemotherapy has been shown to be palliative in the treatment of lymphomas and breast carcinoma metastatic to the heart, but it has not been adequately evaluated in the treatment of alveolar soft-part sarcoma. The postoperative course in our patient continues to be clinically benign despite echocardiographic evidence of marked septal thickening. This case not only serves to extend the known clinical spectrum of alveolar soft-part sarcoma, but it also underscores the importance of maintaining a high clinical index of suspicion when confronted with unanticipated cardiac abnormalities in a patient with a history of malignancy. ACKNOWLEDGMENT We are indebted to Dr. L. Henry Edmunds who performed the difficult surgery with remarkable skill; to Dr. Gary S. Hill who reviewed the histopathology of the original primary tumor and the cardiac metastasis; and especially to Dr. Emmons G. Paine of Haddonfield, New Jersey, who referred the patient to the Hospital of the University of Pennsylvania.
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REFERENCES
2.
3.
4.
5.
6.
7. 8. 9.
10.
Hanfling SM: Metastatic cancer to the heart. Circulation 22: 474, 1960. Rosler OA: Vier seltenere Herzbefunde. Ein Beitrag zur Herz-diagnostik. Zentralbl Herz-u. Gefasskr 26: 261, 1924. Fishberg AM: Auricular fibrillation and flutter in metastatic growth of the right auricle. Am J Med Sci 180: 629, 1930. Willius FA, Amberg S: Two cases of secondary tumor of the heart in children, in one of which the diagnosis was made during life. Med Clin North Am 13: 1307, 1930. Lieberman PH. Foote FW Jr, Stewart FW, et al: Alveolar soft-part sarcoma. JAMA 198: 121, 1966. Christopherson WM, Foote FW Jr, Stewart FW: Alveolar soft-part sarcomas: structurally characteristic tumors of uncertain histogenesis. Cancer 5: 100, 1952. Shipkey FH, Lieberman PH. Foote FW Jr, et al.: Ultrastructure of alveolar soft part sarcoma. Cancer 17: 82 1, 1964. Welsh RA. Bray DM Ill, Shipkey FH, et al.: Histogenesis of alveolar soft part sarcoma. Cancer 29: 191, 1972. Griffiths GC: A review of primary tumors of the heart. Prog Cardiovasc Dis 7: 465, 1965. Malaret GE, Aliaga P: Metastatic disease to the heart. Cancer
11. 12.
13. 14.
15.
16.
17.
18.
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22: 457, 1968. Harvey WP: Clinical aspects of cardiac tumors. Am J Cardiol 21: 328, 1968. Riba AL, Stark RM, Hodess AB, et al.: Echocardiographic manifestations of metastatic cardiac tumors. In preparation. Quaife MA, Wilson WJ: Detection of cardiac tumor by rectilinear imaging with ‘31Cs. J Nucl Med 11: 605, 1970. Steiner RM. Bull MI, Kumpel F, et al.: The diagnosis of intracardiac metastasis of colon carcinoma by radioisotopic and roentgenographic studies. Am J Cardiol 26: 300, 1970. Strauss HW, Zaret BL, Hurley PJ, et al.: A scintiphotographic method for measuring left ventricular ejection fraction in man without cardiac catheterization. Am J Cardio128: 575, 1972. Cham WC, Freiman AH, Carstens PHB, et al.: Radiation therapy of cardiac and pericardial metastases. Radiology 114: 701, 1975. Bailey CP. Schechter DC, Folk FS: Extending operability in lung cancer involving the heart and great vessels. Ann Thorac Surg 11: 140, 1971. Rubenfeld S: Radiation therapy in alveolar soft part sarcoma. Cancer 28: 577, 1971.
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ROBERT M. STARK, M.D.’ JOSEPH K. PERLOFF. M.D. JOHN H. GLICK, M.D. JOHN W. HIRSHFELD, Jr., M.D. RICHARD B. DEVEREUX. M.D. Philadelphia, Pennsylvania
From the Hospital of the University of Pennsylvania, and the Cardiovascular and HematologyOncology Sections, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Dr. Joseph K. Perloff, Cardiovascular Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104. Manuscript accepted September 29, 1976.
* Present address: National Heart and Lung Institute, Building 10, Room 7B 15, National Institutes of Health, Bethesda, Maryland 20014.
A 22 year old woman presented with a three month history of progressive dyspnea, orthopnea and pedal edema. She had previously been in excellent health with the exception of surgery five years before for a tumor of her left thigh. The histopathologic diagnosis was alveolar soft-part sarcoma, a slow-growing granular cell sarcoma not previously known to metastasize to the heart. Her clinical course was characterized by increasingly severe dyspnea, edema, and ascites unresponsive to digitalis and diuretic therapy. Echocardiography during the most acute phase of the illness showed right ventricular dilitation, paradoxic septal motion and a normal left ventricle. Cardiac catheterization and angiography revealed a severely-obstructing filling defect moving with systole and diastole from the pulmonary trunk to the right ventricular outflow tract. At surgery, a mass of friable tumor tissue was removed from the right ventricular cavity, outflow tract, and pulmonary trunk with dramatic postoperative relief of symptoms and virtual abolition of the major hemodynamic abnormalities. Histopathologic examination showed the resected cardiac tumor to be alveolar soft-part sarcoma. To our knowledge, cardiac metastasis from alveolar soft-part sarcoma is thus far unique to the patient described in this report. Her unusual presentation and course, which extend the known clinical spectrum of this tumor, are discussed in the broader context of clinical recognition and management of cardiac metastatic disease. Metastatic cancer to the heart is not rare, occurring in 1.5 to 18.3 per cent of the patients who die from malignancies and who are examined at autopsy [ 11. Even though the first clinical observations were made as early as 1924 [2] and 1930[3,4], metastatic cardiac tumor is still infrequently diagnosed during life despite the availability of refined noninvasive and angiocardiographic technics. The difficulty in clinical recognition lies in the protean clinical manifestations of cardiac metastaies which may mimic far more common types of acquired pericardial, myocardial or valvular heart disease. The irnproved survival afforded by aggressive treatment of many malignancies has increased
October 1977
The American Journal of Medlcine
Volume 63
653
CARDIAC
METASTATIC
DISEASE-STARK
ET AL
1. Electrocardiogram obtained on admission shows a vertical axis, a bizarre right ventricular conduction defect, tall right precordial R waves, and widespread nonspecific ST-T abnormalities in limb and precordial leads. Figure
the potential frequency with which late and seemingly-unrelated metastatic disease is encountered in clinical practice. Concurrent advances in chemotherapy, radiotherapy and open heart surgery improve the prognosis for patients with symptomatic or life-threatening cardiac metastases, and underscore the need for heightened clinical suspicion in cases of unexplained cardiovascular disease in the setting of a history of malignancy, recent or remote. Alveolar soft-part sarcoma, a granular-cell tumor histologically similar to chemodectoma, is a slow-
growing malignancy arising from skeletal muscle and metastasizing widely to lung, brain, bone, lymph nodes and other organs [6]. This neoplasm exhibits a number of unusual features among which are a striking tendency to originate from muscles on the right side of the body, to pursue an indolent course and to metastasize both very early and very late [5]. Considering its origin in contractile tissue and its propensity to infiltrate surrounding blood vessels [6], it is curious that soft-part sarcoma has not been observed to metastasize to or originate in the heart.
A, normal chest roentgenogram taken three months prior to admission. B, chest roentgenogram mission shows marked cardiomegaly and a right pleural effusion.
Figure 2.
654
October 1977
The American Journal of Medicine
Volume 63
obtained on ad-
CARDIAC
METASTATIC
DISEASE-STARK
ET AL.
CASE REPORT A 22 year old housewife presented with a history of rapidly progressive dyspnea and orthopnea. She had been entirely well until three months prior to admission when effort dyspnea and intermittent or-thopnea began. She became increasingly symptomatic over the next two months until she was bedridden and able to sleep only when sitting upright in a chair. One month prior to admission, edema of both lower extremities developed and she had a progressive weight gain of 20 to 30 pounds. She was admitted to another hospital where chest films revealed massive cardiomegaly and a right pleural effusion. An echocardiogram was reported to show minimal pericardial effusion. Treatment with furosemide and digoxin afforded no improvement, and she was transferred to the Hospital of the University of Pennsylvania with a provisional diagnosis of congestive cardiomyopathy. fhere was no past history of heart disease. A tumor (tissue diagnosis, alveolar soft-part sarcoma) had been resected from her left thigh five years prior to admission with no subsequent symptoms or signs of recurrence on careful yearly follow-up. Physical examination on admission revealed a pale, anxious white woman, dyspneic at rest. Blood pressure was 105/88 mm Hg with 15 mm Hg paradox, heart rate 1 lG/min and respirations 36/min. There was slight cyanosis of the lips and nail beds. The jugular venous pressure was 12 cm HP0 with a markedly increased V wave. There was dullness to percussion and decreased. breath sounds over the right hemithorax up to the scapula. A left ventricular impulse was barely palpable in the fifth intercostal space just beyond the mid-clavicular line. There was a right ventricular impulse at the lower left sternal edge. The first heart sound was normal and the second sound single. The pulmonic component of the second sound was not heard. A long, grade 316 slightly crescendo-decrescendo systolic murmur was heard at the lower left sternal border. The murmur did not radiate or change with respiration. There were prominent third and fourth heart sounds which increased with inspiration. Peripheral arterial pulses were of low amplitude but normal contour. The liver edge was palpable 4 cm below the right costal margin. There was moderate ascites and pitting edema of both legs up to the knees; a well-healed surgical scar was present on the lateral aspect of the left thigh. The remainder of the physical examination was unrevealing. Laboratory values on admission included a hematocrit of 45 per cent and a white cell count of 8,000/mm3 with a normal differential. Electrolytes were normal, but arterial blood gases showed a respiratory alkalosis with hypoxemia (pH 7.49, oxygen tension (~0~) 58 mm Hg, carbon dioxide tension (pCOz) 30 mm Hg and bicarbonate (HCOs) 23 mm Hg. Blood urea nitrogen was 23 mg/dl, creatinine 2.0 mg/dl, total bilirubin 1.4 mg/dl, lactic dehydrogenase 897 IWliter (normal 140 to 270 Ill/liter), cu-hydroxybutyrate dehydrogenase (HBD) 689 Ill/liter (normal 110 to 230 IWliter), creatine phosphokinase 17 Ill/liter (normal 14 to 60 Ill/liter) and serum aspartate transaminase 32 IWliter (normal 9 to 22 Ill/liter). The electrocardiogram (Figure 1) showed sinus tachycardia, a vertical axis, a bizarre right ventricular conduction defect, tall R waves in the right precordial leads, and widespread nonspecific ST-T abnormalities in limb and precordial leads.
Figure 3, Echocardiograms taken while the patient was acutely ill (recording quality limited by severe dyspnea and orthopnea). A mass of echoes (arrow, tumor) is shown, particularly in systole, anterior to the tricuspid valve (TV). The right ventricle (RV) is dilated and the motion of the interventricular septum (IVS) is reversed. L V = left ventricle.
Vectorcardiogram (Frank lead system) recorded a bizarre intraventricular conduction~defect of uncertain type, abnormal TsE loop consistent with conduction abnormality, and anterior displacement of the QRS SE loop suggesting right ventricular enlargement. A chest film showed massive cardiomegaly and a large right pleural effusion (Figure 2B). In contrast, a chest film obtained three months prior to the illness was entirely within normal limits (Figure 2A). Thoracentesis resulted in considerable symptomatic improvement and yielded 900 cc of straw-colored, sterile transudate which was negative for acid-fast and bacterial organisms. There was class I cytology on cell block. The echocardiogram is shown in Figure 3 and described in detail in the legend. Cardiac catheterization demonstrated right ventricular outflow obstruction with data shown in Table I. Using the Gorlin formula, the zone of obstruction ‘to right ventricular outflow was estimated at 0.5 cm*. Right ventriculography (in both oblique projections) demonstrated a mobile filling defect that protruded into the pulmonary trunk during systole and descended into the right ventricular outflow tract during diastole (Figure 4). The right ventricular outflow tract, itself, was deformed and relatively immobile, with persistent filling defects. Tricuspid regurgitation was seen in the right anterior oblique projection.
October 1977
The American Journal of Medlclne
Volume 63
855
CARDIAC
METASTATIC
TABLE I
DISEASE-STARK
ET AL.
Cardiac Catheterization Findings Before and After Resection of Intracardiac Metastasis Intracardiac Site
Pressures (mm Hg)
Preop
Postop 118/66 -
Aorta Left ventricle
95/68 9515
Pulmonary artery Right ventricle Right atrium
1617 (10) 65/15
20/10 24112
(16)
(9)
(78)
(82)
increased septal thickness.
(13)
COMMENTS
NOTE: Mean values are given in parentheses.
Open heart surgery (Dr. L. Henry Edmund@ was performed through a midline sternotomy. The right atrium was markedly enlarged and tense. A large tumor mass infiltrated the entire wall of the right ventricle and septum, presenting on the epicardial surface (Figure 5A). The right atrium was free of tumor except for two nodules on the tricuspid valve. Tumor projected through the pulmonary valve into the proximal pulmonary trunk, but the valve, itself, was not involved. The right ventricle was almost entirely filled with spongy tumor, including the infundibular cavity (Figure 5B). lntracavity tumor was excised between the tricuspid valve and pulmonic trunk; a large mass was also excised from the papillary muscles and crista supraventricularis to improve the outflow tract. The apex of the right ventricle, however, was filled with solid, infiltrating tumor which could not be removed. On microscopic examination, the cardiac tumor demonstrated characteristic villous structures lined with malignant ceils which showed crystalline inclusion bodies on periodic acid-Schiff stain (Figure 6B). This was similar to the findings on the
Cineangiogram (right anterior oblique projection) shows outline (dashed line) of right ventricle (RV) and pulmonary artery (PA). Arrows denote two large filling defects in the right ventricular cavity and a smaller defect in the pulmonary outflow tract. Figure 4.
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October 1977
original slides of tumor from the thigh (Figure 6A) and was diagnostic of alveolar soft-part sarcoma metastatic to myocardium. Postoperatively, there was dramatic symptomatic relief and an uncomplicated convalescence. Cardiac catheterization 11 days after surgery recorded the results shown in Table I. Postoperative echocardiograms showed an appreciable decrease in right ventricular size but persistence of
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Tumor Characteristics. Alveolar soft-part sarcoma is a malignant granular cell tumor of obscure histogenesis characteristically originating in skeletal muscle [6]. Although it is histologically very similar to granular cell myoblastoma and nonchromaffin paraganglioma, it fails, on detailed examination by light and electron microscopy, to demonstrate any of the characteristic structures associated with muscle or nerve [7]. Its name derives from the characteristic histologic pattern of granular tumor cells arranged in alveolar nests surrounded by thin-walled vascular sinusoids. The cellular granules are actually intracytoplasmic protein-carbohydrate crystals which are unique to this tumor [a]. Clinical Features. There are a number of clinical features which serve to distinguish alveolar soft-part sarcoma from other tumors. Peak incidence is in the second and third decades with a female:male predominance of 2:l. The tumor has a striking anatomic predisposition to originate in skeletal muscles on the right side of the body (over two thirds of the cases) [5]. This tendency toward laterality remains unexplained and has not been observed in other malignancies. The tumor is slow growing with a five year survival of 59 per cent and a 10 year survival of 47 per cent [5], but its tendency toward early and widespread metastasis is suggested from the histology which frequently reveals budding of the granular tumor cells into the surrounding vascular sinusoids with invasion of the local vessels [6]. The most frequent sites for this presumably hematogenous dissemination are lung 42 per cent, bone 19 per cent, brain 15 per cent and lymph nodes 7 per cent [5]. Considering the unusual vascular affinity of this tumor, and its origin in contractile tissue, the conspicuous absence of cardiac metastasis is peculiar and unexplained. In the patient under discussion, the initial presentation at age 17 with a slowly enlarging tumor of the left thigh was in accord with many of the features of alveolar soft-part sarcoma. Although we were aware of this diagnosis at the time of admission five years later for fulminant congestive heart failure, we did not initially connect the two events owing to complete absence of previously reported cardiac metastases. The diagnosis
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Figure 5. A, tumor mass (arrows) infiltrating the right ventricular wall and presenting on the epicardial surface. B, tumor tissue filling the right ventricular cavity (viewed through right ventriculotomy}.
on admission of idiopathic congestive cardiomyopathy appeared reasonable. However, since congestive cardiomyopathy is virtually always a disease involving the left ventricle, echocardiographic evidence of a small left ventricular cavity with very good posterior wall motion warned against this diagnosis (and explained why the left ventricular impulse was clinically so inconspicuous). A mass of echoes anterior to the tricuspid valve together with marked dilatation of the right ventricle and paradoxic motion of the septum directed attention to the right side of the heart. The long systolic murmur at the lower left sternal edge proved to be the
sum of tricuspid regurgitation and ob:struction to right ventricular outflow. The pulmonic component of the second heart sound was absent because tumor straddled the valve. It was regretably impossible to record echoes from the pulmonary leaflets because of technical limitations in an acutely ill patient and because tumor mass projected from right ventricle through the valve into the pulmonary trunk. The third and fourth heart sounds were clearly right-sided events, even at the bedside. Clinical suspicion therefore shifted to rightsided cardiac tumor, dramatically outlined in the cineangiogram and confirmed at surgery.
Figure 6. A, photomicrograph of the original tumor from the thigh. On the left, is shown the typical appearance of an alveolar soft-part sarcoma with coarsely granular cells lining the septums of alveolar subunits. On the right, the tumor has invaded a vein and the alveolar subunits are growing freely in papillary fashion in the blood stream. Periodic acid-Schiff stain; original magnification X 120, reduced by 22 per cent. B, representative area from the intracardiac metastasis showing numerous papillary fronds composed of the basic alveolar subunits. The cells are granular and contain the periodic acid-SchiffCpositive crystalline inclfsion bodies characteristic of alveolar soft-part sarcoma. Periodic acid-Schiff stain; original magnification X 80, reduced by 22 per cent.
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Cardiac Metastasis. Metastatic tumors of the heart are 16 times more common than primary cardiac tumors [ 91, and are found in up to 20 per cent of the patients who die from malignancies [ 11. There is a consistent trend toward higher incidence figures in more recent series [l] due, possibly, to the increasingly aggressive Combined-modality treatment of both primary and metastatic disease, improving long-term survival of patients with cancer. Approximately 13 per cent of cardiac metastases are symptomatic or lifethreatening [lo]. A significant number of these patients might benefit from early diagnosis and appropriate palliative treatment, but antemortem diagnosis of cardiac metastases remains difficult, owing, in great measure, to their protean clinical manifestations. Clinical Manifestations. The clinical manifestations of cardiac metastases can be grouped on the basis of predominance of pericardial, myocardial or endocardial involvement [ 111. Patients with pericardial metastases often present with signs of effusion, constriction, tamponade or pericardial inflammation. Associated electrocardiographic findings are persistent S-T segment elevation, low voltage and/or electrical alternans in some cases of malignant effusion. Patients with myocardial involvement present most commonly with ectopic electrical activity, tachyarrhythmias or conduction defects, but more extensive infiltration can result in intractable congestive heart failure. The electrocardiogram, in addition to recording arrhythmias and conduction defects, may also exhibit “infarct” patterns due to transmural replacement of myocardium by solid tumor. Further, tumor emboli to the coronary arterial bed (especially the intramural portion of the left anterior descending coronary artery) can produce myocardial infarction. Endocardial or intracavitary involvement is characterized by ventricular inflow/outflow obstruction due to encroachment on valve orifices. In addition, valvular regurgitation can develop due to the constant traumatic impact inflicted on the valve by mobile or pedunculated tumors. lntracavitary tumor can also give rise to recurrent, unexplained systemic or pulmonary emboli. Diagnosis. Although each of these manifestations can occur with cardiac metastases, none is distinctive. A high index of suspicion is therefore necessary when evaluating a patient with a history of malignancy and new, unexplained or bizarre cardiovascular abnormalities. The diagnosis, once suspected, can be pointedly investigated with noninvasive modalities of considerable potential value. Echocardiography, already employed in detecting left atrial myxomas as well as other primary tumors of the heart, has been useful in the investigation of cardiac me&stases. Echocardiographic demonstration of hypokinesis and increased thickness
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of the interventricular septum preceded the discovery of unsuspected intracardiac metastases in another patient of ours with primary carcinoma of the lung [ 121. In the patient presently described, the first important laboratory information was the echocardiogram which effectively ruled out congestive (dilated) cardiomyopathy by recording normal left ventricular and left atrial dimensions, and directing attention to the paradoxically moving septum and dilated right ventricle. Radionuclide imaging has also been useful in the antemortem diagnosis of both primary [ 131 and metastatic [ 141 tumors of the heart, and promises to be of even greater utility with the advent of new radiopharmaceuticals and improved imaging synchronization for electrocardiographic-gated radionuclide scinticardiography [ 151. Treatment. The goal of therapy in cases of symptomatic or life-threatening cardiac metastases is relief of symptoms and arrest or regression of tumor growth. The degree of potential palliation, and the aggressiveness justified in achieving it, depend to a large extent on the biology and natural history of the tumor. In both aggressive and slow-growing tumors, radiation delivered by external beam to cardiac metastases has resulted in clinical improvement in 60 per cent of the patients so treated [ 161. In radioresistant tumors, particularly those indolent malignancies in which rapid progression of the primary or metastases is not expected to be a limiting factor, surgery may be successful in ameliorating symptoms and significantly prolonging survival [ 171. Since radioresistance [ 181 and indolent growth are both characteristics of alveolar soft-part sarcoma, surgical intervention was selected for treating the cardiac metastasis in the patient under discussion. Chemotherapy has been shown to be palliative in the treatment of lymphomas and breast carcinoma metastatic to the heart, but it has not been adequately evaluated in the treatment of alveolar soft-part sarcoma. The postoperative course in our patient continues to be clinically benign despite echocardiographic evidence of marked septal thickening. This case not only serves to extend the known clinical spectrum of alveolar soft-part sarcoma, but it also underscores the importance of maintaining a high clinical index of suspicion when confronted with unanticipated cardiac abnormalities in a patient with a history of malignancy. ACKNOWLEDGMENT We are indebted to Dr. L. Henry Edmunds who performed the difficult surgery with remarkable skill; to Dr. Gary S. Hill who reviewed the histopathology of the original primary tumor and the cardiac metastasis; and especially to Dr. Emmons G. Paine of Haddonfield, New Jersey, who referred the patient to the Hospital of the University of Pennsylvania.
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REFERENCES
2.
3.
4.
5.
6.
7. 8. 9.
10.
Hanfling SM: Metastatic cancer to the heart. Circulation 22: 474, 1960. Rosler OA: Vier seltenere Herzbefunde. Ein Beitrag zur Herz-diagnostik. Zentralbl Herz-u. Gefasskr 26: 261, 1924. Fishberg AM: Auricular fibrillation and flutter in metastatic growth of the right auricle. Am J Med Sci 180: 629, 1930. Willius FA, Amberg S: Two cases of secondary tumor of the heart in children, in one of which the diagnosis was made during life. Med Clin North Am 13: 1307, 1930. Lieberman PH. Foote FW Jr, Stewart FW, et al: Alveolar soft-part sarcoma. JAMA 198: 121, 1966. Christopherson WM, Foote FW Jr, Stewart FW: Alveolar soft-part sarcomas: structurally characteristic tumors of uncertain histogenesis. Cancer 5: 100, 1952. Shipkey FH, Lieberman PH. Foote FW Jr, et al.: Ultrastructure of alveolar soft part sarcoma. Cancer 17: 82 1, 1964. Welsh RA. Bray DM Ill, Shipkey FH, et al.: Histogenesis of alveolar soft part sarcoma. Cancer 29: 191, 1972. Griffiths GC: A review of primary tumors of the heart. Prog Cardiovasc Dis 7: 465, 1965. Malaret GE, Aliaga P: Metastatic disease to the heart. Cancer
11. 12.
13. 14.
15.
16.
17.
18.
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22: 457, 1968. Harvey WP: Clinical aspects of cardiac tumors. Am J Cardiol 21: 328, 1968. Riba AL, Stark RM, Hodess AB, et al.: Echocardiographic manifestations of metastatic cardiac tumors. In preparation. Quaife MA, Wilson WJ: Detection of cardiac tumor by rectilinear imaging with ‘31Cs. J Nucl Med 11: 605, 1970. Steiner RM. Bull MI, Kumpel F, et al.: The diagnosis of intracardiac metastasis of colon carcinoma by radioisotopic and roentgenographic studies. Am J Cardiol 26: 300, 1970. Strauss HW, Zaret BL, Hurley PJ, et al.: A scintiphotographic method for measuring left ventricular ejection fraction in man without cardiac catheterization. Am J Cardio128: 575, 1972. Cham WC, Freiman AH, Carstens PHB, et al.: Radiation therapy of cardiac and pericardial metastases. Radiology 114: 701, 1975. Bailey CP. Schechter DC, Folk FS: Extending operability in lung cancer involving the heart and great vessels. Ann Thorac Surg 11: 140, 1971. Rubenfeld S: Radiation therapy in alveolar soft part sarcoma. Cancer 28: 577, 1971.
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