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Cardiac metastases associated with gynecologic malignancies
GYNECOLOGIC
ONCOLOGY
10,
75-83 (1980)
Cardiac Metastases Associated with Gynecologic Malignancies EARL
F. GREENWALD,
M.D.,* JAMES L. BREEN, M.D.,“f,S AND A. GRRGORI, M.D.7
CATERINA
*Department of Obstetrics and Gynecology, Hahnemann Medical College and Hospital, 230 North Broad Street, Philadelphia, Pennsylvania 19102, tSt. Barnabas Medical Center, Old Short Hills Road, Livingston, New Jersey 07039, and /Jefferson Medical College, llth and Walnut Streets, Philadelphia, Pennsylvania 19107
Received November 22, 1979 Metastasis to the heart of malignancies arising within the pelvis is a rarely reported phenomenon. In fact, review of the literature and personal experience demonstrate that cardiac metastases occur more frequently than expected. Clinical suspicion would enable its antemortem diagnosis in many patients and would permit appropriate therapy in carefully selected individuals.
Despite the fact that disseminated malignancy ranks second only to heart disease as a cause of death in the United States [63, metastatic cardiac involvement has rarely been reported. Many statistical analyses of large series of unselected autopsies have documented the relative infrequency of the heart as a focus of tumor spread [1,2,5,7,8]. Antemortem recognition of cardiac metastases was first reported in 1913 [2], and the first antemortem diagnosis of heart metastasis recorded in American literature appeared in 1928 131. Pelvic malignancy as a primary site for cardiac metastases is rarely reported. In one series of 716 autopsies performed on patients dying of a variety of neoplasms, it was noted that 71 patients suffered from pelvic malignancies. In this series, 9% had cardiac metastases, only one of which originated within the pelvis (a primary leiomyosarcoma of the uterine corpus) [5]. In another series of 189 patients with cardiac metastases documented at postmortem examination, only 2 had primary pelvic disease, both adenocarcinomas of the uterine corpus [Sl. MATERIALS
AND METHODS
During a 4-year period, 1100 gynecologic cancer patients were evaluated at St. Barnabas Medical Center. This report is based on a study of the clinical data and pathological material from six patients with genital tract malignancy metastatic to the myocardium. Hemotoxylin and eosin-stained histological preparations were studied in all but one case. CASE REPORTS Case 1
A 77-year-old female was evaluated on September 2, 1970 for profuse vaginal bleeding. A bulky, friable, exophytic, necrotic mass, arising from the cervix and 75 00%8258/80/040075-09$01.00/O Copyright @ 1980 by Academic Press, Inc. All rights of reproduction in any form reserved.
76
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AND
GREGORI
occluding the entire upper third of the vagina, was found. Extension along the anterior wall to the introitus and to both pelvic sidewalls was noted. Biopsies revealed invasive squamous cell carcinoma. The clinical stage was IIIB. External radiation therapy was delivered. The patient was readmitted on November 10, 1970 for radium application. While radium was in situ, she complained of dyspnea. Chest X ray showed left ventricular enlargement with normal pulmonary fields. The patient was discharged, without complaints, on completion of her radiation therapy. She was readmitted on December 11, 1970 with a 5-day history of progressive dyspnea and weakness of the extremeties. Her pulse was irregular, the blood pressure was 130/80, and no peripheral edema or hepatomegaly were noted. An electrocardiogram (ECG) showed regular sinus rhythm with frequent premature ventricular contractions and myocardial ischemia. Cardiac enlargement with congestive changes in the right lower lung field were noted. The patient experienced a rapid downhill course, with progressive cyanosis, dyspnea, and disorientation. She expired on December 16, 1970. Autopsy revealed squamous cell carcinoma of the cervix with metastases to the right ventricle, supraclavicular, paraaortic, and pelvic lymph nodes; severe vascular congestion of the lungs, liver, spleen, and kidneys; and massive hemorrhagic infarction of the lungs secondary to multiple pulmonary emboli, thought to be the immediate cause of death. Cardiac metastases infiltrated the endocardium and portions of the myocardium, with surrounding necrosis (Fig. 1). Case 2 This 62-year-old nulligravida presented with invasive squamous cell carcinoma of the vulva in December 1972. Multiple large, matted, hard, fixed, suppurating nodes were noted in the left inguinal area. An 8 x 5-cm ulcerative vulvar lesion was noted, extending to the forchette, but not involving the anus. Marked edema of the left leg was present, with superficial phlebitis involving the left long saphenous vein. No calf tenderness or Homan’s sign could be elicited. The clinical stage was T,N3M,. ECG was normal. Appropriate therapy resulted in resolution of phlebitis of the left leg and suppuration of left inguinal nodes. Radical vulvectomy, bilateral inguinal, femoral, and pelvic lymphadenectomy were performed. Surgery was complicated by the sudden onset of a bigeminy rhythm. Postoperatively she experienced recurrent episodes of bigeminy, which responded to intravenous lidocaine. Ten days after release she was readmitted obtunded and severely dehydrated. ECG showed sinus tachycardia. Her clinical course was downhill, and she expired. Autopsy revealed residual squamous cell carcinoma of the vulva with widespread involvement of pelvic structures, including the uterus, left uterine tube and ovary, left ureter and the bladder; neoplastic necrosis of the left medial thigh and left inguinal region with metastatic left pelvic nodes; and metastases to the liver, paraaortic lymph nodes, ribs, vertebrae, and myocardium.
CARDIAC
FIG.
1.
METASTASES
77
Sheets and islands of malignant squamous cells may be seen inliltrating myocardial fibers.
78
GREENWALD,
BREEN,
AND
GREGORI
Case 3 A 44-year-old patient was admitted for evaluation of invasive squamous cell carcinoma of the cervix on November 10, 1972. Examination revealed a large exophytic cervical lesion involving the upper third of the vagina, the right lateral vaginal fomix, and the cul-de-sac of Douglas. Hard nodularity was noted extending along the right parametrium, attaching to the right pelvic sidewall. The uterus was slightly enlarged and fixed. The patient was confused and disoriented. Her speech was slurred, and left facial, upper and lower extremity paresis were noted. The clinical stage was IIIB. ECG showed sinus tachycardia and ST wave changes. The patient experienced an inexorable downhill course and expired on the fourth day after admission. Autopsy revealed sqamous cell carcinoma of the cervix with multiple metastatic paraaortic and mediastinal lymph nodes, malignant vegetations on the mitral valve, multiple recent infarcts in both kidneys and in the spleen secondary to thromboses of small branches of the renal and splenic vasculature, marked dilatation of all chambers of the heart, malignant left femoral vein and popliteal artery thromboses with ischemic necrosis of the left toes, and impending gangrene of the foot and lower leg. Death was attributed to massive pulmonary embolism involving both main pulmonary arteries, originating in the left femoral vein. Case 4 A %-year-old white female was admitted on February 18, 1973 with invasive squamous cell carcinoma of the vulva. Examination was unremarkable except for a well-demarcated 2 x l-cm lesion on the anterior one-third of the left labium majus. The clinical stage was T,N,M,. On February 23, 1973, radical vulvectomy and bilateral inguinal and femoral lymphadenectomy were performed. Histologic evaluation revealed metastases to two left inguinal nodes. The margins of resection were free of tumor. The patient was discharged in 10 days without significant postoperative problems. Five months later the patient developed a nonproductive cough. Chest X ray showed multiple pulmonary metastases. Long bone X rays demonstrated metastatic disease in the right femur and tibia. ECG revealed sinus tachycardia. Chemotherapy was instituted. Final admission occurred on July 16, 1973 when the patient presented in a semicomatose condition. Her course ran rapidly downhill, and she expired on the fourth hospital day. Autopsy revealed residual carcinoma in vulvar subcutaneous tissue and metastases in the lower anterior cervical, mediastinal, both hilar, peribronchial, mesenteric, and lower paraaortic lymph nodes; both upper pulmonary lobes; left ventricular myocardium; liver; both adrenals, right kidney; appendix; right seventh through ninth, and left sixth through ninth posterior ribs and intercostal soft tissues (with pathological fractures); thoracic, lumbar and upper sacral vertebml bodies, with collapse of several vertebrae; right midfemur and adjacent soft tissues, right upper tibia and adjacent soft tissues. The cause of death was attributed to the widespread metastatic disease.
CARDIAC
METASTASES
79
Case 5
This 72-year-old patient was evaluated in October 1970 for adenocarcinoma of the cervix with vaginal metastases. In 1948 the patient underwent left radical mastectomy and radiation castration for adenocarcinoma of the breast. In 1969, she was subjected to right radical mastectomy for adenocarcinoma of the right breast. Evaluation for rectal bleeding revealed adenocarcinoma of the large intestine, requiring hemicolectomy in 1960. Physical examination was normal, with the exception of a 2 x 4-cm hard, necrotic, friable mass involving the cervix and cul-de-sac of Douglas. The uterus was anterior, small, and mobile. No adnexal pathology could be palpated. Paracolpos was clinically free of involvement. The final clinical stage was HA. Radiation therapy was administered. The patient was readmitted on December 10, 1970 because of shortness of breath, dyspnea on exertion, and orthopnea. Examination revealed tachycardia and an irregular cardiac rhythm; no murmurs could be heard. Dullness to percussion and decreased breath sounds were noted over the right lower hemithorax. ECG demonstrated atria1 fibrillation and myocardial ischemia. Progressive ECG changes were noted, with superimposition of multifocal premature ventricular contractions, low voltage QRS complexes, and ST segment depression in precordial leads. The patient’s clinical course was inexorably downhill, and cardiac metastases were suspected in view of the absence of another reason for sudden, rapid progressive myocardial dysfunction. She expired on January 8, 1971. No autopsy was obtained. Case 6
This 72-year-old patient was admitted on September 30, 1974 for treatment of squamous cell carcinoma of the vulva, Stage T,N,M,,. She had experienced vulvar pruritis and contact bleeding for approximately 2 years, intermittently treated with corticosteroids and a variety of topical preparations. A discrete lesion was eventually noted and biopsied. Physical examination on admission was unremarkable except for a 1.5 x 1 x 2-cm ulcerative lesion involving the anterior two-thirds of the right labium minus and majus. A 1 x l-cm mobile, discrete, nontender lymph node was noted in the right inguinal area. Hepatosplenomegaly to the level of the umbilicus was noted. ECG demonstrated ventricular hypertrophy with occasional premature ventricular contractions. On October 4, 1974 the patient underwent radical vulvectomy and bilateral inguinal and femoral lymphadenectomy. One right and two left inguinal lymph nodes demonstrated metastatic disease. The patient was discharged on October 15, 1974. On March 10, 1975, left femoral lymphadenopathy and multiple nodules distributed over the back, arms, and tongue were noted. She was anorectic and debilitated. ECG revealed sinus tachycardia, left anterior hemiblock, and left ventricular hypertrophy. The patient experienced a rapid downhill course and expired on April 18, 1975.
80
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BREEN,
AND
GRBGORI
Postmortem examination demonstrated widespread metastatic disease involving the left lung; heart and pericardium; liver and spleen; adrenals, thyroid, and pancreas; diaphragms; bone marrow; subcutaneous tissue of the trunk and back; tongue; and peritrachael, mediastinal, hilar, peripancreatic, paraaortic, iliac, and inguinal lymph nodes. DISCUSSION
Cardiac metastases occur primarily in the sixth and seventh decades of life, with ages ranging between 26 and 85 [5]. This represents the natural age distribution of malignancy in our population; the incidence of cardiac metastasis is probably not influenced by the age of the patient. There appears to be an equal sex distribution among patients with heart involvement [51. It is estimated that metastatic disease to the heart is 16 to 40 times more common than primary cardiac malignancy. Among unselected autopsies, 0.2 to 6.5% of patients demonstrate cancer with dissemination to the heart [5]. The incidence of cardiac metastasis is as high as 21% among patients dying of disseminated cancer [2-5,8]. The most common malignancies complicated by cardiac involvement include bronchogenic and breast carcinoma, malignant melanoma, lymphoma, and pancreatic, esophageal, and, in Japan, gastric carcinomas [l-3,5,7,8]. Of the lymphomas, lymphocytic and lymphoblastic lymphosarcomas most frequently involve the heart [ 1,8]. Much of this apparent predilection for cardiac involvement is probably related to the relative frequency of these tumors, anatomic proximity to the heart, and lymphatic access to the heart and its adnexal structures. There does, however, appear to be some propensity for cardiac implantation of malignancies of certain histologic types. Of patients with leukemia, 11.1% show cardiac metastases, as do 10.4% of patients with bronchogenic carcinoma, 20.9% of patients with breast carcinoma, and 64.3% of patients with malignant melanoma [2]. A study of 716 consecutive adult autopsies performed on patients dying of malignancy showed a relative incidence of carcinoma to sarcoma of 3: 1. In contrast, only 6.4% of carcinomas metastasized to the heart, as compared to 15% of sarcomas. Of 61 cardiac metastases, 41% were of sarcomatous origin, and 5% of carcinomatous origin [5]. The relative infrequency of the heart as a metastatic focus is attributed to the following factors: (1) the vigorous kneading action of the myocardium; (2) the relative avascularity of the endocardium [8]; (3) the peculiar metabolic pathways used by cardiac striated musculature; (4) the rapidity of blood flow through the heart chambers; (5) the paucity of lymphatic communication between the heart and surrounding structures, making lymphatic extension difficult; (6) the fact that the coronary arteries arise from the aorta at right angles, creating a difficult pathway for malignant cells disseminated by the hematogenous route [2,8]. It is estimated that only 4% of heart metastases are diagnosed prior to death [8]. There appears to be a recent increase in the incidence of cardiac metastasis, probably related to the increased duration of survival of patients with malignancies because of development of new techniques of radical surgery, radiation, and chemotherapy. It is expected that more frequent and earlier recognition of this
CARDIAC
METASTASES
81
complication will continue, making palliative management of carefully selected cases feasible and desirable. The pathways of dissemination to the heart, as to all areas of the body include: (1) direct extension from contiguous structures; (2) hematogenous dissemination; (3) lymphatic permeation [2,5,81. Of these three mechanisms, direct extension from surrounding areas of malignancy is least common [5]. Opinion is divided as to whether the hematogenous or lymphatic route is more common. Isolated, diffuse intramural nodules, frequently observed with malignant melanomas, suggest an hematogenous mechanism for this tumor. Apparently the essential initial step in lymphatic spread to the heart is mediastinal node involvement, followed by retrograde extension along lymphatic channels [5]. Widespread malignancy, including metastasis to mediastinal nodes, almost invariably exists when cardiac involvement is present [ 1,7]. Occasionally, cardiac involvement produces the initial symptoms of the malignancy. Very rarely the cardiac lesion is the only detectable metastasis at autopsy. Two such caseshave been reported: a retroperitoneal fibroliposarcoma with extension directly to the coronary vessels, and an adrenocortical tumor with malignant thrombosis of the cardiac vessels [2]. The most common site of metastasis in the middle mediastinum is the pericardium. Myocardial invasion is not uncommon in disseminated sarcomas, malignant melanomas, and lymphomas. Endocardial implantation is a relatively rare phenomenon, but, when it does occur, it usually occurs on the cardiac valves. The paucity of the reported metastatic involvement of the valves and endocardium is probably related to the relative avascularity of this tissue [4]. The first prerequisite for antemortem diagnosis of cardiac involvement by metastatic cancer is an index of suspicion. Among patients with known widely disseminated malignancy, the development of cardiac dysfunction without other apparent cause is probably the earliest and most common phenomenon warning of metastatic cardiac tumor [1,8]. Such dysfunctions include: (1) congestive heart failure not responsive to usual cardiotonic regimens; (2) recent development of second- or third-degree artrioventricular block; (3) ectopic foci for premature atria1 or ventricular contractions; (4) acute pericarditis; (5) bizarre cardiac contour or rapid increase in size of cardiac silhouette; (6) cardiac constriction or tamponade; (7) unexplained new ECG changes; (8) superior or inferior vena caval syndromes; (9) angina pectoris [1,2,4,5,7,8]. Only 2% of all cardiac metastasesare symptomatic; the remaining are not clinically apparent and are discovered at autopsy. There is no correlation between the extent of cardiac involvement and the severity of the clinical manifestations [3,4,71. Signs and symptoms, when present, with pericardial involvement include dyspnea, orthopnea, chest pain, dysphagia, cyanosis, rales, cardiomegaly, venous distension, hepatomegaly, pleural effusion, and peripheral edema [7,8]. These signs and symptoms, when present, are more likely to be caused by systemic effects of advanced disease, or by involvement of intrathoracic structures other than the heart. Dyspnea, cough, pleural effusion, thoracic pain, orthopnea, cyanosis, and rales are more frequently caused by pulmonary metastases than by cardiac metastases. Hepatomegaly more often reflects liver involvement than heart failure caused by cardiac metastases. Peripheral edema is more likely to be
a2
GREENWALD,
BREEN,
AND
GREGORI
related to hypoalbuminemia. Venous distension and dysphagia more commonly reflect vena caval and esophageal compression, and tachycardia is generally attributable to anemia and diffuse pulmonary metastases [ 1,8]. Diagnosis of pericardial involvement is generally made on the basis of changes in cardiac silhouette [2,4]. ECG signs include decreased voltage of the main deflection in all three standard leads, electrical alternans, and simultaneous alternation of atrial and ventricular complexes [7,8]. The most direct means of documenting the diagnosis of malignant pericardial effusion is pericardiocentesis for exfoliative cytology [2,7]. At pericardiocentesis air may be introduced into the pericardial sac in order to delineate, on X ray, irregularity of the pericardial or cardiac silhouettes secondary to tumor implantation [2]. Even without documentation, a trial of external radiation of the heart may be justified in far-advanced disease if pericardial involvement is suspected. A decrease in the size of the cardiac silhouette on X ray due to resorption of pericardial effusion during radiation therapy would confirm the malignant etiology of the fluid
lx. Myocardial invasion is usually symptomatic because of intraventricular septal invasion with conduction defects, frequently expressed as an arrhythmia [2,7]. Tumor emboli may occasionally occlude the coronary vessels, producing coronary insufficiency, angina pectoris, or frank myocardial infarction [2]. Endocardial involvement, usually involving the tricuspid valve alone or both tricuspid and mitral valves, is detected by signs and symptoms typical of subacute bacterial endocarditis [4]. These include fever, changing cardiac murmurs, increase in erythrocyte sedimentation rate, and anemia in the absence of superimposed bacterial infection. The majority of patients with cardiac involvement, as noted above, are asymptomatic and die of unrelated causes. Among patients with asymptomatic cardiac metastases, the most common causes of death are bronchopneumonia, gram-negative septicemia, and cerebrovascular hemorrhage [ 1,5,7]. Among patients whose cardiac involvement is symptomatic, 83% died of their heart metastases, usually from congestive heart failure, arrhythmias, or tamponade [3,5,7]. Less common forms of cardiac compromise by tumor include: mechanical constriction; restriction of the inflow into or outflow from the heart by compression of the major vessels; interference with cardiac circulation by compression, neoplastic embolism, or direct invasion of the coronary arteries and/or veins; and encroachment on the myocardial nerve supply [7]. With the recent increase in incidence of antemortem recognition of cardiac involvement, the desirability and feasibility of treatment must be considered. Although prognosis is extremely poor, prolonged survivals of 34 to 21 months have been reported using various modalities, including pleural-pericardid windows, external radiation, and chemotherapy, alone or in combination [3]. Among patients whose general condition is commensurate with prolonged survival, attempts at palliation may be rewarding [3,7]. Megavoltage radiation to the precordial area has been reported on several occasions to successfully reverse heart block and arrhythmias secondary to metastatic tumor, and to stimulate
CARDIAC
METASTASES
83
resorption of malignant pericardial effusions [2,5]. Radiation therapy of the heart has been complicated by radiation myocarditis. Recurrent pericardial effusion after pericardiocentesis has been managed with some success by instillation of a variety of therapeutic agents, including radioactive chromic phosphate and colloidal gold, alkylating agents, antimetabolites, and sclerosing compounds [3]. Finally, recurrent pericardial effusions have been successfully controlled by creation of a pleural-pericardial window [3]. This is reserved for patients in generally good condition, and it is contraindicated in the presence of rapidly growing malignancies or extensive visceral metastases. CONCLUSIONS
With the recent advent of effective palliation of advanced malignancies, an index of suspicion has developed which has made possible antemortem recognition of metastatic involvement of the heart and its anatomically related structures. In the absence of extensive metastases to other vital organs, significant and desirable prolongation of comfortable survial may be obtained by aggressive palliative management of disseminated disease to the heart in carefully selected patients. REFERENCES 1. Giancy, D. L., and Roberts, W. C. The heart in malignant melanoma. A study of seventy autopsy cases, Amer. J. Cardiol. 21, 555 (1%8). 2. Hanfling, S. M. Metastatic cancer to the heart. Review of the literature and report of one hundred and twenty-seven cases, Circulation 22, 414 (1960). 3. Hill, G. J. II, and Cohen, B. I. Pleural pericardial window for palliation of cardiac tamponade due to cancer, Cancer 26, 81 (1970). 4. Hood, R. P., Geraci, J. E., Broadbent, J. C., and Titus, J. L. Metastatic Squamous Cell Carcinoma of the Heart Presenting as Fever of Unknown Origin, Mayo Clin. hoc. 42, 556 (1%7). 5. Kline, I. K. Cardiac lymphatic involvement by metastatic tumor, Cancer 29, 799 (1972). 6. United States Department of Health, Education and Welfare, Public Health Service. Mortalityfrom selected causes by marital status, United States, Part B, National Center for Health Statistics Series 20, No. 8b. Health Services and Mental Health Administration, December 1970. 7. Thurber, D. L., Edward, J. E., and Anchor, R. W. P. Secondary malignant tumors of the pericardium, Circulation 26, 288 (I 962). 8. Young, J. M., and Goldman, I. R. Tumor metastasis to the heart. Circulation 9, 220 (1954).
ONCOLOGY
10,
75-83 (1980)
Cardiac Metastases Associated with Gynecologic Malignancies EARL
F. GREENWALD,
M.D.,* JAMES L. BREEN, M.D.,“f,S AND A. GRRGORI, M.D.7
CATERINA
*Department of Obstetrics and Gynecology, Hahnemann Medical College and Hospital, 230 North Broad Street, Philadelphia, Pennsylvania 19102, tSt. Barnabas Medical Center, Old Short Hills Road, Livingston, New Jersey 07039, and /Jefferson Medical College, llth and Walnut Streets, Philadelphia, Pennsylvania 19107
Received November 22, 1979 Metastasis to the heart of malignancies arising within the pelvis is a rarely reported phenomenon. In fact, review of the literature and personal experience demonstrate that cardiac metastases occur more frequently than expected. Clinical suspicion would enable its antemortem diagnosis in many patients and would permit appropriate therapy in carefully selected individuals.
Despite the fact that disseminated malignancy ranks second only to heart disease as a cause of death in the United States [63, metastatic cardiac involvement has rarely been reported. Many statistical analyses of large series of unselected autopsies have documented the relative infrequency of the heart as a focus of tumor spread [1,2,5,7,8]. Antemortem recognition of cardiac metastases was first reported in 1913 [2], and the first antemortem diagnosis of heart metastasis recorded in American literature appeared in 1928 131. Pelvic malignancy as a primary site for cardiac metastases is rarely reported. In one series of 716 autopsies performed on patients dying of a variety of neoplasms, it was noted that 71 patients suffered from pelvic malignancies. In this series, 9% had cardiac metastases, only one of which originated within the pelvis (a primary leiomyosarcoma of the uterine corpus) [5]. In another series of 189 patients with cardiac metastases documented at postmortem examination, only 2 had primary pelvic disease, both adenocarcinomas of the uterine corpus [Sl. MATERIALS
AND METHODS
During a 4-year period, 1100 gynecologic cancer patients were evaluated at St. Barnabas Medical Center. This report is based on a study of the clinical data and pathological material from six patients with genital tract malignancy metastatic to the myocardium. Hemotoxylin and eosin-stained histological preparations were studied in all but one case. CASE REPORTS Case 1
A 77-year-old female was evaluated on September 2, 1970 for profuse vaginal bleeding. A bulky, friable, exophytic, necrotic mass, arising from the cervix and 75 00%8258/80/040075-09$01.00/O Copyright @ 1980 by Academic Press, Inc. All rights of reproduction in any form reserved.
76
GREENWALD,
BREEN,
AND
GREGORI
occluding the entire upper third of the vagina, was found. Extension along the anterior wall to the introitus and to both pelvic sidewalls was noted. Biopsies revealed invasive squamous cell carcinoma. The clinical stage was IIIB. External radiation therapy was delivered. The patient was readmitted on November 10, 1970 for radium application. While radium was in situ, she complained of dyspnea. Chest X ray showed left ventricular enlargement with normal pulmonary fields. The patient was discharged, without complaints, on completion of her radiation therapy. She was readmitted on December 11, 1970 with a 5-day history of progressive dyspnea and weakness of the extremeties. Her pulse was irregular, the blood pressure was 130/80, and no peripheral edema or hepatomegaly were noted. An electrocardiogram (ECG) showed regular sinus rhythm with frequent premature ventricular contractions and myocardial ischemia. Cardiac enlargement with congestive changes in the right lower lung field were noted. The patient experienced a rapid downhill course, with progressive cyanosis, dyspnea, and disorientation. She expired on December 16, 1970. Autopsy revealed squamous cell carcinoma of the cervix with metastases to the right ventricle, supraclavicular, paraaortic, and pelvic lymph nodes; severe vascular congestion of the lungs, liver, spleen, and kidneys; and massive hemorrhagic infarction of the lungs secondary to multiple pulmonary emboli, thought to be the immediate cause of death. Cardiac metastases infiltrated the endocardium and portions of the myocardium, with surrounding necrosis (Fig. 1). Case 2 This 62-year-old nulligravida presented with invasive squamous cell carcinoma of the vulva in December 1972. Multiple large, matted, hard, fixed, suppurating nodes were noted in the left inguinal area. An 8 x 5-cm ulcerative vulvar lesion was noted, extending to the forchette, but not involving the anus. Marked edema of the left leg was present, with superficial phlebitis involving the left long saphenous vein. No calf tenderness or Homan’s sign could be elicited. The clinical stage was T,N3M,. ECG was normal. Appropriate therapy resulted in resolution of phlebitis of the left leg and suppuration of left inguinal nodes. Radical vulvectomy, bilateral inguinal, femoral, and pelvic lymphadenectomy were performed. Surgery was complicated by the sudden onset of a bigeminy rhythm. Postoperatively she experienced recurrent episodes of bigeminy, which responded to intravenous lidocaine. Ten days after release she was readmitted obtunded and severely dehydrated. ECG showed sinus tachycardia. Her clinical course was downhill, and she expired. Autopsy revealed residual squamous cell carcinoma of the vulva with widespread involvement of pelvic structures, including the uterus, left uterine tube and ovary, left ureter and the bladder; neoplastic necrosis of the left medial thigh and left inguinal region with metastatic left pelvic nodes; and metastases to the liver, paraaortic lymph nodes, ribs, vertebrae, and myocardium.
CARDIAC
FIG.
1.
METASTASES
77
Sheets and islands of malignant squamous cells may be seen inliltrating myocardial fibers.
78
GREENWALD,
BREEN,
AND
GREGORI
Case 3 A 44-year-old patient was admitted for evaluation of invasive squamous cell carcinoma of the cervix on November 10, 1972. Examination revealed a large exophytic cervical lesion involving the upper third of the vagina, the right lateral vaginal fomix, and the cul-de-sac of Douglas. Hard nodularity was noted extending along the right parametrium, attaching to the right pelvic sidewall. The uterus was slightly enlarged and fixed. The patient was confused and disoriented. Her speech was slurred, and left facial, upper and lower extremity paresis were noted. The clinical stage was IIIB. ECG showed sinus tachycardia and ST wave changes. The patient experienced an inexorable downhill course and expired on the fourth day after admission. Autopsy revealed sqamous cell carcinoma of the cervix with multiple metastatic paraaortic and mediastinal lymph nodes, malignant vegetations on the mitral valve, multiple recent infarcts in both kidneys and in the spleen secondary to thromboses of small branches of the renal and splenic vasculature, marked dilatation of all chambers of the heart, malignant left femoral vein and popliteal artery thromboses with ischemic necrosis of the left toes, and impending gangrene of the foot and lower leg. Death was attributed to massive pulmonary embolism involving both main pulmonary arteries, originating in the left femoral vein. Case 4 A %-year-old white female was admitted on February 18, 1973 with invasive squamous cell carcinoma of the vulva. Examination was unremarkable except for a well-demarcated 2 x l-cm lesion on the anterior one-third of the left labium majus. The clinical stage was T,N,M,. On February 23, 1973, radical vulvectomy and bilateral inguinal and femoral lymphadenectomy were performed. Histologic evaluation revealed metastases to two left inguinal nodes. The margins of resection were free of tumor. The patient was discharged in 10 days without significant postoperative problems. Five months later the patient developed a nonproductive cough. Chest X ray showed multiple pulmonary metastases. Long bone X rays demonstrated metastatic disease in the right femur and tibia. ECG revealed sinus tachycardia. Chemotherapy was instituted. Final admission occurred on July 16, 1973 when the patient presented in a semicomatose condition. Her course ran rapidly downhill, and she expired on the fourth hospital day. Autopsy revealed residual carcinoma in vulvar subcutaneous tissue and metastases in the lower anterior cervical, mediastinal, both hilar, peribronchial, mesenteric, and lower paraaortic lymph nodes; both upper pulmonary lobes; left ventricular myocardium; liver; both adrenals, right kidney; appendix; right seventh through ninth, and left sixth through ninth posterior ribs and intercostal soft tissues (with pathological fractures); thoracic, lumbar and upper sacral vertebml bodies, with collapse of several vertebrae; right midfemur and adjacent soft tissues, right upper tibia and adjacent soft tissues. The cause of death was attributed to the widespread metastatic disease.
CARDIAC
METASTASES
79
Case 5
This 72-year-old patient was evaluated in October 1970 for adenocarcinoma of the cervix with vaginal metastases. In 1948 the patient underwent left radical mastectomy and radiation castration for adenocarcinoma of the breast. In 1969, she was subjected to right radical mastectomy for adenocarcinoma of the right breast. Evaluation for rectal bleeding revealed adenocarcinoma of the large intestine, requiring hemicolectomy in 1960. Physical examination was normal, with the exception of a 2 x 4-cm hard, necrotic, friable mass involving the cervix and cul-de-sac of Douglas. The uterus was anterior, small, and mobile. No adnexal pathology could be palpated. Paracolpos was clinically free of involvement. The final clinical stage was HA. Radiation therapy was administered. The patient was readmitted on December 10, 1970 because of shortness of breath, dyspnea on exertion, and orthopnea. Examination revealed tachycardia and an irregular cardiac rhythm; no murmurs could be heard. Dullness to percussion and decreased breath sounds were noted over the right lower hemithorax. ECG demonstrated atria1 fibrillation and myocardial ischemia. Progressive ECG changes were noted, with superimposition of multifocal premature ventricular contractions, low voltage QRS complexes, and ST segment depression in precordial leads. The patient’s clinical course was inexorably downhill, and cardiac metastases were suspected in view of the absence of another reason for sudden, rapid progressive myocardial dysfunction. She expired on January 8, 1971. No autopsy was obtained. Case 6
This 72-year-old patient was admitted on September 30, 1974 for treatment of squamous cell carcinoma of the vulva, Stage T,N,M,,. She had experienced vulvar pruritis and contact bleeding for approximately 2 years, intermittently treated with corticosteroids and a variety of topical preparations. A discrete lesion was eventually noted and biopsied. Physical examination on admission was unremarkable except for a 1.5 x 1 x 2-cm ulcerative lesion involving the anterior two-thirds of the right labium minus and majus. A 1 x l-cm mobile, discrete, nontender lymph node was noted in the right inguinal area. Hepatosplenomegaly to the level of the umbilicus was noted. ECG demonstrated ventricular hypertrophy with occasional premature ventricular contractions. On October 4, 1974 the patient underwent radical vulvectomy and bilateral inguinal and femoral lymphadenectomy. One right and two left inguinal lymph nodes demonstrated metastatic disease. The patient was discharged on October 15, 1974. On March 10, 1975, left femoral lymphadenopathy and multiple nodules distributed over the back, arms, and tongue were noted. She was anorectic and debilitated. ECG revealed sinus tachycardia, left anterior hemiblock, and left ventricular hypertrophy. The patient experienced a rapid downhill course and expired on April 18, 1975.
80
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BREEN,
AND
GRBGORI
Postmortem examination demonstrated widespread metastatic disease involving the left lung; heart and pericardium; liver and spleen; adrenals, thyroid, and pancreas; diaphragms; bone marrow; subcutaneous tissue of the trunk and back; tongue; and peritrachael, mediastinal, hilar, peripancreatic, paraaortic, iliac, and inguinal lymph nodes. DISCUSSION
Cardiac metastases occur primarily in the sixth and seventh decades of life, with ages ranging between 26 and 85 [5]. This represents the natural age distribution of malignancy in our population; the incidence of cardiac metastasis is probably not influenced by the age of the patient. There appears to be an equal sex distribution among patients with heart involvement [51. It is estimated that metastatic disease to the heart is 16 to 40 times more common than primary cardiac malignancy. Among unselected autopsies, 0.2 to 6.5% of patients demonstrate cancer with dissemination to the heart [5]. The incidence of cardiac metastasis is as high as 21% among patients dying of disseminated cancer [2-5,8]. The most common malignancies complicated by cardiac involvement include bronchogenic and breast carcinoma, malignant melanoma, lymphoma, and pancreatic, esophageal, and, in Japan, gastric carcinomas [l-3,5,7,8]. Of the lymphomas, lymphocytic and lymphoblastic lymphosarcomas most frequently involve the heart [ 1,8]. Much of this apparent predilection for cardiac involvement is probably related to the relative frequency of these tumors, anatomic proximity to the heart, and lymphatic access to the heart and its adnexal structures. There does, however, appear to be some propensity for cardiac implantation of malignancies of certain histologic types. Of patients with leukemia, 11.1% show cardiac metastases, as do 10.4% of patients with bronchogenic carcinoma, 20.9% of patients with breast carcinoma, and 64.3% of patients with malignant melanoma [2]. A study of 716 consecutive adult autopsies performed on patients dying of malignancy showed a relative incidence of carcinoma to sarcoma of 3: 1. In contrast, only 6.4% of carcinomas metastasized to the heart, as compared to 15% of sarcomas. Of 61 cardiac metastases, 41% were of sarcomatous origin, and 5% of carcinomatous origin [5]. The relative infrequency of the heart as a metastatic focus is attributed to the following factors: (1) the vigorous kneading action of the myocardium; (2) the relative avascularity of the endocardium [8]; (3) the peculiar metabolic pathways used by cardiac striated musculature; (4) the rapidity of blood flow through the heart chambers; (5) the paucity of lymphatic communication between the heart and surrounding structures, making lymphatic extension difficult; (6) the fact that the coronary arteries arise from the aorta at right angles, creating a difficult pathway for malignant cells disseminated by the hematogenous route [2,8]. It is estimated that only 4% of heart metastases are diagnosed prior to death [8]. There appears to be a recent increase in the incidence of cardiac metastasis, probably related to the increased duration of survival of patients with malignancies because of development of new techniques of radical surgery, radiation, and chemotherapy. It is expected that more frequent and earlier recognition of this
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complication will continue, making palliative management of carefully selected cases feasible and desirable. The pathways of dissemination to the heart, as to all areas of the body include: (1) direct extension from contiguous structures; (2) hematogenous dissemination; (3) lymphatic permeation [2,5,81. Of these three mechanisms, direct extension from surrounding areas of malignancy is least common [5]. Opinion is divided as to whether the hematogenous or lymphatic route is more common. Isolated, diffuse intramural nodules, frequently observed with malignant melanomas, suggest an hematogenous mechanism for this tumor. Apparently the essential initial step in lymphatic spread to the heart is mediastinal node involvement, followed by retrograde extension along lymphatic channels [5]. Widespread malignancy, including metastasis to mediastinal nodes, almost invariably exists when cardiac involvement is present [ 1,7]. Occasionally, cardiac involvement produces the initial symptoms of the malignancy. Very rarely the cardiac lesion is the only detectable metastasis at autopsy. Two such caseshave been reported: a retroperitoneal fibroliposarcoma with extension directly to the coronary vessels, and an adrenocortical tumor with malignant thrombosis of the cardiac vessels [2]. The most common site of metastasis in the middle mediastinum is the pericardium. Myocardial invasion is not uncommon in disseminated sarcomas, malignant melanomas, and lymphomas. Endocardial implantation is a relatively rare phenomenon, but, when it does occur, it usually occurs on the cardiac valves. The paucity of the reported metastatic involvement of the valves and endocardium is probably related to the relative avascularity of this tissue [4]. The first prerequisite for antemortem diagnosis of cardiac involvement by metastatic cancer is an index of suspicion. Among patients with known widely disseminated malignancy, the development of cardiac dysfunction without other apparent cause is probably the earliest and most common phenomenon warning of metastatic cardiac tumor [1,8]. Such dysfunctions include: (1) congestive heart failure not responsive to usual cardiotonic regimens; (2) recent development of second- or third-degree artrioventricular block; (3) ectopic foci for premature atria1 or ventricular contractions; (4) acute pericarditis; (5) bizarre cardiac contour or rapid increase in size of cardiac silhouette; (6) cardiac constriction or tamponade; (7) unexplained new ECG changes; (8) superior or inferior vena caval syndromes; (9) angina pectoris [1,2,4,5,7,8]. Only 2% of all cardiac metastasesare symptomatic; the remaining are not clinically apparent and are discovered at autopsy. There is no correlation between the extent of cardiac involvement and the severity of the clinical manifestations [3,4,71. Signs and symptoms, when present, with pericardial involvement include dyspnea, orthopnea, chest pain, dysphagia, cyanosis, rales, cardiomegaly, venous distension, hepatomegaly, pleural effusion, and peripheral edema [7,8]. These signs and symptoms, when present, are more likely to be caused by systemic effects of advanced disease, or by involvement of intrathoracic structures other than the heart. Dyspnea, cough, pleural effusion, thoracic pain, orthopnea, cyanosis, and rales are more frequently caused by pulmonary metastases than by cardiac metastases. Hepatomegaly more often reflects liver involvement than heart failure caused by cardiac metastases. Peripheral edema is more likely to be
a2
GREENWALD,
BREEN,
AND
GREGORI
related to hypoalbuminemia. Venous distension and dysphagia more commonly reflect vena caval and esophageal compression, and tachycardia is generally attributable to anemia and diffuse pulmonary metastases [ 1,8]. Diagnosis of pericardial involvement is generally made on the basis of changes in cardiac silhouette [2,4]. ECG signs include decreased voltage of the main deflection in all three standard leads, electrical alternans, and simultaneous alternation of atrial and ventricular complexes [7,8]. The most direct means of documenting the diagnosis of malignant pericardial effusion is pericardiocentesis for exfoliative cytology [2,7]. At pericardiocentesis air may be introduced into the pericardial sac in order to delineate, on X ray, irregularity of the pericardial or cardiac silhouettes secondary to tumor implantation [2]. Even without documentation, a trial of external radiation of the heart may be justified in far-advanced disease if pericardial involvement is suspected. A decrease in the size of the cardiac silhouette on X ray due to resorption of pericardial effusion during radiation therapy would confirm the malignant etiology of the fluid
lx. Myocardial invasion is usually symptomatic because of intraventricular septal invasion with conduction defects, frequently expressed as an arrhythmia [2,7]. Tumor emboli may occasionally occlude the coronary vessels, producing coronary insufficiency, angina pectoris, or frank myocardial infarction [2]. Endocardial involvement, usually involving the tricuspid valve alone or both tricuspid and mitral valves, is detected by signs and symptoms typical of subacute bacterial endocarditis [4]. These include fever, changing cardiac murmurs, increase in erythrocyte sedimentation rate, and anemia in the absence of superimposed bacterial infection. The majority of patients with cardiac involvement, as noted above, are asymptomatic and die of unrelated causes. Among patients with asymptomatic cardiac metastases, the most common causes of death are bronchopneumonia, gram-negative septicemia, and cerebrovascular hemorrhage [ 1,5,7]. Among patients whose cardiac involvement is symptomatic, 83% died of their heart metastases, usually from congestive heart failure, arrhythmias, or tamponade [3,5,7]. Less common forms of cardiac compromise by tumor include: mechanical constriction; restriction of the inflow into or outflow from the heart by compression of the major vessels; interference with cardiac circulation by compression, neoplastic embolism, or direct invasion of the coronary arteries and/or veins; and encroachment on the myocardial nerve supply [7]. With the recent increase in incidence of antemortem recognition of cardiac involvement, the desirability and feasibility of treatment must be considered. Although prognosis is extremely poor, prolonged survivals of 34 to 21 months have been reported using various modalities, including pleural-pericardid windows, external radiation, and chemotherapy, alone or in combination [3]. Among patients whose general condition is commensurate with prolonged survival, attempts at palliation may be rewarding [3,7]. Megavoltage radiation to the precordial area has been reported on several occasions to successfully reverse heart block and arrhythmias secondary to metastatic tumor, and to stimulate
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resorption of malignant pericardial effusions [2,5]. Radiation therapy of the heart has been complicated by radiation myocarditis. Recurrent pericardial effusion after pericardiocentesis has been managed with some success by instillation of a variety of therapeutic agents, including radioactive chromic phosphate and colloidal gold, alkylating agents, antimetabolites, and sclerosing compounds [3]. Finally, recurrent pericardial effusions have been successfully controlled by creation of a pleural-pericardial window [3]. This is reserved for patients in generally good condition, and it is contraindicated in the presence of rapidly growing malignancies or extensive visceral metastases. CONCLUSIONS
With the recent advent of effective palliation of advanced malignancies, an index of suspicion has developed which has made possible antemortem recognition of metastatic involvement of the heart and its anatomically related structures. In the absence of extensive metastases to other vital organs, significant and desirable prolongation of comfortable survial may be obtained by aggressive palliative management of disseminated disease to the heart in carefully selected patients. REFERENCES 1. Giancy, D. L., and Roberts, W. C. The heart in malignant melanoma. A study of seventy autopsy cases, Amer. J. Cardiol. 21, 555 (1%8). 2. Hanfling, S. M. Metastatic cancer to the heart. Review of the literature and report of one hundred and twenty-seven cases, Circulation 22, 414 (1960). 3. Hill, G. J. II, and Cohen, B. I. Pleural pericardial window for palliation of cardiac tamponade due to cancer, Cancer 26, 81 (1970). 4. Hood, R. P., Geraci, J. E., Broadbent, J. C., and Titus, J. L. Metastatic Squamous Cell Carcinoma of the Heart Presenting as Fever of Unknown Origin, Mayo Clin. hoc. 42, 556 (1%7). 5. Kline, I. K. Cardiac lymphatic involvement by metastatic tumor, Cancer 29, 799 (1972). 6. United States Department of Health, Education and Welfare, Public Health Service. Mortalityfrom selected causes by marital status, United States, Part B, National Center for Health Statistics Series 20, No. 8b. Health Services and Mental Health Administration, December 1970. 7. Thurber, D. L., Edward, J. E., and Anchor, R. W. P. Secondary malignant tumors of the pericardium, Circulation 26, 288 (I 962). 8. Young, J. M., and Goldman, I. R. Tumor metastasis to the heart. Circulation 9, 220 (1954).