Cardiovascular collapse and death in a 55-year-old woman with cervical cancer

CLlNlCOPATHOLOGlC CONFERENCE

Cardiovascular Collapse and Death in a 55Year-Old Woman with Cervical Cancer

Stenographic reports of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal. Members of the Departments of Internal Medicine, Radiology, and Pathology of the Washington University School of Medicine participate jointly in these conferences. Kenneth M. Ludmerer, M.D., and John M. Kissane, M.D., are the editors of this feature.

A 55year-old white woman was admitted to the Barnes Hospital medical intensive care unit on March 19, 1984, and died later that day.

The patient was found to have stage IIIB epidermoid carcinoma of the cervix in January of 1983, after presentation at that time with a five- month history of abdominal pain. Her evaluation included an intravenous urogram showing left hydronephrosis and hydroureter, and a lymphangiogram showing disease of the external iliac lymph nodes. She received 2,000 rads of total pelvic irradiation, 4,000 rads of split-field external irradiation, 700 additional rads externally to the left pelvis, and 16,000 rads to the vaginal apex via three intracavitary implants. This therapy was completed in May of 1983 and was well tolerated. An intravenous urogram on May 27, 1983, revealed persistent irregular filling of the left external iliac lymph nodes in comparison with the previous lymphangiogram, but normal kidneys, ureters, and bladder. Physical examination revealed induration of the pelvic structures with no masses or other gross evidence of malignancy.

She was reported to be doing well until approximately three days prior to her admission on March 19, 1984, when she began to notice increasing shortness of breath, a nonproductive cough, and left-sided chest pain that increased with movement. She denied hemoptysis, orthopnea, and paroxysmal nocturnal dyspnea.

Her initial evaluation on March 19, 1984, disclosed distended neck veins and tachypnea. An emergent two-dimensional echocardiogram revealed (1) mitral valve prolapse, (2) paradoxical motion of the interventricular septum, (3) a moderate to large, predominantly anterior pericardial effusion, without tamponade, and (4) an echogenic mass within the right ventricle deforming the right ventricular cavity. The right atrium appeared enlarged.

In the medical intensive care unit, a physical examination revealed a pulse rate of 70/minute, a respiratory rate of 45/minute, a blood pressure of 100/60 mm Hg without an appreciable pulsus paradoxus, jugular venous distention to the jaw at 90 degrees with prominent V wave and Y descent, a questionable right ventricular heave, a normal, nondisplaced apical impulse, normal S1 and S2 sounds, a right ventricular S3 gallop, no appreciable murmur or friction rub, a clear chest, a soft nontender liver

March 1988 The American Journal of Medicine Volume 84 463

CPC-CARDIOVASCULAR COLLAPSE AND DEATH

with a 14-cm span, a normal rectal vault containing guaiac-negative stool, unremarkable extremities, and no palpable lymphadenopathy. A chest radiograph disclosed increased heart size from May of 1983, multiple nodular densities in the lung fields, and destruction of the left eighth rib compatible with metastatic cancer. An electrocardiogram was interpreted to show normal sinus rhythm, biatrial enlargement, right bundle branch block, probable lateral myocardial infarction (new from May of 1983), and poor precordial R wave progression. A ventilation-perfusion lung scan demonstrated inhomogenous deposition of inhaled aerosol and multiple perfusion defects and was interpreted as technically intermediate for pulmonary embolism, but suspicious for pulmonary embolism because of the nature of the perfusion defects. Admitting laboratory data included a white blood cell count of 12,400/mm3 and a hemoglobin level of 13.4 g/dl. Other data included sodium of 134 mmol/liter, potassium of 4.6 mmol/liter, chloride of 98 mmol/liter, carbon dioxide of 16.6 mmol/ liter, glucose of 119 mg/dl, creatinine of 1.3 mg/dl, serum urea nitrogen of 32 mg/dl, albumin of 3.4 mg/dl, calcium of 9.3 mg/dl, phosphate of 6.5 mg/dl, uric acid of 10.5 mg/dl, alkaline phosphatase of 147 units/liter, as- partate transaminase of 350 units/liter, lactate dehydro- genase of 815 units/liter, creatinine kinase of 47 units/ liter, and bilirubin of 0.8 mg/dl. Arterial blood gases while receiving 3 liters of nasal oxygen revealed a pH of 7.39, an arterial carbon dioxide pressure of 20 mm Hg, and an arterial oxygen pressure of 70 mm Hg. A lactate level of 7.8 mmol/liter was also reported.

Swan-Ganz catheterization yielded a right atrial pressure of 18 mm Hg, a right ventricular pressure of 36110 mm Hg, a pulmonary arterial pressure of 35/22 mm Hg, and a pulmonary artery occlusive pressure of less than 2 mm Hg. Soon after the procedure, bradypnea and bradycardia were noted; apnea and hypotension ensured. Dur- ing cardiopulmonary resuscitation, she was treated with atropine, sodium bicarbonate, calcium chloride, dopa- mine, levarterenol, heparin (10,000 units intravenous push), and streptokinase (250,000 units intravenous push). She showed a response of sinus tachycardia and a systolic blood pressure of 80 to 90 mm Hg. Arterial blood gases with 100 percent oxygen and mechanical ventilation included a pH of 7.02, an arterial carbon dioxide pressure of 45 mm Hg, and an arterial oxygen pressure of 90 mm Hg. A second episode of bradycardia prompted transvenous pacemaker placement. Persistent acidosis and hypotension, however, were unresponsive to aggres- sive supportive therapy.

CLINICAL DISCUSSION

Dr. Allan Jaffe: This is a woman who presented with abdominal pain approximately one year prior to her final admission and was found to have cervical carcinoma. There was some confusion initially, and I will ask Dr.

Safdar to clarify whether she had stage IIB or IIIB disease. Subsequently, it became clear that she had stage IIIB disease. Hydronephrosis and hydroureter developed, and a lymphangiogram revealed lymphatic involvement of the external iliac chain. She was treated with external and implanted radiation therapy. She received one more additional implant than is usually routinely employed because the upper one third of the vagina was involved. The additional radiotherapy was done in May of 1983 and required an admission to the hospital at the hospital’s expense because the physicians caring for her obviously believed strongly that this was an important part of her treatment.

When she returned on March 19, 1984, she presented with shortness of breath, cough, and chest pain that was described as increasing with motion but not with respira- tion. She had an increased respiratory rate but was not markedly tachycardic. She was described as having signs of right-sided congestive heart failure, including a ventricular gallop localized to the left sternal border that was thought to be a right ventricular Ss. It is probably worth noting at this point how difficult it is to identify the origin of S3 gallops based on location alone. I believe it is likely a correct conclusion in this instance because of the associated findings. However, when cardiac enlargement oc- curs, especially of the right ventricle, the location of gallops may be altered, and decisions based on location alone can be inaccurate. In this case, there also was jugular venous distension with prominent V waves and very brisk Y descents as well. The morphology of the jugular venous pressure tracing is important in this case because it effectively excludes pericardial tamponade and therefore obviates the rationale used in this case to justify hemodynamic monitoring. She had hepatomegaly that was most likely secondary to passive congestion of the liver. There was no evidence of left ventricular failure.

She had an elevated white blood cell count, but no differential is available in the chart. She had a metabolic acidosis as reflected by low arterial carbon dioxide pressure and bicarbonate values and marked lactic acidemia. Her creatine kinase level was normal and the results of her liver function studies were abnormal. Her initial radiographic studies were interpreted differently by different observers. The house staff interpreted the chest radiograph as showing cardiomegaly and no acute cardiopulmonary disease, but the radiologists detected multiple nodular masses or infiltrates and destruction of the eighth rib. The nuclear medicine physicians noted a right pleural effusion. I will ask Dr. Semenkovich to clarify the radiographic interpretations later. A ventilation-perfusion scan was done and interpreted intermediate for pulmonary embolism. Matching plain radiographic and perfusion abnormalities made this scan technically intermediate, but because of the large number of segmental defects, pulmonary embolism was considered likely. The house staff

464 March 1966 The American Journal of Medicine Volume 64


were aware of this fact, and I congratulate them ‘for scrutinizing the scan. The echocardiogram as reported in the chart was interpreted as mitral valve prolapse, paradoxical motion of the interventricular septum, and right ventricular enlargement, which defines a pattern known as right ventricular volume overload. As Dr. Barzilai will show us later, right ventricular pressure overload also was present. There was an anterior pericardial effusion, which we will comment on in a few minutes, and a right ventricular mass just below the tricuspid valve with some sugges- tion of infiltration of the anterior free wall, likely by tumor.

According to the protocol, the patient’s electrocardiogram was changed from one obtained a year ago. That is true, but the electrocardiogram from a month prior to this admission was very similar to the electrocardiogram on admission, an important point only in the sense that it establishes the chronic@ of the electrocardiographic changes (Figure 1). Right bundle branch block and ST- segment elevation in V2 and V3 with poor precordial R- wave transition was present. This could be due to anterior myocardial infarction, infiltration of the anterior free wall of the right ventricle with tumor if that is what we eventual- ly decide was present, or right ventricular hypertrophy. As the right ventricle enlarges, it takes over the anterior part of the chest and displaces the left ventricle posteriorly, inducing delayed R wave transition and/or large persistent S waves laterally. The only difference between the electrocardiogram taken one month earlier and the one taken at the time of the terminal admission is subtle. There now is a small Q wave lead in V2. There is no Q wave in lead VI. Right ventricular hypertrophy could be responsible for all of the changes. Q waves in VI and V2 with the pattern of right ventricular hypertrophy are thought by some to be indicative of severe right ventricular hypertrophy with rotation of the ventricular septum. As the right ventricle enlarges, it displaces the left ventricle posteriorly, revers- ing normal septal depolarization. It could be that a Q wave in VI might have been detected had additional lead posi- tions been utilized. Alternatively, right atrial dilatation also has been suggested as a cause for a Q wave in lead VI when right ventricular hypertrophy is present [I]. We cannot totally exclude acute anterior infarction, although the chronicity of this change makes this unlikely. There also is marked right axis deviation, and I spent yesterday with my electron microscope to try to see if there was a tiny R wave in lead I. I do think that despite the very low voltage complex there is a tiny R wave, which is helpful information because I would have no real way of explain- ing a QS complex in that lead in the absence of infarction in a woman whose only risk factors for coronary artery disease were her age and her post-menopausal status. I asked Dr. John Boineau to use his electron microscope as well, and we both think there is small but definite evidence of an R wave in lead I. The morphology of the electrocardiogram suggests right ventricular hypertrophy. However,

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Figure 1. Electrocardiogram taken on March 19, 1984 See text for discussion.

right ventricular hypet-trophy alone usually does not cause the type of ST-segment elevation observed in this patient. Thus, it is possible that infarction or tumor infiltration of the anterior wall is present. Pulmonary embolism due to clot or tumor can lead to this type of an electrocardiogram, and that would explain the ST-segment elevation, right axis deviation, and right bundle branch block. The electrocardiographic manifestations of pulmonary embolic disease fit the clinical situation better since right bundle branch block and ST-segment elevation can occur even in patients without prior cardiac or pulmonary disease, if massive or submassive pulmonary embolism is present [21.

She was taken to the respiratory intensive care unit, where a Swan-Ganz catheter was placed. It is not really clear that a Swan-Ganz catheter was required at this time, and since a right ventricular mass had been documented by echocardiography, the procedure was potentially dan- gerous. There was no question of left-sided congestive heart failure raised, only ambivalence about pericardial tamponade, which I think had been effectively excluded by the physical assessment of all examiners in their description of a very brisk Y descent. I would have been afraid to put a Swan-Ganz catheter through that echocardiographic mass for fear of dislodging something, and that appears to be what happened. The right atrial pressure was measured as 18 mm Hg and the right ventricular pressure as 36110 mm Hg. A discrepancy between the right ventricular end-diastolic pressure and the right atrial pressure is frequently reported but very infrequently accu- rate. It usually is due to poor quality control of the hemodynamic measurements because this finding would suggest a component of tricuspid stenosis. When one observes such a gradient in the absence of an appropriate clinical setting, it should lead to another look at how the hemody- namics have been obtained. On the other hand, the mass in the right ventricle that we will show later is sufficiently close to the right ventricular inflow track that I cannot



TABLE I Staging of the International Federation of Gynecology and Obstetrics

Stage Description

IA Confined to the cervix; cannot be diagnosed by clinical examinations; no stage IA cases are included in this study

IB Confined to the cervix (disregarding corpus extension) HA Involvement of the upper two thirds of the vagina. No

parametrial involvement IIB Practical involvement, but with a tumor-free space be-

tween the pelvic side wall and the parametrial extension

IIIA Involvement of one pelvic side wall or the lower one third of the vagina

IIIB Involvement of both pelvic side walls or one pelvic side wall and the lower one third of the vagina

IVA Involvement of the mucosa of the bladder or rectum (bullous edema as such does not permit allocation of a case to stage IV)

IVB Extension beyond the true pelvis

exclude the possibility that there is a component of functional tricuspid stenosis. The pulmonary artery pressure was elevated to 35/22 mm Hg, and the pulmonary artery occlusive pressure was very low (2 mm Hg). The discrepancy between the pulmonary artery occlusive pressure and the pulmonary artery end-diastolic pressure suggests increased pulmonary vascular resistance. The patient had a low cardiac output syndrome judging from her clinical status and very high systemic lactate level. I have little doubt that had this woman had a more normal cardiac output, these pressures would have been even more impressively elevated. Thus, it is highly likely that she had severe pulmonary hypertension. High pulmonary artery and right ventricular pressures suggest that at least part of the process was chronic because right ventricular systolic pressures greater than 40 mm Hg only occur when prior cardiac or pulmonary disease is present [3]. Immediately after insertion of the Swan-Ganz catheter, bradypnea and bradycardia developed. This is not a terribly uncommon finding when patients are observed after an acute submassive pulmonary embolism. If one reads the older literature, acute episodes of bradycardia and hypotension are clearly described very early after pulmonary embolism [4]. It was thought initially that this response was a manifestation of the so-called Bezold-Jarisch reflex and it was said to last no more than 15 minutes. The Bezold- Jarisch reflex originally was thought to be pharmacologi- cally mediated. We now know, as reviewed recently by Mark [5], that vagally mediated cardiac effects are common and important in patients with ischemic heart disease, especially in the inferoposterior aspect of the heart, during coronary arteriography, in patients with aortic stenosis and syncope, in the mechanism of vasovagal syncope, in mediating the neurohormonal excitation associated with heart failure, and in response to the therapeutic effects of digitalis.

Thus, bradycardia and bradypnea could be due to either cardiac or pulmonary reflexes. She had inadequate stroke volume due to right heart failure and was severely acidot- ic, hypotensive, and continually bradycardic. I might have used judicious volume expansion and dobutamine rather than vasopressors and bicarbonate in an attempt to im- prove right ventricular output. My approach would have been similar to that used in the treatment of right ventricular infarction where dobutamine is the drug of choice [6], although I would have to acknowledge that the primary abnormality here was increased pulmonary arterial impedance rather than the loss of right ventricular mass. However, I would have wanted to avoid the increases in systemic arterial impedance induced by pressors that would have further reduced left ventricular output, and I would have wanted to avoid bicarbonate, which has po- tent negative inotropic effects when lactic acidosis is present [ 71.

A putative diagnosis of pulmonary embolism obviously was made and led to the administration of streptokinase and heparin. Nonetheless, the patient died. According to the chart, no postmortem examination was performed, but Dr. Saffitz would not be here unless there was one. To start, I have asked Dr. Safdar to educate us about cervical carcinoma. The naive idea that is predominantly a benign malignancy in most patients is not necessarily correct. I have asked Dr. Safdar to discuss the incidence, causes, prevention, staging, and prognosis of cervical carcinoma and whether this woman was typical or atypical of patients with this malignancy. Dr. Shabbir Safdar: This patient’s course was typical for stage Ill carcinoma of the cervix. Cervical carcinoma follows a rapidly progressive and fatal course in the majority of patients with disease more advanced than stage II. The notion that cervical carcinoma is not a fatal disease has evolved because of our ability to diagnose the disease in its early stages when it is curable in most patients. The spectrum of disease also has changed with the advent of frequent Pap smears [8]. Most cases of cervical carcinoma are now diagnosed in stage I, a stage at which nearly 80 percent are curable. For that reason, some physicians have developed the notion that cervical carcinoma is not a serious disease. Unfortunately, advanced carcinoma of the cervix is still a very serious and fatal disease. The annual report on the treatment of gynecologic cancer, which tabulates the experience of 52 institutions and thousands of cases, has reported a five- year survival of 80 percent for stage I, 59 percent for stage II, 31 percent for stage Ill, and 8 percent for stage IV patients [9]. The stage of the cervical carcinoma is the critical prognostic factor. The classification of the Interna- tional Federation of Gynecology and Obstetrics is the most widely accepted classification for staging (Table I). In their annual report of 1979 [lo], stage I cases com- prised 33 percent, stage II cases 35 percent, stage Ill cases 27 percent, and stage IV cases 5 percent. It is of



paramount importance to diagnose disease in its earliest possible diagnosable stage. ideally, the disease should be diagnosed when it is still in stage IA (severe dysplasia or carcinoma in situ) before it advances to invasive carcinoma. This can best be accomplished by serial Pap smears beginning at the age of 20 to 2 1, or even younger in sexually active women. According to the recommenda- tions of the American Cancer Society Task Force, which is the most definitive authority in this area. Pap smears should be repeated every three years for patients between the ages of 20 to 40 and annually thereafter. Pap smears are recommended annually for all symptomatic patients [l 11. A three-year interval for those without evidence of disease or symptoms is appropriate because in general it takes five years for dysplasia to progress to carcinoma in situ. It generally takes IO years to progress from carcinoma in situ to invasive carcinoma. These estimates, which are based on data from large screening studies, are probably on the conservative side [ 121.

After tumor stage, the presence of lymph node involvement is the next most important prognostic factor. Surviv- al is shorter and recurrence rates higher in women with involvement of pelvic or periaortic lymph nodes [ 131. Unfortunately, although staging laparotomy permits more precise detection of lymphadenopathy, it does not result in improved survival with current therapy [ 141. Distant metastases are most commonly encountered in lung (35 percent), liver (29 percent), omentum/peritoneum (25 percent), and gastrointestinal tract (21 percent) and are presumed to occur by hematogenous spread [ 151.

Treatment modalities for all stages of cervical cancer are tabulated in Table II. In general, radiation is delivered with intracavitary cesium-137 implants, but this is aug- mented frequently by irradiation of the entire pelvic region. Dr. Carlos Perez and his associates from our institu- tion have documented better control of stage IIB and IIIA disease with high doses (9,000 rads) of radiation [ 161.

The complications of high-dose radiation include ve- sico-vaginal and rectovaginal fistulas, cystitis, proctitis, and small bowel obstruction. The incidence of these complications is about 7 percent [ 171 in most series. It is remarkable that no complications were observed in this patient despite the intensive radiation. She received 200 rads to the entire pelvic region, 4,000 rads split-field irradiation, an additional 700 rads to the left pelvis, and 16,000 rads to the vaginal apex via intracavitaty implants. The ability to deliver such higher doses without complica- tion underscores the tremendous advances made in radiation therapy and is indicative of the safety and efficacy that can be provided at good radiation oncobgy centers.

The survival of patients with stage IIB, Ill, and IV is dismal (Table II). Radiation therapy has not changed the survival of this group of patients over the past two de- cades. The addition of surgery to radiation also has not resulted in increased survival. Patients with recurrent disease can be treated with chemotherapy, but until recently

TABLE II Treatment Options for Carcinoma of Cervix

Fise-Year Clinical Stage Treatment Option Survival

Dysplasia Carcinoma in situ IA, IA,

IA2

IB, IIA

IIB IIA, IIIB

IV

Cryosurgery, conization 100% Simple hysterectomy lntracavitary radiation versus 95100%

simple hysterectomy Radical hysterectomy f 95%

lymphadenectomy or radiation external and intracavitary

Radical hysterectomy -I bilat- 75% eral lymphadenectomy or radiation

Radiation therapy 50% Radiation therapy f chemo- 30%

therapy Radiation therapy -I chemo- 5%

therapy

TABLE Ill Single-Agent Chemotherapy in Cervical Carcinoma

Drua Percent Overall ResDonse Rate

Alkylating agent Cyclophosphamide Chlorambucil

Antimetabolites 5Fluorouracil Methotrexate

Mitotic inhibitor Vincristine

Other agents Cis-platinum

Antitumor antibiotics Doxorubicin Bleomycin

15 25

20 16

23

44

18 10

Adapted from Young, RC. In: Pinedo HM, ed. Cancer chemotherapy. Amsterdam: Excerpta Medica, 1979; 356.

success has been variable. The agents that have been effective in the treatment of cervical carcinoma are listed in Table Ill. Cis-platinum is clearly the most effective single agent. Its use with other modalities (e.g., radiatiqn) is currently under intensive study. Current data suggest that treatment with ci$platinum alone may be as effective as combination chemotherapy in recurrent cervical cancer.

Surgery or radiation can effectively eradicate stage I disease, and radiation is capable of palliating favorable stage II and Ill disease. However, because the results in recurrent or advanced stages of disease are so dismal, the major thrust of clinical research of late has been towards improving remission rates in patients with advanced stage II, 111, and IV disease. Preliminary results



Figure 2. Apical four-chamber view from the two-dime* sional echocardiogram. Note the large echo-dense mass filling the right ventricle and the echo-free space indicative of a pericardial effusion. The indentation indicated by the arrow is an area of possible tumor infiltration. RV = right ventricle, LV = left ventricle, M = mass, PE = pericardial effusion.

TABLE IV Differential Diagnosis of Echocardiographically Detected Right Ventricular Mass

Primary cardiac tumors Right ventricular myxoma Tricuspid valve papillary fibroelastoma lntramyocardial fibroma

Noncardiac tumors invading the heart Leiomyomata Cervical squamous cell carcinoma Colon carcinoma

Right ventricular thrombus Vegetations associated with infected ventral septal defects

have been optimistic. Initially Piver et al [ 181 and later the Gynecologic Oncology Group demonstrated improved control and prolonged survival after combined treatment with hydroxyurea and radiation than after radiation alone in a randomized trial. Kalra and co-workers [ 191 treated 15 patients with advanced cervical cancer (including four with recurrent disease) with mitomycinC, 5-fluorouracil, and radiation simultaneously with excellent survival at two years. Similar encouraging results have been reported by Wertheim et al [20] in stage IB and IIA patients with poor prognostic factors. After surgery, patients treated with chemotherapy followed by radiation had an 84 percent disease-free survival at two years. These results need to be confirmed by randomized control trials, but they represent promising new approaches to the’treatment of advanced and recurrent carcinoma of the cervix.

This patient had stage IIB disease at presentation. I

suspect her pulmonary lesions were metastatic cervical carcinoma, which is not an uncommon pattern of recurrence. She is precisely the type of patient who needs to be treated with a combination of modalities because of the advanced stage of her carcinoma of the cervix. Dr. Jaffe: Thank you, Dr. Safdar. This unfortunate woman no doubt had pulmonary and hepatic metastases, which are thought to occur through hematogenous spread. The short time (slightly more than one year) from initial diagnosis to the development of metastasis is characteristic [21]. The real question is whether or not the mass that Dr. Barzilai is going to describe is in some way related to metastatic disease or to some other process. Dr. Benico Barzilai: Let me begin by reviewing the 6$hocardiogram. We should focus on three findings: (1) the right ventricular mass; (2) the abnormal septal motion; and (3) the pericardial effusion with deformation of the right ventricle.

On the parasternal long axis view, a large mass is seen in the right veritricle that moves with each cardiac cycle. The border of the mass is echogenic but the center is echolucent. On the short axis view, the mass is again seen in the right ventricle. In addition, the left ventricle has nearly a pancake shape. This is related to the paradoxical septal motion that we will discuss in detail later. The final view is the ,apical four-chamber view, which shows the mass in the,right ventricle very well (Figure 2). The mass appears attached to a chordal structure of the tricuspid valve. There is an echolucent space surrounding the apex of the heart, which is a pericardial effusion. The right ventricle is enlarged with indentation of the free wall of the right ventricle near the apex.

I would like to b&n my discussion with a differential diagnosis of echocardiographicalty detected right ventricular masses (Table IV). This is not meant to be an exhaus- tive list of the causes of right ventricular masses but rather those thus far described in the echocardiographic literature. The first category is primary cardiac tumors. Al- though myxomas are most commonly found in the atria, they can occur in the right ventricle as well. The mass seen in this patient is reminiscent of a myxoma because it is echolucent in the center, a characteristic of myxomas. Other tumors that have been detected by echocardiography are tricuspid valve papillary fibroelastomas and intra- myocardial fibromas.

Noncardiac tumors that can involve the heart include uterine leiomyomata, which grow up the inferior vena cava and invade the right atrium. There is one case report of a cervical squatious cell carcinoma that was detected in the right ventricle by echocardiography. In that case, described in thk American Heart Journal, the ventricular metastasis occurred three and one-half years after radiation therapy of a stage IIA cervical carcinoma. The echocardiographic features of that case were very similar to the case we are discussing today [22]. Finally, there is a



report of a colon cancer that invaded the right ventricle and that was detected by echocardiography.

There also can be nonmalignant causes of right ventricular masses, such as right ventricular thrombus. There has been a recent surge of interest in right ventricular thrombi occurring in the setting of an right ventricular infarction. Echocardiographically, the mass in the current case does not look like a mural thrombus. It is not located in an area of the right ventricle that is hypokinetic, and I would be surprised if this was a thrombus with right ventricular infarction. However, it is possible that part of the right ventricular mass consists of thrombotic material.

For the sake of completeness I should mention vegetations. There have been cases of vegetations in the right ventricle associated with infected ventral septal defects, particularly in children”

I next want to review the paradoxical septal motion. A representative portion of the M-mode echocardiogram is shown in Figure 3. As opposed to the posterior wall, which is moving toward the septum as it thickens, the first motion of the septum during systole is anterior or away from the posterior wall. This is termed paradoxical septal motion. Paradoxical septal motion may be related to abnormalities of the left ventricle. For example, it is possible that this patient had an anteroseptal infarction with resultant dyskinesis of the septum. I think that the waif thickens appropriately. I do not think that this is the situation in this case. I will limit ,my discussion to right ventricular causes of paradoxical septal motion. Right ventricular enlargement with paradoxical septal motion is termed right ventricular volume overload and is commonly associated with atrial septal defects, tricuspid regurgita- tion, and/or anomalous pulmonary venous return. In addition, this pattern of septal motion can also be seen with right ventricular pressure overload. Dr. Jaffe has already commented that the right-sided pressures would have been markedly elevated in this patient if the cardiac output had been normal. Consequently, I believe that this septal pattern is probably related to right ventricular pressure overload.

Finally, I would like to comment on the pericardial effusion. Although we observe pericardial effusions frequently in the echocardiographic laboratory, the feature that was unusual about this case was the associated indentation of the right ventricular apex, which is highly suspicious of involvement of the tumor in the right ventricular free wall. It most likely represents metastases growing from the pericardial space into the heart itself. Dr. Jaffe: It is not uncommon for there to be metastatic disease to the heart. If one looks at large series, the tumors most apt to metastasize to the heart are broncho- genie carcinomas, breast carcinomas, malignant melano- mas, and acute leukemias [23]. One has to search assidu- ously to find case reports similar to this one with what was thought to be a solitary metastasis [22,24]. If one search-

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es enough, there is a tabulation of autopsy series with an incidence of cardiac metastasis for all tumor types of about 4 percent. Of all the masses reported, there are five cases of cervical cancer metastatic to the heart. If one totals the results of series of patients with invasive cervical carcinomas, one can find 11 cases of metastatic disease to the heart [24]. Of the cases where the morphology is really well described, only three including our case today, involve the right side of the heart.

How does cervical carcinoma get to the heart? Is it by hematogenous or lymphatic spread? The majority of data concerning the access tumors have to the heart concerns breast and lung carcinomas. It suggests that tumors in- variably metastasize to the heart via lymphatics and that hematogenous spread, at least with the common tumors, is very unusual. In one series, only 10 of 61 instances of disease metastatic to heart occurred via hematogenous spread [25]. Given that she had pulmonary metastases and that the tumor appears to involve at least the epicardi- al surface of the heart, I have to surmise that the tumor most likely reached the heart via lymphatics or contiguous spread.

I think what is in the heart is at least in part tumor, but it also could be thrombus, albeit with an atypical appearance. There are two ways a thrombus might get there. A thrombus could occur in the periphery and cases have been described in which right heart thrombi have come from the periphery [26]. In this case, I would think of a possible pelvic source, given her history of tumor infiltration and radiation therapy. Emboli that lodge in the right heart can be very large but rarely appear attached to the heart. In addition, patients with right ventricular infarction can have clots in the right ventricle. Jugdutt and co-



cardiomegaly, widespread nodular densities in both lungs, and fracture of the left eighth rib associated with bone destruction.

workers [27] recently reported that six of 17 consecutive patients with right ventricular infarction had right ventricular clots. But this woman’s electrocardiogram does not show an inferior infarct. Recently, there was a report of a patient with right ventricular infarction who had electrocardiographic findings of anterior infarction and a total anterior descending coronary occlusion. Presumably, extensive involvement of the posterior portion of the septum, i.e., the right ventricular part, evoked a clinical syndrome very similar to right ventricular infarction [28]. There were changes of an inferior infarction as well in that case; however, pathologically the infarction was predominantly anterior. I do not think that this patient had an infarction at all, but since this diagnosis cannot be excluded definitively, neither can a very atypical presentation of a right ventricular mural thrombosis associated with it.

It seems to me that the crux of the differential diagnosis in our patient is whether the mass in the right ventricle is tumor alone, tumor and thrombus, or thrombus alone. I have asked Dr. Semenkovich to look at the chest radiograph and nuclear medicine studies and tell us if one can distinguish radiographically between tumor, clot, and, for our education, entities such as septic and fat emboli as well. Dr. Janice Semenkovich: The admission chest radiograph demonstrates cardiomegaly, which is new com- pared with findings on a chest radiograph obtained 14 months earlier (Figure 4). There has been during the interval development of widespread nodular densities in both lungs and a fracture of the left eighth rib; the fracture is associated with bone destruction, suggesting that it is a pathologic fracture. The technetium-99m diethylenetria- mine pentaacetic acid aerosol images from the patient’s lung scan show markedly inhomogeneous distribution of

the tracer (Figure 5). There is significant central bronchial hyperdeposition of the radiopharmaceutical, a finding most consistent with bronchial disease. The alveolar deposition of the radiopharmaceutical also is inhomogenous, with the most marked areas of decreased activity at both lung bases. The perfusion images show multiple, bilateral, medium and large perfusion defects (Figure 6). Because of the significant radiographic and ventilatory abnormalities, it was not possible to define any perfusion defect that is unequivocally associated with normal lung. Therefore, interpretation was somewhat difficult. How- ever, it was noted that pulmonary embolism was likely because of the multiplicity, segmental nature, and large size of the perfusion defects.

There are a number of different types of emboli, including thrombotic, tumor, and septic and fat emboli. In many cases, the etiologic type is obvious because of the patient’s clinical history and/or physical findings. I will discuss briefly whether it is possible to utilize radiographic and scintigraphic findings to help differentiate among the various types of emboli in cases in which the clinical diagnosis is not so apparent.

The radiographic features of thrombotic pulmonary emboli are neither sensitive nor specific. The lower lobes tend to be more affected than the upper lobes, in keeping with the increased flow to the lower lobes. In cases of pulmonary embolism without infarction, focal or general- ized oligemia may be present, Which is also known as Westermarkls sign. Enlargement of the pulmonary artery due to distension from thrombus may occur, and with massive pulmonary embolism, cardiac enlargement may also occur, reflecting acute right ventricular dilatation. Loss of lung volume is another frequent radiographic finding. In cases of pulmonary embolism with associated infarction, additional findings may include the typical “Hampton’s hump” or pleural effusion [29].

The scintigraphic features of thrombotic pulmonary embolism have been well described [30]. Multiple segmental or subsegmental perfusion defects without corre- sponding radiographic abnormalities are associated with a high likelihood of pulmonary embolism. Matched ventilation and perfusion abnormalities are unlikely to represent pulmonary emboli.

Most patients with lymphangitic spread of carcinoma are classically described as having an interstitial or reti- culo-nodular pattern on chest radiographs; these radiographs may be abnormal in up to 20 percent of cases [31]. These patients typically present with severe dyspnea that may stimulate the presentation of pulmonary embolism. Several authors have suggested that ventilation-perfusion imaging may be very helpful in suggesting the possibility of tumor microemboli and lymphangitic carcinomatosis in these patients. The scintigraphic pattern described with tumor microemboli and lymphangitic spread is distinctly different from that seen with typical



aal hyperdeposition of the radiopharmaceutical and decreased activity at both lung bases.

thromboembolism. Perfusion images manifest a larger number of small defects that are generally located more in the periphery. The typical lower lobe predominance of thrombotic pulmonary emboli is not seen; perfusion defects are randomly distributed throughout both lungs [32- 34]. Sostman et al [35] have also described another unusual feature of perfusion lung scans in these patients, the so-called “contour mapping” of the pulmonary segments. In their report, patients who had tumor microemboli or lymphangitic carcinomatosis were identifiable by small perfusion defects that outlined the bronchopulmon- ary segments. It should also be noted that larger tumor emboli occasionally may occur and simulate thrombotic emboli scintigraphically.

In contrast to patients with bland thrombotic emboli or tumor emboli in whom plain radiographs are frequently normal, patients with septic emboli virtually always have distinctly abnormal chest radiographs early during the course of their disease. Thus, nuclear medicine imaging usually does not provide any additioinal information [36]. Chest radiographs generally demonstrate multiple round- ed, ill-defined densities in the periphery of the lung. These densities may develop all at once are sequentially and

Figure 6. Perfusion images showing multiple, bilate medium and large perfusion defects.

may be uniform or variable in sire. Although cavitation is uncommon with bland thrombotic emboli, it is frequent with septic emboli and can occur rapdily. Thus, the chest ratiograph is frequently the best tip-off that septic emboli are present.

The initial chest radiographs in patients with fat emboli are usually normal. Radiographs then may progress to widespread air space consolidation, which tends to be peripheral and basal in distribution. In a study of patients with the fat embolism syndrome, 70 percent had abnormal pulmonary perfusion images; these changes occasionally preceded other manifestations [37]. In the same series, perfusion defects were typically small and multiple, resulting in a mottled appearance of the image. This appearance, which corresponds to that seen in other published cases of fat emboli, is explained by the fact that fat globules in the blood of patients with fat embolism are small (40 to 80 ,u in diameter) [38,39]. The appearance of perfusion images in patients who have fat emboli depends on whether the patient is studied early or late in the course of the disease. If the patient is studied late, when chemical pneumonitis is present, larger perfusion defects are seen.

In summary, it is frequently difficult to discern the



Figure 7. Gross anatomy of the left and right ventricles. There was a localized deformity of the right ventricular free wall(/ower arrow) due to tumor infiltration of the moderator band, anterior papillary muscle, and tricuspid valve that were encased in tumor (upper arrow). R V = right ventricle, LV = left ventricle, VS = ventricular septum.

etiology of an embolic event on the basis of radiographic or scintigraphic findings alone. In the case under discussion, rib destruction on the chest radiograph suggests the diagnosis of malignancy, but the scintigraphic findings are more typical of thrombotic rather than tumor emboli. Dr. Jaffe: I was confounded initially after reading this case because it became clear that the emboli ought to be pulmonary emboli and yet I did not want to say that the mass we saw in the right ventricle was thrombus. I then came across a case from the New England Journal of Medicine in which carcinoma of the tongue metastasized to the heart. It turns out that carcinoma of the tongue has a predilection to metastasize to heart. In that circumstance, the tumor eroded through the cardiac wall and formed the nidus for thrombus formation. The patient then died of multiple pulmonary emboli formed on the tumor [40]. Thus, I would like to suggest that we shall find active cervical carcinoma in the pelvis and that metastases will be present in the ribs, lungs, epicardium, pericardium, and probably in the endocardium as well. Because of the extensive pulmonary involvement, I believe that the metastases came from the lungs, likely through lymphatic or

contiguous spread. It is also possible that the cardiac metastases induced some functional tricuspid stenosis that would validate the hemodynamic findings. But the immediate cause of death was most likely pulmonary thromboemboli, probably from a nidus on the right ventricular tumor metastasis.

PATHOLOGIC DISCUSSION

Dr. Jeffrey Saffitz: At autopsy, metastatic epidermoid carcinoma was observed in the heart, the visceral and parietal surfaces of the pericardium and pleurae, the diaphragm, and the thoracic cage, including the left eighth rib. Below the diaphragm, tumor was found in a calyx of the left kidney, in the left adrenal, and in the periureteral soft tissue on the left side. No residual tumor was identi- fied in the pelvis, although considerable radiation effect was seen.

Multiple pulmonary thromboemboli and recent pulmonary infarcts were observed bilaterally. The emboli were impacted primarily in the small and medium-sized pulmonary arteries; the major segmental branches were not involved. Pelvic veins were thickened and hyalinized as a result of the previous radiotherapy, but they contained no thrombi. The presumed source of the pulmonary thromboemboli was the deep veins of the left calf, which were occluded by thrombus.

Tumor involving the mesothelial surfaces of the pericardium and pleurae grew as discrete masses with mini- mal vision. Modest bilateral serous pleural effusions were present. Approximately 200 ml of serous fluid was present in the pericardial space, an amount insufficient to significantly impair right ventricular filling.

The pathologic anatomy of the heart correlated with the echocardiographic and electrocardiographic findings. Ex- amination of the external configuration disclosed a localized deformity of the right ventricular free wall roughly midway between the ‘apex of the heart and the right atrioventricular groove (Figure 7). On cut surface, the moderator band, the anterior papillary muscle of the tricuspid valve, and a circumscribed transmural region of the right ventricular free wall were virtually replaced by dense grey-white fibrous tissue. Microscopically, these regions contained metastatic epidermoid carcinoma growing in small nests and cords of cells surrounded by densely fibrotic desmoplastic stroma. Bundles of residual myocardium were seen coursing through the dense stroma (Figure 8). Microfocal mural thrombus was observed on the right ventricular endocardial surface, but a large mobile mural or pedunculated thrombus, as suggested by the two-dimensional echocardiogram, was not observed.

In the lungs, tumor was widely distributed in a pattern indicative of lymphangitic spread. However, the extensive but highly localized right ventricular tumor mass suggests hematogenous metastasis via the moderator band artery. The moderator band, a distinct muscle band that connects



the ventricular septum and the right ventricular free wall, originates at the apical limit of the septal band of the crista supraventricularis and inserts on the free wall at the base of the anterior papillary muscle. In most individuals, the moderator band contains a branch of the right coronary artery that supplies the anterior papillary muscle and free wall in the same distribution observed to be replaced by tumor in this case. Thus, the pattern of metastatic tumor involvement of the right heart strongly suggests hematogenous metastasis via the moderator band artery. The moderator band also supplies a major branch of the right bundle of the cardiac conduction system. Destruction of the moderator band by tumor accounts for the recent development of right bundle branch block in this patient.

Despite echocardiographic evidence of a freely mobile mass in the right ventricle and the expectation that a right ventricular mural thrombus would be found, no such thrombus or mobile mass was discovered at autopsy. It is possible that the echocardiographic appearance was cre- ated by abnormal movement of the involved portion of the right ventricular free wall. Fibrous distortion of the anterior papillary muscle and moderator band may have caused the free wall at the base of the anterior papillary muscle to undergo abnormal, exaggerated excursion into the chamber during the cardiac cycle. Alternatively, thrombus with or without tumor may have been present before death, simulating the appearance of a mass but embolizing to the

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Cardiovascular collapse and death in a 55-year-old woman with cervical cancer