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(Circulation. 1995;91:882-896.)
© 1995 American Heart Association, Inc.
Articles |
A 69-Year-Old Woman With Recurrent Symptomatic Pleural Effusions
From the Texas Heart Institute (R.H.), St Luke's Episcopal Hospital; and the Departments of Internal Medicine (Division of Cardiology) (A.V., R.S., E.B.), Radiology (P.C.), and Pathology and Laboratory Medicine, and Cardiology (L.M.B.), The University of Texas Medical School at Houston, The University of Texas-Houston Health Science Center (Houston).
Key Words: Clinicopathological conference • radiation
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Case Presentation |
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History
The patient is a 69-year-old woman from Venezuela who was referred for evaluation of chronically recurring symptomatic pleural effusions. She had a history of stage II invasive ductal carcinoma of the left breast treated with mastectomy and radiation therapy in 1982, autoimmune cholangitis, and severe osteoporosis.
On admission, the patient had bilateral pleural effusions and complained of severe dyspnea on exertion. She could not walk further than 20 ft without severe shortness of breath. The patient noted that the dyspnea improved with laying flat in bed. She also complained of a chronic nonproductive cough and bilateral swelling of her lower extremities. She had no complaints of chest pain, sputum production, fever, or night sweats. She did note a 15-lb weight loss over the previous 6 months.
The patient's evaluation had begun before this admission, in part in Venezuela as well as in our medical center. The patient had undergone several thoracenteses, all of which produced fluid characterized as a transudate that was negative for malignancy and infectious disease. Pleural biopsy likewise was nondiagnostic, revealing fibrosis and mesothelial hyperplasia. Pulmonary function tests revealed mild airway obstruction in May 1993 and August 1994. There was significant improvement in airway mechanics after inhalation of a bronchodilator. The diffusion capacity for carbon monoxide was substantially reduced to 49% of predicted in 1994, whereas the diffusion limit for carbon monoxide (DLCO) was 81% of predicted in 1993.
Cardiac catheterization performed in February 1994 revealed normal coronary arteries. Multiple gated acquisition (MUGA) radionucleotide ventriculography revealed an ejection fraction of 65%. Echocardiogram was reported to show that the left and right ventricles were normal in size and systolic function, the left atrium was mildly dilated, and there was minimal mitral regurgitation and no pericardial effusion.
The patient's past medical history revealed she had breast cancer in 1982 and was treated with mastectomy and radiation therapy. She was known to have osteoporosis with kyphosis secondary to vertebral compression fractures. She was also diagnosed to have autoimmune cholangitis associated with a serum anti-nuclear antibody (ANA) of 1:2560 with a anticentromere pattern. All other serum antibody levels were negative, and the complement levels were normal. She had a liver biopsy in May 1993 that was reported to show bridging fibrosis and early cirrhosis. She had a history of previous hepatitis B infection. She had experienced recurrent pleural effusions since 1985.
The patient's past surgical history included a mastectomy, an appendectomy, and removal of an ectopic pregnancy. Her present medications were 300 mg ursodiol as prescribed, 100 mg allopurinol QD, 5 mg/2.5 mg prednisone QOD, 50 mg Aldactone BID, 90 mg verapamil QD, potassium chloride as prescribed, and 80 mg furosemide QD.
Physical Examination
The patient's temperature was
96.8°C; blood pressure,
100/70 mm Hg, pulse paradoxus, 6 mm Hg; heart rate, 95 beats per
minute; and respirations, 16. The patient was a well-developed,
well-nourished woman in no acute distress who was alert and oriented.
Examination of the head, eyes, ears, nose, and throat were
normocephalic, atraumatic, and extraoccular. The nose and throat were
clear, and the tongue was normal in size. Scratch purpura was absent.
There was jugular venous distention to the mandible with the patient
sitting upright secondary to engorgement of jugular veins. No Kussmaul
sign or x and y descent were appreciated. The carotid pulses were full
without bruits. There was no palpable lymphadenopathy. The patient's
chest revealed a mastectomy scar and thickened skin over the left
chest. Marked kyphosis was present. Her lungs showed decreased
breath sounds at each base and dry friction rub one half the way up on
the left side of the chest. On cardiac examination, the point of
maximal impulse was not palpable. The S1 and S were normal.
An early diastolic sound was heard but without thrills or heaves. Her
abdomen was soft and nontender; the liver span was 6 cm. There was no
splenomegaly. The bowel sounds were normal. She had 2+ pitting edema of
the lower extremities. The pulses were 1+ bilaterally.
Initial Diagnostic Studies
The ECG showed low voltage in the
standard leads, sinus
tachycardia, left atrial enlargement, and nonspecific ST-T–wave
abnormalities (Fig 1
). The chest radiograph showed left
breast absent, multiple compression fractures in thoracic spine T6-T8,
bilateral pleural effusions, thickening of major fissures bilaterally,
calcified aortic knob, no significant enlargement of the pulmonary
arteries, and heart size within normal limits (Fig 2).
Results of several tests were obtained from the clinical pathology
laboratory (Table 1). Additional diagnostic studies were
then performed.
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Clinical Discussion (Robert J. Hall, MD, Director of Education, The Texas Heart Institute, St Luke's Episcopal Hospital) |
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 TopCase Presentation  Clinical Discussion (Robert J.... Summary Radiological Findings (Phebe...Echocardiographic Findings (Eddy...Diagnostic Cardiac...Pathological Findings (L....Final Diagnosis References |
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The patient is a 69-year-old woman who underwent mastectomy and irradiation for carcinoma of the breast in 1982. The thickened skin over the left chest is evidence of heavy radiation as part of her treatment after mastectomy. There is no history of concomitant chemotherapy. Also, she has had a diagnosis of "autoimmune cholangitis."
Her current evaluation was for severe exertional dyspnea and recurrent pleural effusions. She has undergone several thoracocenteses, and these were nondiagnostic; the fluid was characterized as a transudate, and a pleural biopsy was nonspecific.
The significant physical findings included marked elevation of the jugular venous pressure to the level of the mandible with the patient seated upright. The degree of elevation of the right-sided filling pressure would be seen in superior vena cava syndrome, advanced congestive heart failure, pericardial effusion and tamponade, and constrictive pericarditis. A superior vena cava syndrome secondary to malignant obstruction is possible in this patient. However, there is evidence of liver enlargement and lower extremity edema, and I expect there is elevation of both superior and inferior vena caval pressures. Also, on radiography, there is no evidence of a tumor mass in the region of the superior vena cava in the right mediastinum. Advanced congestive heart failure would be accompanied by marked elevation of the jugular venous pressure. There is, however, no evidence of advanced myocardial failure. The heart appears normal in size on chest radiography, the left ventricular ejection fraction by MUGA scanning is 65%, and the echocardiogram is reported to reveal normal size and systolic function of both the left and right ventricles. In addition, coronary angiography is reported to have disclosed normal coronary arteries without significant obstruction. All these features are evidence against the possibility of advanced congestive heart failure.
Pericardial effusion and tamponade would cause marked elevation of the jugular venous column. This is usually accompanied by a significant pulsus paradoxus and by a positive Kussmaul sign. The absence of a significant collection of pericardial fluid on echocardiography excludes pericardial tamponade.
Constrictive pericarditis classically causes marked elevation in the jugular venous pressure, together with hepatomegaly, ascites, and peripheral edema, presenting signs that mimic heart failure but are the result of the presence of external constriction rather than myocardial dysfunction.1
The description of an early diastolic sound is helpful. There are four early diagnostic sounds: the opening snap of mitral (or tricuspid) stenosis, the third heart sound of left or right heart failure, the tumor sound of a mobile atrial tumor, and the pericardial knock sound heard in constrictive pericarditis. The mitral opening snap is a high-frequency sound that is usually distributed widely over the chest and almost always present in patients with rheumatic mitral stenosis. There is no recorded evidence of murmurs, and although silent mitral stenosis is a possibility, this is excluded by the absence of any echocardiographic evidence of rheumatic valvular involvement.
A third heart sound or ventricular diastolic gallop is a low-frequency sound that is not usually widely radiated. It accompanies ventricular failure or other states with high output or rapid atrioventricular filling. The third heart sound of left ventricular origin is best heard at the apex over the point of maximum intensity. A third heart sound is unlikely since there is no evidence of congestive heart failure or ventricular dilatation or valvular dysfunction on MUGA or echocardiography. A tumor sound (the "tumor plop") is also unlikely because there is no suggestion of an intracardiac tumor on two-dimensional echocardiography. The early diastolic sound therefore must be the pericardial knock sound of constrictive pericarditis. A pericardial knock is a loud, high-frequency sound heard 0.06 to 0.12 second after the second sound and is widely distributed over the precordium. This sound is present in more than two thirds of patients with constrictive pericarditis, is frequently palpable, and is often the loudest of the cardiac sounds. It is frequently mistaken for an opening snap when it is first heard.
The presence of bibasilar rales and rub on the left would indicate continued pleural and perhaps parenchymal involvement and evidence of active pleuritis at the time of the examination. The liver span of "6 cm" is bothersome. This is too small for even a normal liver, and I suspect the protocol really meant that the liver was enlarged 6 cm below the costal margin; at least, this would better fit my diagnosis. I also expect ascites to be present; none is described. There is two+ pitting edema of the lower extremities.
The ECG reveals a regular sinus rhythm and a left atrial abnormality, suggesting atrial enlargement. The QRS complexes are of low voltage, and nonspecific ST-T changes are present. An interatrial conduction defect is quite common in constrictive pericarditis, as is low voltage of the QRS complexes. The latter finding is also commonly seen with amyloid infiltrative disease of the myocardium.
Review of the chest radiographs demonstrates bilateral pleural effusions, which progress and develop rapidly. There is thickening of the fissures, and there is a suggestion of Kerley lines, especially in the right lung base, which would raise the question of possible mitral stenosis, which I have already ruled out, or the possibility of recurrent breast cancer with lymphangitic spread in the lung. This seems unlikely in the face of pleural transudates and a nonspecific pleural biopsy. The chest radiograph, at least on several of the studies, reveals what appears to be a normal size heart.
The echocardiogram, which I have already commented on, reveals normal ventricular size and ventricular systolic function. No significant hypertrophy, valvular disease, or pericardial effusion is present. The echocardiogram per se is a poor imaging technique for determining thickness of the pericardium, although there are mitral inflow Doppler findings that are quite characteristic of constrictive pericarditis.1
The physical and associated findings that this patient are most consistent with the diagnosis of constrictive pericarditis. The severe dyspnea, elevated jugular venous pressure, peripheral edema, absence of valvular and myocardial disease, chronic pleural effusions and hepatomegaly all fit this diagnosis.
The possible causes of constrictive pericarditis include infectious etiologies, neoplastic diseases, radiation-induced pericardial disease, and hypersensitivity or collagen-vascular pericardial diseases.1 There is no evidence to favor an infectious etiology, especially because other causes are more likely. Neoplastic disease is always a possibility, and recurrent carcinoma of the breast may involve the lung, pleura, and pericardium. The chest radiograph, to some degree, raises the possibility of lymphangitic spread to the lung, but as I have indicated, the pleural effusions were a transudate and not an exudate and the pleural biopsy was nonspecific and showed no evidence of recurrent malignancy.
Radiation-induced pericardial disease is a strong possibility. There is usually a latency period of 50 to 300 months, and the process is frequently an effusive-constrictive process in the early stage and then constrictive without effusion in the later stage. Most of the experience gathered with this diagnosis has been following the treatment of patients with Hodgkin's disease, usually following anterior ports of radiation exceeding 3000 to 4000 rads. The etiology of radiation-induced pericardial disease is not clear but includes damage to the microcirculation, reactivation of a latent viral infection, and/or damage to the pericardial lymphatics. It occurs more frequently in patients who have had adjunctive chemotherapy, and there is usually concomitant involvement of the pulmonary parenchyma and pleura. Radiation injury to the heart is not confined to the pericardium but also causes myocardial changes, including myocardial fibrosis and endocardial changes, especially in the cardiac valves.2 3 The coronary arteries may also be injured, and radiation is a cause of accelerated or premature atherosclerosis.4 The visceral pericardium in postirradiation constrictive pericarditis may be difficult to resect surgically, and the surgical outcome is frequently disappointing.5 6
Hypersensitivity and collagen-vascular diseases are also causes of pericardial disease.1 6 Pericardial involvement in rheumatoid arthritis is common and is seen in as many as 30% of patients at necropsy. Constriction requiring surgery is infrequent but has been reported. Systemic lupus erythematosus almost universally involves the pericardium and frequently causes large effusions and tamponade but rarely results in constrictive pericarditis. Systemic sclerosis (scleroderma) more commonly includes involvement of the myocardium, yet involvement in the pericardium to some degree occurs in 50% of patients.7 8 Constrictive pericarditis can occur late and may require surgical removal. The CREST syndrome (calcinosis, Raynaud's phenomena, esophageal dysfunction, sclerodactyly, and teleangiectasia) has also been reported to involve the pericardium, producing severe effusion with tamponade.9,10 In the CREST syndrome, the pulmonary microcirculation can also be involved, and patients with severe pulmonary hypertension have been reported.11
Infiltrated diseases such as amyloid of the heart present as a restrictive cardiomyopathy, and this may mimic constrictive pericarditis; heart failure, markedly elevated venous pressure, and low-voltage QRS on the ECG are common. The echocardiogram reveals evidence of diastolic dysfunction with increased myocardial thickness, with a very reproducible granular sparking on two-dimensional echocardiography. In addition, there is considerable cardiomegaly on radiography. I do not believe this patient had amyloid disease.12
Some discussion of the antinuclear antibodies is in order.13 The patient is reported to have a titer of 1:2560 with a anticentromere pattern. The anticentromere pattern14 15 is found in more than 75% of patients with CREST syndrome,16 in 22% of patients with systemic sclerosis (scleroderma),17 and in 12% of patients with primary biliary cirrhosis.18 19 Our patient demonstrated a negative antimitochondrial antibody titer with elevated antinuclear antibodies, consistent with the syndrome of autoimmune cholangitis.20 Regarding her other antibody studies, she is reported to have negative anti-dsDNA, which is specific for systemic lupus erythematosus; negative anti-Ro, which is detected in 95% of patients with the Sjogren's syndrome; negative anti-LA, which is found in patients with primary and secondary Sjogren's syndrome; and negative anti–smooth muscle antibodies, which are specific for systemic lupus erythematosus. Her hepatitis antibodies also appear to indicate an absence of current viral hepatitis as well as an immunity to hepatitis.
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Summary |
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I believe this patient has constrictive pericarditis with evidence of pleuritis and pulmonary fibrosis. Two possibilities exist: postirradiation injury of the pericardium of pleura and lung and the CREST syndrome. With regard to the latter, her examination disclosed none of the clinical indicators of the CREST syndrome (calcinosis, Raynaud's, esophageal symptoms, sclerodactyly, or telangiectasia), and therefore the positive anticentromere antibody pattern is likely associated with her primary biliary cirrhosis.19 I believe therefore that she has postirradiation pericardial and lung disease. It remains possible that there is an associated autoimmune process going on and that this is a secondary operative factor or that the two coexist.
The studies that will be performed are right- and left-side catheterization, which will show elevated filling pressures on the right and left sides of the heart with a monotony of diagnostic pressures, the early diastolic dip-and-plateau characteristic of constrictive pericarditis, pulmonary and right ventricular systolic pressures to not exceed 50 mm Hg, and the diastolic pressure in the right ventricle to be equal to or more than one third of the diastolic pressure. I believe they will also perform a computed axial tomography scan21 or magnetic resonance imaging (MRI) to characterize the thickness of the pericardium. The ultrafast cine computed tomography (CT) scan is more effective in demonstrating the thickening of the pericardium because of the more rapid acquisition of the images and the ability to characterize pericardial thickness without interference from the moving heart.23 MRI is also an effective technique for demonstrating the thickness of the pericardium.22 24
Surgical resection is a treatment of choice, but the outcome is not always favorable. Postirradiation pericarditis presents a form of pericardial fibrosis and scarring that is very difficult to "peel" surgically. In addition, there is often associated myocardial involvement, and both of these features tend to produce a continuation of symptoms even after surgical resection of the pericardium.5 6 Also, the involvement of the pleura and pericardium foster continued symptoms even after successful surgical pericardiectomy.
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Radiological Findings (Phebe Chen, MD, Assistant Professor of Radiology) |
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The admission chest radiograph (Fig 2
) showed bilateral
pleural
effusions. Abnormal linear densities in the left lower lung associated
with pleural thickening were most likely related to prior radiation and
appeared stable for the past year. These chronic changes of the left
lung were seen on a CT scan of the chest (Fig 3)
performed 8 months before admission. A repeat CT scan obtained the day
after admission (Fig 4) showed bilateral pleural
effusions and a pericardial effusion. There was no evidence for
metastases. An MRI was performed 1 week after admission (Figs 5
and 6). This showed a thickened and
shaggy pericardium and enlarged atria with relative narrowing of the
ventricles. The pulmonary arteries were normal in size.
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Echocardiographic Findings (Eddy Barasch, MD, Assistant Professor, Department of Internal Medicine, Division of Cardiology) |
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TopCase Presentation Clinical Discussion (Robert J....Summary Radiological Findings (Phebe...Echocardiographic Findings (Eddy...Diagnostic Cardiac...Pathological Findings (L....Final Diagnosis References |
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We reviewed two echocardiographic studies. The first one, done 18 months before the patient's present admission, showed normal size and function of the both ventricles and mild left atrial dilatation. Pericardial thickness was appreciated as normal. The Doppler study was normal. A second study was performed after surgery. The possibility of residual constriction was considered.
The assessment of pericardial thickness by M-mode or two-dimensional echocardiography is not very accurate, and the value of transesophageal echocardiography for this diagnosis has yet to be determined. The severe limitation of diastolic filling makes every change in volume and pressure in one ventricle accurately reflected in the opposite direction in the other ventricle. Because the right ventricle compliance is higher than the left ventricle compliance, every volume change in the right ventricle is transmitted to the left ventricle.
On M-mode echocardiography, abrupt middiastolic left ventricular filling cessation is suggested by middiastolic flatting of left ventricular posterior wall.25 26 Atrial systole and its ventricular volumetric contribution are diagnosed by the late diastolic dip on interventricular septum motion, and increase in middiastolic pulmonary artery pressure is suggested by diastolic opening of pulmonic valve.27 28 More recently described, Doppler signs of constriction are related to the diastolic filling changes in both ventricles with respiratory phase.29 30 Inspiratory decrease of pulmonary wedge pressure will subsequently diminish the pulmonic vein–left atrium gradient and therefore delay mitral valve opening, prolonging isovolumetric relaxation time by approximately 50%. The mitral valve peak E velocity will manifest an inspiratory decrease by a mean >30% with a reciprocal increase of peak E velocity of the tricuspid valve by similar values. Inspiration will decrease peak systolic aortic flow, slightly increasing the peak pulmonary systolic flow. The inferior vena cava will be dilated with lack of inspiratory collapse and hepatic venous flow will exhibit a prominent atrial systolic reverse flow, keeping the same relation between forward systolic and diastolic flow waves (x and y, respectively).31 32
The second echocardiographic study showed an inspiratory decrease in
peak E velocity of the mitral valve by 20% and an increase in peak E
velocity of the tricuspid valve by 34% (Figs 7 and
8).
The hepatic vein pattern displayed an inspiratory increase in systolic
reverse wave, A wave, and deep Y wave, suggesting a restrictive pattern
of right ventricular filling (Fig 9). Therefore, we
diagnosed a mixed diastolic filling pattern of constriction and
restriction, which could be compatible with some residual pericardial
constriction and with radiation-induced myocardial fibrosis.
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Diagnostic Cardiac Catheterization (Annie Varughese, MD, Cardiology Fellow, Department of Internal Medicine, and Richard Smalling, MD, Professor) |
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Right-side heart pressures were measured with a fluid-filled Swan-Ganz catheter with transducer setting of zero at the midchest. Left-side heart pressure was measured with a pigtail catheter placed in the left ventricle. The pressures were recorded on a multichannel recorder with paper speed of 50 to 100 mm/s. The patient was not exercised in the cardiac catheterization laboratory. The data obtained at cardiac catheterization were interpreted as evidence of cardiac constriction (Table 2
, Figs 9 through
12).
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No significant obstructive disease was noted in the left main, left anterior descending, left circumflex, or right coronary artery. The left circumflex coronary artery was noted to be tortuous. An endomyocardial biopsy was performed, with postbiopsy right ventricular pressure documented at 38/24 mm Hg (no significant change from before the biopsy).
The patient subsequently underwent pericardiectomy 3 days after
cardiac catheterization. Findings at surgery were as follows: extremely
dense and constrictive pericardium and epicardium, approximately 100 mL
of bloody pericardial effusion, and systolic blood pressure increased
with release of pericardial tension from 90 to 120 mm Hg. The
patient's hemodynamic parameters after surgical intervention showed
improvement (Table 3).
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The patient's signs of jugular venous distention and pedal edema improved initially, but dyspnea was not totally resolved as her right pleural effusion recurred and subsequently necessitated two additional hospital admissions for evaluation of the unresolving dyspnea. The question was raised as to whether the patient had a restrictive physiological component to her symptomatology.
The differentiation of constrictive versus restrictive disease has been a challenging and often difficult task with the use of hemodynamic data alone. In 1976, Meaney et al33 examined the similarities and differences of patients with constrictive versus constrictive disease. The similarities were impaired ventricular filling and no clinical, plain radiological, or ECG features that were pathognomonic.
Chest radiographic calcification of pericardium was seen in only 50% to 70% of constrictive disease patients, and cardiomegaly was not helpful in that 30% to 60% of patients with constrictive disease had an enlarged heart (usually expected to be small), whereas amyloid cardiac silhouettes were not necessarily increased (against what would be expected). The ECG in pericardial constrictive disease reveals P mitral, low voltage, atrial fibrillation, and T-wave abnormalities, whereas in myocardial restrictive disease one expects to see QRS abnormalities and conduction disturbances. However, pericardial constriction may reveal similar findings to restrictive disease with QRS abnormalities suggestive of myocardial infarction as well as conduction disturbances. In 1973, Levine34 obtained similar data regarding these ECG findings.
Meaney and coinvestigators found the similarities and differences between constrictive and restrictive disease to be such that determination of the exact diagnosis was often difficult. Hallmarks of both pericardial disease and constrictive disease are the square-root sign in the cardiac catheterization laboratory, an early diastolic dip and plateau in right and left ventricular filling pressures due to the absence of impediment to ventricular filling in early diastole and stiffened pericardium that abruptly checks further flow (in constrictive disease) or is due to the physical properties and distribution of the infiltrative process in the myocardium (in restrictive disease). The square-root sign is abolished with tachycardia and often due to ventricular suction, described as a diastolic force created by elastic recoil of the ventricular mass that expands left ventricular volume in early diastole faster than blood can enter it. These investigators also noted that the right ventricular end-diastolic pressure increased with inspiration in both constrictive and restrictive disease. Right atrial and pulmonary capillary wedge pressure tracings were noted to have the M pattern created by a rapid Y descent (exaggerated and abruptly terminating right atrial emptying after tricuspid or mitral valve opening) in both constrictive and restrictive disease. Left ventricular systolic function was found to be either normal or abnormal in both disease processes.
Both constrictive and restrictive disease revealed increased left ventricular stiffness as measured by plotting volume versus log of pressure. It was noted that operational compliance or maximal stiffness changes little from the end of rapid filling to end diastole. One fairly consistent difference between constrictive and restrictive disease was that of diastolic pressure measurements between the left and right ventricles. Constrictive disease revealed left and right ventricular end-diastolic pressures to be elevated and essentially equal at rest, with a difference range of 0 to 5 mm Hg. Restrictive disease revealed a left ventricular end-diastolic pressure differential of more than 5 mm Hg, with a greater reduction in left ventricular diastolic compliance. This differential was noted to increase with exercise. The investigators stressed the importance of obtaining left and right ventricular pressures simultaneously, as was done in our patient. The investigators also noted that despite the introduction of left-side heart catheterization and quantitative left ventriculography, the differential diagnosis of constrictive versus restrictive disease remains difficult and may not be possible without thoracotomy.1 Our patient presented a challenging clinical picture in that although the hemodynamics by cardiac catheterization were consistent with a constrictive etiology (as suspected by equalization of right and left ventricular end-diastolic pressures and proved by thoracotomy), an additive effect of restrictive disease emerged as her symptoms remained despite pericardiectomy. This finding is not inconsistent with her history of left-side chest irradiation. The clinical recognition of consequences of chest irradiation have become increasingly important as patients with breast cancer and Hodgkin's disease have prolonged survival curves.
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Pathological Findings (L. Maximilian Buja, MD, Professor and Chairman, Department of Pathology and Laboratory Medicine) |
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Multiple specimens from the patient were submitted for examination and interpretation by the pathologist. Although none of the findings are pathognomonic, taken together, they provide significant insight into the patient's clinical problems. I will describe the pathological findings and relate them to the clinical findings in an attempt to confirm the diagnoses (Figs 13 through 16
).
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This patient's initial problem started in 1982 when she was diagnosed as having breast cancer, specifically invasive ductal carcinoma. The diagnosis is made by finding nests of tumor cells that extend from their normal confines in the ducts and lobules into the connective tissue. This diagnosis has several implications for our patient's subsequent clinical course. The prognosis in patients with breast cancer is influenced by evidence of regional lymph node involvement at the time of mastectomy and by biological properties of the tumor cells as manifest by features such as the presence or absence of estrogen and progesterone receptors. So we have to be concerned about recurrent breast cancer as well as complications of the treatment of breast cancer in the subsequent clinical course of this patient. We know that she received radiation, although we have no details of the therapeutic protocol. We are not told whether she received chemotherapy, but many patients with breast cancer are treated with adriamycin, which is a cardiotoxin. So, we have to consider the possible contributions of breast cancer, radiotherapy, and possibly chemotherapy on the patient's subsequent cardiac problems.
The patient had at least two liver biopsies that showed changes
consistent with chronic hepatitis/cholangitis. The portal tracts were
expanded with increased amounts of collagen as well as inflammatory
cells (Fig 13). Lymphocytes extended from the portal tracts
out into
the adjacent portions of the lobules. The changes were those of a
relatively indolent form of chronic hepatitis or cholangitis.
The pleural biopsy that was obtained on this admission showed a
thickened pleura with dense fibrous connective tissue, reactive
mesothelial cells with uniform nuclei and low nuclear-to-cytoplasmic
ratio, and focal fibrin deposits indicative of fibrous and fibrinous
pleuritis (Fig 14). The biopsy showed reactive changes without
evidence
of breast cancer. The myocardial biopsy yielded several fragments of
tissue. One piece included the endocardial surface and showed fibrous
thickening of the endocardium (Fig 15). There also was
extension of the
fibrous tissue into the adjacent myocardial interstitium surrounding
and engulfing adjacent myocytes. Elsewhere, the myocardium showed focal
fibrosis, minimal hypertrophy of the myocytes, and no inflammatory
infiltrate. Stains for iron and amyloid were negative.
The final specimen was the portion of pericardium removed at the
time of pericardial stripping and creation of a pericardial window.
There was marked fibrous thickening of the pericardium with some
fibrinous material present on the pericardial surface (Fig
16). Focal
chronic inflammation of a nonspecific type was present without
granulomas or caseous necrosis. The findings were those of significant
fibrous and fibrinous pericardial disease.
Thus, the pathological findings suggest the patient had a mixture of pericardial and myocardial disease. This combination would explain the patient's improvement but not complete resolution after pericardial stripping. Causes of pericardial disease are infections, immunologically mediated diseases, and a series of miscellaneous conditions. There was no evidence for either pyogenic infection or tuberculous infection or any other specific infectious agent. Probably the most common cause of acute fibrinous pericarditis is viral infection, but our patient had evidence of a chronic process with some acute component indicating chronic progressive activity. Although it might be tempting to relate this to immunological disease, we do not have any compeling proof of immunologically mediated pericardial disease. Furthermore, there was evidence of both endomyocardial disease and pericardial disease. I think that the most likely etiology for this combination of problems is radiation.
The case can also be considered in terms of the cardiomyopathies. The clinicopathological classification includes dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy. This patient fit into a constrictive pericarditis/restrictive cardiomyopathy picture. If we now consider the causes of restrictive cardiomyopathy, amyloidosis was excluded as well as marked hypertrophy and fibrosis of the myocardium.35 However, the history is compatible with radiation-induced fibrosis, which as Dr Hall pointed out, not only causes thickening of the pericardium but also can involve the myocardium and the endocardium, including the mural and valvular endocardium. The most logical diagnosis encompassing all of the clinical and pathological features is radiation-induced endomyocardial, pericardial, and pleural disease.
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Final Diagnosis |
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The final diagnosis is constrictive pericarditis, restrictive cardiomyopathy, and chronic pleuritis probably secondary to radiation therapy for breast cancer, and chronic hepatitis/cholangitis, of uncertain etiology.
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Footnotes |
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Reprint requests to L. Maximilian Buja, MD, Professor and Chairman, Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, 6431 Fannin St, MSB 2.136, Houston, TX 77030.
This Clinicopathological Conference was presented at The University of Texas Medical School at Houston on October 31, 1994.
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