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Clinical pathologic conference
Clinical pathologic
conference
Harvey Wolinsky, M.D. Johanna VarzderBel, M.D. Louis Cohen, M.D. Klaus Ranniger, M.D. Seymour Glagov, M.D.* Chicago, Ill.
Case report A 61-year-old Caucasian retired school teacher was first admitted to the University of Chicago Hospitals and Clinics on April 1, 1965, with complaints of diarrhea, loss of appetite, weight loss, weakness, and swelling of her lower extremities. She died on April 4, 1965. History. For 2.5 years the patient had had intermittent episodes of syncope that lasted x to 2 hours. She would fall, but would rarely hurt herself during these episodes. No involuntary movements or fecal or urinary incontinence were noted. For five years prior to her admission, the patient had episodes of diarrhea with foul-smelling, occasionally bulky stools. These episodes often followed a period of cramping abdominal pain and were associated with faintness and at times with vomiting. Lomotilt brought some relief, but relapses occurred approximately every six months. In July, 1964, she entered another hospital, following six weeks of a “peculiar sensation” in the abdomen and awareness of a movable “palpable mass.” Tissue obtained by biopsy showed only chronic inflammation and fibrosis, so an entero-enterostomy was performed in an attempt to bypass the obstructed segment. During that hospitalization, the patient had four episodes of syncope and hypotension which resembled the episodes which had occurred at home; a normal heart rate was maintained at these times. Although she lost 20 to 30 pounds in the hospital, she regained this weight by the fall of 1964. HOWever, by the end of 1964, the patient had become quite depressed, was markedly anorexic, continued to have diarrhea, and was again losing weight. A trial on a gluten-free diet did not result in improvement of her symptoms. She was hospitalized again
in February, 196.5, following a brief episode of unconsciousness, described as a petit ma1 seizure by a nurse present at the time. Results of laboratory tests performed during that hospitalization were as follows: peripheral white blood cells, 10,000 per cu. mm.; hemoglobin concentration, 14.2 grams per cent. Urinalysis showed a trace of albumin and an occasional red blood cell. Serum amylase was 50 units (normal 50 to 120), blood urea nitrogen, 36 mg. per cent; Bromsulphalein retention, 37.3 per cent; 24 hour fecal fat, 0.34 Gm. (normal 2 to 6 Gm.). A liver biopsy was reported as unremarkable; upper gastrointestinal and small-bowel x-rays showed rapid transit of barium; a colon x-ray was essentially unremarkable. The patient was discharged unimproved and her symptoms rapidly became worse at home. On April 1, 1965, two days after she became febrile, she was transferred to the University of Chicago Hospitals. She had an abdominal hysterectomy and left salpingo-oophorectomy in 1958 for fibroid tumors. Both parents had died of tuberculosis before the age of 50. Physical emmination. At the time of admission, the patient was depressed and thin with peripheral cyanosis. Blood pressure was 78/60 mm. Hg (right arm recumbent); pulse rate, 96 per minute; temperature, 37S”C.; respirations, 24 per minute. Malar erythema was noted and the tongue was dry. Slight jugular venous distention was present. Auscultation of the chest revealed decreased breath sounds in both bases, but no rPles or rhonchi were heard. The heart was not enlarged to percussion. On auscultation, an occasional premature beat was heard, Sl and S2 were unremarkable, and a Grade III/VI systolic murmur was heard at the apex. Peripheral pulses were uniformly diminished. Her
From the Departments of Pathology and Medicine, University of Chicago, Chicago, The Conference wa8 arranged and directed by Dr. Glagov. The work by Dr. Glagov was done during the tenure of an Established Investigatorship tion. *Address: Department of Pathology, University of Chicago Hospitals, Chicago, Ill. tG. D. Searle and Co., Chicago, 111.
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abdomen was distended, but the liver, palpable 8 cm. below the right costal margin in the midclavicular line, had a smooth edge and was slightly tender. Neither the spleen nor any abdominal masses were palpable. No guarding was present; the bowel sounds were normal. On examination of the genitalia, marked erythema of the labial mucosa was noted. The remainder of the pelvic examination was not remarkable. Pitting edema of both lower extremities was present (2+ to 3+), and both calves were slightly tender. Neurologic examination revealed symmetrical deep tendon reflexes; no pathologic reflexes were elicited. Muscle strength was generally diminished. Laboratory data. Peripheral leukocytes, 13,200 per cu. mm.; hemoglobin concentration, 13.1 grams per cent; red blood cells, 4.27 million per cu. mm.; hematocrit, 44 per cent; platelets, 185,900 per cu. mm.; reticulocytes, 1.7 per cent; and total eosinophils, 425 per cu. mm. The differential count was as follows: neutrophils, 79 per cent; small lymphocytes, 11 per cent; monocytes, 5 per cent; eosinophils, 5 per cent. Urinalysis: pH, 5.5; specific gravity, 1.022; protein, lf ; no reduction; a few granular casts and 2 to 3 white cells per high-power field. Fasting blood sugar was 80 mg. per cent; serum sodium, 135 mEq. per liter; serum potassium, 4.3 mEq. per liter; serum chloride, 9’2 mM. per liter; serum CO*, 23.4 mM. per liter; serum calcium, 8.9 mg. per cent; serum phosphorus, 3.7 mg. per cent; serum alkaline phosphatase, 5.2 units per cent (normal 1.5 to 4); total plasma proteins, 7.1 Gm. per cent; albumin, 2.3 Gm. per cent; globulin, 4.8 Gm. per cent. The blood urea nitrogen concentration was 31 mg. per cent. Total serum bilirubin was 1.0 mg. per cent; direct, 0.7 mg. per cent; thymol flocculation. I+ : thvmol turbiditv. 2.7. Serum lactic dehydrogenase’ was i,OlO units; giutamic-oxaloacetic transaminase, 124 units; glutamic-pyruvic transaminase, 122 units.
Fig. 1. A, The frontal chest film shows a diffuse ground bowel is seen.
The patient’s condition deteriorated rapidly. Her systolic blood pressure remained below 90 mm. Hg. On April 3, 196.5, a left thoracentesis was performed, and 500 cc. of yellow, clear fluid with a specific gravity of 1.012 was removed; smears revealed no microorganism. Upon return from a chest x-ray examination after the thoracentesis, no blood pressure reading could be obtained. Jugular vein distention was present when the patient was seated inclined at 4.5 degrees; digitalis was administered. No fluid was obtained from an attempted pericardiocentesis. After this, the patient began to vomit dark brown material. The blood pressure remained low, and heart sounds were barely audible. Vasopressor agents were used to no avail; her pupils became dilated and she died. X-ray examination (Dr. Klaus Ranninger). The chest x-ray on admission here in ApriI, 1965, shows a left pleural effusion and probably a small pleural effusion on the right as well (Fig. 1, A). The heart is of normal size. The film of the abdomen shows a diffuse ground-glass appearance suggestive of ascites and a slightly dilated loop of small bowel in the midabdomen (Fig. 1, B). No upper gastrointestinal examination was done during her hospitalization here; no outside films accompanied the patient.
Discussion
DR. COHEN: Although the patient was apparently well for the first 36 years of her life, syncopal episodes lasting from x to 2 hours occurred between ages 36 and 61. This is the first problem which requires our attention. The second problem is the nature of her gastrointestinal disorder, i.e., her complaints of cramping abdominal pain, diarrhea, nausea, vomiting, and foul
film shows a left pleural effusion. The heart is of normal size. B, The abdominal glass appearance indicative of ascites. A single loop of slightly distended small
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bulky stools during the last five years of her life. The third problem to be considered is the nature of her terminal illness. Let us discuss the syncope first. The possible causes can be divided into two groups: those of cardiovascular origin and those of neurological origin. Neurological syncope can be attributed to anatomic lesions or functional chemical disorders. What possible chemical derangements could result in syncope of up to two hours’ duration occurring over a 2.5 year period? Severe hypoglycemic episodes could be responsible. However, convulsions are usually associated with hypoglycemic coma, and these were not a feature of her clinical history. The absence of convulsions and the repeated occurrence of syncope over a period of 25 years make hypoglycemia an unlikely possibility. Could this woman have had episodes of hypoxia? Could she have somehow been exposed to some environmental factor which resulted in repeated syncope? There is no evidence to support these possibilities. Did she have a hyperventilation syndrome? Decreased CO2 in the blood resulting from hyperventilation could result in reduced cerebral blood flow since CO2 is a potent vasodilator of the cerebral blood vessels. In addition, the respiratory alkalosis associated with hyperventilation will lower blood ionized calcium levels which can result in syncope. However, the patient had no tetanic convulsions, which would have reflected the hyperirritability of nerve and muscle related to decreased ionized calcium levels. The long duration of the symptoms also makes this possibility unlikely. What anatomic lesions could be responsible for neurological syncope? The sudden onset of syncope at age 36 suggests the presence of primary or metastatic intracranial tumor, but again the 25 year duration stands against this. What about congenital or acquired vascular disease? A congenital vascular anomaly would be unlikely to produce syncopal episodes for 25 years; acquired disease, particularly occlusive disease of the branches of the vertebral or the internal carotid arteries, would also be quite unlikely to be present for such a long time without the appearance of convulsions or a cerebrovascular accident. A cerebral scar, due to past, forgotten
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trauma, might serve as a focus for akinetic seizures; “idiopathic” seizures usually have their onset at an earlier age. Cardiovascular causes of the syncope include simple syncope, i.e., peripheral vasodilatation due to some “fright or delight” or a vasovagal reaction which could produce a severe bradycardia. Again, the long duration of symptoms and the persistently normal heart rate during the episodes eliminate these possibilities. Complete atrioventricular block punctuated by periods of asystole should produce convulsions at least occasionally, but would probably not recur over a 25 year period. Other causes of reduced cerebral perfusion such as the vagotonia, carotid sinus stimulation, or arrhythmias are also unlikely to continue for 25 years. Orthostatic hypotension should also be mentioned in passing. It can be present in some patients with neuropathy, generalized vascular disease (usually atherosclerotic), after long confinement to bed, or during treatment with ganglionic blocking agents. I, therefore, consider the most likely cause of her syncope to be a cerebral scar, independent of the events in the last five years of her life. The outstanding problem of the last five years of her life was her gastrointestinal symptomatology. The weight loss, diarrhea, and bulky, foul-smelling stools suggest a malabsorption syndrome. An acquired enterocolic fistula as a result of inflammatory or neoplastic disease-trauma or some sort of functional neuromuscular hypermotility could have produced a rapid transit of food through the gastrointestinal tract which we know occurred in this individual. A fistula in the region of her enteroenterostomy, for example, could account for malabsorption; but her symptoms began prior to that surgery, so that another cause must be sought. Malabsorption could be due to a non-p cell islet adenoma of the pancreas which is presumably capable of secreting gastrin, stimulating the stomach to produce excessive amounts of hydrochloric acid and altering the pH of the small bowel so as to prevent activation of pancreatic and other digestive enzymes and resulting in malabsorption. This disorder has been called the Zollinger-Ellison syndrome. Other features include jejunal ulcers and multiple
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endocrine adenomas involving the parathyroid, pituitary, and adrenal glands. Evidence in favor of this diagnosis is lacking. No mention is made of the acidity or volume of gastric secretions and gastrointestinal x-rays taken elsewhere were not remarkable. Another possibility is obstruction of the common bile dnct, for bile salts are necessary for emulsification of fat and the adequate absorption of the fat-soluble vitamins A, E, D, and K. We are given little information about the status of this woman’s liver function. Although she was presumably never icteric, Bromsulphalein retent tion was increased during one of her lashospitalizations. However, her abnormal liver function tests during the terminal illness may be explained adequately on a different basis; her hepatic insufficiency was not serious enough to account for a malabsorption syndrome. What about the pancreas? Usually, malabsorption results only from extraordinary destruction of pancreatic tissue. Nevertheless, multiple episodes of acute pancreatitis could account for the attacks of acute abdominal cramping pain and her diarrhea and malabsorption could have resulted from destruction of pancreatic parenchyma. Some evidence for this hypothesis was found at the time of the surgery which was performed to clarify the nature of the palpable abdominal mass, for a tumor was seen which appeared to be originating in the pancreas. This could have been a pancreatic cyst. Since the biopsy showed only chronic inflammatory tissue histologically, the underlying disease remains obscure, but chronic pancreatitis or a neoplasm involving the pancreas cannot be excluded as the basis of her abdominal symptoms and her malabsorption. Cebiac disease was suspected at one time, for her physicians removed gluten from her diet for a period of time. Individuals with celiac disease exhibit a peculiar and exquisite sensitivity to inclusion in their diet of gluten, a protein found in wheat, barley, oats, and rye. The removal of gluten from this patient’s diet did little to ameliorate her symptoms. Stasis of food trapped in a normally sterile segment of small bowel could favor bacterial growth
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interfering with absorption of vitamins and nutrients; this results in the so-called “blind loop” syndrome. In this patient, such a “loop” could have been produced surgically inadvertently or could have resulted from an intestinal inflammatory process, perhaps associated with pancreatitis or some other chronic intraabdominal disease. Other less common diseases of the small intestine which are associated with malabsorption include lymphangiectasia, a disorder in which intestinal lymphatic channels are abnormally dilated and acanthocytosis, a disorder in which an unusual spiny erythrocyte is associated with anemia, malabsorption, and p-lipoproteinemia. She was not anemic, and we do not have information concerning her blood lipids. Also, these diseases tend to occur in young patients. Amyloidosis, primary or secondary, scleroderma, and disseminated sarcoidosis are other uncommon causes of malabsorption which could be mentioned but for which evidence is lacking. Disaccharidase deJiciency is another unlikely cause because of both the severity and age of onset of her symptoms. Whipple’s disease can also be excluded in the absence of lymphadenopathy or arthritis. Regional enteritis should be mentioned, but she was not anemic and involvement of the small intestine seemed to be limited to the proximal portion. Lymphoma of the small bowel can cause malabsorption, but in the absence of lymphadenopathy, enlargement of her spleen, or lymphocytosis it should be ruled out. 1 have already alluded to one neoplastic disorder associated with endocrinopathy, the Zollinger-Ellison syndrome; I would now like to discuss another, the carcinoid syndrome in which the neoplasm is a metastatic carcinoid tumor. The carcinoid syndrome can produce hypermotility of the bowel with diarrhea and episodes of hypotension, both of which were prominent in the patient. The peripheral vasodilatation associated with this disease may be confused with peripheral cyanosis, and about 50 per cent of patients with carcinoid syndrome have conspicuous violaceous facial flushing. About 50 per cent develop pulmonary stenosis as a consequence of endocardial and valvular fibrosis on the
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Fig. 2. The ECG on Feb. 2.5, 1965, shows a QRS axis of +90 degrees and flattened T waves in Leads I, AVL, V3, V4, and Vs. T waves in Vs are inverted.
right side of the heart. This patient had a malar flush and we are told that she also had a red, erythematous vulva; in the carcinoid syndrome erythema of all mucosal surfaces is not uncommon. Thus, the carcinoid syndrome could explain many of our patient’s symptoms including the malabsorption syndrome; liver metastases could have produced the hepatomegaly and resulted in ascites. Finally, I wish to discuss her terminal illness. We are told that the patient had bilateral peripheral edema and that the skin of the lower extremities was shiny
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and smooth. This is evidence of bilateral venous thrombosis in the iliac or femoral veins in a chronically ill woman with a reduced intravascular volume who has been confined to bed. Multiple episodes of pulmonary emboli could have accounted for her pleural effusions and some of her terminal hepatomegaly. The extraordinarily high serum enzyme levels indicate that severe hepatic central venous congestion with necrosis was occurring. Since the pleural effusion could have been partly due to pancreatitis, determination of the amylase content of the pleural fluid would have been helpful. The electrocardiogram (ECG) taken elsewhere three months prior to her death (Fig. 2) reveals a sinus rhythm and normal atrioventricular conduction, a QRS axis of +90”, and minor nonspecific ST changes in the left lateral leads. These findings support the diagnosis of pulmonary embolism. The only ECG taken here (April, 1965) showed low voltage in all leads, which is compatible with the presence of a pleural effusion. The patient’s total hospital stay here prior to her demise was only three days, and surely her fate was sealed before she came to the hospital. Many of the features of her terminal illness could be manifestations of recurrent pulmonary emboli possibly with massive embolization at the very end. Her symptoms during the last five years of her life could be due to a pancreatic cyst and multiple episodes of acute pancreatitis leading to pancreatic insufficiency. Nevertheless, I am still intrigued with the possibility that this is a case of the carcinoid syndrome and that the biopsy of the tumor at laparotomy was inadequate. Had the patient lived longer, the diagnosis of carcinoid tumor might have been established by measurement of the 24 hour urinary excretion of S-hydroxyindole acetic acid, a liver biopsy, and repeated careful cardiac auscultation. The pulmonary stenosis murmur is an ejectiontype flow murmur; an associated thrill over the pulmonic area may be present. Of course, the presence of both the murmur and the thrill depends on adequate flow; their absence in this case could be explained by hypotension. Another sign of pulmonary valve disease is a single second heart
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sound, presumably resulting from impaired movement of the diseasedvalve. DR. GLAGOV: If indeed this were a case of the carcinoid syndrome, would the heart lesions usually seen in this disease be sufficient to explain the ascites and the pleural effusion? DR. COHEN: The right axis deviation seen on the outside ECG is consistent with that possibility. It is perfectly possible that most of the cardiovascular symptoms resulted from pulmonic valve stenosis and/or tricuspid valve lesions such as are seen in the carcinoid syndrome. However, the murmur described was located at the apex, not in the pulmonary area, where I would have expected it to be if there were a predominant pulmonary valve lesion. If the right heart were involved as it is in the carcinoid syndrome, it could explain the pleural effusion, hepatomegaly, ascites, peripheral edema, and the electrocardiographic right-axis deviation. As a matter of fact, the moderately severe hepatic function abnormalities could be attributed to the combined effects of extensive liver metastases and chronic passive congestion due to congestive heart failure. DR. GLAGOV: I am told that the physicians who saw her terminally also were very confused by the murmur. DR. MALCOLM PAGE: Although a murmur of pulmonary stenosis is characteristic of the carcinoid syndrome, I might add that in a number of series’s3a tricuspid insufficiency murmur was of equal prevalence with a pulmonary stenosis murmur. AUDIENCE QUESTION: How COmmOIl is it for an islet-cell tumor to cause malabsorption? Could an islet-cell tumor explain the many years of syncope? DR. COHEN: Zollinger and Ellison called attention to the syndrome in 1955; the number of reported cases totaled 260 by 1964.4 In these reports, the tumor did not regularly cause diarrhea; I believe that it is probably responsible for only a very small fraction of the total number of cases of malabsorption. Your second question deals with the possible relationship between the syncope and the ZollingerEllison syndrome. In these “non-P” islet cell adenomas, the (Y, y, or 6 cells may secrete gastrin, but hyperinsulinism is not seen in this disorder.5
DR. GLAGOV: Let us proceed to the pathologic findings in this fascinating case. DR. VANDER BEL: At autopsy, the body was that of an emaciated elderly woman; the abdomen was distended, and there was cyanosis of the malar area and of the neck. The skin of the upper anterior chest was telangiectatic. The palms of the hands and the fingertips were cyanotic; both lower legs were edematous. 2% L. of fluid were found in the abdominal cavity and 1,000 C.C. of fluid in the left pleural cavity. The loops of the small intestine were matted together by fibrous serosal adhesions. The heart weighed 300 grams; both right chambers were dilated, particularly the right atrium. The endocardium lining the ventricles was intact, but the endocardium lining the atria was thickened and opacified. Except for the aortic valve, the valve leaflets were markedly deformed. The mitral valve (Fig. 3,A) was 8.5 cm. in circumference with thickened leaflets and shortened, thickened chordae tendineae; the posterior leaflet was more involved than the anterior leaflet. The tricuspid valve (Fig. 3,B) measured 12.5 cm.; leaflets were thickened and shortened and chordae tendineae shortened and thickened. The pulmonic valve was most severely involved (Fig. 4,B); thickened and fused leaflets resulted in both stenosis and insufficiency with a luminal cross-sectional area of ap-
Fig. 3. A, Mildly B, Severely
fibrotic
fibrotic and stenotic mitral and insufficient tricuspid
valve. valve.
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proximately 1 sq. cm. The distribution of the valve lesions was not typical of rheumatic heart disease, for, despite severe alteration of the pulmonic valve, the aortic valve was spared (Fig. 4,A). The microscopic appearance of the valve lesions were more characteristic of carcinoid heart disease than of rheumatic heart disease. A section of the pulmonic valve stained with hematoxylin and eosin (Fig. 5,A) shows only marked sclerotic thickening of the leaflet. However, special stains reveal that the deformity and thickening of the valve leaflet is not due merely to scarification by increased collagen and elastin, but results primarily from an accumulation
Fig. 4. A, Normal fibrotic pulmonary
aortic valve.
Fig. 5. Markedly thickened C, Alcian blue-P.A.S. stain.
valve.
pulmonary (X 7.)
B, Stenotic
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of ground substance in loose connective tissue containing both acid and neutral mucopolysaccharides. This material appears as an accretion on the valve surface and leaves a discernible underlying valve structure (Fig. 5,B and C) as has been described in carcinoid heart disease by others.2,6s7 In contrast, rheumatic heart disease results in marked destruction of valve structure and replacement of valve substance by scars including both collagen and elastin; conservation of a valve “skeleton” within the lesion is rarely seen. The microscopic appearance of the tricuspid and mitral valves in this case was similar to that of the pulmonic valve, but changes were not as severe. In addition to the lesions of the cardiac valves, there were subendothelial thickenings of the anterior descending branch of the left coronary artery (Fig. 6,A) and the superior vena cava (Fig. 63) as well as fibrinoid necrosis of small intramyocardial arteries (Fig. 6,C). The subendothelial thickenings of the vena cava and coronary artery were similar; no siderophages or cholesterol clefts, characteristic of atherosclerosis, were seen. The myocardium was diffusely infiltrated by lymphocytes and atrophic muscle fibers were numerous. The exact nature of these changes were not clear and could reflect prolonged ischemia or associated viral myocarditis. The liver weighed 2,000 grams and was approximately 40 per cent replaced by nodules of firm, grayish-white, glistening, tumor nodules with focal hemorrhagic areas but no evidence of softening or necrosis. The microscopic appearance of
and eosin
stain;
B, Verhoeff-van
Gieson
stain;
Fig. 6. A, Anterior descending branch of the left coronary artery Gieson; X 30.) B, Superior vena cava with similarly thickened branch of coronary artery with fibrinoid necrosis in the media.
with a greatly thickened intima. (Verhoeff-van intima. (Verhoeff-van Gieson; X 30.) C, Small (P.A.S.; X 450.)
Fig. 7. A, Gross appearance of the 1.0 on primary carcinoid lesion in the small bowel. B, Microscopic appearance ot the primary carcinoid tumor in the wall of the small bowel. (Hematoxylin and eosin; X 20.) C, Detailed microscopic appearance of the primary tumor. (Hematoxylin and eosin; X 350.) D, Detailed microscopic appearance of hepatic metastasis of carcinoid tumor. (Hematoxylin and eosin; X 3.50.)
Fig. 8. A, Gross appearance of the superior mesenteric artery which is surrounded B, Microscopic appearance of A, showing clumps of carcinoid tumor cells and rounding the artery. (Hematoxylin and eosin; X 20.)
by tumor abundant
and fibrous tissue. fibrous tissue sur-
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the neoplastic tissue was characteristic of carcinoid tumor; uniform small cells were arranged in nests which were separated by delicate fibrous strands (Fig. 7,O). In some nests small glands could be discerned. Acute and chronic passive congestion, fatty change, and mild pericholangitis were evident in liver sections without tumor tissue. The pancreas was grossly and microscopically normal. About the presumed site of the abdominal surgery the superior mesenteric artery was surrounded by firm gray-white tissue (Fig. 84). Microscopically, carcinoid tumor resembling that seen in the liver encircled the artery (Fig. 83). However, nearby, relatively acellular sclerotic hyaline tissue was abundant and tumor cells were scant; the biopsy could well have been taken from such a fibrous area. Metastatic carcinoid tumor nodules were found in the ovary and in periaortic, peripancreatic, and mesenteric lymph nodes. The only lesion which could have been the primary focus was a round nodule projecting from the mucosal surface of the small intestine, 90 cm. from the ileocecal valve. It measured 1.0 cm. in diameter and had a central depression (Fig. 74). The cut surface of the nodule was gray-white and microscopic examination revealed a carcinoid tumor nearly identical to that described in the metastatic sites (Fig. 7, B and C). It had extended into the muscularis and serosa causing marked local thickening of the bowel wall. The site of surgical anastomosis was healed without any evidence of anatomic obstruction. No other abnormalities of the intestines were found. Attempts to stain both the primary and metastatic tumor tissue for argentaffine granules with the Fontana-Masson and Diazo stains were unsuccessful, but this does not exclude the diagnosis of carcinoid tumor in the presence of such characteristic morphology.3 In summary, this woman with a clinical history of diarrhea, episodes of hypotenand subsequent sion, malar erythema, right ventricular failure had metastatic carcinoid tumor. A small infiltrating intestinal tumor was probably the primary site. The abdominal metastatic tumor tissue about the mesenteric artery was densely sclerotic, so that the biopsy at laparotomy probably did not contain
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recognizable carcinoid tumor. The cardiac lesions were characteristic of carcinoid heart disease and included endocardial thickening involving both atria and the pulmonic, tricuspid, and mitral valves; functionally, the aortic valve seemed normal, the pulmonic valve stenotic and insufficient, the mitral valve insufficient and possibly stenotic, and the tricuspid valve insufficient. The right ventricle was dilated. Edema, ascites, and passive congestion of the liver had resulted from right ventricular failure. The inflammatory reaction in the myocardium and the changes in the small coronary artery branches remain without a definite explanation. I cannot provide an adequate organic explanation for the syncope, especially since examination of the brain was not permitted. However, the syncope could be associated with the hypotensive episodes which accompanied the carcinoid syndrome in this patient. No diffuse gross or microscopic lesions of the intestine which could be associated with malabsorption were found. Again, this disturbance could be attributable to functional consequences of the diarrhea associated with the carcinoid syndrome. A “blind loop” syndrome can probably be excluded, especially since episodes of hypotension and diarrhea antedated her surgery by four years and the anastomosis was anatomically intact. The abnormal liver function tests may be attributed to the widespread metastases and the chronic passive congestion. DR. COHEN: I might add that the cramping abdominal pain could be related to the fibrotic process about the superior mesenteric artery which may have resulted in intermittent intestinal ischemia. REFERENCES Thorson, A., Biorck, G., Bjorkman, G., and Waldenstrom, J.: Malignant carcinoid of the small intestine with metastasis to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis. A clinical and pathological syndrome, Am. HEART J. 47:795, 1954. McDonald, R. A. A.: A study of 356 carcinoids of the gastrointestinal tract, Am. J. Med.
21:867, 19.56. Thorson, A.: Studies on carcinoid med. scandinav. (Suppl.) 3343122,
disease, 1958.
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4. Ellison, E. H., and Wilson, S. D.: The ZollingerEllison syndrome: reappraisal and evaluation of 260 registered cases, Ann. Surg. 160:512, 1964. 5. Zollinger, R. M., Elliott. D. W., Endahl, G. L., Grant, G. N., Goswitz, J. T., and Taft, D. A.: Origin of the &erogenic hormone in endocrine induced ulcer, Ann. Surg. 156:.570, 1962.
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6. Roberts, W. C., and Sjoerdsma, A.: The cardiac disease associated with the carcinoid syndrome (carcinoid heart disease), Am. J. Med. 36:5, 1964. 7. Wenger, R.: Ein Fall von Endokardfibrosierung bei Karzinoidsyndrom, Ztschr. Kreislaufforsch. 54:(2), 123, 1965.
conference
Harvey Wolinsky, M.D. Johanna VarzderBel, M.D. Louis Cohen, M.D. Klaus Ranniger, M.D. Seymour Glagov, M.D.* Chicago, Ill.
Case report A 61-year-old Caucasian retired school teacher was first admitted to the University of Chicago Hospitals and Clinics on April 1, 1965, with complaints of diarrhea, loss of appetite, weight loss, weakness, and swelling of her lower extremities. She died on April 4, 1965. History. For 2.5 years the patient had had intermittent episodes of syncope that lasted x to 2 hours. She would fall, but would rarely hurt herself during these episodes. No involuntary movements or fecal or urinary incontinence were noted. For five years prior to her admission, the patient had episodes of diarrhea with foul-smelling, occasionally bulky stools. These episodes often followed a period of cramping abdominal pain and were associated with faintness and at times with vomiting. Lomotilt brought some relief, but relapses occurred approximately every six months. In July, 1964, she entered another hospital, following six weeks of a “peculiar sensation” in the abdomen and awareness of a movable “palpable mass.” Tissue obtained by biopsy showed only chronic inflammation and fibrosis, so an entero-enterostomy was performed in an attempt to bypass the obstructed segment. During that hospitalization, the patient had four episodes of syncope and hypotension which resembled the episodes which had occurred at home; a normal heart rate was maintained at these times. Although she lost 20 to 30 pounds in the hospital, she regained this weight by the fall of 1964. HOWever, by the end of 1964, the patient had become quite depressed, was markedly anorexic, continued to have diarrhea, and was again losing weight. A trial on a gluten-free diet did not result in improvement of her symptoms. She was hospitalized again
in February, 196.5, following a brief episode of unconsciousness, described as a petit ma1 seizure by a nurse present at the time. Results of laboratory tests performed during that hospitalization were as follows: peripheral white blood cells, 10,000 per cu. mm.; hemoglobin concentration, 14.2 grams per cent. Urinalysis showed a trace of albumin and an occasional red blood cell. Serum amylase was 50 units (normal 50 to 120), blood urea nitrogen, 36 mg. per cent; Bromsulphalein retention, 37.3 per cent; 24 hour fecal fat, 0.34 Gm. (normal 2 to 6 Gm.). A liver biopsy was reported as unremarkable; upper gastrointestinal and small-bowel x-rays showed rapid transit of barium; a colon x-ray was essentially unremarkable. The patient was discharged unimproved and her symptoms rapidly became worse at home. On April 1, 1965, two days after she became febrile, she was transferred to the University of Chicago Hospitals. She had an abdominal hysterectomy and left salpingo-oophorectomy in 1958 for fibroid tumors. Both parents had died of tuberculosis before the age of 50. Physical emmination. At the time of admission, the patient was depressed and thin with peripheral cyanosis. Blood pressure was 78/60 mm. Hg (right arm recumbent); pulse rate, 96 per minute; temperature, 37S”C.; respirations, 24 per minute. Malar erythema was noted and the tongue was dry. Slight jugular venous distention was present. Auscultation of the chest revealed decreased breath sounds in both bases, but no rPles or rhonchi were heard. The heart was not enlarged to percussion. On auscultation, an occasional premature beat was heard, Sl and S2 were unremarkable, and a Grade III/VI systolic murmur was heard at the apex. Peripheral pulses were uniformly diminished. Her
From the Departments of Pathology and Medicine, University of Chicago, Chicago, The Conference wa8 arranged and directed by Dr. Glagov. The work by Dr. Glagov was done during the tenure of an Established Investigatorship tion. *Address: Department of Pathology, University of Chicago Hospitals, Chicago, Ill. tG. D. Searle and Co., Chicago, 111.
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abdomen was distended, but the liver, palpable 8 cm. below the right costal margin in the midclavicular line, had a smooth edge and was slightly tender. Neither the spleen nor any abdominal masses were palpable. No guarding was present; the bowel sounds were normal. On examination of the genitalia, marked erythema of the labial mucosa was noted. The remainder of the pelvic examination was not remarkable. Pitting edema of both lower extremities was present (2+ to 3+), and both calves were slightly tender. Neurologic examination revealed symmetrical deep tendon reflexes; no pathologic reflexes were elicited. Muscle strength was generally diminished. Laboratory data. Peripheral leukocytes, 13,200 per cu. mm.; hemoglobin concentration, 13.1 grams per cent; red blood cells, 4.27 million per cu. mm.; hematocrit, 44 per cent; platelets, 185,900 per cu. mm.; reticulocytes, 1.7 per cent; and total eosinophils, 425 per cu. mm. The differential count was as follows: neutrophils, 79 per cent; small lymphocytes, 11 per cent; monocytes, 5 per cent; eosinophils, 5 per cent. Urinalysis: pH, 5.5; specific gravity, 1.022; protein, lf ; no reduction; a few granular casts and 2 to 3 white cells per high-power field. Fasting blood sugar was 80 mg. per cent; serum sodium, 135 mEq. per liter; serum potassium, 4.3 mEq. per liter; serum chloride, 9’2 mM. per liter; serum CO*, 23.4 mM. per liter; serum calcium, 8.9 mg. per cent; serum phosphorus, 3.7 mg. per cent; serum alkaline phosphatase, 5.2 units per cent (normal 1.5 to 4); total plasma proteins, 7.1 Gm. per cent; albumin, 2.3 Gm. per cent; globulin, 4.8 Gm. per cent. The blood urea nitrogen concentration was 31 mg. per cent. Total serum bilirubin was 1.0 mg. per cent; direct, 0.7 mg. per cent; thymol flocculation. I+ : thvmol turbiditv. 2.7. Serum lactic dehydrogenase’ was i,OlO units; giutamic-oxaloacetic transaminase, 124 units; glutamic-pyruvic transaminase, 122 units.
Fig. 1. A, The frontal chest film shows a diffuse ground bowel is seen.
The patient’s condition deteriorated rapidly. Her systolic blood pressure remained below 90 mm. Hg. On April 3, 196.5, a left thoracentesis was performed, and 500 cc. of yellow, clear fluid with a specific gravity of 1.012 was removed; smears revealed no microorganism. Upon return from a chest x-ray examination after the thoracentesis, no blood pressure reading could be obtained. Jugular vein distention was present when the patient was seated inclined at 4.5 degrees; digitalis was administered. No fluid was obtained from an attempted pericardiocentesis. After this, the patient began to vomit dark brown material. The blood pressure remained low, and heart sounds were barely audible. Vasopressor agents were used to no avail; her pupils became dilated and she died. X-ray examination (Dr. Klaus Ranninger). The chest x-ray on admission here in ApriI, 1965, shows a left pleural effusion and probably a small pleural effusion on the right as well (Fig. 1, A). The heart is of normal size. The film of the abdomen shows a diffuse ground-glass appearance suggestive of ascites and a slightly dilated loop of small bowel in the midabdomen (Fig. 1, B). No upper gastrointestinal examination was done during her hospitalization here; no outside films accompanied the patient.
Discussion
DR. COHEN: Although the patient was apparently well for the first 36 years of her life, syncopal episodes lasting from x to 2 hours occurred between ages 36 and 61. This is the first problem which requires our attention. The second problem is the nature of her gastrointestinal disorder, i.e., her complaints of cramping abdominal pain, diarrhea, nausea, vomiting, and foul
film shows a left pleural effusion. The heart is of normal size. B, The abdominal glass appearance indicative of ascites. A single loop of slightly distended small
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bulky stools during the last five years of her life. The third problem to be considered is the nature of her terminal illness. Let us discuss the syncope first. The possible causes can be divided into two groups: those of cardiovascular origin and those of neurological origin. Neurological syncope can be attributed to anatomic lesions or functional chemical disorders. What possible chemical derangements could result in syncope of up to two hours’ duration occurring over a 2.5 year period? Severe hypoglycemic episodes could be responsible. However, convulsions are usually associated with hypoglycemic coma, and these were not a feature of her clinical history. The absence of convulsions and the repeated occurrence of syncope over a period of 25 years make hypoglycemia an unlikely possibility. Could this woman have had episodes of hypoxia? Could she have somehow been exposed to some environmental factor which resulted in repeated syncope? There is no evidence to support these possibilities. Did she have a hyperventilation syndrome? Decreased CO2 in the blood resulting from hyperventilation could result in reduced cerebral blood flow since CO2 is a potent vasodilator of the cerebral blood vessels. In addition, the respiratory alkalosis associated with hyperventilation will lower blood ionized calcium levels which can result in syncope. However, the patient had no tetanic convulsions, which would have reflected the hyperirritability of nerve and muscle related to decreased ionized calcium levels. The long duration of the symptoms also makes this possibility unlikely. What anatomic lesions could be responsible for neurological syncope? The sudden onset of syncope at age 36 suggests the presence of primary or metastatic intracranial tumor, but again the 25 year duration stands against this. What about congenital or acquired vascular disease? A congenital vascular anomaly would be unlikely to produce syncopal episodes for 25 years; acquired disease, particularly occlusive disease of the branches of the vertebral or the internal carotid arteries, would also be quite unlikely to be present for such a long time without the appearance of convulsions or a cerebrovascular accident. A cerebral scar, due to past, forgotten
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trauma, might serve as a focus for akinetic seizures; “idiopathic” seizures usually have their onset at an earlier age. Cardiovascular causes of the syncope include simple syncope, i.e., peripheral vasodilatation due to some “fright or delight” or a vasovagal reaction which could produce a severe bradycardia. Again, the long duration of symptoms and the persistently normal heart rate during the episodes eliminate these possibilities. Complete atrioventricular block punctuated by periods of asystole should produce convulsions at least occasionally, but would probably not recur over a 25 year period. Other causes of reduced cerebral perfusion such as the vagotonia, carotid sinus stimulation, or arrhythmias are also unlikely to continue for 25 years. Orthostatic hypotension should also be mentioned in passing. It can be present in some patients with neuropathy, generalized vascular disease (usually atherosclerotic), after long confinement to bed, or during treatment with ganglionic blocking agents. I, therefore, consider the most likely cause of her syncope to be a cerebral scar, independent of the events in the last five years of her life. The outstanding problem of the last five years of her life was her gastrointestinal symptomatology. The weight loss, diarrhea, and bulky, foul-smelling stools suggest a malabsorption syndrome. An acquired enterocolic fistula as a result of inflammatory or neoplastic disease-trauma or some sort of functional neuromuscular hypermotility could have produced a rapid transit of food through the gastrointestinal tract which we know occurred in this individual. A fistula in the region of her enteroenterostomy, for example, could account for malabsorption; but her symptoms began prior to that surgery, so that another cause must be sought. Malabsorption could be due to a non-p cell islet adenoma of the pancreas which is presumably capable of secreting gastrin, stimulating the stomach to produce excessive amounts of hydrochloric acid and altering the pH of the small bowel so as to prevent activation of pancreatic and other digestive enzymes and resulting in malabsorption. This disorder has been called the Zollinger-Ellison syndrome. Other features include jejunal ulcers and multiple
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endocrine adenomas involving the parathyroid, pituitary, and adrenal glands. Evidence in favor of this diagnosis is lacking. No mention is made of the acidity or volume of gastric secretions and gastrointestinal x-rays taken elsewhere were not remarkable. Another possibility is obstruction of the common bile dnct, for bile salts are necessary for emulsification of fat and the adequate absorption of the fat-soluble vitamins A, E, D, and K. We are given little information about the status of this woman’s liver function. Although she was presumably never icteric, Bromsulphalein retent tion was increased during one of her lashospitalizations. However, her abnormal liver function tests during the terminal illness may be explained adequately on a different basis; her hepatic insufficiency was not serious enough to account for a malabsorption syndrome. What about the pancreas? Usually, malabsorption results only from extraordinary destruction of pancreatic tissue. Nevertheless, multiple episodes of acute pancreatitis could account for the attacks of acute abdominal cramping pain and her diarrhea and malabsorption could have resulted from destruction of pancreatic parenchyma. Some evidence for this hypothesis was found at the time of the surgery which was performed to clarify the nature of the palpable abdominal mass, for a tumor was seen which appeared to be originating in the pancreas. This could have been a pancreatic cyst. Since the biopsy showed only chronic inflammatory tissue histologically, the underlying disease remains obscure, but chronic pancreatitis or a neoplasm involving the pancreas cannot be excluded as the basis of her abdominal symptoms and her malabsorption. Cebiac disease was suspected at one time, for her physicians removed gluten from her diet for a period of time. Individuals with celiac disease exhibit a peculiar and exquisite sensitivity to inclusion in their diet of gluten, a protein found in wheat, barley, oats, and rye. The removal of gluten from this patient’s diet did little to ameliorate her symptoms. Stasis of food trapped in a normally sterile segment of small bowel could favor bacterial growth
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interfering with absorption of vitamins and nutrients; this results in the so-called “blind loop” syndrome. In this patient, such a “loop” could have been produced surgically inadvertently or could have resulted from an intestinal inflammatory process, perhaps associated with pancreatitis or some other chronic intraabdominal disease. Other less common diseases of the small intestine which are associated with malabsorption include lymphangiectasia, a disorder in which intestinal lymphatic channels are abnormally dilated and acanthocytosis, a disorder in which an unusual spiny erythrocyte is associated with anemia, malabsorption, and p-lipoproteinemia. She was not anemic, and we do not have information concerning her blood lipids. Also, these diseases tend to occur in young patients. Amyloidosis, primary or secondary, scleroderma, and disseminated sarcoidosis are other uncommon causes of malabsorption which could be mentioned but for which evidence is lacking. Disaccharidase deJiciency is another unlikely cause because of both the severity and age of onset of her symptoms. Whipple’s disease can also be excluded in the absence of lymphadenopathy or arthritis. Regional enteritis should be mentioned, but she was not anemic and involvement of the small intestine seemed to be limited to the proximal portion. Lymphoma of the small bowel can cause malabsorption, but in the absence of lymphadenopathy, enlargement of her spleen, or lymphocytosis it should be ruled out. 1 have already alluded to one neoplastic disorder associated with endocrinopathy, the Zollinger-Ellison syndrome; I would now like to discuss another, the carcinoid syndrome in which the neoplasm is a metastatic carcinoid tumor. The carcinoid syndrome can produce hypermotility of the bowel with diarrhea and episodes of hypotension, both of which were prominent in the patient. The peripheral vasodilatation associated with this disease may be confused with peripheral cyanosis, and about 50 per cent of patients with carcinoid syndrome have conspicuous violaceous facial flushing. About 50 per cent develop pulmonary stenosis as a consequence of endocardial and valvular fibrosis on the
Clinical
Fig. 2. The ECG on Feb. 2.5, 1965, shows a QRS axis of +90 degrees and flattened T waves in Leads I, AVL, V3, V4, and Vs. T waves in Vs are inverted.
right side of the heart. This patient had a malar flush and we are told that she also had a red, erythematous vulva; in the carcinoid syndrome erythema of all mucosal surfaces is not uncommon. Thus, the carcinoid syndrome could explain many of our patient’s symptoms including the malabsorption syndrome; liver metastases could have produced the hepatomegaly and resulted in ascites. Finally, I wish to discuss her terminal illness. We are told that the patient had bilateral peripheral edema and that the skin of the lower extremities was shiny
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and smooth. This is evidence of bilateral venous thrombosis in the iliac or femoral veins in a chronically ill woman with a reduced intravascular volume who has been confined to bed. Multiple episodes of pulmonary emboli could have accounted for her pleural effusions and some of her terminal hepatomegaly. The extraordinarily high serum enzyme levels indicate that severe hepatic central venous congestion with necrosis was occurring. Since the pleural effusion could have been partly due to pancreatitis, determination of the amylase content of the pleural fluid would have been helpful. The electrocardiogram (ECG) taken elsewhere three months prior to her death (Fig. 2) reveals a sinus rhythm and normal atrioventricular conduction, a QRS axis of +90”, and minor nonspecific ST changes in the left lateral leads. These findings support the diagnosis of pulmonary embolism. The only ECG taken here (April, 1965) showed low voltage in all leads, which is compatible with the presence of a pleural effusion. The patient’s total hospital stay here prior to her demise was only three days, and surely her fate was sealed before she came to the hospital. Many of the features of her terminal illness could be manifestations of recurrent pulmonary emboli possibly with massive embolization at the very end. Her symptoms during the last five years of her life could be due to a pancreatic cyst and multiple episodes of acute pancreatitis leading to pancreatic insufficiency. Nevertheless, I am still intrigued with the possibility that this is a case of the carcinoid syndrome and that the biopsy of the tumor at laparotomy was inadequate. Had the patient lived longer, the diagnosis of carcinoid tumor might have been established by measurement of the 24 hour urinary excretion of S-hydroxyindole acetic acid, a liver biopsy, and repeated careful cardiac auscultation. The pulmonary stenosis murmur is an ejectiontype flow murmur; an associated thrill over the pulmonic area may be present. Of course, the presence of both the murmur and the thrill depends on adequate flow; their absence in this case could be explained by hypotension. Another sign of pulmonary valve disease is a single second heart
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sound, presumably resulting from impaired movement of the diseasedvalve. DR. GLAGOV: If indeed this were a case of the carcinoid syndrome, would the heart lesions usually seen in this disease be sufficient to explain the ascites and the pleural effusion? DR. COHEN: The right axis deviation seen on the outside ECG is consistent with that possibility. It is perfectly possible that most of the cardiovascular symptoms resulted from pulmonic valve stenosis and/or tricuspid valve lesions such as are seen in the carcinoid syndrome. However, the murmur described was located at the apex, not in the pulmonary area, where I would have expected it to be if there were a predominant pulmonary valve lesion. If the right heart were involved as it is in the carcinoid syndrome, it could explain the pleural effusion, hepatomegaly, ascites, peripheral edema, and the electrocardiographic right-axis deviation. As a matter of fact, the moderately severe hepatic function abnormalities could be attributed to the combined effects of extensive liver metastases and chronic passive congestion due to congestive heart failure. DR. GLAGOV: I am told that the physicians who saw her terminally also were very confused by the murmur. DR. MALCOLM PAGE: Although a murmur of pulmonary stenosis is characteristic of the carcinoid syndrome, I might add that in a number of series’s3a tricuspid insufficiency murmur was of equal prevalence with a pulmonary stenosis murmur. AUDIENCE QUESTION: How COmmOIl is it for an islet-cell tumor to cause malabsorption? Could an islet-cell tumor explain the many years of syncope? DR. COHEN: Zollinger and Ellison called attention to the syndrome in 1955; the number of reported cases totaled 260 by 1964.4 In these reports, the tumor did not regularly cause diarrhea; I believe that it is probably responsible for only a very small fraction of the total number of cases of malabsorption. Your second question deals with the possible relationship between the syncope and the ZollingerEllison syndrome. In these “non-P” islet cell adenomas, the (Y, y, or 6 cells may secrete gastrin, but hyperinsulinism is not seen in this disorder.5
DR. GLAGOV: Let us proceed to the pathologic findings in this fascinating case. DR. VANDER BEL: At autopsy, the body was that of an emaciated elderly woman; the abdomen was distended, and there was cyanosis of the malar area and of the neck. The skin of the upper anterior chest was telangiectatic. The palms of the hands and the fingertips were cyanotic; both lower legs were edematous. 2% L. of fluid were found in the abdominal cavity and 1,000 C.C. of fluid in the left pleural cavity. The loops of the small intestine were matted together by fibrous serosal adhesions. The heart weighed 300 grams; both right chambers were dilated, particularly the right atrium. The endocardium lining the ventricles was intact, but the endocardium lining the atria was thickened and opacified. Except for the aortic valve, the valve leaflets were markedly deformed. The mitral valve (Fig. 3,A) was 8.5 cm. in circumference with thickened leaflets and shortened, thickened chordae tendineae; the posterior leaflet was more involved than the anterior leaflet. The tricuspid valve (Fig. 3,B) measured 12.5 cm.; leaflets were thickened and shortened and chordae tendineae shortened and thickened. The pulmonic valve was most severely involved (Fig. 4,B); thickened and fused leaflets resulted in both stenosis and insufficiency with a luminal cross-sectional area of ap-
Fig. 3. A, Mildly B, Severely
fibrotic
fibrotic and stenotic mitral and insufficient tricuspid
valve. valve.
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proximately 1 sq. cm. The distribution of the valve lesions was not typical of rheumatic heart disease, for, despite severe alteration of the pulmonic valve, the aortic valve was spared (Fig. 4,A). The microscopic appearance of the valve lesions were more characteristic of carcinoid heart disease than of rheumatic heart disease. A section of the pulmonic valve stained with hematoxylin and eosin (Fig. 5,A) shows only marked sclerotic thickening of the leaflet. However, special stains reveal that the deformity and thickening of the valve leaflet is not due merely to scarification by increased collagen and elastin, but results primarily from an accumulation
Fig. 4. A, Normal fibrotic pulmonary
aortic valve.
Fig. 5. Markedly thickened C, Alcian blue-P.A.S. stain.
valve.
pulmonary (X 7.)
B, Stenotic
valve.
and
A, Hematoxylin
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of ground substance in loose connective tissue containing both acid and neutral mucopolysaccharides. This material appears as an accretion on the valve surface and leaves a discernible underlying valve structure (Fig. 5,B and C) as has been described in carcinoid heart disease by others.2,6s7 In contrast, rheumatic heart disease results in marked destruction of valve structure and replacement of valve substance by scars including both collagen and elastin; conservation of a valve “skeleton” within the lesion is rarely seen. The microscopic appearance of the tricuspid and mitral valves in this case was similar to that of the pulmonic valve, but changes were not as severe. In addition to the lesions of the cardiac valves, there were subendothelial thickenings of the anterior descending branch of the left coronary artery (Fig. 6,A) and the superior vena cava (Fig. 63) as well as fibrinoid necrosis of small intramyocardial arteries (Fig. 6,C). The subendothelial thickenings of the vena cava and coronary artery were similar; no siderophages or cholesterol clefts, characteristic of atherosclerosis, were seen. The myocardium was diffusely infiltrated by lymphocytes and atrophic muscle fibers were numerous. The exact nature of these changes were not clear and could reflect prolonged ischemia or associated viral myocarditis. The liver weighed 2,000 grams and was approximately 40 per cent replaced by nodules of firm, grayish-white, glistening, tumor nodules with focal hemorrhagic areas but no evidence of softening or necrosis. The microscopic appearance of
and eosin
stain;
B, Verhoeff-van
Gieson
stain;
Fig. 6. A, Anterior descending branch of the left coronary artery Gieson; X 30.) B, Superior vena cava with similarly thickened branch of coronary artery with fibrinoid necrosis in the media.
with a greatly thickened intima. (Verhoeff-van intima. (Verhoeff-van Gieson; X 30.) C, Small (P.A.S.; X 450.)
Fig. 7. A, Gross appearance of the 1.0 on primary carcinoid lesion in the small bowel. B, Microscopic appearance ot the primary carcinoid tumor in the wall of the small bowel. (Hematoxylin and eosin; X 20.) C, Detailed microscopic appearance of the primary tumor. (Hematoxylin and eosin; X 350.) D, Detailed microscopic appearance of hepatic metastasis of carcinoid tumor. (Hematoxylin and eosin; X 3.50.)
Fig. 8. A, Gross appearance of the superior mesenteric artery which is surrounded B, Microscopic appearance of A, showing clumps of carcinoid tumor cells and rounding the artery. (Hematoxylin and eosin; X 20.)
by tumor abundant
and fibrous tissue. fibrous tissue sur-
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the neoplastic tissue was characteristic of carcinoid tumor; uniform small cells were arranged in nests which were separated by delicate fibrous strands (Fig. 7,O). In some nests small glands could be discerned. Acute and chronic passive congestion, fatty change, and mild pericholangitis were evident in liver sections without tumor tissue. The pancreas was grossly and microscopically normal. About the presumed site of the abdominal surgery the superior mesenteric artery was surrounded by firm gray-white tissue (Fig. 84). Microscopically, carcinoid tumor resembling that seen in the liver encircled the artery (Fig. 83). However, nearby, relatively acellular sclerotic hyaline tissue was abundant and tumor cells were scant; the biopsy could well have been taken from such a fibrous area. Metastatic carcinoid tumor nodules were found in the ovary and in periaortic, peripancreatic, and mesenteric lymph nodes. The only lesion which could have been the primary focus was a round nodule projecting from the mucosal surface of the small intestine, 90 cm. from the ileocecal valve. It measured 1.0 cm. in diameter and had a central depression (Fig. 74). The cut surface of the nodule was gray-white and microscopic examination revealed a carcinoid tumor nearly identical to that described in the metastatic sites (Fig. 7, B and C). It had extended into the muscularis and serosa causing marked local thickening of the bowel wall. The site of surgical anastomosis was healed without any evidence of anatomic obstruction. No other abnormalities of the intestines were found. Attempts to stain both the primary and metastatic tumor tissue for argentaffine granules with the Fontana-Masson and Diazo stains were unsuccessful, but this does not exclude the diagnosis of carcinoid tumor in the presence of such characteristic morphology.3 In summary, this woman with a clinical history of diarrhea, episodes of hypotenand subsequent sion, malar erythema, right ventricular failure had metastatic carcinoid tumor. A small infiltrating intestinal tumor was probably the primary site. The abdominal metastatic tumor tissue about the mesenteric artery was densely sclerotic, so that the biopsy at laparotomy probably did not contain
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recognizable carcinoid tumor. The cardiac lesions were characteristic of carcinoid heart disease and included endocardial thickening involving both atria and the pulmonic, tricuspid, and mitral valves; functionally, the aortic valve seemed normal, the pulmonic valve stenotic and insufficient, the mitral valve insufficient and possibly stenotic, and the tricuspid valve insufficient. The right ventricle was dilated. Edema, ascites, and passive congestion of the liver had resulted from right ventricular failure. The inflammatory reaction in the myocardium and the changes in the small coronary artery branches remain without a definite explanation. I cannot provide an adequate organic explanation for the syncope, especially since examination of the brain was not permitted. However, the syncope could be associated with the hypotensive episodes which accompanied the carcinoid syndrome in this patient. No diffuse gross or microscopic lesions of the intestine which could be associated with malabsorption were found. Again, this disturbance could be attributable to functional consequences of the diarrhea associated with the carcinoid syndrome. A “blind loop” syndrome can probably be excluded, especially since episodes of hypotension and diarrhea antedated her surgery by four years and the anastomosis was anatomically intact. The abnormal liver function tests may be attributed to the widespread metastases and the chronic passive congestion. DR. COHEN: I might add that the cramping abdominal pain could be related to the fibrotic process about the superior mesenteric artery which may have resulted in intermittent intestinal ischemia. REFERENCES Thorson, A., Biorck, G., Bjorkman, G., and Waldenstrom, J.: Malignant carcinoid of the small intestine with metastasis to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis. A clinical and pathological syndrome, Am. HEART J. 47:795, 1954. McDonald, R. A. A.: A study of 356 carcinoids of the gastrointestinal tract, Am. J. Med.
21:867, 19.56. Thorson, A.: Studies on carcinoid med. scandinav. (Suppl.) 3343122,
disease, 1958.
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4. Ellison, E. H., and Wilson, S. D.: The ZollingerEllison syndrome: reappraisal and evaluation of 260 registered cases, Ann. Surg. 160:512, 1964. 5. Zollinger, R. M., Elliott. D. W., Endahl, G. L., Grant, G. N., Goswitz, J. T., and Taft, D. A.: Origin of the &erogenic hormone in endocrine induced ulcer, Ann. Surg. 156:.570, 1962.
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6. Roberts, W. C., and Sjoerdsma, A.: The cardiac disease associated with the carcinoid syndrome (carcinoid heart disease), Am. J. Med. 36:5, 1964. 7. Wenger, R.: Ein Fall von Endokardfibrosierung bei Karzinoidsyndrom, Ztschr. Kreislaufforsch. 54:(2), 123, 1965.