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Diagnosis Of Diseases Of The Pancreas
DIAGNOSIS OF DISEASES OF THE PANCREAS FRANK F. ALLBRITTEN, JR.,
M.D., F.A.C.S. * M.D.t
AND
C. LOWRY PRESSLY,
THE diagnosis of diseases of the pancreas amenable to surgical treatment is dependent, as is the diagnosis of disease in other organs, upon the symptoms produced, the findings of the physical examination, and the laboratory determination of changes in function. The impossibility of palpating the organ by physical examination, the lack of adequate laboratory estimation of its exocrine function, and the inability to visualize the gland radiologically all make the diagnosis of pancreatic disease especially difficult. Since effective means of treatment for various diseases of the pancreas are now available there has been increasing interest in early and accurate diagnosis. The symptoms and findings are influenced considerably by certain anatomical features that require particular considerations. 1. The deep retroperitoneal position of the organ makes it inaccessible to satisfactory direct examination. Interposition of the stomach, omentum and transverse .colon anteriorly and the lumbar muscles posteriorly precludes adequate palpation of the organ. 2. Juxtaposition of the common bile duct to the head of the pancreas or the passage of the duct through the pancreas exposes the duct to the influence of changes occurring within the pancreas. Edema, scar formation, or a neoplasm within this organ may then be first recognized by symptoms or obstruction of the common bile duct rather than by obstruction of the exocrine or endocrine secretion of the pancreas. .3. The pancreas lies in close relationship to the celiac, superior mesenteric and splenic plexuses. Peripancreatic edema or inflammation directly involves these structures. Consideration of these few anatomical features largely explains the presence or absence of symptoms and physical findings of pancreatic diseases amenable to surgical treatment. THE LABORATORY TESTS FOR PANCREATIC DISEASE AND THEIR INTERPRETATION
As suggested by its structure the pancreas has two primary physiologic functions: (1) the secretion of digestive juice by the acinar portion From the Benjamin Franklin Clinic of the Pennsylvania Hospital, Philadelphia. * Surgeon to the Pennsylvania Hospital and Benjamin Franklin Clinic; Assitant Surgeon, Jefferson Medical College Hospital; Surgical Director, Barton Memorial Hospital; Assistant Professor of Surgery, Jefferson Medical College, and Graduate School of Medicine of the University of Pennsylvania. t Instructor in Surgery and Clinical Assistant, Jefferson Medical .College and Hospital. Now at Charlotte, N. C.
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
of the gland and (2) the elaboration by the interacinar system, or the islets of Langerhans, of internal secretions affecting the metabolism of sugar. Changes in the latter function are reflected in the raising or lowering of the sugar content of the blood. The measurement of the exocrine function of the gland offers help in diagnosis but must be interpreted with full recognition of the limitation of the tests involved. Duodenal Drainage and Ferment Estimations. The study of the exocrine function of the pancreas has been largely concerned with the volume of secretion and the ferment content of the secrction.t " 4, 8 Secretin and mecholyl have been used as stimulants; the former stimulant gives a large volume flow while the latter increases flow to a lesser extent but increases the concentration of the ferments. 9 It is felt by some that following stimulation of the pancreas concentration of the ferments is a more reliable index of pancreatic function than the total values per unit time. The tests are conducted in the early morning while the patient is in a fasting state. Specimens are obtained through a double lumen tube. The end of the tube is manipulated through the pylorus, the distal opening drains the duodenum, the proximal opening drains the stomach and reduces the amount of gastric secretion reaching the duodenum. Ten cubic centimeters of a 25 per cent emulsion of calcium carbonate in gum acacia is instilled into the stomach to neutralize excess acid and this may be repeated if the duodenal drainage is acid. Duodenal specimens are collected for ten minute periods by continuous suction. After the first specimen is obtained the pancreatic stimulant is given and three additional specimens are obtained; each is collected through a ten minute period. All specimens are preserved in iced water during collection and until ferment determinations are completed. There is dilution of pancreatic secretion by unknown quantities of gastric, hepatic and duodenal secretions and tests must be interpreted with this consideration. Amylase activity is expressed as milligrams of glucose liberated from starch by 0.001 cc. of pancreatic juice; protease activity is measured by the milligrams of amino nitrogen liberated from casein by 1 cc. of pancreatic juice; lipase activity is expressed as the amount of N/O.1 butyric acid liberated from tributyrin by 0.1 cc. of pancreatic juice. Using the Free and Myers method for determining ferment activity after pancreatic stimulation by acetyl-beta-methylcholine chloride the minimal ferment activity in patients without disease of the pancreas is 4 mg. of reducing sugar for amylase, 50 mg. of nonprotein nitrogen for protease and 8 cc. of N/O.l butyric acid for lipase." The changes encountered in pancreatic diseases are summarized in Table 1.4 McClure 20 assessed the diagnostic value of duodenal drainage and ferment estimations as follows: "(a) Normal enzymatic concentrations and no bile demonstrate that the lesion is in the biliary tract above the ampulla of Vater. If bile
DIAGNOSIS OF DISEASES OF PANCREAS
1629
reappears after repeated instillation of magnesium sulfate solution into the duodenum it is highly probable that the obstruction of the biliary tract is of benign character. The more concentrated the bile that is obtained the more probably benign is the lesion. But if bile does not reappear, the chance that the lesion is benignis much more remote. "(b) Abnormal enzymatic concentrations, with the initial presence of bile, especially if the bile is relatively concentrated, or if it reappears after intraduodenal instillation of magnesium sulfate solution, suggest TABLE 1 EXOCRINE FUNCTION OF PANCREAS
pH
Disease
Volume
Amylase
Protease
Lipase
Average median value for the 4 fractions (before and after mecholyl stimulation) (Bauman) Acute pancreatitis Recurrent pancreatitis Advanced pancreatitis Carcinoma of pancreas (head) Carcinoma of bile ducts Pe rnicious anemia Sprue (nontroppical)
16 cc.
9
141
13
Increased
Decreased
Decreased
Increased
Increased
Decreased
Increased
Increased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
benign obstruction in the region of the ampulla of Vater. In such cases the reappearance of bile may be accompanied by increase in enzymatic concentrations. "(c) Abnormal decreased enzymatic concentrations, when bile remains absent from the duodenum in spite of repeated intraduodenal administration of magnesium sulfate, suggest cancer of the head of the pancreas. "(d) Duodenal contents grossly discolored with blood, with abnormal enzymatic concentrations, and containing no bile denote cancer in-
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
volving the head of the pancreas, common bile duct and wall of the duodenum." The pancreas has a remarkable functional reserve and small remnants of normal pancreatic tissue will produce sufficient insulin to meet the usual metabolic demands and an external secretion that cannot be differentiated from that of a normal gland. As much as 90 per cent of the gland may be involved by disease without giving rise to symptoms.' This suggests low ferment concentrations in the external secretion would be found only with very extensive disease. However this is not true as ferment values below the accepted normal range may be present 'without demonstrable morphologic change.' Large lesions in the body or tail of the pancreas may not demonstrably effect pancreatic activity while a small obstructive lesion in the head of the organ may give rise to appreciable changes. When the results of the laboratory studies of pancreatic ferment are correlated with clinical findings it can be seen such studies are a useful diagnostic tool. Intestinal Absorption Studies. Intestinal absorption studies in pancreatic disease have resulted in considerable variation in the results reported. Factors other than pancreatic secretion are concerned in fat digestion and absorption. In the absence of pancreatic secretion there is an increased lipolytic activity of the gastric juice that is probably due to the maintenance of an acid chyme in the upper portion of the small bowel. When pancreatic ferments are absent gastric lipase may initiate emulsification of fat. In the presence of increased acid the fatty acid-bile combination results in the splitting of fats and their subsequent absorption. Carbohydrate absorption from the gastrointestinal tract is not appreciably altered by the absence of pancreatic ferments. Protein absorption is impaired in the absence of pancreatic ferments but the prolonged action of the acid gastric juice through the upper small bowel in combination with the protein-splitting properties of the succus entericus results in relatively good absorption. From these considerations it is evident that absorption studies based on fecal analysis are of limited diagnostic value in that only an advanced degree of impaired function would be detectable. In instances of impaired fat or protein absorption the changes in absorption produced by pancreatic substitutes would seem to be a reliable index of their value." Blood Amylase Test. The blood serum amylase test affords one of the most reliable laboratory tests for pancreatic disease. Elman" recognized the elevation of serum amylase in acute pancreatitis and since the development of a better quantitative test by Somogyi" it has become a standard laboratory diagnostic test. The test serum, standard starch substrate, and a buffer are incubated at 40°C. for thirty minutes. Enzymatic activity is terminated by precipitating the proteins in the solution. A filtrate of the solution is then tested for reducing sugar by a
•
DIAGNOSIS OF DISEASES OF PANCREAS
1631
copper reagent. Control determinations are run simultaneously and their sugar values subtracted from that of the unknown. Amylase activity in units is expressed as milligrams of reducing sugar formed as glucose by 100 cc. of serum. Normal values vary between 80 and 180 units. There are lesions other than inflammation of the pancreas that give rise to elevation of the serum amylase (Table 2). Though an elevated serum amylase may indicate pancreatic disease a normal value cannot rule out the diagnosis. The test is more reliable in acute disease and will be considered further under the specific disease entity of acute pancreatitis. The urine amylase values parallel the serum amylase except in the presence of renal disease. The reliability of the blood amylase is such that there is no longer use for urine amylase studies for diagnosis. Blood Lipase Test. Blood lipase measurements show trends comparable to amylase determinations but as the technic is more difficult it has been largely supplanted by the latter test. TABLE 2 SERUM AMYLASE ACTIVITY IN
Acute pancreatitis Recurrent pancreatitis Advanced pancreatitis Peptic ulcer with perforation into pancreas Simple duodenal and gastric ulcer Carcinoma of pancreas Stone in common duct Cholecystitis Salivary gland disease Chronic nephritis
V ARIOusDISEASES Increased Increased Decreased Increased Normal Increased 50% normal Increased 70% Slight increase or decrease Increased Increased
Serum Phosphatase Test. Serum phosphatase shows no alteration in uncomplicated pancreatic disease. However pancreatic disease is commonly associated with disease of the liver and biliary tract and a differentiation between the primary sites is useful. The use of the serum phosphatase test in conjunction with the serum amylase and serum lipase determinations may distinguish one primary site from the other. If the amylase and lipase values are normal and the phosphatase is elevated, the liver alone is involved. If all three show elevation both organs are Involved. The time element must be taken into consideration in such tests as the phosphatase will remain elevated throughout the period of hepatic obstruction while the serum amylase and lipase may be elevated only during the early stages of pancreatic disease. All blood studies will be of more value if they can be interpreted simultaneously with duodenal ferment values. Serum Calcium Determinations, Serum calcium may be decreased in acute pancreatic necrosis." This is accounted for by the utilization of
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
the calcium in soap formation at the site of fat necrosis from lipase activity.It has been found the diffusible serum calcium tends to remain normal though there is a decrease in the total serum calcium. A high calcium content was found within the tissues of the pancreas itself early in the disease; the surrounding tissue had only a slight increase in calcium content. Late in the disease both pancreas and peripancreatic tissue had a high calcium content indicating the lipase activity had extended beyond the confines of the pancreas with a more extensive deposition of calcium soaps. SPECIFIC PANCREATIC DISEASES
Congenital Abnormalities of the Pancreas. Pancreatic tissue may be present outside its usual location and have no anatomical or vascular continuity with the pancreas. There are two usual aberrant types of surgical significance. The annular pancreas usually encircles the second portion of the duodenum. The aberrant pancreatic nodule usually lies in the wall of the stomach, duodenum or jejunum though it may be present in other locations. The annular pancreas may give rise to symptoms of duodenal obstruction. Its presence may be demonstrated by a barium meal. The majority are asymptomatic and are found at autopsy as incidental findings though it must be considered as a possible etiologic agent in duodenal obstruction. Aberrant pancreatic nodules may show inflammation, hemorrhage, necrosis, cyst formation, benign and malignant changes. The tissue adjacent to the nodules may show fat necrosis, ulceration, hemorrhage and diverticulum formation. The symptoms produced vary and are dependent upon the location of the lesion but generally are those produced by gastroduodenal lesions. The lesion is usually 1 to 4 cm. in diameter and can be demonstrated in the stomach and duodenum by roentgenograms. When the mass is demonstrated in the stomach it is usually diagnosed as a benign tumor, an ulcer or malignant tumor. Duodenal masses are generally diagnosed roentgenologically- as duodenal ulcers. Direct examination of the mass at operation generally permits a diagnosis of a benign tumor." Cysts of the Pancreas. Cysts may be divided into the following types: (1) congenital cysts, (2) retention cysts, (3) cystadenomas, (4) echinococcus cysts and (5) psuedocysts. Congenital cysts are only occasionally of .surgical significance. In this group multiple obstructions of large and small pancreatic ducts result in pancreatic insufficiency that varies in intensity with the extent of the lesions. It is commonly associated with narrowing or atresias of other epithelial lined structures such as bowel, bronchi, cystic ducts and ureters.' The disease should be suspected when
DIAGNOSIS OF DISEASES OF PANCREAS
1633
delay of body development and steatorrhea occurs. Laboratory studies will show absence of lipase and protease in duodenal contents with a high neutral fat content of the stool on a normal diet. In the presence of cystic change throughout the pancreas a single large cyst may present as an abdominal tumor and require operative intervention. The other cystic lesions of the pancreas produce symptoms referrable to (1) regional pressure or (2) pancreatic insufficiency. The latter group may vary from a mild insufficiency that is hardly detectable by present tests to a severe insufficiency. The symptoms of insufficiency are generally much less prominent than those of regional pressure from a tumor mass in the epigastrium. Local symptoms depend upon the size of the mass. Duodenal obstruction common duct compression, portal vein obstruction, torsion of the mesenteric vessels, ureteral obstruction or vena caval obstruction with consequent appropriate findings may result fro~ local pressure of the mass. The mass can change in size rather quickly if hemorrhage into the cyst occurs or if it is partially evacuated into the gastrointestinal tract by way of the pancreatic ducts. Roentgenographic findings depend upon the location of the cyst in the pancreas. Under fluoroscopic observation the mass can be palpated outside the stomach and duodenum, the curve of the duodenum may be expanded and pressure defects in the greater curvature of the stomach and on the duodenum may occur. Simultaneous use of a barium enema may clearly locate the cystic mass. The differential diagnosis of other retroperitoneal tumors may prove difficult and is based largely upon history, and special studies of suspected organs. Inflammatory Diseases of Pancreas. Acute Pancreatitis. In 1889 Fitz" recognized and described acute pancreatitis. Little has been added to the description of symptoms and findings of the disease though the accuracy of diagnosis has been increased through accumulation of great numbers of cases and the use of laboratory tests. The acute inflammatory changes may show edema, hemorrhage or necrosis as the predominant finding depending upon the severity and duration of the inflammatory process. Although no ageis exempt, the disease strikes most frequently during the middle years of life, chiefly among obese individuals; females are affected more frequently than males. Alcoholism, recent dietary intemperance or chronic disease of the biliary tract is often associated with acute pancreatitis." The onset is usually rapid with a spreading epigastric pain generally the first and most prominent symptom. It is severe and excruciating, filling the entire upper abdomen and frequently radiating to the back. Persistent nausea and vomiting soon appear. Tenderness and muscle guarding are early signs which are most prominent over the involved area. The abdomen is usually distended and 4
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
ordinarily has a doughy feeling to palpation that is in contrast to the rigidityassociated with conditions that produce upper abdominal pain of comparable severity. The pain may be of such severity that respiration is greatly limited and the cyanosis of the lips is accentuated by the facial pallor due to pain. Soon after the onset of pain peristalsis is absent and may remain absent if chemical peritonitis occurs. It is impossible to determine the course the inflammatory process will follow immediately after the onset of the illness. Each phase may follow in rapid progression without demarcating clinical manifestations. There seems to be a great individual difference in the response to the disease. One patient may run a fulminating clinical course ending in death, with' necropsy showing only pancreatic edema, while another will progress through hemorrhage, necrosis and abscess formation, and recover from the disease. However after an interval of twenty-four to forty-eight hours, one can usually determine by the clinical course whether the process is progressive. Invaluable and remarkably accurate in establishing the diagnosis of acute pancreatitis is the serum amylase test. Unless the venous channels of the pancreas are rapidly destroyed by the fulminating necrotic process, the enzymatic level of the blood will be significantly elevated within six to twelve hours after onset. The value remains elevated during the first three to five days of the disease. An estimation of the serum lipase activity is also an accurate test for acute pancreatitis. Although it is preferred by some to the serum amylase test, it is not generally considered as useful. Hyperglycemia and glycosuria mayor may not be present but if persistent and increasing, are a grave prognostic sign. The differential diagnosis of acute pancreatitis includes acute cholecystitis, ruptured peptic ulcer, acute intestinal obstruction, coronary artery disease, renal calculi, acute appendicitis, tabetic crisis and dissecting aortic aneurysm. Chronic Pancreatitis. Chronic relapsing pancreatitis is characterized by acute exacerbations and remissions which frequently lead to disturbances in both the exocrine and endocrine functions of the pancreas. During the acute episodes, the epigastric pain may be more prominent to the right or left and frequently radiates to the back. It is described as steady, aching or burning with varying degrees of severity and frequently lasts for days before a remission. Nausea and vomiting accompany the pain. Abdominal tenderness and muscle guarding vary in intensity and location according to the underlying pathology. Between attacks of severe pain the patient may be entirely symptom-free though mild dyspepsia, postprandial fullness and gaseous eructations between acute episodes are not infrequent. Since food is frequently associated with the onset of pain, these patients usually show marked weight loss. Men are affected more frequently than women. During the acute phase, the serum enzymatic activity will show an
in and Re
194
scle per pan Com
pre sho the to b pale Du acin
DIAGNOSIS OF DISEASES OF PANCREAS
1635
increase unless the gland has been severely damaged beyond the point of response. Since necrosis and fibrosis are progressive, the islets of Langerhans may be destroyed with resulting diabetes mellitus. When pancreatic secretions are markedly diminished, fat digestion is incomplete resulting in steatorrhea; concomitantly, undigested starches and protein are found in the stools. Radiologic studies may show the
Fig. 465. Roentgenogram showing calcification of the pancreas, milk of calcium in the gallbladder associated with recurrent pancreatitis, sclerosing pancreatitis and stenosis of common bile duct. Acute pancreatitis proved at operation in 1941. Recurrent attacks of epigastric pain. Onset of jaundice in 1949. Exploration in 1949 showed obliteration of lumen of pancreatic portion of common duct by sclerosing pancreatitis. Gallbladder and common duct drained. Acholic stools persisted. Second exploration with anastomosis of end of jejunum to side of suprapancreatic portion of common duct and distal Roux type jejunojejunostomy. Complete relief of symptoms.
presence of calculi or diffuse calcification. Barium contrast studies may show widening of the duodenal loop or evidence of extrinsic pressure on the stomach if cysts are present. At exploration, the pancreas is found to be enlarged, firm and irregular. When the gland is cut the surface is pale and lobules project from gray bands of dense connective tissue. Duct dilatation may be present. Lobulation may ~be lost,~the individual acini separated by connective tissue strands of varying widths. Acinar
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
cells show degenerative and atrophic changes. In general, the picture is one of diffuse fibrosis and commonly involves the islets of Langerhans as well as the acini. Calcifications of the Pancreas. Calcifications within the pancreas (both calculi and interstitial calcification) are relatively rare conditions. The etiology is not known. Calcification in the pancreas is in approximately half of the patients with chronic pancreatitis. Calcifications may be present in the parenchyma or as true stones found within the ducts. The calcifications consist of a matrix of leukocytic and cellular debris and precipitated fatty acids in which are deposited organic and inorganic salts of calcium, chiefly calcium carbonate. The ducts show inflammatory changes and dilatation; interstitial pancreatitis usually exists. The diagnosis is made by demonstration of the shadows on the roentgenogram (Fig. 465) but can be suspected from the history of recurrent attacks of upper abdominal pain suggestive .of pancreatitis. Impairment of exocrine function may be manifest by changes in the stool. Glycosuria is present in about one-third of the cases. Hyperinsulinism. Following the discovery of insulin by Banting and Best, Harris conceived the existence of hyperinsulinism.!" The first instance of organic hyperinsulinism was reported by R. Graham who excised an islet cell adenoma in 1929.15 Recently Howard and his coworkers! 8 were able to collect 398 cases of islet cell tumors reported in the literature. The symptomatology of hyperinsulinism is explained by the increased secretion of insulin and a consequent decrease in the blood sugar. The brain is dependent upon an adequate glucose level for metabolism and when this is not available increased central nervous system activity may occur and is manifest as a convulsion. This is followed by central nervous system depression manifest in coma. The phylogenetically newer areas of the brain react first to hypoglycemia. In studies of induced hypoglycemia brain metabolism was studied by determinations of cerebral blood flow, and cerebral arterial venous differences of oxygen and glucose. Himwich-? determined the arteriovenous oxygen difference preceding hypoglycemia was 6.8 volumes per cent. This was reduced to 2.6 volumes per cent when patients lost contact with their environment, while it was only 1.8 volumes per cent when the patient was comatose. In hypoglycemic coma the cerebral arteriovenous oxygen difference was a more reliable guide to the depth of coma than was the glucose content of the blood. This indicates that in hyperinsulinism the blood sugar level is not high enough for adequate brain metabolism, those centers with the highest metabolic activity being the first to be affected. In the event metabolism is disrupted for a prolonged period, nerve cell death occurs with permanent neurological sequelae. A slow functional degeneration
DIAGNOSIS OF DISEASES OF PANCREAS
1637
of cortical centers may occur with repeated attacks. Administration of glucose in sufficient quantity before nerve changes become irreversible promptly relieves the symptoms. Spontaneous remission of an attack may occur; this is probably due to release of adrenalin which mobilized enough glycogen to overcome the hypoglycemia. The classical diagnostic criteria are: "1. Signs and symptoms of insulin shock, frequently induced by the fasting state or during exercise. 2. Repeated fasting blood sugar concentrations below 50 mg. per cent. 3. Relief of symptoms by glucose administration. 4. Lack of relief by low carbohydrate diet to exclude functional hypoglycemia as far as possible. "18 The psychic changes are the most constant symptoms of hypoglycemia and may vary from simple irritability to the far-advanced stages of convulsion and coma. Emotional instability, lack of personal care and unaccountable changes in behavior may be prominent symptoms. The relief of symptoms by eating is characteristic though some will complain of indigestion and inability to swallow. Foods high in carbohydrates are desired. Cramplike left upper quadrant abdominal pain is not infrequent. Though the extreme hypoglycemia in far-advanced hyperinsulinism is not found in other diseases, other causes of hypoglycemia must be eliminated. These include Addison's disease, hypothyroidism, pituitary cachexia, starvation or severe exertion. Liver intoxicants as arsenic, phosphorus and chloroform may give severe hypoglycemia. Though these diseases may be ruled out by history, they merit consideration. Though findings may indicate the presence of an islet cell adenoma it is not always possible to demonstrate a tumor. This has been reported in 118 instances; in thirty-seven of these a tumor was subsequently demonstrated by examination of the portion of the pancreas removed at operation or at autopsy.!" Approximately half of the patients had satisfactory relief of symptoms and findings when a partial pancreatectomy was done though no tumor was found at operation or subsequent to operation. Functioning tumors are found throughout the pancreas and may occur in heterotopic pancreatic tissue. They have been reported found in the wall of the duodenum, near the duodenum, gastrosplenic omentum, and" near but separated from both the head and the tail of the pancreas. There is no reason to believe that any site where heterotopic pancreatic tissue is found could not give rise to a functioning adenoma. Approximately 10 per cent of islet cell tumors are clinically malignant and of these two-thirds are functioning tumors. There has been some difficulty in distinguishing histologically between benign and malignant tumors.'! At present the lesions are considered malignant only if metastases can be demonstrated.
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
Cancer of the Pancreas. Early diagnosis of cancer of the pancreas remains a challenge to medicine. Though painless jaundice has been thought to be the most reliable finding for recognition of the disease it has been clearly shown to be not only an infrequent [but also a late sign of thedisease. From a careful analysis of the literature Berk! has shown that the average duration of symptoms preceding hospitalization in verified cases of carcinoma of the pancreas was six months, while the TABLE 3 CLINICAL AND LABORATORY DATA IN CANCER OF PANCREAS
Signs and Symptoms
Pain As initial symptom . As chief complaint . During course of disease . Jaundice Painless jaundice . As initial symptom . As chief complaint . During course of disease . Weight loss, average of 6.8 pounds per week . Fatigue and weakness . Anorexia . Constipation . Nausea and vomiting . Diarrhea . Physical data Palpable liver . Palpable gallbladder with jaundice at examination Palpable gallbladder with jaundice at operation or necropsy . Palpably distended gallbladder . Palpable gallbladder at operation or necropsy . Palpable pancreatic tumor .
(Berk")
Number of Collected Cases in Which Symptom or Finding Was Noted
Per Cent of Cases
379 173 1,181
49.8 48.5 76.4
217 174 157 1,361 813 186 290 573 290 679
13.8 21.8 30.5 68.8 87.4 51.1 44.4 38.7 42.3 10.8
454 175
63.2 30.9
175 729 729 707
87.3 37.5 66.6 37.3
duration of life from onset of symptoms was only slightly over seven months. From such facts one can conclude that usually patients with carcinoma of the pancreas are hospitalized only when moribund. An increasing awareness of the frequency of occurrence of the disease, the initial symptoms of pain and weight loss, and the realization of an effective treatment should substantially decrease the mortality of this condition.
s m d
b d t c f o t c c o a
DIAGNOSIS OF DISEASES OF PANCREAS
1639
Between 1 and 2 per cent of all carcinomas originate in the pancreas. The average age is in the fifth decade with males predominating in the ratio of 2:1. The head of the gland was involved in 81.7 per cent of the series analyzed by Berk." It is extremely difficult to tell the extent of involvement at the operating table and it is doubtful if symptoms and findings permit an exact localization of origin. The absence of jaundice does not indicate the head of the gland is not involved. Abdominal pain is the most common initial symptom, the most common chief complaint, and is only secondary to weight loss as the most common finding (Table 3). The pain is usually epigastric or umbilical, of aching or boring character but may be paroxysmal. Radiation to the
Fig. 466. Roentgenogram showing anterior displacement of duodenum and stomach by tumor mass in pancreas. Symptoms of pain and weight loss of four months' duration. Positive roentgenographic findings would indicate far-advanced disease and likelihood of nonresectability.
back is not infrequent. There is no special characteristic of the pain to distinguish it from other diseases of the pancreas. The loss of weight is the most frequent finding. Jaundice, unfortunately, remains the most common indication for exploratory operation though it is relatively infrequent as an initial symptom or complaint. The differential diagnosis of jaundice may be of some value in preoperative assessment of the patient. (Tables 4 and 5). Owing to the anatomical location of the pancreas, only huge pancreatic tumors can be palpated (Fig. 466). In the collected cases reviewed by Berk the gallbladder could be palpated in only half the patients when jaundice was present and in only a third of all patients with carcinoma of the pancreas." When examined during
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
TABLE 4 CLINICAL AIDS IN THE DIFFERENTIATION OF PARENCHYMAL AND OBSTRUCTIVE JAUNDICE
Factors
Age
Sex Previous history
Clinical findings 1. Pain and tenderness
2. Weight loss 3. Chills, fever, etc.
4. Characteristics of jaundice
Parenchymal Jaundice
Obstructive Jaundice Calculous
Neoplastic
~ost
frequent in Usually over 40 Usually over 50 young adults and children No sex predomi- More frequent in More frequent in nance women men May be history of Recurring n,ttacks Symptoms usually exposure to infecwith or without of moderately tious diseases, jaundice for short duration.. toxic chemicals, months or years Six months or less plasma infusion. History usually of short duration
May be present but Frequent severe Usually a dull achnot a striking feaing or gnawing pain in right ture. Tenderness type of pain in upper quadrant usually mild and epigasRUQ and epigastrium. Tendertric area. Radiation to back. May ness and muscle guarding combe very severe especially in Ca of mon pancreas and less frequently in Ca of ampulla of Vater and common bile ducts. Tenderness and muscle guarding not prominent Usually slight Moderate to se- Common vere Usually moderate Chills and fever Not characteristic temperature elefrequently ac-usually absent vation company acute unless accompanying cholangitis, attacks etc. Pre-icteric stage of Usually seen Usually gradual and 1-7 days marked progressive but shortly after atby anorexia, nautack of acute remissions occur. sea and vomiting. biliary colic. May progre ss to Symptoms usually Jaundice usucomplete obstrucsubside as clinical ally moderately tion of common jaundice appears bile duct intense and intermittent
t
o o c a p a p l
1641
DIAGNOSIS OF DISEASES OF PANCREAS
TABLE 4 (Continued)
Factors
5. Gallbladder Palpable 6. Li ve ran d spleen enlargement
Parenchymal Jaundice
Obstructive Jaundice Calculous
Neoplastic
Infrequent
Infrequent
Frequent
Liver, frequent Liver, frequent Spleen, infreSpleen, infrequent quent
Frequent
Fig. 467. Gross specimen showing stenosis of common duct by pancreatic mass. Painless jaundice of two months' duration. Barium meal showed duodenal scar. Operative finding of dilated common duct, hard pancreatic mass. Excision of head of pancreas, duodenum and distal stomach. End-to-end choledochojejunostomy and anastomosis of pancreatic duct to side of jejunum 20 em. proximal to gastrojejunostomy. Uneventful postoperative course with relief of all symptoms.
operation the gallbladder was enlarged in approximately 90 per cent of the jaundiced and in two-thirds of all patients". The diagnosis of cancer of the pancreas at operation may prove to be difficult. The clinical and laboratory findings must be evaluated carefully. In the jaundiced patient common duct stone, tumors of the common duct, ampulla and duodenum must be eliminated as etiologic agents. A mass in the pancreas is not necessarily carcinomatous. The similarity of the histologic features of inflammatory and carcinomatous change of the pan-
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F. F. ALLBRITTEN, JR., C. L. PRESSLY
TABLE 5 LABORATORY AIDS IN THE DIFFERENTIATION OF PARENCHYMAL AND OBSTRUCTIVE JAUNDICE
Factors
Parenchymal Jaundice
Obstructive Jaundice Calculous
Leukocyte count
Leukopenia with Frequently elerelative or absovated lute lymphocytosis or monocytosis or both Clay-colored stools Varies from slightly Fluctuates decreased pigmentation to clay-colored. Fluctuates Blood in stools Absent Absent
Urobilinogen in Increased urine Increased Bile in urine Van den Bergh Direct qualitative reaction Van den Bergh Rarely very high quantitative reexcept in massive necrosis. Fluctuaction ates Hyperglycemia and Absent glycosuria Duodenal drainage Bile absent early, later bile-stained leukocytes and epithelium X-ray stomach and Nothing significant duodenum (contrast study) Blood cholesterol
Alkaline phosphatase
Neoplastic Usually normal
Persistent
May be present if there is ulcerating lesion within lumen of duct or ampulla Usually decreased Usually absent or or absent decreased Increased Increased Direct Direct
Fluctuates rapidly
Usually progressive increase
Absent
Frequently present
Cholesterol and calcium bilirubinate crystals
No bile present. Blood may be present with ulcerating lesion May find distortion of stomach or duodenum by spacetaking lesion Frequently increased
Stone may be radiopaque
Frequently increased with parallel rise in cholesterol esters ·Usually less than Usually above 10 Usually above 10 10 Bodansky units Bodansky units Bodansky units Normal or decreased
DIAGNOSIS OF DISEASES OF PANCREAS
1643
rrABLE 5 (Continued)
Fig. 468. Photograph of representative section of lesion shown in Figure 467. No tumor tissue found. Diagnosis was chronic stenosing pancreatitis secondary to chronic posterior duodenal ulcer with perforation into head of pancreas.
creas adequately account for the difficulty in distinguishing between them grossly, as even the microscopic diagnosis requires care (Figs. 467 and 468). A negative biopsy and frozen section of the lesion does not eliminate carcinoma. In a group of twenty-eight patients thought to have carcinoma of the pancreas Probstein" found biopsies of the masses revealed
1644
F. F. ALLBRITTEN, JR., C. L. PRESSl.. Y
cancer in ten, while eighteen failed to show cancer. Of the latter group eleven were subsequently proved to have cancer. The presence of biliary tract disease increases the likelihood that a pancreatic mass is inflammatory rather than neoplastic," but this is only suggestive. There is no positive means of eliminating carcinoma in the presence of a pancreatic mass, though the suggestive evidence mentioned will aid the surgeon in making the final decision regarding the advisability of resection.. As the technic of the surgery of the pancreas has become established the risk of resection has been greatly decreased. The progressive and debilitating nature of chronic pancreatitis has been established." The inability to positively eliminate carcinoma as the etiologic factor in a pancreatic mass has been demonstrated. 22·The best chance of cure is in those lesions that are small. The risk of not removing the doubtful lesion may soon be greater than that of excision.
SUMMARY 1. Significant anatomical features and peculiarities of the pancreas with relation to the diagnosis of pancreatic diseases have been reviewed. 2. A review of the laboratory tests available for study of pancreatic function has been given. 3. The diagnosis of specific pancreatic diseases has been discussed.
REFERENCES 1. Anderson, D. H.: Cystic Fibrosis of the Pancreas and Its Relat.ion to Celiac
Disease. Am. J. Dis. Child. 56 :344. 1938. 2. Banting, F. G. and Best, C. H.: The Internal Secretion of the Pancreas. J. Lab. & Clin. Med. 7 :251,1922. 3. Barbosa, J. J., de C., Dockerty, M. B. and Waugh, J. M.: Pancreatic Heterotopia; Review of Literature and Report of 41 Authenticated Surgical Cases of which 25 were Clinically Significant. Surg., Gynec. & Obst., 82:527, 1946. 4. Bauman, S.: Diagnosis of Pancreatic Disease, Philadelphia, J. B. Lippincott Co., 1949. 5. Berk, J. Edward: Diagnosis of Carcinoma of the Pancreas. Arch. Int. Med. 68 :525, 1941. 6. Carter, S. J.: Serum Amylase in Chronic Alcoholism with Acute Abdominal Symptoms. Ann. Surge 122 :117,1945. 7. Child, Charles G., III: Advances in the Management of Pancreatico-Duodenal Cancers, Advances in Surgery, Vol. II. New York, Interscience Publishers, Inc., 1949. 8. Comfort, M. W.: Test of Pancreatic Function. J.A.M.A. 115:2044, 1940. 9. Comfort, M. W. and Osterberg, A. E.: Pancreatic Secretion in Man After Stimulation with Secretin and Acetyl-beta-methylcholine Chloride. Comparative Study. Arch. Int. Int. Med. 66 :688, 1940. 10. Edmondson, H. A .. and Berne, C. J.: Calcium Changes in Acute Pancreatic Necrosis. Surg., Gynec. & Obst. 79:240, 1944 11. Free, A. H. and Myers, V. C.: The Estimation of Enzymes, Amylase, Proteinase, and Lipase in Duodenal Contents. J. Lab. & Clin. Med. 28 :1387, 1943.
DIAGNOSIS OF DISEASES OF PANQREAS
1645
12. Elman, Robert: Blood Amylase in Pancreatic Disease. Proc. Soc. Exper. BioI. & Med. 25 :173, 1927. 13. Fitz, R. H.: Acute Pancreatitis. A Consideration of Pancreatic Hemorrhage, Hemorrhagic, Suppurative, and Gangrenous Pancreatitis and of Disseminated Fat Necrosis. M. Rec. 35 :197,1889. 14. Frantz, V. K.: Tumors of Islet Cells with Hyperinsulinism; Benign, Malignant, and Questionable. Ann Surg. 112:161,1940. 15. Graham, R. R.: Quoted by Howland, G., Campbell, W. R., Maltby, E. J., and Robinson, W. L.: Dysinsulinism, J.A.M.A. 93 :674,1929. 16. Harris, D.: Hyperinsulinism and Dysinsulinism. J.A.M.A. 83 :729, 1924. 17. Himwich, H. E., Frostig, J. P., Fazekas, J. F. and Hadidian, Z.: The Mechanism of the symptoms of Insulin Hypoglycemia. Am. J. Psychiat. 96 :371, 1939. 18. Howard, John M., Moss, N. Henry, and Rhoads, Jonathan E.: Hyperinsulinism and Islet Cell Tumor of the Pancreas. Internat. Abst. Surg. 90:417, 1950. 19. Lagerloef, H.: Pancreatic Function and Pancreatic Disease. New York, Macmillan Co. 1942. 20. McClure, C. W.: Observations on Physiology and Pathologic Physiology of External Pancreatic Functions. Rev. GastroenteroI. 3 :1, 1936. 21. Peterson, L. W. and Cole, W. H.: Chronic Sclerosing Pancreatitis Causing Complete Stenosis of the Common Bile Duct. Arch. Surg. 51 :12, 1945. 22. Probstein, J. G., Sachar, Leo, A. and Rindskopf, Wallace: Biopsies of Pancreatic Masses, Surgery 27: 356, 1950. 23. Somogyi, M.: Micromethods for the Estimation of Diastase. J. BioI. Chem. 125:399, 1938. 24. Wollaeger, E. E., Comfort, M. W., Clagett, O. T. and Osterberg, A. E.: Efficiency of the Gastrointestinal Tract After Resection of the Head of the Pancreas. J.A.M.A. 137 :838, 1948.
M.D., F.A.C.S. * M.D.t
AND
C. LOWRY PRESSLY,
THE diagnosis of diseases of the pancreas amenable to surgical treatment is dependent, as is the diagnosis of disease in other organs, upon the symptoms produced, the findings of the physical examination, and the laboratory determination of changes in function. The impossibility of palpating the organ by physical examination, the lack of adequate laboratory estimation of its exocrine function, and the inability to visualize the gland radiologically all make the diagnosis of pancreatic disease especially difficult. Since effective means of treatment for various diseases of the pancreas are now available there has been increasing interest in early and accurate diagnosis. The symptoms and findings are influenced considerably by certain anatomical features that require particular considerations. 1. The deep retroperitoneal position of the organ makes it inaccessible to satisfactory direct examination. Interposition of the stomach, omentum and transverse .colon anteriorly and the lumbar muscles posteriorly precludes adequate palpation of the organ. 2. Juxtaposition of the common bile duct to the head of the pancreas or the passage of the duct through the pancreas exposes the duct to the influence of changes occurring within the pancreas. Edema, scar formation, or a neoplasm within this organ may then be first recognized by symptoms or obstruction of the common bile duct rather than by obstruction of the exocrine or endocrine secretion of the pancreas. .3. The pancreas lies in close relationship to the celiac, superior mesenteric and splenic plexuses. Peripancreatic edema or inflammation directly involves these structures. Consideration of these few anatomical features largely explains the presence or absence of symptoms and physical findings of pancreatic diseases amenable to surgical treatment. THE LABORATORY TESTS FOR PANCREATIC DISEASE AND THEIR INTERPRETATION
As suggested by its structure the pancreas has two primary physiologic functions: (1) the secretion of digestive juice by the acinar portion From the Benjamin Franklin Clinic of the Pennsylvania Hospital, Philadelphia. * Surgeon to the Pennsylvania Hospital and Benjamin Franklin Clinic; Assitant Surgeon, Jefferson Medical College Hospital; Surgical Director, Barton Memorial Hospital; Assistant Professor of Surgery, Jefferson Medical College, and Graduate School of Medicine of the University of Pennsylvania. t Instructor in Surgery and Clinical Assistant, Jefferson Medical .College and Hospital. Now at Charlotte, N. C.
1627
1628
F. F. ALLBRITTEN, JR., C. L. PRESSLY
of the gland and (2) the elaboration by the interacinar system, or the islets of Langerhans, of internal secretions affecting the metabolism of sugar. Changes in the latter function are reflected in the raising or lowering of the sugar content of the blood. The measurement of the exocrine function of the gland offers help in diagnosis but must be interpreted with full recognition of the limitation of the tests involved. Duodenal Drainage and Ferment Estimations. The study of the exocrine function of the pancreas has been largely concerned with the volume of secretion and the ferment content of the secrction.t " 4, 8 Secretin and mecholyl have been used as stimulants; the former stimulant gives a large volume flow while the latter increases flow to a lesser extent but increases the concentration of the ferments. 9 It is felt by some that following stimulation of the pancreas concentration of the ferments is a more reliable index of pancreatic function than the total values per unit time. The tests are conducted in the early morning while the patient is in a fasting state. Specimens are obtained through a double lumen tube. The end of the tube is manipulated through the pylorus, the distal opening drains the duodenum, the proximal opening drains the stomach and reduces the amount of gastric secretion reaching the duodenum. Ten cubic centimeters of a 25 per cent emulsion of calcium carbonate in gum acacia is instilled into the stomach to neutralize excess acid and this may be repeated if the duodenal drainage is acid. Duodenal specimens are collected for ten minute periods by continuous suction. After the first specimen is obtained the pancreatic stimulant is given and three additional specimens are obtained; each is collected through a ten minute period. All specimens are preserved in iced water during collection and until ferment determinations are completed. There is dilution of pancreatic secretion by unknown quantities of gastric, hepatic and duodenal secretions and tests must be interpreted with this consideration. Amylase activity is expressed as milligrams of glucose liberated from starch by 0.001 cc. of pancreatic juice; protease activity is measured by the milligrams of amino nitrogen liberated from casein by 1 cc. of pancreatic juice; lipase activity is expressed as the amount of N/O.1 butyric acid liberated from tributyrin by 0.1 cc. of pancreatic juice. Using the Free and Myers method for determining ferment activity after pancreatic stimulation by acetyl-beta-methylcholine chloride the minimal ferment activity in patients without disease of the pancreas is 4 mg. of reducing sugar for amylase, 50 mg. of nonprotein nitrogen for protease and 8 cc. of N/O.l butyric acid for lipase." The changes encountered in pancreatic diseases are summarized in Table 1.4 McClure 20 assessed the diagnostic value of duodenal drainage and ferment estimations as follows: "(a) Normal enzymatic concentrations and no bile demonstrate that the lesion is in the biliary tract above the ampulla of Vater. If bile
DIAGNOSIS OF DISEASES OF PANCREAS
1629
reappears after repeated instillation of magnesium sulfate solution into the duodenum it is highly probable that the obstruction of the biliary tract is of benign character. The more concentrated the bile that is obtained the more probably benign is the lesion. But if bile does not reappear, the chance that the lesion is benignis much more remote. "(b) Abnormal enzymatic concentrations, with the initial presence of bile, especially if the bile is relatively concentrated, or if it reappears after intraduodenal instillation of magnesium sulfate solution, suggest TABLE 1 EXOCRINE FUNCTION OF PANCREAS
pH
Disease
Volume
Amylase
Protease
Lipase
Average median value for the 4 fractions (before and after mecholyl stimulation) (Bauman) Acute pancreatitis Recurrent pancreatitis Advanced pancreatitis Carcinoma of pancreas (head) Carcinoma of bile ducts Pe rnicious anemia Sprue (nontroppical)
16 cc.
9
141
13
Increased
Decreased
Decreased
Increased
Increased
Decreased
Increased
Increased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
benign obstruction in the region of the ampulla of Vater. In such cases the reappearance of bile may be accompanied by increase in enzymatic concentrations. "(c) Abnormal decreased enzymatic concentrations, when bile remains absent from the duodenum in spite of repeated intraduodenal administration of magnesium sulfate, suggest cancer of the head of the pancreas. "(d) Duodenal contents grossly discolored with blood, with abnormal enzymatic concentrations, and containing no bile denote cancer in-
1630
F. F. ALLBRITTEN, JR., C. L. PRESSLY
volving the head of the pancreas, common bile duct and wall of the duodenum." The pancreas has a remarkable functional reserve and small remnants of normal pancreatic tissue will produce sufficient insulin to meet the usual metabolic demands and an external secretion that cannot be differentiated from that of a normal gland. As much as 90 per cent of the gland may be involved by disease without giving rise to symptoms.' This suggests low ferment concentrations in the external secretion would be found only with very extensive disease. However this is not true as ferment values below the accepted normal range may be present 'without demonstrable morphologic change.' Large lesions in the body or tail of the pancreas may not demonstrably effect pancreatic activity while a small obstructive lesion in the head of the organ may give rise to appreciable changes. When the results of the laboratory studies of pancreatic ferment are correlated with clinical findings it can be seen such studies are a useful diagnostic tool. Intestinal Absorption Studies. Intestinal absorption studies in pancreatic disease have resulted in considerable variation in the results reported. Factors other than pancreatic secretion are concerned in fat digestion and absorption. In the absence of pancreatic secretion there is an increased lipolytic activity of the gastric juice that is probably due to the maintenance of an acid chyme in the upper portion of the small bowel. When pancreatic ferments are absent gastric lipase may initiate emulsification of fat. In the presence of increased acid the fatty acid-bile combination results in the splitting of fats and their subsequent absorption. Carbohydrate absorption from the gastrointestinal tract is not appreciably altered by the absence of pancreatic ferments. Protein absorption is impaired in the absence of pancreatic ferments but the prolonged action of the acid gastric juice through the upper small bowel in combination with the protein-splitting properties of the succus entericus results in relatively good absorption. From these considerations it is evident that absorption studies based on fecal analysis are of limited diagnostic value in that only an advanced degree of impaired function would be detectable. In instances of impaired fat or protein absorption the changes in absorption produced by pancreatic substitutes would seem to be a reliable index of their value." Blood Amylase Test. The blood serum amylase test affords one of the most reliable laboratory tests for pancreatic disease. Elman" recognized the elevation of serum amylase in acute pancreatitis and since the development of a better quantitative test by Somogyi" it has become a standard laboratory diagnostic test. The test serum, standard starch substrate, and a buffer are incubated at 40°C. for thirty minutes. Enzymatic activity is terminated by precipitating the proteins in the solution. A filtrate of the solution is then tested for reducing sugar by a
•
DIAGNOSIS OF DISEASES OF PANCREAS
1631
copper reagent. Control determinations are run simultaneously and their sugar values subtracted from that of the unknown. Amylase activity in units is expressed as milligrams of reducing sugar formed as glucose by 100 cc. of serum. Normal values vary between 80 and 180 units. There are lesions other than inflammation of the pancreas that give rise to elevation of the serum amylase (Table 2). Though an elevated serum amylase may indicate pancreatic disease a normal value cannot rule out the diagnosis. The test is more reliable in acute disease and will be considered further under the specific disease entity of acute pancreatitis. The urine amylase values parallel the serum amylase except in the presence of renal disease. The reliability of the blood amylase is such that there is no longer use for urine amylase studies for diagnosis. Blood Lipase Test. Blood lipase measurements show trends comparable to amylase determinations but as the technic is more difficult it has been largely supplanted by the latter test. TABLE 2 SERUM AMYLASE ACTIVITY IN
Acute pancreatitis Recurrent pancreatitis Advanced pancreatitis Peptic ulcer with perforation into pancreas Simple duodenal and gastric ulcer Carcinoma of pancreas Stone in common duct Cholecystitis Salivary gland disease Chronic nephritis
V ARIOusDISEASES Increased Increased Decreased Increased Normal Increased 50% normal Increased 70% Slight increase or decrease Increased Increased
Serum Phosphatase Test. Serum phosphatase shows no alteration in uncomplicated pancreatic disease. However pancreatic disease is commonly associated with disease of the liver and biliary tract and a differentiation between the primary sites is useful. The use of the serum phosphatase test in conjunction with the serum amylase and serum lipase determinations may distinguish one primary site from the other. If the amylase and lipase values are normal and the phosphatase is elevated, the liver alone is involved. If all three show elevation both organs are Involved. The time element must be taken into consideration in such tests as the phosphatase will remain elevated throughout the period of hepatic obstruction while the serum amylase and lipase may be elevated only during the early stages of pancreatic disease. All blood studies will be of more value if they can be interpreted simultaneously with duodenal ferment values. Serum Calcium Determinations, Serum calcium may be decreased in acute pancreatic necrosis." This is accounted for by the utilization of
1632
F. F. ALLBRITTEN, JR., C. L. PRESSLY
the calcium in soap formation at the site of fat necrosis from lipase activity.It has been found the diffusible serum calcium tends to remain normal though there is a decrease in the total serum calcium. A high calcium content was found within the tissues of the pancreas itself early in the disease; the surrounding tissue had only a slight increase in calcium content. Late in the disease both pancreas and peripancreatic tissue had a high calcium content indicating the lipase activity had extended beyond the confines of the pancreas with a more extensive deposition of calcium soaps. SPECIFIC PANCREATIC DISEASES
Congenital Abnormalities of the Pancreas. Pancreatic tissue may be present outside its usual location and have no anatomical or vascular continuity with the pancreas. There are two usual aberrant types of surgical significance. The annular pancreas usually encircles the second portion of the duodenum. The aberrant pancreatic nodule usually lies in the wall of the stomach, duodenum or jejunum though it may be present in other locations. The annular pancreas may give rise to symptoms of duodenal obstruction. Its presence may be demonstrated by a barium meal. The majority are asymptomatic and are found at autopsy as incidental findings though it must be considered as a possible etiologic agent in duodenal obstruction. Aberrant pancreatic nodules may show inflammation, hemorrhage, necrosis, cyst formation, benign and malignant changes. The tissue adjacent to the nodules may show fat necrosis, ulceration, hemorrhage and diverticulum formation. The symptoms produced vary and are dependent upon the location of the lesion but generally are those produced by gastroduodenal lesions. The lesion is usually 1 to 4 cm. in diameter and can be demonstrated in the stomach and duodenum by roentgenograms. When the mass is demonstrated in the stomach it is usually diagnosed as a benign tumor, an ulcer or malignant tumor. Duodenal masses are generally diagnosed roentgenologically- as duodenal ulcers. Direct examination of the mass at operation generally permits a diagnosis of a benign tumor." Cysts of the Pancreas. Cysts may be divided into the following types: (1) congenital cysts, (2) retention cysts, (3) cystadenomas, (4) echinococcus cysts and (5) psuedocysts. Congenital cysts are only occasionally of .surgical significance. In this group multiple obstructions of large and small pancreatic ducts result in pancreatic insufficiency that varies in intensity with the extent of the lesions. It is commonly associated with narrowing or atresias of other epithelial lined structures such as bowel, bronchi, cystic ducts and ureters.' The disease should be suspected when
DIAGNOSIS OF DISEASES OF PANCREAS
1633
delay of body development and steatorrhea occurs. Laboratory studies will show absence of lipase and protease in duodenal contents with a high neutral fat content of the stool on a normal diet. In the presence of cystic change throughout the pancreas a single large cyst may present as an abdominal tumor and require operative intervention. The other cystic lesions of the pancreas produce symptoms referrable to (1) regional pressure or (2) pancreatic insufficiency. The latter group may vary from a mild insufficiency that is hardly detectable by present tests to a severe insufficiency. The symptoms of insufficiency are generally much less prominent than those of regional pressure from a tumor mass in the epigastrium. Local symptoms depend upon the size of the mass. Duodenal obstruction common duct compression, portal vein obstruction, torsion of the mesenteric vessels, ureteral obstruction or vena caval obstruction with consequent appropriate findings may result fro~ local pressure of the mass. The mass can change in size rather quickly if hemorrhage into the cyst occurs or if it is partially evacuated into the gastrointestinal tract by way of the pancreatic ducts. Roentgenographic findings depend upon the location of the cyst in the pancreas. Under fluoroscopic observation the mass can be palpated outside the stomach and duodenum, the curve of the duodenum may be expanded and pressure defects in the greater curvature of the stomach and on the duodenum may occur. Simultaneous use of a barium enema may clearly locate the cystic mass. The differential diagnosis of other retroperitoneal tumors may prove difficult and is based largely upon history, and special studies of suspected organs. Inflammatory Diseases of Pancreas. Acute Pancreatitis. In 1889 Fitz" recognized and described acute pancreatitis. Little has been added to the description of symptoms and findings of the disease though the accuracy of diagnosis has been increased through accumulation of great numbers of cases and the use of laboratory tests. The acute inflammatory changes may show edema, hemorrhage or necrosis as the predominant finding depending upon the severity and duration of the inflammatory process. Although no ageis exempt, the disease strikes most frequently during the middle years of life, chiefly among obese individuals; females are affected more frequently than males. Alcoholism, recent dietary intemperance or chronic disease of the biliary tract is often associated with acute pancreatitis." The onset is usually rapid with a spreading epigastric pain generally the first and most prominent symptom. It is severe and excruciating, filling the entire upper abdomen and frequently radiating to the back. Persistent nausea and vomiting soon appear. Tenderness and muscle guarding are early signs which are most prominent over the involved area. The abdomen is usually distended and 4
1634
F. F. ALLBRITTEN, JR., C. L. PRESSLY
ordinarily has a doughy feeling to palpation that is in contrast to the rigidityassociated with conditions that produce upper abdominal pain of comparable severity. The pain may be of such severity that respiration is greatly limited and the cyanosis of the lips is accentuated by the facial pallor due to pain. Soon after the onset of pain peristalsis is absent and may remain absent if chemical peritonitis occurs. It is impossible to determine the course the inflammatory process will follow immediately after the onset of the illness. Each phase may follow in rapid progression without demarcating clinical manifestations. There seems to be a great individual difference in the response to the disease. One patient may run a fulminating clinical course ending in death, with' necropsy showing only pancreatic edema, while another will progress through hemorrhage, necrosis and abscess formation, and recover from the disease. However after an interval of twenty-four to forty-eight hours, one can usually determine by the clinical course whether the process is progressive. Invaluable and remarkably accurate in establishing the diagnosis of acute pancreatitis is the serum amylase test. Unless the venous channels of the pancreas are rapidly destroyed by the fulminating necrotic process, the enzymatic level of the blood will be significantly elevated within six to twelve hours after onset. The value remains elevated during the first three to five days of the disease. An estimation of the serum lipase activity is also an accurate test for acute pancreatitis. Although it is preferred by some to the serum amylase test, it is not generally considered as useful. Hyperglycemia and glycosuria mayor may not be present but if persistent and increasing, are a grave prognostic sign. The differential diagnosis of acute pancreatitis includes acute cholecystitis, ruptured peptic ulcer, acute intestinal obstruction, coronary artery disease, renal calculi, acute appendicitis, tabetic crisis and dissecting aortic aneurysm. Chronic Pancreatitis. Chronic relapsing pancreatitis is characterized by acute exacerbations and remissions which frequently lead to disturbances in both the exocrine and endocrine functions of the pancreas. During the acute episodes, the epigastric pain may be more prominent to the right or left and frequently radiates to the back. It is described as steady, aching or burning with varying degrees of severity and frequently lasts for days before a remission. Nausea and vomiting accompany the pain. Abdominal tenderness and muscle guarding vary in intensity and location according to the underlying pathology. Between attacks of severe pain the patient may be entirely symptom-free though mild dyspepsia, postprandial fullness and gaseous eructations between acute episodes are not infrequent. Since food is frequently associated with the onset of pain, these patients usually show marked weight loss. Men are affected more frequently than women. During the acute phase, the serum enzymatic activity will show an
in and Re
194
scle per pan Com
pre sho the to b pale Du acin
DIAGNOSIS OF DISEASES OF PANCREAS
1635
increase unless the gland has been severely damaged beyond the point of response. Since necrosis and fibrosis are progressive, the islets of Langerhans may be destroyed with resulting diabetes mellitus. When pancreatic secretions are markedly diminished, fat digestion is incomplete resulting in steatorrhea; concomitantly, undigested starches and protein are found in the stools. Radiologic studies may show the
Fig. 465. Roentgenogram showing calcification of the pancreas, milk of calcium in the gallbladder associated with recurrent pancreatitis, sclerosing pancreatitis and stenosis of common bile duct. Acute pancreatitis proved at operation in 1941. Recurrent attacks of epigastric pain. Onset of jaundice in 1949. Exploration in 1949 showed obliteration of lumen of pancreatic portion of common duct by sclerosing pancreatitis. Gallbladder and common duct drained. Acholic stools persisted. Second exploration with anastomosis of end of jejunum to side of suprapancreatic portion of common duct and distal Roux type jejunojejunostomy. Complete relief of symptoms.
presence of calculi or diffuse calcification. Barium contrast studies may show widening of the duodenal loop or evidence of extrinsic pressure on the stomach if cysts are present. At exploration, the pancreas is found to be enlarged, firm and irregular. When the gland is cut the surface is pale and lobules project from gray bands of dense connective tissue. Duct dilatation may be present. Lobulation may ~be lost,~the individual acini separated by connective tissue strands of varying widths. Acinar
1636
F. F. ALLBRITTEN, JR., C. L. PRESSLY
cells show degenerative and atrophic changes. In general, the picture is one of diffuse fibrosis and commonly involves the islets of Langerhans as well as the acini. Calcifications of the Pancreas. Calcifications within the pancreas (both calculi and interstitial calcification) are relatively rare conditions. The etiology is not known. Calcification in the pancreas is in approximately half of the patients with chronic pancreatitis. Calcifications may be present in the parenchyma or as true stones found within the ducts. The calcifications consist of a matrix of leukocytic and cellular debris and precipitated fatty acids in which are deposited organic and inorganic salts of calcium, chiefly calcium carbonate. The ducts show inflammatory changes and dilatation; interstitial pancreatitis usually exists. The diagnosis is made by demonstration of the shadows on the roentgenogram (Fig. 465) but can be suspected from the history of recurrent attacks of upper abdominal pain suggestive .of pancreatitis. Impairment of exocrine function may be manifest by changes in the stool. Glycosuria is present in about one-third of the cases. Hyperinsulinism. Following the discovery of insulin by Banting and Best, Harris conceived the existence of hyperinsulinism.!" The first instance of organic hyperinsulinism was reported by R. Graham who excised an islet cell adenoma in 1929.15 Recently Howard and his coworkers! 8 were able to collect 398 cases of islet cell tumors reported in the literature. The symptomatology of hyperinsulinism is explained by the increased secretion of insulin and a consequent decrease in the blood sugar. The brain is dependent upon an adequate glucose level for metabolism and when this is not available increased central nervous system activity may occur and is manifest as a convulsion. This is followed by central nervous system depression manifest in coma. The phylogenetically newer areas of the brain react first to hypoglycemia. In studies of induced hypoglycemia brain metabolism was studied by determinations of cerebral blood flow, and cerebral arterial venous differences of oxygen and glucose. Himwich-? determined the arteriovenous oxygen difference preceding hypoglycemia was 6.8 volumes per cent. This was reduced to 2.6 volumes per cent when patients lost contact with their environment, while it was only 1.8 volumes per cent when the patient was comatose. In hypoglycemic coma the cerebral arteriovenous oxygen difference was a more reliable guide to the depth of coma than was the glucose content of the blood. This indicates that in hyperinsulinism the blood sugar level is not high enough for adequate brain metabolism, those centers with the highest metabolic activity being the first to be affected. In the event metabolism is disrupted for a prolonged period, nerve cell death occurs with permanent neurological sequelae. A slow functional degeneration
DIAGNOSIS OF DISEASES OF PANCREAS
1637
of cortical centers may occur with repeated attacks. Administration of glucose in sufficient quantity before nerve changes become irreversible promptly relieves the symptoms. Spontaneous remission of an attack may occur; this is probably due to release of adrenalin which mobilized enough glycogen to overcome the hypoglycemia. The classical diagnostic criteria are: "1. Signs and symptoms of insulin shock, frequently induced by the fasting state or during exercise. 2. Repeated fasting blood sugar concentrations below 50 mg. per cent. 3. Relief of symptoms by glucose administration. 4. Lack of relief by low carbohydrate diet to exclude functional hypoglycemia as far as possible. "18 The psychic changes are the most constant symptoms of hypoglycemia and may vary from simple irritability to the far-advanced stages of convulsion and coma. Emotional instability, lack of personal care and unaccountable changes in behavior may be prominent symptoms. The relief of symptoms by eating is characteristic though some will complain of indigestion and inability to swallow. Foods high in carbohydrates are desired. Cramplike left upper quadrant abdominal pain is not infrequent. Though the extreme hypoglycemia in far-advanced hyperinsulinism is not found in other diseases, other causes of hypoglycemia must be eliminated. These include Addison's disease, hypothyroidism, pituitary cachexia, starvation or severe exertion. Liver intoxicants as arsenic, phosphorus and chloroform may give severe hypoglycemia. Though these diseases may be ruled out by history, they merit consideration. Though findings may indicate the presence of an islet cell adenoma it is not always possible to demonstrate a tumor. This has been reported in 118 instances; in thirty-seven of these a tumor was subsequently demonstrated by examination of the portion of the pancreas removed at operation or at autopsy.!" Approximately half of the patients had satisfactory relief of symptoms and findings when a partial pancreatectomy was done though no tumor was found at operation or subsequent to operation. Functioning tumors are found throughout the pancreas and may occur in heterotopic pancreatic tissue. They have been reported found in the wall of the duodenum, near the duodenum, gastrosplenic omentum, and" near but separated from both the head and the tail of the pancreas. There is no reason to believe that any site where heterotopic pancreatic tissue is found could not give rise to a functioning adenoma. Approximately 10 per cent of islet cell tumors are clinically malignant and of these two-thirds are functioning tumors. There has been some difficulty in distinguishing histologically between benign and malignant tumors.'! At present the lesions are considered malignant only if metastases can be demonstrated.
1638
F. F. ALLBRITTEN, JR., C. L. PRESSLY
Cancer of the Pancreas. Early diagnosis of cancer of the pancreas remains a challenge to medicine. Though painless jaundice has been thought to be the most reliable finding for recognition of the disease it has been clearly shown to be not only an infrequent [but also a late sign of thedisease. From a careful analysis of the literature Berk! has shown that the average duration of symptoms preceding hospitalization in verified cases of carcinoma of the pancreas was six months, while the TABLE 3 CLINICAL AND LABORATORY DATA IN CANCER OF PANCREAS
Signs and Symptoms
Pain As initial symptom . As chief complaint . During course of disease . Jaundice Painless jaundice . As initial symptom . As chief complaint . During course of disease . Weight loss, average of 6.8 pounds per week . Fatigue and weakness . Anorexia . Constipation . Nausea and vomiting . Diarrhea . Physical data Palpable liver . Palpable gallbladder with jaundice at examination Palpable gallbladder with jaundice at operation or necropsy . Palpably distended gallbladder . Palpable gallbladder at operation or necropsy . Palpable pancreatic tumor .
(Berk")
Number of Collected Cases in Which Symptom or Finding Was Noted
Per Cent of Cases
379 173 1,181
49.8 48.5 76.4
217 174 157 1,361 813 186 290 573 290 679
13.8 21.8 30.5 68.8 87.4 51.1 44.4 38.7 42.3 10.8
454 175
63.2 30.9
175 729 729 707
87.3 37.5 66.6 37.3
duration of life from onset of symptoms was only slightly over seven months. From such facts one can conclude that usually patients with carcinoma of the pancreas are hospitalized only when moribund. An increasing awareness of the frequency of occurrence of the disease, the initial symptoms of pain and weight loss, and the realization of an effective treatment should substantially decrease the mortality of this condition.
s m d
b d t c f o t c c o a
DIAGNOSIS OF DISEASES OF PANCREAS
1639
Between 1 and 2 per cent of all carcinomas originate in the pancreas. The average age is in the fifth decade with males predominating in the ratio of 2:1. The head of the gland was involved in 81.7 per cent of the series analyzed by Berk." It is extremely difficult to tell the extent of involvement at the operating table and it is doubtful if symptoms and findings permit an exact localization of origin. The absence of jaundice does not indicate the head of the gland is not involved. Abdominal pain is the most common initial symptom, the most common chief complaint, and is only secondary to weight loss as the most common finding (Table 3). The pain is usually epigastric or umbilical, of aching or boring character but may be paroxysmal. Radiation to the
Fig. 466. Roentgenogram showing anterior displacement of duodenum and stomach by tumor mass in pancreas. Symptoms of pain and weight loss of four months' duration. Positive roentgenographic findings would indicate far-advanced disease and likelihood of nonresectability.
back is not infrequent. There is no special characteristic of the pain to distinguish it from other diseases of the pancreas. The loss of weight is the most frequent finding. Jaundice, unfortunately, remains the most common indication for exploratory operation though it is relatively infrequent as an initial symptom or complaint. The differential diagnosis of jaundice may be of some value in preoperative assessment of the patient. (Tables 4 and 5). Owing to the anatomical location of the pancreas, only huge pancreatic tumors can be palpated (Fig. 466). In the collected cases reviewed by Berk the gallbladder could be palpated in only half the patients when jaundice was present and in only a third of all patients with carcinoma of the pancreas." When examined during
1640
F. F. ALLBRITTEN, JR., C. L. PRESSLY
TABLE 4 CLINICAL AIDS IN THE DIFFERENTIATION OF PARENCHYMAL AND OBSTRUCTIVE JAUNDICE
Factors
Age
Sex Previous history
Clinical findings 1. Pain and tenderness
2. Weight loss 3. Chills, fever, etc.
4. Characteristics of jaundice
Parenchymal Jaundice
Obstructive Jaundice Calculous
Neoplastic
~ost
frequent in Usually over 40 Usually over 50 young adults and children No sex predomi- More frequent in More frequent in nance women men May be history of Recurring n,ttacks Symptoms usually exposure to infecwith or without of moderately tious diseases, jaundice for short duration.. toxic chemicals, months or years Six months or less plasma infusion. History usually of short duration
May be present but Frequent severe Usually a dull achnot a striking feaing or gnawing pain in right ture. Tenderness type of pain in upper quadrant usually mild and epigasRUQ and epigastrium. Tendertric area. Radiation to back. May ness and muscle guarding combe very severe especially in Ca of mon pancreas and less frequently in Ca of ampulla of Vater and common bile ducts. Tenderness and muscle guarding not prominent Usually slight Moderate to se- Common vere Usually moderate Chills and fever Not characteristic temperature elefrequently ac-usually absent vation company acute unless accompanying cholangitis, attacks etc. Pre-icteric stage of Usually seen Usually gradual and 1-7 days marked progressive but shortly after atby anorexia, nautack of acute remissions occur. sea and vomiting. biliary colic. May progre ss to Symptoms usually Jaundice usucomplete obstrucsubside as clinical ally moderately tion of common jaundice appears bile duct intense and intermittent
t
o o c a p a p l
1641
DIAGNOSIS OF DISEASES OF PANCREAS
TABLE 4 (Continued)
Factors
5. Gallbladder Palpable 6. Li ve ran d spleen enlargement
Parenchymal Jaundice
Obstructive Jaundice Calculous
Neoplastic
Infrequent
Infrequent
Frequent
Liver, frequent Liver, frequent Spleen, infreSpleen, infrequent quent
Frequent
Fig. 467. Gross specimen showing stenosis of common duct by pancreatic mass. Painless jaundice of two months' duration. Barium meal showed duodenal scar. Operative finding of dilated common duct, hard pancreatic mass. Excision of head of pancreas, duodenum and distal stomach. End-to-end choledochojejunostomy and anastomosis of pancreatic duct to side of jejunum 20 em. proximal to gastrojejunostomy. Uneventful postoperative course with relief of all symptoms.
operation the gallbladder was enlarged in approximately 90 per cent of the jaundiced and in two-thirds of all patients". The diagnosis of cancer of the pancreas at operation may prove to be difficult. The clinical and laboratory findings must be evaluated carefully. In the jaundiced patient common duct stone, tumors of the common duct, ampulla and duodenum must be eliminated as etiologic agents. A mass in the pancreas is not necessarily carcinomatous. The similarity of the histologic features of inflammatory and carcinomatous change of the pan-
1642
F. F. ALLBRITTEN, JR., C. L. PRESSLY
TABLE 5 LABORATORY AIDS IN THE DIFFERENTIATION OF PARENCHYMAL AND OBSTRUCTIVE JAUNDICE
Factors
Parenchymal Jaundice
Obstructive Jaundice Calculous
Leukocyte count
Leukopenia with Frequently elerelative or absovated lute lymphocytosis or monocytosis or both Clay-colored stools Varies from slightly Fluctuates decreased pigmentation to clay-colored. Fluctuates Blood in stools Absent Absent
Urobilinogen in Increased urine Increased Bile in urine Van den Bergh Direct qualitative reaction Van den Bergh Rarely very high quantitative reexcept in massive necrosis. Fluctuaction ates Hyperglycemia and Absent glycosuria Duodenal drainage Bile absent early, later bile-stained leukocytes and epithelium X-ray stomach and Nothing significant duodenum (contrast study) Blood cholesterol
Alkaline phosphatase
Neoplastic Usually normal
Persistent
May be present if there is ulcerating lesion within lumen of duct or ampulla Usually decreased Usually absent or or absent decreased Increased Increased Direct Direct
Fluctuates rapidly
Usually progressive increase
Absent
Frequently present
Cholesterol and calcium bilirubinate crystals
No bile present. Blood may be present with ulcerating lesion May find distortion of stomach or duodenum by spacetaking lesion Frequently increased
Stone may be radiopaque
Frequently increased with parallel rise in cholesterol esters ·Usually less than Usually above 10 Usually above 10 10 Bodansky units Bodansky units Bodansky units Normal or decreased
DIAGNOSIS OF DISEASES OF PANCREAS
1643
rrABLE 5 (Continued)
Fig. 468. Photograph of representative section of lesion shown in Figure 467. No tumor tissue found. Diagnosis was chronic stenosing pancreatitis secondary to chronic posterior duodenal ulcer with perforation into head of pancreas.
creas adequately account for the difficulty in distinguishing between them grossly, as even the microscopic diagnosis requires care (Figs. 467 and 468). A negative biopsy and frozen section of the lesion does not eliminate carcinoma. In a group of twenty-eight patients thought to have carcinoma of the pancreas Probstein" found biopsies of the masses revealed
1644
F. F. ALLBRITTEN, JR., C. L. PRESSl.. Y
cancer in ten, while eighteen failed to show cancer. Of the latter group eleven were subsequently proved to have cancer. The presence of biliary tract disease increases the likelihood that a pancreatic mass is inflammatory rather than neoplastic," but this is only suggestive. There is no positive means of eliminating carcinoma in the presence of a pancreatic mass, though the suggestive evidence mentioned will aid the surgeon in making the final decision regarding the advisability of resection.. As the technic of the surgery of the pancreas has become established the risk of resection has been greatly decreased. The progressive and debilitating nature of chronic pancreatitis has been established." The inability to positively eliminate carcinoma as the etiologic factor in a pancreatic mass has been demonstrated. 22·The best chance of cure is in those lesions that are small. The risk of not removing the doubtful lesion may soon be greater than that of excision.
SUMMARY 1. Significant anatomical features and peculiarities of the pancreas with relation to the diagnosis of pancreatic diseases have been reviewed. 2. A review of the laboratory tests available for study of pancreatic function has been given. 3. The diagnosis of specific pancreatic diseases has been discussed.
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Disease. Am. J. Dis. Child. 56 :344. 1938. 2. Banting, F. G. and Best, C. H.: The Internal Secretion of the Pancreas. J. Lab. & Clin. Med. 7 :251,1922. 3. Barbosa, J. J., de C., Dockerty, M. B. and Waugh, J. M.: Pancreatic Heterotopia; Review of Literature and Report of 41 Authenticated Surgical Cases of which 25 were Clinically Significant. Surg., Gynec. & Obst., 82:527, 1946. 4. Bauman, S.: Diagnosis of Pancreatic Disease, Philadelphia, J. B. Lippincott Co., 1949. 5. Berk, J. Edward: Diagnosis of Carcinoma of the Pancreas. Arch. Int. Med. 68 :525, 1941. 6. Carter, S. J.: Serum Amylase in Chronic Alcoholism with Acute Abdominal Symptoms. Ann. Surge 122 :117,1945. 7. Child, Charles G., III: Advances in the Management of Pancreatico-Duodenal Cancers, Advances in Surgery, Vol. II. New York, Interscience Publishers, Inc., 1949. 8. Comfort, M. W.: Test of Pancreatic Function. J.A.M.A. 115:2044, 1940. 9. Comfort, M. W. and Osterberg, A. E.: Pancreatic Secretion in Man After Stimulation with Secretin and Acetyl-beta-methylcholine Chloride. Comparative Study. Arch. Int. Int. Med. 66 :688, 1940. 10. Edmondson, H. A .. and Berne, C. J.: Calcium Changes in Acute Pancreatic Necrosis. Surg., Gynec. & Obst. 79:240, 1944 11. Free, A. H. and Myers, V. C.: The Estimation of Enzymes, Amylase, Proteinase, and Lipase in Duodenal Contents. J. Lab. & Clin. Med. 28 :1387, 1943.
DIAGNOSIS OF DISEASES OF PANQREAS
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12. Elman, Robert: Blood Amylase in Pancreatic Disease. Proc. Soc. Exper. BioI. & Med. 25 :173, 1927. 13. Fitz, R. H.: Acute Pancreatitis. A Consideration of Pancreatic Hemorrhage, Hemorrhagic, Suppurative, and Gangrenous Pancreatitis and of Disseminated Fat Necrosis. M. Rec. 35 :197,1889. 14. Frantz, V. K.: Tumors of Islet Cells with Hyperinsulinism; Benign, Malignant, and Questionable. Ann Surg. 112:161,1940. 15. Graham, R. R.: Quoted by Howland, G., Campbell, W. R., Maltby, E. J., and Robinson, W. L.: Dysinsulinism, J.A.M.A. 93 :674,1929. 16. Harris, D.: Hyperinsulinism and Dysinsulinism. J.A.M.A. 83 :729, 1924. 17. Himwich, H. E., Frostig, J. P., Fazekas, J. F. and Hadidian, Z.: The Mechanism of the symptoms of Insulin Hypoglycemia. Am. J. Psychiat. 96 :371, 1939. 18. Howard, John M., Moss, N. Henry, and Rhoads, Jonathan E.: Hyperinsulinism and Islet Cell Tumor of the Pancreas. Internat. Abst. Surg. 90:417, 1950. 19. Lagerloef, H.: Pancreatic Function and Pancreatic Disease. New York, Macmillan Co. 1942. 20. McClure, C. W.: Observations on Physiology and Pathologic Physiology of External Pancreatic Functions. Rev. GastroenteroI. 3 :1, 1936. 21. Peterson, L. W. and Cole, W. H.: Chronic Sclerosing Pancreatitis Causing Complete Stenosis of the Common Bile Duct. Arch. Surg. 51 :12, 1945. 22. Probstein, J. G., Sachar, Leo, A. and Rindskopf, Wallace: Biopsies of Pancreatic Masses, Surgery 27: 356, 1950. 23. Somogyi, M.: Micromethods for the Estimation of Diastase. J. BioI. Chem. 125:399, 1938. 24. Wollaeger, E. E., Comfort, M. W., Clagett, O. T. and Osterberg, A. E.: Efficiency of the Gastrointestinal Tract After Resection of the Head of the Pancreas. J.A.M.A. 137 :838, 1948.