26
Pancreas
Gerard M. Doherty, MD
EMBRYOLOGY
The pancreas appears in the fourth week of fetal life from the caudal part of the foregut as dorsal and ventral pancreatic buds. Both anlagen rotate to the right and fuse near the point of origin of the ventral pancreas. Later, as the duodenum rotates, the pancreas shifts to the left. In the adult, only the caudal portion of the head and the uncinate process are derived from the ventral pancreas. The cranial part of the head and all of the body and tail are derived from the dorsal pancreas. Most of the dorsal pancreatic duct joins with the duct of the ventral pancreas to form the main pancreatic duct (duct of Wirsung); a small part persists as the accessory duct (duct of Santorini). In 5%-10% of people, the ventral and dorsal pancreatic ducts do not fuse, and most regions of the pancreas drain through the duct of Santorini and the orifice of the minor papilla. In this case, only the small ventral pancreas drains with the common bile duct through the papilla of Vater.
ANATOMY
The pancreas is a thin elliptic organ that lies within the retroperitoneum in the upper abdomen (Figures 26–1 and 26–2). In the adult, it is 12-15 cm long and weighs 70-100 g. The gland can be divided into three portions—head, body, and tail. The head of the pancreas is intimately adherent to the medial portion of the duodenum and lies in front of the inferior vena cava and superior mesenteric vessels. A small tongue of tissue called the uncinate process lies behind the superior mesenteric vessels as they emerge from the retroperitoneum. Anteriorly, the stomach and the first portion of the duodenum lie partly in front of the pancreas. The common bile duct passes through a posterior groove in the head of the pancreas adjacent to the duodenum. The body of the pancreas is in contact posteriorly with the aorta, the left crus of the diaphragm, the left adrenal gland, and the left kidney. The tail of the pancreas lies in the hilum of the spleen. The main pancreatic duct (the duct of Wirsung) courses along the gland from the tail to the head and joins the common bile duct just before entering the duodenum at the ampulla of Vater. The accessory pancreatic duct (the duct of Santorini) enters the duodenum 2-2.5 cm proximal to the ampulla of Vater (Figure 26–1).
Figure 26–1. Anatomic configuration of pancreatic ductal system. Courtesy of W Silen.
Figure 26–2. Arterial supply and venous drainage of the pancreas. Courtesy of W Silen.
The blood supply of the pancreas is derived from branches of the celiac and superior mesenteric arteries (Figure 26–2). The superior pancreaticoduodenal artery arises from the gastroduodenal artery, runs parallel to the duodenum, and eventually meets the inferior pancreaticoduodenal artery, a branch of the superior mesenteric artery, to form an arcade. The splenic artery provides tributaries that supply the body and tail of the pancreas. The main branches are termed the dorsal pancreatic, pancreatica magna, and caudal pancreatic arteries. The venous supply of the gland parallels the arterial supply. Lymphatic drainage is into the peripancreatic nodes located along the veins.
The innervation of the pancreas is derived from the vagal and splanchnic nerves. The efferent fibers pass through the celiac plexus from the celiac branch of the right vagal nerve to terminate in ganglia located in the interlobular septa of the pancreas. Postganglionic fibers from these synapses innervate the acini, the islets, and the ducts. The visceral afferent fibers from the pancreas also travel in the vagal and splanchnic nerves, but those that mediate pain are confined to the latter. Sympathetic fibers to the pancreas pass from the splanchnic nerves through the celiac plexus and innervate the pancreatic vasculature.
PHYSIOLOGY
Exocrine Function
The external secretion of the pancreas consists of a clear, alkaline (pH 7.0-8.3) solution of 1-2 L/d containing digestive enzymes. Secretion is stimulated by the hormones secretin and cholecystokinin (CCK) and by parasympathetic vagal discharge. Secretin and CCK are synthesized, stored, and released from duodenal mucosal cells in response to specific stimuli. Acid in the lumen of the duodenum causes the release of secretin, and luminal digestion products of fat and protein cause the release of CCK.
The water and electrolyte secretion is formed by the centroacinar and intercalated duct cells principally in response to secretin stimulation. The secretion is modified by exchange processes and active secretion in the ductal collecting system. The cations sodium and potassium are present in the same concentrations as in plasma. The anions bicarbonate and chloride vary in concentration according to the rate of secretion: with increasing rate of secretion, the bicarbonate concentration increases and chloride concentration falls, so that the sum of the two is the same throughout the secretory range. Pancreatic juice helps neutralize gastric acid in the duodenum and adjusts luminal pH to the level that gives optimal activity of pancreatic enzymes.
Pancreatic enzymes are synthesized, stored (as zymogen granules), and released by the acinar cells of the gland, principally in response to CCK and vagal stimulation. Pancreatic enzymes are proteolytic, lipolytic, and amylolytic. Lipase and amylase are stored and secreted in active forms. The proteolytic enzymes are secreted as inactive precursors and are activated by the duodenal enzyme enterokinase. Other enzymes secreted by the pancreas include ribonucleases and phospholipase A. Phospholipase A is secreted as an inactive proenzyme activated in the duodenum by trypsin. It catalyzes the conversion of biliary lecithin to lysolecithin.
Turnover of protein in the pancreas exceeds that of any other organ in the body. Intravenously injected amino acids are incorporated into enzyme protein and may appear in the pancreatic juice within 1 hour. Three mechanisms prevent autodigestion of the pancreas by its proteolytic enzymes: (1) the enzymes are stored in acinar cells as zymogen granules, where they are separated from other cell proteins; (2) the enzymes are secreted in an inactive form; and (3) inhibitors of proteolytic enzymes are present in pancreatic juice and pancreatic tissue.
Endocrine Function
The function of the endocrine pancreas is to facilitate storage of foodstuffs by release of insulin after a meal and to provide a mechanism for their mobilization by release of glucagon during periods of fasting. Insulin and glucagon, as well as pancreatic polypeptide and somatostatin, are produced by the islets of Langerhans.
Insulin, a polypeptide (MW 5734) consisting of 51 amino acid residues, is formed in the beta cells of the pancreas via the precursor proinsulin. Insulin secretion is stimulated by rising or high serum concentrations of metabolic substrates such as glucose, amino acids, and perhaps short-chain fatty acids. The major normal stimulus for insulin release appears to be glucose. The release and synthesis of insulin are stimulated by activation of specific glucoreceptors located on the surface membrane of the beta cell. Insulin release is also stimulated by calcium, glucagon, secretin, CCK, vasoactive intestinal polypeptide (VIP), and gastrin, all of which sensitize the receptors on the beta cell to glucose. Epinephrine, tolbutamide, and chlorpropamide release insulin by acting on the adenylyl cyclase system.
Glucagon, a polypeptide (MW 3485) consisting of 29 amino acid residues, is formed in the α cells of the pancreas. The release of glucagon is stimulated by a low blood glucose concentration, amino acids, catecholamines, sympathetic nervous discharge, and CCK. It is suppressed by hyperglycemia and insulin.
The principal functions of insulin are to stimulate anabolic reactions involving carbohydrates, fats, proteins, and nucleic acids. Insulin decreases glycogenolysis, lipolysis, proteolysis, gluconeogenesis, ureagenesis, and ketogenesis. Glucagon stimulates glycogenolysis from the liver and proteolysis and lipolysis in adipose tissue as well as in the liver. With the increase in lipolysis, there is an increase in ketogenesis and gluconeogenesis. Glucagon increases cAMP in the liver, heart, skeletal muscle, and adipose tissue. The short-term regulation of gluconeogenesis depends on the balance between insulin and glucagon. Studies on insulin and glucagon suggest that the hormones exert their effects via receptors on the cell membrane. Before entering the systemic circulation, blood draining from the islets of Langerhans perfuses the pancreatic acini, and this exposure to high levels of hormones is thought to influence acinar function.
ANNULAR PANCREAS
Annular pancreas is a rare congenital condition in which a ring of pancreatic tissue from the head of the pancreas surrounds the descending duodenum. The abnormality usually presents in infancy as duodenal obstruction with postprandial vomiting. There is bile in the vomitus if the constriction is distal to the entrance of the common bile duct. X-rays show a dilated stomach and proximal duodenum (double bubble sign) and little or no air in the rest of the small bowel.
After correction of fluid and electrolyte imbalance, the obstructed segment should be bypassed by a duodenojejunostomy or other similar procedure. No attempt should be made to resect the obstructing pancreas, because a pancreatic fistula or acute pancreatitis often develops postoperatively.
Occasionally, annular pancreas will present in adult life with similar symptoms.
PANCREATITIS
Pancreatitis is a common nonbacterial inflammatory disease caused by activation, interstitial liberation, and autodigestion of the pancreas by its own enzymes. The process may or may not be accompanied by permanent morphologic and functional changes in the gland. Much is known about the causes of pancreatitis, but despite the accumulation of much experimental data, understanding of the pathogenesis of this disorder is still incomplete.
In acute pancreatitis, there is sudden upper abdominal pain, nausea and vomiting, and elevated serum amylase. Chronic pancreatitis is characterized by chronic pain, pancreatic calcification on x-ray, and exocrine (steatorrhea) or endocrine (diabetes mellitus) insufficiency. Attacks of acute pancreatitis often occur in patients with chronic pancreatitis. Acute relapsing pancreatitis is defined as multiple attacks of pancreatitis without permanent pancreatic scarring, a picture most often associated with biliary pancreatitis. The unsatisfactory term chronic relapsing pancreatitis, denoting recurrent acute attacks superimposed on chronic pancreatitis, will not be used in this chapter. Alcoholic pancreatitis often behaves in this way. The term subacute pancreatitis has also been used by some to denote the minor acute attacks that typically appear late in alcoholic pancreatitis.
Etiology
Most cases of pancreatitis are caused by gallstone disease or alcoholism; a few result from hypercalcemia, trauma, hyperlipidemia, and genetic predisposition; and the remainder are idiopathic. Important differences exist in the manifestations and natural history of the disease as produced by these various factors.
About 40% of cases of pancreatitis are associated with gallstone disease, which, if untreated, usually gives rise to additional acute attacks. For unknown reasons, even repeated attacks of acute biliary pancreatitis seldom produce chronic pancreatitis. Eradication of the biliary disease nearly always prevents recurrent pancreatitis. The etiologic mechanism most likely consists of transient obstruction of the ampulla of Vater and pancreatic duct by a gallstone. Choledocholithiasis is found in only 25% of cases, but because over 90% of patients excrete a gallstone in feces passed within 10 days after an acute attack, it is assumed that most attacks are caused by a gallstone or biliary sludge traversing the common duct and ampulla of Vater. Other possible steps in pathogenesis initiated by passage of the gallstone are discussed below.
In the United States, alcoholism accounts for about 40% of cases of pancreatitis. Characteristically, the patients have been heavy users of hard liquor or wine; the condition is relatively infrequent in countries where beer is the most popular alcoholic beverage. Most commonly, 6 years or more of alcoholic excess precede the initial attack of pancreatitis, and even with the first clinical manifestations, signs of chronic pancreatitis can be detected if the gland is examined microscopically. Thus, alcoholic pancreatitis is often considered to be synonymous with chronic pancreatitis no matter what the clinical findings.
Acute administration of alcohol stimulates pancreatic secretion and induces spasm in the sphincter of Oddi. This has been compared to experiments that produce acute pancreatitis by combining partial ductal obstruction and secretory stimulation. If the patient can be persuaded to stop drinking, acute attacks may be prevented, but parenchymal damage continues to occur owing to persistent ductal obstruction and fibrosis.
Hyperparathyroidism and other disorders accompanied by hypercalcemia are occasionally complicated by acute pancreatitis. With time, chronic pancreatitis and ductal calculi appear. The increased calcium concentrations in pancreatic juice that result from hypercalcemia may prematurely activate proteases. They may also facilitate precipitation of calculi in the ducts.
In some patients—especially alcoholics—hyperlipidemia appears transiently during an acute attack of pancreatitis; in others with primary hyperlipidemia (especially those associated with elevated chylomicrons and very low density lipoproteins), pancreatitis seems to be a direct consequence of the metabolic abnormality. Hyperlipidemia during an acute attack of pancreatitis is usually associated with normal serum amylase levels, because the lipid interferes with the chemical determination for amylase; urinary output of amylase may still be high. One should inspect the serum of every patient with acute abdominal pain, because if it is lactescent, pancreatitis will almost always be the correct diagnosis. If a primary lipid abnormality is present, dietary control reduces the chances of additional attacks of pancreatitis as well as other complications.
In this condition, attacks of abdominal pain usually begin in childhood. Some affected families also have aminoaciduria, but this is not a universal finding. Diabetes mellitus and steatorrhea are uncommon. Chronic calcific pancreatitis develops eventually in most patients, and many patients become candidates for operation for chronic pain. Pancreatic carcinoma is more frequent in patients with familial pancreatitis.
In certain populations where dietary protein intake is markedly deficient, the incidence of chronic pancreatitis is high. The reason for this association is obscure, especially in view of the observation that pancreatitis afflicts alcoholics with higher dietary protein and fat intake than those who consume less protein and fat.
Most cases of postoperative pancreatitis follow common bile duct exploration, especially if sphincterotomy was performed. Two practices, now largely abandoned, were often responsible: (1) use of a common duct T tube with a long arm passing through the sphincter of Oddi and (2) dilation of the sphincter to 5-7 mm during common duct exploration. Operations on the pancreas, including pancreatic biopsy, are another cause. A few cases follow gastric surgery or even operations remote from the pancreas. Pancreatitis is particularly common after cardiac surgery with cardiopulmonary bypass, where the risk factors are preoperative renal failure, valve surgery, postoperative hypotension, and (particularly) the perioperative administration of calcium chloride (> 800 mg calcium chloride per square meter of body surface area). Pancreatitis may also complicate endoscopic retrograde pancreatography or endoscopic sphincterotomy.
Rarely, pancreatitis follows Billroth II gastrectomy, owing to acute obstruction of the afferent loop and reflux of duodenal secretions under high pressure into the pancreatic ducts. The condition has been recreated experimentally in dogs (Pfeffer loop preparation).
Drugs are probably responsible for more cases of acute pancreatitis than is generally suspected. The most commonly incriminated drugs are corticosteroids, estrogen-containing contraceptives, azathioprine, thiazide diuretics, and tetracyclines. Pancreatitis associated with use of estrogens is usually the result of drug-induced hypertriglyceridemia. The mechanisms involved in the case of other drugs are unknown.
Chronic partial obstruction of the pancreatic duct may be congenital or may follow healing after injury or inflammation. Over time, the parenchyma drained by the obstructed duct is replaced by fibrous tissue, and chronic pancreatitis develops. Sometimes there are episodes of acute pancreatitis as well.
Pancreas divisum may predispose to a kind of obstructive pancreatitis. If this anomaly is present and further narrowing of the opening of the minor papilla occurs (eg, by an inflammatory process), the orifice may be inadequate to handle the flow of pancreatic juice. The diagnosis of pancreas divisum may be made by endoscopic retrograde cholangio-pancreatography (ERCP). If a patient with the anomaly is found to have documented episodes of acute pancreatitis and no other cause is found, it is reasonable to assume that the anomaly is the cause.
Surgical sphincteroplasty of the minor papilla or the insertion of a stent has been proposed as treatment, but results have been suboptimal. This may be due to the presence of irreversible parenchymal changes and the persistence of chronic inflammation. In patients with obvious changes of chronic pancreatitis, surgical treatment should consist of pancreatic resection or drainage.
In about 15% of patients, representing the third largest group after biliary and alcoholic pancreatitis, there is no identifiable cause of the condition. If investigated in greater than usual detail (eg, duodenal drainage examination for cholesterol crystals), many of these patients will be found to have gallstones or biliary sludge undetectable by ultrasound scans. Recent data have linked mutations of the cystic fibrosis gene to idiopathic pancreatitis.
Viral infections and scorpion stings may cause pancreatitis.
Pathogenesis
The concept that pancreatitis is due to enzymatic digestion of the gland is supported by the finding of proteolytic enzymes in ascitic fluid and increased amounts of phospholipase A and lysolecithins in pancreatic tissue from patients with acute pancreatitis. Experimentally, pancreatitis can be created readily if activated enzymes are injected into the pancreatic ducts under pressure. Trypsin has not been found in excessive amounts in pancreatic tissue from affected humans, possibly because of inactivation by trypsin inhibitors. Nevertheless, although the available evidence is inconclusive, the autodigestion theory is almost universally accepted. Other proposed factors are vascular insufficiency, lymphatic congestion, and activation of the kallikrein-kinin system.
For many years, trypsin and other proteases were held to be the principal injurious agents, but recent evidence has emphasized phospholipase A, lipase, and elastase as perhaps of greater importance. Trypsin ordinarily does not attack living cells, and even when trypsin is forced into the interstitial spaces, the resulting pancreatitis does not include coagulation necrosis, which is so prominent in human pancreatitis.
Phospholipase A, in the presence of small amounts of bile salts, attacks free phospholipids (eg, lecithin) and those bound in cellular membranes to produce extremely potent lyso-compounds. Lysolecithin, which would result from the action of phospholipase A on biliary lecithin, or phospholipase A itself, plus bile salts, is capable of producing severe necrotizing pancreatitis. Trypsin is important in this scheme, because small amounts are needed to activate phospholipase A from its inactive precursor.
Elastase, which is both elastolytic and proteolytic, is secreted in an inactive form. Because it can digest the walls of blood vessels, elastase has been thought to be important in the pathogenesis of hemorrhagic pancreatitis.
If autodigestion is the final common pathway in pancreatitis, earlier steps must account for the presence of active enzymes and their reaction products in the ducts and their escape into the interstitium. The following are the most popular theories that attempt to link the known etiologic factors with autodigestion.
In animals, ligation of the pancreatic duct generally produces mild edema of the pancreas that resolves within a week. Thereafter, atrophy of the secretory apparatus occurs. On the other hand, partial or intermittent ductal obstruction, which more closely mimics what seems to happen in humans, can produce frank pancreatitis if the gland is simultaneously stimulated to secrete. The major shortcoming of these experiments has been the difficulty encountered in attempting to cause severe pancreatitis in this way. However, since the human pancreas manufactures ten times as much phospholipase A as does the dog or rat pancreas, the consequences of obstruction in humans conceivably could be more serious.
Flow between the biliary and pancreatic ducts requires a common channel connecting these two systems with the duodenum. Although these ducts converge in 90% of humans, only 10% have a common channel long enough to permit biliary-pancreatic reflux if the ampulla contained a gallstone. Experimentally, pancreatitis produced by pancreatic duct obstruction alone is similar in severity to pancreatitis following obstruction of a common channel, so biliary reflux is discounted as an etiologic factor in this disease.
The above theories do not explain activation of pancreatic enzymes, a process that normally takes place through the action of enterokinase in the duodenum. In experimental animals, if the segment of duodenum into which the pancreatic duct empties is surgically converted to a closed loop, reflux of duodenal juice initiates severe pancreatitis (Pfeffer loop). Pancreatitis associated with acute afferent loop obstruction after Billroth II gastrectomy is probably the result of similar factors. Other than in this specific example, there is no direct evidence for duodenal reflux in the pathogenesis of pancreatitis in humans.
Just as the gastric mucosa must serve as a barrier to maintain high concentrations of acid, so must the epithelium of the pancreatic duct prevent diffusion of luminal enzymes into the pancreatic parenchyma. Experiments in cats have shown that the barrier function of the pancreatic duct is vulnerable to several injurious agents, including alcohol and bile acids. Furthermore, the effects of alcohol can occur even after oral ingestion, because alcohol is secreted in the pancreatic juice. Injury to the barrier renders the duct permeable to molecules as large as MW 20,000, and enzymes from the lumen may be able to enter the gland and produce pancreatitis.
Some studies have shown that a very early event in several forms of experimental pancreatitis, including that due to pancreatic duct obstruction, consists of zymogen activation within acinar cells by lysosomal hydrolases (eg, cathepsin B). This may represent the long-sought unifying explanation. Other factors must be postulated, however, to account for the variations in severity of the disease. In biliary pancreatitis, transient obstruction of the ampulla of Vater by a gallstone is most likely the first event. Alcoholic pancreatitis probably has several causes, including partial ductal obstruction, secretory stimulation, acute effects on the ductal barrier, and toxic actions of alcohol on parenchymal cells.
Severe acute pancreatitis may be complicated by multiple organ failure, principally respiratory insufficiency (acute respiratory distress syndrome), myocardial depression, renal insufficiency, and gastric stress ulceration. The pathogenesis of these complications is similar in many respects to that of multiple organ failure in sepsis, and in fact, sepsis due to pancreatic abscess formation is a contributing factor in some of the most severe cases of acute pancreatitis. During acute pancreatitis, pancreatic proteases, bacterial endotoxins, and other active agents are liberated into the systemic circulation. The endotoxin probably originates from bacteria that translocate through an abnormally permeable intestinal mucosa. Within the circulation, the proteases and the endotoxin activate the complement system (especially C5) and kinins. Complement activation leads to granulocyte aggregation and accumulation of aggregates in the pulmonary capillaries. The granulocytes release neutrophil elastase, superoxide anion, hydrogen peroxide, and hydroxide radicals, which in concert with bradykinin exert local toxic effects on the pulmonary epithelium that result in increased permeability. Arachidonate metabolites (eg, PGE2, PGI2, leukotriene B4) may also be involved in some way. Analogous events are thought to occur in other organs.
Ceppa EP et al. Hereditary pancreatitis: endoscopic and surgical management. J Gastrointest Surg 2013;17(5):847-856.
Spanier BW, Dijkgraaf MG, Bruno MJ. Epidemiology, aetiology and outcome of acute and chronic pancreatitis: an update. Best Pract Res Clin Gastroenterol 2008;22(1):45-63.
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 2013;13(4 suppl 2):e1-e15.
ESSENTIALS OF DIAGNOSIS
Abrupt onset of epigastric pain, frequently with back pain
Nausea and vomiting
Elevated serum or urinary amylase
Cholelithiasis or alcoholism (many patients)
General Considerations
While edematous and hemorrhagic pancreatitis are manifestations of the same pathologic processes and the general principles of treatment are the same, hemorrhagic pancreatitis has more complications and a higher death rate. In edematous pancreatitis, the glandular tissue and surrounding retroperitoneal structures are engorged with interstitial fluid, and the pancreas is infiltrated with inflammatory cells that surround small foci of parenchymal necrosis. Hemorrhagic pancreatitis is characterized by bleeding into the parenchyma and surrounding retroperitoneal structures and extensive pancreatic necrosis. In both forms, the peritoneal surfaces may be studded with small calcifications representing areas of fat necrosis.
Clinical Findings
The acute attack frequently begins with severe epigastric pain that radiates through to the back. The pain is unrelenting and usually associated with vomiting and retching. In severe cases, the patient may collapse from shock.
Depending on the severity of the disease, there may be profound dehydration, tachycardia, and postural hypotension. Myocardial function is depressed in severe pancreatitis, presumably because of circulating factors that affect cardiac performance. Examination of the abdomen reveals decreased or absent bowel sounds and tenderness that may be generalized but more often is localized to the epigastrium. Temperature is usually normal or slightly elevated in uncomplicated pancreatitis. Clinical evidence of pleural effusion may be present, especially on the left. If an abdominal mass is found, it probably represents a swollen pancreas (phlegmon) or, later in the illness, a pseudocyst or abscess. In 1%-2% of patients, bluish discoloration is present in the flank (Grey Turner sign) or periumbilical area (Cullen sign), indicating hemorrhagic pancreatitis with dissection of blood retroperitoneally into these areas.
The hematocrit may be elevated as a consequence of dehydration or low as a result of abdominal blood loss in hemorrhagic pancreatitis. There is usually a moderate leukocytosis, but total white blood cell counts over 12,000/mL are unusual in the absence of suppurative complications. Liver function studies are usually normal, but there may be a mild elevation of the serum bilirubin concentration (usually < 2 mg/dL).
The serum amylase concentration rises to more than three times normal within 6 hours after the onset of an acute episode and generally remains elevated for several days. Values in excess of 1000 IU/dL occur early in the attack in 95% of patients with biliary pancreatitis and 85% of patients with acute alcoholic pancreatitis. Those with the most severe disease are more apt to have amylase levels below 1000 IU/dL.
Elevated serum lipase is detectable early and for several days after the acute attack. Since the lipase level tends to be higher in alcoholic pancreatitis and the amylase level higher in gallstone pancreatitis, the lipase/amylase ratio has been suggested as a means to help distinguishing the two.
Elevated amylase levels may occur in other acute abdominal conditions, such as gangrenous cholecystitis, small bowel obstruction, mesenteric infarction, and perforated ulcer, though levels rarely exceed 500 IU/dL. Episodes of acute pancreatitis may occur without rises in serum amylase; this is the rule if hyperlipidemia is present. Furthermore, high levels may return to normal before blood is drawn.
The methods most commonly used for measuring amylase in the serum detect pancreatic amylase, salivary amylase, and macroamylase. However, hyperamylasemia is sometimes present in patients with abdominal pain when the elevated amylase levels consist entirely of salivary amylase or macroamylase and the pancreas is not inflamed.
In severe pancreatitis, the serum calcium concentration may fall as a result of calcium being complexed with fatty acids (liberated from retroperitoneal fat by lipase) and impaired reabsorption from bone owing to the action of calcitonin (liberated by high levels of glucagon). Relative hypoparathyroidism and hypoalbuminemia have also been implicated.
In about two-thirds of cases, a plain abdominal film is abnormal. The most frequent finding is isolated dilation of a segment of gut (sentinel loop) consisting of jejunum, transverse colon, or duodenum adjacent to the pancreas. Gas distending the right colon that abruptly stops in the mid or left transverse colon (colon cutoff sign) is due to colonic spasm adjacent to the pancreatic inflammation. Both of these findings are relatively nonspecific. Glandular calcification may be evident, signifying chronic pancreatitis. An upper gastrointestinal series may show a widened duodenal loop, swollen ampulla of Vater, and, occasionally, evidence of gastric irritability. Chest films may reveal pleural effusion on the left side. Occasionally, radiopaque gallstones will be apparent on plain x-rays.
Ultrasound study may demonstrate gallstones early in the attack and may be used as a baseline for sequential examinations of the pancreas.
A CT scan of the pancreas using intravenous contrast media should be obtained for one of three reasons: (1) diagnostic uncertainty, (2) confirmation/evaluation of severity based upon other markers or clinical suspicion, or (3) evaluation in the setting of clinical deterioration or failure to respond to therapy. The radiologic findings may be consistent with any of the following: relatively normal appearing pancreas, pancreatic phlegmon, pancreatic phlegmon with extension of the inflammatory process to adjacent extrapancreatic spaces, pancreatic necrosis, or pancreatic pseudocyst, or abscess formation.
Several weeks after the pancreatitis has subsided, ERCP may be of value in patients with a tentative diagnosis of idiopathic pancreatitis (ie, those who have no history of alcoholism and no evidence of gallstones on ultrasound and oral cholecystogram). This examination demonstrates gallstones or changes of chronic pancreatitis in about 40% of such patients.
Differential Diagnosis
To some extent, acute pancreatitis is a diagnosis of exclusion, for other acute upper abdominal conditions such as acute cholecystitis, penetrating or perforated duodenal ulcer, high small bowel obstruction, acute appendicitis, and mesenteric infarction must always be seriously considered. In most cases, the distinction is possible on the basis of the clinical picture, laboratory findings, and CT scans. The critical point is that the diseases with which acute pancreatitis is most likely to be confused are often lethal if not treated surgically.
Chronic hyperamylasemia occurs rarely without any relation to pancreatic disease. Some cases are associated with renal failure, chronic sialadenitis, salivary tumors, ovarian tumors, or liver disease, but often there is no explanation. Analysis of serum amylase isoenzymes is the only way to determine whether the amylase originates from salivary glands or pancreas. Macroamylasemia is a chronic hyperamylasemia in which normal amylase (usually salivary) is bound to a large serum glycoprotein or immunoglobulin molecule and is therefore not excreted into urine. The diagnosis rests on the combination of hyperamylasemia and low urinary amylase. Macroamylasemia has been found in patients with other diseases such as malabsorption, alcoholism, and cancer. Many patients have abdominal pain, but the relationship of the pain and the macroamylasemia is uncertain.
Complications
The principal complications of acute pancreatitis are abscess and pseudocyst formation. These are discussed in separate sections. Gastrointestinal bleeding may occur from adjacent inflamed stomach or duodenum, ruptured pseudocyst, or peptic ulcer. Intraperitoneal bleeding may occur spontaneously from the celiac or splenic artery or from the spleen following acute splenic vein thrombosis. Involvement of the transverse colon or duodenum by the inflammatory process may result in partial obstruction, hemorrhage, necrosis, or fistula formation.
Early identification of patients at greatest risk of complications allows them to be managed more aggressively, which appears to decrease the mortality rate. The criteria of severity that have been found to be reliable are based either on the systemic manifestations of the disease as reflected in the clinical and laboratory findings or on the local changes in the pancreas as reflected by the findings on CT scan. Ranson used the former approach to develop the staging criteria listed in Table 26–1. Just the single finding of fluid sequestration (ie, fluid administered minus urine output) exceeding 2 L/d for more than 2 days is a reasonably accurate dividing line between severe (life-threatening) and mild-to-moderate disease. The local changes in the pancreas as shown on CT scans may be even more revealing. The presence of any of the following indicates a high risk of local infection in the pancreatic bed: involvement of extrapancreatic spaces in the inflammatory process, pancreatic necrosis (areas in the pancreas that do not enhance with intravenous contrast media), and early signs of abscess formation (eg, gas bubbles in the tissue).
Table 26-1. Ranson criteria of severity of acute pancreatitis.1
Treatment
The goals of medical therapy are reduction of pancreatic secretory stimuli and correction of fluid and electrolyte derangements.
Hypoxemia must be suspected in every patient, and oxygen saturation should be monitored periodically or continuously for the first few hospital days. An occasional patient requires endotracheal intubation and mechanical ventilation. Diuretics may be useful in decreasing lung water and improving arterial oxygen saturation.
Biliary pancreatitis is caused by a gallstone becoming lodged in the ampulla of Vater. In most cases, the stone passes into the intestine but occasionally it becomes impacted in the ampulla, which results in more severe disease. Less than 10% of cases of biliary pancreatitis are severe (ie, three or more Ranson criteria), but in severe cases, endoscopic sphincterotomy performed within 72 hours of the onset of the disease has been shown to decrease the incidence of concomitant biliary sepsis and lower the mortality rate from the pancreatitis.
Surgery is generally contraindicated in uncomplicated acute pancreatitis. However, when the diagnosis is uncertain in a patient with severe abdominal pain, diagnostic laparoscopy or laparotomy is not thought to aggravate pancreatitis.
When operative evaluation has been performed for diagnosis and mild to moderate pancreatitis is found, cholecystectomy should be performed if gallstones are present, but the pancreas should be left undisturbed. Although some surgeons place drains and irrigating catheters in the region of the pancreas, we prefer to keep foreign bodies out of this area.
The diagnosis of biliary pancreatitis can usually be suspected on the basis of ultrasound studies of the gallbladder early in the acute attack. Cholecystectomy should be performed on these patients during hospitalization for the acute attack soon after the attack resolves. A longer delay (even a few weeks) is associated with a high incidence (80%) of recurrent pancreatitis. Since life-threatening attacks are uncommon in gallstone pancreatitis, operation or endoscopic therapy early in an attack is rarely justified. However, when the attack is especially severe, elective cholecystectomy should be deferred up to several months to allow complete recovery from pancreatitis.
It is currently thought that debridement of dead peripancreatic tissue, which is often (40% of cases) colonized by bacteria, reduces the mortality rate of acute severe necrotizing pancreatitis. Historical controls place the mortality rate at 50%-80% in the absence of operative treatment and 10%-40% among patients subjected to necrosectomy. The diagnosis of necrotizing pancreatitis is suspected from the clinical findings; patients treated surgically have three or more Ranson criteria and average about 4½ criteria. Contrast-enhanced CT scans obtained early in the course of the disease are studied for the presence of nonenhancing areas, which indicate lack of vascular perfusion and reflect the presence of necrotic peripancreatic fat or pancreatic parenchyma. Percutaneous needle aspiration of these areas is used to detect the presence of bacterial colonization. A distinction is made between these cases of “infected necrotizing pancreatitis” and “pancreatic abscess,” which may appear later in the course of the disease. Patients with infected necrotizing pancreatitis and severe clinical findings benefit most from surgical therapy, but laparotomy may be undertaken just because of a deteriorating condition in patients with necrotizing pancreatitis in the absence of bacterial colonization. At surgery, all peripancreatic spaces are opened and any necrotic tissue is removed by gentle blunt dissection. This can be accomplished with less invasive videoscopic techniques. Other than CT evidence of necrotic tissue with or without infection, there are presently no other criteria in general use that call for pancreatic surgery in patients with severe pancreatitis.
Surgery for complications of acute pancreatitis, such as abscess, pseudocyst, and pancreatic ascites, is discussed below.
Prognosis
The death rate associated with acute pancreatitis is about 10%, and nearly all deaths occur in a first attack and among patients with three or more Ranson criteria of severity. Respiratory insufficiency and hypocalcemia indicate a poor prognosis. The death rate associated with severe necrotizing pancreatitis is 50% or more, but surgical therapy lowers the figure to about 20%. Persistent fever or hyperamylasemia 3 weeks or longer after an attack of pancreatitis usually indicates the presence of a pancreatic abscess or pseudocyst.
Freeman ML et al. International Multidisciplinary Panel of Speakers and Moderators. Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference. Pancreas2012;41(8):1176-1194.
van Santvoort HC et al. Dutch Pancreatitis Study Group. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 2010;362(16):1491-1502.
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 2013:13(4 suppl 2):e1-e15.
ESSENTIALS OF DIAGNOSIS
Epigastric mass and pain
Mild fever and leukocytosis
Persistent serum amylase elevation
Pancreatic cyst demonstrated by ultrasound or CT scan
General Considerations
Pancreatic pseudocysts are encapsulated collections of fluid with high enzyme concentrations that arise from the pancreas. They are usually located either within or adjacent to the pancreas in the lesser sac. The walls of a pseudocyst are formed by inflammatory fibrosis of the peritoneal, mesenteric, and serosal membranes, which limits spread of the pancreatic juice as the lesion develops. The term pseudocyst denotes absence of an epithelial lining, whereas true cysts are lined by epithelium.
Two different processes are involved in the pathogenesis of pancreatic pseudocysts. Many occur as complications of severe acute pancreatitis, where extravasation of pancreatic juice and glandular necrosis form a sterile pocket of fluid that is not reabsorbed as inflammation subsides. Superinfection of such collections leads to pancreatic abscess instead of pseudocyst. In other patients, usually alcoholics or trauma victims, pseudocysts appear without preceding acute pancreatitis. The mechanism in these cases consists of ductal obstruction and formation of a retention cyst that loses its epithelial lining as it grows beyond the confines of the gland. In posttraumatic pseudocyst, symptoms usually do not appear until several weeks after the injury. Some are iatrogenic, eg, occurring during splenectomy; others follow an external blow to the abdomen.
Pseudocysts develop in about 2% of cases of acute pancreatitis. The cysts are single in 85% of cases and multiple in the remainder.
Clinical Findings
A pseudocyst should be suspected when a patient with acute pancreatitis fails to recover after a week of treatment or when, after improving for a time, symptoms return. Since it is now fairly routine to obtain a CT scan early in an attack of severe acute pancreatitis, the early stages of pseudocyst formation are often demonstrated radiographically before specific clinical findings appear. The first clinical manifestation is usually a palpable tender mass in the epigastrium, consisting of a swollen pancreas and contiguous viscera (a phlegmon). With time, the mass may subside, but if it persists it most likely represents a pseudocyst.
In other cases, the pseudocyst develops insidiously without an obvious attack of acute pancreatitis.
Regardless of the type of prodromal phase, pain is the most common finding. Fever, weight loss, tenderness, and a palpable mass are present in about half of patients. A few have jaundice, a manifestation of obstruction of the intrapancreatic segment of the bile duct.
An elevated serum amylase and leukocytosis are present in about half of patients. When present, elevated bilirubin levels reflect biliary obstruction. Of those patients with acute pancreatitis whose serum amylase remains elevated for as long as 3 weeks, about half will have a pseudocyst.
CT scan (Figure 26–3) is the diagnostic study of choice. The size and shape of the cyst and its relationship to other viscera can be seen. Acute pseudocysts are often irregular in shape; chronic pseudocysts are most often circular or nearly so. An enlarged pancreatic duct may be demonstrated in patients with chronic pancreatitis. A dilated common bile duct would suggest biliary obstruction, either from the cyst or from underlying chronic pancreatitis.
Figure 26–3. CT scan of a large pancreatic pseudocyst impinging on the posterior wall of the stomach. The large arrow indicates the pseudocyst; the smaller area indicates the stomach. A : More cephalad in the abdomen, the pseudocyst abuts the stomach and liver. B : More caudad in the abdomen, the pseudocyst is immediately posterior to the gastric antrum. The stomach is compressed against the anterior wall of the abdomen, and the duodenum is stretched over the pseudocyst, causing early satiety. A cyst in this location is usually best drained into the stomach.
The gallbladder should be studied by ultrasound to look for stones, especially in patients with acute pancreatitis. Although ultrasound can also demonstrate pseudocysts, the amount of important detail obtained is limited compared to CT scan, and consequently the role of ultrasound is mainly to follow changes in size of an acute pseudocyst already imaged by CT scan, so the amount of x-ray exposure can be minimized.
MRCP and/or ERCP should be performed if there is concern about significant abnormalities of the bile or pancreatic duct as suggested by CT scans or the results of liver function tests. Either duct may be dilated and in need of surgical drainage in conjunction with drainage of the pseudocyst. ERCP usually opacifies the pseudocyst as well, but the information is not usually of major value in planning treatment, so ERCP is not obtained routinely.
An upper gastrointestinal series will often reveal a mass in the lesser sac that distorts the stomach or duodenum, but this is not particularly useful information. The principal indication for an upper gastrointestinal series is to search for a site of gastric or duodenal obstruction in patients who are vomiting.
With wide use of sensitive imaging studies in the diagnosis of pancreatic disease, small asymptomatic pseudocysts are often demonstrated. The natural history of these subclinical lesions is benign, and there is no indication for prophylactic surgical treatment.
Differential Diagnosis
Pancreatic pseudocysts must be distinguished from pancreatic abscess and acute pancreatic phlegmon. Patients with an abscess exhibit signs of infection.
Rarely, patients with pseudocyst present with weight loss, jaundice, and a nontender palpable gallbladder and are first thought to have pancreatic carcinoma. CT scans show that the lesion is fluid-filled, which suggests the correct diagnosis.
Neoplastic cysts—either cystadenoma or cystadenocarcinoma—account for about 5% of all cases of cystic pancreatic masses and may be indistinguishable preoperatively from pseudocyst. The correct diagnosis can be made from the gross appearance supplemented by a biopsy obtained at operation.
Complications
Infection is a rare complication resulting in high fever, chills, and leukocytosis. Drainage is required as soon as the diagnosis is suspected. Some lesions can be drained externally via a catheter placed percutaneously using ultrasound guidance. Internal drainage of infected pseudocysts adherent to the stomach can be achieved surgically by cystogastrostomy; otherwise, drainage should be external, because the suture line of a Roux-en-Y cystojejunostomy may not heal.
Sudden perforation into the free peritoneal cavity produces severe chemical peritonitis, with abdominal rigidity and severe pain. Rapid enlargement of the pseudocyst is sometimes noted before it ruptures. The treatment is emergency surgery with irrigation of the peritoneal cavity and a drainage procedure for the pseudocyst. The wall of a ruptured pseudocyst is usually too flimsy to hold sutures securely, so most ruptured cysts must be drained externally. Rupture of a pseudocyst occurs in less than 5% of cases, and even with prompt treatment it may be fatal.
Bleeding may occur into the cyst cavity or an adjacent viscus into which the cyst has eroded. Intracystic bleeding may present as an enlarging abdominal mass with anemia resulting from blood loss. If the cyst has eroded into the stomach, there may be hematemesis, melena, and blood in the nasogastric aspirate. The rapidity of the blood loss often produces hemorrhagic shock, which may preclude arteriography. If time permits, however, emergency arteriography should be performed to delineate the site of bleeding, which is usually a false aneurysm of an artery in the cyst wall, and to embolize it if possible. If embolization successfully occludes the bleeding vessel, several weeks should elapse to ensure that bleeding will not recur, and at that point the pseudocyst should be drained surgically in the same fashion as a nonbleeding pseudocyst. If the bleeding cannot be stopped by embolization, emergency surgery should be performed. Usually all that can be done is to open the cyst and suture ligate the bleeding vessel in the cyst wall, followed by external or internal drainage of the cyst. Sometimes it is possible to excise the cyst, which is desirable because doing so more certainly avoids the risk of recurrent hemorrhage.
Treatment
The principal indications for treating pancreatic pseudocysts are to improve symptoms and to prevent complications. Recent data indicate that the natural history of these lesions is more benign than previously thought—that in the absence of symptoms or radiographic evidence of enlargement (and irrespective of cyst size), expectant management is not unreasonable, and that a few untreated cysts resolve spontaneously even after being stable for months. Expectant management is especially important in the first 6-12 weeks of existence of cysts that have arisen during an attack of acute pancreatitis. The chances of spontaneous resolution are about 40%; catheter drainage at this stage is meddlesome; and internal drainage of the cyst by surgery may be difficult or even impossible. Thereafter, for cysts greater than 5 cm, treatment is usually recommended over expectant management (in the absence of contraindications, such as serious concomitant disease), because most cysts can be promptly eliminated by percutaneous catheter drainage or surgical drainage into the stomach or intestine. This obviates the need for prolonged follow-up with repeated ultrasound or CT scans and avoids the risks, albeit low, of complications. Patients who present with a symptomatic pseudocyst and no history of recent acute pancreatitis may be treated without the 6- to 12-week delay, because their cyst wall is tough (mature) enough to hold sutures and allow an anastomosis with the gut. Jaundice in a patient with a pseudocyst is usually caused by pressure from the cyst on the bile duct. Draining the pseudocyst usually relieves the obstruction, but an operative cholangiogram should be obtained to make sure.
Excision is the most definitive treatment but is usually confined to chronic pseudocysts in the tail of the gland. This approach is recommended especially for cysts that follow trauma, where the head and body of the gland are normal. Most cysts should be drained either externally or internally into the gut.
External drainage is best for critically ill patients or when the cyst wall has not matured sufficiently for anastomosis to other organs. A large tube is sewn into the cyst lumen, and its end is brought out through the abdominal wall. External drainage is complicated in a third of patients by a pancreatic fistula that sometimes requires surgical drainage but on the average closes spontaneously in several months. The incidence of recurrent pseudocyst is about four times greater after external drainage than after drainage into the gut.
The preferred method of treatment is internal drainage, where the cyst is anastomosed to a Roux-en-Y limb of jejunum (cystojejunostomy), to the posterior wall of the stomach (cystogastrostomy), or to the duodenum (cystoduodenostomy). The interior of the cyst should be inspected for evidence of a tumor and biopsy performed as appropriate. Cystogastrostomy is preferable for cysts behind and densely adherent to the stomach. This may well be done laparoscopically in the future. To accomplish free, dependent drainage, Roux-en-Y cystojejunostomy provides better drainage of cysts in various other locations. Cystoduodenostomy is indicated for cysts deep within the head of the gland and adjacent to the medial wall of the duodenum—lesions that would be difficult to drain by any other technique. The procedure consists of making a lateral duodenotomy, opening into the cyst through the medial wall of the duodenum, and then closing the lateral duodenotomy. Following internal drainage, the cyst cavity becomes obliterated within a few weeks. Even after cystogastrostomy, an unrestricted diet can be allowed within a week after surgery, and x-rays taken at this time usually show only a small residual cyst cavity.
External drainage can be established by a percutaneous catheter placed into the cyst under radiographic or ultrasound control. This is the preferred method for infected pseudocysts. In some centers, it is also used for the majority of uncomplicated pseudocysts as the primary mode of therapy. About two-thirds of cysts so treated are permanently eradicated. It may also be useful to shrink a truly huge pseudocyst (eg, one that occupies half of the abdominal cavity), because it is technically difficult to obtain adequate internal drainage of these lesions into the gut. Occasionally, a sterile cyst may become infected when a narrow catheter is inserted into it. This is more likely when the cyst lumen contains debris that is not drained effectively by this technique. Chronic external pancreatic fistula is a potential complication of this method.
Two other drainage techniques have been tried: (1) passing a catheter percutaneously through the anterior abdominal wall, the anterior wall of the stomach, and through the posterior stomach into the cyst. After several weeks, the catheter is removed, and a chronic tract remains from cyst to gastric lumen. (2) Using a fiberoptic gastroscope to make a small incision through the back wall of the stomach into the cyst.
Prognosis
The recurrence rate for pancreatic pseudocyst is about 10%, and recurrence is more frequent after treatment by external drainage. Serious postoperative hemorrhage from the cyst occurs rarely—most often after cystogastrostomy. In most cases, however, surgical treatment of pseudocysts is uncomplicated and definitively solves the immediate problem. Many patients later experience chronic pain as a manifestation of underlying chronic pancreatitis.
Martin RF, Hein AR. Operative management of acute pancreatitis. Surg Clin North Am 2013;93(3):595-610.
Varadarajulu S, Bang JY, Sutton BS, et al. Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes. HPB (Oxford) 2012;14(8):539-547.
Pancreatic abscess, which complicates about 5% of cases of acute pancreatitis, is invariably fatal if it is not treated surgically. It tends to develop in severe cases accompanied by hypovolemic shock and pancreatic necrosis and is an especially frequent complication of postoperative pancreatitis. Abscess formation follows secondary bacterial contamination of necrotic pancreatic debris and hemorrhagic exudate. The organisms may spread to the pancreas hematogenously as well as directly through the wall of the transverse colon. It is unknown whether prophylactic antibiotics given early in the course of severe acute pancreatitis decrease the incidence of abscess.
Clinical Findings
An abscess should be suspected when a patient with severe acute pancreatitis fails to improve and develops rising fever or when symptoms return after a period of recovery. In most cases, there is improvement for a while before signs of infection appear 2-4 weeks after the attack began. Epigastric pain and tenderness and a palpable tender mass are clues to diagnosis. In many cases, the findings are not especially striking—ie, the temperature is only modestly elevated and the patient does not appear septic. Vomiting or jaundice may be present, but in some cases fever and leukocytosis are the only findings. The serum amylase may be elevated but usually is normal. Characteristically, the serum albumin is below 2.5 g/dL and the alkaline phosphatase is elevated. Pleural fluid and diaphragmatic paralysis may be evident on chest x-rays. An upper gastrointestinal series may show deformity of the stomach or duodenum by a mass, but it usually does not, and the changes are nonspecific in any case. Diagnostic CT scans will usually indicate the presence of a fluid collection in the area of the pancreas. Gas in the collection on plain films or CT scans is virtually diagnostic. Percutaneous CT scan-guided aspiration may be used to aid in diagnosis and obtain a specimen for Gram stain and culture.
In general, the diagnosis is difficult, treatment is often instituted late, illness is severe, and death rates are high.
Treatment
The infected collection must be drained. Percutaneous catheter drainage may be helpful as a first step in order to decrease toxicity or to obtain a specimen for culture. In some cases, catheter drainage will prove to be definitive, but most often the infected retroperitoneal space is honeycombed and contains necrotic debris that cannot pass through the catheter, so surgical debridement is necessary. It is best to consider catheter drainage as a preparatory step for surgery rather than a curative treatment, for that is the usual relationship. Otherwise, there may be a tendency to delay surgery for too long as futile efforts are repeatedly made to manipulate the catheters into better positions. In fact, the two measures—surgical debridement and catheter drainage—are complementary.
Preoperatively, the patient should be given broad-spectrum antibiotics, since the organisms are usually a mixed flora, most often Escherichia coli, Bacteroides, Staphylococcus, Klebsiella, Proteus, Candida albicans, etc. Necrotic debris should be removed and external drainage instituted.
Postoperative hemorrhage (immediate or delayed) from the abscess cavity occurs occasionally.
Prognosis
The death rate is about 20%, a consequence of the severity of the condition, incomplete surgical drainage, and the inability in some cases to make the diagnosis.
Martin RF, Hein AR. Operative management of acute pancreatitis. Surg Clin North Am 2013;93(3):595-610.
Pancreatic ascites consists of accumulated pancreatic fluid in the abdomen without peritonitis or severe pain. Since many of these patients are alcoholic, they are often thought at first to have cirrhotic ascites. The syndrome is most often due to chronic leakage of a pseudocyst, but a few cases are due to disruption of a pancreatic duct. The principal causative factors are alcoholic pancreatitis in adults and traumatic pancreatitis in children. Marked recent weight loss is a major clinical manifestation, and unresponsiveness of the ascites to diuretics is an additional diagnostic clue. The ascitic fluid, which ranges in appearance from straw-colored to blood-tinged, contains elevated protein (> 2.9 g/dL) and amylase levels. Once this condition is suspected, definitive diagnosis is based on chemical analysis of the ascitic fluid and endoscopic retrograde pancreatography. The latter procedure frequently demonstrates the point of fluid leak and allows a rational surgical approach if operation is required.
Initial therapy should consist of a period of intravenous hyperalimentation and somatostatin. This often cures the problem. If considerable improvement has not occurred within 2-3 weeks, surgery should be performed. A preoperative ERCP is essential to demonstrate the site of the leak. If it is not entirely obvious from the films taken during ERCP, a CT scan should be performed immediately afterward, while contrast media is still in the pancreatic duct. The greater sensitivity of the CT scan will be enough to reveal the tiny trickle from the pancreatic duct into the abdomen. The operation involves suturing a Roux-en-Y limb of jejunum to the site of the leak on the surface of the pancreas or a pancreatic pseudocyst. With appropriate therapy, the outlook is excellent. The death rate is low in patients treated before debilitation becomes severe.
Chronic pleural effusions of pancreatic origin represent a variant in which the pancreatic fistula drains into the chest. The diagnosis is made by measuring high concentrations of amylase (usually > 3000 IU/dL) in the fluid. A CT scan of the pancreas and retrograde pancreatogram should be obtained. Medical therapy consists of draining the fluid with a chest tube, somatostatin, and total parenteral nutrition. If after several weeks the fistula persists or if it recurs after the tube has been removed, the source of the leak on the pancreas should either be drained into a Roux-en-Y limb of jejunum or excised as part of a distal pancreatectomy.
Martin RF, Hein AR. Operative management of acute pancreatitis. Surg Clin North Am 2003;93(3):595-610.
ESSENTIALS OF DIAGNOSIS
Persistent or recurrent abdominal pain
Pancreatic calcification on x-ray in 50%
Pancreatic insufficiency in 30%; malabsorption and diabetes mellitus
Most often due to alcoholism
General Considerations
Chronic alcoholism causes most cases of chronic pancreatitis, but a few are due to gallstones, hypercalcemia, hyperlipidemia, duct obstruction from any cause, or inherited predisposition (familial pancreatitis). Direct trauma to the gland, either from an external blow or from surgical injury, can produce chronic pancreatitis if a ductal stricture develops during the healing process. In such cases, disease is often localized to the segment of gland drained by the obstructed duct. Although gallstone disease may cause repeated attacks of acute pancreatitis, this uncommonly leads to chronic pancreatitis.
Pressure within the duct is increased in patients with chronic pancreatitis (about 40 cm H2O) compared with normal subjects (about 15 cm H2O). This is a result of increased viscosity of pancreatic juice, partial obstruction by calculi, and impaired distensibility of the gland because of diffuse fibrosis. Sphincteric pressure remains in the normal range. The increased pressure causes dilation of the duct in the patient whose pancreas has not yet become fixed by scarring. It may also impair nutrient blood flow, causing further functional damage. Pathologic changes in the gland include destruction of parenchyma, fibrosis, dedifferentiation of acini, calculi, and ductal dilation.
Clinical Findings
Chronic pancreatitis may be asymptomatic, or it may produce abdominal pain, malabsorption, diabetes mellitus, or (usually) all three manifestations. The pain is typically felt deep in the upper abdomen and radiating through to the back, and it waxes and wanes from day to day. Early in the course of the disease, the pain may be episodic, lasting for days to weeks and then vanishing for several months before returning again. Attacks of acute pancreatitis may occur, superimposed on the pattern of chronic pain. Many patients become addicted to the narcotics prescribed for pain.
Abnormal laboratory findings may result from: (1) pancreatic inflammation, (2) pancreatic exocrine insufficiency, (3) diabetes mellitus, (4) bile duct obstruction, or (5) other complications such as pseudocyst formation or splenic vein thrombosis.
MRCP or endoscopic retrograde pancreatography is helpful in establishing the diagnosis of chronic pancreatitis, in ruling out pancreatic pseudocyst and neoplasm, and in preoperative planning for patients thought to be candidates for surgery. The typical findings are ductal stones and irregularity, with dilation and stenoses and, occasionally, ductal occlusion. The discovery of small, unsuspected pseudocysts is common. Retrograde cholangiography should be performed simultaneously to determine whether the common bile duct is narrowed by the pancreatitis, to determine whether biliary calculi are present, and to aid the surgeon in avoiding injury to the bile duct during operation.
Complications
The principal complications of chronic pancreatitis are pancreatic pseudocyst, biliary obstruction, duodenal obstruction, malnutrition, and diabetes mellitus. Adenocarcinoma of the pancreas occurs with greater frequency in patients with familial chronic pancreatitis than in the general population.
Treatment
Medical Treatment
Malabsorption and steatorrhea are managed with support and measures. Controlled trials have shown that administering pancreatic enzymes has little effect on the pain.
Patients with chronic pancreatitis should be urged to discontinue the use of alcohol. Abstention from alcohol will reduce chronic or episodic pain in more than half of cases even though damage to the pancreas is irreversible. Psychiatric treatment may be beneficial. Diabetes in these patients usually requires insulin.
Surgical therapy is principally of value to relieve chronic intractable pain. It is essential that every effort be made to eliminate alcohol abuse. The best surgical candidates are those whose pain persists after alcohol has been abandoned.
Surgical treatment in most cases involves a procedure that facilitates drainage of the pancreatic duct or resects diseased pancreas or that serves both purposes. The choice of operation can usually be made preoperatively based on the findings of a retrograde pancreatogram and CT scans. Coincidental bile duct obstruction is common and should be treated by simultaneous choledochoduodenostomy.
The usual finding is an irregular, widely dilated duct (1-2 cm in diameter) with points of stenosis (“chain of lakes” appearance) and ductal calculi. For such patients, a longitudinal pancreaticojejunostomy (Puestow procedure) is appropriate (Figure 26–4). The duct is opened anteriorly from the tail into the head of the gland and anastomosed side-to-side to a Roux-en-Y segment of proximal jejunum. Pain improves postoperatively in about 80% of patients, but improvement of pancreatic insufficiency is uncommon. This procedure, however, has a low rate of success when the pancreatic duct is narrow (ie, < 8 mm).
Figure 26–4. Longitudinal pancreaticojejunostomy (Puestow) for chronic pancreatitis.
Sphincteroplasty and distal (caudal) pancreaticojejunostomy (DuVal procedure) are other drainage techniques that were used more often in the past. The latter is only of historical interest, but surgical sphincteroplasty plus extraction of pancreatic ductal calculi continues in use, more often now through endoscopic access to the pancreatic duct.
Prognosis
Longitudinal pancreaticojejunostomy relieves pain in about 80% of patients with a dilated duct. Weight gain is common but less predictable. The results of pancreaticoduodenectomy are good in 80% of patients, but removal of the distal pancreas is less successful. Total pancreatectomy, which is principally reserved for failures of other operations, gives satisfying relief in 30%-90% of patients depending on the series. The reasons for these widely differing results are not known. Celiac plexus block is of lasting benefit to no more than 30% of patients. In some patients, pain subsides with advancing pancreatic insufficiency.
Except in advanced cases with continuous pain, alcoholics who can be persuaded to stop drinking often experience relief from pain and recurrent attacks of pancreatitis. In familial pancreatitis, the progress of the disease is inexorable, and many of these patients require surgery. The results of longitudinal pancreaticojejunostomy are excellent in familial pancreatitis. Narcotic addiction, diabetes, and malnutrition are serious problems in many patients.
Bachmann K et al. Is the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis? 15-years follow-up comparing the outcome after pylorus-preserving pancreatoduodenectomy and Frey procedure in chronic pancreatitis. Ann Surg 2013;258(5):815-820.
Familiari P, Boškoski I, Bove V, Costamagna G. ERCP for biliary strictures associated with chronic pancreatitis. Gastrointest Endosc Clin N Am 2013;23(4):833-845.
Issa Y, van Santvoort HC, van Goor H, et al. Surgical and endoscopic treatment of pain in chronic pancreatitis: a multidisciplinary update. Dig Surg 2013;30(1):35-50.
PANCREATIC INSUFFICIENCY (STEATORRHEA; MALABSORPTION)
Pancreatic exocrine insufficiency may follow pancreatectomy or pancreatic disease, especially chronic pancreatitis. Many patients with varying degrees of pancreatic insufficiency have no symptoms and require no treatment, whereas others may benefit greatly from a rational medical regimen.
Malabsorption and steatorrhea do not appear until more than 90% of pancreatic exocrine function is lost; with 2%-10% of normal function, steatorrhea is mild to moderate; with less than 2% of normal function, steatorrhea is severe. On a diet containing 100 g of fat/d, normal subjects excrete 5-7 g/d, and the efficiency of assimilation is similar over a wide range of fat intake. Total pancreatectomy causes about 70% fat malabsorption. If the pancreatic remnant is normal, subtotal resections may have little effect on absorption.
Pancreatic insufficiency affects fat absorption more than that of protein or carbohydrate, because protein digestion is aided by gastric pepsin and carbohydrate digestion by salivary and intestinal amylase. Malabsorption of vitamins is rarely a significant problem. Water-soluble B vitamins are absorbed throughout the small intestine, and fat-soluble vitamins, although dependent on micellar solubilization by bile salts, do not require pancreatic enzymes for absorption. Vitamin B12 malabsorption has been detected in some patients with pancreatic insufficiency, but it is rarely a clinical problem, and vitamin B12 replacement is unnecessary.
Thus, the principal problem in otherwise uncomplicated pancreatic insufficiency is fat malabsorption and accompanying caloric malnutrition.
Tests of Pancreatic Exocrine Function
Pancreatic juice is obtained by peroral duodenal intubation, and the response to an intravenous injection of secretin or CCK is measured. The results vary, depending on the dose and preparation of hormone used. Both tests (using purified hormones or the synthetic octapeptide of CCK) seem to be reliable. Pancreatic fluid should normally have a bicarbonate concentration greater than 80 mEq/L and bicarbonate output above 15 mEq/30 min.
Fluorescein dilaurate is given orally with breakfast, and urinary fluorescein excretion is measured. Release and absorption of fluorescein depend on the action of pancreatic esterase. The test is relatively specific, but considerable exocrine insufficiency is required for a positive result. It is currently the most widely used test of exocrine function because it is inexpensive and easy to do.
The patient ingests 1 g of the synthetic peptide bentiromide (Bz-Ty-PABA), and urinary excretion of aromatic amines (PABA) is measured. Cleavage of the peptide to liberate PABA depends on intraluminal chymotrypsin activity. Patients with chronic pancreatitis excrete about 50% of the normal amount of PABA.
The patient ingests a diet containing 75-100 g fat each day for 5 days. The amounts of dietary fat should be measured and should be the same each day. Excretion of less than 7% of ingested fat is normal. Clinically significant steatorrhea is present when fat malabsorption exceeds about 25%. Total pancreatectomy results in about 70% fat malabsorption.
Examination of a stool specimen for fat globules (obviously much simpler than the fat balance test) is specific and relatively sensitive for fat malabsorption.
Treatment
The diet should aim for 3000-6000 kcal/d, emphasizing carbohydrate (400 g or more) and protein (100-150 g). Patients with steatorrhea may or may not have diarrhea, and dietary restriction of fat is important mainly to control diarrhea. Patients with diarrhea may be restricted to 50 g of fat and the amount increased until diarrhea appears. Permissible fat intake averages 100 g/d distributed equally among four meals.
Pancrelipase replacement may be accomplished with pancreatic extracts containing 30,000-50,000 units of lipase distributed throughout each of four daily meals. Lesser amounts are much less effective; an hourly dosage regimen probably has no advantages.
If enzymes alone do not improve the malabsorption enough, the problem is probably due to destruction of lipase by gastric acid. This can be largely alleviated by adding an H2 receptor blocking agent to the enzyme regimen. A preparation of enzymes as enteric-coated microspheres (Pancrease) is less vulnerable to low pH and may be more effective in refractory cases.
Medium-chain triglycerides (MCT), which can be obtained as a powder or an oil, may be used as a caloric supplement. This product is more rapidly hydrolyzed and the fatty acids more readily absorbed than are long-chain triglycerides, which make up 98% of the fat in a normal diet. Unfortunately, MCT oil is relatively unpalatable and is frequently associated with nausea and vomiting, bloating, and diarrhea, which limit patient acceptance.
ADENOCARCINOMA OF THE PANCREAS
An estimated 46,420 patients will develop pancreatic cancer in the United States in 2014, and 39,590 will die of the disease. These nearly equal numbers illustrate the dismal prognosis generally associated with pancreatic carcinoma. The death rate per 100,000 people has been basically unchanged since the mid 1960s at about 10/100,000 for men and 27/100,000 for women. After tumors of the lung, prostate and colon, pancreatic carcinoma is the fourth leading cause of death due to cancer in men, and trails lung, breast and colon in women. Factors associated with an increased risk of pancreatic cancer are cigarette smoking, dietary consumption of meat (especially fried meat) and fat, previous gastrectomy (> 20 years earlier), and race.
The peak incidence is in the fifth and sixth decades. In two-thirds of cases, the tumor is located in the head of the gland; the remainder occurs in the body or tail. Ductal adenocarcinoma, mainly of a poorly differentiated cell pattern, accounts for 80% of the cancers; the remainder is islet cell tumors and cystadenocarcinomas, tumors that are discussed later in this chapter. Pancreatic adenocarcinoma is characterized by early local extension to contiguous structures and metastases to regional lymph nodes and the liver. Pulmonary, peritoneal, and distant nodal metastases occur later.
Clinical Findings
The diagnosis of pancreatic carcinoma can be extremely difficult. The typical patient who presents with abdominal pain, weight loss, and obstructive jaundice rarely presents a problem, but those with just weight loss, vague abdominal pain, and nondiagnostic x-rays are occasionally labeled psychoneurotics until the existence of cancer becomes obvious. If back pain predominates, orthopedic or neurosurgical causes may be sought at first. One characteristic feature is the tendency for the patient to seek relief of pain by assuming a sitting position with the spine flexed. Recumbency, on the other hand, aggravates the discomfort and sometimes makes sleeping in bed impossible. Sudden onset of diabetes mellitus is an early manifestation in 25% of patients.
Elevated alkaline phosphatase and bilirubin levels reflect either common duct obstruction or hepatic metastases. The bilirubin level with neoplastic obstruction averages 18 mg/dL, much higher than that generally seen with benign disease of the bile ducts. Only rarely are serum aminotransferase levels markedly elevated. Repeated examination of stool specimens for occult blood gives a positive reaction in many cases.
Serum levels of the tumor marker CA 19-9 are elevated in most patients with pancreatic cancer, but the sensitivity in resectable (< 4 cm) lesions is too low (50%) for this to serve as a screening tool. Elevated levels also occur with other gastrointestinal cancers. The greatest usefulness of CA 19-9 measurements may be in following the results of treatments. After complete resection of a tumor, elevated levels drop to normal, but they rise again with recurrence.
Nearly all patients should have a CT scan.
Percutaneous aspiration biopsy of pancreatic mass lesions is positive in 85% of malignant tumors. The procedure is relatively safe, but there is a risk of spreading a localized (resectable) tumor, so it is contraindicated in patients who are candidates for surgery. Percutaneous aspiration biopsy is principally of value to verify a presumptive diagnosis of adenocarcinoma of the pancreas in patients with radiographic evidence of unresectability. In these cases, cytologic proof is important, for treatment decisions should not be made solely on the basis of the indirect evidence provided by CT scans and other imaging tests. There is too great a risk of misdiagnosing something unusual, such as a retroperitoneal lymphoma or sarcoma, and administering inappropriate treatment.
Differential Diagnosis
The other periampullary neoplasms—carcinoma of the ampulla of Vater, distal common bile duct, or duodenum—may also present with pain, weight loss, obstructive jaundice, and a palpable gallbladder. Preoperative cholangiography and gastrointestinal x-rays may suggest the correct diagnosis, but laparotomy is sometimes required.
Complications
Obstruction of the splenic vein by tumor may cause splenomegaly and segmental portal hypertension with bleeding gastric or esophageal varices.
Treatment
Pancreatic resection for pancreatic cancer is appropriate only if all gross tumor can be removed with a standard resection. The lesion is considered resectable if the following areas are free of tumor: (1) the hepatic artery near the origin of the gastroduodenal artery; (2) the superior mesenteric artery where it courses under the body of the pancreas; and (3) the liver and regional lymph nodes. Since the pancreas is so close to the portal vein and the superior mesenteric vessels, these structures may be involved early. About 20% of cancers of the head of the pancreas can be resected, but because of local and distant spread, this is rarely possible for lesions of the body and tail.
A histologic diagnosis can usually be made at operation by aspiration biopsy. With small lesions of the head of the gland, it may be difficult to obtain a specimen for histologic diagnosis because much of the palpable mass may consist of inflamed pancreatic tissue. Occasionally, histologic diagnosis is impossible, and clinical decisions must rest on indirect evidence.
For curable lesions of the head, pancreaticoduodenectomy (Whipple procedure) is required (Figure 26–5). This involves resection of the common bile duct, the gallbladder, the duodenum, and the pancreas to the mid body. There is an increasing tendency to preserve the antrum and pylorus. Involvement of a short (< 1.5 cm) segment of the portal vein is not a contraindication to a curative resection. This is managed by a partial or circumferential resection of the affected area.
Figure 26–5. Pancreaticoduodenectomy (Whipple procedure). A : Preoperative anatomic relationships showing a tumor in the head of the pancreas. B: Postoperative reconstruction showing pancreatic, biliary, and gastric anastomoses. A cholecystectomy and bilateral truncal vagotomy are also part of the procedure. In many cases, the distal stomach and pylorus can be preserved, and vagotomy is then unnecessary.
When the procedure is performed by surgeons who do it frequently, the operative mortality rate is less than 5%. When it is performed by less experienced surgeons, the mortality rate is as high as 20%-30%. Postoperative deaths are due to complications such as pancreatic and biliary fistulas, hemorrhage, and infection.
For unresectable lesions, cholecystojejunostomy or choledochojejunostomy provides relief of jaundice and pruritus. A cholangiogram should be obtained to verify patency between the cystic and common bile ducts unless it is grossly obvious. Percutaneous or endoscopically placed biliary stents may also provide effective palliation and are preferable to surgical biliary decompression if the lesion is known to be unresectable. Gastrojejunostomy is required if the tumor blocks the duodenum. If laparotomy has been performed, gastrojejunostomy should be considered regardless of the presence of duodenal obstruction, because with time this often develops before other life-threatening complications.
Laparoscopy is a useful first step in patients scheduled for a possible Whipple procedure. If metastases are seen that militate against a curative resection, laparoscopic gastrojejunostomy or cholecystojejunostomy (or both) can be performed. If not, one should proceed with the laparotomy. About 15% of patients thought to have localized disease from preoperative studies are found to be unresectable at laparoscopy.
Gemcitabine-based chemotherapy has clear benefits in patients with metastatic disease. Its utility in combination with radiation therapy and as adjuvant therapy is being defined.
Prognosis
The mean survival following palliative therapy is 7 months. Following a Whipple procedure, survival averages about 18 months. Factors associated with tumor recurrence and shorter survival include lymph node involvement, tumor size over 2.5 cm, blood vessel invasion, and amount of blood transfused. If tumor cells extend to the margins of the resected specimen, long-term survival is rare. If the margins are clear, about 20% of patients live more than 5 years. Overall 5-year survival is about 10%, but only 60% of these patients are actually free of tumor.
Tempero MA et al. National Comprehensive Cancer Networks. Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012;10(6):703-713.
Visser BC, Ma Y, Zak Y, et al. Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes. HPB (Oxford) 2012;14(8):539-547.
CYSTIC NEOPLASMS
Cystic neoplasms of the pancreas usually present with abdominal pain, a mass, or jaundice and are diagnosed from the findings on CT scans.
Cystadenomas can be classified as serous or mucinous. Serous cystadenomas, which are usually microcystic adenomas, are well-circumscribed lesions consisting of multiple small cysts ranging in size from microscopic to about 2 cm. The cut surface has the appearance of a sponge. The multicystic nature of the lesion is usually—but not always—evident on CT scans, which may also show a few calcifications. The epithelium, which is flat to cuboidal, has no malignant potential. Treatment usually entails excision, but in the rare case where this is too hazardous, the lesion may be left in place with the knowledge that complications are rare. An occasional serous cystadenoma will consist of one or more large cysts (ie, macrocystic).
Mucinous cystadenomas (macrocystic adenomas), which are much more common in women than in men, are unilocular or, more often, multilocular lesions that have a smooth lining with papillary projections. The septate appearance on CT scans is characteristic. The cystic spaces measure 2-20 cm in diameter and contain mucus. The lining consists of tall columnar and goblet cells, which are often arranged in a papillary pattern. In time, most mucinous cystadenomas will evolve into cystadenocarcinomas, so total excision is the required treatment.
Cystadenocarcinomas invariably present as a focus of malignancy within an existing mucinous cystadenoma. The tumors are often quite large (eg, 10-20 cm) at the time of diagnosis. Metastases occur in about 25% of cases. Complete excision results in a 5-year survival rate of 70%.
An uncommon lesion, referred to as solid and papillary or papillary-cystic neoplasm of the pancreas, occurs almost exclusively in young women (under age 25 years). The tumor is usually large. It may be locally invasive, but metastases are uncommon, and cure is to be expected after resection.
Farrell JJ, Fernández-del Castillo C. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology 2013;144(6):1303-1315.
Lee LS, Clancy T, Kadiyala V, Suleiman S, Conwell DL. Interdisciplinary management of cystic neoplasms of the pancreas. Gastroenterol Res Pract 2012; 2012:513163.
ADENOMA & ADENOCARCINOMA OF THE AMPULLA OF VATER
Adenoma and adenocarcinoma of the ampulla of Vater account for about 10% of neoplasms that obstruct the distal bile duct. One-third are adenomas and two-thirds adenocarcinomas. Since a remnant of benign adenoma can be found in a majority of adenocarcinomas, it is suspected that malignant change in an adenoma gives rise to most carcinomas. The presenting symptom is most often jaundice or occasionally gastrointestinal bleeding. Weight loss and pain are more common with carcinoma than with adenoma, but the differences are not great enough to allow a distinction to be made on this basis alone.
CT and ultrasound scans reveal dilation of the biliary tree and pancreatic duct. Gallstones are an incidental finding in 20% of patients, and when common duct stones are present, they may incorrectly be held responsible for the biliary obstruction. ERCP can be an important diagnostic study. In 75% of cases, tumor is visible on duodenoscopy as an exophytic papillary lesion, an ulcerated tumor, or an infiltrating mass. An adequate biopsy usually can be obtained of these lesions. In 25% of cases, there is no intraduodenal growth, and endoscopic sphincterotomy is necessary to display the tumor. It is best to wait 10-14 days to biopsy these tumors because of transient artifacts that result from the sphincterotomy. ERCP also demonstrates dilation of the biliary and pancreatic ducts. It has become common to perform a sphincterotomy whenever possible, not only to facilitate performance of a biopsy but also to decompress the biliary tree and allow jaundice to subside in anticipation of subsequent surgical therapy. The value of this step has not been established.
Although some adenomas have been successfully treated by snare excision or, preferably, by neodymium:YAG laser destruction, local resection, or pancreaticoduodenectomy is preferable because of the significant chance that an invasive carcinoma will be undertreated at a time that it is curable. These nonsurgical methods should be reserved for patients who are poor candidates for resection.
Treatment of adenocarcinoma consists of pancreaticoduodenectomy as for pancreatic carcinoma. The operative mortality rate is less than 5%, and the 5-year survival rate is about 50%. The presence of metastases in resectable peripancreatic lymph nodes is not a contraindication to pancreaticoduodenectomy, for the 5-year survival rate under these circumstances is still a respectable 25%. Local excision is an alternative for noninfiltrating papillary adenocarcinomas in patients who are too poor a risk for pancreaticoduodenectomy, but this operation is not as successful as pancreaticoduodenectomy. Endoscopic sphincterotomy alone or with retrograde stent placement (the combination is usually required) is indicated when there is definite evidence (eg, hepatic metastases) that the tumor is incurable. Survival averages less than a year with this approach, however.
Tempero MA et al. National Comprehensive Cancer Networks. Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2012;10(6):703-713.
PANCREATIC ISLET CELL TUMORS
Islet cell tumors may be functioning (ie, hormone-producing) or nonfunctioning, malignant or nonmalignant. More than half are functioning; less than half are malignant. Insulinoma, the most common functioning islet cell neoplasm, arises from beta cells and produces insulin and symptoms of hypoglycemia. Tumors of the {d} or {a}1 cells produce gastrin and the Zollinger–Ellison syndrome. Alpha2 cell neoplasms may produce excess glucagon and hyperglycemia. Non-beta islet cell tumors may secrete serotonin, ACTH, MSH, and kinins (and evoke the carcinoid syndrome). Some produce pancreatic cholera, a severe diarrheal illness.
Most of these lesions are malignant tumors of the head of the gland, which present with abdominal and back pain, weight loss, and, in many cases, a palpable abdominal mass. Jaundice is encountered occasionally. CT scans reveal a pancreatic mass, and angiography typically shows it to be hypervascular. The histologic pattern on biopsy specimens is diagnostic of islet cell tumor, but whether or not the lesion is malignant rests on evidence of invasiveness or metastases, not the appearance of the cells. Immunohistochemical staining of the tissue is positive for chromogranin and neuron-specific enolase (markers of APUD tumors). Metastases are present at the time of diagnosis in 80% of patients. Resection of all gross tumor (eg, by a Whipple procedure), the preferred treatment, is possible in less than half of patients because of local extension or distant metastases. A combination of streptozocin and doxorubicin is the most effective chemotherapeutic regimen. The 5-year disease-free survival rate is about 15%.
Kulke MH et al. National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10(6):724-764.
Oberstein PE, Remotti H, Saif MW, Libutti SK. Pancreatic neuroendocrine tumors: entering a new era. JOP 2012;13(2):169-173.
Insulinomas have been reported in all age groups. About 75% are solitary and benign. About 10% are malignant, and metastases are usually evident at the time of diagnosis. The remaining 15% are manifestations of multifocal pancreatic disease—either adenomatosis, nesidioblastosis, or islet cell hyperplasia.
The symptoms (related to cerebral glucose deprivation) are bizarre behavior, memory lapse, or unconsciousness. Patients may be mistakenly treated for psychiatric illness. There may be profuse sympathetic discharge, with palpitations, sweating, and tremulousness. Hypoglycemic episodes are usually precipitated by fasting and are relieved by food, so weight gain is common. The classic diagnostic criteria (Whipple triad) are present in most cases: (1) hypoglycemic symptoms produced by fasting, (2) blood glucose below 50 mg/dL during symptomatic episodes, and (3) relief of symptoms by intravenous administration of glucose.
The most useful diagnostic test and the only one indicated in all but a few patients is demonstration of fasting hypoglycemia in the presence of inappropriately high levels of insulin. The patient is fasted, and blood samples are obtained every 6 hours for glucose and insulin measurements. The fast is continued until hypoglycemia or symptoms appear or for a maximum of 72 hours (some investigators truncate the test at 48 hours). Although insulin levels are not always elevated in patients with insulinoma, they will be high relative to the blood glucose concentration. A ratio of plasma insulin to serum glucose greater than 0.3 is diagnostic. Ratios should be calculated before and during the fast. Proinsulin, which constitutes more than 25% of total insulin (the upper limit of normal) in about 85% of patients with insulinomas, should also be measured. Proinsulin levels greater than 40% suggest a malignant islet cell tumor.
Drugs that release insulin (tolbutamide, glucagon, leucine, arginine, calcium) were used in the past as provocative tests. No provocative tests are currently used.
Localization of the tumor is important but may be difficult. In about 10% of cases, the tumor is so small or located so deeply that it is difficult or impossible to find at laparotomy. High-resolution CT and MR scans are successful in demonstrating about 40% of tumors. Endoscopic ultrasound examination of the pancreas may be able to show a much higher percentage. The most important examination is intraoperative ultrasound, which can identify a pancreatic tumor in nearly all cases. It is more sensitive than any preoperative test.
In patients who have had previous resection or significant upper abdominal surgery, exploration with intraoperative ultrasound may be difficult. Invasive preoperative testing may then be useful. Angiography gives a yield of about 50%. Transhepatic portal venous sampling has proved an accurate preoperative localizing method, demonstrating the position in the pancreas in about 95% of lesions. However, this test is time-consuming and somewhat invasive, involving entering the portal vein with a catheter passed percutaneously through the liver and testing blood at various sites within the portal, superior mesenteric, and splenic veins for insulin levels. The point where insulin concentrations rise sharply indicates the site of the tumor. An alternative invasive localizing test uses arteriography with selective calcium infusion into arteries supplying the pancreas. Blood samples from the hepatic veins reveal an increase in insulin level when calcium is infused into an artery supplying the tumor.
Differential Diagnosis
Fasting hypoglycemia may be a manifestation of some nonpancreatic, nonislet cell tumors. Clinically, the condition is identical to that resulting from insulinoma, but the cause is rarely secretion of insulin by the tumors, as serum insulin levels are normal. Most nonislet cell tumors associated with hypoglycemia are large and readily detected on physical examination. The majority are of mesenchymal origin (eg, hemangiopericytoma, fibrosarcoma, leiomyosarcoma) and are located in the abdomen or thorax, but hepatoma, adrenocortical carcinoma, and a variety of other lesions may also produce hypoglycemia. The principal means by which these tumors produce hypoglycemia are the following: (1) secretion by the tumor of insulin-like growth factor II (IGF-II), an insulin-like peptide that normally mediates the effects of growth hormone; and (2) inhibition of glycogenolysis or gluconeogenesis. Rapid utilization of glucose by the tumor, replacement of liver tissue by metastases, and secretion of insulin are other postulated mechanisms that are probably uncommon.
Surreptitious self-administration of insulin is seen occasionally, most often in an individual with access to insulin on the job. If insulin injections have been given for as long as 2 months, insulin antibodies will be detectable in the patient’s serum. Circulating C peptide levels are normal in these patients but elevated in most patients with insulinoma. Sulfonylurea ingestion can be detected by measuring the drug in plasma.
Treatment
Surgery should be done promptly, because with repeated hypoglycemic attacks, permanent cerebral damage occurs and the patient becomes progressively more obese. Moreover, the tumor may be malignant. Medical treatment is reserved for surgically incurable lesions.
Diazoxide is administered to suppress insulin release. For incurable islet cell carcinomas, streptozocin is the best chemotherapeutic agent. Sixty percent of patients live up to 2 additional years. Toxicity is considerable; streptozocin is not recommended as a routine adjunct to surgical therapy.
At operation, the entire pancreas must be palpated carefully because the tumors are usually small and difficult to find. The gland should also be examined intraoperatively with ultrasound, which may be able to locate a tumor that cannot be felt, or to demonstrate signs of invasion (ie, irregular borders) that indicate malignancy—something that cannot be detected by palpation. When the tumor is found, it may be enucleated if it is superficial or resected as part of a partial pancreatectomy if it is deep-seated or invasive. Insulinomas in the head of the gland can nearly always be enucleated.
Tumors that can be localized preoperatively, and that are placed in favorable anatomic locations, can sometimes be resected using a laparoscopic approach. The same principles of local, complete resection should be followed. Laparoscopic ultrasound is often useful to guide this exploration.
In the past, the tumor could not be detected in about 5% of cases by these methods. The traditional recommendation was to resect the distal half of the pancreas and have the pathologist slice the specimen into thin sections and look for the tumor. If the tumor was found, the operation was concluded; if it was not found, additional pancreas would be resected until an 80% distal pancreatectomy had been performed. Since the tumors are evenly distributed, this strategy is 80% successful in removing the tumor. Intraoperative monitoring of blood glucose is often done as a means of determining if the tumor has been excised, but it is unreliable. With the use of operative ultrasound scanning, however, no more than 1%-2% of insulinomas remain occult, and blind distal pancreatectomy is rarely even considered.
Patients with insulinoma associated with MEN-1 usually have multiple (average of three) lesions. Because persistence of the disease is much more likely in this condition following the standard surgical approach, the operation recommended here is distal pancreatectomy plus enucleation of any lesions found in the head of the gland.
For islet cell hyperplasia, nesidioblastosis, or multiple benign adenomas, distal subtotal pancreatectomy usually decreases insulin levels enough that medical management is simplified. For islet cell carcinomas, resection of both primary and metastatic lesions is warranted if technically feasible.
Patients with sporadic insulinomas lead a normal life after the tumor has been removed. The outcome is less predictable in patients with MEN-1, who may have several insulin-producing tumors.
Kulke MH et al. National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10(6):724-64.
Most cases of pancreatic cholera are caused by a non-beta islet cell tumor of the pancreas that secretes VIP and peptide histidine isoleucine. The syndrome is characterized by profuse watery diarrhea, massive fecal loss of potassium, low serum potassium, and extreme weakness. Gastric acid secretion is usually low or absent even after stimulation with betazole or pentagastrin. Stool volume averages about 5 L/d during acute episodes and contains over 300 mEq of potassium (20 times normal). Severe metabolic acidosis frequently results from loss of bicarbonate in the stool. Many patients are hypercalcemic, possibly from secretion by the tumor of a parathyroid hormone-like substance. Abnormal glucose tolerance may result from hypokalemia and altered sensitivity to insulin. Patients who complain of severe diarrhea must be studied carefully for other causes before the diagnosis of WDHA syndrome is entertained seriously. Chronic laxative abuse is a frequent explanation.
CT scan is the best initial imaging test; somatostatin receptor scintigraphy is also very useful for localization. Approximately 80% of the tumors are solitary, located in the body or tail, and can be removed easily. About half of the lesions are malignant, and three-fourths of those have metastasized by the time of exploration. Even if all of the tumor cannot be removed, resection of most of it alleviates symptoms in about 40% of patients even though the average survival is only 1 year. Streptozocin has produced remissions in several cases, but nephrotoxicity may limit its effectiveness. Treatment with long-acting somatostatin analogues decreases VIP levels, controls diarrhea, and may even reduce tumor size. The effect persists indefinitely in most patients, but in a few it is transient.
Kulke MH et al. National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10(6):724-764.
Glucagonoma syndrome is characterized by migratory necrolytic dermatitis (usually involving the legs and perineum), weight loss, stomatitis, hypoaminoacidemia, anemia, and mild to moderate diabetes mellitus. Scotomas and changes in visual acuity have been reported in some cases. The age range is 20-70 years, and the condition is more common in women. The diagnosis may be suspected from the distinctive skin lesion; in fact, the presence of a prominent rash in a patient with diabetes mellitus should be enough to raise suspicions. Glucagonoma should also be suspected in any patient with new onset of diabetes after the age of 60. Confirmation of the diagnosis depends on measuring elevated serum glucagon levels. CT scans demonstrate the tumor and sites of spread. Angiography is not essential but reveals a hypervascular lesion.
Glucagonomas arise from {a}2 cells in the pancreatic islets. Most are large at the time of diagnosis. About 25% are benign and confined to the pancreas. The remainder has metastasized by the time of diagnosis, most often to the liver, lymph nodes, adrenal gland, or vertebrae. A few cases have been the result of islet cell hyperplasia.
Severe malnutrition should be corrected preoperatively with a period of total parenteral nutrition and treatment with somatostatin analogues. Surgical removal of the primary lesion and resectable secondaries is indicated if technically feasible. If the tumor is confined to the pancreas, cure is possible. Even if it is not possible to remove all the tumor deposits, considerable palliation may result from subtotal removal, so surgery is indicated in almost every case. Low-dose heparin therapy should be administered pre- and postoperatively because of a high risk of deep venous thrombosis and pulmonary embolism. Streptozocin and dacarbazine are the most effective chemotherapeutic agents for unresectable lesions. Somatostatin therapy normalizes serum glucagon and amino acid levels, clears the rash, and promotes weight gain. The clinical course generally parallels changes in serum levels of glucagon in response to therapy.
Kulke MH et al. National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10(6):724-764.
Somatostatinomas are characterized by diabetes mellitus (usually mild), diarrhea and malabsorption, and dilation of the gallbladder (usually with cholelithiasis). Serum calcitonin and IgM concentrations may be elevated. The syndrome results from secretion of somatostatin by an islet cell tumor of the pancreas, half of which are malignant and accompanied by hepatic metastases. The lesion is usually large and readily demonstrated by CT scan. The diagnosis may be made by recognizing the clinical syndrome and measuring increased concentrations of somatostatin in the serum. Often, however, the somatostatin syndrome is unsuspected until histologic evidence of metastatic islet cell carcinoma has been obtained. When the disease is localized, resection is able to cure about 50% of cases. Enucleation is inappropriate for these tumors. Chemotherapy with streptozocin, dacarbazine, or doxorubicin is the best treatment for unresectable tumors. Small somatostatin-rich tumors of the duodenum or ampulla of Vater have also been reported, but none of these lesions have been associated with high serum levels of somatostatin or the clinical syndrome.
Kulke MH et al. National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10(6):724-764.
MULTIPLE CHOICE QUESTIONS