Pancreatic Cancer, Ampullary Cancer, Cystic Tumors, and Neuroendocrine Tumors of the Pancreas

Exocrine pancreatic cancer accounts for 95% of all the cancers that arise in the pancreas. Between 75% and 95% of exocrine pancreatic cancers arise from the ductular epithelium. Other cancers, such as acinar cell carcinoma, giant cell carcinoma, adenosquamous carcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic tumor, mucinous ductal ectasia, intraductal papillary neoplasm, fibrosarcoma, leiomyosarcoma, and lymphoma are rare and account for less than 10% of the exocrine tumors.

Islet cell tumors of the pancreas make up approximately 5% of the carcinomas of the pancreas. These tumors often manifest themselves by the hormones they secrete. Tumors secreting gastrin, insulin, glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide (PIP), neurotensin, and somatostatin may present as single tumors or as part of multiple neoplasm syndromes.

I. ADENOCARCINOMA OF THE PANCREAS

A. Epidemiology.

The prevalence of adenocarcinoma of the pancreas is nine to ten per 100,000 persons in most Western countries. It is the fourth most common cause of death from carcinoma in males (after lung, colon, and prostate) and the fifth in females (after breast, colon, lung, and ovary). It can occur at any age but is most commonly seen in the sixth to eighth decades of life. It is more common in men than in women (1.3:1), in blacks than in whites (incidence 15.2/100,000 black men), and in Jews than in non-Jews.

There has been an increase in the incidence of pancreatic cancer in the last 30 years. Various substances have been implicated as possible etiologic factors. The risk of pancreatic cancer developing is increased 1.5 times in cigarette smokers. The risk increases as the number of cigarettes smoked increases, and the excess risk levels off 10 to 15 years after smoking cessation.

Diets rich in fat, red meat, or both have been implicated as risk factors. There seems to be a protective effect of diets rich in fruits and vegetables, carotenoids, and selenium. Other risk factors include history of peptic ulcer surgery (partial gastrectomy); cholecystectomy, possibly by increasing cholecystokinin (CCK) secretion; chronic pancreatitis (mostly hereditary and tropical types); hereditary nonpolyposis colorectal cancer; ataxia-telangiectasia; Peutz-Jeger syndrome; familial breast cancer; familial atypical multiple mole melanoma; and prolonged exposure to the gasoline derivatives 2-naphthylamine and benzidine and metal dusts. There is no conclusive evidence that drinking alcohol is related to the development of pancreatic cancer.

B. Pathophysiology. Adenocarcinoma of the pancreas

forms a dense, fibrotic mass in the pancreas associated with a desmoplastic reaction. Seventy percent of the lesions are located in the head; the remainder is in the body and the tail of the gland or are multifocal or diffusely infiltrate the gland. By itself, the tumor may not cause symptoms. However, because the pancreas, which is a retroperitoneal organ without a mesentery, lies close to the porta hepatis, common bile duct, duodenum, stomach, and colon, the tumor mass may impinge on or penetrate into any of these structures and cause symptoms.

Pancreatic cancer metastasizes widely. It spreads locally by direct extension and to distant sites by lymphatic and vascular channels. It also invades nerves and
nervous plexuses, especially in the celiac and mesenteric areas. The most common sites of extralymphatic metastasis are the liver, peritoneum, lungs, intestines, adrenals, kidneys, bones, and the diaphragm. Pancreatic tumors other than ductal adenocarcinomas (e.g., cystadenocarcinomas, islet cell tumors) often have a more indolent course. Tumors such as carcinomas of the breast, lung, thyroid, kidney, ovary, uterus, and prostate, and melanomas may metastasize to the pancreas and present as mass lesions in the organ.

C. Diagnosis

1. Clinical presentation

a. History. The early symptoms of pancreatic cancer are vague and nonspecific. The most common symptoms are abdominal pain, back pain, weight loss, anorexia, nausea, jaundice, diarrhea, malabsorption, depression, and abdominal mass.

i. An insidious weight loss with anorexia and nausea, accompanied by upper abdominal pain radiating to the back, is the most common presentation. Greater than 90% of the patients initially have jaundice. Common bile duct obstruction by a tumor in the head of the pancreas may result in jaundice while the mass is still small. Tumors located in the body and tail of the organ may result in jaundice in later stages either by extension or due to metastasis to the porta hepatis or the liver parenchyma.

ii. Up to 70% of the patients may present with diabetes mellitus or glucose intolerance. The decreased or delayed insulin secretion is thought to arise from loss of B cells due to the desmoplastic reaction of the tumor.

iii. Migratory thrombophlebitis (Trousseau’s sign) may be a mode of presentation. However, this entity is not specific for pancreatic cancer. It may occur with other malignancies such as carcinomas of the stomach, colon, ovary, and lung.

iv. A minority of the patients may also present with a picture of acute pancreatitis, cholangitis, gastrointestinal bleeding, polyarthritis, and skin nodules due to fat necrosis.

b. The physical examination in most instances is not helpful. The major findings in a subpopulation of patients are jaundice, palpable gallbladder, epigastric mass, and nodular liver if metastases are present.

c. Warning signs for early diagnosis. The initial symptoms of pancreatic cancer are usually ignored by the patient (patient delay) and the physician (physician delay). The mean duration of symptoms before diagnosis in most series is 3 to 4 months. Most of the tumors are unresectable and, therefore, the disease is fatal. The following warning signs may facilitate an early diagnosis of this malignancy:

i. Recent upper abdominal or back pain consistent with retroperitoneal lesion.

ii. Recent upper abdominal pain or discomfort with negative gastrointestinal investigations.

iii. Jaundice with or without pruritus.

iv. Weight loss greater than 5% of normal body weight.

v. Unexplained acute pancreatitis.

vi. Unexplained onset of diabetes mellitus.

d. Differential diagnosis. A variety of malignant and benign disorders of other organs may present with features similar to pancreatic cancer. Also, it is important to remember that pancreatic cancer may coexist in a patient with a common benign disorder such as gallstones or peptic or diverticular disease, and normal contrast studies of the gastrointestinal tract, serum chemistries, and hemogram do not rule out the presence of pancreatic cancer, especially if the tumor is small.

2. Diagnostic studies

a. Laboratory tests. There are no specific laboratory tests for the early detection of pancreatic cancer. If there is involvement of the liver or the biliary
tract, this will be reflected in the serum chemistries. The serum amylase and lipase in most instances are normal. A subgroup of patients has elevated blood glucose levels.

b. Tumor markers. Various serologic tumor markers including tumor associated antigens, enzymes, and hormones have been investigated for early detection of pancreatic cancer. These are carcinoembryonic antigen (CEA), CA 19-9, alpha-fetoprotein, pancreatic oncofetal antigens, pancreatic ribonuclease, and galactosyl transferase isoenzyme II. The sensitivity and specificity of these assays have not been adequate for early diagnosis of this disease.

The most extensively studied serum marker is CA 19-9, which is used widely. It is not specific for pancreatic cancer, however, because it also can be elevated in other gastrointestinal tumors such as those in the bile ducts and colon. Because levels of CA 19-9 are frequently normal in the early stages of pancreatic cancer, the test is not reliable for use in screening. The presence of high levels may help differentiate between benign diseases of the pancreas and pancreatic cancer. When the pancreatic cancer is completely resected, the CA 19-9 levels fall, suggesting that it is a useful marker for follow-up surveillance.

The ratio of testosterone to dihydrotestosterone is below 5 (normal is 10) in more than 70% of men with pancreatic cancer, presumably because of increased conversion of testosterone by the pancreatic tumor. This ratio may be more sensitive than CA 19-9 in detecting smaller pancreatic cancers and more specific than the other markers.

c. Ultrasound and computed tomography. Ultrasonography usually is the first examination for suspected pancreatic cancer. Computed tomography (CT) with intravenous (IV) contrast is used when satisfactory imaging is not obtained with ultrasound (US). These two techniques are by far the most sensitive and specific for pancreatic disease. They both demonstrate enlargement of the gland, alteration in contour or consistency of the gland, the presence of masses, and biliary or pancreatic duct dilatation. CT scans may also delineate peripancreatic nodal enlargement as well as invasion of other organs and vessels. Metastasis to the liver and porta hepatis may be detected.

US and CT are complementary in imaging the pancreas. The lesions in the head of the pancreas are seen well by US, whereas those in the body and tail are detected better by CT scan. However, small lesions, especially in the body or tail, may be missed by both techniques. Helical thin section CT scan with IV contrast and CT angiography (CTA) increase the diagnostic yield.

d. Magnetic resonance imaging, contrast-enhanced magnetic resonance imaging (MRI) using IV gadolinium-DPTA is useful for detecting small pancreatic tumors. Ductal size is evaluated by magnetic resonance cholangiopancreatography (MRCP). MR arteriography (MRA) has obviated the need for angiography and improves the examination of the pancreas for tumor. Fat-saturation MRI is especially valuable in looking for suspected tumors in a pancreas that is not enlarged.

e. Endoscopic retrograde cholangiopancreatography (ERCP). The diagnosis of pancreatic cancer by ERCP depends on radiographic demonstration of pancreatic duct stenosis or obstruction caused by the tumor. An accompanying cholangiogram may further delineate abnormalities along the course of the common bile duct. It can also visualize and differentiate ampullary and duodenal carcinomas. In experienced hands, it has greater than 90% sensitivity and specificity in providing a definitive diagnosis of pancreatic cancer.

In addition, biopsies of periampullary tissue and cytologic examination of aspirated pancreatic juice may increase the diagnostic yield further. ERCP is usually performed if an abnormality is noted on the US or CT scan or if an abnormality is suspected but cannot be demonstrated by these methods.

In addition to diagnosis, ERCP may be used to place stents in the obstructed biliary and pancreatic ducts to relieve obstruction and palliate patients with unresectable tumors.

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