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Table of Contents

Published May 12, 2005

Tyler
Stevens, MD

Department of
Gastroenterology
and Hepatology

Darwin L. Conwell, MD

Department of
Gastroenterology
and Hepatology

Print Chapter

PANCREATIC ADENOCARCINOMA

     Prevalence

     Risk Factors

     Signs and
     Symptoms

     Diagnosis

     Therapy

The AGA guidelines list several genetic, environmental, and disease-related risk factors for pancreatic adenocarcinoma.¹ A consistent association has been demonstrated between cigarette smoking and the development of pancreatic cancer. The AGA guidelines recommend cessation of smoking for the purpose of pancreatic cancer prevention.¹ Dietary factors such as high meat and fish consumption also increase the risk. Based on animal experiments, the aromatic amines present in cigarette smoke, meats, and fish oil may be the specific pathogenic factor predisposing to neoplastic transformation. Occupations with a high exposure to amines (chemistry, hairdressing, rubber work) have been found to confer an increased risk for pancreatic cancer. Certain diseases predispose toward pancreatic cancer, including chronic pancreatitis, diabetes mellitus, and hereditary cancer syndromes (eg, familial adenomatous polyposis, hereditary dysplastic nevus syndromes). A family history of pancreatic cancer is another important risk factor.³ Hereditary pancreatitis is a genetic disease caused by a mutation of the cationic trypsinogen gene.⁴ Patients with this disease develop acute recurrent pancreatitis in childhood, which usually progresses to chronic pancreatitis and pancreatic cancer in early adulthood.

There is no compelling evidence to support a screening strategy for at-risk patients. However, the AGA guidelines recommend initiating screening with CT and endoscopic ultrasound (if the CT findings are negative) 10 years before the earliest known case of pancreatic cancer in families with cancer syndromes and after age 35 in hereditary pancreatitis.¹

Sixty percent of pancreatic cancers develop in the pancreatic head; 40% develop in the body and tail. The major symptoms include abdominal pain, anorexia, weight loss, and jaundice. The pain is located in the epigastrium and has a quality characterized as deep and boring. The pain may be intermittent or constant, and is progressive. Painless jaundice indicates a potentially resectable lesion located in the pancreatic head. A predominance of abdominal pain suggests neural plexus involvement, location in the tail, unresectability, and a poor prognosis.

Pruritis and steatorrhea are suggestive of biliary and pancreatic duct obstruction, respectively. Physical examination findings include jaundice, cachexia, a palpable abdominal mass, ascites, left cervical lymphadenopathy (Virchow's node), a palpable gallbladder (Courvoisier's sign), and migratory superficial thrombophlebitis (Trousseau's syndrome). Commonly observed laboratory features of pancreatic cancer include a mild, normocytic anemia, hypoalbuminemia, hyperbilirubinemia, hypercalcemia, and elevated sedimentation rate.

The diagnosis and staging of pancreatic cancer is accomplished through imaging tests and pathologic diagnosis. According to the AGA guidelines, the best initial imaging test for diagnosis and staging of pancreatic cancer is contrast-enhanced, dual-phase, helical computed tomography (CT) with thin cuts through the pancreas.⁵ CT allows assessment of the primary tumor, local invasiveness, regional lymph node involvement, liver metastases, and peritoneal spread (Figure 1). The sensitivity of helical CT for the detection of pancreatic cancer ranges from 85% to 95%; however, this is highly dependent on tumor size. Dual-phase CT helps to determine surgical resectability through assessment of invasion of major vessels. Although CT is the best imaging test for metastatic disease, it may underestimate hepatic and lymph node involvement because small nodes may contain cancer and diminutive hepatic lesions may be missed.

Magnetic resonance imaging (MRI) with gadolinium enhancement compares favorably with CT in the assessment of local tumor extent, relationship to vascular structures, lymph node involvement, and distant metastases.⁶ MRI may improve differentiation of a pancreatic cancer from chronic pancreatitis in evaluating a pancreatic head mass, and offers simultaneous assessment of the pancreatic and bile ducts by heavily T₂-weighted imaging (MR-cholangiopancreatography). (See Disease Management chapter, Chronic Pancreatitis).

Endoscopic ultrasound (EUS) is an accurate test for diagnosing and staging pancreatic ductal cancer. Several studies have demonstrated increased sensitivity and specificity of EUS compared with conventional, single-phase CT for the detection and local staging of pancreatic cancer.^7,8 However, more recent studies have shown similar test characteristics for EUS compared with dual-phase CT.⁹ The AGA guidelines suggest that EUS has the greatest role in the detection of small tumors missed by CT.^1,10 EUS may offer a better assessment of local blood-vessel involvement, and allows fine needle aspiration (FNA) of tumor and lymph nodes. Disadvantages include increased invasiveness, operator dependence, lack of widespread availability, and inability to detect distant metastasis.

The role of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of pancreatic disease has diminished in recent years as a result of improved noninvasive and less-risky imaging techniques. ERCP is most useful for detecting small tumors not visualized by CT, palliating unresectable tumors causing biliary obstruction, and ruling out differential causes of pain or jaundice (ie, bile duct stones, chronic pancreatitis, intraductal papillary mucinous tumor, or ampullary cancer). ERCP has a >90% sensitivity for the diagnosis of pancreatic cancer. Diagnostic features detectable on ERCP include an irregular, solitary pancreatic duct stenosis >1 cm long, an abrupt cutoff of the main pancreatic duct, or an obstruction of both pancreatic and bile ducts (double-duct sign) (Figure 2). Importantly, none of these findings is specific for pancreatic cancer as they may also be observed in chronic pancreatitis. Brush cytology from the pancreatic duct has fair sensitivity (about 70%) but excellent specificity for the diagnosis of adenocarcinoma.

Tumor markers are valuable adjunctive tests in the diagnosis of gastrointestinal cancers. A CA19-9 concentration >70 U/mL has a sensitivity of 70% and specificity of 87% for pancreatic cancer.¹¹ CA19-9 may also be significantly elevated in benign conditions such as choledocholithiasis and cholangitis. In the absence of a mass, elevated CA19-9 and other tumor markers are difficult to interpret, and tests for those markers should not be routinely ordered. Elevated levels of islet amyloid polypeptide have been found in pancreatic cancer compared with controls, and may hold promise in the early detection of pancreatic cancer.¹² Specific genetic mutations of the K-ras oncogene, c-erb B-12 oncogene, and p16 tumor suppressor genes have also been described in pancreatic cancer and may have a future role in screening high-risk individuals.

Biopsy of a pancreatic mass or metastasis may be obtained percutaneously under CT guidance or by EUS with FNA. EUS/FNA has been shown to be relatively safe and offers improved sensitivity for small tumors in close proximity to vascular structures. Biopsy is indicated in unresectable disease to confirm the diagnosis and aid in decision-making regarding chemotherapy and radiation therapy. The use of biopsy in presumed resectable disease is more controversial. Critics of routine biopsy argue that the theoretical risk of peritoneal seeding and inherent risks of the biopsy procedure (hemorrhage, perforation) outweigh the low potential benefit. Proponents of routine biopsy cite the rare possibility of detecting a chemosensitive tumor (lymphoma) and the desire of many patients to know their diagnosis before major surgery. The AGA guidelines recommend FNA only for patients with unresectable lesions; however, individual circumstances may dictate otherwise.¹

All the current imaging tests may underestimate tumor, nodal, and metastatic staging. Staging laparoscopy with or without laparoscopic ultrasound improves accuracy through detection of small hepatic or peritoneal metastases, widespread sampling of regional lymph nodes, and direct visualization of the primary tumor and its relationship to peripancreatic vessels. The AGA guidelines recommend staging laparoscopy if there is a high likelihood of unresectability that has not been confirmed by imaging tests.¹ See Figure 3 for a suggested diagnostic algorithm for pancreatic cancer incorporating the AGA guidelines.

The only potentially curative therapy for pancreatic cancer is surgical resection. Pancreatic cancer is resectable if the tumor is confined to the pancreas without: (1) encasement of adjacent surrounding major vessels (superior mesenteric artery or vein, portosplenic confluence, celiac trunk or aorta); (2) extensive peripancreatic lymph node involvement; or (3) distant metastases. Unfortunately, because of late presentation and delay in diagnosis, only 20% of patients present with resectable disease. The long-term prognosis is poor even among those who undergo resection and have tumor-free margins (5-year survival after resection, 10% to 25%); however, outcomes may be improving with the advent of superior diagnostic and surgical techniques. Because the only chance of cure is through resection, all patients with potentially resectable lesions by CT criteria should be referred for surgical consultation in a high-volume center. The AGA guidelines state, "the bias is toward interpretation of imaging test results as indicating resectable tumors because an aggressive surgical approach is safe in experienced hands."¹

The standard operation for adenocarcinoma in the pancreatic head or uncinate process is the pancreaticoduodenectomy, or "Whipple operation." The Whipple operation involves resection of the pancreatic head, duodenum, common bile duct, distal stomach, and gallbladder. Reconstruction involves pancreaticojejunostomy, hepatoicojejunostomy, and gastrojejunostomy. This extensive surgery is best performed in a high-volume center to minimize the risk of perioperative complications. Although the perioperative mortality in high-volume centers is <2%, several short- and long-term complications may occur, including anastomotic leaks and ulcerations, dumping syndrome, and bile gastritis.^13,14 Newer alternative types of pancreatic resections and modifications on the Whipple procedure may be employed based on the location and extent of the tumor and the expertise of the surgeon.

The AGA guidelines stress the importance of cardiac, pulmonary, and nutritional optimization before pancreatic surgery.¹ Although frequently performed, routine preoperative endoscopic biliary decompression is not beneficial and may actually worsen outcomes.¹⁵ The AGA guidelines recommend preoperative biliary stenting for jaundiced patients in whom surgery will be delayed for several weeks or in patients with unresectable tumors.

Although chemo- and radiotherapy are not curative, they may offer some clinical benefits, including shrinkage of the primary tumor, improvement of symptoms, and prolongation of survival. These modalities have been studied in locally metastatic disease, advanced disease, and as surgical adjuvant therapies. The AGA guidelines state: "all patients with unresectable locoregional or metastatic pancreatic cancer should be considered for inclusion into investigational trials."¹

Single-agent gemcitabine is often administered in patients with advanced, metastatic pancreatic cancer. Studies with gemcitabine have demonstrated a significant clinical response (decreased pain, increased functional status) even in the absence of a measurable tumor response.¹⁶ The AGA guidelines state that gemcitabine is an option for treatment of all patients with poor performance status and/or pain or for management of metastatic disease.¹ Patients with locally advanced cancer may be considered for combined 5-fluorouracil-based chemotherapy and external beam radiation. The combination of these modalities has been shown to improve median survival by several months compared with radiation therapy alone. The benefit of chemotherapy and radiation as therapies adjuvant to surgical resection is not yet settled. The AGA guidelines state that 5-fluorouracil-based adjuvant chemotherapy should be considered after surgical resection.¹ Patients who undergo surgical resection may also be encouraged to enter therapeutic trials of adjuvant therapy.

The palliation of symptoms is arguably the most important goal in patients with locally advanced and metastatic disease. Patients with pancreatic cancer may develop debilitating symptoms of pain (neural plexus invasion), jaundice (biliary obstruction), or vomiting (gastric outlet obstruction). Pain can usually be managed with escalating doses of narcotic agents. In spite of their benefits, narcotics may produce constipation and depressed mental status. Celiac nerve blocks (CT- or EUS-guided) or thorascopic splanchnicectomy may offer significant pain control and decrease narcotic requirements. Diarrhea and weight loss from maldigestion may be palliated through the use of pancreatic enzymes (30,000 IU or 90,000 US Pharmacopeia units lipase per meal). Enzymes are best dosed as follows: one third of the dose at onset of meal, one third during meal, and one third at the end of meal.

Surgical biliary bypass is the optimal management of biliary obstruction; however, many patients do not undergo this procedure because of increased surgical risk. Patients with high surgical risk may receive percutaneous or endoscopic stenting of the bile duct.¹⁷ Metal stents offer more prolonged patency; however, they cannot be removed and should be reserved for patients with severely advanced disease. Endoscopic plastic stents should be changed every 3 months to minimize the risk of cholangitis.

Gastric outlet obstruction develops in 10% to 15% of patients and may be managed by surgical gastrojejunostomy or endoscopic stenting. Not all vomiting arises from outlet obstruction; many patients have impaired gastric motility as a result of the local invasion of nerve fibers.

Also known as islet-cell tumors, neuroendocrine tumors (NETs) are rare tumors (incidence rate, 5 cases per million person years) that arise from endocrine cells within or near the pancreas (Figure 4). The National Comprehensive Cancer Network (NCCN) has practice guidelines for diagnosis and management of the different types of NETs.¹⁸ NETs may occur sporadically or as part of the multiple endocrine neoplasia type 1. Most primary NETs arise within the "gastrinoma triangle," composed of the joining of the cystic and common hepatic ducts, the joining of the second and third portions of the duodenum, and the border of the body and tail of the pancreas. Although a subset of NETs is nonfunctional, most secrete hormones leading to a variety of clinical syndromes (Table 1). Patients with insulinoma present with symptomatic hypoglycemia from hyperinsulinemia. Gastrinomas produce recalcitrant peptic ulcer disease resulting from hypergastrinemia (Zollinger-Ellison syndrome). Less commonly encountered NETs include glucagonoma, VIPoma (secreting vasoactive intestinal polypeptide), somatostatinoma, and PPoma (secreting pancreatic polypeptide). Carcinoid tumors are also NETs; however, they are rarely found in the pancreas. Most NETs are listed in the differential diagnosis for secretory diarrhea, although the yield of testing in this setting is extremely low. NETs may be suspected based on symptoms related to the secretory product.

Nonfunctional tumors are occasionally detected on imaging tests done for other indications or for abdominal pain in patients with significant tumor growth. They are most often indolent but may demonstrate malignant behavior, including metastases. The prognosis for nonfunctional tumors may be poorer than that of functional tumors because of a delay in diagnosis.

When a NET is suspected based on laboratory testing, imaging tests are important to locate the primary tumor and determine the presence of metastases. NETs may be difficult to localize with available imaging tests. Both contrast-enhanced CT and MRI may be employed as initial tests; however, they have a low yield for small tumors. EUS is a more sensitive test for detecting small pancreatic neuroendocrine tumors, and allows simultaneous FNA for tissue diagnosis. Disadvantages of EUS include increased invasiveness, inability to consistently visualize the pancreatic tail, and lack of widespread availability. Functional tests may be helpful in localizing NETs not detected on standard imaging tests. Nuclear imaging after administration of radiolabeled octreotide can aid in location of most neuroendocrine tumors. Insulinomas are not well visualized with octreotide scans because they do not possess high concentrations of somatostatin receptors.

NETs confined to the pancreas should be surgically resected, either through enucleation or more extensive resection of the head (Whipple procedure), body, or tail of the pancreas. Before resection, symptoms of hormonal excess must be treated and controlled. Treatment measures for hormonal excess syndromes are summarized in Table 1. Patients with metastatic disease can be managed medically with octreotide, chemotherapy (streptazocin), or radiographic embolization of the primary tumor and metastases. Debulking of primary and metastatic disease may also be considered for patients with debilitating symptoms related to tumor secretory products. A general management approach to pancreatic NETs is shown in Figure 5. More detailed recommendations for diagnosis and treatment of specific types of NETs are found on the NCCN website.¹⁸

Up to 90% of pancreatic cysts are inflammatory pseudocysts arising from acute or chronic pancreatitis. Other types of pancreatic cysts include simple cysts and cystic neoplasms. Cystic neoplasms are reported to account for <1% of pancreatic cancers. Generally, they are indolent tumors with varying malignant potential (Table 2). Serous cystadenomas are composed of multiple small cysts (microcystadenoma) that are lined by glycogen-rich cells. Although serous tumors may be large and cause pain, they have a low potential for malignant transformation. Mucinous cystadenomas and cystadenocarcinomas are composed of one or a few large cysts, often with thickened and irregular walls. All mucinous neoplasms (including cystadenomas) have malignant potential and should be resected when possible. Intraductal papillary mucinous neoplasms (IPMN) arise from either the main pancreatic ductal epithelium or side-branches. IPMNs consist of dilated ductal segments, often with papillary projections that secrete mucin. Like mucinous cysts, IPMNs have a high potential for malignant transformation.

The primary aim of diagnosis is to differentiate benign (pseudocysts, serous tumors) from malignant (mucinous tumors, IPMNs) cysts. Small (<1 cm), simple, asymptomatic cysts that are discovered incidentally may be observed using follow-up imaging. A history of past acute pancreatitis or imaging criteria suggestive of chronic pancreatitis should increase suspicion of a pseudocyst.
In the absence of pancreatitis, radiographic features are poorly reliable in differentiating mucinous from other types of pancreatic cysts. If there is no history of pancreatitis to suggest a pseudocyst, cystic masses greater than 1cm in size and producing symptoms should be resected. In asymptomatic patients, EUS allows improved characterization of cyst features and also simultaneous aspiration of cyst fluid for chemical analysis. Fluid may be analyzed for cytology, tumor markers (CEA, CA19-9, CA15-3), and amylase. A positive mucin stain of cyst fluid may also be helpful in ruling in a mucinous cystic neoplasm.¹⁹ The primary diagnostic test for IPMN is ERCP. The ERCP features of IPMN include a gaping papilla with extrusion of mucin and global or segmental main-duct or side-branch dilation with papillary projections (Figure 6). Because the ERCP findings are similar, patients previously diagnosed with large-duct chronic pancreatitis may actually have IPMN.
Mucinous cystic neoplasms and IPMNs should be resected, given the potential for malignant transformation. Resection should also be considered for serous cysts that are symptomatic or enlarging. Symptomatic or enlarging pancreatic pseudocysts may be drained surgically, endoscopically, or percutaneously. A diagnostic algorithm for managing pancreatic cysts based on a recent excellent review²⁰ is shown in Figure 7.

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