Pancreatic ductal adenocarcinoma accounts for 90% of cancers of the pancreas. The diagnostic and therapeutic approaches outlined here integrate the AGA guidelines for the diagnosis and treatment of pancreatic ductal adenocarcinoma (Figure 1).

Prevalence

Pancreatic cancer is the fourth and fifth most common cancer in men and women, respectively. It accounts for more than 30,000 new cases and 20,000 cancer-related deaths each year. Most patients are older than 60 years. The male-to-female ratio is 2 : 1. Overall, less than 5% of patients diagnosed with pancreatic cancer is alive at 5 years, reflecting late diagnosis and poor prognosis even with resection.

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Risk Factors

The AGA guidelines have recommended smoking cessation for preventing pancreatic cancer. 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 (e.g., chemistry, hairdressing, rubber work) can confer an increased risk. However, causative relationship has been established only with smoking. Certain diseases, including chronic pancreatitis, diabetes mellitus, and hereditary cancer syndromes, predispose toward pancreatic cancer. Patients with hereditary pancreatitis develop acute recurrent pancreatitis in childhood, which usually progresses to chronic pancreatitis and pancreatic cancer in early adulthood. Family history is another important risk factor where the degree of risk correlates with the number of family members affected by the disease. Patients with a significant familial risk (>2 first-degree relatives, multiple second-degree relatives, early onset of pancreatic cancer before age 50 years) may be an appropriate target population to do surveillance endoscopic ultrasound (EUS). However, research is ongoing to define exactly who should undergo screening EUS.

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Signs and Symptoms

Of pancreatic cancers, 60% develop in the pancreatic head and 40% develop in the body and tail. Depending on the location of the cancer, symptoms may include abdominal pain, anorexia, weight loss, and jaundice. Some patients can present with pancreatitis due to obstruction of the pancreatic duct by the mass. Therefore, in elderly patients presenting with acute pancreatitis without an obvious cause, pancreatic cancer should be considered. The pain from pancreatic cancer is located in the epigastrium and has a quality characterized as deep and boring. Severe abdominal pain suggests neural plexus involvement, location in the tail, unresectability, and a poor prognosis. Painless jaundice indicates a potentially resectable lesion located in the pancreatic head.

Pruritis and steatorrhea suggest 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).

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Diagnosis

The diagnosis and staging of pancreatic cancer is accomplished through imaging tests and pathologic diagnosis (see Figure 1). The best initial imaging test for diagnosis and staging of pancreatic cancer is contrast-enhanced, dual-phase, helical CT, with thin cuts through the pancreas. CT allows assessment of the primary tumor, local invasiveness, regional lymph node involvement, liver metastases, and peritoneal spread (Figure 2). The sensitivity of helical CT for detecting pancreatic cancer ranges from 85% to 95%. Dual-phase CT helps determine surgical resectability through assessment of invasion of major vessels. CT can underestimate hepatic and lymph node involvement.

Magnetic resonance imaging (MRI) with gadolinium enhancement compares favorably with CT in the assessment of local tumor extent, relation to vascular structures, lymph node involvement, and distant metastases. MRI can improve differentiation of a pancreatic cancer from chronic pancreatitis and offers simultaneous assessment of the pancreatic and bile ducts by heavily T2-weighted imaging (MRCP).

Several studies have suggested increased sensitivity of endoscopic ultrasound (EUS) compared with conventional, single-phase CT for detecting and local staging of pancreatic cancer. The greatest advantage of EUS is that it allows fine needle aspiration (FNA) of the tumor to provide a tissue diagnosis. Problems with EUS include operator dependency and lack of widespread availability. The AGA guidelines have suggested that EUS has the greatest role in detecting small tumors missed by CT and in tissue acquisition.

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 palliating unresectable tumors that cause biliary obstruction. Diagnostic features on ERCP include an irregular solitary pancreatic duct stenosis more than 1 cm long, an abrupt cutoff of the main pancreatic duct, or an obstruction of both pancreatic and bile ducts (double-duct sign). Importantly, these findings are nonspecific, because they may also be observed in chronic pancreatitis.

Tumor markers are adjunctive tests for diagnosing gastrointestinal cancers. A Carbohydrate antigen 19-9 (CA19-9) concentration higher than 70 U/mL has a sensitivity of 70% and specificity of 87% for pancreatic cancer. However, there are some major drawbacks of using CA19-9 as a diagnostic marker. For example, it may be elevated in benign conditions such as choledocholithiasis and cholangitis and up to 10% of pancreatic cancer do not synthesize CA19-9 even in advanced stages. Therefore, clinical utility of CA19-9 lies more with monitoring response to therapy, prognostication and surveillance for recurrence after treatment.

Biopsy of a pancreatic mass or metastasis may be done percutaneously under CT guidance or by EUS with FNA. 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 resectable disease is more controversial. Critics have argued that the theoretical risk of peritoneal seeding and procedure complications outweigh the benefit. Proponents of routine biopsy have cited 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 have recommended FNA only for patients with unresectable lesions. However, individual circumstances may dictate otherwise.

All the current imaging tests can underestimate tumor, nodal, and metastatic staging. Staging laparoscopy with or without laparoscopic ultrasound improves accuracy through the detection of small hepatic or peritoneal metastases, widespread sampling of regional lymph nodes, and direct visualization of the primary tumor and its relation to peripancreatic vessels. The AGA guidelines have recommended staging laparoscopy if there is a high likelihood of unresectability that has not been confirmed by imaging tests.

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Treatment

The only potentially curative therapy for pancreatic cancer is surgical resection. Pancreatic cancer is resectable if the tumor is confined to the pancreas and does not have encasement of adjacent surrounding major vessels (superior mesenteric artery or vein, portosplenic confluence, celiac trunk, or aorta), does not have extensive peripancreatic lymph node involvement, or does not have 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 rate after resection is 10%-25%). Because the only chance of cure is through resection, all patients with potentially resectable lesions by CT criteria should be referred for surgical consultation.

The standard operation for adenocarcinoma in the pancreatic head or uncinate process is pancreaticoduodenectomy, or Whipple procedure. This involves resection of the pancreatic head, duodenum, common bile duct, distal stomach, and gallbladder. Reconstruction involves pancreaticojejunostomy, hepaticojejunostomy, and gastrojejunostomy. Although the perioperative mortality in high-volume centers is less than 2%, several short- and long-term complications can occur, including anastomotic leaks and ulcerations, dumping syndrome, delayed gastric emptying and bile gastritis. The AGA guidelines have stressed the importance of cardiac, pulmonary, and nutritional optimization before pancreatic surgery. Preoperative endoscopic biliary drainage is not recommended except for cases of cholangitis or symptomatic obstructive jaundice. In fact, routine biliary decompression can actually worsen outcomes. The AGA guidelines have recommended preoperative biliary stenting for jaundiced patients in whom surgery will be delayed for several weeks or in patients with unresectable tumors.

Although chemotherapy and radiotherapy are not curative, they can offer some clinical benefits, including reducing primary tumour burden, shrinkage of the borderline resectable cancer for resection,,improvement of symptoms, and prolongation of survival. These modalities have been studied in locally metastatic disease and advanced disease and as surgical adjuvant therapies. The AGA guidelines have stated “all patients with unresectable locoregional or metastatic pancreatic cancer should be considered for inclusion into investigational trials.” For years, single-agent gemcitabine has been the standard first-line agent for patients with advanced metastatic pancreatic cancer based on studies that demonstrated a significant clinical response (decreased pain, increased functional status), even in the absence of a measurable tumor response. However, recent data suggests a 5-fluorouracil based combination regimen known as FOLFIRINOX (5-FU, leucovorin, oxaliplatin and irinotecan) leads to better survival and higher response rate in selected patients with good performance status.¹ Patients with locally advanced cancer with good performance status may be considered for combined gemcitabine or 5-fluorouracil-based chemotherapy and external beam radiation, which have been shown to improve median survival compared with radiation therapy alone. Studies have now established that surgical adjuvant chemotherapy leads to modest mortality benefit especially in patients with negative resection margins after surgery.

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 can cause constipation and depressed mental status. EUS-guided celiac nerve neurolysis can offer significant pain control and decrease narcotic requirements. Diarrhea and weight loss from maldigestion may be palliated through the use of pancreatic enzymes. Patients with biliary obstruction might require surgical or endoscopic biliary decompression. Gastric outlet obstruction can 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.

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Uncommon Pancreatic Tumors

Pancreatic Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare tumors (incidence rate, 5 cases per 1 million person-years) that arise from endocrine cells within or near the pancreas and account for less than 5% of all pancreatic tumors. NETs can occur sporadically or as part of inherited genetic syndromes such as multiple endocrine neoplasia type 1, neurofibromatosis, von-Hippel Lindau disease and tuberous sclerosis complex. Most primary NETs arise within the gastrinoma triangle, composed of the joining of the cystic and common hepatic ducts, second and third portions of the duodenum, and border of the body and tail of the pancreas. While majority of NETs are non-functional, small subset secrete hormones that can result in various clinical syndromes (Table 1). Carcinoid tumors are considered NETs but 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. Nonfunctional tumors are most often indolent but can demonstrate malignant behavior, including metastases.

When a NET is suspected, imaging tests are used to locate the primary tumor and determine the presence of metastases (Figure 3). NETs may be difficult to localize. Contrast-enhanced CT and MRI may be used 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. Nuclear imaging after administration of radiolabeled octreotide aids in localizing some 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 after symptoms of hormonal excess have been treated and controlled (see Table 2). Patients with metastatic disease can be managed medically with octreotide, chemotherapy (streptozocin), or radiographic embolization of the primary tumor and metastases. Recently advances have been made in treatment of progressive, metastatic pancreatic NETs. Biologic agents targeting pathways implicated in proliferation of NET cells (Everolimus, an mTOR inhibitor) and angiogenesis (Sunitinib, a tyrosine kinase inhibitor) have been shown to improve progression free survival in metastatic pancreatic NETs in randomized control trials.^2,3 Debulking of primary and metastatic disease may also be considered for patients with debilitating symptoms related to tumor secretory products.

Pancreatic Cystic Neoplasms

Up to 90% of pancreatic cysts are inflammatory pseudocysts arising from acute or chronic pancreatitis. Cystic neoplasms are reported to account for less than 1% of pancreatic cancers. Generally, they are indolent tumors with varying malignant potential (Table 3). The primary aim of diagnosis is to differentiate benign cysts (e.g., pseudocysts, serous cystadenoma) from malignant cysts (e.g., mucinous cystadenoma, premalignart intraductal papillary mucinous neoplasms [IPMNs]) (Figure 4). Small (<1 cm), simple, asymptomatic cysts discovered incidentally may be observed using follow-up imaging. A history of past acute pancreatitis or imaging criteria suggesting chronic pancreatitis should increase suspicion of a pseudocyst. Significant data have been published over the years that led to development of consensus guidelines.⁴ In this guideline, obstructive jaundice from the cyst, dilation of main pancreatic duct (MPD) more than 10mm not attributable to mucus, stone or CP and enhancing solid components within the cyst are identified as indications for resection. Features that should prompt further evaluation by EUS include presence of mural nodule, MPD between 5-9mm, size ≥3cm, thickened/enhancing cyst wall and abrupt change in duct caliber with distal atrophy.

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 (carcinoembyonic antigen [CEA]), and amylase. A positive mucin stain of cyst fluid may also be helpful in ruling in a mucinous cystic neoplasm. The primary diagnostic test for IPMN is ERCP. The ERCP features of IPMN include a gaping papilla, with the extrusion of mucin, and global or segmental main duct or side branch dilation, with papillary projections (Figure 5).

Mucinous cystic neoplasms and IPMNs should be resected because they have potential for malignant transformation. Resection should also be considered for serous cystademomas that are symptomatic or enlarging.

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Summary

• Dual phase contrast-enhanced computed tomography scanning is the initial test of choice in the diagnosis and staging of pancreatic cancer.
• Radical pancreaticoduodenectomy (Whipple procedure) is the treatment of choice for patients with resectable pancreatic cancer.
• Although chemotherapy and radiation therapy have roles in the management of unresectable pancreatic cancer, palliation of symptoms is the primary therapeutic goal.
• EUS-guided fine needle aspiration and fluid analysis aid in differentiating pancreatic cysts with and without malignant potential.

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Suggested Readings

• DiMagno EP, Reber HA, Tempero MA: AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological Association. Gastroenterology 1999;117:1464-1484.
• Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605-1617.
• Scheiman JM: Cystic lesions of the pancreas. Gastroenterology 2005;128:463-469.

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