Darwin L. Conwell
Pancreatic ductal adenocarcinoma accounts for 90% of cancers of the pancreas and will be the main focus of this chapter. The diagnostic and therapeutic approaches outlined in this chapter integrate the American Gastroenterological Association (AGA) guidelines for the diagnosis and treatment of pancreatic ductal adenocarcinoma (Fig. 1).
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. It has the lowest 5-year survival of any cancer, reflecting late diagnosis and low resection rates.
The AGA guidelines have recommended cessation of smoking for the purpose of pancreatic cancer prevention. 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) have been found to confer an increased risk. 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. The AGA guidelines have recommended screening with computed tomography (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 those with hereditary pancreatitis.
Signs and symptoms
Of pancreatic cancers, 60% develop in the pancreatic head and 40% develop in the body and tail. 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. 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 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).
The diagnosis and staging of pancreatic cancer are accomplished through imaging tests and pathologic diagnosis. 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 (Fig. 2). The sensitivity of helical CT for the detection of pancreatic cancer ranges from 85% to 95%. Dual-phase CT helps determine surgical resectability through assessment of invasion of major vessels. CT may 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 may improve differentiation of a pancreatic cancer from chronic pancreatitis and offers simultaneous assessment of the pancreatic and bile ducts by heavily T2-weighted imaging (MR cholangiopancreatography, MRCP).
Several studies have demonstrated increased sensitivity and specificity of endoscopic ultrasound (EUS) compared with conventional, single-phase CT for the detection and local staging of pancreatic cancer. The AGA guidelines have suggested that EUS has the greatest role in the detection of small tumors missed by CT. EUS may offer a better assessment of local blood vessel involvement, and allows fine needle aspiration (FNA) of tumor and lymph nodes.
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 and ruling out differential causes of pain or jaundice (e.g., chronic pancreatitis). 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 valuable adjunctive tests for the diagnosis of gastrointestinal cancers. A CA19-9 concentration higher than 70 U/mL has a sensitivity of 70% and specificity of 87% for pancreatic cancer. The CA19-9 level may also be significantly elevated in benign conditions such as choledocholithiasis and cholangitis. In the absence of a mass, elevated levels of CA19-9 and other tumor markers are difficult to interpret.
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 presumed 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 may 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.
The only potentially curative therapy for pancreatic cancer is surgical resection. Pancreatic cancer is resectable if the tumor is confined to the pancreas without the following: (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 rate after resection is 10% to 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 the 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 may occur, including anastomotic leaks and ulcerations, dumping syndrome, and bile gastritis. The AGA guidelines have stressed the importance of cardiac, pulmonary, and nutritional optimization before pancreatic surgery. Although frequently performed, routine preoperative endoscopic biliary decompression is not beneficial and may 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 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 and advanced disease, and as surgical adjuvant therapies. The AGA guidelines have stated that “all patients with unresectable locoregional or metastatic pancreatic cancer should be considered for inclusion into investigational trials.” 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. Patients with locally advanced cancer may be considered for combined 5-fluorouracil–based chemotherapy and external beam radiation, which has been shown to improve median survival compared with radiation therapy alone. The benefits of chemotherapy and radiation as therapies adjuvant to surgical resection have not been proved.
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. 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. Metal stents offer more prolonged patency, but 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; this 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.
Types of tumors
Pancreatic Neuroendocrine Tumors
Also known as islet-cell tumors, neuroendocrine tumors (NETs) are rare tumors (incidence rate, 5 cases/1,000,000 person-years) that arise from endocrine cells within or near the pancreas. NETs may occur sporadically or as part of multiple endocrine neoplasia type 1. Most primary NETs arise within the gastrinoma triangle, comprised 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. Although a subset of NETs is nonfunctional, most 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 may demonstrate malignant behavior, including metastases.
Table 1: Pancreatic Neuroendocrine Tumors
|Tumor Type||Number (%) *||Secretory Products||Clinical Features||Laboratory Tests||Symptomatic Treatment|
|Insulinoma||40-60||Insulin||Hypoglycemia; symptoms of catecholamine excess; 90% benign||Insulin level, C-reactive protein; 72-hr inpatient fasting, with monitoring of glucose and insulin levels||Dietary measures; octreotide; diazoxide|
|Gastrinoma||20-50||Gastrin||Peptic ulcer disease; GERD; secretory diarrhea; most common NET in MEN-I; 60%-90% malignant||Fasting serum gastrin; gastric pH analysis; gastrin provocation testing (calcium or secretin challenge)||Proton pump inhibitor; octreotide|
|Glucagonoma||Rare||Glucagon||Glucose intolerance; migratory necrolytic erythema; weight loss; anemia; 90% malignant||Serum glucagon||Octreotide; insulin; zinc supplement (rash); TPN (malnutrition)|
|Somatostatinoma||Rare||Somatostatin||Diabetes; gallstones; secretory diarrhea||Clinical and pathologic diagnoses; increased somatostatin-like immunoreactivity in resected tumor||Octreotide|
|VIPoma||Rare||Vasoactive intestinal peptide||Cholera-like, secretory diarrhea; hypokalemia; hypochlorhydria||Serum VIP||Octreotide|
* Percentage among neuroendocrine tumors.
GERD, gastroesophageal reflux disease; MEN-I, multiple endocrine neoplasia type I; NET, neuroendocrine tumor; TPN, total parenteral nutrition; VIP, vasoactive intestinal polypeptide.
When a NET is suspected, imaging tests are important to locate the primary tumor and determine the presence of metastases (Fig. 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 radio-labeled octreotide can help locate 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 after symptoms of hormonal excess have been treated and controlled (see Table 1 ). Patients with metastatic disease can be managed medically with octreotide, chemotherapy (streptozocin), 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.
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 2 ). The primary aim of diagnosis is to differentiate benign cysts (e.g., pseudocysts, serous tumors) from malignant cysts (e.g., mucinous tumors, intrapapillary mucinous neoplasias [IPMNs]) (Fig. 4). Small (less than 1 cm), simple, asymptomatic cysts 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. Cystic masses larger than 1 cm 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 (carcinoembryonic 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 (Fig. 5). 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.
Table 2: Types of Pancreatic Cysts
|Type||Demographic||Malignant Potential||Location||Radiographic Features||Cyst Fluid Analysis|
|Pseudocyst||History of pancreatitis||No||Throughout||Unilocular; thick-walled||↑ amylase level|
|Serous cystadenoma||Middle-aged women||No||Throughout||Multicystic; calcifications; central scar||↑ Ca19-9 level|
|Mucinous cystadenoma or cystadenocarcinoma||Middle-aged women||Yes||Body and tail||One or few cysts; thick or irregular walls||Positive mucin stain; ↑ CEA level; positive cytology|
|Intrapapillary mucinous neoplasia||Middle-aged and older men||Yes||Diffuse or localized||Pancreatic duct dilation; papillary projections|
|Papillary cystic neoplasm||Rare; young women||Yes; locally aggressive||Body and tail|
CEA, carcinoembryonic antigen.
- Pancreatic cancer is usually unresectable at the time of diagnosis, leading to an overall poor prognosis.
- 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 play roles in unresectable pancreatic cancer, palliation of symptoms is the primary therapeutic goal.
- EUS-guided fine needle aspiration and fluid analysis aid in differentiating cysts with and without malignant potential.
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