Jana G. Hashash, MD and Randall E. Brand, MD
The vast majority of primary malignant tumors of the pancreas are of what histological type?
Ductal adenocarcinomas and its variants constitute approximately 90% of primary malignant tumors of the pancreas. About 5% of pancreatic tumors are of islet cell origin. The rarer types of primary pancreatic cancer include squamous cell carcinoma, giant cell carcinoma, carcinosarcoma, cystadenocarcinoma, acinar cell carcinoma, sarcoma, malignant fibrous histiocytoma, lymphoma, and pancreaticoblastoma.
The majority of adenocarcinomas are derived from what part of the pancreas?
Pancreatic ductal epithelium. Over half of tumors are found in the head of the pancreas.
What are the three established precursor lesions for development of an adenocarcinoma?
Pancreatic intraepithelial lesions (PanINs), mucinous cystadenomas (MCNs), and intraductal papillary mucinous neoplasms (IPMNs).
Diabetes mellitus or impaired glucose intolerance occurs in what percentage of patients with pancreatic cancer?
Sixty percent to 80% of patients with pancreatic cancer have diabetes mellitus or impaired glucose tolerance with the majority of patients found to be diabetic within 2 years of the diagnosis of pancreatic cancer. Glucose intolerance is noted to improve after pancreatic tumor resection.
What hormone is felt to be responsible for the occurrence of diabetes in patients with pancreatic cancer?
The overproduction of amylin (islet amyloid polypeptide) has been reported in patients with pancreatic cancer.
What are some epidemiologic and etiologic factors that are associated with an increased risk for the development of pancreatic cancer?
Cigarette smoking, animal fat-rich diet (reduced levels of lycopene), idiopathic chronic pancreatitis, alcoholic chronic pancreatitis, diabetes mellitus, and gallstones.
True/False: Cigarette smoking is the most consistent environmental risk factor predisposing to pancreatic cancer.
True. Cigarette smoking is the only risk factor consistently found in epidemiological studies to predispose to pancreatic cancer.
Why does CA 19-9 only have a maximum sensitivity of 95% for the diagnosis of pancreatic cancer?
The carbohydrate antigen, CA 19-9, is not expressed in the 5% of individuals who are sialylated Lewisa antigen negative.
What are the more common presenting symptoms in patients with pancreatic cancer?
Epigastric pain, weight loss, anorexia, and obstructive jaundice.
What is the most common presentation in patients with resectable pancreatic carcinoma?
Painless jaundice is seen in about 50% of patients with a resectable lesion.
What is the most common genetic alteration detected in pancreatic carcinomas?
A K-ras mutation is detected in 95% of cases.
True/False: A mutation at codon 15 of K-ras is the most commonly identified gene abnormality in pancreatic cancer.
False. Mutations of K-ras almost uniformly occur at codon 12 in pancreatic cancer.
Approximately what percentage of pancreatic carcinoma cases are related to hereditary factors?
A genetic predisposition for adenocarcinoma of the pancreas may account for up to 10% of cases. Such genetic predispositions include hereditary pancreatitis, Peutz–Jeghers syndrome and BRCA-2-positive individuals among others.
True/False: The risk of pancreatic cancer is increased in all familial atypical multiple mole melanoma (FAMMM) syndrome kindreds.
False. Only in those kindreds with a p16 germ-line mutation.
What other disorders can lead to elevations in serum CA 19-9 levels?
Most commonly, those disorders that cause biliary tract obstruction such as cholangitis, cholangiocarcinoma, gallbladder carcinoma, and benign biliary tract diseases. Additionally, elevations may be seen in acute and chronic pancreatitis and chronic liver disease.
What imaging techniques can be used to assist in obtaining tissue to make the diagnosis of pancreatic cancer?
Fine-needle aspiration can be performed under endoscopic ultrasound (EUS), CT, or transabdominal ultrasound guidance. In addition, brushings can be obtained during endoscopic retrograde cholangiopancreatography (ERCP).
What imaging modality is generally considered to be the best initial study when evaluating patients presenting with symptoms that suggest pancreatic disease?
A pancreatic-protocol multidetector CT scan is recommended since it can detect tumors in the pancreas, stage for resectability, and evaluate for liver metastases.
What imaging study is most accurate in the detection of small (<2 cm) pancreatic neoplasms?
EUS has been found in several studies to be the most accurate imaging study available for the detection of small carcinomas.
Which structures are technically difficult to assess via EUS?
Superior mesenteric vessels. EUS is better at imaging the portal and splenic veins. EUS may lack accuracy in assessing vascular invasion at the level of the superior mesenteric vessels.
What percentage of patients with adenocarcinoma of the pancreas are unresectable at the time of diagnosis?
Due to the insidious nature of the disease, more than 80% of patients are unresectable at the time of diagnosis.
What helical CT scanning criteria are used to define unresectability in pancreatic cancer?
• Presence of extrapancreatic (metastatic) disease.
• Evidence of direct tumor extension to the celiac axis and/or superior mesenteric artery.
What is the perioperative mortality rate of pancreaticoduodenectomy (Whipple procedure) when performed at experienced centers?
Current perioperative mortality rates are less than 5% at experienced centers.
True/False: Poorly differentiated pancreatic adenocarcinomas have significant cellular atypia, significant mitotic activity, and significant mucin production.
False. Well-differentiated pancreatic adenocarcinoma cells produce a significant amount of mucin.
How many long-term survivors of pancreatic cancer die of recurrent or metastatic disease?
Unlike most other types of cancer, 5-year survival with this disease does not ensure that the patient has been cured of it. One study of long-term survivors (>5 years) reported that almost half of these patients died of recurrent or metastatic disease.
What is the preferable method of nonoperative palliative biliary decompression?
For reasons of less morbidity, it is preferable to place a stent by ERCP rather than percutaneously through a transhepatic approach.
True/False: Preoperative stenting of the bile duct to relieve jaundice decreases perioperative morbidity and mortality.
False. Recent studies do not support preoperative stenting of the bile duct except in cases of acute cholangitis. This seems to be due to an increased rate of complications in patients undergoing routine preoperative biliary stenting.
What is the double-duct sign?
This sign is caused by a mass in the head of the pancreas causing dilation of both the pancreatic and common bile duct. When this sign is present, the patient should be assumed to have pancreatic cancer until proven otherwise.
What are the advantages of preoperative chemoradiation therapy compared to postoperative chemoradiation therapy in resectable patients?
A recent study demonstrated no change in survival advantage; however, 24% of patients were unable to receive postoperative treatment as a result of delayed recovery after surgery. Additionally, there is a subset of patients that develop metastatic cancer while receiving preoperative therapy, thereby eliminating a group of patients that would not have benefited from a surgery (due to the presence of unrecognized pancreatic cancer).
What options are available for treatment of gastric outlet obstruction caused by a pancreatic adenocarcinoma?
The use of expandable metallic stents offers an endoscopic method for palliation of this complication. Prior to endoscopic palliation, the traditional management was a surgical bypass procedure such as a gastrojejunostomy. Depending upon the clinical scenario, the placement of a venting gastrostomy tube and/or a feeding jejunostomy is another option.
What pathologic characteristics predict long-term survival following surgical resection for pancreatic cancer?
Negative resection margins, negative nodal status, and tumor size < 1–2 cm are strong predictors of long-term survival.
After a patient is initially diagnosed with pancreatic cancer, what are the next management decisions?
There are three categories into which a newly diagnosed pancreatic cancer patient can be placed depending on spread of the disease: 1) metastatic and unresectable tumors will require chemotherapy +/- palliation, 2) locally advanced and border-line resectable tumors are candidates for chemotherapy or chemoradiation, and 3) resectable tumors are surgical candidates. The third group should receive either neoadjuvant or adjuvant therapy in addition to surgery.
True/False: Total pancreatectomy and extensive retroperitoneal lymphadenopathy excision have shown survival benefits over pancreaticoduodenectomy in patients with pancreatic cancer.
False. Whipple pancreaticoduodenectomy is the most common surgery for pancreatic cancer. Total pancreatectomy has not shown to improve survival compared to the Whipple operation and is associated with a higher rate of exocrine insufficiency and brittle diabetes. Also, extensive retroperitoneal lymphadenopathy excision, in addition to the Whipple surgery, has shown no significant survival benefit over the Whipple procedure alone.
True/False: About 3% of cystic pancreatic tumors are neoplastic.
False. About 15% are neoplastic. These cystic neoplasms include serous cystadenomas, IPMNs, cystic neuroendocrine tumors, and solid pseudopapillary tumors.
True/False: Once a pancreatic cyst is discovered, the possibility of the lesion being a pseudocyst should be excluded.
True. Patient evaluation should be directed toward exclusion of a pancreatic pseudocyst including inquiring about a history of acute pancreatitis. Pseudocysts lack the epithelial lining that true cysts have. Radiographically, pseudocysts tend to lack septae, loculations, solid components, or cyst wall calcifications.
What elements present in pancreatic cysts have been evaluated in attempt to improve the diagnostic yield of cyst fluid aspiration?
Fluid color and viscosity, cytology, amylase, and a variety of tumor markers including carcinoembryonic antigen (CEA), CA 19-9, CA 125, and CA 72-4. Genetic markers may also be checked but are generally reserved for cysts in which the cytology and CEA testing yields indeterminate premalignant or malignant findings.
What is the single most clinically useful test done on a pancreatic cyst fluid aspirate in the evaluation of a cystic lesion of the pancreatic tail?
A CEA level is the most informative test to discriminate between a mucinous and nonmucinous cystic lesion with an accuracy of about 80%.
True/False: A serous cystadenoma occurs more commonly in females than males.
True/False: A serous cystadenoma is most commonly diagnosed in patients before the age of 40.
False. These neoplasms are most commonly detected in the sixth decade of a patient’s life.
What are the most common presenting symptoms of a serous cystadenoma?
Abdominal pain (50%), asymptomatic abdominal mass (33%), and weight loss (20%).
What is the typical ultrasonographic appearance of a serous cystadenoma?
It appears as a complex echo-lucent cystic structure with septae, similar to a honeycomb structure. The individual cysts are usually small.
What is the classic calcification pattern of a serous cystadenoma seen on abdominal plain films?
Central calcification known as a “sunburst” pattern.
How does a serous cystadenoma usually appear on CT scan?
A multiloculated cystic mass ranging in size from 4 to 6 cm. A central stellate calcification may be present. The neoplasm can occur anywhere within the pancreas but is found most commonly in the body or tail.
True/False: Serous cystadenomas are generally benign.
True/False: MCNs are more common in women and occur around the age of 50.
What is the usual appearance of a mucinous cystadenoma on either ultrasonography or CT scan?
A loculated cystic mass that does not communicate with the main pancreatic duct and is located in the body or tail of the pancreas. Malignant lesions tend to be larger (8–11 cm) and often have rim calcifications within the wall identified on CT scan.
What is the treatment of choice for a mucinous cystic neoplasm?
Surgical resection is the treatment of choice due to difficulties in differentiating a benign versus malignant lesion by biopsy of the cyst wall or by fine needle aspiration of the cyst contents.
How are IPMNs classified?
IPMNs can be classified as main duct, side-branch (either single or multifocal), or mixed main duct-side-branch on the basis of their appearance of imaging studies.
What are the classic characteristics of a main duct intraductal papillary mucinous tumor of the pancreas as seen during ERCP?
A dilated and irregular main pancreatic duct with filling defects and extrusion of mucin through the major papilla.
True/False: Surgical resection is recommended for all main duct and mixed variant IPMNs regardless of whether symptomatic.
True. Resection is also recommended for symptomatic side-branch IPMNs in surgically fit patients with reasonable life expectancy.
Which pancreatic tumors are associated with peripheral fat necrosis?
A minority of patients with acinar cell carcinoma present with lipase hypersecretion syndrome, which results in peripheral fat necrosis.
Which is the most likely type of pancreatic tumor being demonstrated in the following figure?
The hypervascular, necrotic nature of the pancreatic head mass is most suggestive of a neuroendocrine tumor.
What neuroendocrine tumor is associated with a syndrome of large volume diarrhea, achlorhydria, and hypokalemia?
VIPoma. This syndrome, caused by overproduction of vasoactive intestinal peptide, is characterized by the acronym WDHA (watery diarrhea, hypokalemia, and achlorhydria).
What neuroendocrine tumor is associated with a dermatitis, glucose intolerance, weight loss, and anemia?
Glucagonoma. Up to 90% of cases will present with characteristic skin lesions and glucose intolerance.
What is the characteristic skin rash that may be seen in patients with glucagonoma?
Necrolytic migratory erythema. This rash may wax and wane and occurs in 64%–90% of cases.
Deficiencies of amino acids are a common occurrence in what pancreatic neuroendocrine tumor?
Glucagonoma. The severity of the deficiency is correlated with the intensity of the disease.
A 55-year-old white man with a history of diabetes and steatorrhea underwent an emergent cholecystectomy for acute cholecystitis. Intraoperatively, he is found to have a small tumor in the head of the pancreas. The patient most likely has what neuroendocrine tumor?
Somatostatinoma. Diabetes occurs in 95%, gallstone disease in 94%, and steatorrhea is found in 83% of cases of pancreatic somatostatinomas.
The majority of gastrinomas are found in what anatomic area?
The gastrinoma triangle, which is bordered superiorly by the confluence of the common bile duct (CBD), inferiorly by the junction of the second and third portions of the duodenum, and medially by the junction of the neck and body of the pancreas.
Gastrinomas are classically associated with what syndrome?
Multiple endocrine neoplasia (MEN) type 1 is reported in approximately 25% of gastrinoma patients.
Describe Whipple’s triad?
Whipple’s triad consists of hypoglycemic symptoms, blood glucose levels of less than 50 mg/dL, and symptom relief after glucose ingestion. It may be seen in patients with an insulinoma.
Besides a CT scan of the abdomen, what is the best imaging study to evaluate for metastatic gastrinoma?
An octreotide scan (somatostatin receptor scintigraphy). In most series, it assists in the localization of gastrinomas more than 90% of the time.
Where is the most common extrapancreatic site for a gastrinoma?
The duodenal wall.
What is the neuroendocrine tumor with the lowest rate of metastasis?
Insulinoma, with a rate of < 10%.
True/False: Both EUS and somatostatin receptor scintigraphy are useful in the localization of insulinomas and gastrinomas.
False. Although both modalities are useful in the evaluation of gastrinomas, only 10% of insulinomas are detected with an octreotide scan.
What type of lymphoma may affect the pancreas?
Non-Hodgkin’s lymphoma accounts for 1%–2% of all pancreatic neoplasms. About 1% of non-Hodgkin lymphomas appear to arise from the pancreas. At autopsy, about one-third of all patients with non-Hodgkin’s lymphoma will have some microscopic involvement of the pancreas.
What is a typical presentation of pancreatic lymphoma?
Weight loss and jaundice. Some patients may also have night sweats.
True/False: Surgical resection is usually required in cases of pancreatic lymphoma.
False. Combination chemotherapy and radiation therapy results in a cure rate of 30%. Surgery may occasionally be performed either for tissue diagnosis or for resection of small, localized tumors.
• • • SUGGESTED READINGS • • •
Costello E, Neoptolemos JP. Pancreatic cancer in 2010: new insights for early intervention and detection. Nat Rev Gastroenterol Hepatol. 2011;8(2):71-73.
Al-haddad M, Schmidt MC, Sandrasegaran K, Dewitt J. Diagnosis and treatment of cystic pancreatic tumors. Clin Gastroenterol Hepatol. 2011;9:635-648.
Matthaei H, Schulick RD, Hruban RH, Maitra A. Cystic precursors to invasive pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2011;8(3):141-150.
Batcher E, Madaj P, Gianoukakis AG. Pancreatic neuroendocrine tumors. Endocr Res. 2011;36(1):35-43.