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Pancreatic Cancer
Alma M. Guerrero, MD
Edward Feller, MD, FACP, FACG
image BASICS
DESCRIPTION
  • Adenocarcinoma of the exocrine pancreas (85% of pancreatic cancers) is the fourth most common cause of cancer death in the United States (1).
  • Rarely curable: overall 5-year relative survival rate of 6.7%
  • 60-70% occurs in the head, 20% in the body and tail, 20% diffusely involve the gland.
  • As few as 10% are localized at diagnosis. For localized, small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule, surgical resection has 5-year survival of about 25%.
  • Majority of tumors have metastasized at diagnosis and are thus, largely incurable and have a 5-year survival rate of 2-3%.
  • In apparently resectable disease, 20-40% have unresectable lesions at surgery.
  • Ampullary, duodenal, or distal bile duct tumors may mimic pancreatic carcinoma and are more likely to be resectable and curable.
  • For advanced or unresectable cancers, survival is <1% at 5 years; most patients die within 1 year.
EPIDEMIOLOGY
During 2003 to 2007, median age at diagnosis = 72 years; rare <45 years; after 45 years of age, occurrence rises (2).
Incidence
  • An estimated 46,000 people diagnosed in 2014; 40,000 deaths (3)[A].
  • More common in black and white races, 16.7 and 10.3 in 100,000 men and 14.4 and 10.3 in 100,000 women, respectively. Among Hispanic and Asian/Pacific Islanders, there is an incidence of 10.9 and 8.3 in 100,000 men and 10.1 and 8.3 in 100,000 women, respectively.
Prevalence
In 2008, in the United States, ˜34,600 men and women (16,811 men and 17,846 women) were alive who had a history of pancreatic cancer.
RISK FACTORS
  • Smoking: relative risk (RR) = 2 to 3; correlates with amount smoked
  • Diabetes: RR = 2.1 (95% CI [1.6, 2.8]); 1 in 6 become diabetic within 6 months before diagnosis
  • Prior partial gastrectomy or cholecystectomy: 2- to 5-fold increased risk 15 to 20 years after gastrectomy
  • Familial aggregation/genetic factors: 5-10% of patients have a first-degree relative with the disease, which confers a 9-fold increase in risk versus the general population; subgroup may carry germline mutations of DNA repair genes (BRCA2).
  • Hereditary chronic pancreatitis (autosomal dominant, highly penetrant): cumulative risk by ages 50 and 75 years is 10% and 54%, respectively.
  • Peutz-Jeghers syndrome: RR 30 to 40
  • Sporadic chronic pancreatitis
  • Non-O blood type: RR 1 to 2
  • High intake of dietary fat and obesity
  • Alcohol: Recent data indicate a modest increase in risk confined to heavy alcohol consumers.
  • Coffee intake and NSAID use NOT regarded as risk factors.
GENERAL PREVENTION
No effective screening modality exists to detect early cancer. Even with a strong family history or predisposition syndromes, use and cost-effectiveness of screening are unclear.
COMMONLY ASSOCIATED CONDITIONS
  • Chronic pancreatitis, diabetes mellitus, cystic fibrosis (4)
  • Subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole, multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from BRCA2).
  • Majority of familial pancreatic cancers have no genetic underpinnings.
  • Precursor lesions are potentially curable—pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasia, and mucinous cystic neoplasms.
image DIAGNOSIS
PHYSICAL EXAM
  • Muscle wasting and malnutrition are common; skin lesions are indicative of pruritus. Exam can be normal.
  • Palpable abdominal mass or ascites in 20%
  • Jaundice: 70% if tumor obstructs bile duct; 10% with body or tail carcinoma
  • Courvoisier sign (painless jaundice with a palpable gallbladder): uncommon; usually associated with pancreatic head tumors, periampullary or primary bile duct tumors; hepatomegaly in advanced disease
  • Virchow node (left supraclavicular) and Sister Mary Joseph node (umbilical) in metastatic disease; palpable rectal shelf (nonspecific sign of carcinomatosis)
  • Migratory thrombophlebitis (Trousseau sign) (uncommon) due to hypercoagulability in mucinproducing pancreatic cancer
  • GI bleeding from tumor erosion into adjacent viscera (colon); portal hypertension-related bleeding (uncommon)
  • Pancreatic panniculitis: subcutaneous areas of nodular fat necrosis
DIFFERENTIAL DIAGNOSIS
  • Chronic pancreatitis, duodenal cancer, cholangiocarcinoma, lymphoma, islet cell tumor, sarcoma, cystic neoplasms, tumor metastatic to pancreas (rare)
  • Nonmalignant conditions: choledocholithiasis, acute or chronic pancreatitis, biliary tract stricture, adenoma; chronic mesenteric ischemia
  • Tuberculosis or fungal abscess in AIDS
  • Patients may present with back pain mimicking musculoskeletal disease.
DIAGNOSTIC TESTS & INTERPRETATION
  • Cross-sectional imaging (usually CT scan as first-line choice) to evaluate symptoms or abnormal lab results
  • Endoscopic ultrasound-guided biopsy: best modality for tissue diagnosis; sensitivity 75-90%; specificity ˜100% for diagnosis of a mass
  • Routine laboratory tests may reveal elevated serum bilirubin and alkaline phosphatase (cholestasis), anemia, or decreased serum albumin (malnutrition).
Initial Tests (lab, imaging)
  • Most patients do not require measurement of serum tumor markers (CA19-9) for diagnosis or management. Some evidence suggests use in predicting outcome and response to adjuvant chemotherapy.
  • CEA and CA19-9 are not recommended as screening tests; useful in following patients with known disease (3)[A]
  • Elevated CA19-9 antigen: 80% sensitivity; 90% specificity; individuals with Lewis-negative blood group antigen phenotype (5-10%) are unable to synthesize CA19-9; elevations can occur in benign pancreatic or biliary diseases and in nonpancreatic malignancy.
Follow-Up Tests & Special Considerations
  • During therapy, increase in CA19-9 may identify progressive tumor growth. Normal CA19-9 does not exclude recurrence.
  • CT scan (pancreatic protocol) using thin section, multiphase multidetector helical CT with a pancreatic protocol is the choice for diagnosis and staging: 85-90% sensitivity; 90-95% specificity; useful for evaluation of distant metastasis and prediction of resectability.
  • Abdominal ultrasound: common initial test to assess jaundice and duct dilatation; less sensitive than CT for pancreatic masses
  • P.755

  • Endoscopic ultrasound (EUS) is accurate for tissue biopsy, local tumor and node staging, predicting vascular invasion (90% specificity; 73% sensitivity), and when no mass is identified on CT.
  • Endoscopic retrograde cholangiopancreatography (ERCP): 90% sensitivity; 95% specificity for ductal cancer; useful if endoscopic stent is indicated for biliary obstruction; generally confined to high probability for therapeutic intervention on biliary or pancreatic ductal systems
  • MRI: no advantage over contrast-enhanced CT
  • MR cholangiopancreatography: 90% sensitivity; 95% specificity. Preferred in specific settings: gastric outlet or duodenal stenosis or after surgical rearrangement (Billroth II) or ductal disruption; to detect bile duct obstruction, after attempted ERCP is unsuccessful or provides incomplete information
  • Cystic pancreatic lesions may be benign or malignant; must be differentiated from pancreatic pseudocysts. Cystadenocarcinomas have better prognoses than typical pancreatic cancers.
Diagnostic Procedures/Other
  • Percutaneous fine-needle biopsy with US or CT guidance: 80-90% sensitivity; 98-100% specificity
  • EUS-guided biopsy: 85-90% sensitivity; virtually 100% specificity for pancreatic mass
  • Staging laparoscopy and US: 92% sensitivity; 88% specificity; 89% accuracy
  • Positive peritoneal cytology has a positive predictive value of 94%; specificity of 98%; sensitivity of 25% for determining unresectability.
  • PET scan: 90% sensitivity but 70% specificity; limited anatomic information
  • Tumor staging
    • Stage I: tumors limited to the pancreas
    • Stage II: regionally invasive; may involve lymph nodes but without celiac or mesenteric artery involvement
    • Stage III: direct involvement of celiac or superior mesenteric artery involvement
    • Stage IV: distant metastases
Test Interpretation
  • Duct cell carcinoma: 90%
  • Other less common tumors: acinar, papillary mucinous, signet ring, adenosquamous, mucinous, giant or small cell, cystadenocarcinoma, undifferentiated, unclassified carcinoma
image TREATMENT
  • Surgical resection: only chance of cure; no role for pancreatic resection in metastatic disease. As few as 15-20% are candidates for resection.
  • Criteria for unresectability: extrapancreatic spread, encasement or occlusion of major vessels, distant metastases
  • New combination chemotherapy regimens may offer advantages over gemcitabine. Standard therapies remain unsatisfactory; thus, patients should be considered for clinical trials (3).
MEDICATION
  • Analgesics
  • Stages I and II
    • Radical pancreatic resection plus chemotherapy
    • ESPAC-3 trial after resection: compared with 5-fluorouracil (5-FU) and folinic acid, gemcitabine did not improve overall survival.
    • Currently, postoperative gemcitabine alone or in combination with 5-FU-based chemoradiation is the current standard of care; preoperative neoadjuvant treatment trials are in progress.
  • Stage III
    • Standard: Chemotherapy with gemcitabine-based regimens; added chemoradiation is controversial.
    • FLOFIRINOX and gemcitabine—nab-paclitaxel were recently shown to have a benefit in patients with metastatic disease; may be tried in patients with locally advanced disease
    • Palliation of biliary obstruction by endoscopic, surgical, or radiologic methods
    • Intraoperative radiation therapy and/or implantation of radioactive substances
  • Stage IV
    • Chemotherapy: Gemcitabine with erlotinib, or paclitaxel, or a fluoropyrimidine may modestly prolong survival compared with gemcitabine alone.
    • Pain-relieving procedures (celiac or intrapleural block); supportive care; palliative decompression
ADDITIONAL THERAPIES
  • For resected tumors: postoperative radiation therapy with other chemotherapeutic agents
  • Intraoperative radiation therapy and/or implantation of radioactive substances (ongoing trials)
  • Biliary decompression with endoprosthesis or transhepatic drainage for bile duct obstruction
  • Celiac axis and intrapleural nerve blocks can provide effective pain relief for some patients.
  • Opiates may be needed for pain control.
SURGERY/OTHER PROCEDURES
  • Standard treatment options
    • Pancreaticoduodenectomy, Whipple procedure, en bloc resection of the head of the pancreas, distal common bile duct, duodenum, jejunum, and gastric antrum
    • Total pancreatectomy
    • Distal pancreatectomy for body and tail tumors
  • Nonstandard surgeries
    • Pylorus-preserving pancreaticoduodenectomy, regional pancreatectomy
    • Palliative bypass
      • Biliary decompression; gastrojejunostomy for gastric outlet obstruction; duodenal endoprosthesis for obstruction
image ONGOING CARE
DIET
  • Anorexia, asthenia, pain, and depression may contribute to cachexia.
  • Fat malabsorption due to exocrine pancreatic insufficiency may contribute to malnutrition; pancreatic enzyme replacement may help to alleviate symptoms.
  • Fat-soluble vitamin deficiency may require replacement therapy.
PROGNOSIS
  • 90% diagnosed with pancreatic cancer die from the disease, predominantly from metastatic disease (3).
  • 5-year survival: ˜30% if node-negative; 10% if node-positive. Median survival: 10 to 20 months
  • Metastatic cancer: 1-2% 5-year survival
  • For localized disease and small cancers (<2 cm) with no lymph node involvement and no extension beyond the capsule, complete surgical resection can yield a 5-year survival of 18-24%.
  • Detection of curable precursor lesions is a focus of current efforts to improve diagnosis and prognosis.
REFERENCES
1. Chari ST, Kelly K, Hollingsworth MA, et al. Early detection of sporadic pancreatic cancer: summative review. Pancreas. 2015;44(5):693-712.
2. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252-1261.
3. Ryan DR, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039-1049.
4. De La Cruz MS, Young AP, Ruffin MT. Diagnosis and management of pancreatic cancer. Am Fam Physician. 2014;89(8):626-632.
Codes
&NA;
ICD10
  • C25.9 Malignant neoplasm of pancreas, unspecified
  • C25.0 Malignant neoplasm of head of pancreas
  • C25.1 Malignant neoplasm of body of pancreas
Clinical Pearls
&NA;
  • Sudden onset of diabetes mellitus in nonobese adults aged >40 years may warrant consideration of pancreatic cancer in selected cases.
  • Cancer of the exocrine pancreas is rarely curable; overall 5-year survival rate of <4%. Fewer than 20% of cases are localized at diagnosis.
  • Be wary of chronic pancreatitis, which can present with similar pain pattern, weight loss, jaundice, and an inflammatory mass on imaging.
  • Because of the dismal prognosis on standard therapy, all patients with pancreatic cancer should be considered for appropriate clinical trials