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A. Biliary Tree Cancers Overviewnavigator

  1. Epidemiology
    1. About 28,000 new cases diagnosed in 1996 in USA
    2. Overall five year survival rate is ~4%
  2. Pancreas: overall, 3% of all neoplasms
    1. Adenocarcinoma of the Ducts (90% of cases - various histologies)
    2. Islet cell tumor
    3. Cystic neoplasms of the pancreas (see below)
    4. Carcinoid
    5. Lymphoma
    6. Often jaundice without pain
  3. Tumors of Common Bile Duct
    1. Cholangiocarcinoma = Klatskin Tumor
    2. Cholangioma
    3. Often Pain with Jaundice
  4. Periampullary Carcinoma
  5. Duodenal Neoplasms
    1. Malignant
    2. Carcinoid

B. Cystic Neoplasms [1,2]navigator

  1. Cystic neoplasms including cystadenoma
  2. Uncertain malignant potential
  3. Presentation
    1. Identified on radiographic studies performed for other reasons (asymptomatic)
    2. Non-specific abdominal pain
    3. Early symptoms of obstruction: bloating, fullness, early satiety
    4. Larger lesions present with pain, weight loss, jaundice
  4. Variety of Histopathologies
    1. Mucinous cystic neoplasm: cystadenoma, borderline tumor, adenocarcinoma
    2. Intraductal papillary mucinous neoplasms: adenoma, borderline, intraductal carcinoma
    3. Invasive intraductal tubular type papillary neoplasm or colloid carcinoma
  5. Major Types (Table 1, Ref [1])
    1. Serous cystadenoma: ~35%, mean age ~65, resection curative for non-adenocarcinoma
    2. Mucinous cystic neoplasm: 25%, mean age 45, resection curative for non-adenocarcinoma
    3. Intraductal papillary mucinous neoplasm: ~25%, mean age ~60, good prognosis for benign
    4. Solid pseudopapillary neoplasm: <10%, mean age ~35, resection usually curative
    5. Cystic endocrine neoplasm: <10%, mean age ~50, prognosis similar to other neuroendocrine tumors
    6. Ductal adenocarcinoma with cystic degeneration: <1%, mean age ~60, dismal prognosis
    7. Acinar-cell cystadenocarcinoma: <1%, mean age ~60, aggressive neoplasm
  6. Evaluation
    1. Computerized tomography (CT) or magnetic resonance imaging (MRI) required
    2. Various tumor markers present in cyst fluid may help with diagnosis
    3. Tissue required for definitive histology
    4. Risks versus benefits of surgical intervention
  7. Surgery usually required for good prognosis
  8. Chemotherapy for adenocarcinoma may be of some benefit (see below)

C. Pancreatic CA [3,4]navigator

  1. Epidemiology
    1. Annual Incidence USA: >30,000
    2. Annual Deaths USA: 28,9000
    3. Ratio of male to female is about 2:1
    4. Increased incidence in Blacks
    5. Risk increased 1.7X in obese persons [5]
    6. Average age onset 60 years
  2. Properties of Tumors
    1. About 70% of cancers occur in the head of the pancreas, 20% in body, 10% in tail
    2. Estrogen Receptor Positive
    3. Has usually invaded adjacent structures or metastasized at diagnosis
    4. Spread to abdomen and liver
  3. Tumor Classification at Diagnosis [4]
    1. Locally invasive, resectable ~20% (20 month survival with 5FU+radiation)
    2. Locally advanced, unresectable (~40%; 6-8 month survival with gemcitabine)
    3. Metastatic (~40%; 4-6 month survival with gemcitabine)
  4. Histology
    1. Ductal adenocarcinoma (with several variant histologies)
    2. Mucinous cystadenocarcinoma
    3. Acinar cell carcinoma
    4. Unclassified large cell carcinoma
    5. Small cell carcinoma
    6. Pancreatoblastoma
  5. Risk Factors [4]
    1. Alcoholism
    2. Smoking - ~3 fold risk increase over age matched controls
    3. Smoking estimated to account for ~30% of pancreatic cancer [3]
    4. Chronic pancreatitis
    5. Diabetes mellitus associated with ~2X risk increase over age matched controls [13]
    6. Insulin resistance in general associated with 2X increased pancreatic risk in men [13]
    7. Increased dietary fat intake
    8. Reduced intake of fruits and vegetables
    9. Occupational exposure to petroleum and other toxic chemicals
    10. Tropical calcifying pancreatitis
    11. Organochlorine (including DDT, DDE, PCB) exposure
    12. May be associated with sclerosing cholangitis [6]
    13. About 10% of cases are inherited
  6. Hereditary Predisposition [7]
    1. About 10% of pancreatic cancers have hereditary predisposition
    2. Many of these cases have familial pancreatic cancer
    3. Also inludes patients with FAP or HNPCC
    4. Cystic fibrosis patients also at increased risk
    5. Familial pancreatic cancer is characterized by autosomal dominant inheritance
    6. Penetrance of cancer in these patients is ~50%
    7. Thorough screening of patients with ERCP, ultrasound, and other modalities
    8. Screening with serum CEA and CA-19-9 has low sensitivity for early lesions
    9. Analysis of pancreatic tissue for K-ras mutations may be useful as well (see below)
    10. BRCA2 locus may be important contributor in familial disease
  7. Tumor Genetics [3]
    1. K-Ras oncogene activation (chr 12p) found in >80% of pancreatic adenocarcinomas
    2. HER2/neu (chr 17q) amplification ~65%
    3. p53 (TP53, chr 17p) is overexpressed in >50% of the cases
    4. Tumor suppressor gene mutations in DCC (50%) and MTS1 (70%) are found
    5. CDKN2A (p16ink4a on chr 9p) deleted or mutated ~65%
    6. CDKN2A (p19arf on chr 9p) deleted or mutated ~65%
    7. CDKN2B (chr 9p) deleted or mutated ~40%
    8. DPC4 (MADH4, SMAD4, chr 18q) inactivated in 55%
    9. DPC4 and TP53 inactivation are late events
    10. Despite presence of mutant ras genes, farnesyl transferase inhibitors have been disappointing

D. Symptoms navigator

  1. Jaundice due to obstruction (head of pancreas)
    1. Highly elevated alkaline phosphatase and elevated bilirubin
    2. Moderate to mild elevations of AST and ALT
    3. Most lesions diagnosed when <5cm
    4. "Painless Jaundice"
    5. Patients >60 years old and total bilirubin >10mg/dL --> 90% likelihood of Pancreatic CA
  2. Non-obstructing lesions may present with pain
    1. Usually ~10cm at presentation
    2. Tail and body of pancreas
  3. Weight loss, usually marked
  4. Dark urine (Biliuria)
    1. Failure to excrete bilirubin into bile
    2. Conjugated bilirubin in blood secreted by kidney
    3. Unconjugated bilirubin cannot be secreted
  5. Malabsorption Syndrome
    1. Partially responsible for weight loss
    2. Fat malabsorption usually most marked leading to Steatorrhea
  6. Severe Pain
    1. Mainly due to direct effects on local structures
    2. Some metastatic pain
  7. Thrombophlebitis [8]
    1. Migratory thromboses, formerly "Trousseau Syndrome"
    2. Associated with carcinomas, usually of the pancreas
    3. Multiple arterial thrombi leading to myocardial infarction and/or stroke may occur
    4. This represents a highly hypercoagulable state
    5. Warfarin prophylaxis is of only minimal benefit in Trousseau syndrome
  8. Painful cutaneous nodules (panniculitis, fat necrosis) [9]

E. Diagnosis navigator

  1. Serum Tests
    1. CA 19-9 marker (mucin marker)
    2. CAM 17.1/WGA Mucin - particularly in nonjaundiced patients with abdominal pain [4]
    3. CA 125 not usually elevated in this tumor
    4. High Amylase and/or lipase levels may be present also
  2. Non-Invasive Radiology
    1. Ultrasound: shows duct dilation
    2. Ultrasound normal is <6mm, in elderly or post-cholecystectomy <9mm
    3. Computerized Tomographic (CT) scan: better demonstration of anatomy than ultrasound
    4. Magnetic Resonance Studies: anatomic resolution similar to ERCP
  3. Magnetic Resonance Cholangiopancreatograhy (MRCP) [11,12]
    1. Non-invasive method for evaluation of biliary tract
    2. Especially useful for evaluation of masses (tumors) in the biliary tree
    3. Good visualization of ducts with clarity similar to ERCP (see below)
    4. Does not evaluate the ampulla as well as ERCP
    5. Sensitivity and visualization may be increased after giving secretin
    6. Does not require administration of any contrast dye
    7. May precede ERCP in patients with low likelihood of intervention [12]
  4. 99mTc-DesHIDA (HIDA) Scan
    1. Nuclear medicine scan
    2. Compound is sequestered by liver secreted into bile ducts
    3. Gall bladder normally fills by 15-20 minutes
    4. Duodenum normally fills by 20-30 minutes
    5. Less useful now with advent of MRCP and other methods
  5. Angiogram
    1. Venous phase of superior mesenteric artery injection
    2. Superior mesenteric and portal vein
    3. Assess resectability of tumors
    4. Generally avoided
  6. Invasive Studies and Biopsy
    1. Biopsy material to confirm diagnosis very important
    2. Percutaneous Transhepatic Cholangiogram (PTCA): better for upper (proximal) lesions
    3. Endoscopic Retrograde Cholangiopancreatography (ERCP): better for distal lesions
    4. ERCP can also be used to obtain brushings for pathology
    5. CT guided fine needle aspiration (FNA)
    6. Endoscopic ultrasonography guided FNA has low false-negative rates [10]
    7. ERCP obtain biliary fluid can be analyzed for insulin-like growth factor 1 (IGF-1) levels
    8. IGF-1 highly elevated in cholangiocarcinoma versus normal in pancreatic ca and benign diseases [24]
  7. Analysis of Endoscopically obtained Pancreatic Juice (investigational)
    1. ERCP can be used to obtain pancreatic fluid samples
    2. This fluid can be analyzed for presence of K-Ras mutations in cellular DNA
    3. This method is very specific and ~75% sensitive
  8. MicroRNA expression pattern can be used to differentiate normal pancreas, chronic pancreatitis, and pancreatic adenocarcinoma; and outcome in the tumor groups [23]

F. Therapy [3,4]navigator

  1. Definition of Resectable Pancreatic Cancer
    1. Defined preoperatively as pancreatic tumor:
    2. Without evidence of involvement of superior mesenteric artery or celiac axis
    3. Patent superior mesenteric-portal venous confluence
    4. No evidence of distant metastatic disease
    5. Resectable pancreatic adenocarcinoma represents 15-20% of cases
  2. Surgery for Resectable Cancers
    1. Despite apparently curative surgery, only 15-20% 5 year survival
    2. Local recurrence after surgery in ~65% and median survival is 10-18 months
    3. Initial tumor size correlates extremely well with survival
    4. Size <2-3cm is "cutoff" for true resectability
    5. Most cases utilize surgery for paliation of symptoms (jaundice, pain)
    6. Adjuvant chemotherapy is usually given and demonstrates clear survival benefits [19]
    7. Adjuvant chemotherapy is usually 6 cycles of 5-fluorouracil (5-FU) with leukovorin
    8. Adjuvant radiation added to chemotherapy is of no benefit in resectable cases [14,19]
    9. Preoperative chemoradiation (neoadjuvant) therapy may reduce local relapse and could improve long term survival in localized resectable disease [4]
    10. Preoperative chemoradiation (50.4Gy) with 5-FU (250mg/m2 continuous infusion) is generally standard in resected pancreatic adenocarcinoma [25]
    11. Gemcitabine adjuvant therapy for resectable pancreatic Ca significantly improved disease free survival and trended toward improvement of overall survival [22]
    12. Gemcitabine before and after 5-FU chemoradiation improved survival >3.5 months in locally advanced metastatic pancreatic adenocarcinoma (16.9 versus 20.5 months) [25]
  3. Palliation of Unresectable Disease (85% of cases)
    1. About half of these are locally advanced and unresectable; others are metastatic
    2. Biliary (expandable metal) stent - by ERCP or percutaneous routes [15]
    3. Percutaneous biliary drainage
    4. Celiac plexus nerve block for severe pain reduces pain but variable on quality of life [16]
    5. Radiation Therapy
    6. Chemotherapy
    7. Combination chemotherapy and radiation median survival 43 weeks
  4. Preparation for Surgery
    1. Internal Drainage
    2. Enteral nutrition
    3. Operate after 2-3 weeks
    4. Better outcomes depend on clinical status of patient
  5. Operation
    1. Resectable Lesions: Whipple procedure (Head of Pancreas), Subtotal pancreatectomy
    2. Gastroenterostomy to prevent GI (duodenal) obstruction
    3. Biliary Stents - T tubes (allow bile drainage)
  6. Whipple Procedure
    1. Pancreaticoduodenectomy
    2. May spare antrum of stomach
    3. Resect head of pancreas, duodenum, ± stomach antrum, distal bile duct, gall bladder
    4. End-to-side anastomosis of jejunum to stomach
    5. Tail of pancreas is stuffed into end of jejunum
    6. Connect proximal hepatic bile duct to jejunum (end to side)
  7. Chemotherapy for Resectable Disease [17]
    1. For resectable disease, adjuvant chemotherapy recommended
    2. 5-FU/leukovorin or preferably gemcitabine recommended for adjuvant chemotherapy [22]
    3. Adjuvant therapy with gemcitabine following Whipple offers benefit [22]
    4. Paclitaxel+Etoposide+Cisplatin+Radiation has been investigated also after Whipple
    5. Doxorubicin and mitomycin have some activity
    6. Radiation added to 5-FU/leukovorin is of no benefit
  8. Chemotherapy for Unresectable / Metastatic Disease
    1. Gemcitabine for unresectable/metastatic disease superior to 5-FU for quality of life [18]
    2. Combinations with gemcitabine and taxotere or platinum under investigation
    3. Gemcitabine + various anti-vascular endothelial growth factor (VEGF) under investigation
    4. Gemcitabine provided 18% 1 year survival for metastatic disease (2% for 5-FU)
    5. Bevacizumab + gemcitabine did not improve survival over gemcitabine alone
    6. Axitinib (an oral anti-VEGF drug) + gemcitabine showed trends toward improved survival compared with gemcitaine alone (6.9 versus 5.6 months) [26]
  9. Erlotinib (OSI-774, Tarceva®) [20,21]
    1. Potent anti-EGF-R1 agent, 150mg po qd, FDA approved for NSCLC and pancreatic cancer
    2. Improved mortality when used in first line pancreatic cancer with gemcitabine
    3. Main side effects are acne-like rash and some diarrhea, mainly at higher doses
  10. Other Experimental Agents
    1. Farnesyl transferase inhibitors (FTI's)
    2. Other EGF receptor antibodies antagonists
    3. VEGF blockers
    4. Matrix metalloproteinase (MMP) inhibitors
  11. Malnutrition Therapy
    1. Symptoms: poor Immune function (anergy), Weight loss, low albumin, low transferrin
    2. Enteral is better than Parenteral therapy
    3. Pancreatic enzyme replacement

References navigator

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  2. Warshaw AL, Brugge Lewandrowski KB, Pitman MB. 2003. NEJM. 349(20):1964 (Case Record)
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  4. Ryan DP, Fernandez-del Castillo C, Willett CG, et al. 2005. NEJM. 352(26):2734 (Case Record) abstract
  5. Michaud DS, Giovannucci E, Willett WC, et al. 2001. JAMA. 286(8):921 abstract
  6. Ross AM IV, Anupindi SA, Balis UJ. 2003. NEJM. 348(15):1464 (Case Record) abstract
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  9. Ashley SW and Lauwers GY. 2002. NEJM. 347(22):1783 (Case Record) abstract
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  11. Barish MA, Yucel EK, Ferrucci JT. 1999. NEJM. 341(4):258 abstract
  12. Adamek HE, Albert J, Breer H, et al. 2000. Lancet. 356(9225):190 abstract
  13. Stolzenberg-Solomon RZ, Graubard BI, Chari S, et al. 2005. JAMA. 294(22):2872 abstract
  14. Neoptolemos JP, Dunn JA, Stocken DD, et al. 2001. Lancet. 358(9293):1576 abstract
  15. Baron TD. 2001. NEJM. 344(22):1680
  16. Wong GY, Schroeder DR, Carns PE, et al. 2004. JAMA. 291(9):1092
  17. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83
  18. Gemcitabine. 1996. Med Let. 38(987):102 abstract
  19. Neoptolemos JP, Stocken DD, Friess H, et al. 2004. NEJM. 350(12):1200 abstract
  20. Erlotinib. 2005. Med Let. 47(1205):25 abstract
  21. Shepherd FA, Pereira JR, Ciuleanu T, et al. 2005. NEJM. 353(2):123 abstract
  22. Oettle H, Post S, Neuhaus P, et al. 2007. JAMA. 297(3):267 abstract
  23. Bloomston M, Frankel WL, Petrocca F, et al. 2007. JAMA. 297(17):1901 abstract
  24. Alvaro D, Macarri G, Mancino MG, et al. 2007. Ann Intern Med. 147(7):451 abstract
  25. Regine WF, Winter KA, Abrams RA, et al. 2008. JAMA. 299(9):1019 abstract
  26. Spano JP, Chodkiewicz C, Maurel J, et al. 2008. Lancet. 371(9630):2101 abstract