Cholangiocarcinoma

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Cholangiocarcinoma

• Rachel B. Wellner MD, MPH Mount Sinai
  HospitalDepartment of Surgery
• Team III Conference

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Definition of Cholangiocarcinoma

• Bile duct cancers arising from ductal epithelial
  cells
• Refers to cancers arising in the intrahepatic
  (5-15), perihilar (60-70), or distal
  (extrahepatic 25) biliary tree
• Represents approx. 3 of all gastro-intestinal
  malignancies

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Definition of Cholangiocarcinoma

• Bismuth-Corlette Classification subdivides
  perihilar cholangiocarcinomas based on pattern of
  involvement of hepatic ducts
• Type I tumors occurring below the confluence of
  the left and right hepatic ducts
• Type II tumors reaching the confluence
• Types IIIA/IIIb tumors occluding the common
  hepatic duct and either the right or left hepatic
  duct
• Type IV tumors that are multicentric, or that
  involve the confluence and both the right or left
  hepatic duct
• Klatskin tumors occur at the bifurcation of the
  proper hepatic duct

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Risk Factors

• Primary Sclerosing Cholangitis
• 0.6-1.5 annual incidence of cholangioCA.
• Choledocal Cysts and Carolis Disease
• 0.7 risk for first 10 years, 6.8 risk for
  second ten years, and 14.3 thereafter
• Clonorchis and Opisthorchis
• Cholelithiasis and hepatolithiasis
• Toxic exposure (Thorotrast)
• Lynch syndrome II and multiple biliary
  papillomatosis

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Pathology

• Adenocarcinoma (90)
• Slow growing, locally invasive, mucin-producing
• Perineural spread, metastases uncommon
• Three subtypes of adenocarcinoma
• Sclerosing
• Majority of cholangiocarcinomas
• Characterized by an intense desmoplastic
  reaction
• Early ductal invasion leads to low resectability
  rates
• Nodular
• Constricting annular lesion of the bile duct
• Papillary
• Present as bulky masses occurring in the bile
  duct lumen
• Present early with biliary obstruction
• Highest resectability rates

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Clinical

• Triad
• Cholestasis
• Abdominal pain (30-50 )
• Weight loss (30-50 )
• Pruritus (66 )
• Clay-colored stools, dark urine.
• Jaundice (90 )
• Hepatomegaly
• RUQ mass
• Courvoisier's sign
• Intrahepatic cholangioCA typically presents
  without biliary obstruction

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Laboratory

• Elevations in
• Total bilirubin (gt10 mg/dL)
• Direct bilirubin
• Alkaline phosphatase (usually increased 2- to
  10-fold)
• 5'-nucleotidase
• Gamma glutamyltransferase
• Transaminase levels initially normal
• With chronic biliary obstruction, liver
  dysfunction may ensue with elevation in ALT/AST
  and PT

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Differential Diagnosis

• Choledocholithiasis
• Benign bile duct strictures (usually
  postoperative),
• Sclerosing cholangitis
• Compression of the CBD (secondary to chronic
  pancreatitis or pancreatic cancer)

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Diagnosis

• Tumor markers
• Serum CEA gt5.2 ng/mL(sensitivity 68,
  specificity 82)
• Biliary CEA
• CA 19-9
• Radiographic studies
• Transabdominal ultrasound- may reveal ductal
  dilatation (intrahepatic gt6mm)
• CT/helical CT- can also detect vascular invasion
  
• Helical CT (esp. portal venous phase)- can
  delinieate nodal basins
• May be superior to MRI with respect to
  predicting resectability
• MRCP- may be coming the imaging modality of
  choice (high PPV,NPV)

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Diagnosis

• Cholangiography
• ERCP or PTC
• Useful if suspected level of obstruction is
  distal
• Preoperative drainage of the biliary tree
• Obtain diagnostic bile samples or brush cytology
  (low sensitivity)
• Endoscopic ultrasound
• Useful for visualizing distal tumors and
  regional nodes
• Can be used for EUS-guided biopsy of tumors and
  enlarged nodes
• PET
• High glucose uptake of biliary duct epithelium
• Angiography (rarely used)
• Staging laparoscopy

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Diagnosis

• Role of Staging laparoscopy
•  Tissue diagnosis important in the setting of
• Strictures of unknown origin (e.g. bile duct
  stones, PSC)
• Family/patient request for a definitive
  diagnosis
• Prior to chemotherapy or radiation therapy

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Management

• Poor prognosis- avg. 5-year survival 5-10
• Resectability rate superior for distal tumors
• resectability rates for intrahepatic 60,
  perihilar 56, and distal lesions 91 (Nakeeb A
  Pitt HA, JHU 1996)
• Negative margins achieved in 20-40 of proximal
  tumors cases, 50 of distal tumor cases
• Current data in evolution

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Management

• Accepted guidelines for resectability
  (accurately determined at operative exploration)
• Absence of N2 nodal metastases or distant liver
  metastases
• Absence of vascular (portal vein, hepatic
  artery) invasion
• Absence of extrahepatic adjacent organ invasion
• Absence of disseminated disease

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Management

• Pre-operative biliary decompression
• Liver dysfunction increases postoperative
  morbidity and mortality
• Arch Surg 2000 (Cherqui et. al.)
• Study demonstrated increased post-op morbidity
  in jaundiced patients not undergoing
  pre-operative drainage (vs. nonjaundiced
  patients)
• Pre-operative portal vein embolization
• Induce liver hypertrophy to increase limits of
  safe resection
• No demonstrated improvement in clincial outcome

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Management

• Surgical Procedures
• Distal lesions pancreaticoduodenectomy (5-yr
  survival rates 15-25)
• Intrahepatic cholangiocarcinoma hepatic
  resection (3-yr survival rates 22- 66)
• Perihilar cholangiocarcinoma (5-yr survival
  rates 10-45 outcomes in PSC patients dismal)
• Type I and II lesions en bloc resection of
  extrahepatic bile ducts and gallbladder with 5 to
  10 mm bile duct margins, regional lymphadenectomy
  with Roux-en-Y hepaticojejunostomy.
• Type III and Type IV lesions hepatectomy and
  portal vein resection

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Management

• Adjuvant radiation therapy
• Adjuvant radiation aimed at achieving local
  contral, decreased recurrence (no RCTs)
• Retrospective series demonstrate a benefit in
  patients with incompletely resectable lesions
• Unclear benefit in patients with completely
  resected tumors
• Adjuvant chemotherapy (mitomycin, 5-FU)
• Benefit of adjuvant chemoradiotherapy for
  completely resected patients unclear
• Some benefit seen when combined with radiation
  in patients with incomplete resection
• Single multi-center prospective randomized trial
  (Japan, Takada et. al. in Cancer, 2002) showed no
  benefit with chemotherapy in patients with both
  curative and non-curative resections

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Management

• Neoadjuvant therapy
• Typically not offered to patients with
  cholangiocarcinoma due to poor functional status
  at presentation
• Used in selected patients (McMasters, Am J Surg
  1997)
• 3/9 patients had a pathologic complete response
  (6/9 showed different degrees of histologic
  response)
• Margin-negative resections were possible in all
  nine patients receiving neoadjuvant therapy.
• Palliative treatment aimed at relieving biliary
  obstruction, pain
• 50-90 of patients with cholangiocarcinoma
  present with unresectable disease

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References

• Bismuth, H, Nakache, R, Diamond, T. Management
  strategies in resection for hilar
  cholangiocarcinoma. Ann Surg 1992 21531.
• Cherqui, D, Benoist, S, Malassagne, B, et al.
  Major liver resection for carcinoma in jaundiced
  patients without preoperative biliary drainage.
  Arch Surg 2000 135302.
• McMasters, KM, Tuttle, TM, Leach, SD, et al.
  Neoadjuvant chemoradiation for extrahepatic
  cholangiocarcinoma. Am J Surg 1997 174605.
• Nakeeb, A, Pitt, HA, Sohn, TA, et al.
  Cholangiocarcinoma. A spectrum of intrahepatic,
  perihilar, and distal tumors. Ann Surg 1996
  224463.
• Roayaie, S, Guarrera, JV, Ye, MQ, et al.
  Aggressive surgical treatment of intrahepatic
  cholangiocarcinoma predictors of outcomes. J Am
  Coll Surg 1998 187365.
• Takada, T, Amano, H, Yasuda, H, et al. Is
  postoperative adjuvant chemotherapy useful for
  gallbladder carcinoma?. A phase III multicenter
  prospective randomized controlled trial in
  patients with resected pancreaticobiliary
  carcinoma. Cancer 2002 951685.