Cholangiocarcinoma
Definition of Cholangiocarcinoma
q Bile duct cancers arising from ductal epithelial cells
q Refers to cancers arising in the intrahepatic (~5-15%), perihilar (~60-70%), or distal (extrahepatic ~25%) biliary tree
q Represents approx. 3% of all gastro-intestinal malignancies
q Bismuth-Corlette Classification
subdivides perihilar cholangiocarcinomas based on pattern of involvement of hepatic ducts
q Type I: tumors occurring below the confluence of the left and right hepatic ducts
q Type II : tumors reaching the confluence
q Types IIIA/IIIb: tumors occluding the common hepatic duct and either the right or left hepatic duct
q Type IV: tumors that are multicentric, or that involve the confluence and both the right or left hepatic duct
q Klatskin tumors occur at the bifurcation of the proper hepatic duct
Risk Factors
q Primary Sclerosing Cholangitis
q 0.6-1.5% annual incidence of cholangioCA.
q Choledocal Cysts and Caroli’s Disease
q 0.7 % risk for first 10 years, 6.8 % risk for second ten years, and 14.3 % thereafter
q Clonorchis and Opisthorchis
q Cholelithiasis and hepatolithiasis
q Toxic exposure (Thorotrast)
q Lynch syndrome II and multiple biliary papillomatosis
Pathology
q Adenocarcinoma (90%)
q Slow growing, locally invasive, mucin-producing
q Perineural spread, metastases uncommon
q Three subtypes of adenocarcinoma
q Sclerosing
q Majority of cholangiocarcinomas
q Characterized by an intense desmoplastic reaction
q Early ductal invasion leads to low resectability rates
q Nodular
q Constricting annular lesion of the bile duct
q Papillary
q Present as bulky masses occurring in the bile duct lumen
q Present early with biliary obstruction
q Highest resectability rates
Clinical
q Triad
q Cholestasis
q Abdominal pain (30-50 %)
q Weight loss (30-50 %)
q Pruritus (66 %)
q Clay-colored stools, dark urine.
q Jaundice (~90 %)
q Hepatomegaly
q RUQ mass
q Courvoisier's sign
q Intrahepatic cholangioCA typically presents without biliary obstruction
Laboratory
qElevations in:
q Total bilirubin (>10 mg/dL)
q Direct bilirubin
q Alkaline phosphatase (usually increased 2- to 10-fold)
q 5'-nucleotidase
q Gamma glutamyltransferase
qTransaminase levels initially normal
q With chronic biliary obstruction, liver dysfunction may ensue with elevation in ALT/AST and PT
Differential Diagnosis
q Choledocholithiasis
q Benign bile duct strictures (usually postoperative),
q Sclerosing cholangitis
q Compression of the CBD (secondary to chronic pancreatitis or pancreatic cancer)
Diagnosis
q Tumor markers
q Serum CEA >5.2 ng/mL(sensitivity 68%, specificity 82%)
q Biliary CEA
q CA 19-9
q Radiographic studies
q Transabdominal ultrasound- may reveal ductal dilatation (intrahepatic >6mm)
q CT/helical CT- can also detect vascular invasion
q Helical CT (esp. portal venous phase)- can delinieate nodal basins
q May be superior to MRI with respect to predicting resectability
q MRCP- may be coming the imaging modality of choice (high PPV,NPV)
q Cholangiography
q ERCP or PTC
q Useful if suspected level of obstruction is distal
q Preoperative drainage of the biliary tree
q Obtain diagnostic bile samples or brush cytology (low sensitivity)
q Endoscopic ultrasound
q Useful for visualizing distal tumors and regional nodes
q Can be used for EUS-guided biopsy of tumors and enlarged nodes
q PET
q High glucose uptake of biliary duct epithelium
q Angiography (rarely used)
q Staging laparoscopy
q Role of Staging laparoscopy
q Tissue diagnosis important in the setting of:
q Strictures of unknown origin (e.g. bile duct stones, PSC)
q Family/patient request for a definitive diagnosis
q Prior to chemotherapy or radiation therapy
Management
q Poor prognosis- avg. 5-year survival ~5-10%
q Resectability rate superior for distal tumors
q resectability rates for intrahepatic 60%, perihilar 56%, and distal lesions 91% (Nakeeb A; Pitt HA, JHU 1996)
q Negative margins achieved in 20-40% of proximal tumors cases, 50% of distal tumor cases
q Current data in evolution
Management
q Accepted guidelines for resectability (accurately determined at operative exploration)
q Absence of N2 nodal metastases or distant liver metastases
q Absence of vascular (portal vein, hepatic artery) invasion
q Absence of extrahepatic adjacent organ invasion
q Absence of disseminated disease
q Pre-operative biliary decompression
q Liver dysfunction increases postoperative morbidity and mortality
q Arch Surg 2000 (Cherqui et. al.)
q Study demonstrated increased post-op morbidity in jaundiced patients not undergoing pre-operative drainage (vs. nonjaundiced patients)
q Pre-operative portal vein embolization
q Induce liver hypertrophy to increase limits of safe resection
q No demonstrated improvement in clincial outcom
q Surgical Procedures
q Distal lesions: pancreaticoduodenectomy (5-yr survival rates 15-25%)
q Intrahepatic cholangiocarcinoma: hepatic resection (3-yr survival rates 22- 66%)
q Perihilar cholangiocarcinoma (5-yr survival rates 10-45%; outcomes in PSC patients dismal)
q 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.
q Type III and Type IV lesions: hepatectomy and portal vein resection
q Adjuvant radiation therapy
q Adjuvant radiation aimed at achieving local contral, decreased recurrence (no RCTs)
q Retrospective series demonstrate a benefit in patients with incompletely resectable lesions
q Unclear benefit in patients with completely resected tumors
q Adjuvant chemotherapy (mitomycin, 5-FU)
q Benefit of adjuvant chemoradiotherapy for completely resected patients unclear
q Some benefit seen when combined with radiation in patients with incomplete resection
q 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 resection
q Neoadjuvant therapy
qTypically not offered to patients with cholangiocarcinoma due to poor functional status at presentation
qUsed in selected patients (McMasters, Am J Surg 1997)
q 3/9 patients had a pathologic complete response (6/9 showed different degrees of histologic response)
q Margin-negative resections were possible in all nine patients receiving neoadjuvant therapy.
q Palliative treatment aimed at relieving biliary obstruction, pain
q50-90% of patients with cholangiocarcinoma present with unresectable disease
References
q Bismuth, H, Nakache, R, Diamond, T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992; 215:31.
q Cherqui, D, Benoist, S, Malassagne, B, et al. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000; 135:302.
q McMasters, KM, Tuttle, TM, Leach, SD, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997; 174:605.
q Nakeeb, A, Pitt, HA, Sohn, TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224:463.
q Roayaie, S, Guarrera, JV, Ye, MQ, et al. Aggressive surgical treatment of intrahepatic cholangiocarcinoma: predictors of outcomes. J Am Coll Surg 1998; 187:365.
q 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; 95:1685.
