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.