Cholangiocarcinoma

Rachel B. Wellner MD, MPH Rachel B. Wellner MD, MPH Mount Sinai HospitalMount Sinai Hospital

Department of SurgeryDepartment of Surgery

Team III ConferenceTeam III Conference

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

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 ductsType II : tumors reaching the confluenceTypes 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

Risk Factors

Primary Sclerosing Cholangitis 0.6-1.5% annual incidence of cholangioCA.

Choledocal Cysts and Caroli’s 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

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

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

Laboratory

Elevations in: Total bilirubin (>10 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

Differential Diagnosis

Choledocholithiasis Benign bile duct strictures (usually

postoperative), Sclerosing cholangitis Compression of the CBD (secondary to

chronic pancreatitis or pancreatic cancer)

Diagnosis

Tumor markers Serum CEA >5.2 ng/mL(sensitivity 68%,

specificity 82%) Biliary CEA CA 19-9

Radiographic studies Transabdominal ultrasound- may reveal ductal

dilatation (intrahepatic >6mm) 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)

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

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

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

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

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

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

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

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, pain50-90% of patients with cholangiocarcinoma present

with unresectable disease

References

Bismuth, H, Nakache, R, Diamond, T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992; 215:31.

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.

McMasters, KM, Tuttle, TM, Leach, SD, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 1997; 174:605.

Nakeeb, A, Pitt, HA, Sohn, TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224:463.

Roayaie, S, Guarrera, JV, Ye, MQ, et al. Aggressive surgical treatment of intrahepatic cholangiocarcinoma: predictors of outcomes. J Am Coll Surg 1998; 187:365.

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.