Cholangiocarcinoma CC

CC is the second commonest primary liver tumour worldwide, after hepatocellular carcinoma (HCC).

CC kills approximately 1500 people annually in the UK, with approximately equal numbers of men and women.

Risk factors:

Account for  more than 30% of all cases. Most cases of CC are sporadic.

-Primary sclerosing cholangitis (PSC), with or without ulcerative colitis, is the

commonest known predisposing factor for CC in the Western world (lifetime risk 35%).

-Age, chronic intraductal stones, Bile duct adenoma,choledocal cysts, liver flukes.

-Less established but likely risk factors include: 

cirrhosis of any cause ,chronic viral hepatitis B or C,obesity, diabetes, fatty liver disease, alcohol, smoking, IBD without PSC 

Classification:

Bismuthe-Corlette classification:

Type I: below confluence of left and right hepatic ducts.

Type II: reaching confluence but not involving left or right

hepatic ducts.

Type III: occluding common hepatic duct and either right

(IIIa) or left (IIIb) hepatic duct.

Type IV: multicentric or bilateral intrahepatic segmental involvement; or involving confluence and both right and left hepatic ducts.

Bismuthe-Corlette classification

This classification is commonly used but has limitations as It does not take into account vascular encasement and distant metastases.

Histology:

Over 90% of CCs are adenocarcinomas and are classified  according to the percentage of tumour composed of glandular tissue.

CC is often associated with inactivation of tumour suppressor genes, for example, p53, Smad-4, bcl-2 and p16.

Presentation:

Perihilar or extrahepatic CCs typically present with features of biliary obstruction (jaundice, pale stool, dark urine and pruritus). 

Cholangitis is unusual without prior biliary instrumentation.

CC is usually advanced at presentation, particularly with more proximal intrahepatic and perihilar tumours obstructing one duct. 

These often present with systemic manifestations of malignancy including malaise, fatigue and weight loss.

Some cases are detected incidentally as a result of scans performed for other indications.

Investigations:

-Liver function tests often show an obstructive picture.

-CA19-9 is elevated in up to 85% of patients with CC with a sensitivity of 40-70%, specificity of 50-80% 

Novel potential tumour markers linked to CC include Mac-2BP, matrix metalloproteinase-7, insulin-like growth factor 1, interleukin 6, trypsinogen and MUCIN-5AC. None has yet been

validated in large clinical studies.

-IgG4 cholangiopathy should be excluded in suspected cases of CC by testing for increased IgG4 in serum and biliary samples.

Patients with suspected CC should have:

- Combined MRI and MRCP 

- Contrast enhanced high resolution CT.

- Invasive cholangiography should be reserved for histological diagnosis, or therapeutic decompression where there is cholangitis, or stent insertion in irresectable cases.

The above techniques are complementary and may all be necessary as part of a surgical assessment.

FISH may enhance the diagnostic sensitivity of cytology samples 

Therapy:

-Stent:

Most patients with CC have unresectable disease. In such patients, stenting cost significantly less and was associated with longer survival than surgical treatment

Initial stent insertion for biliary obstruction should be plastic or covered SEMS, particularly if the diagnosis and resectability are undecided.

If the initial plastic stent becomes blocked, replacement with a metal stent is favoured if the estimated survival is expected to be more than 4 months.

Covered stents cannot be recommended for routine use based on current evidence.

-Chemotherapy:

Gemcitabine and Cisplatin combination chemotherapy is recommended for locally advanced or metastatic unresectable CC.
All operable patients should be offered adjuvant treatment trials. 

-Surgery:
Surgery is the only curative treatment for patients with CC; however, fewer than one-third of patients are resectable at diagnosis.
Five-year survival rates following resection of intrahepatic CC, distal extrahepatic CC and hilar tumours are 22-44%, 27-37% and 11-41%, respectively.

Surgical bypass should be reconsidered in patients with a good estimated life expectancy where stenting has failed.

-Transplantation:
Historically, liver transplantation for CC was associated with rapid recurrence of disease and poor survival rates: around 10% for intrahepatic CC and 25% for extrahepatic CC.

CC screening

BSG guidelines