In 1965, the surgeon Gerald Klatskin reported the first series of patients with cholangiocarcinoma of the hepatic hilum, and introduced the concept of radical resection of the diseased bile duct.However, at this time surgery was associated with high morbidity and mortality rates.
- Cholangiocarcinoma is an uncommon epithelial malignancy of the biliary tract.
- Cholangiocarcinomas may arise at any level of the biliary tree.
- They are highly lethal because most are locally advanced at presentation.
- More recently, the term cholangiocarcinoma has been used to refer to bile duct cancers arising in the intrahepatic, perihilar, or distal (extrahepatic) biliary tree, exclusive of the gallbladder or ampulla of Vater.
- Intrahepatic cholangiocarcinomas usually present as liver masses, and extrahepatic cholangiocarcinomas tend to obstruct bile ducts and present with jaundice.
- Sporadic cholangiocarcinomas are relatively uncommon, but the incidence increases significantly in certain inflammatory and infectious conditions.
- Surgical resection is the most effective treatment and is currently the only option that provides a chance for cure, but the majority of patients are not eligible for surgical resection.
Incidence and natural history
- Cholangiocarcinomas account for approximately 3 percent of all gastrointestinal malignancies, with a prevalence in autopsy studies of 0.01 to 0.46 percent.
- As a general rule, the incidence of biliary tract cancers increases with age; the typical patient with cholangiocarcinoma is between 50 and 70 years of age.
- However, patients with primary sclerosing cholangitis (PSC) and those with choledochal cysts present nearly two decades earlier.
- In contrast to gallbladder cancer, where female gender predominates, the incidence of cholangiocarcinoma is slightly higher in men.
- This probably reflects the higher incidence of PSC in men.
- This probably reflects the higher incidence of PSC in men.
- Asians are affected twice as often as whites or black.
- Patients with intrahepatic cholangiocarcinoma, the 1-year relative survival increased from 16.4% in the period from 1975 to 1979 to 27.6% in the period from 1995 to 1999, but the 5-year survival rate remains unchanged and below 5%.
- Death is often related to infectious complications secondary to biliary obstruction and is rarely a result of tumour burden.
- Although nodal, peritoneal and haematogenous metastases have been described, local disease is the most common finding at presentation.
- Haematogenous metastases are uncommon, and nodal disease is present in about one-third of cases in series of resected patients.
- Extended survival depends almost entirely on complete surgical resection.
- Survival has traditionally been considered to be worse for lesions at the confluence and better for lesions at the ampulla, but this probably reflects relatively later presentation and more complex operative management as opposed to a difference in biology.
- Location within the biliary tree may have little impact on survival provided that complete resection can be achieved.
PATHOGENESIS
- Conversion from normal to malignant bile epithelium probably requires a stepwise accumulation of successive genetic abnormalities, similar to the sequence of events that underlies colorectal carcinogenesis.
- A variety of molecular defects involving both oncogenes (K-ras, c-myc, c-neu, c-erbB-2, and c-met) and tumor suppressor genes (eg, p53, SMAD4) have been described in specimens of biliary tract tumors.
- As an example, between 37 and 80 percent of tumors overexpress p53 (implying the presence of mutations in this tumor suppressor gene), while abnormal expression of K-ras is found in 21 to 100 percent of cases.
- These genetic alterations are associated with a more aggressive tumor phenotype.
- The detection of these mutations in bile specimens may improve the sensitivity of cytopathology for diagnosing cholangiocarcinoma, although this technique is not widely used.
Some data suggest that p16INK4a promoter point mutations contribute to initiation and progression of cholangiocarcinoma in the setting of PSC. Others propose that intrahepatic cholangiocarcinomas share some common carcinogenic steps with hepatocellular carcinoma such as loss of heterozygosity (LOH) of chromosomes 4q and 6q, and/or inactivation of tumor suppressor genes on chromosome 1p.
RISK FACTORS
Endemic infections
- Liver fluke infestations with Opisthorchis species (
- In these countries, raw fish is more frequently consumed by men, partially explaining the higher incidence of cholangiocarcinoma in men.
- The larval stage of flukes, as consumed in raw fish, establishes a chronic infection and inflammation in the biliary tree.
- The risk of cancer has been associated with the degree of infestation as measured by the stool egg count.
- In areas where these parasites are endemic, the incidence of cholangiocarcinoma is as high as 87 per 100 000.
- In these countries, raw fish is more frequently consumed by men, partially explaining the higher incidence of cholangiocarcinoma in men.
Autoimmune diseases
- PSC is an autoimmune disease characterized by periductal inflammation, as seen on histological sections, and multifocal strictures of both intrahepatic and extrahepatic bile ducts, as demonstrated by cholangiography.
- The majority of PSC patients (70–80%) have associated ulcerative colitis, but the converse is not true.
- Approximately 10% of patients with ulcerative colitis have PSC.
- The incidence of cholangiocarcinoma remains elevated in patients with PSC even when medical or surgical management appears to control the inflammatory process.
- In other words, treatment of ulcerative colitis by colectomy does not offer protection from development of cholangiocarcinoma in patients with PSC.
- Nearly 30 percent of cholangiocarcinomas are diagnosed in patients with PSC with or without UC.
- The annual incidence of cholangiocarcinoma in patients with PSC has been estimated to be between 0.6 and 1.5 percent per year, with a lifetime risk of 10 to 15 percent.
- However, the incidence is much higher (30 percent or more) in autopsy series.
- Cholangiocarcinoma develops at a significantly younger age (between the ages of 30 and 50) in patients with PSC than in patients without this condition.
- It is also more difficult to diagnose because of the diffusely abnormal biliary tree.
- Over one-third of these cases are diagnosed within two years of the initial diagnosis of PSC, and the risk appears unrelated to the duration of the inflammatory disease.
- The majority of PSC patients (70–80%) have associated ulcerative colitis, but the converse is not true.
- However, the number of patients who smoked or were former smokers was significantly higher in the cancer group.
- Alcohol consumption has been suggested to be a risk factor for the development of cholangiocarcinoma in patients with PSC.
- Certain genetic polymorphisms have been implicated as risk factors for cholangiocarcinoma in PSC.
Choledochal cysts and anatomical anomalies
The risk of development of cholangiocarcinoma in congenital biliary cysts may also be related to inflammation.
- Many patients with choledochal cysts have an anomalous pancreatobiliary junction (APBJ).
- In such patients, the confluence of the pancreatic duct and bile duct occurs at a greater distance from the ampulla than usual, thereby lengthening the common channel.
- This predisposes to reflux of pancreatic secretions into the biliary ducts.
- Presumably, the pancreatic enzymes become activated by bile and an inflammatory response follows.
Stasis in the ducts might also lead to bacterial contamination and additional inflammation.
- In patients who have early surgical intervention for choledochal cysts, the risk of cholangiocarcinoma is greatly reduced.
- There is some evidence that the incidence of cholangiocarcinoma increases dramatically in patients not treated until after the age of 20 years or in patients treated with cyst drainage as opposed to cyst resection.
- Seven per cent of patients developed a cholangiocarcinoma in a series of 119 patients who had previously received a transduodenal sphincteroplasty for benign disease and who were followed for up to 22 years.
- Presumably, bacterial contamination and inflammation may result from surgical sphincteroplasty.
- There is currently no evidence to suggest that endoscopic sphincterotomy carries the same degree of risk.
Cholelithiasis and hepatolithiasis
While cholelithiasis is a well-described strong risk factor for gallbladder cancer, the association between gallstones and cholangiocarcinoma is less well established.
Toxic exposures
A clear association exists between exposure to the radiologic contrast agent Thorotrast (a radiologic contrast agent banned in the 1960s for its carcinogenic properties) and subsequent cholangiocarcinoma; malignancy usually develops 30 to 35 years after exposure.
Lynch syndrome and biliary papillomatosis
- At least two genetic disorders are associated with an increased risk of cholangiocarcinoma: the inherited "cancer family" syndrome termed Lynch syndrome II, and a rare inherited disorder called multiple biliary papillomatosis.
- The latter condition is characterized by multiple adenomatous polyps in the bile ducts, and repeated episodes of abdominal pain, jaundice, and acute cholangitis.
- Biliary papillomatosis should be considered a premalignant condition since a high proportion of these lesions (83 percent in one study) undergo malignant transformation.
Chronic liver disease
Hepatitis B virus (HBV) and hepatitis C virus (HCV) as well as liver cirrhosis regardless of etiology, have been examined as risk factors for intrahepatic cholangiocarcinoma.
Viral hepatitis
An association between hepatitis C viral infection (HCV) and cholangiocarcinoma was initially suggested in 1991. Since then, several reports have noted a higher than expected rate of HCV-associated cirrhosis in patients with cholangiocarcinoma, although the risk is much lower than for hepatocellular cancer.
Nonviral chronic liver disease
As with hepatocellular carcinoma, chronic liver disease of nonviral etiology also appears to be associated with intrahepatic cholangiocarcinoma.
Diabetes
An association between diabetes mellitus and cancer of the biliary tract has been suggested in several studies. The risk was increased by approximately two-fold in the population-based case-control study described above.
Obesity and HIV infection are also considered to be the risk factors for cholangiocarcinoma.
Classification
Pathology and classification
- The most widely used classifications are that of Weinbren and Mutum, who described the histological features of three subtypes of cholangiocarcinomas,
- nodular,
- sclerosing and
- papillary,
- and that of Klatskin, who described three major macroscopic subtypes of hilar cholangiocarcinomas:
- a small hard nodule,
- a segmental stenosis and
- a papillary growth.
- a small hard nodule,
Recently, the Liver Cancer Study Group of
- mass-forming,
- periductal-infiltrating and
- intraductalgrowing
MF tumours are less common than the PI type and more common than the IG type.
- MF tumours are the most common intrahepatic variant and have frequently been classified as nodular grossly and histologically.
- They are characterized by a nodular mass that projects into the lumen of the duct and out into the surrounding tissues.
- The tumour is firm and whitish grey on account of the large amount of fibrous stroma.
- The margin is often well circumscribed but may be lobulated.
- Multicentricity is more common for this subtype and may be the result of the propensity of the tumour to invade adjacent branches of the portal vein.
- Multicentricity may also be due to the fact that the MF growth pattern results in late onset of symptoms and thus provides more time for tumour growth compared with the IG or PI subtypes.
- Central necrosis is a common feature when the tumours are large.
- Bile ducts peripheral to the mass may or may not be dilated.
- Regional lymph node metastases are more common with large tumour masses and are therefore more common with this subtype.
- Enlarged metastatic lymph nodes are most commonly located in the porta hepatis.
- In contrast to MF tumours, PI cholangiocarcinomas grow along the bile duct and are commonly described as elongated, branchlike or spiculated.
- They penetrate the bile duct wall, growing both in the wall and along the exterior of it for extended distances.
- Irregular narrowing or obliteration of the involved bile duct commonly occurs, and the proximal biliary tree is almost universally dilated.
- PI tumours are the most common variant and are the predominant subtype found at the biliary confluence.
- PI lesions are frequently described as sclerosing and fibrotic on histological examination.
- The overlying epithelium may appear atypical or may be absent.
- PI tumours are characterized by annular thickening with diffuse infiltration and fibrosis of the periductal tissues.
- PI lesions may be poorly differentiated and may show signet ring cells.
- In pure PI tumours, there is no mass, and differentiation from benign disease is occasionally difficult.
Intraductal-growing (IG)
- IG tumours account for approximately 10% of all cholangiocarcinomas.
- IG tumours grow into the lumen.
- Although they originate in the wall, they do not usually penetrate it, and the outer margin of the bile duct remains intact.
- IG tumours may be polypoid, sessile or can be elongated sheets of tumour spreading along the bile duct lumen, or skip lesions.
- These tumours can grow to several centimetres in size and may expand rather than constrict the bile duct, in sharp contrast to the sclerotic process seen in PI tumours.
- The majority of IG tumours are of the papillary subtype comprised of numerous frond-like infoldings of proliferated columnar epithelial cells.
- Atypical epithelium is easily identified in this variant and may be classified as well differentiated, meaning that much of the normal epithelial architecture is preserved.
- These may arise from a stalk or may be broader based, spreading superficially along the surface.
- Biliary obstruction may result from a large tumour blocking the duct, from an excessive amount of mucin or pieces of tumour that have broken off and embolized lower levels of the biliary tree.
- In some instances, these tumour emboli have even obstructed the common channel, leading to pancreatitis.
- There is a variant of this subtype that is very similar to intraductal papillary mucinous tumour (IPMT) of the pancreas, in which mucinous secretions are the predominant feature.
- Patients with IG tumours usually have a better outcome than those with other subtypes, in part because they tend to present at an earlier stage.
- Patients with the papillary subtype fare better than patients with the nodular sclerosing subtypes (MF, PI) even when compared stage for stage.
- This suggests that at least some of the observed difference in patient outcome is derived from the more favourable biological behaviour of the well-differentiated papillary subtype.
- Variants of adenocarcinoma of the bile duct include pleomorphic, giant cell, adenosquamous, oat cell and colloid carcinoma.
- The microscopic extent of these cancers frequently extends for long distances beyond the palpable tumour.
- In a series of 29 cases, the mean distance of microscopic invasion beyond the gross margin was 16.8 mm towards the liver and 6.5 mm towards the duodenum.
- Well-differentiated cancers with little invasion are difficult to differentiate from inflammatory pseudotumour.
- Often, perineural invasion, a prominent feature of cholangiocarcinoma that is not present in PSC or other benign lesions, is the single most useful feature in sorting out the true nature of the disease.
- In series of upper duct lesions, benign inflammation accounted for 13–15% of resections. Poorly differentiated tumours of the lower duct may be difficult to distinguish from pancreatic or duodenal cancers.
- Biliary tumours of the lower duct, although often poorly differentiated, tend to present early.
- Therefore, lower duct biliary tumours are less likely to have spread to surrounding lymph nodes or to have metastasized distantly than pancreatic cancers, portending a more favourable prognosis following a pancreaticoduodenectomy.
Anatomical classification
Most authorities in this area now classify cholangiocarcinoma into three types depending upon anatomical location.
These are
- intrahepatic cholangiocarcinomas,
- hilar cholangiocarcinomas and
- lower duct cholangiocarcinomas.
- Synonyms for hilar cholangiocarcinoma are upper duct extrahepatic cholangiocarcinomas and Klatskin tumours.
- Synonyms for lower duct cholangiocarcinomas are intrapancreatic bile duct tumours (or cholangiocarcinomas)
- and distal bile duct tumours (or cholangiocarcinomas).
Hilar cholangiocarcinomas have been estimated to account for between 40% and 60% of all cholangiocarcinomas.
- Intrahepatic cholangiocarcinomas account for approximately 10% of cases with distal tumours making up the difference.
- Approximately 10% of patients with cholangiocarcinoma have multifocal disease.
Cancers arising in the perihilar region have been further classified according to their patterns of involvement of the hepatic ducts (the Bismuth-Corlette classification):
- Tumors below the confluence of the left and right hepatic ducts (Type I)
- Tumors reaching the confluence (Type II)
- Tumors occluding the common hepatic duct and either the right or left hepatic duct (Types IIIA and IIIb, respectively)
- Tumors that are multicentric, or that involve the confluence and both the right or left hepatic duct (Type IV)
Bile duct tumors that involve the common hepatic duct bifurcation are referred to as Klatskin tumors regardless of whether they arise from the intrahepatic or extrahepatic portion of the biliary tree.
TNM staging classification
Cholangiocarcinomas involving the intrahepatic bile ducts are staged similarly to hepatocellular carcinoma.
TNM staging for hepatocellular cancer and intrahepatic bile duct cancer
| Primary tumor (T) | |||
| TX | Primary tumor cannot be assessed | ||
| T0 | No evidence of primary tumor | ||
| T1 | Solitary tumor without vascular invasion | ||
| T2 | Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm | ||
| T3 | Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) | ||
| T4 | Tumors with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum | ||
| Regional lymph nodes (N) | |||
| NX | Regional lymph nodes cannot be assessed | ||
| N0 | No regional lymph node metastasis | ||
| N1 | Regional lymph node metastasis | ||
| Distant metastasis (M) | |||
| MX | Distant metastasis cannot be assessed | ||
| M0 | No distant metastasis | ||
| M1 | Distant metastasis | ||
| Fibrosis score (F) | |||
| F0 | Fibrosis score 0-4 (none to moderate fibrosis) | ||
| F1 | Fibrosis score 5-6 (severe fibrosis or cirrhosis) | ||
| Stage grouping | |||
| Stage I | T1 | N0 | M0 |
| Stage II | T2 | N0 | M0 |
| Stage IIIA | T3 | N0 | M0 |
| Stage IIIB | T4 | N0 | M0 |
| Stage IIIC | Any T | N1 | M0 |
| Stage IV | Any T | Any N | M1 |
In contrast, the TNM staging system for hilar and distal tumors differs in the definition of T stage and stage grouping.
TNM classification for extrahepatic bile duct tumors
| Primary tumor (T) | |||
| TX | Primary tumor cannot be assessed | ||
| T0 | No evidence of primary tumor | ||
| Tis | Carcinoma in situ | ||
| T1 | Tumor confined to the bile duct histologically | ||
| T2 | Tumor invades beyond the wall of the bile duct | ||
| T3 | Tumor invades the liver, gallbladder, pancreas, and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left) | ||
| T4 | Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures such as the colon, stomach, duodenum, or abdominal wall. | ||
| Regional lymph nodes (N) | |||
| NX | Regional lymph nodes cannot be assessed | ||
| N0 | No regional lymph node metastasis | ||
| N1 | Regional lymph node metastasis* | ||
| Distant metastasis (M) | |||
| MX | Distant metastasis cannot be assessed | ||
| M0 | No distant metastasis | ||
| M1 | Distant metastasis | ||
| Stage Grouping | |||
| Stage 0 | Tis | N0 | M0 |
| Stage IA | T1 | N0 | M0 |
| Stage IB | T2 | N0 | M0 |
| Stage IIA | T3 | N0 | M0 |
| Stage IIB | T1-3 | N1 | M0 |
| Stage III | T4 | Any N | M0 |
| Stage IV | Any T | Any N | M1 |
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