Malignant lesions of the biliary tract

Primary sclerosing cholangitis

The most common risk factor for cholangiocarcinoma is primary sclerosing cholangitis (PSC). PSC is also strongly associated with inflammatory bowel disease which is present in 70–80% of patients with PSC; however, only a minority of patients with inflammatory bowel disease develop PSC. Unlike sporadic cases of cholangiocarcinoma, the age at presentation in patients with PSC is younger and typically occurs between 30 and 50 years. The natural history of PSC is variable, and the true incidence of cholangiocarcinoma in this population varies between studies. In a Swedish series of 305 patients, 8% of patients developed cancer with a median follow-up of 63 months. On the other hand, occult cholangiocarcinoma has been reported in up to 40% of autopsy specimens and in up to 36% of liver explants from patients with PSC. Additional studies have noted that the relative risk of developing cholangiocarcinoma in patients with PSC ranges more than 200-fold compared with patients without PSC. ^, Unfortunately, the subset of patients with PSC-associated cholangiocarcinoma are not candidates for resection because of multifocal disease or severe underlying hepatic dysfunction. Additionally, these patients are often disqualified from transplantation because of the cancer diagnosis.

Congenital cysts

Congenital biliary tree abnormalities (choledochal cysts and Caroli’s disease) are associated with an increased risk of developing cholangiocarcinoma, with the estimated risk ranging 3–20%. ^{, ,} Soares et al. published a multi-institutional study of 354 adults and children undergoing resection for choledochal cysts. The authors demonstrated that a concomitant cholangiocarcinoma was diagnosed in 2.5% of patients, and during a median follow-up of 28 months 3.3% of patients were diagnosed with cholangiocarcinoma. Additionally, in a series of 119 patients undergoing transduodenal sphincteroplasty, Hakamada et al. found a 7.4% incidence of cholangiocarcinoma over a follow-up period of 18 years. Although the cause is unknown, the belief is that the abnormal pancreaticobiliary duct junction found in this patient population predisposes the patients to reflux of pancreatic secretions into the biliary tree, resulting in chronic inflammation and bacterial contamination, ultimately leading to malignant transformation.

Hepatolithiasis

Hepatolithiasis is a well-established risk factor for the development of cholangiocarcinoma. In Japan and parts of South-East Asia, up to 10% of patients with hepatolithiasis will develop cholangiocarcinoma. This association has also been demonstrated in Western countries. ^, The pathophysiology is thought to be secondary to a recurrent inflammatory state. Chronic portal bacteraemia and portal phlebitis lead to intrahepatic pigment stone formation, obstruction of intrahepatic ducts and recurrent episodes of cholangitis and stricture formation. ^,

Parasitic infection

The literature has suggested a pathogenic association between liver fluke infestation ( Opisthorchis viverrini , Clonorchis sinensis ) and the development of cholangiocarcinoma. Although exceedingly rare in the USA, these organisms are endemic in South-East Asia.

Viral hepatitis and cirrhosis

Hepatitis B, hepatitis C infection and cirrhosis have been linked to the development of cholangiocarcinoma. In a prospective study from Japan, the risk of developing cholangiocarcinoma in patients infected with hepatitis C virus was 3.5% at 10 years compared with their non-infected counterparts who harboured a rate 1000 times less. Moreover, the fact that cholangiocytes and hepatocytes arise from the same progenitor cell and that the hepatitis C virus has been found within cholangiocarcinoma tumour specimens allude to a strong probable pathogenic association.

Metabolic risk factors

The incidence of metabolic syndrome and associated comorbidities has been increasing in the USA and worldwide. Studies have demonstrated that type 2 diabetes, hyperlipidaemia, obesity and non-alcoholic fatty liver disease are associated with an increased risk of both intrahepatic and ECC. ^,

Chemical exposure

Tobacco use and smoking are well-established risk factors for many cancers, including cholangiocarcinoma. Several chemical agents have been implicated in the development of cholangiocarcinoma. Exposure to Thorotrast (a radiological agent used in the 1960s) is associated with a 300-fold increase in the development of biliary malignancy. Additional environmental toxins, such as dioxin and vinyl chloride, have also been associated with an increased risk of developing cholangiocarcinoma.

Histopathology

Cholangiocarcinoma is classified according to the site of origin within the biliary tree—hilar, intrahepatic and extrahepatic. Malignancies arising from the biliary confluence are classified as hilar cholangiocarcinoma and are the most common type of cholangiocarcinoma (approximately 60% of all cases), while those that originate within the extrahepatic bile duct account for 20–30% of cases, and the remaining 10% arise from the intrahepatic biliary tree. Of note, patients can present with multifocal or diffuse involvement of the biliary tree, although this is quite rare. The vast majority of ICC, ECC and hilar cholangiocarcinoma are adenocarcinoma, whereas other histologic variants comprise approximately 5% of tumours. These include different patterns with focal areas of papillary carcinoma with mucous production, signet-ring cells, squamous cell, mucoepidermoid and spindle cell variants.

ICC is divided into three morphologic subtypes based on the classification established by the Liver Cancer Study Group of Japan: (1) mass-forming type; (2) periductal infiltrating type; and (3) intraductal growth type. ^, Each subtype is characterised by a different growth pattern. The mass-forming subtype is characterised by discrete mass formation within the liver, which is in comparison with the periductal infiltrating subtype which grows along the biliary tree, resulting in fibrosis of periductal tissues and annular bile duct thickening. ^{, ,} The intraductal subtype is characterised by growth within the lumen of the bile duct, resulting in papillary-like projections. ^,

ECC can be further classified based on both macroscopic appearance and location within the extrahepatic biliary tree. Three macroscopic subtypes of ECC are described: sclerosing, nodular and papillary, of which the first two are often combined into one (i.e. nodular-sclerosing) since features of both types are often seen together. Papillary tumours represent a less common variant, accounting for approximately 10% of ECCs, and are more common in the lower bile duct than at the hilum. ^, Papillary tumours are characterised by a mass that expands rather than contracts the duct, and may be associated with little transmural invasion. They may grow to significant size, yet they often arise from a well-defined stalk, with the majority of tumour being mobile within the ductal lumen. While less common, recognition of this entity is important since they are more often resectable and have a more favourable overall prognosis than other histologic subtypes. ECCs, primarily tumours of the mid- and distal bile duct, can be classified according to their anatomical location, although there may be overlap. Mid-bile duct tumours arise between the upper border of the duodenum and the cystic duct, while distal bile duct tumours arise from the duodenum to the ampulla of Vater. Tumours of the distal bile duct represent approximately 5–10% of all periampullary tumours, while true mid-duct tumours are uncommon.

Clinical presentation

The clinical presentation of cholangiocarcinoma is determined by the location of the primary tumour and the level of biliary involvement. Patients with ECC may present earlier due to outflow obstruction of the biliary tree, and may demonstrate classic signs and symptoms of hyperbilirubinaemia (painless jaundice, pruritus, pale stool and dark urine). Patients with papillary tumours may give a history of intermittent jaundice, perhaps due to small fragments of tumour having passed into the common bile duct or the ball-valve effect of a pedunculated mass within the lumen.

In contrast, patients with ICC are typically asymptomatic. In the majority of cases, early symptoms are nebulous (weight loss, abdominal discomfort) and many tumours are identified incidentally on cross-sectional imaging or following work-up for abnormal liver function tests. In patients with no previous biliary intervention, cholangitis is rare at initial presentation. Occasionally, patients with long-standing biliary obstruction and/or portal vein involvement may present with symptoms related to portal hypertension. Additionally, in those with PSC, distal ductal or periductal lesions can be difficult to differentiate from benign biliary strictures.

Ultrasonography

Ultrasonography of the abdomen is a non-invasive, but operator-dependent, imaging modality that is often used early in the course of work-up. Characteristic appearance of ICC includes a hypoechoic, heterogeneous liver mass with minimal internal blood flow. Early studies demonstrated that Doppler ultrasonography had comparable results as other imaging modalities for detecting tumour invasion of the portal vein and extent of biliary involvement; however, it is limited in the detection of extrahepatic disease.

Computed tomography

Multiphasic computed tomography (CT) of the chest, abdomen and pelvis including portal venous, arterial and delayed phases, is the modality of choice to assess for extent of the primary tumour and metastasis. Characteristic findings of ICC on contrast-enhanced CT include variable rim-like enhancement on arterial phase images with gradual centripetal enhancement on delayed phase.

Cross-sectional CT is an important study for evaluating patients with biliary obstruction and can provide valuable information regarding the level of obstruction, vascular involvement and liver atrophy. CT offers excellent assessment of the radial extent of soft-tissue involvement, direct liver invasion of perihilar lesions and the relationship to portal structures. For instance, dilated intrahepatic ducts with a normal or collapsed gallbladder allude to a perihilar cholangiocarcinoma, particularly if there is any evidence of a soft-tissue mass. This is in comparison to a distended gallbladder with normal intrahepatic ducts which alludes to either stone disease or tumour obstructing the cystic duct, and a distended gallbladder with dilated intra- and extrahepatic ducts that suggests either choledocholithiasis or a distal biliary malignancy. Segmental or lobar atrophy may be evident on CT that would suggest portal venous occlusion or long-standing biliary obstruction in the absence of portal venous involvement ( Fig. 14.2 ).

CT has been found to identify cholangiocarcinoma in 94–100% of patients and the positive and negative predictive values for determining resectability are 92% and 85%, respectively. Reported accuracy for detecting the longitudinal spread along bile ducts is 81% compared with an accuracy of 100% for detecting radial spread into adjacent structures. Another limitation is the detection of lymph node metastases since CT has a documented sensitivity of 35–65%.

Magnetic resonance imaging/cholangiopancreatography

Cholangiocarcinoma is hypointense on T1-weighted images and hyperintense on T2-weighted imaging on magnetic resonance imaging (MRI). These tumours demonstrate initial rim enhancement characterised by progressive and concentric enhancement post administration of contrast material, but the lesions usually do not completely enhance post-contrast. ICCs may only enhance completely on delayed imaging obtained hours after contrast administration—a finding related to the desmoplastic nature of the tumour. Capsular retraction may also be seen ( Fig. 14.3 ). ^, A lesion in the liver with this morphology on MRI evaluation is pathognomonic for cholangiocarcinoma, even without a tissue diagnosis.

Several studies have demonstrated the utility of magnetic resonance cholangiopancreatography (MRCP) in evaluating patients with biliary obstruction. ^, MRCP identifies the tumour and the level of biliary obstruction, and can also demonstrate obstructed and isolated ducts not appreciated at endoscopic or percutaneous study. By virtue of being an axial imaging modality, MRCP has further advantages over standard cholangiography by providing information regarding the patency of hilar vascular structures, the presence of nodal or distant metastases, the presence of lobar atrophy and with its high tissue contrast helps to detect hepatic parenchymal involvement or metastatic hepatic disease. Compared with invasive cholangiopancreatography, MRCP has comparable rates of detecting the location and extent of tumour within the biliary tree, yet is associated with decreased infectious complications compared with standard cholangiography as it does not require biliary intubation. ^, Furthermore, as MRCP images the biliary tree both below and above the level of obstruction, MRCP can more accurately evaluate biliary ducts proximal to a lesion that may not be adequately filled with contrast during endoscopic retrograde cholangiopancreatography (ERCP). Reported accuracy in determining the extent of bile duct involvement is 71–96%. ^, Limitations of MRCP include understaging up to 20% of perihilar cases, overstaging patients with indwelling biliary stents and can be limited by motion artifact.

Positron emission tomography

The utility of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is not routinely used in all centres in the work-up of cholangiocarcinoma, although can be used in select cases, particularly those where there is concern for metastatic disease. The possibility of false positives with the use of PET-CT should be considered, especially in patients with other causes of inflammation or indwelling biliary stents.

Several studies have demonstrated that the addition of PET-CT to CT alone does not improve the diagnostic accuracy or resectability of the primary tumour, ^, but it can aid in the detection of distant metastases. Identification of regional lymphadenopathy varies based on the study, with some demonstrating poor detection of lymph nodes, and others demonstrating improved diagnosis compared with CT alone. ^{, ,} For example, Kim et al. demonstrated that PET-CT improved the diagnostic accuracy of regional lymph node metastases compared with CT alone (76% vs 61%, P = 0.004). The use of PET-CT has been shown to improve the accuracy of diagnosis of distant metastases. A meta-analysis that included 2125 patients from 47 studies demonstrated that the overall sensitivity and specificity for distant metastases was 85% and 90%, respectively.

Studies have demonstrated that there is an association between maximum standardised uptake value (SUVmax) and outcomes following resection. For example, Ma et al. demonstrated that an SUVmax of greater than 8 was associated with worse OS (3-year, 29% vs 74%, P = 0.048) and recurrence-free survival (RFS) (3-year, 21% vs 63%, P = 0.004) following resection in patients with resectable cholangiocarcinoma. Ultimately, PET-CT changes surgical management in 20–30% of cases, and therefore, should be used in select cases where there is uncertainty regarding the presence of metastatic disease.

Invasive modalities