Diagnosis
Clinical Features
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.
Blood Tests
No blood tests are diagnostic for CC. Liver function tests often show an obstructive picture. Aminotransferases are frequently normal but may be markedly raised in acute obstruction or cholangitis. Prolonged biliary obstruction can cause a reduction in fat soluble vitamins and an increase in prothrombin time. In advanced disease, non-specific markers of malignancy such as albumin, erythrocyte sedimentation rate, C-reactive protein and haemoglobin may be altered.
Serum Tumour Markers. Carbohydrate antigen (CA) 19-9 and CA-125 are the most used serum tumour markers. Overall, their sensitivity and specificity are low and they are not helpful for monitoring disease progression. They may be useful in conjunction with other diagnostic modalities.
CA19-9 is elevated in up to 85% of patients with CC with a sensitivity of 40–70%, specificity of 50–80% and positive predictive value (PPV) of 16–40%, depending on cut-off values. CA19-9 elevation frequently occurs in PSC and other causes of non-malignant obstructive jaundice, but persistently raised levels of CA19-9 after decompression suggest malignancy. CA19-9 does not discriminate between CC, pancreatic or gastric malignancy and may also be elevated in severe hepatic injury from any cause. Furthermore, 10% of individuals lack Lewis antigen and cannot produce CA19-9.
CA-125 is detectable in up to 65% of patients with CC. In a chemotherapy trial setting, a raised baseline CA-125 was found to be prognostic for survival. CA-125 is often raised in parenchymal liver disease and may not be helpful in this context.
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.
Immunoglobulin G4 (IgG4) Cholangiopathy. Immunoglobulin (Ig) G4-associated cholangiopathy, the biliary presentation of a multisystem inflammatory disorder in which affected organs have a lymphoplasmacytic infiltrate rich in IgG4-positive cells, can mimic CC. A review of 53 such cases reported that most were men (85%), presented with obstructive jaundice (77%), were associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%) and abundant IgG4-positive cells in bile duct biopsy specimens (88%). Strictures were confined to intrapancreatic bile ducts in 51% of cases, and proximal extrahepatic/intrahepatic ducts were involved in 49%. Following successful steroid therapy, relapse occurred in 53% of cases after steroid withdrawal. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalised liver biochemistry in 61% and biliary stents were safely removed in 17 of 18 patients. IgG4 cholangiopathy should be excluded in suspected cases of CC by testing for increased IgG4 in serum and biliary samples.
Imaging
Imaging is the main diagnostic modality for CC. Appearances include an intrahepatic mass lesion with characteristics of a metastasis, a hilar stricture or distal bile duct obstruction, with or without a discernible mass. Differentiating between benign and malignant biliary strictures is challenging.
Ultrasonography. CC should be suspected when there is biliary ductal dilation, particularly with a related mass lesion and consistent clinical history. In suspected biliary obstruction, ultrasonography (US) is reliable for excluding gallstones but is operator-dependent and is insufficient alone for investigating suspected CC. For detecting advanced CC in patients with PSC, US offers specificity and negative predictive value of 90%, but sensitivity and PPV are only 50%. US may miss small tumours and cannot accurately define tumour extent. Colour-Doppler US may also detect tumour-induced compression or vascular thrombosis.
High Resolution/Spiral CT. Contrast CT has higher sensitivity for CC detection than US (up to 80%), providing good views of intrahepatic mass lesions, dilated intrahepatic ducts, localised lymphadenopathy and extrahepatic metastases. However, the extent of CC is often not well-defined. Abdominal lymphadenopathy is common in PSC and does not necessarily indicate metastatic disease.
MRI. Contrast MRI is the optimal imaging investigation for suspected CC. In addition to avoiding radiation, MRI delineates hepatobiliary anatomy, local extent of duct involvement by MR cholangiopancreatography (MRCP), parenchymal abnormalities including the presence of liver metastases and hilar vascular involvement (MR angiography). However, MRI is inferior to CT for detecting distant metastases, particularly in the lungs and bone.
Cholangiography (MRCP, ERCP, PTC). Cholangiography is essential for assessing the extent of bile duct involvement and resectability. MRCP is non-invasive, thus avoiding risks of endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) and avoiding radiation. In a retrospective study, MRCP had superior sensitivity (96%), specificity (85%) and accuracy (91%) compared with ERCP (80%, 75% and 78%, respectively) for differentiating between CC and benign strictures. A UK study comparing MRCP with ERCP in biliary obstruction predominantly relating to gallstone disease found in favour of MRCP with respect to cost-saving and quality of life. Similar studies on malignant biliary disease are lacking. ERCP and PTC allow bile sampling for cytology and stent insertion for relief of biliary obstruction. There is no clear evidence that PTC should generally be favoured over ERCP on the basis of the level of obstruction. Although ERCP is usually preferred above PTC, experience of and facilities for PTC should be available in treating centres for cases where ERCP has failed.
Histology and Cytology. Although positive histology and/or cytology findings are often difficult to obtain, they are essential for confirming a diagnosis of CC, particularly in patients not proceeding to resection, and for clinical trials. Tumours are usually adenocarcinomas and have prominent desmoplastic stroma. However, except in cases where there is co-existing biliary dysplasia, it may not be possible, even with immunohistochemistry, to differentiate between CC and metastatic tumour. Examples of this include intraductal papillary neoplasm with associated invasive neoplasia, and mucinous cystic neoplasm with associated invasive neoplasia.
Standard cytology from brushings at ERCP/PTC is positive in <50% of CC cases, hence negative cytology findings do not exclude malignancy. Combining cytology with biopsy increases the positive yield to 40–70%. Applying fluorescence in situ hybridisation (FISH), which uses fluorescently-labelled DNA probes to detect aneuploidy in cells, reportedly confirmed cancer in 60% of patients in whom standard brush cytology was negative. A subsequent study confirmed the ability of FISH to improve the diagnostic accuracy in indeterminate biliary strictures, increasing the sensitivity of brush cytology from 21% to 58%. Including the presence of 9p21 deletion increased the sensitivity to 89%. The specificity of FISH was 97% compared with 100% for cytology.
Endoscopic Ultrasound. Endoscopic ultrasound (EUS) allows good views of the distal extrahepatic biliary tree, hilar lesions, gall bladder, regional lymph nodes and vasculature. EUS facilitates fine needle aspiration of distal lesions and nodes which can enhance the sensitivity and PPV of CC detection to nearly 100%. However, the negative predictive value is low, which does not permit exclusion of malignancy following a negative biopsy. The potential risk of tumour seeding has led some centres around the world to advise against EUS fine needle aspiration in potentially resectable tumours. However, this is not the case in most centres. Rates of tumour seeding are unclear, being reported as between 1:10 000 and 1:40 000, although this may be an underestimate.
Positron Emission Tomography (PET) and PET-CT. In a study comparing CT plus MR versus positron emission tomography (PET)-CT, PET-CT exhibited no advantage for CC diagnosis but did have higher accuracy for detecting regional lymph node and distant metastases. PET-CT may have a potential role in preoperative staging, but this needs validating.
Cholangioscopy. Given the disappointing accuracy of current diagnostic techniques, interest in cholangioscopy has renewed following technical improvements in endoscopes. In a prospective multicentre study, transpapillary cholangioscopy increased the ability to distinguish benign from malignant strictures compared with ERCP alone, and facilitated targeted biopsy. Cholangioscopy may be useful in experienced centres and further data are awaited.
Staging
CC staging is based on the tumour-node-metastasis (TNM) system. The 7th edition of the TNM classification introduced a specific staging system for intrahepatic CC, separate from HCC, providing better prognostic information. The T category is based on the number of tumour nodules, vascular invasion and direct extension into extrahepatic tissues. Unlike HCC, tumour size is not considered important. A positive resection margin (non-R0 resection) is a very poor prognostic factor.
Although distant spread is late and uncommon in CC, comprehensive staging must be carried out to screen for metastatic disease. CT provides more accurate information for this purpose than MRI. At presentation, up to 50% of patients are lymph node-positive and 10–20% have peritoneal involvement. Most centres consider a staging laparoscopy to exclude local metastatic disease in those considered resectable on imaging. Only approximately 50% of patients with perihilar CC who undergo laparotomy are ultimately suitable for curative resection. In a study of 175 patients with suspected perihilar CC who underwent staging laparoscopy during the past decade, the overall yield and accuracy of staging laparoscopy decreased compared with earlier reports, possibly due to improved imaging techniques during this time period. Further studies on the benefit of staging laparoscopy in suspected CC are warranted.
Metastatic adenocarcinoma mimicking CC may arise from several organs, particularly the pancreas, stomach, breast, lung and colon. CC is difficult to differentiate from metastatic adenocarcinoma, particularly if the pathological sample is obtained from outside the biliary tree. Thorough clinical assessment and other investigations are necessary to exclude a primary from elsewhere. The extent to which this is pursued will depend on the individual case.
Screening for CC in PSC
No benefit in screening for CC in PSC has been proven and there is no robust screening test. Nevertheless, most experts agree that early detection of CC in PSC is important to identify cases amenable to curative surgery and to avoid inappropriate liver transplantation. As well as an increased risk of CC, patients with PSC are also at increased risk of HCC; colorectal, gastric and pancreatic cancers; and malignant gall bladder polyps. Up to 50% of CCs are diagnosed within 2 years of PSC diagnosis and the subsequent risk of CC is approximately 1% per year. The severity of liver disease (Child–Pugh or Mayo score) does not appear to be a significant risk factor. Smoking, alcohol, duration of IBD if present, previous CRC/dysplasia and the HLA-DR4, DQ8 haplotype are reported risk factors for malignancy in PSC, but none has been validated as a predictive factor. A suggested algorithm for CC screening in PSC is given in figure 2. This is unproven and based on expert opinion. Regular investigations, including surveillance colonoscopies in patients with PSC and IBD and US for gall bladder lesions, are recommended in both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines.
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Figure 2.
Suggested algorithm for cholangiocarcinoma screening in primary sclerosing cholangitis (Recommendation Grade D). AFP, alpha-fetoprotein; CC, cholangiocarcinoma; CRC, colorectal carcinoma; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FISH, fluorescence in situ hybridisation; FNA, fine-needle aspiration; IBD, inflammatory bowel disease; MDT, multidisciplinary team; MRCP, magnetic resonance cholangiopancreatography; PSC, primary sclerosing cholangitis; US, ultrasonography.
Role of Ursodeoxycholic Acid (UDCA). Small retrospective studies have suggested that ursodeoxycholic acid (UDCA) may reduce the risk of colonic dysplasia and CRC in patients with PSC. No significant protective effect of UDCA on the risk of CC has been demonstrated. Recent guidelines from both EASL and AASLD have concluded that the role of UDCA in PSC is currently unclear and that high-dose UDCA may even be harmful.