Cholangiocarcinoma is difficult to diagnose owing to its silent clinical character, the low specificity of most diagnostic modalities and the lack of absolute diagnostic criteria. The majority of patients with cholangiocarcinoma develop symptoms only at an advanced stage of disease, and the clinical presentation depends upon tumor stage, tumor location and growth pattern. Diagnosis requires a high level of suspicion in the appropriate clinical setting and a confirmatory constellation of clinical, laboratory, endoscopic and radiologic data. The majority of patients with cholangiocarcinoma develop this malignancy de novo
. However, certain conditions and risk factors have been associated with an elevated risk of developing the disease (Box 1
). Primary sclerosing cholangitis (PSC) is the most well-known of these conditions and is associated with a prevalence of cholangiocarcinoma of 5–15%.5
In patients with any of these conditions, symptoms and clinical signs associated with cholangiocarcinoma should prompt an aggressive diagnostic work-up as outlined below.
The Liver Cancer Study Group of Japan (LCSGJ) used retrospective data from 245 patients to distinguish three macroscopic growth types for intrahepatic cholangiocarcinoma: mass-forming type; periductal-infiltrating type; and intraductal-growth type ().6
The mass-forming type is defined as a definite mass located in the liver parenchyma and is the most common form of intrahepatic cholangiocarinoma.7
The mass-forming type tends to invade the hepatic parenchyma via the portal venous system and invades lymphatic vessels at advanced stages.8
The periductal-infiltrating type is described as extending mainly longitudinally along and within the bile duct, often resulting in dilatation of the peripheral bile ducts. The periductal-infiltrating type tends to spread along the Glisson sheath via the lymphatic vessels. The intraductal-growth type proliferates towards the lumen of the bile duct like an intraductal tumor thrombus; this form of cholangiocarcinoma often has papillary growth characteristics. Tumors not following any of these criteria are grouped into a fourth category as ‘undefined’. Tumors with more than one of the above described growth types are described by the corresponding descriptions connected by ‘+’ (for example, mass-forming + periductal-infiltrating).6
Evidence indicates that the mass-forming + periductal-infiltrating type has a worse prognosis than other types, with higher rates of recurrence following resection.9,10
The American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC) classifies cholangiocarcinoma into the mass-forming, periductal-infiltrating and a mixed type but not the intraductal-growth type.11
Figure 2 Intrahepatic cholangiocarcinoma growth types. The Liver Cancer Study Group of Japan (LCSGJ) used retrospective data from 245 patients to distinguish three macroscopic growth types for intrahepatic cholangiocarcinoma: mass-forming type; periductal-infiltrating (more ...)
Clinically, intrahepatic cholangiocarcinoma presents with unspecific symptoms such as abdominal pain, malaise, night sweats and cachexia.12
Makuuchi and colleagues have suggested that primary hepatic malignancies can be identified correctly on the basis of imaging data.13
In our experience, intrahepatic cholangiocarcinoma is the most common etiology of primary, malignant intra-hepatic mass lesions in the absence of other primary solid malignancies or cirrhosis. Several imaging modalities are being used in the evaluation of primary hepatic masses.14
CT and MRI are both helpful for the detection of the primary tumor but both imaging techniques have low specificity.15
The sensitivity and image quality of MRI can be increased by the use of ferumoxide enhancement, although this agent is no longer available commercially.16,17
In particular, dynamic CT or MRI can help to distinguish intrahepatic cholangiocarcinoma from hepatocellular carcinoma (HCC). Up to 81% of intrahepatic cholangiocarcinomas are characterized by a progressive contrast uptake throughout the arterial and venous phase, and especially in the delayed venous phase images; this feature is in contrast to HCC, which is characterized by rapid contrast enhancement during the arterial phase and prompt washout in the delayed venous phase.18
MRI and CT are comparable in the detection of satellite lesions but CT is preferable for the depiction of vascular encasement.19
The sensitivity of PET for the detection of mass-forming intra-hepatic cholangiocarcinoma of >1 cm diameter has been reported as 85–95%, with a sensitivity of 100%; its sensitivity and specificity for detection of nodal and distant metastatic disease is 100% and 94%, respectively.20
In problematic cases, determination of the serum CA 19-9 concentration can be helpful. However, the sensitivity and specificity of this biomarker for intrahepatic cholangiocarcinoma is only 62% and 63%, respectively, and should, therefore, only be used for further confirmation. Other serum markers, such as serum cytokeratin-19 fragment (CYFRA 21-1) and CA242, have been reported to have higher specificities than CA 19-9 for intrahepatic cholangiocarcinoma in a limited number of studies, but are not in routine use.21–23
It should be emphasized that imaging is not always reliable for the diagnosis of some intrahepatic cholangiocarcinomas. For instance, intrahepatic cholangiocarcinomas <2 cm in size mimic HCC because of the absence of the progressive enhancement pattern.18
The need for a liver biopsy and a histopathologic diagnosis depends upon the clinical setting and preoperative imaging. In patients with cirrhosis and an indeterminate lesion within Milan criteria, a biopsy is justified because the distinction between HCC and cholangiocarcinoma changes management (patients with intrahepatic cholangiocarcinoma should not undergo liver transplantation) and could thus have an important effect on outcome. In noncirrhotic patients who qualify for surgery, a liver biopsy may not be required if a decision has been made to proceed with surgical resection. However, in patients who are not candidates for surgical treatment and, therefore, curative treatment, a liver biopsy is usually performed before initiation of systemic therapy.
According to the AJCC/UICC11
and WHO classification systems,24
intrahepatic cholangiocarcinoma can arise from biliary epithelia at any portion of the intrahepatic biliary system, from the segmental bile ducts (lined by mucin-producing cylindrical cells) to the ductules (lined by cuboidal cholangiocytes without mucin production).25,26
Mucin-producing cells can give rise to mucin-producing tubular adenocarcinoma with or without micropapillary structures ().24
These features are also observed in perihilar cholangiocarcinoma and distal extrahepatic cholangiocarcinoma, as their tumor locations (liver hilar bile duct and extrahepatic bile duct) are lined with a similar phenotype of cholangiocytes. On the other hand, ductular-related intrahepatic cholangiocarcinoma can present with mixed hepatocellular and/or cholangiocellular features, since ductules are composed of hepatic progenitor cells capable of differentiating to both hepatocytes and cholangiocytes.27
For example, cholangiolocellular carcinoma, which is thought to originate from ductules, presents with mixed histopathological features, including both an HCC-like area and a mucin-producing cholangiocarcinoma area ().27
Imaging these cancers shows mixed histopathological features indicating both HCC and cholangiocarcinoma patterns.28,29
In addition, cholangiocellular carcinoma can occur in chronic liver disease conditions, and mimicking the HCC image pattern can lead to problems for preoperative diagnosis. Thus, there is a need to address the issue of preoperative diagnosis of intrahepatic cholangiocarcinoma.
Figure 3 Histpathological features of mucin-producing cholangiocarcinoma and cholangiolocellular carcinoma with mixed features. a | Well differentiated intrahepatic cholangiocarcinoma. Tubular structure with abundant fibrous stroma. b | Cholangiolocellular carcinoma. (more ...)
Other rare histologic types have been included in the 7th
edition of the AJCC/UICC staging system (Box 2
However, it is questionable if these should be included in the same category as cholangiocarcinoma as these malignancies originate from different cell types and can, therefore, be expected to display different biologic behavior. Hence, prognostic information observed in adenocarcinomas might not be reliable in these cancers. The accuracy of distinguishing metastatic adenocarcinomas can be improved by immunoprofiling with a combination of cytokeratin (K) 7 and K20 immuno-histochemical staining.30,31
However, metastatic liver tumors, especially from pancreatic cancers, are still challenging to diagnose. The use of liver biopsy is limited by its potential complications, including hemorrhage and tumor spread, as well as by its frequently unspecific histopathology. Makuuchi and colleagues have suggested that the diagnosis of an intrahepatic cholangiocarcinoma can be made with up to 100% accuracy based upon a combination of clinical presentation, laboratory analysis and radiologic evaluation.13
However, the Barcelona liver cancer group have presented the diagnostic problem that intrahepatic cholangiocarcinoma in patients with cirrhosis is difficult to diagnose radiographically,18,32
requiring histopathology for definitive diagnosis.
Box 2. Histologic type of cholangiocarcinomas
- Clear cell adenocarcinoma
- Mucinous carcinoma
- Signet ring cell carcinoma
- Squamous cell carcinoma
- Adenosquamous carcinoma
- Small cell carcinoma
- Undifferentiated carcinoma
- Spindle and giant cell types
- Small cell types
- Papillary carcinoma, noninvasive
- Papillary carcinoma, invase
In summary, clinically, intrahepatic cholangiocarcinoma can be assumed on the basis of its venous phase contrast enhancement on dynamic imaging in the absence of other, extrahepatic primary malignancies and cirrhosis. Tumor markers such as CA 19-9 can be used for additional evidence but are not sufficient for diagnosis. However, for a definitive diagnosis of intrahepatic cholangiocarcinoma, a histological diagnosis is required. Intrahepatic cholangiocarcinoma arising from ductules may present with mixed histological and imaging features of both HCC and cholangiocarcinoma. Patients with intrahepatic cholangiocarcinoma or mixed HCC/intrahepatic cholangiocarcinoma should not undergo liver transplantation because of the risk of suboptimal outcomes.33
A diagnostic approach for intrahepatic cholangiocarcinoma is depicted in .
Algorithm for the diagnosis and management of intrahepatic cholangiocarcinoma.
Although the definition of intrahepatic cholangiocarcinoma is the same in both the UICC11
and WHO classification,24
the definition of perihilar cholangiocarcinoma differs between the two. According to the UICC classification,11
perihilar cholangiocarcinoma is proximally separated from intrahepatic cholangiocarcinoma by the second-order bile ducts, and is distally separated from distal extrahepatic cholangiocarcinoma by the insertion of the cystic duct into the extrahepatic biliary tree. By contrast, the WHO classification defines hilar cholangiocarcinoma, often called ‘Klatskin tumor’, as arising from the right and left hepatic ducts at or near their junction, but does not include the level of cystic bile duct insertion.24
On the other hand, perihilar intrahepatic cholangiocarcinoma defined by the WHO classification corresponds to intrahepatic cholangiocarcinoma arising from the intrahepatic large bile ducts. These definitions are confusing. Given the differences in biology and management, we believe perihilar cholangiocarcinoma is a separate entity from intrahepatic cholangiocarcinoma and distal extrahepatic cholangiocarcinoma.
Macroscopically, perihilar cholangiocarcinoma can display an exophytic or an intraductal growth pattern, with the former either displaying a nodular or a periductal-infiltrating anatomy.34
The periductal-infiltrating form of this cancer is the most common; as the tumor progresses it looses its tropism for bile and then forms a mass-forming + periductal-infiltrating lesion. Histopathologically, the majority of perihilar cholangiocarcinomas are adenocarcinomas that are moderately to well differentiated with mucin production and abundant fibrous stroma.35–37
Perihilar cholangiocarcinoma often spreads by perineural invasion and lymph node involvement (). As perihilar cholangiocarcinoma involves the main bile duct, intrahepatic cholangitis and/or secondary sclerosing-cholangitis-like features are seen in the nontumoral liver tissue. In addition, 90% of patients with perihilar cholangiocarcinoma clinically present with biliary problems such as painless jaundice, and 10% of patients present with cholangitis.38,39
Therefore, perihilar cholangiocarcinoma can be diagnosed earlier and at a smaller size than intrahepatic cholangiocarcinoma. Systemic signs of malignancy (that is, weight loss, anorexia and fatigue) are observed in up to 56% of patients with perihilar cholangiocarcinoma at presentation.39
Unilateral hepatic lobe hypertrophy with contralateral hepatic lobar atrophy, which is known as a hypertrophy–atrophy complex, is secondary to unilobar biliary obstruction often with ipsilateral vascular encasement. On physical examination, this may present as a palpable prominence of one hepatic lobe.40
Patients presenting with the above signs and symptoms—in particular, in patients with known risk factors as outlined in Box 1
—should be evaluated for cholangiocarcinoma. presents an algorithm for the management of patients who present with a malignant hilar biliary obstruction. Laboratory analysis is mostly unspecific and reflects the associated cholestasis and cholangitis.41
Immunoglobulin G4 (IgG4) cholangiopathy should be ruled out by evaluation for increased IgG4 in serum and biliary samples.42
Tumor markers, in particular serum CA 19-9 determination, can be helpful in cases of indeterminate biliary strictures but are not diagnostic. Serum CA 19-9 levels can be increased in patients with cholangitis, which can be surprisingly indolent in patients who have biliary stents in place.43
In patients with PSC, the sensitivity and specificity of CA 19-9 is 79% and 98%, respectively, at a serum concentration of >129 U/ml.44
In patients who do not have PSC, a CA 19-9 serum concentration of >100 U/ml has a sensitivity of 76% and a negative predictive value of 92% compared with patients who have benign strictures.45
Of note, 10% of individuals lack the Lewis antigen and do not produce CA 19-9, and occasionally tumor cells lose the ability to express a tumor marker.46
Diagnostic criteria for perihilar and distal extrahepatic cholangiocarcinoma.
Radiologic evaluation is critical for detection and evaluation of tumor extent, as well as for preoperative planning. In the past, the use of CT was limited due to its low accuracy.47
However, technical advances, such as multidetector technology and multiphase scanning, have significantly improved the accuracy of CT in perihilar cholangiocarcinoma.19
The accuracy for detection of portal vein involvement has been reported to be up to 87% and for arterial involvement as high as 93%.48
The accuracy of CT in the assessment of resectability has been reported as 60–88% with negative predictive values of 85–100%.49,50
However, its sensitivity for detection of regional lymph node metastases is only 54% and CT tends to underestimate the extent of the proximal tumor.19,48,51
Magnetic resonance cholangiopancreatography (MRCP) is the imaging modality of choice for perihilar cholangiocarcinoma. Its accuracy in assessing local extent and resectability is up to 95%, and is comparable to endoscopic retrograde cholangiopancreaticography (ERCP).52–55
However, its accuracy in the assessment of vascular involvement and hepatic parenchyma invasion is only 67–73% and 75–80%, respectively.53,54
The sensitivity and specificity of PET for perihilar cholangiocarcinoma is only 69% and 67%, respectively; for the detection of regional lymph node metastases, its sensitivity is 13–38%.51,56
The role of PET is further limited due to false-positive results in the setting of inflammation and false-negative results due to the high desmoplastic reaction that occurs in these tumors.14
Invasive diagnostic tests, such as ERCP, percutaneous transhepatic cholangiography (PTC) and endoscopic ultrasonography (EUS), have an important diagnostic and therapeutic role in perihilar cholangiocarcinoma. ERCP and PTC allow assessment of strictures, sampling of biliary epithelial cells and therapeutic dilatation and stent placement. EUS has the highest sensitivity for the assessment of regional lymphadenopathy and allows fine needle aspiration of suspicious lymph nodes; however, the primary tumor should not be biopsied as discussed below.38
A tissue diagnosis of perihilar cholangiocarcinoma is difficult for several reasons. First, techniques for sampling the biliary tree, usually endoscopically directed brushings, frequently provide only a limited number of cells such that sampling errors can result in false-negative results. Also, desmoplasia limits the number of cells obtained by brush cytology. Hence, the sensitivity of conventional cytology in perihilar cholangiocarcinoma is approximately 20%.57
The vast majority of perihilar cholangiocarcinomas are periductal, infiltrating cancers, and as such do not demonstrate mass lesions on cross-sectional imaging studies. The lack of a mass lesion precludes percutaneous biopsy techniques. Even in the presence of a hilar mass, we discourage percutaneous or EUS-guided biopsies of primary lesions in patients who are potential candidates for treatment with curative intent because of the potential for tumor spread. For example, the Mayo Clinic transplant protocol for perihilar cholangiocarcinoma excludes patients who have undergone biopsy of the primary tumor. Given the limitations of conventional cytology, additional cytologic approaches are needed to diagnose this cancer. Chromosomal analysis using fluorescent in situ
hybridization (FISH) has been established as an additional test for biliary tissue samples, with a resulting sensitivity of 47% and a specificity of 97% for detection of cholangiocarcinoma in patients with PSC.58
In FISH analysis, three subsets of chromosomal amplification can occur: trisomy 7; tetra-somy or duplication of all chromosomes labeled; and polysomy or amplification of at least two chromosomes beyond tetrasomy. Polysomy is observed in up to 77% of cholangiocarcinoma cases,59
and we consider the combination of a dominant stricture and polysomy as a diagnostic criteria for this disease. Trisomy 7 describes an amplification of chromosome 7 alone; it is frequently observed in inflammatory conditions and, although not diagnostic for cholangiocarcinoma, it is associated with an increased risk of its development over time and warrants close follow-up. Tetrasomy must be interpreted with caution, because high mitotic rates yield tetrasomy during the M phase of the cell cycle.
In summary, the diagnostic criteria for perihilar cholangiocarcinoma consist of a constellation of different clinical data. These include a dominant stricture in the perihilar biliary tree with either the presence of adenocarcinoma cells revealed by conventional cytology and/or polysomy on FISH analysis of cytologic specimens. In the absence of cytologic abnormalities— a frequent problem in the clinical setting owing to the low sensitivity of cytologic techniques and sampling errors—a hilar mass on axial imaging with an associated biliary stricture, and/or hypertrophy–atrophy complex can also serve as a combination diagnostic for perihilar cholangiocarcinoma. Vascular encasement is almost always a malignant feature. Serum levels of CA 19-9 can help to provide further evidence but are not sufficient as a sole diagnostic criterion; very high serum levels of this marker in the absence of cholangitis can be indicative of metastatic disease (for example, peritoneal carcinomatosis).
Distal extrahepatic cholangiocarcinoma
Distal extrahepatic cholangiocarcinomas are defined as growing along the common bile duct between the cystic duct and the ampulla of Vater; however, they are clearly separated from ampullary carcinomas. Histologically, they are predominantly well-to-moderately differentiated adenocarcinomas.24
The latest WHO classification proposes two types of precursor lesions; intraductal papillary neoplasms and biliary intraepithelial neoplasia (BillN).24
Clinically, distal cholangiocarcinomas present similarly to perihilar cholangiocarcinoma—causing symptoms of cholestasis and cholangitis.36,60
Although jaundice, abdominal pain and weight loss are observed at equal rates for perihilar and distal extrahepatic cholangiocarcinoma, fever is more common in perihilar cholangiocarcinoma.41
Lymph node metastases are less common than in perihilar cholangiocarcinoma.28
In most clinical studies evaluating diagnostic modalities, perihilar and distal extrahepatic cholangiocarcinoma have been grouped together as extrahepatic cholangiocarcinoma. Therefore, there are no studies evaluating the different tumor markers and radiologic modalities for distal extrahepatic cholangiocarcinoma as a separate entity. Given the similar clinical presentation, we apply the same diagnostic criteria described above for perihilar cholangiocarcinoma. However, we stress that perihilar cholangiocarcinoma and distal extrahepatic cholangiocarcinoma are separate entities in their biology and treatment, and should, therefore, be treated as such.
In summary, the diagnosis of distal extrahepatic cholangiocarcinoma requires the presence of a dominant stricture and a positive cytology for adenocarcinoma cells and/or polysomy on FISH. Mass lesions are unusual in this type of cholangiocarcinoma.