Clinical diagnosis and management of intrahepatic cholangiocarcinoma

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Of the three distinct types of cholangiocarcinomas—intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma, and distal cholangiocarcinoma—iCCA is most frequently confused with hepatocellular cancer (HCC). iCCA is not as common as HCC but is the second most common primary malignancy of the liver. The lack of distinction between these two cancers in previous population‐based reporting has obscured an understanding of the true incidence and mortality rate of iCCA. Recent studies reported a 9.1% annual increase in the incidence of iCCA and a 9.4% increase in the mortality rate between 1973 and 1997 in the United States.1 Similar trends have been noted in reports from several other parts of the world. There remains some uncertainty about the extent to which these trends reflect more frequent diagnoses resulting from an increased awareness of the disease and the use of abdominal imaging studies or from the misclassification of other cancers, such as perihilar cholangiocarcinoma.

Risk Factors for iCCA

Most tumors occur sporadically and do not have any identifiable risk factors. Well‐characterized risk factors that have been identified include liver fluke infections, choledochal cysts, hepatolithiasis, and primary sclerosing cholangitis (Fig. 1).2 A recent meta‐analysis of case‐control studies of selected risk factors showed an increased risk for patients with cirrhosis, hepatitis B or C, obesity, and diabetes.3 Occupational and environmental risk factors such as exposure to volatile compounds in printing works and asbestos have been recognized. Risk factors that are specific for iCCA in comparison with other types of cholangiocarcinomas such as perihilar cholangiocarcinoma and distal cholangiocarcinoma are not well defined.

Diagnosis of iCCA

The clinical presentation of iCCA is often not specific enough for a diagnosis to be made. Most tumors present with nonspecific symptoms, or they are identified when a mass lesion is noted on radiographic studies or occasionally during a pathological examination of a resected lesion. Likewise, serological markers such as carbohydrate antigen 19‐9 are insensitive. Although they may provide confirmatory or prognostic information in some cases, they are insufficient to establish a diagnosis.

A presumed diagnosis can be made with radiological criteria. In iCCA, contrast uptake occurs progressively during arterial and venous phases. The presence of desmoplasia, a common feature of these tumors, results in a slower uptake of contrast. Thus, unlike HCC, venous phase contrast enhancement may be seen on dynamic computed tomography or magnetic resonance imaging of iCCA (Fig. 2). In some instances, a rim pattern of enhancement may be present in the periphery of the lesion. These criteria are insensitive for lesions that are smaller than 2 cm or when cirrhosis is present. Radiographic studies are needed to determine resectability and to provide an assessment of the extent of venous or arterial invasion and intrahepatic and extrahepatic spread.

Figure 2.

Radiological features of iCCA. Morphologically, iCCA can be recognized as mass‐forming, periductal‐infiltrating, or intraductal lesions or a combination of these. The imaging characteristics of these subtypes on computed tomography and magnetic resonance imaging are described. Periductal lesions are not readily detected with either ultrasound or positron emission tomography scanning, although mass‐forming lesions may show avidity on the latter.

Figure 1.

Traditional and emerging risk factors for biliary cancers. Traditional risk factors for biliary tract cancers are depicted within the blue circles. The specific risk for iCCA with these factors is presumed but for most risk factors has not been precisely determined because most studies have not distinguished iCCA from other biliary tract cancers. Emerging risk factors that are being recognized as risk factors for iCCA are depicted in green circles and include liver cirrhosis, obesity, diabetes, viral hepatitis B and C, and possibly also asbestos and some organic solvents.

A presumed radiographic diagnosis is sufficient if a decision has been made to proceed with surgical resection in a patient without cirrhosis. In a patient with cirrhosis, core biopsy should be considered for mass lesions that do not exhibit the characteristic radiological features of HCC, that is, enhancement during the arterial phase and washout during the venous phase of imaging. A definitive diagnosis requires pathological verification (Fig. 3). The histological findings of iCCA can overlap with those of metastatic adenocarcinoma or primary liver cancers with a mixed hepatocellular and cholangiocellular component. Immunostaining for markers of hepatocytic origin (e.g., glypican 3, heat shock protein 70, and glutamine synthetase) or progenitor cell features (e.g., cytokeratin 17 and epithelial cell adhesion molecule), along with additional clinical, radiographic, or endoscopic evaluations, may be helpful in distinguishing these other malignancies from iCCA.

Figure 3.

Imaging findings of mass lesions in patients with underlying risk factors should prompt a consideration of the diagnosis of iCCA. A pathological examination is required for a definitive diagnosis. In patients without cirrhosis or if surgical resection is being considered, radiological findings may suffice for a presumed diagnosis before surgery. In patients with cirrhosis, lesions with imaging findings that are characteristic of HCC are managed as such. However, in the presence of atypical imaging features, core biopsy should be considered for a definitive diagnosis.

Management of iCCA

There are limited treatment options that are effective for iCCA.4 An algorithm that may be useful for its evaluation and management is shown in Fig. 4. Treatment options will be determined by the performance status of the patient, the extent of the spread and resectability of the tumor, and the presence or absence of cirrhosis and portal hypertension.

Figure 4.

An approach to the management of iCCA involves an initial assessment of its resectability, the presence of cirrhosis or portal hypertension, and the performance status. Surgery is recommended if the tumor is resectable, with further interventions based on whether or not complete resection (R0) was achieved. For tumors that are inoperable or in the presence of multifocal or metastatic disease, locoregional therapies may be considered for the local control of tumor growth. The choice of approach is based on the size and location of the lesion and available expertise. For progressive or metastatic lesions, systemic chemotherapy with gemcitabine and cisplatin is appropriate. If the performance status is poor, 5FU or best supportive care may be considered.

For resectable tumors, consider surgery. In recent studies, the median overall survival period has ranged from 18 to 39 months, and the 5‐year survival rate has ranged from 25% to 40% after surgical resection.5 The prognosis is poorer for patients with vascular or nodal involvement, multifocal disease, or cirrhosis. The presence of portal hypertension with a Model for End‐Stage Liver Disease score > 9 and a Child score of B or C are relative contraindications for resection. Multifocality also precludes resection. If margins are positive (R1) or lymph nodes or residual tumors are present (R2), adjuvant chemotherapy can be considered.

Liver transplantation is associated with a high rate of tumor recurrence (>70%) and a median disease‐free survival of 8 months. Because of these poor outcomes, transplantation is not typically considered for iCCA. This situation is in contrast to perihilar cholangiocarcinoma. Carefully selected patients with perihilar cholangiocarcinoma may benefit from transplantation as part of a multimodality approach.6

Other options for inoperable iCCA include locoregional therapies such as radiofrequency or microwave ablation, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). The experience with these modalities has been limited. Patients with tumors smaller than 3 cm who received radiofrequency ablation had an overall median survival time of 38.5 months. Median survival times of 13.2 and 43.7 months have been reported with TACE7 and TARE,8 respectively. Stereotactic body radiotherapy (SBRT) may be considered, and one study reported a median overall survival period of 11 months with a complete response in 11% of patients.9

Systemic chemotherapy with a combination of gemcitabine and cisplatin was shown to prolong the survival of patients with unresectable or inoperable tumors in the Advanced Biliary Cancer 02 study.10 Combination therapy was better than gemcitabine monotherapy, and it was particularly more effective for patients with iCCA, with an increase in the survival time of approximately 3 months. Although molecular targeted therapies may have a role, there are no current data to guide their use.11 Gene expression profiling has identified two distinct classes of iCCAs that may potentially differ in their responses to such therapies. Future progress in iCCA therapy will require a concerted effort to enroll patients in carefully designed therapeutic clinical trials that encompass integrated analysis for well‐characterized patient cohorts.

Abbreviations

5FU

5‐fluorouracil

HCC

hepatocellular cancer

HIV

human immunodeficiency virus

iCCA

intrahepatic cholangiocarcinoma

SBRT

stereotactic body radiotherapy

TACE

transarterial chemoembolization

TARE

transarterial radioembolization.