Intrahepatic cholangiocarcinoma (ICC) is a rare tumor, with an increasing incidence worldwide and an overall poor prognosis. Symptoms are usually nonspecific, contributing to an advanced tumor stage at diagnosis. The staging system for ICC has recently been updated and is based on number of lesions, vascular invasion, and lymph node involvement. Complete surgical resection to negative margins remains the only potentially curable treatment for ICC. Gemcitabine-based adjuvant therapy can be offered based on limited data from patients with unresectable ICC. Overall 5-year survivals after resection range from 17% to 44%, with median survivals of 19 to 43 months.
Key points
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Intrahepatic cholangiocarcinomas (ICCs) are aggressive, locally invasive tumors with limited 5-year survival. Multifocality, vascular invasion, lymphatic spread, and tumor histology are all determinants of staging and prognosis.
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Both the incidence and the mortality of ICCs have risen over the past several decades.
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Surgical resection is the only viable treatment option for patients who present with ICCs. Minimally invasive hepatectomy is increasingly becoming a valid option in select cases.
Introduction: nature of the problem
Epidemiology
Intrahepatic cholangiocarcinoma (ICC) is a subtype of a family of aggressive cholangiocarcinomas, tumors that arise from cholangiocytes of the biliary tree. There are several key epidemiologic considerations of ICC:
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ICCs are rare, accounting for 20% to 25% of all cholangiocarcinomas; perihilar (50%–60%) or distal common bile duct (20%–25%) tumors are more common ( Fig. 1 ). They are still the second most common primary liver malignancy, following hepatocellular carcinoma.
Fig. 1
Anatomic distribution of cholangiocarcinomas. Intrahepatic lesions such as the lesion in the right lobe of the liver shown in this image are many times asymptomatic and as a result present at a later stage. dCCA, distal cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma.
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The incidence rate of ICCs for Americans has increased from 3.2 per 1,000,000 in 1975 to 1979 to 8.5 per 1,000,000 in 1995 to 1999, but this trend has stabilized over the last decade.
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The reasons underlying this increasing incidence are unclear, but potential reasons include changes in the classification system or a recent increase in the incidence of Hepatitis C. This increased incidence does not seem to be related to increased tumor detection, as there has been no change in the proportion of early stage or smaller tumors detected over time.
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Population-based data demonstrate that men are 1.5 times as likely to develop ICCs as women in the United States.
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The average age of diagnosis worldwide is 50 years old, and patients are rarely diagnosed younger than age 40.
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ICCs are lethal malignancies with more aggressive tumor biology than the more common liver malignancy, hepatocellular carcinoma. Overall 3-year and 5-year survival rates are a dismal 30% and 18%, respectively.
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Mortality from ICCs has risen over the last several decades. Data from the World Health Organization database indicate that although mortality has improved for extrahepatic biliary tumors, mortality has actually increased worldwide for ICCs since the 1970s. For the United States, age-adjusted mortality has risen from 0.7 per 1,000,000 in 1973 to 6.9 per 1,000,000 in 1997, paralleling the rising incidence of ICCs ( Fig. 2 ).
Fig. 2
Age-adjusted mortality for ICC, 1973–1997.
( From Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33(6):1354; with permission.)
Risk Factors
Risk factors for ICC can range from established precursors such as choledochal cysts, cholangitis, and toxin exposure to potential associations such as smoking and diabetes. Patients with chronic inflammatory processes such as primary sclerosing cholangitis and patients infected with the parasites Opisthorchis viverrini or Clonorchis sinensis are at particularly increased risk for ICC. Other risk factors are listed in Box 1 . Although these factors are key considerations in the diagnosis of ICC, most of these cancers occur de novo in the absence of any underlying liver disease.
Established risk factors
Primary sclerosing cholangitis
Choledochal cyst
Parasitic infection (Opisthorchis viverrini or Clonorchis sinensis)
Inflammatory bowel disease
Drug or toxin exposure (thorotrast)
Biliary cirrhosis
Cholelithiasis
Bile duct adenoma and biliary papillomatosis
Alcoholic liver disease
Associated risk factors
Diabetes
Thyrotoxicosis
Chronic pancreatitis
Obesity
Nonalcoholic liver disease
Hepatitis B/C infection
Typhoid
Smoking
Subtypes
The Liver Cancer Study Group of Japan has distinguished 3 different histologic subtypes of ICCs: mass-forming, periductal infiltrating, and intraductal growth ( Fig. 3 ).
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Mass-forming ICCs are the most common and are characteristically solid nodules that are discrete from the surrounding liver parenchyma. Intrahepatic metastases are more commonly observed with this subtype.
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Periductal infiltrating ICCs invade the liver parenchyma along portal structures and metastasize to hilar lymph nodes; this subtype rarely forms a discrete liver mass. A combined mass-forming–periductal-infiltrating tumor type is an aggressive subtype correlating with decreased survival in the Japanese series, but this finding has not been observed in Western populations.
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Intraductal growth ICCs are the least common subtype and can be characterized by growth into the biliary tract lumen. These ICCS may represent less aggressive variants with a more favorable prognosis.
Introduction: nature of the problem
Epidemiology
Intrahepatic cholangiocarcinoma (ICC) is a subtype of a family of aggressive cholangiocarcinomas, tumors that arise from cholangiocytes of the biliary tree. There are several key epidemiologic considerations of ICC:
- •
ICCs are rare, accounting for 20% to 25% of all cholangiocarcinomas; perihilar (50%–60%) or distal common bile duct (20%–25%) tumors are more common ( Fig. 1 ). They are still the second most common primary liver malignancy, following hepatocellular carcinoma.
Fig. 1
Anatomic distribution of cholangiocarcinomas. Intrahepatic lesions such as the lesion in the right lobe of the liver shown in this image are many times asymptomatic and as a result present at a later stage. dCCA, distal cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma.
- •
The incidence rate of ICCs for Americans has increased from 3.2 per 1,000,000 in 1975 to 1979 to 8.5 per 1,000,000 in 1995 to 1999, but this trend has stabilized over the last decade.
- •
The reasons underlying this increasing incidence are unclear, but potential reasons include changes in the classification system or a recent increase in the incidence of Hepatitis C. This increased incidence does not seem to be related to increased tumor detection, as there has been no change in the proportion of early stage or smaller tumors detected over time.
- •
Population-based data demonstrate that men are 1.5 times as likely to develop ICCs as women in the United States.
- •
The average age of diagnosis worldwide is 50 years old, and patients are rarely diagnosed younger than age 40.
- •
ICCs are lethal malignancies with more aggressive tumor biology than the more common liver malignancy, hepatocellular carcinoma. Overall 3-year and 5-year survival rates are a dismal 30% and 18%, respectively.
- •
Mortality from ICCs has risen over the last several decades. Data from the World Health Organization database indicate that although mortality has improved for extrahepatic biliary tumors, mortality has actually increased worldwide for ICCs since the 1970s. For the United States, age-adjusted mortality has risen from 0.7 per 1,000,000 in 1973 to 6.9 per 1,000,000 in 1997, paralleling the rising incidence of ICCs ( Fig. 2 ).
Fig. 2
Age-adjusted mortality for ICC, 1973–1997.
( From Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33(6):1354; with permission.)
Risk Factors
Risk factors for ICC can range from established precursors such as choledochal cysts, cholangitis, and toxin exposure to potential associations such as smoking and diabetes. Patients with chronic inflammatory processes such as primary sclerosing cholangitis and patients infected with the parasites Opisthorchis viverrini or Clonorchis sinensis are at particularly increased risk for ICC. Other risk factors are listed in Box 1 . Although these factors are key considerations in the diagnosis of ICC, most of these cancers occur de novo in the absence of any underlying liver disease.
Established risk factors
Primary sclerosing cholangitis
Choledochal cyst
Parasitic infection (Opisthorchis viverrini or Clonorchis sinensis)
Inflammatory bowel disease
Drug or toxin exposure (thorotrast)
Biliary cirrhosis
Cholelithiasis
Bile duct adenoma and biliary papillomatosis
Alcoholic liver disease
Associated risk factors
Diabetes
Thyrotoxicosis
Chronic pancreatitis
Obesity
Nonalcoholic liver disease
Hepatitis B/C infection
Typhoid
Smoking
Subtypes
The Liver Cancer Study Group of Japan has distinguished 3 different histologic subtypes of ICCs: mass-forming, periductal infiltrating, and intraductal growth ( Fig. 3 ).
- •
Mass-forming ICCs are the most common and are characteristically solid nodules that are discrete from the surrounding liver parenchyma. Intrahepatic metastases are more commonly observed with this subtype.
- •
Periductal infiltrating ICCs invade the liver parenchyma along portal structures and metastasize to hilar lymph nodes; this subtype rarely forms a discrete liver mass. A combined mass-forming–periductal-infiltrating tumor type is an aggressive subtype correlating with decreased survival in the Japanese series, but this finding has not been observed in Western populations.
- •
Intraductal growth ICCs are the least common subtype and can be characterized by growth into the biliary tract lumen. These ICCS may represent less aggressive variants with a more favorable prognosis.
Clinical presentation and diagnosis
Clinical Presentation
The clinical presentation of ICCs is usually nonspecific, and symptoms can include generalized abdominal pain, or less commonly, weight loss and jaundice.
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In a retrospective review of a 31-year experience at Johns Hopkins University, patients with ICC most commonly presented with abdominal pain and were less likely to experience jaundice or weight loss than patients with extrahepatic cholangiocarcinoma. This finding was confirmed in other studies.
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Because these tumors are discrete from the main bile ducts and rarely cause obstructive jaundice, clinical diagnoses are rare, and many patients initially present with advanced disease. In addition, incidental diagnoses of ICCs in asymptomatic patients are also relatively common, accounting for 12% to 30% of diagnoses in some series.
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A single-institution retrospective review at the Memorial Sloan Kettering Cancer Center demonstrated that 54% of these tumors are unresectable at presentation.
Diagnosis and Initial Evaluation
The nonspecific, aggressive presentation of ICC, coupled with its relatively rare incidence, makes the initial diagnosis challenging. ICCs are most commonly identified on cross-sectional imaging, which is also used for staging and determining tumor resectability. Determining the diagnosis before intervention has significant treatment implications given the unique tumor biology of these cancers relative to others (hepatocellular carcinoma, metastatic adenocarcinoma). Laboratory tests are rarely helpful, with occasional exceptions:
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CA 19-9 is the most widely used laboratory test, but it is nonspecific and may be elevated in any number of benign or malignant diseases. It may serve a role as an ancillary test in patients with PSC who present with a suspicious intrahepatic lesion. In these patients a value greater than 100 U/mL carries a sensitivity and specificity of 89% and 86%, respectively, for the diagnosis of cholangiocarcinoma.
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α-Fetoprotein is similarly controversial and has been suggested to play a role in differentiating ICCs from hepatocellular carcinoma. In one study by Koh and colleagues these values were typically lower or normal in patients with ICCs compared with patients with hepatocellular carcinoma, but this finding was not statistically significant.
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On ultrasound there are no characteristic findings to differentiate these lesions from secondary metastases or hepatocellular carcinoma.
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Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) rarely identifies any pathognomonic features of ICC compared with other liver lesions. As a result, neither is superiorto the other in the initial diagnosis of these tumors. However, there are findings on these studies that can aid in the diagnosis, particularly when the 2 modalities are used in conjunction.
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Characteristic findings of ICC on CT include the following:
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Thin rimlike contrast enhancement on both arterial and portal venous phases;
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Areas of low attenuation within the tumor with areas of high attenuation scattered throughout, also on both phases ;
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Delayed contrast enhancement, which may also correlate with poor prognosis. In a retrospective comparison of patients with tumors with delayed contrast enhancement versus those without enhancement, patients in the former group experienced worse overall survival.
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Characteristic findings of ICC on MRI include the following:
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Hypointensity on T1-weighted imaging and hyperintensity on T2-weighted imaging;
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Peripheral enhancement, progressive concentric filling, and contrast pooling on delayed images in contrast-enhanced MRI.
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The utility of PET-CT in the initial diagnosis and staging of suspected ICC is unclear. Studies have been mixed, with some finding a sensitivity and specificity greater than 85%, whereas others observed limited specificity in the presence of infectious or inflammatory processes.
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Patients who present with a hepatic lesion, biopsy-proven to be adenocarcinoma with an unknown primary lesion, represent special diagnostic cases. In these patients the aim is to discern primary ICC from secondary metastases, and patients should undergo a thorough evaluation to identify a potential primary lesion. These evaluations should include cross-sectional imaging of the chest, abdomen, and pelvis, upper and lower endoscopy, mammography, and gynecologic evaluation as indicated.
Staging and prognosis
7th Edition AJCC Staging
Previous iterations of the American Joint Committee on Cancer (AJCC) staging for ICCs had been based on data from patients with hepatocellular carcinoma. Findings from population-based studies and basic science literature have demonstrated that ICCs are pathologic entities with a more aggressive tumor biology and distinct phenotype than hepatocellular carcinoma. Recognizing this, Nathan and colleagues used Surveillance, Epidemiology, and End Results-Medicare data from 1988 to 2004 to (1) assess the validity of the 6th edition staging system and (2) identify prognostic findings from pathologically confirmed ICCs. The authors observed that tumor size as defined by the previous staging classification had no prognostic value, whereas vascular invasion, number of tumors, and extent of lymph node invasion had significant prognostic significance. Based on these findings, the AJCC revised the previous classification system to construct the 7th edition staging classification, the first novel staging system for patients with ICCs ( Table 1 ).
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In a multi-institutional study of 12 tertiary academic centers, the AFC-IHCC-2009 study group validated the AJCC 7th edition staging classification as a discriminatory system in which each TNM stage was associated with significantly varying survival outcomes ( Fig. 4 ).
Fig. 4
Kaplan-Meier survival curve of patients with cholangiocarcinoma.
( From Nathan H, Pawlik TM. Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2010;26(3):271; with permission.)
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Another single-institutional Japanese study recognized in a multivariate analysis that this system has some limitations and ignores or underestimates the influence of tumor histology and multiplicity while overemphasizing the influence of periductal invasion.
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Wang and colleagues conducted a multivariate analysis to construct a prognostic nomogram for overall 3-year and 5-year survival. This study confirmed the prognostic implications of tumor multiplicity, vascular invasion, and lymphatic spread, all of which are included in the current AJCC staging system. However, in this retrospective review the addition of carcinoembryonic antigen (CEA) and CA 19-9 levels resulted in improved staging accuracy.
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