Primary hepatic cancers constitute about 30% of all cancer-related deaths globally. The overwhelming proportion of these cancers are hepatocellular carcinomas, accounting for around 8 in every 10 cases; intrahepatic cholangiocarcinomas come in a distant second place, accounting for about 1 in every 10 cases. 

Despite being closely related anatomically, hepatocellular carcinoma and intrahepatic cholangiocarcinoma diverge on many points, starting from how they are typically discovered. 

Hepatocellular carcinoma mostly emerges from a background of cirrhosis. The most common causes of hepatocellular carcinoma are viral infections (mainly hepatitis C), excessive alcohol consumption, and nonalcoholic fatty liver disease. 

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Because hepatocellular carcinoma arises from a background of cirrhosis, patients would typically be already seen in hepatobiliary clinics. This is in contrast to intrahepatic cholangiocarcinoma, which are often discovered incidentally, with patients often presenting without any notable symptoms at all, save for a collection of constitutional symptoms, such as weight loss and loss of appetite, if any. 

Over the last few years, research into these 2 types of cancers have garnered momentum; in this article, we will explore some of the key differences between them.

Epidemiological Differences

In Hepatology, Lee and colleagues presented a study they conducted comparing hepatocellular carcinoma and intrahepatic cholangiocarcinoma in terms of epidemiology in the United States. 

This retrospective study was conducted by analyzing all cases of both types of cancers from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2017. The SEER database encompasses 18 population-based registries, covering around 28% of the United States population. 

The research team identified 96,151 cases of hepatocellular carcinoma and 13,611 cases of intrahepatic cholangiocarcinoma. In terms of sex, 76.3% of hepatocellular carcinoma cases were male, and 23.7% were female; in intrahepatic cholangiocarcinoma, the figures were 50.7% and 49.3%, respectively. This indicates that there is a stronger association between the female sex and intrahepatic cholangiocarcinoma diagnosis. 

Read more about cholangiocarcinoma epidemiology 

“Most patients with intrahepatic cholangiocarcinoma were nonHispanic whites, while only about half of hepatocellular carcinoma patients were nonHispanic whites,” Lee et al wrote. “Patients with intrahepatic cholangiocarcinoma were also significantly older than patients with hepatocellular carcinoma (68 vs 63 years old, P <0.001).”

The research team also discovered that 80.5% of patients with hepatocellular carcinoma have cirrhosis; the figure is merely 35.8% in patients with intrahepatic cholangiocarcinoma, less than half. In addition, patients with intrahepatic cholangiocarcinoma have a more advanced tumor burden upon presentation than patients with hepatocellular carcinoma: they had higher proportions of tumors that were 5 cm or greater in size, greater lymph node involvement and metastatic spread, as well as higher tumor histological grades. 

Lee and colleagues reported that higher socioeconomic status and living in rural areas had a greater association with intrahepatic cholangiocarcinoma compared to hepatocellular carcinoma.

What could explain this discrepancy? The researchers wrote that it is likely that individuals with a higher socioeconomic status had lower risk factors associated with hepatocellular carcinoma, such as hepatitis C infection. As for the relationship between living in rural areas and intrahepatic cholangiocarcinoma diagnosis, they speculated that it could be due to environmental exposure and higher incidences of obesity in rural areas (metabolic syndrome being a key risk factor for liver cancers). 

Diagnosis and Workup 

In Surgical Clinics of North America, Meija and Pasko wrote an insightful paper on how the diagnostic aspects of hepatocellular carcinoma and intrahepatic cholangiocarcinoma differ. 

In terms of diagnosis, alpha fetoprotein (AFP) is the most important and most used tumor marker for hepatocellular carcinoma. However, there are 2 notable caveats: high AFP levels are not diagnostic in the absence of a concerning lesion, and AFP levels can be under the threshold of 20 ng/mL in up to 40% of patients with hepatocellular carcinoma. 

“When elevated, as with other tumors it is often used to assess response to treatment and to detect tumor recurrence after treatment, in conjunction with imaging such as CT or MRI,” Meija and Pasko wrote. 

As for intrahepatic cholangiocarcinoma, carbohydrate antigen 19-9 (CA19-9) is the most important tumor marker measured for the purpose of diagnosis; at a threshold of 100 U/mL or more, it has a sensitivity of 50% and a specificity of up to 90%. However, CA19-9 levels are not always elevated preoperatively, meaning that AFP and carcinoembryonic antigen (CEA) levels are usually taken as well. 

Read more about cholangiocarcinoma diagnosis 

Imaging studies are an essential part of the preoperative workup for both types of cancer. In intrahepatic cholangiocarcinoma, a typical CT scan of the liver reveals a hypodense, irregular lesion in the unenhanced phase. In the arterial phase, peripheral rim enhancement is typically observed; in the venous phase, progressive hyperattenuation can usually be seen. 

In hepatocellular carcinoma, CT or MRI usually reveals 1 of the following 2 features: nonrim arterial phase hyperenhancement between 10-19 mm in size with 2 additional major features, or nonrim arterial-phase hyperenhancement more than 20 mm in size with 1 or more major additional features. Major additional features are enhancing capsule, threshold growth (defined ≥50% size increase of a mass in 6 months), as well as nonperipheral washout. 

In summary, hepatocellular carcinomas and intrahepatic cholangiocarcinomas have clear differences in terms of epidemiology and diagnostic protocol. However, the incidence of both cancers are projected to continue to rise, with primary hepatic cancers projected to become the second leading cause of cancer deaths in the United States by the end of the decade. This means that education and screening programs will become increasingly important to counter the rising incidence of these cancers. 


Lee YT, Wang JJ, Luu M, et al. Comparison of clinical features and outcomes between intrahepatic cholangiocarcinoma and hepatocellular carcinoma in the United StatesHepatology. Published online November 5, 2021. doi:10.1002/hep.32007

Mejia JC, Pasko J. Primary liver cancers: intrahepatic cholangiocarcinoma and hepatocellular carcinomaSurg Clin North Am. Published online May 11, 2020. doi:10.1016/j.suc.2020.02.013