BETHESDA, MD — Intrahepatic cholangiocarcinoma (ICC), the second most commonly occurring liver cancer after hepatocellular carcinoma (HCC), is becoming an increasingly important contributor to liver cancer incidence in the United States, and the increases are most notable in females, according to a new study.
Researchers from the Uniformed Services University of the Health Sciences and the Henry M. Jackson Foundation for the Advancement of Military Medicine, both in Bethesda, MD, noted with colleagues that their previous studies highlighted the contrasting trends in ICC and HCC incidence in recent decades.1
“Although HCC incidence has declined, ICC incidence has risen,” the authors wrote in Clinical Gastroenterology & Hepatology. “Recent analyses have reported that overall liver cancer rates continue to rise among females. To determine whether ICC underlies this increase, we examined long-term trends in ICC incidence and mortality in the U.S. by sex and other demographic characteristics from 1992 to 2022.”1
They used the Surveillance, Epidemiology, and End Results (SEER) program to determine ICC incidence and incidence-based mortality data, finding that, in 2022, the overall age-standardized ICC incidence rate (ASIR) was 2.08 per 100,000, and rates were similar in males (2.19) and females (2.00). “Incidence increased with age, with the highest rates occurring among older adults 70 to 89 years old. In terms of race and/or ethnicity, no major differences were observed, although the highest rates occurred among Hispanics, followed by American Indian or Alaska Native individuals. The lowest rates were among Black patients. The incidence was found to be slightly higher in urban areas than in rural areas.
Overall, the authors advised, mortality rates mirrored incidence rates, with an overall age-standardized mortality rate of 1.73 per 100,000 (males, 1.88; females, 1.63).
“Over the 31-year period, ICC incidence rose, with some fluctuations over time,” the study explained. “There was an initial increase from 1992 to 1998 (estimated annual percentage change [EAPC], 3.50), a decline between 1999 and 2001 (EAPC, -7.53), then rates began a sustained increase starting in 2002 (EAPC, 4.70). Among males, incidence increased from 2003 to 2016 (EAPC, 5.22), then rose more modestly thereafter (EAPC, 1.89). Among females, rates increased continuously starting in 2003 (EAPC, 5.06). The parallelism test found that the trends by sex differed significantly (P = 0.003).”
The investigators also noted that age-specific rates for the 1955 to 1964 birth cohort were the highest of all cohorts, with the oldest members of the 1955 to 1964 cohort (67 years old) not yet attaining the ages of peak ICC incidence (70-89 years) by 2022.
“In notable contrast to ICC, HCC incidence rates are much higher among males (ASIR, 8.62) than females (ASIR, 2.80),” the authors wrote. “HCC incidence has been declining since 2015 (EAPC, −3.52), with a more pronounced decrease among males (EAPC, −3.16 since 2012) than females (EAPC, −1.95 since 2013). By 2022, the incidence of ICC had become nearly the same as the incidence of HCC among females (HCC:ICC ratio, 1.4), but not among males (HCC:ICC ratio, 3.9).”
They said the explanation for the opposing trends in HCC and ICC is not clear, especially because the two types of liver cancer share a number of common risk factors, such as hepatitis B virus, hepatitis C virus and metabolic dysfunction-associated steatotic liver disease, with most of the factors more strongly associated with HCC than ICC.
The study explained that ICC is also associated with a number of bile duct conditions, especially primary sclerosing cholangitis (PSC), adding that the incidence and prevalence of PSC appears to have been increasing. “Although PSC is more common among males, PSC survival is more favorable among females, suggesting that females could be at higher long-term risk of ICC as a result,” according to the researchers, who added, “It is also possible that other, as yet unidentified, environmental risk factors for ICC may be driving risk. In addition, better diagnosis of ICC may be influencing the rising rates. Better diagnosis over time would be consistent with the calendar period effect on risk identified in the age-period-cohort analysis.”
- Alvarez CS, Wojt A, Almeida AA, Miller JS, Graubard BI, Petrick JL, McGlynn KA. Rising Intrahepatic Cholangiocarcinoma Rates in the United States Are Driving Liver Cancer Rates in Females. Clin Gastroenterol Hepatol. 2025 Dec 22:S1542-3565(25)01060-2. doi: 10.1016/j.cgh.2025.12.013. Epub ahead of print. PMID: 41443525.
