Incidence Of Intrahepatic Cholangiocarcinoma Research Articles

Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

Intrahepatic cholangiocarcinoma (ICC) incidence and mortality are increasing in the United States and worldwide. ICC etiologies involve chronic inflammation. We hypothesize that the nonsteroidal anti-inflammatory agent sulindac may prevent ICC by targeting cyclooxygenase-1 and -2 (COX-1, -2) as well as COX-independent pathways. ICC was induced with the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian golden hamsters. Cholangiocarcinogenesis was accelerated by a choline-deficient diet and administration of DL-ethionine and L-methionine. Hamsters were gavaged twice daily for 10 wk with vehicle or sulindac 25, 50, or 75 mg/kg/dose. Harvested livers underwent gross and histopathological examinations. Tissues were analyzed by immunostaining, Western blot, and enzyme-linked immunosorbent assay (ELISA). ICC incidence and multiplicity were decreased in sulindac treatment groups versus control (P < 0.05). In addition, ICC and nontumor lesion sizes decreased in treatment versus control animals. Proliferative indices (Ki-67 immunostaining) decreased and apoptosis (ApopTag immunostaining) increased in treatment versus control (P < 0.05). No changes in COX-1 and -2 protein levels were detected by Western blot. Furthermore, prostaglandin E(2) (PGE(2)) levels were unchanged in treatment and control serum and liver tissues (P > 0.05), suggesting that the antitumor effects of sulindac are mediated by COX-independent mechanisms. Nuclear p65 (activated NF-kappaB) immunostaining decreased (P < 0.05), and protein levels of the NF-kB inhibitor IkappaB-alpha increased in treatment versus control groups. p65 ELISA of liver extracts confirmed decreased NF-kappaB binding activity in sulindac-treated versus control animals (P < 0.05). Sulindac effectively prevents experimental cholangiocarcinogenesis, in part by inhibiting the NF-kappaB pathway.

Intrahepatic Cholangiocarcinoma

Despite data suggesting a rising worldwide incidence, intrahepatic cholangiocarcinoma (IHC) remains an uncommon disease. This study analyzes changes in IHC frequency, demographics, and treatment outcome in a consecutive and single institutional cohort. Consecutive patients with confirmed IHC seen and treated over a 16-year period were included. The trend in IHC frequency over the study period was compared with that of hilar cholangiocarcinoma patients (HCCA) seen during the same time. Demographics and patient disposition, histopathologic, treatment, recurrence, and survival data were analyzed; changes in these variables over time were assessed. From December 1990 through July 2006, 594 patients were evaluated (IHC = 270, HCCA = 324). Over the study period, the average annual increase in new IHC patients was 14.2% (P < 0.001). Relative to HCCA, the proportional increase in IHC was nearly 3-fold, and new IHC patients have outnumbered those with HCCA by 2:1 over the last 3 years. Conditions associated with IHC were rarely seen, with only 7 patients having a history of sclerosing cholangitis and/or inflammatory bowel disease and none with hepatolithiasis or biliary parasitic disease; however, heavy tobacco use (27%) and diabetes mellitus (16.4%) were particularly prevalent. The majority of patients were not candidates for resection, most commonly because of advanced hepatic disease. After resection (n = 82), median disease-specific survival was 36 months; recurrence was observed in 62.2% of patients at a median follow-up of 26 months, with the liver remnant involved most frequently (62.7%). Multiple hepatic tumors (P < 0.001), regional nodal involvement (P = 0.012), and large tumor size (P = 0.016) independently predicted poor recurrence-free survival. Most patients (n = 115, 73.7%) with unresectable disease were treated with chemotherapy, either systemic alone (n = 75) or combined with regional hepatic arterial floxuridine (FUDR) (n = 28). Compared with the first 10 years of the study (1990-2000), the last 6 years saw an overall improvement in disease-specific survival for all patients (22 vs. 12 months, P = 0.002), which was particularly notable for patients with unresectable disease (15 vs. 6 months, P = 0.003). At Memorial Sloan-Kettering Cancer Center, IHC incidence has increased dramatically in the last 16 years. Resection offers the best opportunity for long-term survival but is possible in the minority, and patients with large, node-positive or multifocal IHC seem to derive little benefit. Establishing and maintaining control of the intrahepatic disease remains the biggest problem for all IHC patients. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease.

Risk Factors for Intrahepatic and Extrahepatic Cholangiocarcinoma in the United States: A Population-Based Case-Control Study

Intrahepatic and extrahepatic cholangiocarcinomas are rare and highly malignant cancers of the bile duct. Although the incidence of extrahepatic cholangiocarcinoma (ECC) has remained constant, the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the United States. Because the etiology of both tumors is poorly understood, a population-based case-control study was conducted to examine the association of ECC and ICC with preexisting medical conditions. Medical conditions among 535 ICC patients, 549 ECC patients (diagnosed 1993-1999), and 102,782 cancer-free controls were identified by using the Surveillance, Epidemiology and End Results-Medicare databases. Logistic regression analysis was used to calculate adjusted odds ratios. In addition to established risk factors (choledochal cysts, cholangitis, inflammatory bowel disease), several other conditions were significantly associated with ECC and ICC: biliary cirrhosis (ECC, ICC: P < .001), cholelithiasis (ECC, ICC: P < .001), alcoholic liver disease (ECC, P < .001; ICC, P = .01), nonspecific cirrhosis (ECC, ICC: P < .001), diabetes (ECC, ICC: P < .001), thyrotoxicosis (ECC, P = .006; ICC, P = .04), and chronic pancreatitis (ECC, ICC: P < .001). Conditions only associated with ICC were obesity (ECC, P = .71; ICC, P = .01), chronic nonalcoholic liver disease (ECC, P = .08; ICC, P = .02), HCV infection (ECC, P = .67; ICC, P = .01), and smoking (ECC, P = .07; ICC, P = .04). Several novel associations with ECC and ICC were identified. HCV infection, chronic nonalcoholic liver disease, and obesity, all of which are increasing in incidence, and smoking were associated only with ICC, suggesting that these conditions might explain the divergent incidence trends of the tumors.

Risk factors for intrahepatic cholangiocarcinoma in a low‐risk population: A nationwide case‐control study

Recently, the incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing in a number of developed (Western) countries. However, risk factors in these low-risk populations are poorly understood. In this nationwide population based case-control study in Denmark, we examined the relationship between selected medical conditions and subsequent ICC risk to provide additional clues to etiopathogenesis. All histologically confirmed ICC cases diagnosed in Denmark between 1978 and 1991 were identified from the Danish cancer registry. Population controls were selected from the central population registry and were matched 4:1 to cases on sex and year of birth. Cases and controls were linked to the Danish hospital discharge registry to obtain information on prior hospital diagnoses. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived using conditional logistic regression. A total of 764 ICC cases and 3,056 population controls were included in the study. Chronic liver diseases were significantly related to ICC: alcoholic liver disease (OR = 19.22, 95% CI = 5.55-66.54), unspecified cirrhosis (OR = 75.9, 95% CI 10.2-565.7). Bile duct diseases were also associated with risk: cholangitis (OR = 6.3, 95% CI = 2.3-17.5), choledocholithiasis (OR = 23.97, 95% CI = 2.9-198.9), cholecystolithiasis (OR = 4.0, 95% CI = 2.0-7.99), though gallbladder removal did not change risk (OR = 1.6, 95% CI = 0.65-3.7). Among other conditions, chronic inflammatory bowel disease (OR = 4.7, 95% CI = 1.65-13.9) was significantly associated with ICC. Diabetes was associated with risk in the year prior to diagnosis of ICC (OR = 3.02, 95% CI = 1.05-8.69). Obesity was unrelated to risk. These results confirm that prior bile duct diseases increase risk of ICC and suggest that alcoholic liver disease and diabetes may also increase risk.

Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States.

Despite the global increase in the incidence of intrahepatic cholangiocarcinoma, regional variations occur. To assess the potential contribution of racial/ethnic factors, we assessed the epidemiology of these cancers in different racial and ethnic groups in the United States. Disease prevalence, mortality and survival rates for different racial and ethnic groups were obtained from the surveillance, epidemiology and end results survey database. The age-adjusted prevalence was highest for Hispanics (1.22 per 100 000) and lowest for Blacks (0.3 per 100 000). Age-adjusted mortality rates were higher for American Indian/Alaska Natives and Asian/Pacific Islanders compared with other groups. However, mortality rates increased by greater than 3.5% annual for all racial or ethnic groups except for American Indian/Pacific Islanders in whom mortality rates decreased by 0.2% annually. The increase in mortality rates was greatest for Hispanic women aged between 40 and 49 years. Prevalence and survival were significantly higher in Hispanic women in contrast to gender differences observed in other groups. Significant racial and ethnic variations occur in the epidemiology of intrahepatic cholangiocarcinoma within geographically defined regions in the United States These may reflect genetic, socioeconomic or cultural predispositions to cancer.

A Comparison of Trends in the Incidence of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma in the United States

The incidence rates of liver cancers, both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), are increasing in the U.S. It is possible that the increases are related to common exposures, and if so, similar trends in incidence by gender, age, ethnicity, and calendar period, might exist. To examine this hypothesis, age-specific trends in the incidence of HCC and ICC in the Surveillance, Epidemiology and End Results program (1976-2000) were examined by year of diagnosis and year of birth. Age-period-cohort models were also fit to the data. The incidence of HCC in the most recent time period was twice as high among Black men (8.8/100,000) and women (2.6/100,000) as among White men (4.6/100,000) and women (1.2/100,000). However, between 1976 and 2000, incidence among all four ethnic- and gender-specific groups increased by >90% (White males, 123.2%; White females, 96.8%; Black males, 97.9%; Black females, 91.9%) with young White men experiencing the greatest increases (432%). In contrast, ICC rates were similar for Black (0.93/100,000) and White men (0.92/100,000), but higher for White (0.57/100,000) than Black women (0.39/100,000). Although ICC incidence increased among all groups, the increase was greatest for Black men (138.5%), followed by White men (124.4%), White women (111.1%), and Black women (85.7%) Age-period-cohort analyses of HCC revealed a significant cohort effect among younger men (45-65 years old), but not older men (65-84 years old), suggesting possible differences in etiology. In conclusion, the rates of HCC and ICC approximately doubled between 1976 and 2000. Trends by age, gender, ethnicity, and birth cohort suggest that heterogeneity exists in the factors influencing these rates.

Risk factors of intrahepatic cholangiocarcinoma in the United States: A case-control study

The incidence of intrahepatic cholangiocarcinoma has been recently increasing in the United States. In this case-control study, we used the Surveillance, Epidemiology, and End Results-Medicare database to evaluate the prevalence of known risk factors for intrahepatic cholangiocarcinoma and explore other potential risk factors. We identified all patients with intrahepatic cholangiocarcinoma aged 65 years and older diagnosed between 1993 and 1999 in the population-based Surveillance, Epidemiology, and End Results registries (14% of the US population). Controls were randomly chosen from individuals without any cancer diagnosis in the underlying population of the Surveillance, Epidemiology, and End Results regions. We obtained information on risk factors from Medicare claims (parts A and B) for all cases and controls with at least 2 years of continuous Medicare enrollment. Unadjusted and adjusted odds ratios were calculated in logistic regression analysis. A total of 625 cases and 90,834 controls satisfied the inclusion and exclusion criteria. Cases were older than controls (78.7 vs. 76.5 years; P=.02) and were more likely to be male (48.3% vs. 36.8%; P <.0001). The racial composition was similar between cases and controls. Several risk factors were significantly more prevalent among cases. These included nonspecific cirrhosis (adjusted odds ratio, 27.2; P <.0001), alcoholic liver disease (adjusted odds ratio, 7.4; P <.0001), hepatitis C virus infection (adjusted odds ratio, 6.1; P <.0001), human immunodeficiency virus infection (adjusted odds ratio, 5.9; P=.003), diabetes (adjusted odds ratio, 2.0; P <.0001), and inflammatory bowel diseases (adjusted odds ratio, 2.3; P=.002). This population-based study shows that in addition to previously well described risk factors, several others could be associated with intrahepatic cholangiocarcinoma. These include hepatitis C virus, human immunodeficiency virus, liver cirrhosis, and diabetes.

An increasing incidence of cholangiocarcinoma: Why?

An increasing incidence of cholangiocarcinoma: Why?

The epidemiology of cholangiocarcinoma.

The incidence rates of cholangiocarcinoma (CC) vary greatly among different areas of the world, and this variation is related to distribution of risk factors. Intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) have different epidemiological features. Recent data show that the incidence and mortality rates of ICC have been increasing in several areas around the world. On the other hand, the incidence and mortality rates of ECC have been decreasing. For example, in the United States, the age-adjusted incidence rates of ICC increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in 1995 to 1999, whereas ECC declined by 14%. In the meantime, there has been very little improvement in long-term survival, which remains dismal (3.5%). Men are affected 1.5 times more than women are, and Asians are affected almost 2 times more than whites and blacks. There are few well-established risk factors for CC, including primary sclerosing cholangitis, liver fluke infestations, hepatolithiasis, Thorotrast exposure, and choledochal cysts. None of these risk factors can explain the recent increasing trends of ICC in the United States. Some data, however, point to a potential role for chronic liver disease, hepatitis C, and probably hepatitis B infections in the development of ICC.

Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase?

Background/ Aims: The incidence of intrahepatic cholangiocarcinoma (ICC) has been reported to be increasing in the USA. The aim of this study is to examine whether this is a true increase or a reflection of improved detection or reclassification. Methods: Using data from the Surveillance Epidemiology and End Results (SEER) program, incidence rates for ICC between 1975 and 1999 were calculated. We also calculated the proportions of cases with each tumor stage, microscopically confirmed cases, and the survival rates. Results: A total of 2864 patients with ICC were identified. The incidence of ICC increased by 165% during the study period. Most of this increase occurred after 1985. There were no significant changes in the proportion of patients with unstaged cancer, localized cancer, microscopic confirmation, or with tumor size <5 cm during the period of the most significant increase. The 1-year survival rate increased significantly from 15.8% in 1975–1979 to 26.3% in 1995–1999, while 5-year survival rate remained essentially the same (2.6 vs. 3.5%). Conclusions: The incidence of ICC continues to rise in the USA. The stable proportions over time of patients with early stage disease, unstaged disease, tumor size <5 cm, and microscopic confirmation suggest a true increase of ICC.

Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland

The mortality from intrahepatic cholangiocarcinoma has increased recently in England and Wales and elsewhere. This study aims to examine recent trends in the incidence of intrahepatic cholangiocarcinoma in Scotland, to assess the extent to which changes in diagnostic practice may be influencing the observed trends, and to consider whether the results are compatible with a genuine increase in the risk of this cancer. Cancer registration (intrahepatic cholangiocarcinoma and anatomically adjacent cancers) data from Scotland 1968–1997 were analysed, including examination of trends in the percentage of cases recorded as being microscopically-verified. Since the late 1960s, the incidence of intrahepatic cholangiocarcinoma has increased approximately eight-fold in both sexes in Scotland. However, the proportion of cases verified microscopically has decreased substantially since the late 1970s, presumably due to an increasing reliance on radiological imaging for diagnosis. Despite this change in diagnostic practice, the incidence of microscopically-verified intrahepatic cholangiocarcinoma has also increased. While changes in diagnostic practice and misclassification could explain, at least part of, the observed increase in incidence of intrahepatic cholangiocarcinoma, a genuine increase in the risk of this cancer in the Scottish population seems probable. Further work is indicated to examine international trends in incidence, and to assess whether incidence differs within countries according to characteristics such as area of residence, socio-economic status, ethnic origin or occupation.