The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An Update

By H. B. EL‐SERAG, J. Davila, N. Petersen, K. McGlynn. Annals of Internal Medicine, 2003

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Context Incidence rates of hepatocellular carcinoma have been increasing in the United States. Contribution This large, retrospective, population-based cohort study confirmed an almost 2-fold increase in the incidence of hepatocellular carcinoma from 1975 to 1998. Increases were seen in all ethnic groups and in most age groups after 40 years of age. Although black people and older people remained most at risk, the largest recent increase in rates (from 1995 to 1998) occurred in white men 45 to 54 years of age. Implications The incidence of hepatocellular carcinoma continues to increase rapidly in the United States, especially in white, middle-aged men. The Editors We previously reported an increase in the incidence and mortality rates of hepatocellular carcinoma in the United States (1). Studies among U.S. hospitalized veterans, as well as those conducted in large single centers, indicated that approximately half of the observed increase was attributable to hepatitis C virus (HCV) infection, whereas the incidence of hepatocellular carcinoma related to hepatitis B virus (HBV), alcoholic liver disease, or idiopathic cirrhosis remained relatively stable (2, 3). If HCV were indeed responsible for the increasing rates of hepatocellular carcinoma, this increase would be expected to continue for at least several more years since 2 to 4 decades of chronic HCV infection is required to develop cirrhosis and subsequent hepatocellular carcinoma (4). On the other hand, if the increased rates of hepatocellular carcinoma were related to better detection due to technologically improved diagnostic testing, such an effect would be expected to plateau at some point in the future. The observed increase in hepatocellular carcinoma could have other explanations. Changes in the demographic structure (age, sex, ethnicity, and geography) of the underlying population may have resulted in an increasing number of persons at high risk for hepatocellular carcinoma (older age and increased number of ethnic and racial minorities). Hepatocellular carcinoma is an age-dependent cancer that peaks in incidence between 75 and 79 years of age, and direct standardization methods may not have been sufficient to control for the effect of aging in the underlying population (5). The observed increase could also have resulted from an increase in high-risk sex or racial or ethnic groups or the population residing in 1 or a few high-risk geographic regions (6). For example, rates of hepatocellular carcinoma were severalfold higher in Asian Americans than in white people, and African Americans had rates between those of the other 2 groups (1). The current study was designed to update the recent trends in hepatocellular carcinoma incidence by using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries and to examine the temporal trends in hepatocellular carcinoma through adjustments for potential changes in several influential factors. Methods Data Sources: SEER Beginning in 1973, the SEER registry program was established to identify all new cancer cases diagnosed in 7 geographic areas. By 1975, SEER included 9 geographic regions, 5 states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) and 4 metropolitan areas (San FranciscoOakland in California; SeattlePuget Sound in Washington; Detroit, Michigan; and Atlanta, Georgia). In 1992, the Los Angeles County and San JoseMonterey areas in California joined the SEER program, expanding the representation to approximately 14% of the U.S. population. Overall, the SEER population is similar to the general U.S. population, particularly in measures of poverty and education. However, SEER regions are more urban and have a higher proportion of foreign-born persons than the general U.S. population. Data for this study were obtained from SEER*STAT public-use data files (National Cancer Institute, Bethesda, Maryland), available on CD-ROM from the National Cancer Institute (7). Data from the SEER public-use CD-ROM were converted into SAS datasets for further analyses (SAS software, version 8.2, SAS Institute, Inc., Cary, North Carolina). Demographic and cancer-related information included in this database are obtained by medical record review. Studies are conducted annually at each SEER registry site to verify that data are being collected accurately and that case ascertainment is at least 98%. Types of cancer are coded according to the International Classification of Disease for Oncology (ICD-O) (8). There are several categories of race or ethnicity, including Hispanic white, non-Hispanic white, Chinese, Japanese, Filipino, Pacific Islander, and American Indian. However, accurate information on the underlying population in the areas covered by the SEER program is available only on race classified as white (which includes Hispanic), black, or other (which includes all other ethnic groups listed). As a result, valid incidence rates can be calculated for only these 3 broad racial or ethnic groups (white, black, and other). Study Sample Patients eligible for inclusion in this study were all individuals with hepatocellular carcinoma (ICD-O code 8170) identified from 9 SEER registries between 1975 and 1998. Patients younger than 20 years of age were excluded to avoid including those with hepatoblastoma (<1% of total cases). Cases in which the patient's race or ethnicity was unknown (<1% of total cases) also were excluded. To examine the potential role of diagnostic bias, we calculated the proportion of cases with microscopic confirmation, which is defined by SEER as the presence of a confirmatory histologic or cytologic evidence of hepatocellular carcinoma. Statistical Analysis The age-adjusted incidence rates for hepatocellular carcinoma were calculated for 3-year periods between 1975 and 1998. Sex- and ethnicity-specific, age-adjusted incidence rates and their 95% CIs were calculated. Adjustment was made to the 1990 U.S. population. Age-specific incidence rates were calculated for all patients and for each of the 3 broad categories of race or ethnicity (white, black, and other). Among patients with hepatocellular carcinoma, we calculated the proportions of cases belonging to the following racial or ethnic groups: Hispanic white, non-Hispanic white, Asian (Chinese, Japanese, Filipino, or Pacific Islander), and others. We also calculated the proportion of patients with liver cancer who had microscopic confirmation for each time period. These calculations were made by using the SEER*STAT statistical software (7). The temporal trends of the incidence of hepatocellular carcinoma were examined in linear Poisson multivariate regression models. We used SAS PROC GENMOD for this task. The model was used to analyze the effect of the period of diagnosis (independent variable) on the incidence of hepatocellular carcinoma (dependent variable), while controlling for several other independent variables including age (20 to 49, 50 to 64, 65 to 74, or 75 years), sex, race or ethnicity (white, black, or other), and differences in the geographic regions (9 SEER registries). Similar categories were assembled for the underlying population and were included as an offset variable in the model. Risk estimates (incidence rates and incidence rate ratios) and 95% CIs were calculated for all the independent variables in the final model. The model was tested for interactions between time of diagnosis and each variable of age, sex, and race or ethnicity. Role of the Funding Source The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Between 1975 and 1998, there were 11 547 cases of hepatocellular carcinoma. The overall age-adjusted incidence rates of hepatocellular carcinoma started to increase in the early 1980s, from 1.3 per 100 000 persons in 1981 to 1983 to 3.0 per 100 000 persons in 1996 to 1998 (Figure 1). This is equivalent to a 114% overall increase throughout the study period. There was a 25% increase during the last 3 years of the study (1996 to 1998) compared with the previous 3 years (1993 to 1995). The proportions of patients with liver cancer who underwent microscopic confirmation were relatively stable during the study period: 86%, 86%, 84%, 82%, 78%, and 80% in consecutive 3-year periods between 1981 and 1998, respectively. All hepatocellular carcinoma cases were included in subsequent analyses regardless of microscopic confirmation. Figure 1. The overall age-adjusted incidence rates for hepatocellular carcinoma for consecutive 3-year periods between 1975 and 1998. In addition to the variable of more recent time period, age, sex, race or ethnicity, and geographic region were statistically significant determinants of the incidence of hepatocellular carcinoma. Hepatocellular carcinoma was rare among individuals younger than 40 years of age, and the incidence peaked at 75 to 79 years of age. Concomitant with the increase in incidence, the age distribution of patients with hepatocellular carcinoma progressively shifted toward relatively younger persons. Figure 2 shows the temporal changes in the age distribution of new cases of hepatocellular carcinoma in men, with age-specific incidence rates for consecutive 3-year periods from 1975 to 1998. The incidence has increased in most age groups older than 40 years; the greatest increase occurred in patients 45 to 55 years of age. For example, in the 1990s, the incidence rates increased 110% among white men 45 to 49 years of age and 60% among white men 50 to 54 years of age (Figure 3). Similar trends were seen for women (data not shown); the greatest increase in incidence occurred in women 60 to 69 years of age. Figure 2. Age-adjusted incidence rates for hepatocellular carcinoma broken down by sex and race or ethnicity for consecutive 3-year periods between 1975 and 1998. Figure 3. Temporal trends in the age distribution of hepatocellular carcinoma. Throughout

Subfields: Epidemiology, Hepatology

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  1. T. Tamimi
  2. R. Lopez
  3. Ariel F. Feldstein
  4. N. Zein
  5. Jasmin A. Tiro
  6. Amit G. Singal
  7. Mustafa S. Ascha
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In Hepatology

  1. R. Lopez
  2. Jasmin A. Tiro
  3. Amit G. Singal
  4. A. Pillai
  5. Megan H. Bair-Merritt
  6. D. Lavanchy

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