Jessica A. Davila

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

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 patients 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

Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study

Background: Diabetes has been associated with an increased risk of hepatocellular carcinoma (HCC) in studies of referred patients. This is the first population based case control study in the USA to examine this association while adjusting for other major risk factors related to HCC. Methods: We used the Surveillance Epidemiology and End-Results Program (SEER)-Medicare linked database to identify patients aged 65 years and older diagnosed with HCC and randomly selected non-cancer controls between 1994 and 1999. Only cases and controls with continuous Medicare enrolment for three years prior to the index date were examined. Inpatient and outpatient claims files were searched for diagnostic codes indicative of diabetes, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease, and haemochromatosis. HCC patients without these conditions were categorised as idiopathic. Unadjusted and adjusted odds ratios were calculated in logistic regression analyses. Results: We identified 2061 HCC patients and 6183 non-cancer controls. Compared with non-cancer controls, patients with HCC were male (66% v 36%) and non-White (34% v 18%). The proportion of HCC patients with diabetes (43%) was significantly greater than non-cancer controls (19%). In multiple logistic regression analyses that adjusted for demographics features and other HCC risk factors (HCV, HBV, alcoholic liver disease, and haemochromatosis), diabetes was associated with a threefold increase in the risk of HCC. In a subset of patients without these major risk factors, the adjusted odds ratio for diabetes declined but remained significant (adjusted odds ratio 2.87 (95% confidence interval 2.49–3.30)). A significant positive interaction between HCV and diabetes was detected (p<0.0001). Similar findings persisted in analyses restricted to diabetes recorded between two and three years prior to HCC diagnosis. Conclusions: Diabetes is associated with a 2–3-fold increase in the risk of HCC, regardless of the presence of other major HCC risk factors. Findings from this population based study suggest that diabetes is an independent risk factor for HCC.

The Epidemiology of Malignant Gastrointestinal Stromal Tumors: An Analysis of 1,458 Cases from 1992 to 2000

OBJECTIVES:The epidemiology of gastrointestinal stromal tumor has not been well examined, and prior studies often provide conflicting results. We conducted the first population-based study to evaluate the incidence and survival of malignant gastrointestinal stromal tumor in the United States.METHODS:We utilized the Surveillance, Epidemiology, and End Results registry from the National Cancer Institute to identify all cases of malignant gastrointestinal stromal tumor diagnosed from 1992 to 2000. The age-adjusted incidence rates and the survival rates were calculated. Cox proportional hazards models were used to examine the risk of mortality.RESULTS:Between 1992 and 2000, there were 1,458 cases of diagnosed gastrointestinal stromal tumor. The age-adjusted yearly incidence rate was 0.68/100,000. The mean age at diagnosis was 63 yr. Fifty-four percent were men and 46% were women. The incidence rate was higher among men and among Blacks. Fifty-one percent of cases were in the stomach, 36% small intestine, 7% colon, 5% rectum, and 1% in the esophagus. Fifty-three percent of cases were staged as localized, 19% regional, 23% distant, and 5% unstaged. The 1- and 5-yr relative survival rates were 80% and 45%, respectively. The Cox analysis showed that older age, Black race, advanced stage, and receipt of therapy were independent predictors of mortality.CONCLUSION:Malignant gastrointestinal stromal tumors rare, but are more common in the older population, men, and Blacks. Risk factors for mortality include older age, Black race, advanced stage, and no surgical intervention.

Metabolic syndrome increases the risk of primary liver cancer in the United States: A study in the SEER‐medicare database

Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilsons disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases, and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, P < 0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio = 2.13; 95% confidence interval = 1.96‐2.31, P < 0.0001) and ICC (odds ratio = 1.56; 95% confidence interval = 1.32‐1.83, P < 0.0001). Conclusion: Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population. (HEPATOLOGY 2011;)

Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States

Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown. We conducted a population‐based United States cohort study of patients over 65 years of age to examine use and determinants of prediagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994‐2002 were identified from the linked Surveillance, Epidemiology, and End‐Results registry–Medicare databases. We identified alpha‐fetoprotein (AFP) and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance. We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% received inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both AFP and ultrasound, 46% received AFP only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5‐fold and 2.8‐fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors. Conclusion: Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance. HEPATOLOGY 2010

Utilization of Surveillance for Hepatocellular Carcinoma Among Hepatitis C Virus–Infected Veterans in the United States

BACKGROUND Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown. OBJECTIVE To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States. DESIGN Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry. SETTING 128 VA medical centers. PATIENTS HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005. MEASUREMENTS Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression. RESULTS 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance. LIMITATIONS Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured. CONCLUSION Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice. PRIMARY FUNDING SOURCE Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.

Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study

There have been no population‐based studies of the epidemiology and prognosis of patients with fibrolamellar carcinoma (FLC). We conducted a retrospective cohort study using information collected by population‐based registries of the Surveillance, Epidemiology, and End Results (SEER) program. The demographic features, stage at diagnosis, and type of therapy, as well as age‐adjusted incidence rates and observed and relative survival rates were compared between persons with FLC and those with hepatocellular carcinoma (HCC) diagnosed between 1986 and 1999. A multivariate Cox proportional hazards model was constructed to examine the effect of histology (FLC vs. HCC) on the risk of mortality. There were 68 microscopically confirmed cases of FLC and 7,896 cases of HCC. FLC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases below the age of 40. Compared to HCC, patients with FLC were more likely to be younger (mean age 39 vs. 65), female (51.5% vs. 26.3%), and white (85.3% vs. 56.9%). A greater proportion of case with FLC had localized disease (41.2% vs. 30.9%), or received potentially curative therapy (resection, transplantation), compared to cases with HCC. The age‐adjusted incidence rate for FLC was 0.02 per 100,000; No significant differences in age‐adjusted incidence rates were observed by gender or race. The 1‐ and 5‐year observed and relative survival rates were significantly longer in patients with FLC than HCC. The 5‐year relative survival rate was 31.8% (95% CI, 20.5%‐43.1%) for FLC, compared with 6.8% (95% CI, 6.3 %‐7.4 %) for HCC. Adjusting for differences in age, gender, race, stage of disease, receipt of resection or transplantation, and time of diagnosis, FLC was independently associated with a 46% reduction in risk of mortality within 5years compared with HCC. In conclusion, in a population‐based study, we observed remarkable differences in the epidemiology and prognosis of FLC compared to HCC. (HEPATOLOGY 2004;39:798–803.)

The validity of viral hepatitis and chronic liver disease diagnoses in Veterans Affairs administrative databases

Background  The validity of International Classification of Diseases‐9 codes for liver disease has not been determined.

Population-Attributable Fractions of Risk Factors for Hepatocellular Carcinoma in the United States

OBJECTIVES:Risk factors for hepatocellular carcinoma (HCC) include hepatitis B and C viruses (HBV, HCV), excessive alcohol consumption, rare genetic disorders and diabetes/obesity. The population attributable fractions (PAF) of these factors, however, have not been investigated in population-based studies in the United States.METHODS:Persons ≥68 years diagnosed with HCC (n=6,991) between 1994 and 2007 were identified in the SEER-Medicare database. A 5% random sample (n=255,702) of persons residing in SEER locations were selected for comparison. For each risk factor, odds ratios (ORs), 95% confidence intervals (95% CI) and PAFs were calculated.RESULTS:As anticipated, the risk of HCC was increased in relationship to each factor: HCV (OR 39.89, 95% CI: 36.29–43.84), HBV (OR 11.17, 95% CI: 9.18–13.59), alcohol-related disorders (OR 4.06, 95% CI: 3.82–4.32), rare metabolic disorders (OR 3.45, 95% CI: 2.97–4.02), and diabetes and/or obesity (OR 2.47, 95% CI: 2.34–2.61). The PAF of all factors combined was 64.5% (males 65.6%; females 62.2%). The PAF was highest among Asians (70.1%) and lowest among black persons (52.4%). Among individual factors, diabetes/obesity had the greatest PAF (36.6%), followed by alcohol-related disorders (23.5%), HCV (22.4%), HBV (6.3%) and rare genetic disorders (3.2%). While diabetes/obesity had the greatest PAF among both males (36.4%) and females (36.7%), alcohol-related disorders had the second greatest PAF among males (27.8%) and HCV the second greatest among females (28.1%). Diabetes/obesity had the greatest PAF among whites (38.9%) and Hispanics (38.1%), while HCV had the greatest PAF among Asians (35.4%) and blacks (34.9%). The second greatest PAF was alcohol-related disorders in whites (25.6%), Hispanics (30.1%) and blacks (and 18.5%) and HBV in Asians (28.5%).CONCLUSIONS:The dominant risk factors for HCC in the United States among persons ≥68 years differ by sex and race/ethnicity. Overall, eliminating diabetes/obesity could reduce the incidence of HCC more than the elimination of any other factor.

Measuring Retention in HIV Care: The Elusive Gold Standard

Background:Measuring retention in HIV primary care is complex, as care includes multiple visits scheduled at varying intervals over time. We evaluated 6 commonly used retention measures in predicting viral load (VL) suppression and the correlation among measures. Methods:Clinic-wide patient-level data from 6 academic HIV clinics were used for 12 months preceding implementation of the Centers for Disease Control and Prevention/Health Resources and Services Administration (CDC/HRSA) retention in care intervention. Six retention measures were calculated for each patient based on scheduled primary HIV provider visits: count and dichotomous missed visits, visit adherence, 6-month gap, 4-month visit constancy, and the HRSA HIV/AIDS Bureau (HRSA HAB) retention measure. Spearman correlation coefficients and separate unadjusted logistic regression models compared retention measures with one another and with 12-month VL suppression, respectively. The discriminatory capacity of each measure was assessed with the c-statistic. Results:Among 10,053 patients, 8235 (82%) had 12-month VL measures, with 6304 (77%) achieving suppression (VL <400 copies/mL). All 6 retention measures were significantly associated (P < 0.0001) with VL suppression (odds ratio; 95% CI, c-statistic): missed visit count (0.73; 0.71 to 0.75, 0.67), missed visit dichotomous (3.2; 2.8 to 3.6, 0.62), visit adherence (3.9; 3.5 to 4.3,0.69), gap (3.0; 2.6 to 3.3, 0.61), visit constancy (2.8; 2.5 to 3.0, 0.63), and HRSA HAB (3.8; 3.3 to 4.4, 0.59). Measures incorporating “no-show” visits were highly correlated (Spearman coefficient = 0.83–0.85), as were measures based solely on kept visits (Spearman coefficient = 0.72–0.77). Correlation coefficients were lower across these 2 groups of measures (range = 0.16–0.57). Conclusions:Six retention measures displayed a wide range of correlation with one another, yet each measure had significant association and modest discrimination for VL suppression. These data suggest there is no clear gold standard and that selection of a retention measure may be tailored to context.