Increasing Incidence of Gallbladder Cancer among Non-Hispanic Blacks in the United States: A Birth Cohort Phenomenon

Gallbladder cancer is the most common neoplasm arising within the biliary tract representing 80% to 90% of all biliary tract cancers globally (1). However, in the United States (US), gallbladder cancer represents only 40% to 50% of biliary tract cancers (2, 3). Because of a lack of symptoms in early stages of the disease and lack of sensitive screening tests for early detection, only a small proportion of patients with gallbladder cancer present with early-stage disease amenable to surgical resection. As a result, overall survival for patients with gallbladder cancer is poor (5-year survival <20%; ref. 4).

According to GLOBOCAN data, the worldwide annual incidence rate of gallbladder cancer is approximately 3 per 100,000 person-years (2). However, there are marked geographic variations in annual gallbladder cancer incidence rates and also has well documented sex and racial/ethnic disparities (5). The incidence in the US is relatively low, with a rate of 1.7 per 100,000 person-years females and 1.0 per 100,000 person-years males (6). The disparity between males and females is also found to be greater in the US than around the world (5). Some studies in the US have found gallbladder cancer to be more common among non-Hispanic whites (NHW) than non-Hispanic Blacks (NHB; refs. 7, 8), whereas other studies have found it to be more common among NHBs in the Northeast and Midwest US Census regions (7). Geographic variations in the prevalence of gallstones also contribute to the global patterns in gallbladder cancer incidence (9).

In the US, studies investigating temporal trends in gallbladder cancer incidence rates have in general relied on data from select state cancer registries in the SEER Program, for example, either the SEER 9 (10), SEER 13 (11), or SEER 18 (12) registries (3, 6, 13–15). The total number of registries in SEER 18 covers less than half of the US population from few geographic regions (48%; ref. 16), and this can impact the generalizability of its results particularly for cancers with underlying differences in incidence among race/ethnic groups and geographic regions. Recently, data from 38 cancer registries in the US representing 85% of the population have examined gallbladder cancer trends and uncovered disparate rates among different race/ethnic groups, in particular increasing incidence rates among NHBs (17). Hence, examining data from all states with maximum coverage will further broaden the representativeness of nationwide gallbladder cancer trends. Therefore, this study investigated incidence rates and trends for gallbladder cancer by using data from 50 United States for the period from 2001 to 2018. We stratified the analyses by different age-groups and race/ethnicity, both sex, and geographical region. In addition, we carried out age–period-cohort analyses to better differentiate age effects, period effects and cohort effects on the trends in gallbladder cancer incidence rates overall, and specifically by race/ethnicity.

The gallbladder cancer cases were collected from 2001 to 2018 through the US Cancer Statistics (USCS) registry (18). The USCS registry comprises data obtained from registries in National Program of Cancer Registries (NPCR) of Centers for Disease Control's, as well as National Cancer Institute's (NCI) SEER Program that allows access to data on 98% of cancer cases in the US (19). SEER is commonly judged as the gold standard for reliable and quality data among the US cancer registries. Quality is upheld through prescribed agreements with different regional registries, one that requires that SEER's standards must be maintained before the data are accessible (19). We included cases defined by the SEER*Stat software version 8.3.9 (20) primary site labeled for Gallbladder (ICD-O-3 site C23.9). We merged the incidence data for patients who were younger than 35 years with 35 to 39 years old (defined as “< 40”). This was done due to the small number of cases per year among individuals younger than 35, and the SEER/NPCR practice of suppressing cancer counts below 16. Results were stratified for age (<40, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74, 75–79, 80–84, and ≥85), both sexes, and by race/ethnicity [NHWs, NHBs, Hispanics, American Indians/Alaska Natives (AI/AN), and Asians and Pacific Islanders (API)].

To examine the incidence trends in different US geographical areas, we used US Census Bureau's classification that divides 50 states into four regions (21) namely Northeast; Midwest; South; and West (Supplementary Table S1). There were also cancer registries from the US that had missing reporting years because reported cases were less than 16 and hence state-based examination was not carried out for these registries. However, these gallbladder cancer cases were included when we pooled the state-wide data on regional level (Supplementary Table S2). We examined the geographical trends in three time periods (each including cases for a 5-year calendar period): 2001 to 2006, 2007 to 2012, and 2013 to 2018.

SEER*Stat was used to compute annual incidence rates with a formula implemented in the software. Number of cases were used as numerator and the population size was used as person-years based on US Census Bureau Data (18). The Tiwari method was applied for computing associated 95% confidence intervals (CI; ref. 22). The results are presented as age group–specific and age-standardized incidence rates and 2000 US standard population was used.

Using the year of diagnosis as a regressor variable, we fitted a least-squares regression line to the natural logarithm of the incidence rate for estimating the annual percentage of change (APC) in gallbladder cancer incidence rates. The regression line required a maximum of two joinpoints and a minimum of four observations between those joinpoints (23). For each joinpoints combination, we used Monte Carlo permutation tests to examine trends, and the best fitted trend line for the data was selected (24). We used Joinpoint Trend analysis Software to estimate APC values for each linear segment along with the values of average APC (AAPC) between 2001 and 2018 (25). For AAPC computation, a weighted average of the slope coefficients of the underlying joinpoint regression line was used with the weights equal to the length of each segment over the interval (26).

To search for patterns in secular incidence trends, we used age–period-cohort models to account for age at diagnosis (age), year of diagnosis (period), and year of birth (cohort). NCI's age–period-cohort web tool was used to fit these models and provided estimates of net drifts (i.e., APC in expected age-adjusted rates over time), local drifts (i.e., APC in expected age-specific rates over time), and cohort rate ratios (i.e., ratio of age-specific rates in each birth cohort relative to the reference cohort). It also enabled testing of equality of observed trends (27). Another advantage of the APC model is that it provides a unique set of best-fitting log-incidence rates through the use of maximum likelihood estimators into APC model formulation (27). We used 11 5-year age groups (<40 years to 85+ years), and three 5-year calendar periods (2001–2006 through 2013–2018). Incidence rate ratios (IRR) by birth cohorts were computed in 5-year increments starting from 1916 to 1921. Default reference groups were used for comparisons (i.e., calendar period, 2005–2008; and birth cohort, 1946). Age–period-cohort analyses were conducted among all patients combined, and separately for NHWs, NHBs and Hispanics. Age–period-cohort analyses were not performed separately among other racial/ethnic sub-groups due to small number of gallbladder cancer cases.

The data generated in this study are publicly available in National Cancer Institute's SEER Program through SEER*Stat, including the number of records, percentage of U.S. population covered, geographic regions included, and a dictionary of SEER variables available at https://seer.cancer.gov/data-software/documentation/seerstat/

Between 2001 and 2018, 68,206 individuals were diagnosed with gallbladder cancer in the US as per the USCS registry with an age-standardized incidence rate of 1.59 per 100,000 person-years (total person-years: 4,039,776,597). New cases increased from 3,333 in 2001 to 4,342 in 2018, an increase of 30.3% in absolute number of cases (Table 1). However, the age-standardized incidence rate for gallbladder cancer decreased from 1.67 per 100,000 person-years (95% CI, 1.62–1.73) in 2001 to 1.54 per 100,000 person-years (95% CI, 1.49–1.59) in 2018. Overall, the age-standardized incidence rate for gallbladder cancer decreased by 0.3% annually between 2001 and 2018 (APC, −0.3%; 95% CI, −0.5 to −0.1; Table 2). Joinpoint regression did not identify any significant inflection point, indicating a linear decline during the study period.

Overall, age-specific incidence rates for gallbladder cancer increased with age, from 0.13 per 100,000 person-years in the <40-year age group to 9.6 per 100,000 person-years in the 85+ year age group (Table 2). Also, gallbladder cancer rates increased over time among individuals ages 40–54 years (by 1.2%–1.4% per year) but decreased over time among individuals aged ≥75 years (by −0.7% to −1.6% per year).

The overall age-standardized incidence rate for gallbladder cancer was higher among females (1.40 per 100,000 person-years; 95% CI, 1.37–1.41) than males (1.16 per 100,000 person-years; 95% CI, 1.14–1.17) for the period of 2001 to 2018 (Table 2). Among males, joinpoint regression analysis identified one statistically significant inflection point in 2014. Although gallbladder cancer incidence rates were stable among males between 2001 and 2014, incidence rates decreased by over 2% per year between 2014 and 2018 (APC, −2.1%; 95% CI, −3.9 to −0.3). Gallbladder cancer incidence remained relatively stable between 2001 and 2018 among females (APC, −0.2%; 95% CI, −0.5–0.0).

Among the race/ethnic groups, Hispanics had the highest overall age-standardized incidence rate for gallbladder cancer from 2001 to 2018 (2.01 per 100,000 person-years: 95% CI, 1.99–2.08, Table 2; Supplementary Fig. S1). Among NHWs, joinpoint regression identified one inflection point (2012), with rates decreasing by 0.6% per year between 2001 and 2012 and decreasing by 1.8% per year between 2012 and 2018. Other race/ethnic groups also showed significant declines in incidence most notably AI/AN (APC, −3.7, 95% CI, −5.7 to −1.7) followed by Hispanics (APC, −1.5, 95% CI, −1.9 to −1.0); and API (APC, −1.2; 95% CI, −2.1 to −0.2). However, for NHBs, gallbladder cancer rates increased by 1.4% per year (APC, 1.4; 95% CI, 0.9–2.0) from 2001 to 2018. This change in APC among NHBs is also consistent when age-standardized incidence rates were stratified according to sex (Fig. 1): the rates among NHB-females are catching up to Hispanics and even surpassed them in males from 2008 onwards.

The highest age-standardized incidence rates of gallbladder cancer were found in the Northeast region of US in all three time periods with a small declining trend seen in the most recent time period of 2013 to 2018 (2.45 per 100,000 person-years) compared with 2001 to 2006 where a rate of 2.64 per 100,000 person-years was observed (Supplementary Table S3). The lowest rates were noted in the South region in all three time periods whereas the Midwest region also shows some evidence of decline. Furthermore, we also investigated the age-standardized incidence rates according to five race/ethnicity groups in all four regions (Supplementary Table S4). The only race/ethnicity groups that showed increasing incidence trends in all four regions were among NHBs. Among NHBs, relative to the 2001 to 2006 period, the gallbladder cancer rates in 2013 to 2018 were 19% higher in Northeast (IRR, 1.19; 95% CI, 1.06–1.23); 27% higher in Midwest (IRR, 1.27; 95% CI, 1.12–1.44); 21% higher in South (IRR, 1.21; 95% CI, 1.12–1.31); and 23% higher in West region (IRR, 1.23; 95% CI, 1.05–1.61).

Age–period-cohort modeling demonstrated evidence of cohort effects more than age or period effects (Fig. 2). The overall net drift in primary gallbladder cancer rates (i.e., expected change in age-standardized rates over time) was 0.27% (95% CI, 0.01–0.54) per calendar year. The local drifts (i.e., age-specific APC in incidence rate) in younger age group (Fig. 2A) were consistent with what was observed among younger age groups between 40 and 54 in joinpoint regression analysis (Table 2). There was little evidence for an overall period effect among the US population (Fig. 2B). Conversely, there was an indication of cohort effect such that the IRRs increased linearly across successive birth cohorts (Fig. 2C). The gallbladder cancer incidence rates among individuals born circa 1971 were 32% (IRR, 1.32; 95% CI, 1.13–1.53) and those born circa 1976 were 26% (IRR, 1.26; 95% CI, 1.00–1.60) higher compared with those born in reference year circa 1946.

Figure 3 shows that the birth and cohort effects varied by race/ethnicity. Although there was no period and cohort effects among NHWs (Fig. 3A and B), we found strong evidence of these effects among NHBs (Fig. 3C and D). There were also no period or cohort effects among Hispanics (Fig. 3E and F). Compared with NHBs born circa 1946, gallbladder cancer incidence rates among NHBs born circa 1971 and 1976 were 85% (IRR, 1.85; 95% CI, 1.26–2.72) and 137% (IRR, 2.37; 95% CI, 1.32–4.26) higher, respectively. Conversely, among Hispanics in the US, gallbladder cancer rates decreased across successive birth cohorts such that those born circa 1976 had gallbladder cancer rates 40% lower than those born circa 1946 (IRR, 0.60; 95% CI, 0.37–0.96), whereas among NHWs incidence rates for those born circa 1976 were no different compared with reference cohort of 1946 (IRR, 1.09; 95% CI, 0.68–1.74). Figure 4 shows the period and cohort effects that were further explored among NHBs according to US census regions. In South region that includes 17 states (Supplementary Table S1), period and cohort effects were observed (Fig. 4A and B), whereas cohort effects but not period effects were noted in Northeast (Fig. 4C and D) and Midwest (Fig. 4E and F) regions. West region could not be analyzed in age–period-cohort modeling because of sparce data for NHBs. Relative to cohorts born circa 1946, the rates among NHBs in South region were considerably higher in cohorts born circa 1971 (IRR, 2.17; 95% CI, 1.27–3.73) and were also higher in Northeast (IRR, 1.91; 95% CI, 1.05–3.50) and Midwest region (IRR, 3.09; 95% CI, 1.86–5.15) of the US. Birth cohort IRRs relative to circa 1946 were also examined according to US Southern divisions, for example, in South-Atlantic divisions and West-South-Central divisions (Supplementary Fig. S2).

In this large-scale study of trends in gallbladder cancer covering 98% of the US population, although we found that the rates have overall decreased by 0.3% per year between 2001 and 2018, secular trends varied by age-group, sex and race/ethnicity. Furthermore, the drivers of changes in incidence (i.e., age, period, and cohort effects) varied by race/ethnicity. In contrast with other race/ethnic groups, gallbladder cancer rates are increasing among NHBs in the US, driven by period and birth cohort effects.

We found divergent trends across age groups. Although gallbladder cancer rates decreased among individuals ages 75 years and above, incidence rates among younger individuals in the US (ages <55 years) increased. Recent studies in the US have also reported a decline in gallbladder cancer rates among older individuals with a steady increase in rates among individuals ages <50 years (13). A population-based cancer registry analysis previously indicated a rise in incidence of gallbladder cancer among young adults ages 25–49 years in the US (28). This increase is observed in successively younger cohorts, and in part seems to be due to obesity epidemic over the past four decades (28). The prevalence of overweight or obesity among adults older than 20 in the USA has increased by 73.6% since 1980 (29), and among adults older than 30 years it accounts for 36% of gallbladder cancer (28, 30). There is now growing evidence that supports an association between obesity at younger ages and increased risk of gallbladder cancer (31) Consistent with prior studies, we also noted different secular trends for men and women (32). In line with other studies, gallbladder cancer rates were higher in females than males in current study (17, 32). For females, gallbladder cancer incidence rates remained stable over the entire study period (18 years). For males, rates were stable from 2001 to 2014 but then decreased by over 2% per year between 2014 and 2018. Previously, registries-based data in the US reported stable overall incidence rates among males with a decline among females (13, 17). Finally, gallbladder cancer incidence trends varied by race/ethnicity. For Hispanics, the subgroup with overall highest age-standardized incidence rates, gallbladder cancer rates decreased by 1.5% per year between 2001 and 2018. Similar decreases were observed among NHWs and APIs with a noteworthy annual decline of 3.7% among AI/AN. Conversely, between 2001 and 2018, gallbladder cancer rates increased by 1.4% per year among NHBs. For NHBs, previous SEER analyses reported somewhat stable rates of gallbladder cancer (3), an increasing rate in other studies (15, 17) along with a decline in all other race/ethnic groups. The increase among NHBs in present study was observed across all four regions in the US.

We used APC analyses to describe the simultaneous effects of age, secular trends, as well as variations among those born around the same year or from one generation to the next. To our knowledge, this is the first study to use APC to facilitate in developing an informed opinion on population dynamics in the US regarding gallbladder cancer on race/ethnic disparities. We observed a period and cohort effect among NHBs, with increasing incidence rates among recent birth cohorts (e.g., circa 1971 and 1976) relative to 1945. As reported in the previous studies (15, 17, 33, 34), our results confirm that although the overall incidence rates remain higher among Hispanics as well as AI/AN individuals, there is evidence of steeper decline over time in these race/ethnic groups.

The reasons for the divergent period and cohort effects by race/ethnicity are not completely clear. It is well known that worldwide, gallbladder cancer incidence tends to be higher in regions where prevalence of cholelithiasis (presence of gallstones in gallbladder) is also high (8, 35, 36). Cholelithiasis is thought to increase the risk of developing gallbladder cancer, more so in some race/ethnic groups than others (37). It could be plausible that some ethnic groups, including Hispanics and AI/AN have higher prevalence of gallstones (38), and over time shows a declining trend due to greater number of cholecystectomies (surgical removal of gallstones) being performed in US. A higher burden of gallbladder cancer has also been noted among Hispanics and NHBs in terms of obesity and diabetes (31). Hence our findings also raise an important question whether these divergent trends can be further examined with changing prevalence of certain health conditions such as obesity, diabetes, along with changes in cholecystectomy practices over time that can affect some race/ethnic groups more than others as was previously conjectured (17, 39).

Increasing trends of gallbladder cancer among NHBs and possible generational effects need to be explored. In the current study, gallbladder cancer incidence rates among NHBs born more recently in circa 1971 and 1976 were 85% and 137% higher than those born in circa 1946. Because of obesity epidemic and increasing burden of diabetes, younger generations in the US have been experiencing an earlier and long-lasting exposure to excess adiposity over their lifetime than previous generations (28, 40). More recent reports from National Health and Nutrition Examination Survey also show that the percentage of adolescent NHBs with obesity have been increasing in past several decades in contrast with younger NHWs where the prevalence of obesity has remained unchanged (41–43). Although presence of gallstones among older adults remains the major determinant of gallbladder cancer, the prevalence of gallstone disease at younger age, for example, among adolescents is also increasing in the US (28, 44). Studies have noted that a linear relationship exists between body weight at young age and gallstone development later in life suggesting that excess weight gain is an important determinant of risk (28, 45).

The consistently increasing NHB–NHW disparities in the US, in particular for gastrointestinal cancers have been discussed recently (46, 47). It is likely that the NHB–NHW differences that we observed in gallbladder cancer trends are due to a wide variety of environmental influences ranging from diet and physical activity to access to care, clinical decision-making, racial discrimination and socio-economic stress factors (48). Bliton and colleagues (46) have hypothesized that these measured disparities are partly attributable to failure to deliver surgical care equitably (i.e., NHBs do not receive surgery as frequently as NHWs for gastrointestinal cancers such as pancreatic and colorectal cancers, as well as gallstone pancreatitis). A part of NHB–NHW disparity can also be attributable to disproportionate rates of refusal where NHBs are more likely to be recorded as refusing lifesaving surgeries (46, 49). However, as pointed out previously (46), this simplified assumption of NHBs’ mistrust based on deeply held views and historical discriminations should not be expended without investigation to dismiss the likely roles of inequitable distribution of surgical treatments in the health system.

The main strength of this study is the usage of the SEER/NPCR database, which includes almost all the population of the U.S. The findings on gallbladder cancer are relevant for risk factors’ control and hypotheses development. Despite a modest overall annual decrease of 0.3%, we found relevant disparities among race/ethnic groups. Known risk factors might explain some of these findings, and more research is needed, especially regarding the impact of diet, obesity, diabetes and infections, and other environmental factors on the cohort effects we observed. More importantly, there is a need to explore the implicit hypothesis that the observed disparities over successive generations of NHBs in gallbladder cancer rates are partly attributable to failure to deliver cholecystectomies equitably in US.

One of the study's limitations has to do with the fact that some of our results were observed among smaller subgroups of patients, for example, younger population. Still, we believe that the disparities among different race/ethnic groups demonstrate that even though gallbladder cancer incidence rate has slowed in recent years, it still affects several marginalized sub-groups of the populations. An important extra caveat to keep in mind is that analyses of trends from this study should be interpreted with caution since the changes in incidence rates may be the result of changes in the prevalence of risk factors as well as from changes in the use of screening or diagnostic techniques. Analyses based on some ethnic groups are limited, for example, classifying Hispanics as one ethnic group may disguise important differences by country of origin (50). Moreover, the observed incidence rates can underestimate the true rate because population at risk (i.e., the denominator) was not adjusted for the percentage of people who underwent cholecystectomies and hence had no gallbladder.

In conclusion, the current study found that gallbladder cancer incidence rates between 2001 and 2018 have increased in the U.S among NHBs, and among individuals who are younger than 55 years. Although the overall decrease in incidence rate of gallbladder cancer have been observed, the continuing cohort effect observed among NHBs with increasing incidence rates in different US regions suggests that the gallbladder cancer rates will go on to rise in the US in the nearby future in this group. Increasing attention needs to be focused on the equitable detection and treatment of underlying risk factors for gallbladder cancer.

No disclosures were reported.

The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article; and the decision to submit the article for publication.

S.A. Raza: Conceptualization, resources, software, formal analysis, investigation, methodology, writing–original draft. W.L. da Costa: Conceptualization, software, writing–review and editing. A.P. Thrift: Conceptualization, software, supervision, investigation, methodology, writing–review and editing.

This work was funded (in part) by Research Training Awards from the Cancer Prevention and Research Institute of Texas (CPRIT) for the Cancer Prevention Post-Graduate Training Program in Integrative Epidemiology (RP160097; PI: M. Spitz) and the Systems Epidemiology of Cancer Training (SECT) Program (RP210037; PI: A.P. Thrift).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.