The literature search identified 870 individual publications in selected literature databases and conference proceedings. Of these, 784 were excluded after screening and a further 42 were excluded after full-text analysis. Five additional publications were identified through pragmatic web-based searches and snowballing searches based on reference lists of other relevant publications. Additional data were extracted from the SEER, Globocan, and MyCancerGenome databases. A total of 52 sources were included in the qualitative analysis, of which 33 (63.5%) and 19 (36.5%) contained data on BTC epidemiology and MDM2 amplification, respectively. The flowchart of the study selection is shown in Fig. 2. A summary of the included publications is shown in Table S1 and Table S2 (see ESM).

In 2019, the global age-standardised rate (ASR) of incidence for BTC (cases per 100,000 persons) was 2.5, based on data collected as part of the Global Burden of Disease Study [32]. However, there is considerable variation in reported incidence according to primary site, geographic region and sex [33,34,35]. Incidence data for BTC among countries of interest to this review are summarised in Table 1; global incidence ranges inclusive of other countries are presented in Table S3 (see ESM).

Among the different types of BTC, the combined incidence of iCCA and eCCA is highest, followed by GBC and AC [12, 36,37,38]. The incidence of CCA is mainly driven by iCCA; during 2008 to 2012, the global annualised ASR ranged from 0.26 to 2.80 for iCCA, compared with 0.08 to 2.24 for eCCA during the same time period (Table S3, see ESM) [33]. More recent global data for iCCA in 2018 showed a global incidence rate of 1.4 (Table S3) [34]. No global data published since 2012 were identified for eCCA, reflecting the smaller volume of data available compared with iCCA.

Global incidence data for GBC were available from one source, which reported an ASR of 1.2 for 2020 (ranging from 0.03 to 8.5; Table S3, see ESM) [39]. Similarly, data on AC are generally scarce, with one international study reporting data for 22 countries (2008–2012) showing that AC has the lowest incidence rate of all types of BTC, with ASRs ranging from 0.18 to 0.93 (Table S3) [40].

Geographically, the incidence of BTC varies widely (Table S3, see ESM). Across the geographic regions focused on in this review, locations with the highest incidence of BTC were South and Central Asia, where BTC was estimated to account for 2.9% of all new cancer diagnoses in 2018 [35].

Two studies using global data from 2008 to 2012, available from IARC, showed that, among the countries focused on in this review, the highest incidence rates of iCCA (2.80 and 2.18) and eCCA (2.24 and 2.71) occurred in South Korea (Table 1) [33, 40]. Other countries in Asia, Europe and the US had considerably lower rates in these studies (Table 1) [33].

Beyond this, there is a paucity of recent studies comparing the incidence of eCCA by geography and few individual studies describe country-specific data. Two studies from Asia reported an ASR of eCCA of 4.1 in South Korea (2019; Table 1) and 5.1/2.2 (male/female) in Japan (2016–2017; Table S6, see ESM) [38, 46]. Two studies from Europe report an ASR of eCCA of 0.94 in France (2018–2019) and 0.4/0.3 (male/female) in Finland (2013–2017; Table S5, see ESM) [37, 47]. Three US-based studies reported incidence rates of eCCA for different time periods, with considerable variation: 2.46 (2001–2017), 1.25 (2001–2015) and 0.74 (2000–2017; Table 1) [12, 42, 43]. The inconsistent incidence rates across studies may be due to differences in assessment dates, the population used for age standardisation, and the ICD-10/ICD-Oncology (O)-3 site and morphology codes used for data extraction (Table S2, see ESM).

In contrast, several articles describe the incidence of iCCA by geography, including a global study that published the ASR of iCCA incidence for 2018 by country (Table 1; Table S3, see ESM) [34]. The authors showed a high incidence rate of iCCA in Asian countries (Thailand [5.2], South Korea [3.3] and China [2.1]; Table 1, Table S3) [34]. Estimates of the ASR of iCCA incidence in European countries in 2018 ranged from 0.9 in Norway to 2.2 in the UK, and the ASR of iCCA in the US was 1.1 (Table 1; Table S3) [34]. For reasons that are unclear, estimates for the ASR of iCCA incidence varied somewhat across different US-based studies, which reported rates from 0.64 (2008–2012) to 1.19 (2001–2017) for iCCA (Table 1) [12, 40, 42, 43].

For GBC, incidence rates reported for 2020 varied greatly among countries (Table S3, see ESM), ranging from 0.39 to 2.9 among countries focused on in this review (Table 1) [39]. Incidence rates were relatively high in Asia (ranging from 1.2 in China to 2.9 in South Korea), compared with European countries (ranging from 0.39 in Norway and France, to 0.89 in Sweden), and the US (at 0.68) (Table 1) [39]. However, US-specific data for the same year (2020) available through the SEER database showed a higher ASR rate of 1.1 (Table 1) [45].

Incidence rates of AC reported by one study (2008–2012) were generally low across all regions of interest, with the highest rates reported in Asia (ranging from 0.23 in China to 0.93 in South Korea), followed by European countries (from 0.34 in the UK to 0.45 in Spain), and the US with 0.32 (Table 1) [40].

Data for BTC overall suggest a slightly higher incidence in females (2.6) compared with males (2.4), but this trend varies by primary site (Table S3, see ESM) [32]. Incidence rates of CCA, for example, were typically higher among males than females in the US, Asia, the EU-4, the UK and in Nordic countries (Tables S3–S6, see ESM) [12, 34, 35, 43, 46,47,48,49,50]. Conversely, the incidence of GBC was generally higher in females than in males in most countries (Tables S3–S6) [12, 35, 39, 51]. Exceptions included Thailand and South Korea, where there was a higher incidence of GBC in males compared with females, and Japan where GBC incidence was similar between males and females (Table S6) [39, 46, 50]. Data from a global study, as well as individual studies from the US and Japan (Tables S3, S4, S6, see ESM), showed higher incidence of AC among males than females [12, 35, 40, 46].

Studies reporting changes in the incidence of BTC over time were generally focused on specific primary sites, with the majority of studies reporting on either CCA or GBC. A global study by Florio et al. reported an increase in incidence of both iCCA and eCCA over time (1993–2012) (Table 2) [33]. Furthermore, although taken from separate studies, estimates of iCCA incidence in 2018 were generally higher than those reported for 2008–2012, suggesting a continued increase (Table S3, see ESM) [33, 34]. Among the countries focused on in this report, the largest annual percentage change (APC) in iCCA incidence rate between 1993 and 2012 occurred in China (11.1%), followed by Germany (7.5%) and France (6.5%) (Table 2; Table S7, see ESM) [33]. An increase in the incidence of iCCA is also documented by several US-based studies, which report an APC ranging from 2.0% (1993–2012) to 9.3% (2013–2017) depending on the study period and definitions used (Table S7) [12, 33, 43, 52,53,54]. Using data for 1993 to 2012, only a few countries, including Japan, Thailand and Denmark, showed a slight decrease in the incidence of iCCA (Table S7) [33].

In general, the global study by Florio et al. recorded relatively small increases in the incidence of eCCA between 1993 and 2012 (Table 2, Table S7, see ESM) [33]. Exceptions included Thailand, with an APC of 8.8% and Italy, with an APC of 4.0% (Table 2); results for the US showed an APC of 2.4% for eCCA [33]. However, more recent data (2013–2017) showing incidence trends for eCCA in the US indicate a minimal negative APC of −2.0% (Table 2) [43].

Data on GBC incidence by sex from the Globocan database show that incidence trends vary between countries (Table S7, see ESM) [39]. Based on the most recent 5-year period available, large decreases in GBC incidence in the male population were observed in Norway (−5.5%) and China (−2.7%) (Table S7) [55]. Among the female population, there were large decreases in GBC incidence in Norway (−11.5%), Italy (−5.7%) and Spain (−5.0%) (Table S7) [55]. Large increases in GBC incidence were observed in the male population in Northern Ireland (13.1%), Italy (5.0%) and France (4.5%) and in the female population in Thailand (8.9%) and France (2.9%) (Table S7) [55].

Very few studies investigated trends in the incidence of AC. Data from France show a sharp decline in the incidence of AC in males (−14.6%) and females (−16.6%) between 2012 and 2019 (Table 2), while data for the US show much smaller decreases between 2001 and 2015 (−0.14% in males and −0.08% in females; Table 2) [12, 37].

While several articles reported on the incidence of BTC, there were notably fewer studies reporting on prevalence. Exceptions included one US-based study, in which the 10-year ASR of prevalence of BTC was reported for 2015 as 10.8 per 100,000 persons (Table S9, see ESM) [12]. One study conducted in China (2019) recorded the 1-year prevalence of BTC as 2.40 per 100,000 persons (Table S10, see ESM) [41].

The prevalence of CCA has been reported separately for iCCA and e