Cholangiocarcinoma across England: Temporal changes in incidence, survival and routes to diagnosis by region and level of socioeconomic deprivation.

Background & Aims: While cholangiocarcinoma (CCA) incidence and mortality rates are increasing globally, whether there are regional/temporal variations in these rates for different biliary tract cancer (BTC) subtypes, or whether they differ by sex, socioeconomic status, or route to diagnosis (RtD) remains unknown. In this work, we aimed to perform an in-depth analysis of data on the incidence, mortality, survival and RtD of CCA and other BTCs. Methods: Data on all BTCs diagnosed in England between 2001 and 2018 were extracted from NHS Digital's National Cancer Registration Dataset. Age-standardised incidence rates (ASRs), mortality rates (ASMRs) and net survival rates were calculated, and Kaplan-Meier overall survival estimates and RtD trends were analysed. Analyses were stratified by sex, socioeconomic deprivation, tumour subtype and region. Results: The ASR for CCA rose from 2.9 in 2001-2003 to 4.6 in 2016-2018 and from 1.0 to 1.8 for gallbladder cancers (GBCs). ASMR trends mirror those of incidence, with most deaths due to iCCA. Over 20% of patients with CCA were under 65 years old. The ASRs and ASMRs were consistently higher in the most socioeconomically deprived group for CCA and GBC. The most common RtD was the emergency route (CCA 49.6%, GBC 46.2% and ampulla of Vater cancer 43.0%). The least deprived patients with CCA and ampulla of Vater cancer had better overall survival (p <0.001). Net survival rates rose for all BTCs, with 3-year net survival for CCA increasing from 9.2% in 2001 to 12.6% in 2016-2018. There was notable geographical variation in ASRs, ASMRs and net survival for all BTCs. Conclusions: BTC incidence and mortality rates are increasing, with differences observed between tumour types, socioeconomic deprivation groups, RtDs and geographical regions. This highlights the need for targeted interventions, earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals. Impact and implications: Cholangiocarcinoma (CCA) incidence and mortality rates are rising globally, particularly for intrahepatic CCA. However, it has not previously been reported if, within a single country, there are temporal and regional differences in incidence, mortality and survival rates for different biliary tract subtypes, and whether these differ by sex, socioeconomic status, or route of diagnosis. In this study we show that mortality rates for patients with CCA continue to rise and are almost 40% higher in the most socioeconomically deprived compared to the least; additionally, we observed regional variation within England in incidence, mortality and survival. This study is relevant to researchers and policy makers as it highlights regional variation and inequality, as well as emphasising the need for earlier diagnosis and better awareness of this condition amongst the public and healthcare professionals.

British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Introduction.

Cholangiocarcinoma (CCA) is a lethal cancer arising in the bile ducts within and just outside the liver. It occurs worldwide and falls into two etiologically defined groups, one related to chronic liver fluke infection and the other not. Liver fluke-related CCA is found in continental Southeast Asia (caused by Opisthorchis viverrini with infection leading to opisthorchiasis), East Asia (Clonorchis sinensis), and Eastern Europe and Russia (Opisthorchis felineus). Both O. viverrini and C. sinensis are classified as group one carcinogens, while recent data from O. felineus suggest the same. In Southeast Asia, an estimated 67.3 million people are at risk of O. viverrini infection and subsequently developing CCA. When the three liver fluke species are considered, an estimated 700 million people are at risk of infection and developing CCA globally. The northeast of Thailand (Isan) is the world's hot spot of liver fluke infection and CCA. Early detection, diagnosis, and surgical intervention/curative treatment of CCA are critical to increase life expectancy and quality of life of people in the region and globally. Despite concentrated recent efforts focusing on a multidisciplinary approach to understand the ecology, epidemiology, biology, public health, and social significance of infection by cancer causing liver flukes, it remains an underestimated and under-resourced public health problem. In addition, it is still believed to be a regional problem without global significance-this is not the case. This book focuses on O. viverrini as the main causative agent of CCA in Southeast Asia, but many aspects detailed in the following chapters also relate to the two other liver fluke species. Our aim is to produce a holistic framework including the basic biology of O. viverrini and its relation to the epidemiology of the disease through diagnosis to treatment, including palliative methods, pathology, and control.

Synopsis.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer worldwide. Despite the severity of the disease and its impact on individuals, families, and communities, there remains an overall lack of awareness and interest in this disease. The information contained in the chapters of this book shows that this is indeed a significant public health and socioeconomic problem with varying levels of country-specific awareness. In Southeast Asia liver fluke, O. viverrini related CCA is endemic with the highest incidence worldwide in northeast Thailand, yet it is treatable and preventable. The chapters highlight significant advances in our knowledge of the biology and epidemiology of the O. viverrini species complex, intermediate hosts, systematics, population genetics, and the complexity of the three-host life cycle. A comprehensive conceptual framework has been developed to assist in understanding the complexity of molecular mechanisms of CCA carcinogenesis and cancer development which can result in improvement of targeted CCA therapy. There have been many advances in understanding the pathology of CCA in the biliary tract, including advances in prognosis and molecular pathogenesis. The development of different modalities and their advantages for diagnosis have increased diagnostic accuracy, providing reliable information allowing appropriate treatment and management programs to be selected for each patient. Particularly exciting is the recent development of a urine antigen assay which has revolutionized the diagnostic approach of opisthorchiasis due to its simplicity, the non-invasive nature of sample collection, and its ease of use in field settings. Significant in-roads and advances have been made in the surgical and systemic treatment of CCA patients. Additionally, a sophisticated data collection and analysis system, the Isan Cohort, has been developed and established for the treatment and control of CCA. Importantly, a greater understanding has been made of the social, community, religious, and anthropological issues initiating and sustaining the eating behavior of raw, partially cooked, and/or fermented fresh water fish. Specially designed education programs/curricula, based on currently available multidisciplinary hard data targeting school children, have been introduced since the inception of the Cholangiocarcinoma Screening and Care Program (CASCAP) and the subsequent strategic Fluke Free Thailand Model. The education program is being expanded to other provinces in Thailand and in the near future to other Southeast Asian countries, initially to Lao PDR, where the Fluke Free Lao PDR program has already been implemented. Despite advances that have been made in many disciplines focused on O. viverrini related CCA, raising awareness of CCA at all levels, particularly across endemic regions, is still needed, as is raising the awareness of CCA globally. As parasites and parasite related diseases have no borders, it is critical that an effective common strategic plan is instigated and established between all countries where liver fluke, O. viverrini related CCA is a significant public health problem, thereby increasing the quality of life and life expectancy of millions of people who suffer from this insidious disease.

Epidemiology of cholangiocarcinoma.

Cholangiocarcinoma (CCA) represents a heterogenous set of malignancies arising from the biliary tract. Classification of CCA subdivides tumours into intrahepatic (iCCA) and extrahepatic (eCCA), with eCCA further categorised as perihilar (pCCA) and distal (dCCA) lesions. Tumour subtypes show distinct epidemiological, genetic and clinical characteristics. Global incidence and mortality are rising, with the highest rates seen in Asian populations compared to the West. There has been a divergence in recent mortality trends observed between CCA subtypes, with rising rates of iCCA seen compared with eCCA. There are several drivers for these differing trends, including specific risk factors, misclassification of CCA subtypes and variation in diagnosis and surveillance. Risk factors for CCA can be divided into hepatobiliary, extra-hepatic and environmental, with hepatobiliary diseases conferring the largest risk. Surgery represents the only curative treatment for CCA, but can only be offered to early-stage candidates who are otherwise fit; the majority of patients are therefore treated with chemotherapy and, recently, immunotherapy. Due to late-stage presentation of disease, prognosis is poor, with 5-year survival <20%.

Regional variation in routes to diagnosis of cholangiocarcinoma in England from 2006 to 2017.

BACKGROUND: Incidence of cholangiocarcinoma (CCA) is rising, with overall prognosis re-maining very poor. Reasons for the high mortality of CCA include its late presentation in most patients, when curative options are no longer feasible, and poor response to systemic therapies for advanced disease. Late presentation presents a large barrier to improving outcomes and is often associated with diagnosis via mergency presentation (EP). Earlier diagnoses may be made by Two Week Wait (TWW) referrals through General practitioner (GP). We hypothesise that TWW referrals and EP routes to diagnosis differ across regions in England. AIM: To investigate routes to diagnosis of CCA over time, regional variation and influencing factors. METHODS: We linked patient records from the National Cancer Registration Dataset to Hospital Episode Statistics, Cancer Waiting Times and Cancer Screening Programme datasets to define routes to diagnosis and certain patient characteristics for patients diagnosed 2006-2017 in England. We used linear probability models to investigate geographic variation by assessing the proportions of patients diagnosed via TWW referral or EP across Cancer Alliances in England, adjusting for potential confounders. Correlation between the proportion of people diagnosed by TWW referral and EP was investigated with Spearman's correlation coefficient. RESULTS: Of 23632 patients diagnosed between 2006-2017 in England, the most common route to diagnosis was EP (49.6%). Non-TWW GP referrals accounted for 20.5% of diagnosis routes, 13.8% were diagnosed by TWW referral, and the remainder 16.2% were diagnosed via an 'other' or Unknown route. The proportion diagnosed via a TWW referral doubled between 2006-2017 rising from 9.9% to 19.8%, conversely EP diagnosis route declined, falling from 51.3% to 46.0%. Statistically significant variation in both the TWW referral and EP proportions was found across Cancer Alliances. Age, presence of comorbidity and underlying liver disease were independently associated with both a lower proportion of patients diagnosed via TWW referral, and a higher proportion diagnosed by EP after adjusting for other potential confounders. CONCLUSION: There is significant geographic and socio-demographic variation in routes to diagnosis of CCA in England. Knowledge sharing of best practice may improve diagnostic pathways and reduce unwarranted variation.

Outcomes of National Survey of the Practice of Hepatocellular Carcinoma Surveillance.

Background & Aim: HCC has significantly improved outcomes when detected early. Guidelines recommend biannual surveillance with ultrasound (US) and/or AFP in at-risk individuals. This survey aimed to describe HCC surveillance adherence/practices amongst the NHS hospitals in the UK. Methods: An electronic survey was sent to 79 NHS hospitals via the British Association for the Study of the Liver distribution list. The responses were captured from July 2021 to January 2022. Centres were divided into hepato-pancreato-biliary (HPB) and non-HPB centres, depending on whether the hospital undertakes major liver surgeries. Results: A total of 39 (49.3%) centres responded: 15 HPB and 24 non-HPB centres from across the UK. HCC surveillance eligibility criteria were universally applied, but heterogeneous approaches occur outside these criteria. Eighty per cent of patients undergoing surveillance were estimated to have cirrhosis. Eighty-five per cent of centres do 6-monthly US and AFP requested by clinicians and liver clinical nurse specialists. Compliance was estimated at 80% but not routinely audited. In most centres, general sonographers and/or radiologists perform surveillance US scans without a standard reporting template, although structured reporting was viewed as desirable by the majority. Poor views on US are approached heterogeneously, with patients variably offered ongoing US, CT, or MRI with different protocols. Conclusion: Most responding NHS hospitals follow 6-monthly HCC surveillance guidance. Data recording is variable, with limited routine data collection regarding compliance, yield, and quality. Surveillance US is mostly performed by non-HPB specialists without standardised reporting. There is an inconsistent approach to poor views with US surveillance. Even in a universal healthcare system such as NHS, which is free at the point of care, delivery of HCC surveillance has not improved over the last decade and remains variable.

Cohort study to assess geographical variation in cholangiocarcinoma treatment in England.

BACKGROUND: Outcomes for cholangiocarcinoma (CCA) are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous sub-types. Beyond curative surgery, which is only an option for a minority of patients diagnosed at an early stage, few systemic therapy options are currently recommended to relieve symptoms and prolong life. Stent insertion to manage disease complications requires highly specialised expertise. Evidence is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA patients. AIM: To assess geographic variation in treatments received amongst CCA patients in England. METHODS: Data used in this cohort study were drawn from the National Cancer Registration Dataset (NCRD), Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset. A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the NCRD. Potentially curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of interest. Linear probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis, and for socio-demographic and clinical characteristics at diagnosis. RESULTS: Of 8853 CCA patients, 1102 (12.4%) received potentially curative surgery. The mean [95% confidence interval (CI)] percentage-point difference from the population average ranged from -3.96 (-6.34 to -1.59)% to 3.77 (0.54 to 6.99)% across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics, showing statistically significant variation. Amongst 7751 who did not receive surgery, 1542 (19.9%) received systemic therapy, with mean [95%CI] percentage-point difference from the population average between -3.84 (-8.04 to 0.35)% to 9.28 (1.76 to 16.80)% across Cancer Alliances after adjustment, again showing the presence of statistically significant variation for some regions. Stent insertion was received by 2156 (27.8%), with mean [95%CI] percentage-point difference from the population average between -10.54 (-12.88 to -8.20)% to 13.64 (9.22 to 18.06)% across Cancer Alliances after adjustment, showing wide and statistically significant variation from the population average. Half of 8853 patients (n = 4468) received no treatment with either surgery, systemic therapy or stent insertion. CONCLUSION: Substantial regional variation in treatments received by CCA patients was observed in England. Such variation could be due to differences in case-mix, clinical practice or access to specialist expertise.

Current epidemiology of cholangiocarcinoma in Western countries.

Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.

BMAT's predictive validity for medical school performance: A retrospective cohort study.

BACKGROUND: Although used widely, there is limited evidence of the BioMedical Admissions Test's (BMAT) predictive validity and incremental validity over prior educational attainment (PEA). We investigated BMAT's predictive and incremental validity for performance in two undergraduate medical schools, Imperial College School of Medicine (ICSM), UK, and Lee Kong Chian School of Medicine (LKCMedicine), Singapore. Our secondary goal was to compare the evidence collected with published evidence relating to comparable tools. METHODS: This was a retrospective cohort study of four ICSM (1188 students, entering 2010-2013) and three LKCMedicine cohorts (222 students, 2013-2015). We investigated associations between BMAT Section 1 ('Thinking Skills'), Section 2 ('Scientific Knowledge and Applications') and Section 3a ('Writing Task') scores, with written and clinical assessment performance across all programme years. Incremental validity was investigated over PEA (A-levels) in a subset of ICSM students. RESULTS: When BMAT sections were investigated independently, Section 2 scores predicted performance on all written assessments in both institutions with mainly small effect sizes (standardised coefficient ranges: ICSM: 0.08-0.19; LKCMedicine: 0.22-0.36). Section 1 scores predicted Years 5 and 6 written assessment performance at ICSM (0.09-0.14) but nothing at LKCMedicine. Section 3a scores only predicted Year 5 clinical assessment performance at ICSM with a coefficient <0.1. There were no positive associations with standardised coefficients >0.1 between BMAT performance and clinical assessment performance. Multivariable regressions confirmed that Section 2 scores were the most predictive. We found no clear evidence of incremental validity for any BMAT section scores over A-level grades. DISCUSSION: Schools who wish to assess scientific knowledge independently of A-levels may find BMAT Section 2 useful. Comparison with previous studies indicates that, overall, BMAT seems less useful than comparable tools. Larger scale studies are needed. Broader questions regarding why institutions adopt certain admissions tests, including those with little evidence, need consideration.

Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations and therapeutic approaches. In endemic regions, liver fluke infection is associated with CCA, owing to the oncogenic effect of the associated chronic biliary tract inflammation. In other regions, CCA can be associated with chronic biliary tract inflammation owing to choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration of the anthelmintic drug praziquantel decreases the risk of CCA from liver flukes, but reinfection is common and future vaccination strategies may be more effective. Some patients with CCA are eligible for potentially curative surgical options, such as resection or liver transplantation. Genetic studies have provided new insights into the pathogenesis of CCA, and two aberrations that drive the pathogenesis of non-fluke-associated intrahepatic CCA, fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase gain-of-function mutations, can be therapeutically targeted. CCA is a highly desmoplastic cancer and targeting the tumour immune microenvironment might be a promising therapeutic approach. CCA remains a highly lethal disease and further scientific and clinical insights are needed to improve patient outcomes.

Cholangiocarcinoma miscoding in hepatobiliary centres.

INTRODUCTION: Cholangiocarcinoma (CCA) are sub-divided into intrahepatic (iCCA) or extrahepatic (eCCA). eCCA are further subdivided into perihilar (pCCA) and distal (dCCA). Current and previous versions of the WHO International Coding of Disease and Oncology classifications (ICD) have separate topography codes for iCCA and eCCA, but none for pCCA. Over recent decades, multiple studies report rising incidence rates of iCCA with declining rates of eCCA, without reference to pCCA. We hypothesised the lack of a specific code for pCCA has led to errors CCA coding, specifically with miscoding of pCCA as iCCA. METHODS: Clinical notes of cases coded as hepatobiliary carcinoma using ICD-10 criteria (C22.1/Intrahepatic Bile Duct carcinoma, C24.0/Extrahepatic Bile Duct carcinoma, C23X/Malignant Neoplasm Gall Bladder, C22.0/Malignant Neoplasm Liver Cell Carcinoma) over a 2 year period (2015-2017), were reviewed by two independent clinicians at three independent UK regional HepatoPancreatoBiliary centres. The agreed final diagnosis was compared to the originally allocated ICD-10 code. RESULTS: Of the 625 CCA cases fully reviewed, 226 were coded as C22.1/iCCA. 98 (43%) of these were true iCCA and coded correctly, while 76 cases (34%) were actually pCCA. 92% all pCCA cases were incorrectly coded as iCCA. CONCLUSION: CCA coding misclassification in UK HPB centres is common, particularly the miscoding of pCCA, which is extrahepatic and the commonest form of CCA, as iCCA. This may be contributing to apparent rising incidence rates of iCCA. Our findings confirm the need to implement distinct topographical codes for iCCA, pCCA and dCCA in future iterations of ICD.

Epidemiology of HPB malignancy in the elderly.

The incidence of hepatopancreatobiliary (HPB) cancers is increasing worldwide. Despite improvements in cancer surveillance and earlier access to therapy, these cancers still have poor survival rates, especially in elderly patients. There are several challenges in elucidating the epidemiology of these malignancies especially in view of the heterogeneous exposure to recognised risk factors and the coding systems used. Early diagnosis, crucial to improved survival, remains challenging as many patients present sporadically. Furthermore, the indolent nature of these tumours means they tend to present late, when curative treatments are no longer an option. Importantly, even when patients are diagnosed early and treated with curative intent, recurrence rates remain high. HPB cancers display a heterogenous molecular profile resulting in poorly effective systemic therapies in patients for whom curative treatments cannot be considered. Globally, people now live longer, and it is predicted that the population of individuals older than 85 will double by 2033. With increasing age comes increased cancer risk. There is a plethora of recognised challenges in elderly patients presenting with cancer and this is no different with HPB cancers. Complex co-morbidities including chronic disease, polypharmacy, cognitive decline and increasing psychosocial needs confer an extra layer of complexity in the management of this elderly sub population. The frailty that usually accompanies advancing age often means that patients take longer to recover and develop more complications after cancer therapies. In this article, we review the epidemiology of malignant HPB tumours with a focus on the elderly.

Cholangiocarcinoma 2020: the next horizon in mechanisms and management.

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.

Exploring Metabolic Consequences of CPS1 and CAD Dysregulation in Hepatocellular Carcinoma by Network Reconstruction.

PURPOSE: Hepatocellular carcinoma (HCC) is the fourth commonest cause of cancer-related mortality; it is associated with various genetic alterations, some involved in metabolic reprogramming. This study aimed to explore the potential metabolic impact of Carbamoyl Phosphate Synthase I (CPS1) and carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD) dysregulation through the reconstruction of a network that integrates information from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, Human Metabolome Database (HMDB) and Human Protein Atlas (HPA). METHODS AND RESULTS: Existing literature was used to determine the roles of CPS1 and CAD in HCC. CPS1 downregulation is thought to play a role in hepatocarcinogenesis through an increased glutamine availability for de novo pyrimidine biosynthesis, which CAD catalyzes the first three steps for. KEGG, HMDB and HPA were used to reconstruct a network of relevant pathways, demonstrating the relationships between genes and metabolites using the MetaboSignal package in R. The network was filtered to exclude any duplicates, and those greater than three steps away from CPS1 or CAD. Consequently, a network of 18 metabolites, 28 metabolic genes and 1 signaling gene was obtained, which indicated expression profiles and prognostic information of each gene in the network. CONCLUSION: Information from different databases was collated to form an informative network that integrated different "-omics" approaches, demonstrating the relationships between genetic and metabolic components of urea cycle and the de novo pyrimidine biosynthesis pathway. This study paves the way for further research by acting as a template to investigate the relationships between genes and metabolites, explore their potential roles in various diseases and aid the development of new screening and treatment methods through network reconstruction.

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) carries a poor prognosis, is increasing in incidence and its causes are poorly understood. Although some risk factors are known, they vary globally and collectively account for a minority of cases. The aim of this study was to perform a comprehensive meta-analysis of risk factors for intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), from Eastern and Western world studies. METHODS: A literature search of case-control studies was performed to identify potential risk factors for iCCA and eCCA. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Funnel plots were used to assess publication bias, and meta-regression was used to select risk factors for comparison between Eastern and Western studies. RESULTS: A total of 13 risk factors were selected from 25 case-control studies in 7 geographically diverse countries. The strongest risk factors for both iCCA and eCCA were biliary cysts and stones, cirrhosis, hepatitis B and hepatitis C. Choledochal cysts conferred the greatest risk of both iCCA and eCCA with pooled ORs of 26.71 (95% CI 15.80-45.16) and 34.94 (24.36-50.12), respectively. No significant associations were found between hypertension and obesity for either iCCA or eCCA. Comparing Eastern and Western populations, there was a difference for the association of hepatitis B with iCCA (coefficient = -0.15195; 95% CI -0.278 to -0.025; p = 0.022). CONCLUSION: This is the most comprehensive meta-analysis of CCA risk factors to date. Some risk factors, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of this cancer. LAY SUMMARY: Cholangiocarcinoma (CCA) is a cancer arising in the bile ducts inside (intrahepatic CCA) and connected to the liver (extrahepatic CCA). It is a very aggressive cancer: 95% of patients die within 5 years. CCA rates are increasing globally, but the causes of CCA are poorly understood. The few risk factors that are known account for only a minority of cases. In this study, we found that the strongest risk factors for both intrahepatic and extrahepatic CCA are cysts and stones in the bile ducts, cirrhosis, and hepatitis B and C viruses. Some risk factors for CCA, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of CCA.