Changing patterns of cholangiocarcinoma and gallbladder cancer: A regional perspective from Northeastern Italy

Abstract

Cholangiocarcinoma (CCA) is the second most common primary liver cancer worldwide, with a high mortality rate. Due to the lack of information regarding disease markers, characterization tools, and early detection methods, mortality continues to increase. The disease can be classified into two main groups: Intrahepatic CCA and extrahepatic CCA, the second of which is further subdivided into perihilar CCA and distal CCA. Certain regions are found to be at higher risk due to the presence of different contributing factors. These include hepatobiliary diseases, extrahepatic conditions, and environmental exposures. CCA shows a sex-related disparity, affecting men more than women, and its incidence rises progressively with age. These risk factors likely contribute to the rising incidence observed in certain regions, as each region is predominantly affected by distinct factors, resulting in wide geographical variations in CCA incidence. Epidemiological reports published before 2000 indicate a global increase in the incidence of intrahepatic CCA, whereas the incidence of extrahepatic CCA is reportedly decreasing. The present study offers an important epidemiological perspective by analyzing the incidence trends of gallbladder malignancies over a 17-year period in Northeastern Italy, analyzed according to sex and age groups.

Key Words: Cholangiocarcinoma; Gallbladder cancer; Epidemiology; Intrahepatic cholangiocarcinoma; Extrahepatic cholangiocarcinoma

Core Tip: Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with rising incidence, particularly of intrahepatic CCA, in many regions worldwide. Despite its relatively low overall incidence, CCA poses a major public health concern due to late diagnosis and poor prognosis. This study highlights shifting epidemiological trends over a 17-year period in Northeastern Italy, emphasizing declining hospitalization rates for both intrahepatic and extrahepatic CCA, despite global projections of increased incidence and mortality. The findings underscore the importance of ongoing, population-based surveillance to evaluate evolving risk patterns, sex- and age-related disparities, and regional healthcare responses, essential to guide future preventive and diagnostic strategies.

INTRODUCTION

Cholangiocarcinoma (CCA) is the second most common type of liver cancer. CCA includes a heterogeneous group of aggressive malignancies arising from the epithelial cells of the biliary duct[1]. According to their anatomical site in the biliary duct, they can be classified as intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA), the latter of which is further subdivided into perihilar CCA or distal CCA. Perihilar CCA is the most prevalent, making up 50%-60% of CCA cases, followed by distal CCA (20%-30%) and iCCA (10%-20%)[2].

Clinical features of CCA include jaundice, with or without pain in the right upper quadrant, malaise, weight loss, pruritus, anorexia, nausea, and vomiting[3,4]. The incidence of CCA is less than other types of cancers, most of the cases are late diagnosed because the disease is clinically silent and has poor prognosis[5,6]. Characterization of the risk factors are essential for early diagnosis and clinical prevention of the disease.

Risk factors for the development of CCA mainly can be classified into hepatobiliary diseases, extra-hepatic diseases and environmental factors. Hepatobiliary diseases outline the highest risks including: Choledochal cysts, Caroli disease, cirrhosis and primary sclerosing cholangitis[7]. Underlying risk factors for CCA differs for each subtype and by epidemiology. In Asia, liver flukes caused by Opisthorchis viverrini is considered the leading cause. Primary sclerosing cholangitis is considered as a strong risk factor for both types of CCA[8]. By contrast, in Western countries risk factors associated with chronic liver disease including viral hepatitis, alcohol consumption and non-alcoholic fatty liver disease. These risk factors are associated with iCCA but not eCCA. Biliary diseases are found to be related to the eCCA as a risk factor, and iCCA could be a reason for increased risk of chronic liver disease[9]. Even though there are a lot of identified risk factors for the diagnosis of the disease, the majority of CCA cases arise without a clearly defined risk factor. This may be one of the reasons for the limited early detection efforts, contributing to the poor prognosis and treatment resistance observed in CCA[10-13]. Genetic predisposition holds a significant value in disease presence. Genomic profiling studies of CCA have revealed a range of recurrently mutated genes, including cyclin-dependent kinase inhibitor 2A/B, isocitrate dehydrogenase 1/2, BRCA1-associated protein 1, BRAF, AT-rich interactive domain-containing protein 1A, KRAS, and tumor protein p53, which play key roles in tumor development and progression. However, the frequency and distribution of these mutations vary depending on geographical region, environmental factors, and the methodologies used in mutation detection and analysis[3,11,14].

A study conducted by Baldo et al[15] has contributed significantly to our understanding of the epidemiological trends and hospitalization rates related to CCA and gallbladder cancer in Northeastern Italy, using regional hospital admission data. At present, CCA still remains a malignancy frequently diagnosed at advanced stages and therapeutic options are limited. A key point is that risk factors for CCA may vary by geographic region, leading to differences in etiology and disease dynamics across populations. Region-specific analyses play a crucial role in revealing etiological data in CCA.

The authors conducted a 17-year retrospective analysis (2007-2023) based on hospital discharge records from the Veneto region to investigate trends in biliary tract cancer (BTC) hospitalizations. A total of 10778 first hospital admissions with BTCs listed as either primary or secondary diagnoses were included. To evaluate group differences, categorical variables were analyzed using the χ² test, while continuous variables were assessed with the Student’s t-test. Additionally, joinpoint regression was employed to examine trends in age-standardized hospitalization rates over time, providing estimates of annual percentage changes.

GLOBAL BURDEN AND EPIDEMIOLOGICAL TRENDS IN BTC: PAST TO PRESENT

There is global variation in the incidence of CCA. Between 1994 and 2022, International Agency for Research on Cancer data pointed to a rising global trend in CCA incidence and mortality, accompanied by a persistently high recurrence rate, evident across all major world regions[16]. The highest global incidence of CCA is seen in the Asian continent. Incidence rates in the West are lower than in Asia (range 0.5-3.4), with the highest rates seen in Italy (3.4 cases per 100000)[7]; incidence rates are shown in the Figure 1. CCA mortality is higher in older patients than in younger patients, and in men than in women; the median age for diagnosis is between 50 and 75 years[17]. Tumor stage shows a clear stepwise association with mortality, with advanced stages linked to progressively worse outcomes. In countries with different large ethnic groups, mortality rates can vary between different races because of the genetic factors related[3,8].

Figure 1 Incidence of cholangiocarcinoma. Figures were created using BioRender (Supplementary material). CCA: Cholangiocarcinoma.

Epidemiological evidence indicates that the incidence and characteristics of CCA differ significantly across regions, largely due to the variation in underlying risk factors, etiological origins, and diagnostic practices from one population to another. Thailand exhibits the highest global prevalence of CCA, resulting in a considerable strain on the national healthcare system[18,19]. Data retrieved from the Surveillance, Epidemiology, and End Results Program revealed that the estimated incidence of iCCA has risen by 128% over the past four decades in the United States[20]. A study by Bangolo et al[21] supported this finding through a large population-based study of 5803 United States patients diagnosed with iCCA between 2010 and 2017. The results demonstrated that both incidence and mortality rates were higher in metropolitan counties. In Europe, iCCA is the primary cause of BTC mortality, accounting for 42.1% in Germany (1.6 of 3.8 deaths), 67.7% in France (2.1 of 3.1), and 75.0% in the United Kingdom (2.4 of 3.2). In East Asia, iCCA is also a leading cause of CCA-related mortality, with a rate of 38.2% (4.2 of 11.0) in Korea. By contrast, in Japan, eCCA is the most common contributor to CCA mortality, accounting for 47.2% (3.4 of 7.2)[22]. Recent studies have shown an increasing trend in the incidence of iCCA in Western countries, differing from the stable or declining incidence rates observed for eCCA, while gallbladder cancer shows a higher incidence, particularly in Eastern Europe[9,23]. Recent data indicate that iCCA incidence in Asia has remained stable[18,24]. By contrast, a significant rise has been reported in Western countries, which may be attributed to advancements in diagnostic technologies, changing migration patterns, and an increasing prevalence of chronic liver disease. A 65.3% increase in new CCA cases and 67.6% rise in mortality are expected by 2042[25]. A comparative study analyzing 45 years of sex-based trends in CCA revealed that females are experiencing a greater increase in eCCA compared to iCCA, while males show a steady rise in iCCA with more fluctuating patterns in eCCA[22,26]. Differences in mortality rates are evident across sex and age groups: Males are more affected by CCA, whereas females have higher mortality from gallbladder cancer. In a recent study[3], CCA was found to be slightly more prevalent in women (56%). The incidence rate, ranging from 0.53 to 2 per 100000 population, was noted to be higher among Asian individuals and in men. The disease has shown a higher incidence in older people, and individuals aged 75 years and above show greater mortality across all BTC subtypes compared to younger patients[22]. It is expected to be high-human development index to have the biggest increase in total case numbers, whereas low-human development index countries will likely see the fastest growth in percentage terms[25].

The study conducted by Baldo et al[15] focuses on the epidemiological perspective of gallbladder malignancies over a 17-year period in Northeastern Italy. Epidemiological findings of the authors focused on three main subclasses: Total number of hospitalizations for BTC, hospitalization rates for iCCA and eCCA, and age- and sex-related patterns. The study included 10778 individuals, with a balanced sex distribution (51.3% male, 48.7% female). However, sex varied by diagnosis: ICCA and eCCA were more frequent in men (56.6% and 54.7%, respectively), whereas women were more commonly affected by gallbladder and other BTC (55.9%). The average patient age was 72.9 ± 11.3 years, and a large proportion (78.4%) were aged 65 or older. Patients with extrahepatic tumors were the oldest on average (74.1 ± 11.1), whereas intrahepatic cases had a slightly younger mean age (71.3 ± 11.5). Table 1 provides a summary of the sample characteristics based on the number of patients. All data retrieved from the study suggest a shift in the epidemiology of CCA over the past decade.

Table 1 Description of the sample by number of patients.

Characteristic	Total	Intrahepatic cholangiocarcinoma	Extrahepatic cholangiocarcinoma	Gallbladder cancer and unspecified biliary tract cancer
Sex
Male	5527	1793	1959	1775
Female	5251	1377	1624	2250
Age group (years)
0-44	160	68	44	48
45-54	547	189	165	193
55-64	1615	545	441	629
65-74	3184	1027	1000	1157
> 75	5272	1341	1933	1998
Age	72.9 ± 11.3	71.3 ± 11.5	74.1 ± 11.1	73.2 ± 11.2
Hospital stay	16.9 ± 16.5	15.9 ± 15.5	18.1 ± 18.1	16.6 ± 16.5
Hospitalization regimen
Ordinary	9893	2834	3401	3658
Day surgery	790	326	164	300
Week surgery	95	10	18	67
Biliary tract cancer in main diagnosis	8094	2458	2754	2882
Surgery during hospital stay	9246	2730	3143	3373

Table created by the author based on data from Baldo et al[15].

Several studies have reported an increasing incidence of iCCA and eCCA[22,23,25]. These increasing rates are seen mostly among females for eCCA, indicating a 65.3% increase in new cases and a 67.6% rise in mortality by 2042. By contrast, the study conducted by Baldo et al[15] showed that, over the past 17 years, the total number of BTC admissions remained stable with an average of 5.5. As summarized in the Figure 2, hospitalization rates in the study showed a decrease in iCCA, dropping from 4.9 (in 2009) to 3.4 (in 2023). For eCCA, hospitalization rates decreasing from 6.7 to 3.8 over time. Overall BTC hospitalizations decreased from 18.2 to 12.8. Regarding trends in hospitalization sex patterns, males appeared to be more affected than females (approximately 1.2-1.5:1). For age-related patterns, individuals aged 75 years and older had higher rates of diagnosis and mortality across all BTCs. These subtypes were mostly complex cases like intestinal and pancreatic surgeries, emphasizing the need for careful management in elderly patients. However, no significant change was observed for gallbladder cancer. Data for surgical interventions for digestive system diseases showed that they were predominantly performed in patients over 65, especially patients aged 75 and above[15]. Gallbladder, liver, and diagnostic procedures were most common.

Figure 2 Distribution of hospital admissions for biliary tract cancers, by type of diagnosis and year. Figures were created using BioRender (Supplementary material). CCA: Cholangiocarcinoma.

These differences between the previous studies may arise from improvements in outpatient diagnosis and early detection, resulting in fewer hospitalizations despite rising incidence rates. In earlier studies[23], gallbladder cancer appeared to have a higher incidence in Eastern Europe, whereas hospitalization rates for this subtype have remained stable. These differences in trends can be explained by regional differences in disease burden and healthcare access. Also, this study proves that the trends related to CCA and BTC have been changing and becoming more stable. There is still a need for long-term epidemiological studies, and this study could enlighten the path of upcoming research.

CONCLUSION

CCA remains a challenging disease to diagnose, often identified at advanced stages, and associated with high mortality rates. The wide range of risk factors contributes to the complexity and broad impact of the disease across populations. CCA is a global health problem, and trends of this disease vary across different regions. That is why epidemiological studies maintain their importance in understanding and managing the disease. The need to monitor the development of the disease through long-term, population-based studies is of critical importance. The findings of the study by Baldo et al[15] diverged from those reported in a previous investigation conducted in the same region between 2007 and 2023, indicating a possible shift in the epidemiological profile of CCA in recent decades. If carefully evaluated, the data presented in this study may serve as a valuable resource for assessing disease progression across different regions. Additional research is needed to clarify the underlying causes of this shift and to identify region-specific risk factors contributing to the emerging trend. Beyond enabling comparisons of disease prevalence across populations, this study is also noteworthy for presenting hospitalization rates, including those related to gallbladder cancer and other BTCs, as well as sex- and age-related patterns. This study highlights changing trends in CCA hospitalization rates in Italy and will continue to serve as a valuable reference. Nonetheless, there remains a continuing need for long-term studies encompassing broader geographic regions and more diverse population groups.