Abstract
Background
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major types of primary liver cancer, accounting for approximately 70% and 15% of all cases, respectively. South Korea remains a high-incidence region for both malignancies. Despite advances in surgical and imaging techniques, long-term survival outcomes and their changing trends over time have not been fully evaluated in population-based studies. This study aims to analyze survival rates and their influencing factors among patients with HCC and ICC who underwent hepatic resection in Korea.
Methods
Using the Korea Central Cancer Registry, we analyzed data from 43,537 patients who underwent hepatectomy between 2004 and 2018. Patients were categorized by time period (2004–2008, 2009–2013, 2014–2018), and 5-year survival rates were estimated using the Kaplan–Meier method. Multivariable Cox proportional hazards models identified prognostic factors associated with survival.
Results
A total of 36,380 patients with HCC and 7,157 with ICC underwent liver resection. Both cancers showed a male predominance, more pronounced in HCC. Major hepatectomy was frequent, particularly in ICC, which was associated with longer hospital stays, higher medical costs than HCC. Over time, the proportion of patients residing in metropolitan areas declined, more than half of surgeries continued to be performed there, indicating persistent geographic disparity between residence and treatment location. Surgeries at high-volume centers increased, hospital stays shortened, and 5-year survival improved in HCC but remained unchanged in ICC. Multivariable analysis identified male sex, advanced age, major hepatectomy, surgical region as independent predictors of poorer survival, with low income adversely affecting survival only in HCC.
Conclusion
Postoperative survival following hepatectomy has improved for HCC but remains unchanged for ICC. Better outcomes were observed for surgeries performed in metropolitan areas, likely reflecting differences in institutional experience and resources. These findings highlight persistent disparities in treatment outcomes and underscore the need for regionally balanced healthcare resources and further studies to refine prognostic determinants in primary liver cancers surgery.
Keywords: Hepatocellular Carcinoma, Intrahepatic Cholangiocarcinoma, Hepatic Resection, Population-Based Study
Graphical Abstract
INTRODUCTION
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) represent the two most common types of primary liver cancer, accounting for approximately 70% and 15% of all cases, respectively.1 Historically, the incidence of these malignancies has been markedly higher in East Asian populations compared to Western countries, including the United States. However, recent epidemiological data indicate a rising trend in the incidence of both HCC and ICC in many Western nations, reflecting a shifting global disease burden. Consequently, studies and reviews focusing on primary liver cancers are increasing worldwide.2,3
South Korea is recognized as one of the most highly endemic regions for both HCC and ICC. According to the GLOBOCAN 2020 report, South Korea ranks seventh globally in terms of HCC incidence, and national cancer statistics reveal that the country has the highest incidence of cholangiocarcinoma worldwide.4,5 Although the incidence rate of HCC in South Korea has remained relatively stable in recent years, the associated mortality rate continues to be high, imposing a considerable socioeconomic burden. These findings underscore the importance of proper disease management and the careful selection of therapeutic strategies for these malignancies.6
Hepatic resection remains the mainstay curative treatment for HCC in patients with adequate residual liver function, irrespective of the presence of cirrhosis.7 For ICC, R0 resection with regional lymphadenectomy is regarded as the standard curative approach.8 The reported 5-year survival rate following hepatectomy for HCC ranges from 34% to 50%, whereas that for ICC is approximately 15% to 40%.9,10 Despite the high risk of postoperative recurrence, surgical resection continues to serve as a cornerstone in curative treatment strategies for primary liver cancers.
In recent years, the surgical landscape for liver cancer has undergone substantial transformation. Advances in minimally invasive liver resection techniques have rapidly expanded their indications. Compared with conventional open hepatectomy, minimally invasive approaches are associated with reduced postoperative pain, lower complication rates, and shorter hospital stays, while maintaining comparable recurrence and survival outcomes.6,11 Concurrently, technological improvements in intraoperative imaging and navigation have facilitated the detection of small tumor lesions and enabled safer, more precise resections, further broadening the spectrum of resectable disease.12,13 Given these evolving surgical and technological paradigms, it is essential to understand how survival outcomes and prognostic factors have changed over time.
In addition, growing evidence suggests that geographic and socioeconomic disparities may substantially influence access to specialized surgical care and long-term outcomes in patients with primary liver cancer. In Korea, advanced hepatobiliary surgery is disproportionately concentrated in metropolitan areas, particularly in university-affiliated hospitals, whereas a considerable proportion of patients reside in non-metropolitan regions.6 This mismatch between patients’ residential locations and surgical treatment sites may reflect regional inequalities in healthcare resources, referral patterns, and availability of high-volume centers. Moreover, socioeconomic status has been increasingly recognized as an important determinant of cancer outcomes, potentially affecting timely diagnosis, treatment selection, and perioperative care. Although Korea operates a universal health insurance system, differences in income level may still influence treatment-related financial burden, length of hospitalization, and overall medical costs, which in turn could affect postoperative recovery and survival.14
Therefore, the present study aims to analyze survival rates and their influencing factors among patients with HCC and ICC who underwent hepatic resection in Korea, using population-based data across different eras.
METHODS
Study population
Data from patients diagnosed with HCC and ICC who underwent hepatectomy and were registered in the Korea Central Cancer Registry (KCCR) between January 2004 and December 2018 were included (n = 43,537). The KCCR is a national registry that covers more than 98% of cancer patients in South Korea and includes nationwide data on cancer incidence and survival since 1999. Based on the International Classification of Diseases for Oncology, 10th edition, HCC was defined by code C22.0 and IHC by code C22.1.15 Exclusion criteria included: 1) patients with multiple primary cancers, 2) patients aged ≤ 20 years, and 3) patients with incomplete data, including missing survival time, 4) patients who died within 1 month after surgery (n = 676; 545 with HCC and 131 with ICC). Mortality data were obtained from Statistics Korea, which provides official national sources of vital status information. The date of death was recorded for all deceased patients, and person-years at risk were calculated from the date of diagnosis to either the date of death or the end of follow-up (December 2023). A three-year washout period was applied to exclude prevalent cases. Hepatectomies were categorized as minor resections (Q7221, Q7222; ≤ 2 Couinaud segments) and major resections (Q7223, Q7224; ≥ 3 Couinaud segments). The regions of patient residence and surgery were classified as metropolitan or non-metropolitan areas. The metropolitan area was defined as Seoul and the surrounding Gyeonggi Province, while all other provinces (Chungcheong, Gyeongsang, Gangwon, Jeolla, and Jeju) were classified as non-metropolitan. Patients were also categorized by surgery period: period 1 (2004–2008), period 2 (2009–2013), and period 3 (2014–2018). Hospital volume was classified as high-volume (≥ 100 patient beds) or low-volume (< 100 beds). Hospital stay was defined as the interval between the date of surgery and discharge. Income levels were categorized as low (deciles 1st–2nd) or high (deciles 3rd–4th) according to the Korea Health Insurance Organization’s income data.
Statistical analysis
Continuous variables were expressed as means ± standard deviations, and categorical variables as proportions. Five-year survival rates after hepatectomy were estimated using the Kaplan–Meier method. Cox proportional hazards models were used to calculate hazard ratios with 95% confidence intervals in univariable and multivariable analyses. A forward stepwise method was applied to assess potential confounders, and statistical interactions among variables were also evaluated. A two-sided P value < 0.05 was considered statistically significant. All analyses were conducted using SPSS version 20 for Windows (IBM Corp., Armonk, NY, USA).
Ethics statement
This study was approved by the Institutional Review Board (IRB) of Hallym Medical Center and the requirement for informed consent was waived (IRB No. HUMC 2020-09-001).
RESULTS
Table 1 presents the overall population characteristics of patients who underwent liver resection for HCC and ICC. A total of 36,380 patients with HCC and 7,157 with ICC were included. Both cancers showed a clear male predominance, more pronounced in HCC. HCC resections were most common in patients in their 50s, whereas ICC was most common in patients in their 60s, with nearly one-third aged ≥ 70 years. Regarding the extent of liver resection, major hepatectomy was more frequent in both cancers (58.2% in HCC and 83.5% in ICC). Although fewer than one-fifth of patients resided in metropolitan areas (18.2% for HCC, 16.3% for ICC), more than half of all surgeries were performed there (59.1% for HCC, 54.1% for ICC), reflecting substantial regional centralization of surgical care. In terms of hospital volume, most resections were conducted at high-volume hospitals (81.1% of HCC and 76.6% of ICC). ICC was associated with longer hospital stays, higher medical costs, and poorer 5-year survival compared with HCC (Fig. 1).
Table 1. Clinical characteristics of 43,537 patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma who underwent hepatic resection in Korea.
| Variables | Hepatocellular carcinoma (n = 36,380, 83.5%) | Intrahepatic cholangiocarcinoma (n = 7,157, 16.5%) | |
|---|---|---|---|
| Age, yr | |||
| ≥ 39 | 1,522 (4.2) | 94 (1.3) | |
| 40–49 | 6,088 (16.7) | 411 (5.7) | |
| 50–59 | 12,832 (35.3) | 1,532 (21.4) | |
| 60–69 | 10,920 (30.0) | 2,800 (39.1) | |
| 70–79 | 4,610 (12.7) | 2,072 (29.0) | |
| ≥ 80 | 408 (1.1) | 248 (3.5) | |
| Sex | |||
| Male | 29,074 (79.9) | 4,657 (65.1) | |
| Female | 7,306 (20.1) | 2,500 (34.9) | |
| Extent of liver resection | |||
| Major resection | 21,163 (58.2) | 5,979 (83.5) | |
| Minor resection | 15,217 (41.8) | 1,178 (16.5) | |
| Residence region | |||
| Metropolitan area | 6,616 (18.2) | 1,164 (16.3) | |
| Non-metropolitan area | 29,764 (81.8) | 5,993 (83.7) | |
| Hospital region | |||
| Metropolitan area | 21,499 (59.1) | 3,870 (54.1) | |
| Non-metropolitan area | 14,881 (40.9) | 3,287 (45.9) | |
| Income (quartile) | |||
| 1st–2nd (low) | 13,743 (38.5) | 2,588 (36.9) | |
| 3rd–4th (high) | 21,937 (61.5) | 4,422 (63.1) | |
| Hospital volume | |||
| High | 29,513 (81.1) | 5,480 (76.6) | |
| Low | 6,865 (18.9) | 1,677 (23.4) | |
| Year of surgery | |||
| 2004–2008 | 7,890 (21.7) | 1,707 (24.7) | |
| 2009–2013 | 12,750 (35.0) | 2,809 (39.2) | |
| 2014–2018 | 15,740 (43.3) | 2,578 (36.0) | |
| Hospital stay, day | 17.1 ± 9.0 | 25.6 ± 14.9 | |
| Total cost, $ | 7,216.2 ± 4,602.6 | 10,681.0 ± 6,540.4 | |
| Patients cost, $ | 516.5 ± 371.5 | 787.1 ± 580.5 | |
| 5-year survival rate, % | 61.1 | 32.4 | |
Values are presented as number (%) or mean ± standard deviation unless otherwise indicated.
Fig. 1. Kaplan–Meier curves of overall survival in patients who underwent hepatic resection for (a) hepatocellular carcinoma and (b) intrahepatic cholangiocarcinoma.
Tables 2 and 3 summarize the demographic characteristics of patients undergoing liver resection for HCC and ICC across different time periods. For both cancers, the number of surgeries increased with age over time. For HCC, the proportion of patients aged ≥ 70 years increased to 18% in Period 3, while ICC showed a marked shift toward older age groups, with over 40% aged ≥ 60 years. In both cancers, the proportion of patients residing in metropolitan areas declined over time (HCC: 20.4%, 18.3%, and 17.0%; ICC: 17.3%, 16.8%, and 14.9%), whereas the proportion of surgeries performed in metropolitan areas remained consistently high (HCC: 61.1%, 60.5%, and 56.7%; ICC: 54.5%, 58.8%, and 48.7%), indicating a persistent geographic disparity between patients’ residence and surgical treatment location. Surgeries at high-volume centers increased in later periods, accompanied by a shift toward higher-income patient groups and a reduction in length of hospital stay. Five-year survival improved substantially over time in HCC but remained unchanged in ICC (Figs. 2 and 3).
Table 2. Clinical characteristics of 36,380 patients with hepatocellular carcinoma who underwent hepatic resection over time period.
| Variables | Hepatocellular carcinoma | |||
|---|---|---|---|---|
| Period 1 2004–2008 (n = 7,890; 21.7%) | Period 2 2009–2013 (n = 12,750; 35.0%) | Period 3 2014–2018 (n = 15,740; 43.3%) | ||
| Age, yr | ||||
| ≥ 39 | 517 (6.6) | 536 (4.2) | 469 (3.0) | |
| 40–49 | 1,852 (23.5) | 2,167 (17.0) | 2,069 (13.1) | |
| 50–59 | 2,778 (35.2) | 4,815 (37.8) | 5,239 (33.3) | |
| 60–69 | 2,140 (27.1) | 3,647 (28.6) | 5,133 (32.6) | |
| 70–79 | 581 (7.4) | 1,498 (11.7) | 2,531 (16.1) | |
| ≥ 80 | 22 (0.3) | 87 (0.7) | 299 (1.9) | |
| Sex | ||||
| Male | 6,282 (79.6) | 10,186 (79.9) | 12,606 (80.1) | |
| Female | 1,608 (20.4) | 2,564 (20.1) | 3,134 (19.9) | |
| Extent of liver resection | ||||
| Major resection | 4,702 (59.6) | 7,887 (61.9) | 8,574 (54.5) | |
| Minor resection | 3,188 (40.4) | 4,863 (38.1) | 7,166 (45.5) | |
| Residence region | ||||
| Metropolitan area | 1,608 (20.4) | 2,339 (18.3) | 2,669 (17.0) | |
| Non-metropolitan area | 6,282 (79.6) | 10,411 (81.7) | 10,402 (83.0) | |
| Hospital region | ||||
| Metropolitan area | 4,871 (61.7) | 7,708 (60.5) | 8,920 (56.7) | |
| Non-metropolitan area | 3,019 (38.3) | 5,042 (39.5) | 6,820 (43.3) | |
| Income (quartile) | ||||
| 1st–2nd (low) | 2,642 (34.0) | 4,837 (39.0) | 6,264 (40.4) | |
| 3rd–4th (high) | 5,130 (66.0) | 7,569 (61.0) | 9,238 (59.6) | |
| Hospital volume | ||||
| High | 6,237 (79.1) | 10,112 (79.3) | 13,406 (83.6) | |
| Low | 1,653 (20.9) | 2,637 (20.7) | 2,575 (16.4) | |
| Hospital stay, day | 20.9 ± 10.6 | 17.9 ± 8.8 | 14.6 ± 7.4 | |
| Total expense, $ | 5,728.6 ± 3,200.3 | 6,878.2 ± 4,403.0 | 8,235.7 ± 5,087.8 | |
| Patients expense, $ | 724.6 ± 443.3 | 449.5 ± 330.5 | 466.5 ± 322.7 | |
| 5-yr survival rate, % | 48.3 | 59.1 | 67.1 | |
Values are presented as number (%) or mean ± standard deviation unless otherwise indicated.
Table 3. Clinical characteristics of 7,157 patients with intrahepatic cholangiocarcinoma who underwent hepatic resection over time period.
| Variables | Intrahepatic cholangiocarcinoma | |||
|---|---|---|---|---|
| Period 1 2004–2008 (n = 1,770; 24.7%) | Period 2 2009–2013 (n = 2,809; 39.3%) | Period 3 2014–2018 (n = 2,578; 36.0%) | ||
| Age, yr | ||||
| ≥ 39 | 38 (2.1) | 34 (1.2) | 22 (0.9) | |
| 40–49 | 141 (8.0) | 177 (6.3) | 93 (3.6) | |
| 50–59 | 466 (26.3) | 571 (20.3) | 495 (19.2) | |
| 60–69 | 761 (43.0) | 1,115 (39.7) | 924 (35.8) | |
| 70–79 | 343 (19.4) | 831 (29.6) | 898 (34.8) | |
| ≥ 80 | 21 (1.2) | 81 (2.9) | 146 (5.7) | |
| Sex | ||||
| Male | 1,137 (64.2) | 1,860 (66.2) | 1,660 (64.4) | |
| Female | 633 (35.8) | 949 (33.8) | 918 (35.6) | |
| Extent of liver resection | ||||
| Major resection | 1,453 (82.1) | 2,393 (85.2) | 2,133 (82.7) | |
| Minor resection | 317 (17.9) | 416 (14.8) | 445 (17.3) | |
| Residence region | ||||
| Metropolitan area | 307 (17.3) | 472 (16.8) | 385 (14.9) | |
| Non-metropolitan area | 1,463 (82.7) | 2,337 (83.2) | 2,193 (85.1) | |
| Hospital region | ||||
| Metropolitan area | 964 (54.5) | 1,651 (58.8) | 1,255 (48.7) | |
| Non-metropolitan area | 806 (45.5) | 1,158 (41.2) | 1,323 (51.3) | |
| Income (quartile) | ||||
| 1st–2nd (low) | 633 (36.5) | 994 (36.3) | 961 (37.8) | |
| 3rd–4th (high) | 1,103 (63.5) | 1,741 (63.7) | 1,578 (62.2) | |
| Hospital volume | ||||
| High | 1,323 (74.7) | 2,151 (76.6) | 2,006 (77.8) | |
| Low | 447 (25.3) | 658 (23.4) | 572 (22.2) | |
| Hospital stay, day | 31.1 ± 16.6 | 26.6 ± 14.6 | 20.9 ± 12.4 | |
| Total expense, $ | 8,856.2 ± 5,062.4 | 10,658.9 ± 6,357.5 | 11,957.9 ± 7,296.0 | |
| Patients expense, $ | 1,126.9 ± 716.0 | 658.8 ± 507.4 | 664.1 ± 444.5 | |
| 5-year survival rate, % | 32.7 | 31.8 | 32.9 | |
Values are presented as number (%) or mean ± standard deviation unless otherwise indicated.
Fig. 2. Kaplan–Meier curves of overall survival in patients who underwent hepatic resection for hepatocellular carcinoma, stratified by three operative periods (period 1: 2004–2008, period 2: 2009–2013, and period 3: 2014–2018). The 5-year survival rates for hepatocellular carcinoma improved across the three periods (48.3%, 59.1%, and 67.1%).
Fig. 3. Kaplan–Meier curves of overall survival in patients who underwent hepatic resection for intrahepatic cholangiocarcinoma, stratified by three operative periods (period 1: 2004–2008, period 2: 2009–2013, and period 3: 2014–2018). The 5-year survival rates for intrahepatic cholangiocarcinoma remained relatively stable across the three periods (32.7%, 31.8%, and 32.9%).
Table 4 summarizes the multivariate analysis results of 5-year survival in both cancers. Male sex, age ≥ 80 years, major liver resection and region of surgery were identified as independent prognostic factors for both cancers. Additionally, low-income status was an independent risk factor only in HCC patients. However, region of residence and treatment at high-volume hospitals were not significant prognostic factors in either cancer.
Table 4. Unadjusted and adjusted odds ratios for 5-year survival among patients undergoing surgery for hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Korea.
| Variables | Hepatocellular carcinoma | Intrahepatic cholangiocarcinoma | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Unadjusted OR (95% CI) | P value | Adjusted OR (95% CI) | P value | Unadjusted OR (95% CI) | P value | Adjusted OR (95% CI) | P value | ||
| Sex | < 0.001 | < 0.001 | 0.001 | 0.001 | |||||
| Female | Reference | Reference | Reference | Reference | |||||
| Male | 1.23 (0.94–1.61) | 1.15 (1.06–1.25) | 1.03 (0.94–1.13) | 1.29 (1.24–1.33) | |||||
| Age, yr | |||||||||
| ≥ 39 | Reference | Reference | Reference | Reference | |||||
| 40–49 | 0.96 (0.87–1.05) | 0.187 | 0.94 (0.85–1.03) | 0.169 | 0.91 (0.68–1.22) | 0.530 | 0.91 (0.83–0.99) | 0.634 | |
| 50–59 | 0.90 (0.83–0.99) | 0.026 | 0.93 (0.69–1.25) | 0.035 | 1.07 (0.82–1.40) | 0.603 | 1.09 (0.83–1.43) | 0.555 | |
| 60–69 | 1.04 (0.95–1.14) | 0.359 | 1.08 (1.02–1.15) | 0.515 | 1.22 (0.93–1.58) | 0.146 | 1.23 (1.17–1.29) | 0.135 | |
| 70–79 | 1.51 (1.15–1.97) | < 0.001 | 1.42 (1.29–1.57) | < 0.001 | 1.45 (1.11–1.89) | 0.006 | 1.43 (1.29–1.57) | 0.003 | |
| ≥ 80 | 1.87 (1.38–2.54) | < 0.001 | 2.21 (1.85–2.64) | < 0.001 | 1.78 (1.32–2.40) | < 0.001 | 2.10 (1.77–2.51) | < 0.001 | |
| Extent of liver resection | < 0.001 | < 0.001 | 0.001 | 0.001 | |||||
| Minor resection | Reference | Reference | Reference | Reference | |||||
| Major resection | 1.39 (1.34–1.44) | 1.11 (1.04–1.18) | 1.23 (1.13–1.33) | 1.24 (1.18–1.30) | |||||
| Region of residence | 0.470 | 0.694 | 0.163 | 0.716 | |||||
| Metropolitan area | Reference | Reference | Reference | Reference | |||||
| Non-metropolitan area | 1.06 (0.90–1.26) | 0.89 (0.74–1.08) | 1.06 (0.98–1.16) | 1.11 (1.02–1.21) | |||||
| Region of surgery | < 0.001 | < 0.001 | < 0.001 | 0.006 | |||||
| Metropolitan area | Reference | Reference | Reference | Reference | |||||
| Non-metropolitan area | 1.30 (1.26–1.35) | 1.23 (1.18–1.29) | 1.11 (1.05–1.18) | 1.15 (1.06–1.25) | |||||
| Income (quartile) | < 0.001 | < 0.001 | 0.794 | 0.112 | |||||
| 1st–2nd (low) | Reference | Reference | Reference | Reference | |||||
| 3rd–4th (high) | 0.85 (0.82–0.88) | 0.91 (0.83–0.99) | 0.99 (0.93–1.05) | 0.96 (0.87–1.05) | |||||
| Hospital volume | < 0.001 | 0.450 | 0.075 | 0.864 | |||||
| High | |||||||||
| Low | 1.19 (1.14–1.24) | 1.08 (1.02–1.15) | 1.06 (0.99–1.14) | 1.03 (0.94–1.13) | |||||
OR = odds ratio, CI =confidence interval.
DISCUSSION
According to the 2020 Korean Liver Cancer Association (KLCA)–National Cancer Center Korea Practice Guidelines, the incidence of HCC is 21.2 per 100,000 population, and its mortality rate is the second highest among cancers in South Korea, with 20.6 deaths per 100,000 population.6 The incidence of ICC is approximately 4 per 100,000 population, and the overall 5-year survival rate is reported to be 10.8%.5 In our study, which included only patients who underwent hepatectomy, the overall 5-year survival rates were 61.1% for HCC and 32.4% for ICC. The survival rate for HCC improved gradually over time, whereas that for ICC remained unchanged.
Previous reports have shown comparable findings. Hasegawa et al.,16 using a Japanese nationwide survey, reported 3- and 5-year survival rates of 85.3% and 71.1%, respectively, among 5,361 patients who underwent hepatectomy. Similarly, Zhang et al.,17 using the SEER database in the United States, found that 8.8% of HCC patients underwent hepatectomy, with a 5-year survival rate of 51%. HCC typically occurs in patients with chronic liver disease—most commonly due to chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, or cirrhosis. Among these, chronic HBV infection remains the predominant etiology in Korea. According to the KLCA Randomized Survey Project, between 2012 and 2014, 59.1% of HCC patients were HBV-positive, 10.7% were HCV-positive, and 30.3% had alcohol-related or cryptogenic causes.18 In a single-institution cohort (2010–2015), 74% of patients newly diagnosed with liver cancer were HBV-positive. The number of liver resections for HCC has gradually increased over time in this study.6 Although hepatectomy is primarily indicated for early-stage disease (Barcelona clinic liver cancer stage A), improvements in imaging technology and minimally invasive techniques have expanded surgical indications and likely contributed to this increase.19
In addition, several factors may explain the gradual improvement in prognosis among patients undergoing hepatic resection for HCC over time. First, advances in diagnostic imaging and surveillance programs have enabled earlier detection of tumors, allowing a greater proportion of patients to undergo curative-intent resection at less advanced stages.20 Second, refinements in surgical techniques, including parenchymal-sparing approaches and the increasing adoption of minimally invasive liver resection, have contributed to reduced perioperative morbidity and improved postoperative recovery.21 Third, progress in perioperative management—such as better patient selection, enhanced anesthetic care, and improved management of underlying liver disease—has lowered operative risk and postoperative mortality.22 Collectively, these developments have contributed to the observed serial improvement in survival following hepatic resection for HCC.
In contrast, ICC remains associated with a poorer prognosis. In a 30-year population-based SEER analysis, Nathan et al.23 reported a 5-year postoperative survival rate of 34.4%. Similarly, Olthof et al.,24 using a Dutch nationwide cohort, found that 17% of ICC patients underwent hepatectomy, with 1- and 3-year survival rates of 79.2% and 51.6%, respectively. Our findings align with these results, demonstrating persistently low survival outcomes for ICC across time. The prognosis of patients undergoing resection for ICC has remained largely unchanged due to several fundamental factors. A major contributing factor is late diagnosis, as ICC often presents with nonspecific symptoms, resulting in many patients having locally advanced disease or occult micrometastases at the time of detection. Consequently, unfavorable pathological features such as lymph node metastasis, vascular invasion, and multifocal tumors are common and are closely associated with poor survival.25 Moreover, ICC is characterized by aggressive tumor biology, with a high risk of early intrahepatic recurrence and distant metastasis even after curative (R0) resection. Microscopic tumor spread undetectable at surgery likely contributes to early relapse, limiting the long-term effectiveness of surgical treatment alone. Although surgical strategies, including extended hepatectomy and minimally invasive approaches, have advanced, these technical improvements do not sufficiently address the underlying biological aggressiveness of ICC.26 Additionally, despite ongoing research on adjuvant and neoadjuvant therapies, no systemic treatment has consistently demonstrated a clear overall survival benefit, and reported effects remain modest and inconsistent across studies.27
Risk factors for ICC remain less well-defined than those for HCC, with studies suggesting associations with hepatolithiasis, parasitic infection, HBV, HCV, and primary sclerosing cholangitis, though results vary by region.28,29,30
In our analysis, the extent of hepatic resection was identified as an independent prognostic factor. This is not surprising, given that major hepatectomy can reflect a state of suboptimal hepatic reserve thereby increasing the risk of postoperative liver failure. Furthermore, based on American Joint Committee on Cancer staging criteria, tumor size plays a crucial role in determining the prognosis for both types of cancer.31 The larger the tumor, the greater the likelihood of requiring a major hepatectomy, and consequently, the poorer the patient’s prognosis. This observation aligns with the findings of Shehta et al.,32 who reported a similar correlation between larger tumor size, major hepatectomy, and unfavorable prognosis among 315 patients undergoing hepatectomy for HCC.
Geographical difference in which the surgery was performed was also a significant prognostic factor. For both cancers, the number of surgeries performed in the metropolitan area was similar over time however survival rates were higher in the metropolitan area. In fact, it is difficult to determine the cause. However, in South Korea, the number of university-affiliated hospitals in the metropolitan area is about one-third of the total, and most of these leading hospitals are concentrated in Seoul. Since university-affiliated hospitals are institutions of education and research, they are likely to have more experienced surgeons as well as better access to advanced technology and multidisciplinary care. Therefore, this may affect patient prognosis.
Socioeconomic status may also play a meaningful role in determining prognosis among patients undergoing hepatic resection for liver cancers. As demonstrated in our nationwide analysis, patients with lower income levels exhibited less favorable survival outcomes, particularly in HCC. This finding is consistent with prior population-based studies emphasized that patients from lower socioeconomic strata may experience delayed diagnosis, limited access to specialized centers, and differences in perioperative support, all of which can adversely affect surgical outcomes and long-term survival.14 Even within a national health insurance system, disparities in income may influence treatment-related financial burden, length of hospitalization, postoperative recovery, and adherence to follow-up care. These results underscore the importance of incorporating socioeconomic factors into risk stratification and postoperative management strategies.
This study has several limitations related to the use of national administrative data. Key tumor- and treatment-specific variables—such as tumor stage (including BCLC staging for HCC), resection margin status, operative complexity, and the use of adjuvant therapies—were not available. The absence of these factors may limit adequate adjustment for disease severity and tumor biology. As a result, the observed associations between geographic region, surgical location, and survival should be interpreted with caution, as residual confounding by unmeasured disease characteristics cannot be excluded. Furthermore, lack of pathological detail precludes assessment of oncologic quality of resection, such as margin status, which is known to influence prognosis. Future studies incorporating detailed clinical, pathological, and treatment-level data are warranted to better clarify the independent effects of regional and institutional factors on survival outcomes.
In the present study, surgery performed in metropolitan areas was associated with better survival, despite hospital volume (defined by bed count) and region of residence not being independent prognostic factors. This finding raises several important considerations. First, the definition of hospital volume may be suboptimal. In Korea, hospitals are legally classified as general hospitals based on a minimum of 100 beds, and national administrative data adopt this same definition. As a result, more granular measures of hospital size could not be applied in this study. Second, bed number does not necessarily reflect surgeon expertise or hepatobiliary surgical volume. Ideally, hospitals should be stratified by hepatobiliary case load rather than bed count; however, such data are not currently available in national statistics. Notably, general hospitals in Korea are required to provide multiple specialty services, potentially facilitating multidisciplinary care, which may influence outcomes. Finally, unmeasured factors such as specialist availability, multidisciplinary systems, and institutional infrastructure may partly explain the observed survival advantage. These complex and difficult-to-quantify variables warrant further investigation using more detailed, institution-level data.
Therefore, the findings of this study should be interpreted with caution. In particular, hospital volume in the present analysis was defined according to the number of hospital beds rather than surgical case volume, because the data were derived from the KCCR, in which hospital size is categorized based on bed count rather than procedure volume.
In conclusion, the overall 5-year survival rates for patients who underwent hepatic resection for HCC and ICC in Korea were 61.1% and 32.4%, respectively. While survival outcomes for HCC have gradually improved over time, those for ICC have remained unchanged. Although the number of surgeries performed in metropolitan area remained similar, survival outcomes were better for surgeries performed in metropolitan area in both cancers. The underlying causes remain unclear, and large-scale, controlled studies are needed to further clarify the direct impact of these potential risk factors on long-term outcomes.
ACKNOWLEDGMENTS
This study used data from the Korea Central Cancer Registry (KCCR). The authors thank the National Cancer Center for providing the access to the registry data.
Footnotes
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Lee JM, Kim SJ, Yoo T.
- Data curation: Kim SJ.
- Formal analysis: Kim SJ.
- Investigation: Lee JM, Kim SJ, Yoo T.
- Methodology: Lee JM, Kim SJ, Yoo T.
- Project administration: Lee JM, Kim SJ, Yoo T.
- Resources: Kim SJ.
- Software: Kim SJ.
- Supervision: Cho W.
- Validation: Yoo T.
- Visualization: Lee JM, Kim SJ, Yoo T, Cho W.
- Writing - original draft: Lee JM, Kim SJ, Yoo T.
- Writing - review & editing: Cho W.
References
- 1.Massarweh NN, El-Serag HB. Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Contr. 2017;24(3):1073274817729245. doi: 10.1177/1073274817729245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kim BW, Oh CM, Choi HY, Park JW, Cho H, Ki M. Incidence and overall survival of biliary tract cancers in South Korea from 2006 to 2015: using the National Health Information Database. Gut Liver. 2019;13(1):104–113. doi: 10.5009/gnl18105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hahn JW, Woo S, Park J, Lee H, Kim HJ, Ko JS, et al. Global, regional, and national trends in liver disease-related mortality across 112 countries from 1990 to 2021, with projections to 2050: comprehensive analysis of the WHO mortality database. J Korean Med Sci. 2024;39(46):e292. doi: 10.3346/jkms.2024.39.e292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 5.Kang MJ, Lim J, Han SS, Park HM, Kim SW, Lee WJ, et al. Distinct prognosis of biliary tract cancer according to tumor location, stage, and treatment: a population-based study. Sci Rep. 2022;12(1):10206. doi: 10.1038/s41598-022-13605-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J Liver Cancer. 2023;23(1):1–120. doi: 10.17998/jlc.2022.11.07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Park MS, Cho JY, Kim E, Na HY, Choi Y, Ki NR, et al. Surgical treatment of hepatocellular carcinoma: an expert consensus-based practical recommendation from the Korean Liver Cancer Association. Ann Surg Treat Res. 2025;109(3):123–143. doi: 10.4174/astr.2025.109.3.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wang J, Shu M, Peng H, Li S, Li D, Shen J, et al. The influence of the extent of lymph node metastasis on the prognosis for patients with intrahepatic cholangiocarcinoma. Ann Surg Treat Res. 2023;104(5):258–268. doi: 10.4174/astr.2023.104.5.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lang H, Sotiropoulos GC, Brokalaki EI, Schmitz KJ, Bertona C, Meyer G, et al. Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers. J Am Coll Surg. 2007;205(1):27–36. doi: 10.1016/j.jamcollsurg.2007.03.002. [DOI] [PubMed] [Google Scholar]
- 10.DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755–762. doi: 10.1097/01.sla.0000251366.62632.d3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Jung D, Han DH. The safety and efficacy of minimally invasive re-resection in recurrent hepatocellular carcinoma patients. Annals of Hepato-Biliary-Pancreatic Surgery. 2023;27(1):S179. [Google Scholar]
- 12.Pulumati A, Pulumati A, Dwarakanath BS, Verma A, Papineni RVL. Technological advancements in cancer diagnostics: improvements and limitations. Cancer Rep (Hoboken) 2023;6(2):e1764. doi: 10.1002/cnr2.1764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kwon J, Chun KS, Song IS, Kim SH, Han S. Long-term outcome of intraoperative radiofrequency ablation for hepatocellular carcinoma and its efficacy as a primary treatment. Ann Hepatobiliary Pancreat Surg. 2020;24(1):24–32. doi: 10.14701/ahbps.2020.24.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Son M, Kim HR, Choe SA, Song SY, Lim KH, Ki M, et al. Social inequities in the survival of liver cancer: a nationwide cohort study in Korea, 2007–2017. J Korean Med Sci. 2024;39(12):e130. doi: 10.3346/jkms.2024.39.e130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Li R, Hao Z, Liu KX. Analysis of the quality of coding for tumors in line with International Classification of Diseases. J First Mil Med Univ. 2004;24(2):187–191. [PubMed] [Google Scholar]
- 16.Hasegawa K, Kokudo N, Makuuchi M, Izumi N, Ichida T, Kudo M, et al. Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey. J Hepatol. 2013;58(4):724–729. doi: 10.1016/j.jhep.2012.11.009. [DOI] [PubMed] [Google Scholar]
- 17.Zhang K, Chen R, Gong X, Gao Y. Survival outcomes of liver transplantation versus liver resection among patients with hepatocellular carcinoma: a SEER-based longitudinal study. J Formos Med Assoc. 2019;118(4):790–796. doi: 10.1016/j.jfma.2018.09.015. [DOI] [PubMed] [Google Scholar]
- 18.Chon YE, Jeong SW, Jun DW. Hepatocellular carcinoma statistics in South Korea. Clin Mol Hepatol. 2021;27(3):512–514. doi: 10.3350/cmh.2021.0171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022;76(3):681–693. doi: 10.1016/j.jhep.2021.11.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lee DH, Cho H, Yu SJ, Park MK, Lee YB, Cho EJ, et al. Alternative surveillance improves outcomes by detecting early-stage hepatocellular carcinoma in chronic hepatitis B patients. Gut Liver. 2025;19(5):770–780. doi: 10.5009/gnl240602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Morise Z. Current status of minimally invasive liver surgery for cancers. World J Gastroenterol. 2022;28(43):6090–6098. doi: 10.3748/wjg.v28.i43.6090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Yan LN, Chen XL, Li ZH, Li B, Lu SC, Wen TF, et al. Perioperative management of primary liver cancer. World J Gastroenterol. 2007;13(13):1970–1974. doi: 10.3748/wjg.v13.i13.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11(11):1488–1496. doi: 10.1007/s11605-007-0282-0. [DOI] [PubMed] [Google Scholar]
- 24.Olthof PB, Franssen S, van Keulen AM, van der Geest LG, Hoogwater FJH, Coenraad M, et al. Nationwide treatment and outcomes of intrahepatic cholangiocarcinoma. HPB. 2023;25(11):1329–1336. doi: 10.1016/j.hpb.2023.06.019. [DOI] [PubMed] [Google Scholar]
- 25.Chang YJ, Chang YJ, Chen LJ. Prognostic factors in patients with intrahepatic cholangiocarcinoma. Sci Rep. 2024;14(1):19084. doi: 10.1038/s41598-024-70124-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Song Y, Cai M, Li Y, Liu S. The focus clinical research in intrahepatic cholangiocarcinoma. Eur J Med Res. 2022;27(1):116. doi: 10.1186/s40001-022-00741-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Gujarathi R, Peshin S, Zhang X, Bachini M, Meeks MN, Shroff RT, et al. Intrahepatic cholangiocarcinoma: Insights on molecular testing, targeted therapies, and future directions from a multidisciplinary panel. Hepatol Commun. 2025;9(7):e0743. doi: 10.1097/HC9.0000000000000743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kim HJ, Kang TU, Swan H, Kang MJ, Kim N, Ahn HS, et al. Incidence and prognosis of subsequent cholangiocarcinoma in patients with hepatic resection for bile duct stones. Dig Dis Sci. 2018;63(12):3465–3473. doi: 10.1007/s10620-018-5262-6. [DOI] [PubMed] [Google Scholar]
- 29.Shin HR, Oh JK, Lim MK, Shin A, Kong HJ, Jung KW, et al. Descriptive epidemiology of cholangiocarcinoma and clonorchiasis in Korea. J Korean Med Sci. 2010;25(7):1011–1016. doi: 10.3346/jkms.2010.25.7.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Mukkamalla SKR, Naseri HM, Kim BM, Katz SC, Armenio VA. Trends in incidence and factors affecting survival of patients with cholangiocarcinoma in the United States. J Natl Compr Canc Netw. 2018;16(4):370–376. doi: 10.6004/jnccn.2017.7056. [DOI] [PubMed] [Google Scholar]
- 31.Brown ZJ, Tsilimigras DI, Ruff SM, Mohseni A, Kamel IR, Cloyd JM, et al. Management of hepatocellular carcinoma: a review. JAMA Surg. 2023;158(4):410–420. doi: 10.1001/jamasurg.2022.7989. [DOI] [PubMed] [Google Scholar]
- 32.Shehta A, Elsabbagh AM, Medhat M, Farouk A, Monier A, Said R, et al. Impact of tumor size on the outcomes of hepatic resection for hepatocellular carcinoma: a retrospective study. BMC Surg. 2024;24(1):7. doi: 10.1186/s12893-023-02296-w. [DOI] [PMC free article] [PubMed] [Google Scholar]