Hepatolithiasis and HBV infection as the two most common risk factors for ICC in China, and ICC without a clear cause (conventional-ICC) were the mainly specific pathogenic factors in present studies [14,15,16,17, 20]. Therefore, we divided the etiology of ICC patients into three subtypes, Con-ICC (no identifiable cause), HBV-ICC, and Stone-ICC. Survival analysis showed that the OS and RFS were statistically significant among the three etiological subtypes, and the etiology of ICC was identified as an independent risk factor for OS. To further compare the survival differences between related two etiological subtypes, PSM was conducted to eliminate differences in baseline clinicopathological characteristics. After PSM, the OS of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes, while the RFS of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC. Wang et al. [21] conducted a single institutional study and found that Stone-ICC had a worse prognosis compared to HBV-ICC after PSM. Similarly, Zhang et al. [20] conducted an international multi-institutional study and also found that Stone-ICC had a worse prognosis than Con-ICC and HBV-ICC subtypes, and they further found that Stone-ICC and Con-ICC had statistical differences in OS and RFS, while Stone-ICC and HBV-ICC had no difference on prognosis after PSM. In this study, we also found that there was no statistical difference in the proportion of patients with overall recurrence, early recurrence and OS in non-early recurrence patients with the three etiological subtypes, while there was a statistical difference of OS ≤ 1 year, OS with 1 ~ 3 year and OS > 3 years in early recurrence patients. So, the survival difference of ICC with the different etiological subtypes was mainly in OS, especially in patients with early recurrence.
To further explore the reasons for the differences in the prognosis of ICC with different etiology, we analyzed the differences in clinicopathological characteristics of ICC with the three etiological subtypes. Based on the above results, we considered that the prognostic differences of ICC with different etiology had a strong correlation with its clinicopathological characteristics. Widespread epidemics with HBV infection in China increase integration of HBV gene fragments into liver cells, which contributes to ICC and also causes the HBV-ICC of China with highest distribution in the world [22,23,24]. In this study, the results showed that the prognosis of patients with HBV-ICC was better than those of Con-ICC and Stone-ICC subtypes. Ding et al. [25] have found that the patients with HBV-ICC can activate the immune memory produced by HBV infection previously, thereby enhancing anti-tumor immunity, and Iida et al. [26] have also revealed that HBV-ICC conferred a low risk of lymph node metastasis for postoperative recurrence, which may be the reason that HBV-ICC has a relatively better prognosis than the other two etiological subtypes. Many studies [21, 27, 28] also found that HBV infection was a favorable prognostic factor for ICC after surgery, which was consistent with our results.
Unfortunately, patients with Stone-ICC had the worst prognosis in the study. Wang et al.[21] revealed that patients with Stone-ICC were often difficult to differentiate with benign biliary strictures, resulting in patients who were mostly diagnosed in the advanced stage. Due to the presence of hepatolithiasis, it can lead to long-term chronic inflammation, followed by dysplasia and multiple tumors. In addition, the proportion of Stone-ICC with elevated CA19-9, multiple tumors, and lymph node metastasis was significantly higher than the other two etiological types [21, 29, 30]. In this study, Stone-ICC had a higher proportion of CA19-9 > 39.0 U/ml, presence of perineural invasion, morphologic grape with periductal infiltrating and intraductal growth, and N1 stage compared with HBV-ICC and Con-ICC, which could explain the reason why Stone-ICC had a poor prognosis. Thus, we suggest a more aggressive preventive surgery for those patients with a long-term history of hepatolithiasis to avoid the presence of ICC.
At present, due to limited prospective data on the benefits of systemic ACT for ICC patients after radical resection [9], whether postoperative ACT could improve the prognosis of ICC patients is still controversial [31, 32]. In this study, we found that postoperative ACT could improve the OS and RFS effectively, and non-ACT was identified as an independent risk factor for ICC patients (Table 2). Recently, some studies [33, 34] proved that postoperative ACT was beneficial to the prognosis for ICC after surgery. By analyzing the prognostic improvement value of ACT for different etiological subtypes in ICC patients, the results showed that postoperative ACT was a benefit to Stone-ICC patients on OS and RFS. However, ACT did not significantly improve the prognosis for Con-ICC and HBV-ICC patients. Altman et al. [35] and Ke et al. [36] reported that ACT improving OS was related to more patients with lymph node-positive or T3/T4 stage. We considered that ACT improving the prognosis of Stone-ICC was related to its high proportion of elevated CA19-9, perineural invasion, N1 stage patients. Of course, whether ACT can improve the prognosis of Con-ICC and HBV-ICC patients still needs further research.
However, there were several limitations in our study. The study included 448 ICC patients after radical resection from 10 medical centers in China, which effectively increased the universality of the study, while the sample size was still relatively small. Besides, the study did not include ICC patients from Western countries, because the role of hepatolithiasis and HBV infection was not as important as those patients in China. In addition, the preoperative inflammatory indicators were not available, so the differences of the three etiological subtypes of inflammatory response were not further compared. Accordingly, we should clarify the molecular mechanisms and prognostic monitoring indicators for ICC with different etiology in the future, so as to provide references and decision support for the individualized diagnosis, treatment and prevention for ICC patients.