Cholangiocarcinoma is the most common primary malignancy of the biliary tract [1], with very high incidence rates reported in East and Southeast Asia, especially in Thailand [2]. The incidence of CCA has been reported to be as high as 87.7 per 100,000 in males and 36.3 per 100,000 in females [4].
Our study analyzed the pathological characteristics of CCA depending on its anatomical location (ICCA, PCCA, and DCCA) and morphological characteristics (MF, PI, ID) in order to evaluate the survival rate and median survival time after surgery, as well as to determine the association between these classifications and survival for a total of 746 CCA patients from northeast Thailand. Our results showed that most CCA patients were male (63.9%), almost twice as many as females, while the at risk population that came for CCA screening were predominately females. More than half of the 746 patients (54.6%) were elderly (aged greater than 60 years old), which is consistent with previous studies [22]. In addition, approximately two-thirds of CCA patients were found to be in advance stages of the disease (65.3%) presenting with symptoms indicating CCA. This may be because the CCA screening program (CASCAP) is not comprehensive and that patients are asymptomatic, consequently they present at medical facilities when the disease has progressed and symptoms become apparent. The combination of anatomical and morphological classifications showed that the percentage of patients in the ICM group was highest (31.9%), whereas the lowest percentage was for patients in DCI group with about 2%.
The highest proportionate mortality occurred in PCCA patients (72.1%). Similarly, when separated by the anatomical and morphological classification, the highest mortality rate due to CCA occurred in PCCA patients who were in the MF and PI groups (81% and 77%, respectively). The MF location resulted in the highest mortality for both the PCCA and ICCA groups (81% and 76%, respectively), while the highest mortality rate in DCCA patients was in the ID location (64%) compared to other locations (MF and PI).
The survival analyses showed that the overall incidence rate was 39.6 per 100 patients per year. The highest rate was found in the PCM group followed by the ICM and PCP groups (56.4, 49.2, and 45.6 per 100 patients per year, respectively). Likewise, compared to the incidence rate according to the anatomical classification alone, our study also found the highest rate to be in the PCCA group (42 per 100 patients per year); however, the rate was lower when classified by both anatomical and morphological classifications. The overall median survival times was about 18 months, the longest median survival time was 40.5 months for PCI patients, which was different when only classified anatomically when the longest median survival time was in DCCA patients (21.8 months). The shortest median survival time was found in patients with ICM (12.4 months) which was consistent with ICCA patients without morphological classification (16.2 months). The incidence rate and median survival time according to anatomical classification, and a combination of anatomical and morphological classifications separated by stage of CCA, are detailed in Additional file 1 (Table S1, Figures S1, S2, S3, and S4). The overall survival rate was 60% at 1-year, 31% at 3-years, and 25% at 5-years. The highest survival rate was found in the patients with PCI 78.4%, 52.5%, and 42.6% at 1-year, 3-years, and 5-years, respectively. These rates were different when classified only anatomically, when the highest survival rate in patients with DCCA was 65% at 1 year, 37.5% at 3 years, and 34.8% at 5 years, respectively. The lowest survival rate at 5-years was found in PCP patients (16%), which is lower than for PCCA patients (19%) who were classified only by anatomical characteristics. The survival rate according to the anatomical classification, and a combination of anatomical and morphological classifications separated by the stage of CCA, found that patients with early stage disease have higher survival rates than those with late stage disease (see Additional file 1 Figures S5, S6, and S7). This is consistent with a 5-year population-based study conducted in north Thailand in 2011 which found that CCA patients with stage 0 had a 100% 3-year survival rate [8].
The association between anatomical classification and survival using cox regression, bivariate analyses found no significant associations for all groups. After controlling for the effect of other factors (stage of CCA, gender, age at enrollment, history of O. viverrini infection, education levels, occupation, cigarettes smoking history, alcohol consumption history, and praziquantel treatment) that have been previously reported as associated with CCA [22–24], significant associations were found in DCCA patients. According to a combination of anatomical and morphological classifications, the association of survival using simple cox regression analysis found significant associations for the patients in three groups (ICM, PCM, and PCP). Using multiple cox regression analysis by controlling for the effect of other factors, our results showed that only patients with ICM were significantly associated with overall survival compared to ICI patients. Interestingly, results from CCA patients in two groups PCM and PCP, changed from significant to non-significant from bivariate analyses compared to multivariable analyses. This may be caused by controlling for other factors in the bivariate analyses, whereas those factors cannot be ignored in multivariable analyses and models which previously found relationships with CCA [22–24]. Result from our study show that the strongest association was in the ICM group in which patients with a combination of ICCA and MF are most likely to die with 45% mortality (adjusted HR: 1.45; 95% CI: 1.01–2.09) compared to those who had a combination of ICCA and ID. However, when classified by only anatomical characteristics, we found that patients in the ICCA group were most likely to die 49% (HR: 1.49; 95% CI: 1.10–2.04), compared to the DCCA group. Furthermore, this effect was more than for those CCA patients with a combination of anatomical and morphological classifications.
Limitations of the study were the demographic and some health data were self-reported leading to potential bias in the measurement of liver fluke infection, and praziquantel treatment. Self-reporting could lead to underestimates of the size of effects due to an unwillingness to disclose sensitive or personal information.