Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers

Excretion of biliary compounds during intrauterine life

In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem

Liver metastases of intrahepatic cholangiocarcinoma: implications for a potential new staging system

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases (LM) are perceived to have a poor prognosis but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread.METHODS: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCCv.7) data were eligible. Modified staging was used (mAJCCv.7): Group-A: stages-I-III (excluding T2bN0); Group-B: stage-IVa (excluding T2bN1M0); Group-C: LM (T2bN0/1) and Group-D: stage-IVb (extra-hepatic metastases). Survival analysis (Kaplan Meier and Cox Regression) was performed in an ENS-CCA training cohort (TC) and findings internally [ENS-CCA (iVC)] and externally [SEER] validated. The aim was to assess if LM (Group-C) had a shorter survival compared to other early stages (Group-A). A modified version of AJCCv.8 (mAJCCv.8) is proposed.RESULTS: Total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into the Group-C, respectively. In the ENS-CCA TC, multivariable Cox Regression was adjusted for obesity (p-value 0.026) and performance status (p-value <0.001); patients in Group-C (HR 2.53 (95%CI 1.18-5.42); p-value 0.017) had a higher risk of death (vs Group-A). Findings were validated in the ENS-CCA iVC (HR 2.93 (95%CI 2.04-4.19); p-value <0.001) and in the SEER registry (HR of 1.88 (95%CI 1.68-2.09); p-value <0.001).CONCLUSIONS: iCCA LM have a worse outcome than other early stages. As AJCCv.8 does not take this into consideration, a modification of AJCC v.8 (mAJCCv.8) including "liver metastases: multiple liver lesions, with or without vascular invasion" as a novel "M1a stage" is suggested

Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Background and aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, with increasing incidence and related mortality. This study investigates the clinical course of CCA and subtypes (intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)) in a pan-European cohort. Methods: The ENSCCA Registry is a multicenter observational study. Patients with histologically-proven CCA diagnosis between 2010-2019 were included. Demographic, histomorphological, biochemical, and clinical studies were performed. Results: Overall, 2,234 patients were enrolled (male:female=1.29). iCCA (n=1,243) was associated with overweight/obesity (58.5%) and chronic liver diseases involving cirrhosis (12.6%) and/or viral hepatitis (10.4%); pCCA (n=592) with primary sclerosing cholangitis (8.8%); and dCCA (n=399) with choledocholithiasis (10.3%). At diagnosis, 42.2% of patients had local disease, 29.4% locally-advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity (69.1% and 40.9% below cutoff, respectively), but their concomitant elevation was associated with increased risk of presenting with LAD [OR=2.16;95%CI:1.43-3.27] or MD [OR=5.88;95%CI:3.69-9.25]. Patients undergoing resection (50.3%) showed the best outcome, particularly with negative-resection margin (R0) [median overall survival (mOS)=45.1 months]; however, margin involvement (R1) [HR=1.92;95%CI:1.53-2.41;mOS=24.7 months] and lymph node invasion [HR=2.13;95%CI:1.55-2.94;mOS=23.3 months] compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%). Patients receiving best supportive care (20.6%) had mOS of 4.0 months, with iCCAs showing worst outcome compared to p/dCCAs. ECOG performance status [HR=1.52;95%CI:1.01-2.31], MD [HR=4.03;95%CI:1.82-8.92] and CA19-9 [HR=2.79;95%CI:1.46-5.33] were independently prognostic for OS. Conclusion: CCA is still diagnosed at advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis is dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. Lay summary: This is, to date, the largest and more complete international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of CCA is investigated, comparing the three subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) [i.e., intrahepatic (2C12), perihilar (2C18), or distal (2C15) affected bile ducts] (coming into effect in 2022). General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, among others, are presented and compared, outlining the current European scenario on the clinical state of CCA

Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry

Background & Aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. Methods: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. Results: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. Conclusion: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. Lay summary: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe