Refinement of histologic subtypes and identification of biomarkers linked to unfavorable prognosis in cholangiocarcinoma: The ENSCCA registries' framework for digital twin advancement

Guido Carpino¹, Diletta Overi¹, Rocio I R Macias², Vincenzo Cardinale³, Laura Izquierdo-Sanchez^{4

5}, Pilar Acedo⁶, Marco Rengo^{7

8}, Michail Doukas⁹, Timothy J Kendall¹⁰, Julien Calderaro¹¹, Lara R Heij^{9

12

13

14}, Konrad Reichel¹⁴, Stefano Leone¹, Paolo Onori¹, Barbara Franceschini¹⁵, Cristiana Soldani¹⁵, Luca Di Tommaso^{16

17}, Pedro M Rodrigues^{4

5

18}, Jérémy Augustin¹¹, Raffaele Brustia^{19

20

21}, Guido Torzilli^{16

22}, Manuela Martin-Izquierdo²³, Jose M Hernández-Bayo²³, Diego Bueno-Sacristan²⁴, Ezio Lanza²⁵, Andres Garcia-Sampedro^{6

26}, Alberto Quaglia²⁷, Francesco Ardito²⁸, Agostino Maria De Rose²⁸, Felice Giuliante²⁸, Elio Damato²⁹, Valeria Panebianco²⁹, Bas Groot Koerkamp³⁰, Stephen P Pereira⁶, Gian Luca Grazi³¹, Domenico Alvaro³, Ana Lleo^{16

32}, Jesus M Banales^{4

5

18

33}, Eugenio Gaudio¹

Affiliations

¹ Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.
² Laboratory of Experimental Hepatology and Drug Targeting (HEVEPHARM), National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), IBSAL, University of Salamanca, Salamanca, Spain.
³ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁴ Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
⁵ National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
⁶ Institute for Liver and Digestive Health, University College London, London, UK.
⁷ Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
⁸ Academic Diagnostic Imaging Division, I.C.O.T. Hospital, Latina, Italy.
⁹ Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
¹⁰ University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
¹¹ Department of Pathology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France.
¹² Department of Pathology, University Hospital Essen, Essen, Germany.
¹³ Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁴ Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany.
¹⁵ Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁶ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
¹⁷ Pathology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁸ Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
¹⁹ Department of Digestive and Hepato-pancreatic-biliary Surgery, Université Paris-Est Créteil, UPEC, Créteil, France.
²⁰ Department of Digestive and Hepato-pancreatic-biliary Surgery, INSERM, Team "Virus Hépatologie Cancer," Créteil, France.
²¹ Department of Digestive and Hepato-pancreatic-biliary Surgery, Assistance Publique-Hôpitaux de Paris, Henri Mondor-University Hospital, Créteil, France.
²² Department of Surgery, Division of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
²³ Servicio de Radiodiagnostico, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
²⁴ Servicio de Patologia, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
²⁵ Division of Interventional Radiology, IRCCS Humanitas Research Hospital, Milan, Italy.
²⁶ Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
²⁷ Department of Cellular Pathology, UCL Cancer Institute, Royal Free Hospital, London, UK.
²⁸ Hepatobiliary Surgery Unit, Foundation and Teaching Hospital Sacred Heart IRCCS A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy.
²⁹ Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
³⁰ Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³¹ Department of Experimental and Clinical Medicine, HepatoBiliaryPancreatic Surgery, University of Florence, Florence, Italy.
³² Department of Gastroenterology, Division of Internal Medicine and Hepatology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
³³ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.

PMID: 40513068
DOI: 10.1097/HEP.0000000000001425

Refinement of histologic subtypes and identification of biomarkers linked to unfavorable prognosis in cholangiocarcinoma: The ENSCCA registries' framework for digital twin advancement

Guido Carpino et al. Hepatology. 2025.

. 2025 Jun 16.

doi: 10.1097/HEP.0000000000001425. Online ahead of print.

Authors

Affiliations

¹ Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.
² Laboratory of Experimental Hepatology and Drug Targeting (HEVEPHARM), National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), IBSAL, University of Salamanca, Salamanca, Spain.
³ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁴ Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
⁵ National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
⁶ Institute for Liver and Digestive Health, University College London, London, UK.
⁷ Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
⁸ Academic Diagnostic Imaging Division, I.C.O.T. Hospital, Latina, Italy.
⁹ Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
¹⁰ University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
¹¹ Department of Pathology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France.
¹² Department of Pathology, University Hospital Essen, Essen, Germany.
¹³ Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹⁴ Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany.
¹⁵ Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁶ Department of Biomedical Sciences, Humanitas University, Milan, Italy.
¹⁷ Pathology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁸ Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
¹⁹ Department of Digestive and Hepato-pancreatic-biliary Surgery, Université Paris-Est Créteil, UPEC, Créteil, France.
²⁰ Department of Digestive and Hepato-pancreatic-biliary Surgery, INSERM, Team "Virus Hépatologie Cancer," Créteil, France.
²¹ Department of Digestive and Hepato-pancreatic-biliary Surgery, Assistance Publique-Hôpitaux de Paris, Henri Mondor-University Hospital, Créteil, France.
²² Department of Surgery, Division of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
²³ Servicio de Radiodiagnostico, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
²⁴ Servicio de Patologia, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
²⁵ Division of Interventional Radiology, IRCCS Humanitas Research Hospital, Milan, Italy.
²⁶ Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
²⁷ Department of Cellular Pathology, UCL Cancer Institute, Royal Free Hospital, London, UK.
²⁸ Hepatobiliary Surgery Unit, Foundation and Teaching Hospital Sacred Heart IRCCS A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy.
²⁹ Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
³⁰ Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³¹ Department of Experimental and Clinical Medicine, HepatoBiliaryPancreatic Surgery, University of Florence, Florence, Italy.
³² Department of Gastroenterology, Division of Internal Medicine and Hepatology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
³³ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.

PMID: 40513068
DOI: 10.1097/HEP.0000000000001425

Abstract

Background and aims: Cholangiocarcinoma (CCA) displays remarkable anatomical and histological heterogeneity. Besides diagnosis confirmation, histology currently does not have a major role in the management of CCA. We aimed to study the clinical relevance of histological heterogeneity of CCA and putative tissue biomarkers by creating a multicentric digitalized European CCA Histology Registry.

Approach and results: Nine referral centers, participating in the International Cholangiocarcinoma Clinical Registry, shared samples and data from 293 patients. Histological and immunohistochemistry stains (n=10) were performed. Computed tomography (CT) scans (n=112 cases) were analyzed by morphological and radiomics techniques. A selection of cases (n=18) was processed for spatial transcriptomics analysis. No significant differences in 5-year overall survival (OS) were found in perihilar CCA versus intrahepatic (i) CCA, and in small bile duct (SBD) versus large bile duct (LBD) iCCA. When cases were classified by Periodic acid of Schiff (PAS) positivity (mucin content), PAS HIGH LBD iCCA showed a significantly worse 5-year OS compared to PAS LOW iCCA. Multivariate Cox regression identified PAS HIGH LBD iCCA phenotype as an independent predictor of worse OS. PAS HIGH LBD iCCA subtype showed specific molecular characteristics at spatial transcriptomics and immunohistochemistry; CT scans and serology could distinguish PAS HIGH LBD iCCA phenotype with excellent accuracy.

Conclusions: Our data underline the importance of identifying morphological subclasses with a significant prevalence in CCA as a tool for risk stratification and prognosis. The European CCA Histology Registry represents a valuable platform for integrating digital pathology with clinical, radiological, and molecular information as a framework for digital twin advancement.

Keywords: biliary tract cancer; cell of origin; digital pathology; primary liver cancer; spatial transcriptomics.

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References

1. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428–444.
1. Vogel A, Bridgewater J, Edeline J, Kelley RK, Klümpen HJ, Malka D, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:127–140.
1. Vithayathil M, Khan SA. Current epidemiology of cholangiocarcinoma in Western countries. J Hepatol. 2022;77:1690–1698.
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Refinement of histologic subtypes and identification of biomarkers linked to unfavorable prognosis in cholangiocarcinoma: The ENSCCA registries' framework for digital twin advancement

Affiliations

Refinement of histologic subtypes and identification of biomarkers linked to unfavorable prognosis in cholangiocarcinoma: The ENSCCA registries' framework for digital twin advancement

Authors

Affiliations

Abstract

References

LinkOut - more resources

Full Text Sources