Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Julien Calderaro¹, Luca Di Tommaso², Pascale Maillé³, Aurélie Beaufrère⁴, Cong Trung Nguyen³, Lara Heij⁵, Viviane Gnemmi⁶, Rondell P Graham⁷, Frédéric Charlotte⁸, Suzanne Chartier⁹, Dominique Wendum⁹, Mukul Vij¹⁰, Daniela Allende¹¹, Alba Diaz¹², Carla Fuster¹², Benjamin Rivière¹³, Astrid Herrero¹⁴, Jérémy Augustin³, Katja Evert¹⁵, Diego Francesco Calvisi¹⁵, Wei Qiang Leow¹⁶, Howard Ho Wai Leung¹⁷, Jan Bednarsch¹⁸, Emmanuel Boleslawski¹⁹, Mohamed Rela²⁰, Anthony Wing-Hung Chan¹⁷, Alejandro Forner²¹, Maria Reig²¹, Anaïs Pujals³, Loetitia Favre³, Manon Allaire²², Olivier Scatton²³, Arnaud Uguen²⁴, Eric Trépo²⁵, Lukas Otero Sanchez²⁵, Denis Chatelain²⁶, Myriam Remmelink²⁷, Camille Boulagnon-Rombi²⁸, Céline Bazille²⁹, Nathalie Sturm³⁰, Benjamin Menahem³¹, Eric Frouin³², David Tougeron³³, Christophe Tournigand³⁴, Emmanuelle Kempf³⁴, Haeryoung Kim³⁵, Massih Ningarhari³⁶, Sophie Michalak-Provost³⁷, Jakob Nikolas Kather³⁸, Annette S H Gouw³⁹, Purva Gopal⁴⁰, Raffaele Brustia⁴¹, Eric Vibert⁴², Kornelius Schulze⁴³, Darius F Rüther⁴³, Sören A Weidemann⁴⁴, Rami Rhaiem⁴⁵, Jean-Charles Nault⁴⁶, Alexis Laurent⁴⁷, Giuliana Amaddeo⁴⁸, Hélène Regnault⁴⁹, Eleonora de Martin⁵⁰, Christine Sempoux⁵¹, Pooja Navale⁵², Jayendra Shinde⁵³, Ketan Bacchuwar⁵³, Maria Westerhoff⁵⁴, Regina Cheuk-Lam Lo⁵⁵, Mylène Sebbagh⁵⁶, Catherine Guettier⁵⁶, Marie Lequoy⁵⁷, Mina Komuta⁵⁸, Marianne Ziol⁵⁹, Valérie Paradis⁴, Jeanne Shen⁶⁰, Stefano Caruso³

Affiliations

¹ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France; European Reference Network (ERN) RARE-LIVER. Electronic address: julien.calderaro@aphp.fr.
² Department of Pathology, Humanitas University, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
³ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France.
⁴ Assistance Publique-Hôpitaux de Paris, Beaujon University Hospital, Department of Pathology, F-92110 Clichy, France; Université de Paris, Inflammation Research Center, Inserm, U1149, CNRS, ERL8252, F-75018 Paris, France.
⁵ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
⁶ University Lille, UMR9020-U1277, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France; CHU Lille, Institute of Pathology, Lille, France.
⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, USA.
⁸ Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Pathology, Paris, France.
⁹ Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Pathology, Paris, France; INSERM UMR_S 938, Centre de Recherche Saint Antoine (CRSA), Faculté de Médecine Sorbonne Université, 75012, Paris, France.
¹⁰ Department of Pathology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
¹¹ Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
¹³ Department of Pathology, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
¹⁴ Department of Digestive and Hepatobiliary Surgery, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
¹⁵ Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
¹⁶ Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
¹⁷ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
¹⁸ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
¹⁹ CHU Lille, Department of Digestive and Hepatobiliary Surgery, Lille, France.
²⁰ Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
²¹ European Reference Network (ERN) RARE-LIVER; Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Universidad de Barcelona, Barcelona, Spain.
²² Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Hepatology, Paris, France.
²³ Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
²⁴ CHRU Brest, Department of Pathology, Brest 29220 France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France.
²⁵ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
²⁶ Amiens University Hospital, Department of Pathology, Amiens, France.
²⁷ Erasme University Hospital, Department of Pathology, Brussels, Belgium.
²⁸ Reims University Hospital, Department of Pathology, Reims, France.
²⁹ Caen University Hospital, Department of Pathology, Caen, France.
³⁰ Department of Pathology, University Hospital, Grenoble, France; Translational Innovation in Medicine and Complexity, Centre National de la Recherche Scientifique UMR5525, La Tronche, France.
³¹ Caen University Hospital, Department of Digestive and Hepatobiliary Surgery, Caen, France.
³² Poitiers University Hospital, Department of Pathology, Poitiers, France.
³³ Poitiers University Hospital, Department of Hepatogastroenterology and Oncology, Poitiers, France.
³⁴ Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Medical Oncology, Créteil, France.
³⁵ Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
³⁶ CHU Lille, Department of Hepatology, Lille, France.
³⁷ Angers University Hospital, Department of Pathology, Angers, France.
³⁸ Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
³⁹ Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
⁴⁰ Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
⁴¹ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Inserm, U955, Team 18, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴² Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴³ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁵ Reims University Hospital, Department of Digestive and Hepatobiliary Surgery, Reims, France.
⁴⁶ Liver Unit, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France; University Paris 13, Paris, France; Cordeliers Research Center, Sorbonne University, INSERM UMR 1138 Functional Genomics of Solid Tumors laboratory, F-75006, Paris, France.
⁴⁷ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴⁸ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Inserm, U955, Team 18, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Hepatology, Créteil, France.
⁴⁹ Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Hepatology, Créteil, France.
⁵⁰ Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Hepatology, Paris, France.
⁵¹ Institute of Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.
⁵² Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, 63110, USA.
⁵³ Crosscope, Mountain View, CA, USA; Crosscope, Mountain View, Pune, India.
⁵⁴ Department of Pathology, University of Michigan, Ann Arbor MI, USA.
⁵⁵ Department of Pathology, The University of Hong Kong, Pok Fu Lam, Hong Kong; State Key Laboratory of Liver Research, (The University of Hong Kong), Pok Fu Lam, Hong Kong.
⁵⁶ Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Pathology, Villejuif, France.
⁵⁷ Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Hepatology, Paris, France.
⁵⁸ Department of Pathology, International University of Health and Welfare, School of Medicine, Chiba 286-8520, Japan; Department of Pathology, School of Medicine, Keio University, Tokyo 160-8582, Japan; Department of Pathology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan.
⁵⁹ Assistance Publique-Hôpitaux de Paris, Department of Pathology, Jean Verdier Hospital, Bondy, France; Functional Genomics of Solid Tumors, INSERM-1162, Paris 13 University, Paris, France.
⁶⁰ Center for Artificial Intelligence in Medicine and Imaging, Stanford University, 1701 Page Mill Road, Palo Alto, CA, 94304, USA;; Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.

PMID: 35987274
DOI: 10.1016/j.jhep.2022.07.019

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Julien Calderaro et al. J Hepatol. 2022 Dec.

. 2022 Dec;77(6):1586-1597.

doi: 10.1016/j.jhep.2022.07.019. Epub 2022 Aug 18.

Authors

Affiliations

¹ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France; European Reference Network (ERN) RARE-LIVER. Electronic address: julien.calderaro@aphp.fr.
² Department of Pathology, Humanitas University, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
³ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France; Inserm, U955, Team 18, Créteil, France.
⁴ Assistance Publique-Hôpitaux de Paris, Beaujon University Hospital, Department of Pathology, F-92110 Clichy, France; Université de Paris, Inflammation Research Center, Inserm, U1149, CNRS, ERL8252, F-75018 Paris, France.
⁵ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
⁶ University Lille, UMR9020-U1277, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France; CHU Lille, Institute of Pathology, Lille, France.
⁷ Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, USA.
⁸ Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Pathology, Paris, France.
⁹ Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Pathology, Paris, France; INSERM UMR_S 938, Centre de Recherche Saint Antoine (CRSA), Faculté de Médecine Sorbonne Université, 75012, Paris, France.
¹⁰ Department of Pathology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
¹¹ Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
¹³ Department of Pathology, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
¹⁴ Department of Digestive and Hepatobiliary Surgery, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
¹⁵ Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
¹⁶ Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
¹⁷ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
¹⁸ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
¹⁹ CHU Lille, Department of Digestive and Hepatobiliary Surgery, Lille, France.
²⁰ Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
²¹ European Reference Network (ERN) RARE-LIVER; Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Universidad de Barcelona, Barcelona, Spain.
²² Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Hepatology, Paris, France.
²³ Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
²⁴ CHRU Brest, Department of Pathology, Brest 29220 France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France.
²⁵ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
²⁶ Amiens University Hospital, Department of Pathology, Amiens, France.
²⁷ Erasme University Hospital, Department of Pathology, Brussels, Belgium.
²⁸ Reims University Hospital, Department of Pathology, Reims, France.
²⁹ Caen University Hospital, Department of Pathology, Caen, France.
³⁰ Department of Pathology, University Hospital, Grenoble, France; Translational Innovation in Medicine and Complexity, Centre National de la Recherche Scientifique UMR5525, La Tronche, France.
³¹ Caen University Hospital, Department of Digestive and Hepatobiliary Surgery, Caen, France.
³² Poitiers University Hospital, Department of Pathology, Poitiers, France.
³³ Poitiers University Hospital, Department of Hepatogastroenterology and Oncology, Poitiers, France.
³⁴ Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Medical Oncology, Créteil, France.
³⁵ Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
³⁶ CHU Lille, Department of Hepatology, Lille, France.
³⁷ Angers University Hospital, Department of Pathology, Angers, France.
³⁸ Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
³⁹ Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
⁴⁰ Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
⁴¹ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Inserm, U955, Team 18, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴² Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴³ Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁵ Reims University Hospital, Department of Digestive and Hepatobiliary Surgery, Reims, France.
⁴⁶ Liver Unit, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France; University Paris 13, Paris, France; Cordeliers Research Center, Sorbonne University, INSERM UMR 1138 Functional Genomics of Solid Tumors laboratory, F-75006, Paris, France.
⁴⁷ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
⁴⁸ Université Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; Inserm, U955, Team 18, Créteil, France; Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Hepatology, Créteil, France.
⁴⁹ Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Hepatology, Créteil, France.
⁵⁰ Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Hepatology, Paris, France.
⁵¹ Institute of Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.
⁵² Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, 63110, USA.
⁵³ Crosscope, Mountain View, CA, USA; Crosscope, Mountain View, Pune, India.
⁵⁴ Department of Pathology, University of Michigan, Ann Arbor MI, USA.
⁵⁵ Department of Pathology, The University of Hong Kong, Pok Fu Lam, Hong Kong; State Key Laboratory of Liver Research, (The University of Hong Kong), Pok Fu Lam, Hong Kong.
⁵⁶ Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Pathology, Villejuif, France.
⁵⁷ Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Hepatology, Paris, France.
⁵⁸ Department of Pathology, International University of Health and Welfare, School of Medicine, Chiba 286-8520, Japan; Department of Pathology, School of Medicine, Keio University, Tokyo 160-8582, Japan; Department of Pathology, School of Medicine, Kurume University, Fukuoka 830-0011, Japan.
⁵⁹ Assistance Publique-Hôpitaux de Paris, Department of Pathology, Jean Verdier Hospital, Bondy, France; Functional Genomics of Solid Tumors, INSERM-1162, Paris 13 University, Paris, France.
⁶⁰ Center for Artificial Intelligence in Medicine and Imaging, Stanford University, 1701 Page Mill Road, Palo Alto, CA, 94304, USA;; Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.

PMID: 35987274
DOI: 10.1016/j.jhep.2022.07.019

Abstract

Background & aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.

Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.

Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.

Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy.

Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Keywords: cancer; cholangiocarcinoma; combined hepatocellular-cholangiocarcinoma; hepatocellular carcinoma; liver; nestin.

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Conflict of interest statement

Conflict of interest JC consults for Crosscope, KB is Crosscope Chief Technology Officer, JS is Crosscope Chief Executive Officer. Please refer to the accompanying ICMJE disclosure forms for further details.

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Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Affiliations

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical