Abstract

Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

Details

Title
Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma
Author
Calderaro, Julien 1 ; Ghaffari Laleh, Narmin 2 ; Zeng, Qinghe 3   VIAFID ORCID Logo  ; Maille, Pascale 4 ; Favre, Loetitia 4 ; Pujals, Anaïs 4 ; Klein, Christophe 5   VIAFID ORCID Logo  ; Bazille, Céline 6 ; Heij, Lara R. 7   VIAFID ORCID Logo  ; Uguen, Arnaud 8 ; Luedde, Tom 9   VIAFID ORCID Logo  ; Di Tommaso, Luca 10   VIAFID ORCID Logo  ; Beaufrère, Aurélie 11 ; Chatain, Augustin 12 ; Gastineau, Delphine 12 ; Nguyen, Cong Trung 13 ; Nguyen-Canh, Hiep 14 ; Thi, Khuyen Nguyen 15 ; Gnemmi, Viviane 16 ; Graham, Rondell P. 17   VIAFID ORCID Logo  ; Charlotte, Frédéric 18   VIAFID ORCID Logo  ; Wendum, Dominique 19 ; Vij, Mukul 20 ; Allende, Daniela S. 21 ; Aucejo, Federico 22 ; Diaz, Alba 23   VIAFID ORCID Logo  ; Rivière, Benjamin 24 ; Herrero, Astrid 25   VIAFID ORCID Logo  ; Evert, Katja 26 ; Calvisi, Diego Francesco 26 ; Augustin, Jérémy 4 ; Leow, Wei Qiang 27 ; Leung, Howard Ho Wai 28 ; Boleslawski, Emmanuel 29   VIAFID ORCID Logo  ; Rela, Mohamed 30 ; François, Arnaud 31 ; Cha, Anthony Wing-Hung 28 ; Forner, Alejandro 32   VIAFID ORCID Logo  ; Reig, Maria 32   VIAFID ORCID Logo  ; Allaire, Manon 33 ; Scatton, Olivier 34 ; Chatelain, Denis 35 ; Boulagnon-Rombi, Camille 36 ; Sturm, Nathalie 37 ; Menahem, Benjamin 38 ; Frouin, Eric 39 ; Tougeron, David 40   VIAFID ORCID Logo  ; Tournigand, Christophe 41 ; Kempf, Emmanuelle 41 ; Kim, Haeryoung 42 ; Ningarhari, Massih 43 ; Michalak-Provost, Sophie 44 ; Gopal, Purva 45 ; Brustia, Raffaele 46 ; Vibert, Eric 47 ; Schulze, Kornelius 48 ; Rüther, Darius F. 48 ; Weidemann, Sören A. 49 ; Rhaiem, Rami 50 ; Pawlotsky, Jean-Michel 51   VIAFID ORCID Logo  ; Zhang, Xuchen 52 ; Luciani, Alain 53 ; Mulé, Sébastien 53 ; Laurent, Alexis 46   VIAFID ORCID Logo  ; Amaddeo, Giuliana 54 ; Regnault, Hélène 54 ; De Martin, Eleonora 55 ; Sempoux, Christine 56 ; Navale, Pooja 57 ; Westerhoff, Maria 58 ; Lo, Regina Cheuk-Lam 59 ; Bednarsch, Jan 60 ; Gouw, Annette 61 ; Guettier, Catherine 62 ; Lequoy, Marie 63 ; Harada, Kenichi 64 ; Sripongpun, Pimsiri 65 ; Wetwittayaklang, Poowadon 66 ; Loménie, Nicolas 67   VIAFID ORCID Logo  ; Tantipisit, Jarukit 66 ; Kaewdech, Apichat 65   VIAFID ORCID Logo  ; Shen, Jeanne 68   VIAFID ORCID Logo  ; Paradis, Valérie 11 ; Caruso, Stefano 4 ; Kather, Jakob Nikolas 69   VIAFID ORCID Logo 

1  Université Paris Est Créteil, INSERM, IMRB, Créteil, France (GRID:grid.462410.5) (ISNI:0000 0004 0386 3258); Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Créteil, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109); Inserm, U955, Team 18, Créteil, France (GRID:grid.7429.8) (ISNI:0000 0001 2186 6389); European Reference Network (ERN) RARE-LIVER, Créteil, France (GRID:grid.7429.8) 
2  Technical University Dresden, Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257); University Hospital RWTH Aachen, RWTH Aachen university, Department of Medicine III, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X) 
3  Centre d’Histologie, d’Imagerie et de Cytométrie (CHIC), Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) (ISNI:0000 0004 0620 5824); Université Paris Cité, Laboratoire d’Informatique Paris Descartes (LIPADE), Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
4  Université Paris Est Créteil, INSERM, IMRB, Créteil, France (GRID:grid.462410.5) (ISNI:0000 0004 0386 3258); Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Créteil, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109); Inserm, U955, Team 18, Créteil, France (GRID:grid.7429.8) (ISNI:0000 0001 2186 6389) 
5  Centre d’Histologie, d’Imagerie et de Cytométrie (CHIC), Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) (ISNI:0000 0004 0620 5824); Université Paris Cité, INSERM, Sorbonne Université, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
6  Caen University Hospital, Department of Pathology, Caen, France (GRID:grid.411149.8) (ISNI:0000 0004 0472 0160) 
7  University Hospital RWTH Aachen, Department of Surgery and Transplantation, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X); Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X) 
8  CHRU Brest, Department of Pathology, Brest, France (GRID:grid.411766.3) (ISNI:0000 0004 0472 3249); Univ Brest, Inserm, CHU de Brest, LBAI, Brest, France (GRID:grid.411766.3) 
9  University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Clinic for Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
10  Humanitas University, Humanitas Clinical and Research Center, IRCCS, Rozzano, Department of Pathology, Milan, Italy (GRID:grid.452490.e) (ISNI:0000 0004 4908 9368) 
11  Beaujon University Hospital, Department of Pathology, Assistance Publique–Hôpitaux de Paris, Clichy, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109); Université de Paris, Inflammation Research Center, Inserm, U1149, CNRS, ERL8252, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389) 
12  Inserm, U955, Team 18, Créteil, France (GRID:grid.7429.8) (ISNI:0000 0001 2186 6389) 
13  Hanoi Medical University, Department of Pathology, E Hospital, Hanoi, Vietnam (GRID:grid.56046.31) (ISNI:0000 0004 0642 8489) 
14  Pathology Center, Bachmai Hospital, Hanoi, Vietnam (GRID:grid.56046.31); Kanazawa University Graduate School of Medicine, Department of Human Pathology, Kanazawa, Japan (GRID:grid.9707.9) (ISNI:0000 0001 2308 3329) 
15  Pathology and Molecular biology Center, National Cancer Hospital, Hanoi, Vietnam (GRID:grid.9707.9) 
16  University Lille, UMR9020-U1277, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France (GRID:grid.503422.2) (ISNI:0000 0001 2242 6780); CHU Lille, Institute of Pathology, Lille, France (GRID:grid.410463.4) (ISNI:0000 0004 0471 8845) 
17  Mayo Clinic Rochester, Department of Laboratory Medicine and Pathology, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
18  Pitié-Salpêtrière University Hospital, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
19  Saint-Antoine University Hospital, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
20  Bharath Institute of Higher Education and Research, Department of Pathology, Dr Rela Institute and Medical Centre, Chennai, India (GRID:grid.444347.4) (ISNI:0000 0004 1796 3866) 
21  Cleveland Clinic Foundation, Department of Hepatobiliary Pathology, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725); Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
22  Cleveland Clinic Foundation, Department of Gastrointestinal and Hepatobiliary Surgery, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
23  Universitat de Barcelona, Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
24  Gui-de-Chauliac University Hospital, 80, Department of Pathology, Montpellier, France (GRID:grid.157868.5) (ISNI:0000 0000 9961 060X) 
25  Gui-de-Chauliac University Hospital, 80, Department of Digestive and Hepatobiliary Surgery, Montpellier, France (GRID:grid.157868.5) (ISNI:0000 0000 9961 060X) 
26  University of Regensburg, Franz-Josef-Strauß-Allee 11, Institute of Pathology, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763) 
27  Singapore General Hospital, Department of Anatomical Pathology, Singapore, Singapore (GRID:grid.163555.1) (ISNI:0000 0000 9486 5048) 
28  The Chinese University of Hong Kong, Department of Anatomical and Cellular Pathology, Shatin, Hong Kong (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
29  CHU Lille, Department of Digestive and Hepatobiliary Surgery, Lille, France (GRID:grid.410463.4) (ISNI:0000 0004 0471 8845) 
30  Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India (GRID:grid.444347.4) (ISNI:0000 0004 1796 3866) 
31  Rouen University Hospital, Department of Pathology, Rouen, France (GRID:grid.10400.35) (ISNI:0000 0001 2108 3034) 
32  Universidad de Barcelona, Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
33  Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Hepatology, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
34  Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
35  Centre Hospitalier Universitaire d’Amiens, Département de Pathologie, Amiens, France (GRID:grid.134996.0) (ISNI:0000 0004 0593 702X) 
36  Reims University Hospital, Department of Pathology, Reims, France (GRID:grid.11667.37) (ISNI:0000 0004 1937 0618) 
37  University Hospital, Department of Pathology, Grenoble, France (GRID:grid.410529.b) (ISNI:0000 0001 0792 4829); Translational Innovation in Medicine and Complexity, Centre National de la Recherche Scientifique UMR5525, La Tronche, France (GRID:grid.4444.0) (ISNI:0000 0001 2259 7504) 
38  Caen University Hospital, Department of Digestive and Hepatobiliary Surgery, Caen, France (GRID:grid.411149.8) (ISNI:0000 0004 0472 0160) 
39  Poitiers University Hospital, Department of Pathology, Poitiers, France (GRID:grid.11166.31) (ISNI:0000 0001 2160 6368); LITEC, Université de Poitiers, Poitiers, France (GRID:grid.11166.31) (ISNI:0000 0001 2160 6368) 
40  Poitiers University Hospital, Department of Hepatogastroenterology and Oncology, Poitiers, France (GRID:grid.11166.31) (ISNI:0000 0001 2160 6368) 
41  Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Medical Oncology, Créteil, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
42  Seoul National University Hospital, Seoul National University College of Medicine, Department of Pathology, Seoul, Korea (GRID:grid.412484.f) (ISNI:0000 0001 0302 820X) 
43  CHU Lille, Department of Hepatology, Lille, France (GRID:grid.410463.4) (ISNI:0000 0004 0471 8845) 
44  Angers University Hospital, Department of Pathology, Angers, France (GRID:grid.411147.6) (ISNI:0000 0004 0472 0283) 
45  Department of Pathology, UT Southwestern Medical Center, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
46  Assistance Publique-Hôpitaux de Paris, Henri Mondor University Hospital, Department of Digestive and Hepatobiliary Surgery, Créteil, France (GRID:grid.412116.1) (ISNI:0000 0004 1799 3934) 
47  Paul Brousse University Hospital, Department of Digestive and Hepatobiliary Surgery, Assistance Publique-Hôpitaux de Paris, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
48  University Medical Center Hamburg-Eppendorf, Department of Internal Medicine, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484) 
49  University Medical Center Hamburg-Eppendorf, Department of Pathology, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484) 
50  Reims University Hospital, Department of Digestive and Hepatobiliary Surgery, Reims, France (GRID:grid.11667.37) (ISNI:0000 0004 1937 0618) 
51  Université Paris Est Créteil, INSERM, IMRB, Créteil, France (GRID:grid.462410.5) (ISNI:0000 0004 0386 3258); Inserm, U955, Team 18, Créteil, France (GRID:grid.7429.8) (ISNI:0000 0001 2186 6389); Paul Brousse University Hospital, Department of Digestive and Hepatobiliary Surgery, Assistance Publique-Hôpitaux de Paris, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
52  Yale University School of Medicine, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
53  Henri Mondor University Hospital, Department of Medical Imaging, Assistance Publique-Hôpitaux de Paris, Créteil, France (GRID:grid.412116.1) (ISNI:0000 0004 1799 3934) 
54  Henri Mondor University Hospital, Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Créteil, France (GRID:grid.412116.1) (ISNI:0000 0004 1799 3934) 
55  Paul Brousse University Hospital, Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
56  Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Institute of Pathology, Lausanne, Switzerland (GRID:grid.9851.5) (ISNI:0000 0001 2165 4204) 
57  Washington University in St. Louis, Department of Pathology and Immunology, St. Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
58  Department of Pathology University of Michigan, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347) 
59  The University of Hong Kong, Pok Fu Lam, Department of Pathology, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000 0001 2174 2757); State Key Laboratory of Liver Research, (The University of Hong Kong), Pok Fu Lam, Hong Kong, China (GRID:grid.194645.b) (ISNI:0000 0001 2174 2757) 
60  University Hospital RWTH Aachen, Department of Surgery and Transplantation, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X) 
61  University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
62  University Hospital RWTH Aachen, Department of Surgery and Transplantation, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X); University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); Paul Brousse University Hospital, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Villejuif, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
63  Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Hepatology, Paris, France (GRID:grid.50550.35) (ISNI:0000 0001 2175 4109) 
64  Kanazawa University Graduate School of Medicine, Department of Human Pathology, Kanazawa, Japan (GRID:grid.9707.9) (ISNI:0000 0001 2308 3329) 
65  Prince of Songkla University, Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Hat Yai, Thailand (GRID:grid.7130.5) (ISNI:0000 0004 0470 1162) 
66  Prince of Songkla University, Department of Pathology, Hat Yai, Thailand (GRID:grid.7130.5) (ISNI:0000 0004 0470 1162) 
67  Université Paris Cité, Laboratoire d’Informatique Paris Descartes (LIPADE), Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
68  Stanford University, Center for Artificial Intelligence in Medicine and Imaging, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University School of Medicine, Department of Pathology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
69  Technical University Dresden, Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257); University Hospital Heidelberg, Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
Pages
8290
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-43749-3
ProQuest document ID
2901277347
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.