Nestin as a Diagnostic and Prognostic Marker for Combined Hepatocellular-Cholangiocarcinoma.

Julien Calderaro (1) , Luca Di Tommaso (2) , Pascale Maillé (3) , Aurélie Beaufrère (4) , Cong Trung Nguyen (5) , Lara Heij (6) , Viviane Gnemmi (7, 8) , Rondell P. Graham (6) , Frédéric Charlotte (9) , Suzanne Chartier (10) , Dominique Wendum (11, 12) , Mukul Vij (13) , Daniela Allende (14) , Alba Diaz (15) , Carla Fuster (15) , Benjamin Rivière (16) , Astrid Herrero (17, 16) , Jérémy Augustin (9) , Katja Evert (18) , Diego Francesco Calvisi (18) , Wei Qiang Leow (19) , Howard Ho Wai Leung (20) , Jan Bednarsch (6) , Emmanuel Boleslawski (21) , Mohamed Rela (13) , Anthony Wing-Hung Chan (20) , Alejandro Forner (22) , Maria Reig (23) , Anaïs Pujals (24, 25) , Loetitia Favre (24, 25) , Manon Allaire (9) , Olivier Scatton (11) , Arnaud Uguen (26) , Eric Trépo (27) , Lukas Otero Sanchez (27) , Denis Chatelain (28) , Myriam Remmelink (29) , Camille Boulagnon-Rombi (30) , Céline Bazille (31, 32) , Nathalie Sturm (33) , Benjamin Menahem (34, 35) , Eric Frouin (36) , David Tougeron (36) , Christophe Tournigand (24) , Emmanuelle Kempf (37, 38) , Haeryoung Kim (39) , Massih Ningarhari (8, 40) , Sophie Michalak-Provost (41) , Jakob Nikolas Kather (42) , Annette S. H. Gouw (43) , Purva Gopal (44) , Raffaele Brustia (25) , Eric Vibert (45) , Kornelius Schulze (46) , Darius F. Rüther (46) , Sören A. Weidemann (46) , Rami Rhaiem (47) , Jean-Charles Nault (48, 4) , Alexis Laurent (49) , Giuliana Amaddeo (25, 24) , Hélène Regnault (24) , Eleonora De Martin (50) , Christine Sempoux (51) , Pooja Navale (52) , Jayendra Shinde (53) , Ketan Bacchuwar (54) , Maria Westerhoff (55) , Regina Cheuk-Lam Lo (20) , Mylène Sebbagh (4) , Catherine Guettier (56, 56) , Marie Lequoy (12, 11) , Mina Komuta (57) , Marianne Ziol (58, 59) , Valérie Paradis (60) , Jeanne Shen (61) , Stefano Caruso (58)

1 Hôpital Henri Mondor
2 IRCCS Milan - Istituto Clinico Humanitas [Milan]
3 Hôpital Henri Mondor
4 AP-HP Espace éthique - Assistance publique-Hôpitaux de Paris - Espace éthique
5 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
6 UKA - Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany]
7 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
8 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
9 CHU Pitié-Salpêtrière [AP-HP]
10 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
11 CRSA - Centre de Recherche Saint-Antoine
12 CHU Saint-Antoine [AP-HP]
13 SPIHER - St Peters Institute of Higher Education and Research [Chennai]
14 Cleveland Clinic
15 UB - Universitat de Barcelona
16 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
17 UM - Université de Montpellier
18 University of Regensburg
19 NUH - National University Hospital [Singapore]
20 CUHK - The Chinese University of Hong Kong [Hong Kong]
21 ONCO-THAI - Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189
22 University of Barcelona
23 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
24 IMRB - Institut Mondor de Recherche Biomédicale
25 CHU Henri Mondor [Créteil]
26 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
27 ULB - Université libre de Bruxelles
28 CHIMERE - CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516
29 UZ Brussel - Universitair Ziekenhuis Brussel = University Hospital of Brussels
30 SiRMa - Laboratoire de Signalisation et Récepteurs Matriciels
31 ISTCT - Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales
32 Département de Pathologie [CHU Caen]
33 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
34 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
35 Service de Chirurgie Viscérale et Digestive [CHU Caen]
36 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
37 LIMICS - Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé
38 Groupe Henri Mondor-Albert Chenevier
39 JHU - Johns Hopkins University
40 Hôpital Claude Huriez [Lille]
41 UA - Université d'Angers
42 Heidelberg University Hospital [Heidelberg]
43 UMCG - University Medical Center Groningen [Groningen]
44 Southern Methodist University Dallas
45 Physiopathologie et traitement des maladies du foie
46 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
47 Hôpital universitaire Robert Debré [Reims]
48 FunGeST - Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC]
49 DTU - Danmarks Tekniske Universitet = Technical University of Denmark
50 Hôpital Paul Brousse
51 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
52 Central Washington University
53 U1162 - Génomique Fonctionnelle des Tumeurs Solides
54 Computer History Museum [Mountain View]
55 University of Michigan [Ann Arbor]
56 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
57 Keio University [Tokyo]
58 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
59 Hôpital Avicenne [AP-HP]
60 Service d’Anatomie Pathologique [CHU Beaujon]
61 Stanford University

BACKGROUND AND 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 PLC. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCC) and 221 intrahepatic cholangiocarcinomas (ICCA). 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 AUC of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from ICCA (AUC 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 a 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: Combined Hepatocellular-Cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) that lacks robust tissue biomarkers. We show in different clinical settings that Nestin immunohistochemical staining has a diagnostic value and 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.

Mots clés: cancer; cholangiocarcinoma; combined hepatocellular-cholangiocarcinoma; hepatocellular carcinoma; liver; nestin

Domaines: Médecine humaine et pathologie

Julien Calderaro, Luca Di Tommaso, Pascale Maillé, Aurélie Beaufrère, Cong Trung Nguyen, et al.. Nestin as a Diagnostic and Prognostic Marker for Combined Hepatocellular-Cholangiocarcinoma.. Journal of Hepatology, 2022, pp.S0168-8278(22)02983-X. ⟨10.1016/j.jhep.2022.07.019⟩. ⟨hal-03760904⟩