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

1 Hôpital Henri Mondor
2 IRCCS Milan - Istituto Clinico Humanitas [Milan]
3 Hôpital Henri Mondor
4 Service de Pathologie [Hôpital Beaujon - APHP]
5 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
6 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
7 CHU Lille
8 CHU Pitié-Salpêtrière [AP-HP]
9 CRSA - Centre de Recherche Saint-Antoine
10 Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine]
11 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
12 UM - Université de Montpellier
13 ACP - Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière]
14 ONCO-THAI - Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189
15 University of Barcelona
16 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
17 IMRB - Institut Mondor de Recherche Biomédicale
18 CHU Henri Mondor
19 Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière]
20 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
21 ULB - Université libre de Bruxelles
22 CHIMERE - CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516
23 SiRMa - Laboratoire de Signalisation et Récepteurs Matriciels
24 ISTCT - Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales
25 Département de Pathologie [CHU Caen]
26 CHU Grenoble
27 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
28 Service de Chirurgie Viscérale et Digestive [CHU Caen]
29 CHU Poitiers - Centre hospitalier universitaire de Poitiers
30 LIMICS - Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé
31 Groupe Henri Mondor-Albert Chenevier
32 JHU - Johns Hopkins University
33 Hôpital Claude Huriez [Lille]
34 Physiopathologie et traitement des maladies du foie
35 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
36 CHU Reims - Centre Hospitalier Universitaire de Reims
37 FunGeST - Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC]
38 Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer
39 Service d'Hépatologie [Avicenne]
40 Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny]
41 DTU - Danmarks Tekniske Universitet = Technical University of Denmark
42 CHUV - Centre Hospitalier Universitaire Vaudois [Lausanne]
43 U1162 - Génomique Fonctionnelle des Tumeurs Solides
44 Crosscope
45 University of Michigan [Ann Arbor]
46 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
47 Hôpital Bicêtre
48 Service d'Hépato-gastro-entérologie [CHU Saint-Antoine]
49 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
50 Hôpital Avicenne [AP-HP]
51 Service d’Anatomie Pathologique [CHU Beaujon]
52 Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité - Labex Immuno-oncology [Paris]

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: Sciences du Vivant [q-bio]; 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⟩