Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma,Journal of Hepatology

当前位置： X-MOL 学术 › J. Hepatol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma
Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-08-18 , DOI: 10.1016/j.jhep.2022.07.019
Julien Calderaro ₁ , Luca Di Tommaso ₂ , Pascale Maillé ₃ , Aurélie Beaufrère ₄ , Cong Trung Nguyen ₃ , Lara Heij ₅ , Viviane Gnemmi ₆ , Rondell P Graham ₇ , Frédéric Charlotte ₈ , Suzanne Chartier ₉ , Dominique Wendum ₉ , Mukul Vij ₁₀ , Daniela Allende ₁₁ , Alba Diaz ₁₂ , Carla Fuster ₁₂ , Benjamin Rivière ₁₃ , Astrid Herrero ₁₄ , Jérémy Augustin ₃ , Katja Evert ₁₅ , Diego Francesco Calvisi ₁₅ , Wei Qiang Leow ₁₆ , Howard Ho Wai Leung ₁₇ , Jan Bednarsch ₁₈ , Emmanuel Boleslawski ₁₉ , Mohamed Rela ₂₀ , Anthony Wing-Hung Chan ₁₇ , Alejandro Forner ₂₁ , Maria Reig ₂₁ , Anaïs Pujals ₃ , Loetitia Favre ₃ , Manon Allaire ₂₂ , Olivier Scatton ₂₃ , Arnaud Uguen ₂₄ , Eric Trépo ₂₅ , Lukas Otero Sanchez ₂₅ , Denis Chatelain ₂₆ , Myriam Remmelink ₂₇ , Camille Boulagnon-Rombi ₂₈ , Céline Bazille ₂₉ , Nathalie Sturm ₃₀ , Benjamin Menahem ₃₁ , Eric Frouin ₃₂ , David Tougeron ₃₃ , Christophe Tournigand ₃₄ , Emmanuelle Kempf ₃₄ , Haeryoung Kim ₃₅ , Massih Ningarhari ₃₆ , Sophie Michalak-Provost ₃₇ , Jakob Nikolas Kather ₃₈ , Annette S H Gouw ₃₉ , Purva Gopal ₄₀ , Raffaele Brustia ₄₁ , Eric Vibert ₄₂ , Kornelius Schulze ₄₃ , Darius F Rüther ₄₃ , Sören A Weidemann ₄₄ , Rami Rhaiem ₄₅ , Jean-Charles Nault ₄₆ , Alexis Laurent ₄₇ , Giuliana Amaddeo ₄₈ , Hélène Regnault ₄₉ , Eleonora de Martin ₅₀ , Christine Sempoux ₅₁ , Pooja Navale ₅₂ , Jayendra Shinde ₅₃ , Ketan Bacchuwar ₅₃ , Maria Westerhoff ₅₄ , Regina Cheuk-Lam Lo ₅₅ , Mylène Sebbagh ₅₆ , Catherine Guettier ₅₆ , Marie Lequoy ₅₇ , Mina Komuta ₅₈ , Marianne Ziol ₅₉ , Valérie Paradis ₄ , Jeanne Shen ₆₀ , Stefano Caruso ₃

Affiliation

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.
Department of Pathology, Humanitas University, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
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.
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.
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
University Lille, UMR9020-U1277, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France; CHU Lille, Institute of Pathology, Lille, France.
Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN, USA.
Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Pathology, Paris, France.
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.
Department of Pathology, Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
Department of Gastrointestinal and Hepatobiliary Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA.
Barcelona Clinic Liver Cancer (BCLC) Group, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
Department of Pathology, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
Department of Digestive and Hepatobiliary Surgery, Gui-de-Chauliac University Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier, France.
Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
CHU Lille, Department of Digestive and Hepatobiliary Surgery, Lille, France.
Dr Rela Institute and Medical Centre, Bharath Institute of Higher Education and Research, Chennai, India.
European Reference Network (ERN) RARE-LIVER; Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Universidad de Barcelona, Barcelona, Spain.
Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Hepatology, Paris, France.
Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
CHRU Brest, Department of Pathology, Brest 29220 France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France.
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.
Amiens University Hospital, Department of Pathology, Amiens, France.
Erasme University Hospital, Department of Pathology, Brussels, Belgium.
Reims University Hospital, Department of Pathology, Reims, France.
Caen University Hospital, Department of Pathology, Caen, France.
Department of Pathology, University Hospital, Grenoble, France; Translational Innovation in Medicine and Complexity, Centre National de la Recherche Scientifique UMR5525, La Tronche, France.
Caen University Hospital, Department of Digestive and Hepatobiliary Surgery, Caen, France.
Poitiers University Hospital, Department of Pathology, Poitiers, France.
Poitiers University Hospital, Department of Hepatogastroenterology and Oncology, Poitiers, France.
Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Medical Oncology, Créteil, France.
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
CHU Lille, Department of Hepatology, Lille, France.
Angers University Hospital, Department of Pathology, Angers, France.
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
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.
Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Digestive and Hepatobiliary Surgery, Paris, France.
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Reims University Hospital, Department of Digestive and Hepatobiliary Surgery, Reims, France.
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.
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.
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.
Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Hepatology, Créteil, France.
Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Hepatology, Paris, France.
Institute of Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.
Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, 63110, USA.
Crosscope, Mountain View, CA, USA; Crosscope, Mountain View, Pune, India.
Department of Pathology, University of Michigan, Ann Arbor MI, USA.
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.
Assistance Publique-Hôpitaux de Paris, Paul Brousse University Hospital, Department of Pathology, Villejuif, France.
Assistance Publique-Hôpitaux de Paris, Saint Antoine University Hospital, Department of Hepatology, Paris, France.
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.
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.
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.

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.

中文翻译：

巢蛋白作为联合肝细胞胆管癌的诊断和预后标志物

背景与目标

联合肝细胞胆管癌 (cHCC-CCA) 是一种罕见的原发性肝癌 (PLC)，预后较差。鉴于其识别及其临床意义的挑战，迫切需要生物标志物。我们旨在研究 Nestin（一种祖细胞标记物）在大型多中心系列 PLC 中的免疫组织化学表达的诊断和预后价值。

方法

我们从 32 个不同的临床中心收集了 461 个 cHCC-CCA 样本。对照病例包括 368 例肝细胞癌 (HCC) 和 221 例肝内胆管癌 (iCCA)。对整个肿瘤切片进行巢蛋白免疫组织化学。使用接受者操作特征曲线和 Cox 回归模型确定 Nestin 表达的诊断和预后性能。

结果

Nestin 能够区分 cHCC-CCA 和 HCC，手术和活检样本的 AUC 分别为 0.85 和 0.86。cHCC-CCA 与 iCCA 的区分性能较低（AUC 分别为 0.59 和 0.60）。然而，Nestin 显示出很高的预后价值，允许鉴定 cHCC-CCA 的子集（“Nestin 高”，>30% 的肿瘤细胞具有阳性染色）与最差的临床结果（更短的无病生存和总生存）手术切除和肝移植，以及何时对活检进行评估。