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

Published:August 17, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.019

      Highlights

      • Biomarkers for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) are critically needed.
      • Nestin immunohistochemical expression is able to identify the subset of cHCC-CCA associated with the worst clinical outcome.
      • cHCC-CCA with >30% of neoplastic cells expressing Nestin are classified “Nestin High”.
      • Nestin High cHCC-CCA are associated with an adverse outcome after surgical resection and liver transplantation.

      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.

      Graphical abstract

      Keywords

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      References

        • Sciarra A.
        • Park Y.N.
        • Sempoux C.
        Updates in the diagnosis of combined hepatocellular-cholangiocarcinoma.
        Hum Pathol. 2020; 96: 48-55https://doi.org/10.1016/j.humpath.2019.11.001
        • Calderaro J.
        • Ziol M.
        • Paradis V.
        • Zucman-Rossi J.
        Molecular and histological correlations in liver cancer.
        J Hepatol. 2019; 71: 616-630https://doi.org/10.1016/j.jhep.2019.06.001
      1. Organisation mondiale de la santé Centre international de recherche sur le cancer Digestive system tumours. 5th ed. International agency for research on cancer, Lyon2019
        • Wege H.
        • Schulze K.
        • von Felden J.
        • Calderaro J.
        • Reig M.
        Rare liver tumors working group of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Rare variants of primary liver cancer: fibrolamellar, combined, and sarcomatoid hepatocellular carcinomas.
        Eur J Med Genet. 2021; 64104313https://doi.org/10.1016/j.ejmg.2021.104313
        • Beaufrère A.
        • Calderaro J.
        • Paradis V.
        Combined hepatocellular-cholangiocarcinoma: an update.
        J Hepatol. 2021; 74: 1212-1224https://doi.org/10.1016/j.jhep.2021.01.035
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • Galle P.R.
        • Ducreux M.
        • Kim T.-Y.
        • et al.
        Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
        N Engl J Med. 2020; 382: 1894-1905https://doi.org/10.1056/NEJMoa1915745
        • Abou-Alfa G.K.
        • Lau G.
        • Kudo M.
        • Chan S.L.
        • Kelley R.K.
        • Furuse J.
        • et al.
        Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.
        NEJM Evid. 2022; https://doi.org/10.1056/EVIDoa2100070
        • Andersen J.B.
        • Spee B.
        • Blechacz B.R.
        • Avital I.
        • Komuta M.
        • Barbour A.
        • et al.
        Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.
        Gastroenterology. 2012; 142: 1021-1031.e15https://doi.org/10.1053/j.gastro.2011.12.005
        • Banales J.M.
        • Marin J.J.G.
        • Lamarca A.
        • Rodrigues P.M.
        • Khan S.A.
        • Roberts L.R.
        • et al.
        Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
        Nat Rev Gastroenterol Hepatol. 2020; 17: 557-588https://doi.org/10.1038/s41575-020-0310-z
        • Farshidfar F.
        • Zheng S.
        • Gingras M.-C.
        • Newton Y.
        • Shih J.
        • Robertson A.G.
        • et al.
        Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles.
        Cell Rep. 2017; 19: 2878-2880https://doi.org/10.1016/j.celrep.2017.06.008
        • Sia D.
        • Losic B.
        • Moeini A.
        • Cabellos L.
        • Hao K.
        • Revill K.
        • et al.
        Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
        Nat Commun. 2015; 6: 6087https://doi.org/10.1038/ncomms7087
        • Kam A.E.
        • Masood A.
        • Shroff R.T.
        Current and emerging therapies for advanced biliary tract cancers.
        Lancet Gastroenterol Hepatol. 2021; 6: 956-969https://doi.org/10.1016/S2468-1253(21)00171-0
        • Javle M.
        • Roychowdhury S.
        • Kelley R.K.
        • Sadeghi S.
        • Macarulla T.
        • Weiss K.H.
        • et al.
        Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.
        Lancet Gastroenterol Hepatol. 2021; 6: 803-815https://doi.org/10.1016/S2468-1253(21)00196-5
        • Abou-Alfa G.K.
        • Sahai V.
        • Hollebecque A.
        • Vaccaro G.
        • Melisi D.
        • Al-Rajabi R.
        • et al.
        Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.
        Lancet Oncol. 2020; 21: 671-684https://doi.org/10.1016/S1470-2045(20)30109-1
        • Abou-Alfa G.K.
        • Macarulla T.
        • Javle M.M.
        • Kelley R.K.
        • Lubner S.J.
        • Adeva J.
        • et al.
        Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
        Lancet Oncol. 2020; 21: 796-807https://doi.org/10.1016/S1470-2045(20)30157-1
        • Murugesan K.
        • Sharaf R.
        • Montesion M.
        • Moore J.A.
        • Pao J.
        • Pavlick D.C.
        • et al.
        Genomic profiling of combined hepatocellular cholangiocarcinoma reveals Genomics similar to either hepatocellular carcinoma or cholangiocarcinoma.
        JCO Precis Oncol. 2021; 5 (PO.20.00397)https://doi.org/10.1200/PO.20.00397
        • Xue R.
        • Chen L.
        • Zhang C.
        • Fujita M.
        • Li R.
        • Yan S.-M.
        • et al.
        Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes.
        Cancer Cell. 2019; 35: 932-947.e8https://doi.org/10.1016/j.ccell.2019.04.007
        • Malvi D.
        • de Biase D.
        • Fittipaldi S.
        • Grillini M.
        • Visani M.
        • Pession A.
        • et al.
        Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate-cell carcinoma?.
        Histopathology. 2020; 76: 265-274https://doi.org/10.1111/his.13966
        • Sasaki M.
        • Sato Y.
        • Nakanuma Y.
        Is nestin a diagnostic marker for combined hepatocellular-cholangiocarcinoma?.
        Histopathology. 2022; 80: 859-868https://doi.org/10.1111/his.14622
        • Wiese C.
        • Rolletschek A.
        • Kania G.
        • Blyszczuk P.
        • Tarasov K.V.
        • Tarasova Y.
        • et al.
        Nestin expression--a property of multi-lineage progenitor cells?.
        Cell Mol Life Sci. 2004; 61: 2510-2522https://doi.org/10.1007/s00018-004-4144-6
        • Tschaharganeh D.F.
        • Xue W.
        • Calvisi D.F.
        • Evert M.
        • Michurina T.V.
        • Dow L.E.
        • et al.
        p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer.
        Cell. 2014; 158: 579-592https://doi.org/10.1016/j.cell.2014.05.051
        • Gleiberman A.S.
        • Encinas J.M.
        • Mignone J.L.
        • Michurina T.
        • Rosenfeld M.G.
        • Enikolopov G.
        Expression of nestin-green fluorescent protein transgene marks oval cells in the adult liver.
        Dev Dyn. 2005; 234: 413-421https://doi.org/10.1002/dvdy.20536
        • Krupkova O.
        • Loja T.
        • Zambo I.
        • Veselska R.
        Nestin expression in human tumors and tumor cell lines.
        Neoplasma. 2010; 57: 291-298https://doi.org/10.4149/neo_2010_04_291
        • O’Rourke C.J.
        • Munoz-Garrido P.
        • Andersen J.B.
        Molecular targets in cholangiocarcinoma.
        Hepatology. 2021; 73: 62-74https://doi.org/10.1002/hep.31278
        • Chen R.
        • Yang L.
        • Goodison S.
        • Sun Y.
        Deep learning approach to identifying cancer subtypes using high-dimensional genomic data.
        Bioinformatics. 2019; https://doi.org/10.1093/bioinformatics/btz769
        • Ryuge S.
        • Sato Y.
        • Wang G.Q.
        • Matsumoto T.
        • Jiang S.X.
        • Katono K.
        • et al.
        Prognostic significance of nestin expression in resected non-small cell lung cancer.
        Chest. 2011; 139: 862-869https://doi.org/10.1378/chest.10-1121
        • Kleeberger W.
        • Bova G.S.
        • Nielsen M.E.
        • Herawi M.
        • Chuang A.-Y.
        • Epstein J.I.
        • et al.
        Roles for the stem cell associated intermediate filament Nestin in prostate cancer migration and metastasis.
        Cancer Res. 2007; 67: 9199-9206https://doi.org/10.1158/0008-5472.CAN-07-0806