Skip to main content

Advertisement

SpringerLink
Log in

Concordance of microsatellite instability and mismatch repair status in paired biopsies and surgical specimens of resectable gastroesophageal adenocarcinoma: time for a call to action

  • Original Article
  • Published:
Gastric Cancer Aims and scope Submit manuscript

Abstract

Background

Reliability of mismatch repair proteins and microsatellite instability assessment is essential in order to define treatment strategy and identify candidates to immune checkpoint inhibitors in locally advanced gastroesophageal carcinoma. We evaluated the concordance of deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status between endoscopic biopsies and surgical specimens.

Methods

Consecutive patients with resectable gastric or gastroesophageal junction adenocarcinoma classified as MSI-H/dMMR by polymerase chain reaction (PCR) or immunohistochemistry (IHC) and operated at three referral Institutions were included. The primary endpoint was the rate of concordance between biopsy and surgical samples. If needed, central revision by IHC/PCR was performed by specialized pathologists from coordinating Institutions.

Results

Thirteen (19.7%) out of 66 patients showed discordant MSI-H/dMMR results in the original pathology reports. In most cases (11, 16.7%) this was due to the diagnosis of proficient mismatch repair status on biopsies. Among the ten cases available for central review, four were due to sample issues, four were reclassified as dMMR, one case showed dMMR status but was classified as microsatellite stable by PCR, one was linked to misdiagnosis of endoscopic biopsy by the local pathologist. Heterogeneity of mismatch repair proteins staining was observed in two cases.

Conclusions

Available methods can lead to conflicting results in MSI-H/dMMR evaluation between endoscopic biopsies and surgical samples of gastroesophageal adenocarcinoma. Strategies aiming to improve the reliability of assessment should be primarily focused on the optimization of tissue collection and management during endoscopy and adequate training of dedicated gastrointestinal pathologists within the multidisciplinary team.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

References

  1. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396:635–48. https://doi.org/10.1016/S0140-6736(20)31288-5.

    Article  CAS  PubMed  Google Scholar 

  2. Fornaro L, Vasile E, Aprile G, Goetze TO, Vivaldi C, Falcone A, Al-Batran SE. Locally advanced gastro-oesophageal cancer: recent therapeutic advances and research directions. Cancer Treat Rev. 2018;69:90–100. https://doi.org/10.1016/j.ctrv.2018.06.012.

    Article  PubMed  Google Scholar 

  3. Reynolds JV, Preston SR, O’Neill B, Lowery MA, Baeksgaard L, Crosby T, et al. Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): final primary outcome analysis. J Clin Oncol. 2023;41(suppl 4):295–295. https://doi.org/10.1200/JCO.2023.41.4_suppl.295.

    Article  Google Scholar 

  4. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393:1948–57. https://doi.org/10.1016/S0140-6736(18)32557-1.

    Article  PubMed  Google Scholar 

  5. Han S, Chok AY, Peh DYY, Ho JZ, Tan EKW, Koo SL, et al. The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers. Front Genet. 2022;13:933475. https://doi.org/10.3389/fgene.2022.933475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pietrantonio F, Miceli R, Raimondi A, Kim YW, Kang WK, Langley RE, et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol. 2019;37:3392–400. https://doi.org/10.1200/JCO.19.01124.

    Article  PubMed  Google Scholar 

  7. Kohlruss M, Grosser B, Krenauer M, Slotta-Huspenina J, Jesinghaus M, Blank S, et al. Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein-Barr virus infection and high- and low-microsatellite instability. J Pathol Clin Res. 2019;5:227–39. https://doi.org/10.1002/cjp2.137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lordick F. Chemotherapy for resectable microsatellite instability-high gastric cancer? Lancet Oncol. 2020;21:203. https://doi.org/10.1016/S1470-2045(20)30012-7.

    Article  PubMed  Google Scholar 

  9. Smyth EC. Chemotherapy for resectable microsatellite instability-high gastric cancer? Lancet Oncol. 2020;21:204. https://doi.org/10.1016/S1470-2045(20)30025-5.

    Article  PubMed  Google Scholar 

  10. Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022;33:929–38. https://doi.org/10.1016/j.annonc.2022.05.519.

    Article  CAS  PubMed  Google Scholar 

  11. Pietrantonio F, Randon G, Di Bartolomeo M, Luciani A, Chao J, Smyth EC, Petrelli F. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO Open. 2021;6:100036. https://doi.org/10.1016/j.esmoop.2020.100036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. André T, Tougeron D, Piessen G, de la Fouchardière C, Louvet C, Adenis A, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study. J Clin Oncol. 2023;41:255–65. https://doi.org/10.1200/JCO.22.00686.

    Article  CAS  PubMed  Google Scholar 

  13. Pietrantonio F, Raimondi A, Lonardi S, Murgioni S, Cardellino GG, Tamberi S, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). J Clin Oncol. 2023. https://doi.org/10.1200/JCO.2023.41.3_suppl.358.

    Article  PubMed  Google Scholar 

  14. Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, Vogel A, Smyth EC, ESMO Guidelines Committee. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:1005–20. https://doi.org/10.1016/j.annonc.2022.07.004.

    Article  CAS  PubMed  Google Scholar 

  15. Businello G, Angerilli V, Lonardi S, Bergamo F, Valmasoni M, Farinati F, et al. Current molecular biomarkers evaluation in gastric/gastroesophageal junction adenocarcinoma: pathologist does matter. Updates Surg. 2023;75:291–303. https://doi.org/10.1007/s13304-022-01330-5.

    Article  PubMed  Google Scholar 

  16. Cohen R, Hain E, Buhard O, Guilloux A, Bardier A, Kaci R, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol. 2019;5:551–5. https://doi.org/10.1001/jamaoncol.2018.4942.

    Article  PubMed  Google Scholar 

  17. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. https://doi.org/10.1126/science.aan6733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449–58. https://doi.org/10.1038/s41591-018-0101-z.

    Article  CAS  PubMed  Google Scholar 

  19. Fassan M, Scarpa A, Remo A, De Maglio G, Troncone G, Marchetti A, et al. Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice. Pathologica. 2020;112:248–59. https://doi.org/10.32074/1591-951X-158.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bateman AC. DNA mismatch repair protein immunohistochemistry—An illustrated guide. Histopathology. 2021;79:128–38. https://doi.org/10.1111/his.14367.

    Article  PubMed  Google Scholar 

  21. Malapelle U, Parente P, Pepe F, De Luca C, Cerino P, Covelli C, et al. Impact of pre-analytical factors on MSI test accuracy in mucinous colorectal adenocarcinoma: a multi-assay concordance study. Cells. 2020;9:2019. https://doi.org/10.3390/cells9092019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Angerilli V, Lonardi S, Farinati F, Savarino E, Bergamo F, Fassan M. Mismatch repair status and gastro-oesophageal dysplasia: need for a dedicated gastrointestinal pathologist? Histopathology. 2022;80:1138–40. https://doi.org/10.1111/his.14647.

    Article  PubMed  Google Scholar 

  23. Montgomery E, Bronner MP, Goldblum JR, Greenson JK, Haber MM, Hart J, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol. 2001;32:368–78. https://doi.org/10.1053/hupa.2001.23510.

    Article  CAS  PubMed  Google Scholar 

  24. Vilkin A, Halpern M, Morgenstern S, Brazovski E, Gingold-Belfer R, Boltin D, et al. How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation? Hum Pathol. 2014;45:2029–36. https://doi.org/10.1016/j.humpath.2014.07.005.

    Article  CAS  PubMed  Google Scholar 

  25. Kuan SF, Ren B, Brand R, Dudley B, Pai RK. Neoadjuvant therapy in microsatellite-stable colorectal carcinoma induces concomitant loss of MSH6 and Ki-67 expression. Hum Pathol. 2017;63:33–9. https://doi.org/10.1016/j.humpath.2017.02.003.

    Article  CAS  PubMed  Google Scholar 

  26. Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18:476–84. https://doi.org/10.1007/s10120-014-0402-y.

    Article  CAS  PubMed  Google Scholar 

  27. Coati I, Lotz G, Fanelli GN, Brignola S, Lanza C, Cappellesso R, et al. Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer. 2019;121:257–63. https://doi.org/10.1038/s41416-019-0508-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pellino A, Brignola S, Riello E, Niero M, Murgioni S, Guido M, et al. Association of CLDN18 protein expression with clinicopathological features and prognosis in advanced gastric and gastroesophageal junction adenocarcinomas. J Pers Med. 2021;11:1095. https://doi.org/10.3390/jpm11111095.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhou KI, Peterson B, Serritella A, Thomas J, Reizine N, Moya S, et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin Cancer Res. 2020;26:6453–63. https://doi.org/10.1158/1078-0432.CCR-20-2085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. von Loga K, Woolston A, Punta M, Barber LJ, Griffiths B, Semiannikova M, et al. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. Nat Commun. 2020;11:139. https://doi.org/10.1038/s41467-019-13915-7.

    Article  CAS  Google Scholar 

  31. Wang X, Jiang K, Hu Y, Zhao X, Yin L, Diao X, et al. An exploration of gastric cancer with heterogeneous mismatch repair status. Virchows Arch. 2023;482:517–23. https://doi.org/10.1007/s00428-023-03506-9.

    Article  CAS  PubMed  Google Scholar 

  32. Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB 3rd, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35:446–64. https://doi.org/10.1200/JCO.2016.69.4836.

    Article  CAS  PubMed  Google Scholar 

  33. Pfitzner BM, Lederer B, Lindner J, Solbach C, Engels K, Rezai M, et al. Clinical relevance and concordance of HER2 status in local and central testing-an analysis of 1581 HER2-positive breast carcinomas over 12 years. Mod Pathol. 2018;31:607–15. https://doi.org/10.1038/modpathol.2017.171.

    Article  CAS  PubMed  Google Scholar 

  34. Haffner I, Schierle K, Raimúndez E, Geier B, Maier D, Hasenaue J, et al. HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study. J Clin Oncol. 2021;39:1468–78. https://doi.org/10.1200/JCO.20.02761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was partially supported by Veneto Institute of Oncology IOV-IRCCS research program BIOV19LOUPAK. MF is supported by grants from the Italian Health Ministry/Veneto region research program NET-2016–02363853 and AIRC 5 per mille 2019 (ID. 22759 program). FP is supported by grants from AIRC IG 23624.

Author information

Author notes

  1. Lorenzo Fornaro and Sara Lonardi have contributed equally as first author.

  2. Clara Ugolini and Matteo Fassan have contributed equally as last author.

Authors and Affiliations

  1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Lorenzo Fornaro, Silvia Catanese, Francesca Salani, Caterina Vivaldi & Gianluca Masi

  2. Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy

    Sara Lonardi, Floriana Nappo, Sabina Murgioni, Gianmarco Ricagno, Francesca Bergamo & Matteo Fassan

  3. Unit of Medical Oncology, Ospedale Misericordia, Azienda Toscana Sud-Est, Grosseto, Italy

    Silvia Catanese

  4. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Filippo Pietrantonio

  5. Department of Oncology, Division of Medical Oncology, Azienda Toscana Nord Ovest, Livorno, Italy

    Antonio Pellino

  6. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy

    Valentina Angerilli, Ioana Ancuta Neculaescu & Matteo Fassan

  7. Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy

    Francesca Signorini & Clara Ugolini

  8. Institute of Interdisciplinary Research “Health Science”, Scuola Superiore Sant’Anna, Pisa, Italy

    Francesca Salani

  9. Unit of Pathology 3, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Rossella Bruno

  10. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Caterina Vivaldi & Gianluca Masi

  11. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

    Gianmarco Ricagno

Authors
  1. Lorenzo Fornaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Lonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Catanese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Floriana Nappo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Filippo Pietrantonio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Pellino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Valentina Angerilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesca Signorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francesca Salani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sabina Murgioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ioana Ancuta Neculaescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rossella Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Caterina Vivaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gianmarco Ricagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gianluca Masi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Francesca Bergamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Clara Ugolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Matteo Fassan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LF, SL, CU and MF conceptualized and designed the study. All the authors collected and analysed data. LF, SL, SC, FN, CU and MF supervised analyses and interpreted data. All the authors drafted the article and approved the final manuscript for submission.

Corresponding author

Correspondence to Lorenzo Fornaro.

Ethics declarations

Conflict of interest

LF reports personal honoraria as invited speaker from Incyte, Bristol Myers Squibb, Lilly; research funding (to Institution) from MSD, Bristol Myers Squibb, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, Roche; participation in advisory board for MSD, AstraZeneca, Incyte, Taiho, Servier, Daiichi Sankyo, Lilly. SL reports research funding (to Institution) from Amgen, Astellas, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astra Zeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Incyte, Lilly, Merck Serono, MSD, Servier. FP reports personal fees from Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, MSD, Bristol Myers Squibb, Lilly, AstraZeneca, Astellas, Organon, and research grants from AstraZeneca, Agenus, Incyte and Bristol Myers Squibb. MF has been involved in consulting/advisory roles in Astellas Pharma, Pierre Fabre, MSD, AstraZeneca, Janssen, GlaxoSmithKline, Amgen, Novartis and Roche, and received research funding from Astellas Pharma, QED Therapeutics, Diaceutics and Macrophage Pharma. All other authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 143 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fornaro, L., Lonardi, S., Catanese, S. et al. Concordance of microsatellite instability and mismatch repair status in paired biopsies and surgical specimens of resectable gastroesophageal adenocarcinoma: time for a call to action. Gastric Cancer 26, 958–968 (2023). https://doi.org/10.1007/s10120-023-01411-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10120-023-01411-3

Keywords

Search

Navigation