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Molecular heterogeneity of pancreatic intraductal papillary mucinous neoplasms and implications for novel endoscopic tissue sampling strategies
  1. Charlotte Vestrup Rift1,
  2. Linea Cecilie Melchior1,
  3. David Scheie1,
  4. Carsten Palnæs Hansen2,
  5. Eva Løbner Lund1,
  6. Jane Preuss Hasselby1
  1. 1 Department of Pathology, Rigshospitalet, Copenhagen, Denmark
  2. 2 Department of Surgery, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Dr Charlotte Vestrup Rift, Department of Pathology, Rigshospitalet, Copenhagen 2100, Denmark; charlotte.vestrup.rift{at}


Aims Intraductal papillary mucinous neoplasms (IPMNs) may be precursor lesions of pancreatic cancer. The path towards malignancy is associated with mutations in tumour suppressor—and oncogenes that may serve as biomarkers during diagnostic investigation. A novel micro forceps has made it possible to obtain biopsies from the cyst wall for analysis by next generation sequencing (NGS), providing an opportunity for early detection and intervention. However, the impact of spatial tumour heterogeneity on the representability of the biopsies has not been determined. The primary aim is to characterise the impact of molecular heterogeneity of the luminal cyst wall on tissue sampling strategies with small biopsies.

Methods We performed NGS and immunohistochemical phenotyping on 18 resected IPMNs with varying degrees of dysplasia and for a subset, concomitant carcinoma, using a commercially available NGS-panel of 51 oncogenes. We simulated endoscopic biopsies by performing punch biopsies (PBs) of the cyst wall from resected specimens.

Results In total, 127 NGS analyses were performed. Concomitant KRAS and GNAS was a common feature of the IPMNs. Mutations in KRAS and GNAS were associated with low-grade dysplasia whereas alterations in TP53, SMAD4, CDKN2A and PIK3CA were associated with high-grade dysplasia and/or carcinoma. The mutational analysis of the PBs from the cyst wall was compared with the whole lesion. No difference was detected between PBs and whole lesions when the cumulated mutational profile in increasing order of randomly performed PBs was compared.

Conclusions Small IPMN biopsies from the cyst wall are adequate to yield a molecular diagnosis.

  • pancreatic neoplasms
  • pancreas
  • pathology
  • molecular
  • diagnostic techniques and procedures

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Handling editor Runjan Chetty.

  • Twitter @CVRift

  • Contributors CVR contributed to conceptualisation, methodology, analysis of data, writing—original draft. LCM contributed to conceptualisation, data analysis, review and revision of manuscript. DS contributed to conceptualisation, methodology, interpretation of data, review and revision of paper. CPH contributed to conceptualisation, methodology, data curation, review and revision of paper. ELL contributed to conceptualisation, methodology, review and revision of paper. JPH contributed to conceptualisation, methodology, data curation, review and revision of paper. All authors read and reviewed the paper and approved the final version.

  • Funding The study received funding from Rigshospitalets Research Foundation, The Novo Nordisk Foundation, The Danish Cancer Society, The Danish Cancer Research Foundation, Neye Foundation, Aase & Ejnar Danielsens Foundation and Anita & Tage Therkelsens Foundation.

  • Disclaimer The funding sources had no role in conducting the study or preparing the manuscript.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.