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Mutational profiling and immunohistochemical analysis of a surgical series of ampullary carcinomas
  1. Mads Rohde Harthimmer1,2,
  2. Uffe Stolborg1,3,
  3. Per Pfeiffer2,4,5,
  4. Michael Bau Mortensen2,5,6,
  5. Claus Fristrup5,6,
  6. Sönke Detlefsen1,2,5
  1. 1 Department of Pathology, Odense University Hospital, Odense, Denmark
  2. 2 Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  3. 3 Department of Pathology, Vejle Hospital, Vejle, Denmark
  4. 4 Department of Oncology, Odense University Hospital, Odense, Denmark
  5. 5 Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
  6. 6 Department of Surgery, Odense University Hospital, Odense, Denmark
  1. Correspondence to Dr Sönke Detlefsen, Department of Pathology, Odense Universitetshospital, Odense 5000, Denmark; sonke.detlefsen{at}


Aims Knowledge regarding the genetic features of ampullary carcinoma (AC) in European patients is limited. The utility of tumour markers for the establishment of a malignant diagnosis in biopsies from the ampullary region has not been fully elucidated. We aimed to describe the clinical, pathological, immunohistochemical (IHC) and genetic features of a Danish series of surgically resected ACs.

Methods Surgically resected ACs (n=59) were examined regarding (1) clinicopathological features, (2) histological subtypes, (3) expression of IMP3, maspin, MUC5AC and S100P and (4) next-generation sequencing using a hybrid capture-based platform (Illumina HiSeq2500), including 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. Tumour mutational burden (TMB) and microsatellite instability (MSI) were also evaluated.

Results Pancreatobiliary adenocarcinomas (PB-AC), intestinal adenocarcinomas (INT-AC), other ampullary tumours and mixed adenocarcinomas represented 45.8%, 23.7%, 16.9% and 13.6%. The proportion of IHC-positive ACs (score ≥2) was: Maspin (94.9%), IMP3 (67.8%), S100P (39.0%) and MUC5AC (18.6%). Most frequently altered genes were TP53 (59.3%), KRAS (40.7%), APC (27.8%), SMAD4 (20.4%), CDKN2A (16.7%) and ARID2/PIK3CA (each 11.1%). MUC5AC and S100P were frequently expressed in PB-AC, APC alterations frequent in INT-AC, SOX9 alterations were exclusive in INT-AC and MDM2 and FRS2 alterations in PB-AC. Four of 49 ACs (8.2%) were TMB-high/MSI-high and showed loss of MLH1 and PMS2.

Conclusions PB-AC was the most frequent histological subtype of AC. Maspin and IMP3 were the IHC tumour markers with the highest sensitivity. Adenocarcinoma subtypes differed regarding several genetic alterations, whose predictive value remains to be evaluated.

  • ampullary carcinoma
  • intestinal adenocarcinoma
  • pancreatobiliary adenocarcinoma
  • next-generation sequencing
  • immunohistochemistry
  • subtyping

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  • Handling editor Runjan Chetty.

  • Contributors The study was designed by SDE. MRH, UST and SDE conducted the study, all authors contributed to data collection and data analysis. MRH and SDE prepared the manuscript draft. All authors discussed the results, commented on and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Scientific Ethics Committee of the Region of Southern Denmark (project-IDs S-20180002 and S-20180023) and by the Danish Data Protection Agency (project-IDs 18/19243 and 18/19247).

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

  • Data availability statement Participant data will be retained at the study facility for five years after completion of the trial according to Danish law. After this time period, it will be deidentified and made available for other researchers upon reasonable request to the corresponding author.