Mutational profiling and immunohistochemical analysis of a surgical series of ampullary carcinomas

J Clin Pathol. 2019 Nov;72(11):762-770. doi: 10.1136/jclinpath-2019-205912. Epub 2019 Jun 29.

Abstract

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.

Keywords: ampullary carcinoma; immunohistochemistry; intestinal adenocarcinoma; next-generation sequencing; pancreatobiliary adenocarcinoma; subtyping.

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / surgery
  • Aged
  • Aged, 80 and over
  • Ampulla of Vater / chemistry*
  • Ampulla of Vater / pathology
  • Ampulla of Vater / surgery
  • Biomarkers, Tumor* / analysis
  • Biomarkers, Tumor* / genetics
  • Calcium-Binding Proteins / analysis
  • Calcium-Binding Proteins / genetics
  • Denmark
  • Digestive System Neoplasms / chemistry*
  • Digestive System Neoplasms / genetics*
  • Digestive System Neoplasms / pathology
  • Digestive System Neoplasms / surgery
  • Female
  • Gene Expression Profiling*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry*
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Mucin 5AC / analysis
  • Mucin 5AC / genetics
  • Mutation*
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / genetics
  • Phenotype
  • Predictive Value of Tests
  • Registries
  • Ribonucleoproteins, Small Nucleolar / analysis
  • Ribonucleoproteins, Small Nucleolar / genetics
  • Serpins / analysis
  • Serpins / genetics

Substances

  • Biomarkers, Tumor
  • Calcium-Binding Proteins
  • IMP3 protein, human
  • MUC5AC protein, human
  • Mucin 5AC
  • Neoplasm Proteins
  • Ribonucleoproteins, Small Nucleolar
  • S100P protein, human
  • SERPIN-B5
  • Serpins