Molecular and clinicopathological features of appendiceal mucinous neoplasms

Virchows Arch. 2021 Mar;478(3):413-426. doi: 10.1007/s00428-020-02906-5. Epub 2020 Aug 21.


Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.

Keywords: Appendiceal mucinous tumor; GNAS; KRAS; Low-grade appendiceal mucinous neoplasm; Mucinous adenocarcinoma; Next-generation sequencing; RNF43; TP53.

Publication types

  • Comparative Study
  • Multicenter Study

MeSH terms

  • Adenocarcinoma, Mucinous / chemistry
  • Adenocarcinoma, Mucinous / genetics*
  • Adenocarcinoma, Mucinous / pathology
  • Adenocarcinoma, Mucinous / surgery
  • Adult
  • Aged
  • Aged, 80 and over
  • Appendiceal Neoplasms / chemistry
  • Appendiceal Neoplasms / genetics*
  • Appendiceal Neoplasms / pathology
  • Appendiceal Neoplasms / surgery
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Chromogranins / genetics
  • DNA Mutational Analysis
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Grading
  • Neoplasm Staging
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Tokyo
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Young Adult


  • Biomarkers, Tumor
  • Chromogranins
  • KRAS protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • RNF43 protein, human
  • Ubiquitin-Protein Ligases
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs
  • Proto-Oncogene Proteins p21(ras)