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APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum

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Abstract

Background

Recent studies highlighted the clinicopathological heterogeneity of non-ampullary duodenal adenomas and adenocarcinomas, but the detailed process of the malignant transformation remains unclear.

Methods

We analyzed 144 adenomas and 54 adenocarcinomas of the non-ampullary duodenum for immunohistochemical phenotypes, genetic alterations, and mismatch repair (MMR) status to probe their histogenetic relationship.

Results

The median ages of patients with adenoma and adenocarcinoma were the same (66 years). Adenomas were histologically classified as intestinal-type adenoma (n = 124), pyloric gland adenoma (PGA, n = 10), gastric-type adenoma, not otherwise specified (n = 9), and foveolar-type adenoma (n = 1). Protein-truncating APC mutations were highly frequent in adenomas (85%), with the highest prevalence in intestinal-type adenomas (89%), but rare in adenocarcinomas (9%; P = 2.1 × 10–23). Close associations between phenotypic marker expression and genetic alterations were observed in adenomas, but not in adenocarcinomas, excluding the common association between GNAS mutations and MUC5AC expression. MMR deficiency was more frequent in adenocarcinomas (20%) than in adenomas (1%; P = 2.6 × 10–6). One MMR-deficient adenoma and three MMR-deficient adenocarcinomas occurred in patients with Lynch syndrome. Additionally, three other patients with an MMR-deficient adenocarcinoma fulfilled the revised Bethesda criteria.

Conclusion

The discrepant APC mutation frequency between adenomas and adenocarcinomas suggests that APC-mutated adenomas, which constitute the large majority of non-ampullary duodenal adenomas, are less prone to malignant transformation. Non-ampullary duodenal adenocarcinomas frequently exhibit MMR deficiency and should be subject to MMR testing to determine appropriate clinical management, including the identification of patients with Lynch syndrome.

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Acknowledgements

We thank Ms. Reiko Ogawa, Ms. Sachiko Miura, Ms. Toshiko Sakaguchi, and Ms. Chizu Kina for their skillful technical assistance. This work was supported by JSPS KAKENHI Grant Number 20K07401.

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Authors and Affiliations

  1. Division of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Kenichi Ishizu, Taiki Hashimoto, Tomoaki Naka, Yasushi Yatabe & Shigeki Sekine

  2. Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan

    Kenichi Ishizu & Takaki Yoshikawa

  3. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Yasushi Yatabe & Shigeki Sekine

  4. Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan

    Motohiro Kojima & Takeshi Kuwata

  5. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan

    Satoru Nonaka & Ichiro Oda

  6. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan

    Minoru Esaki

  7. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Chiba, Japan

    Masashi Kudo & Naoto Gotohda

  8. Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan

    Teruhiko Yoshida

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  1. Kenichi Ishizu
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Contributions

KI, TH, and SS designed the study. TH and SS performed mutation analyses. KI, TH, TN, YY, and SS performed histological and immunohistochemical analyses. MK, TK, SN, IO, ME, MK, NG, TYoshida, and TYoshikawa provided tissue samples and clinical information. KI and SS wrote the manuscript. All authors contributed to discussions and gave final approval of the submitted manuscript.

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Correspondence to Shigeki Sekine.

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Ishizu, K., Hashimoto, T., Naka, T. et al. APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum. J Gastroenterol 56, 988–998 (2021). https://doi.org/10.1007/s00535-021-01823-x

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  • DOI: https://doi.org/10.1007/s00535-021-01823-x

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