Tumors of the duodenum and ampulla
2026-06-10 Paola Dal Cin, PhD , Matteo Fassan, MD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.University of Padua (Italy)
Keywords
Duodenum,ampulla, non-ampullary adenomas,ampullary adenomas,ampullary adenocarcinoma ,non-ampullary adenocarcinoma, APS mutation genetic syndromes, omaClassification
Definition
The duodenum and ampulla are grouped because of their overlapping epidemiological and pathogenetic features. Among benign duodenal lesions, ampullary lesions should be distinguished from non-ampullary duodenal adenomas. 1 Histologically, non-ampullary duodenal adenomas (NADAs) are classified as intestinal-type and gastric-type with Intestinal-type lesions been the predominant subtype, with lower potential for malignant transformation compared to gastric-type. Mutations of APC were more frequent than KRAS in intestinal-type lesions, while both GNAS and KRAS alterations were significantly more common in gastric-type neoplasms. Ampullary duodenal adenomas (ADAs) involve the duodenal surface and may develop sporadically or in hereditary syndromes, such as FAP. However, APC mutations appeared different between sporadic and associated with APC syndrome. 2 Microsatellite instability and TP53 alterations have been reported to be absent or very rare in both NADAs and ADAs. 3
The discrepant APC mutation frequency between non-ampullary duodenal adenomas and adenocarcinomas suggests that APC-mutated adenomas, which constitute most of the NADAs are less prone to malignant transformation. 4
Most ampullary carcinomas are adenocarcinomas, with different histology subtypes. 5 A slight increase in incidence of these lesions has been observed and could be related to mucosal irritating factors, such as gastric acids, bile and pancreatic enzymes, or Helicobacter pylori infection, resulting from lifestyle habits. 6,7
Genetic syndromes, such as Lynch syndrome, familial adenomatous polyposis, and Peutz–Jeghers syndrome, are all associated with an increased risk of developing ampullary and extra-ampullary duodenal cancer. 1,7 In particular, the ampulla and the periampullary duodenum represent the most common localization for familial adenomatous polyposis–associated adenomas and adenocarcinomas in the small intestine. 8
| Tumors of the duodenum and ampulla | |
|---|---|
| Benign epithelial tumors and precursors | Genetic events |
| Non-ampullary adenoma | Non-ampullary duodernal adenomas (NADAs} , are histologiclly classified as as intestinal-type and gastric-type, arising through separate carcinogenetic molecular pathways. 1 Intestinal-type lesions are the predominant subtype,mainly as sporadic cases , with lower potential for malignant transformation compared to gastric-type. Mutations of APC were more frequent than KRAS one in intestinal-type lesions . 1,4 They may arise also in the background of genetic polyposis syndromes, most frequently in patients with familial adenomatous polyposis (FAP) OMIM:175100, and less also in those with MUTYH-associated polyposis (MAP) OMIM:608456, 9,10 but involvement of other new adenomatous polyposis syndromes have been described.1 |
| Pyloric gland adenomas (PGAs) are mostly located in the proximal duodenum in elderly women in a setting of autoimmune gastritis 11 GNAS mutations, often coexisting with KRAS mutations, were initailly reported, 12 and PGAs in familial adenomatous polyposis have a similar genetic background were observed in PGAs in familial adenomatous polyposis.13 However, next-generation sequencing identified 2 genomically distinct groups among PGAs, acoording the grade of dysplasias : 1) PGAs with low-grade dysplasias showed consistently in a triad {APC), KRAS and GNAS mutations with a few other genomic alterattions 2) PGAs with high-grade dysplasias/ adenocarcinomas included mutations in several genes including mutations in TP53 , CTNBB1 and EPHA5, but not the consistent triad of APC , KRAS, and GNAS genes. In addition, PGAs with high-grade dysplasia/ adenocarcinoma had more chromosomal gains and losses than PGAs with low-grade dysplasia. 14 | |
| Ampullary adenomatous neoplasm | Ampullary duodenal adenomas (ADAs), are often asymptomatic and incidentally discovered on endoscopy. In patients with FAP syndrome OMIM:175100, the duodenum is the second most common site of polyp formation. Sporadic and FAP-related ampullary adenomas have similar molecular features affecting the WNT signalling pathway, including mutations in APC and KRAS. Both BRAF mutations ad microsatellite instability (MSI) were rarely detected, mainly likely affecting intestinal type ADAs . 1 In addition, sporadic ADAs have been shown: 1) to differ from those of FAP, with regards to APC somatic mutation prevalence and site of mutation, 2 and 2) to contain loss of heterozygosity (LOH) at 5q21. 2 , 15 suggesting a distinct molecular pathogenesis for the two conditions, as well as, its contribution in the early phase of carcinomas development. 1 |
| A rare form of ampullary adenoma is the intra-ampullary papillary-tubular neoplasm (IAPN), is a rare lesions that originate in and grow within the ampullary channel, predominantly nonintestinal commonly invasive, displaying aggressive features and lymph node metastasis. However, their prognosis is still better than that of the ampullary-ductal carcinoma. 16 No specific information on the molecular background of this subtype of pre-invasive lesion is yet available. | |
| Malignant epithelial tumours | |
| Non-ampullary adenocarcinoma | Non-ampullary duodenal adenocarcinomas (NADCs) are rare diseases with limited studies, with risk factors less commonly associated with an adenoma component than are colorectal cancers. APC mutations are common in NADAs but infrequent in NADCs, instead they frequently exhibit mismatch repair (MMR) deficiency and should be subject to MMR testing fir identifying of patients with Lynch syndrome. 4 Genetic analyses also revealed molecular heterogeneity among them. In sporadic type APC and CTNNB1 mutations were found in intestinal- and gastrointestinal-type , but were absent in gastric-type.17 The most frequently mutated genes were TP53 , KRAS, SMAD4 , PIK3CA, CDKN2A , ARID1A, BRAF (mainly non-p.Val600Glu), and ERBB2/ERBB2 alterations, among a number of other genes. 18,19 Microsatellite instability in the high-grade dysplasia component of duodenal adenoma is associated with progression to adenocarcinoma. 20 |
| Ampullary adenocarcinoma | Although ampulla of Vater carcinomas (AVCs) are usually sporadic neoplasms, they can also arise in the context of familial syndromes e.g., familiar adenomatous polyposis (FAP) Four different histologic type of ampullary adenocarcinomas have been recognized bases of its site of origin, and have important clinical associations e.g., as peri-ampullary-duodenal, ampullary-ductal, intra-ampullary papillary-tubular neoplasm-associated, and ampullary- NOS (papilla of Vater), and have important clinical associations e.g., intra-ampullary cancers predominantly occur in males and have a very good prognosis , while ampullary-ductal cases with pancreatobiliary lineage have an aggressive clinical behavior. 21 Common molecular alterations among different subtypes, such as TP53, KRAS and ELF3 mutations were common molecular alterations among different subtypes,suggesting common biological mechanisms in the development of ampullary carcinomas. While other genetic alterations, as SMAD4 and CDKN2A, belonging to the Wnt-pathway and those characterizing the pancreatobiliary type, may occur at later stages of tumor growth. 5 ERBB2 amplification has been also demonstrated regardless of histological subtypes and was virtually mutually exclusive with downstream mutations. 22 As many as 10–15% of ampullary carcinomas are mismatch repair–deficient, even more frequent than in colon cancer, often with with a often has a Lynch-suggestive profile, thus routine testing is warranted. 23 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 33922305 | 2021 | Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations. | Vanoli A et al |
| 2 | 8903471 | 1996 | APC gene mutations and allelic losses in sporadic ampullary tumours: evidence of genetic difference from tumours associated with familial adenomatous polyposis. | Achille A et al |
| 3 | 18670349 | 2008 | Immunohistochemical and molecular features of sporadic and FAP-associated duodenal adenomas of the ampullary and nonampullary mucosa. | Wagner PL et al |
| 4 | 34514550 | 2021 | APC mutations are common in adenomas but infrequent in adenocarcinomas of the non-ampullary duodenum. | Ishizu K et al |
| 5 | 30487949 | 2018 | Ampulla of Vater carcinoma: Molecular landscape and clinical implications. | Pea A et al |
| 6 | 30884915 | 2019 | Epidemiology of Cancers of the Small Intestine: Trends, Risk Factors, and Prevention. | Barsouk A et al |
| 7 | 34000722 | 2022 | Risk Factors for Non-Ampullary Duodenal Adenocarcinoma: A Systematic Review. | Yabuuchi Y et al |
| 8 | 38142452 | 2024 | Clinical features and distribution of the APC variant in duodenal and ampullary polyps in patients with familial adenomatous polyposis: a multicenter retrospective cohort study in Japan. | Miyakura Y et al |
| 9 | 33130102 | 2021 | Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study. | Thomas LE et al |
| 10 | 39794684 | 2025 | Genetic predisposition to polyposis syndromes. | García-Simón N et al |
| 11 | 31529725 | 2020 | Clinicopathological features of pyloric gland adenomas of the duodenum: a multicentre study of 57 cases. | Miller GC et al |
| 12 | 23208952 | 2013 | Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. | Matsubara A et al |
| 13 | 27767239 | 2017 | Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis. | Hackeng WM et al |
| 14 | 31783043 | 2020 | Next-generation sequencing identifies 2 genomically distinct groups among pyloric gland adenomas. | Setia N et al |
| 15 | 9862579 | 1998 | Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer. | Achille A et al |
| 16 | 38938087 | 2024 | Intra-ampullary Papillary Tubular Neoplasm (IAPN): Clinicopathologic Analysis of 72 Cases Highlights the Distinctive Characteristics of a Poorly Recognized Entity. | Tarcan ZC et al |
| 17 | 41008809 | 2025 | Insight into the Wnt Pathway in Sporadic Small Bowel Adenocarcinoma. | Nishimoto T et al |
| 18 | 28617917 | 2017 | Genomic Profiling of Small-Bowel Adenocarcinoma. | Schrock AB et al |
| 19 | 29522538 | 2018 | Exome-wide somatic mutation characterization of small bowel adenocarcinoma. | Hänninen UA et al |
| 20 | 35871406 | 2023 | Microsatellite instability in the high-grade dysplasia component of duodenal adenoma is associated with progression to adenocarcinoma. | Aso N et al |
| 21 | 23026934 | 2012 | Ampullary region carcinomas: definition and site specific classification with delineation of four clinicopathologically and prognostically distinct subsets in an analysis of 249 cases. | Adsay V et al |
| 22 | 25975284 | 2015 | Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2). | Hechtman JF et al |
| 23 | 32857459 | 2020 | Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated. | Xue Y et al |
Citation
Paola Dal Cin, PhD ; Matteo Fassan, MD
Tumors of the duodenum and ampulla
Atlas Genet Cytogenet Oncol Haematol. 2026-06-10
Online version: http://atlasgeneticsoncology.org/solid-tumor/209375
