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This heterogeneous group of tumours encompasses both non-invasive and invasive epithelial neoplasms, which are associated with variable clinical presentations and prognoses. Defining the exact origin\u2014whether duodenal or ampullary\u2014is determined by the localization of the centre of the tumour, the identification of which requires meticulous specimen grossing. While histomorphological evaluation remains the cornerstone of establishing a correct diagnosis, immunohistochemistry may be required for characterizing less common neoplasms. Moreover, antibody panels targeting lineage-specific markers (intestinal, pancreatobiliary, and gastric) yield ancillary information for the subtyping of ampullary carcinomas, thereby guiding the selection of systemic chemotherapy. Furthermore, in view of the rapid expansion of targeted therapies, routine molecular profiling for relevant predictive biomarkers is warranted. This review outlines the morphological and immunohistochemical diagnostic criteria for the classification of this group of neoplasms and addresses their pathogenesis and the clinical relevance of molecular testing within the current standard of care.<\/jats:p>","DOI":"10.1007\/s00428-026-04682-0","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:02:55Z","timestamp":1787731375000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumours of the duodenum and the ampulla of Vater: An overview of the key criteria for their classification, pathogenesis, and molecular assessment"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-0259","authenticated-orcid":false,"given":"Maia Blomhoff","family":"Holm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3825-2935","authenticated-orcid":false,"given":"Andrea Rebecka","family":"Sander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-9715","authenticated-orcid":false,"given":"Caroline Sophie","family":"Verbeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"4682_CR1","unstructured":"WHO Classification of Tumours Editorial Board (2019) Digestive system tumours. 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