{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:28:51Z","timestamp":1790897331445,"version":"4.1.0"},"reference-count":96,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ampullary carcinoma (AC) is a rare gastrointestinal malignancy with dual intestinal and pancreatobiliary differentiation, complicating diagnosis, staging, and treatment. This review synthesizes current epidemiology, pathology, and multi-omic data to outline a pragmatic care pathway: lineage-first at presentation, mutation-fast at progression. Histology remains the primary classifier: the intestinal subtype generally aligns with colorectal regimens, whereas pancreatobiliary and mixed subtypes favor pancreaticobiliary therapy. In selected fit patients, modified FOLFIRINOX may address mixed phenotypes. Next-generation sequencing adds precision by identifying therapeutically relevant alterations, including ERBB2\/HER2 amplifications, MSI-high\/dMMR, BRAF V600E, and rare NTRK or RET fusions, while KRAS mutations are enriched in pancreatobiliary tumors. We recommend early application of a rapid-core panel (KRAS\/BRAF, MSI\/dMMR, ERBB2\/HER2, RNA-based fusions) to capture high-impact targets, followed by comprehensive profiling at first progression. Liquid biopsy, plasma circulating tumor DNA (ctDNA), or bile-derived DNA may complement tissue and help identify the dominant lineage. Research priorities include ampulla-enriched umbrella trials, explicit AC subcohorts in tissue-agnostic studies, and ctDNA-informed endpoints. This lineage-first, mutation-fast paradigm supports precision care and evidence generation in AC.<\/jats:p>","DOI":"10.3390\/ijms27031597","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:05:47Z","timestamp":1770372347000},"page":"1597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rare, Yet Targetable: New Perspectives on Ampullary Carcinomas"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9050-2267","authenticated-orcid":false,"given":"James","family":"Gutmans","sequence":"first","affiliation":[{"name":"Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Friedlaender","sequence":"additional","affiliation":[{"name":"Clinique G\u00e9n\u00e9rale Beaulieu, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9784-0333","authenticated-orcid":false,"given":"Hiba","family":"Mechahougui","sequence":"additional","affiliation":[{"name":"Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104480","DOI":"10.1016\/j.esmoop.2025.104480","article-title":"Genomic Profiling Unlocks New Treatment Opportunities for Ampullary Carcinoma","volume":"10","author":"Castet","year":"2025","journal-title":"ESMO Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.14694\/EdBook_AM.2014.34.112","article-title":"Ampullary Cancer: An Overview","volume":"34","author":"Ahn","year":"2014","journal-title":"Am. 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