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The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73% male; median age: 63\u00a0years). All six patients who underwent lymphadenectomy were staged as pN1, and liver metastases were found in three cases; however, no tumor-related deaths occurred (median follow-up: 104\u00a0months). Common histologic features that can pose diagnostic challenges in the differential diagnosis with adenocarcinoma included a tubulo-glandular architecture (100%), periodic Acid\u2013Schiff (PAS)-positive intraluminal mucin (73%), MUC1 expression (100%), and carcinoembryonic antigen (45%) expression. All tumors exhibited dot-like cytoplasmic reactivity for cytokeratins (CK) CAM5.2 or CK AE1\/AE3, and 82% were CK7-positive. ISL1 and PDX1 were diffusely expressed in all cases, while CDX2 was positive in 54% and ARX showed only focal expression in four tumors. Genomic profiling revealed microsatellite stability and low tumor mutational burden. Alterations in the RAS pathway, including\n                    <jats:italic>HRAS<\/jats:italic>\n                    mutations (4 cases, 36%), a\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutation (1 case), and\n                    <jats:italic>NF1<\/jats:italic>\n                    alterations (one case), were identified in 54% of cases and in all tumors with liver metastases. Additional molecular findings included a\n                    <jats:italic>CDK12<\/jats:italic>\n                    splice-site alteration and an\n                    <jats:italic>NTRK3<\/jats:italic>\n                    ::\n                    <jats:italic>PRDM4<\/jats:italic>\n                    fusion. Potentially actionable alterations affecting kinase-related pathways were detected in 64% of tumors. Our findings support SAMSOM-NET as a peculiar neuroendocrine tumor subtype showing distinctive histologic and molecular characteristics with potential diagnostic and therapeutic implications.\n                  <\/jats:p>","DOI":"10.1007\/s12022-026-09934-y","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:27:01Z","timestamp":1789187221000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Clinicopathologic, Immunohistochemical, and Genomic Profiling of Sporadic Ampullary Somatostatin-producing D-cell Neuroendocrine Tumors Identifies Recurrent HRAS Hotspot Mutations"],"prefix":"10.1007","volume":"37","author":[{"given":"Alessandro","family":"Vanoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Travaglino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frediano","family":"Inzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Orione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Grillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Parente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Spaggiari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Uccella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Zerbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Caterina","family":"Milanetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Lecca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Peri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Di Sabatino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Paulli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"La Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Fassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Errichiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"9934_CR1","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.5858\/2009-0697-OAR.1","volume":"134","author":"J Albores-Saavedra","year":"2010","unstructured":"Albores-Saavedra J, Hart A, Chabl\u00e9-Montero F, Henson DE (2010) Carcinoids and high-grade neuroendocrine carcinomas of the ampulla of Vater: a comparative analysis of 139 cases from the Surveillance, Epidemiology, and End Results Program\u2014a population-based study. 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