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We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1\/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38\/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1\/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1\/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.<\/jats:p>","DOI":"10.1007\/s00428-021-03202-6","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T07:03:19Z","timestamp":1631170999000},"page":"359-368","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features"],"prefix":"10.1007","volume":"480","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1130-1744","authenticated-orcid":false,"given":"Atsuko","family":"Kasajima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Konukiewitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Melissa","family":"Schlitter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilko","family":"Weichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Kl\u00f6ppel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"3202_CR1","first-page":"210","volume-title":"WHO classification of Tumours of Endocrine Organs","author":"G Kl\u00f6ppel","year":"2017","unstructured":"Kl\u00f6ppel G, Couvelard A, Hruban R, Klimstra D, Komminoth P, Osamura RY, Perren A, Rindi G (2017) Neuroendocrine neoplasms of the pancreas. 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