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This coding change is not a mere terminological substitution but represents a profound reconceptualization of the biological nature of PitNETs\u2014transitioning from the classical paradigm of \u201cindolent benign adenoma\u201d to a novel framework of \u201cfull-spectrum neuroendocrine tumors with malignant potential.\u201d This article systematically reviews the historical context and driving forces behind the evolution of the ICD-O code from \/0 to \/3. It then elaborates on the molecular advances underpinning this coding change across three levels: genetic mutations, epigenetic remodeling, and post-transcriptional regulation. Crucially, it emphasizes that the clinically validated morphologic subtyping, which has proven prognostic value, often but not always correlates with these molecular alterations, and remains the cornerstone of patient management. Finally, it discusses unresolved issues in the current classification system and future directions. In conclusion, the transition of the ICD-O code from \/0 to \/3 marks a critical milestone in PitNET taxonomy, signifying its shift from a \u201chistological\u201d paradigm, where molecular insights complement, but do not replace, a precise morphologic classification.<\/jats:p>","DOI":"10.1177\/10668969261460043","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T17:44:48Z","timestamp":1784051088000},"page":"1958-1968","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["The End of \u201cBenign\u201d: Drivers of the ICD-O Code Upgrade for Pituitary Neuroendocrine Tumors and the Molecular Revolution"],"prefix":"10.1177","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1052-8146","authenticated-orcid":false,"given":"Kaijian","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Anhui Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.23736\/S2724-6507.24.04126-5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-022-09703-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.25259\/SNI_102_2022"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-23-0021"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1530\/eje.0.1330686"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.79.1.8027215"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0998"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-16-0496"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-024-09819-y"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.672178"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.19.6.0350"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc926"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn112137-20220417-00825"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-17-0004"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2025.40.e56"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02785-z"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.604644"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13302"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-26-0030"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-024-02836-5"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44276-025-00155-0"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.11.002"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1159\/000514862"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102455"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1126100"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2556"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1084-y"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.2.5432"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-07-0062"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-09-0100"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa749"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8050695"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2689"},{"issue":"5","key":"e_1_3_2_35_2","first-page":"2635","article-title":"Epithelial-mesenchymal transition (EMT) markers in human pituitary adenomas indicate a clinical course","volume":"35","author":"Jia W","year":"2015","unstructured":"Jia W, Zhu J, Martin TA, et al. 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