{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:37:21Z","timestamp":1792089441960,"version":"4.4.0"},"reference-count":86,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T00:00:00Z","timestamp":1725148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The vast majority of pituitary neuroendocrine tumors (PitNETs) are benign and slow growing with a low relapse rate over many years after surgical resection. However, about 40% are locally invasive and may not be surgically cured, and about one percentage demonstrate an aggressive clinical behavior. Exceptionally, these aggressive tumors may metastasize outside the sellar region to the central nervous system and\/or systemically. The 2017 (4th Edition) WHO Classification of Pituitary Tumors abandoned the terminology \u201catypical adenoma\u201d for tumors previously considered to have potential for a more aggressive behavior since its prognostic value was not established. The 2022 (5th Edition) WHO Classification of the Pituitary Tumors emphasizes the concept that morphological features distinguish indolent tumors from locally aggressive ones, however, the proposed histological subtypes are not consistent with the real life clinical characteristics of patients with aggressive tumors\/carcinomas. So far, no single clinical, radiological or histological parameter can determine the risk of growth or malignant progression. Novel promising molecular prognostic markers, such as mutations in\n                    <jats:italic>ATRX, TP53, SF3B1,<\/jats:italic>\n                    and epigenetic DNA modifications, will need to be verified in larger tumor cohorts. In this review, we provide a critical analysis of the WHO guidelines for prognostic stratification and diagnosis of aggressive and metastatic PitNETs. In addition, we discuss the new WHO recommendations for changing ICD\u2010O and ICD\u201011 codes for PitNET tumor behavior from a neoplasm either \u201cbenign\u201d or \u201cunspecified, borderline, or uncertain behavior\u201d to \u201cmalignant\u201d neoplasm regardless of the clinical presentation, histopathological subtype, and tumor location. We encourage multidisciplinary initiatives for integrated clinical, histological and molecular classification, which would enable early recognition of these challenging tumors and initiation of more appropriate and aggressive treatments, ultimately improving the outcome.\n                  <\/jats:p>","DOI":"10.1111\/bpa.13302","type":"journal-article","created":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T20:08:55Z","timestamp":1725221335000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The 2022\n                    <scp>WHO<\/scp>\n                    classification of tumors of the pituitary gland: An update on aggressive and metastatic pituitary neuroendocrine tumors"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-7331","authenticated-orcid":false,"given":"Olivera","family":"Casar\u2010Borota","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Rudbeck Laboratory Uppsala University  Uppsala Sweden"},{"name":"Department of Clinical Pathology Uppsala University Hospital  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4844-8336","authenticated-orcid":false,"given":"Pia","family":"Burman","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Sk\u00e5ne University Hospital, Lund University  Malm\u00f6 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8661-6727","authenticated-orcid":false,"given":"M. Beatriz","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Medicine, University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"37(52):1205","article-title":"Beitr\u00e4ge zur normalen und pathologischen Histologie der menschlichen Hypophysis cerebri","author":"Benda C","year":"1900","journal-title":"Klin Wochenschr"},{"key":"e_1_2_9_3_1","first-page":"159","article-title":"Die Beziehungen der Zellen des Vorderlappens des menschlichen Hypophyse zeuinander unter normalen Verh\u00e4ltnissen und in Tumoren","volume":"58","author":"Kraus EJ","year":"1914","journal-title":"Beitr z Path Anat u z Alg Path"},{"key":"e_1_2_9_4_1","first-page":"137","article-title":"The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)","author":"Cushing 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