{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T18:46:19Z","timestamp":1782413179104,"version":"3.54.5"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Health Sciences"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pituitary"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Immature PIT-1 lineage tumors are classified as high-risk pituitary adenomas\/pituitary neuroendocrine tumors (PitNETs) under the 2022 WHO Classification, yet clinical outcome data remain scarce. This study aimed to characterize clinicopathological features and treatment outcomes of this rare entity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed 13 patients with pathologically confirmed immature PIT-1 lineage tumors who underwent surgery at our tertiary center between January 2022 and December 2024. Diagnoses were established according to WHO 2022 criteria using comprehensive transcription factor (TF) immunohistochemistry. Clinical, radiological, histopathological, treatment, and follow-up data were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Immature PIT-1 lineage tumors accounted for 4% (21\/525) of surgically treated pituitary adenomas, of whom 13 with complete follow-up data constituted the primary analysis cohort. Median age was 37 years (range: 25\u201373), with female predominance (61.5%). Notably, 61.5% presented with hormonal hypersecretion: acromegaly (38.5%), TSH-secreting tumors (15.4%), and GH-PRL co-secretion (7.7%). All patients had macroadenomas (median diameter 28\u00a0mm (range: 15\u201359\u00a0mm)); 38.5% demonstrated cavernous sinus invasion (Knosp grades 3\u20134). Immunohistochemically defined plurihormonal phenotype was present in 77% of cases; cytologic atypia was identified in all cases. Despite maximal surgical resection, residual disease persisted in 46% and 31% required reoperation at 16-month follow-up (range: 4\u201351 months). The median Ki-67 proliferation index was 4% (IQR: 2\u201310%; range: 1\u201335%), and the median mitotic count was 4 per 2\u00a0mm\u00b2 (IQR: 1\u20138; range: 1\u201320).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Immature PIT-1 lineage tumors exhibit aggressive behavior with high residual disease rates, with 31% of patients requiring reoperation, 23% receiving adjuvant radiotherapy, and somatostatin analogue resistance observed in two patients. Routine TF immunohistochemistry is essential for accurate diagnosis; management requires maximal safe surgical resection and intensive long-term surveillance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11102-026-01691-9","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:56:06Z","timestamp":1778676966000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinicopathological features and outcomes of immature PIT-1 lineage tumors: A high-risk pituitary neuroendocrine tumor\/pituitary adenoma subtype per WHO 2022"],"prefix":"10.1007","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-1672","authenticated-orcid":false,"given":"Aysel Unver","family":"Ozkahraman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8269-2607","authenticated-orcid":false,"given":"Aslihan","family":"Pekmezci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4217-2834","authenticated-orcid":false,"given":"Huseyin","family":"Karatay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4069-0021","authenticated-orcid":false,"given":"Ebubekir","family":"Akpinar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8586-0613","authenticated-orcid":false,"given":"Buruc","family":"Erkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1631-8975","authenticated-orcid":false,"given":"Mehmet","family":"Karagulle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7307-396X","authenticated-orcid":false,"given":"Burak","family":"Kocak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutlu","family":"Niyazoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8361-8866","authenticated-orcid":false,"given":"Esra","family":"Hatipoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"1691_CR1","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1017\/cjn.2015.301","volume":"43","author":"K Al-Dahmani","year":"2016","unstructured":"Al-Dahmani K, Mohammad S, Imran F, Theriault C, Doucette S, Zwicker D, Yip C-E, Clarke DB, Imran SA (2016) Sellar masses: an epidemiological study. Can J Neurol Sci 43:291\u2013297. https:\/\/doi.org\/10.1017\/cjn.2015.301","journal-title":"Can J Neurol Sci"},{"key":"1691_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","volume":"33","author":"SL Asa","year":"2022","unstructured":"Asa SL, Mete O, Perry A, Osamura RY (2022) Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol 33:6\u201326. https:\/\/doi.org\/10.1007\/s12022-022-09703-7","journal-title":"Endocr Pathol"},{"key":"1691_CR3","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1007\/s12022-021-09678-x","volume":"32","author":"SL Asa","year":"2021","unstructured":"Asa SL (2021) Challenges in the diagnosis of pituitary neuroendocrine tumors. Endocr Pathol 32:222\u2013227. https:\/\/doi.org\/10.1007\/s12022-021-09678-x","journal-title":"Endocr Pathol"},{"key":"1691_CR4","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1097\/PAS.0000000000002339","volume":"49","author":"Y Lang","year":"2025","unstructured":"Lang Y, Guo S, Tuo Y, Tian T, Wang Y, Li Q, Chen Y, Chen W, Zhu Y, Liu D (2025) Immature PIT1-lineage pituitary neuroendocrine tumors\/adenomas, a morphologically unique pituitary neuroendocrine tumors\/adenomas commonly with cytologic atypia features and a predilection for aggressive clinical potential. Am J Surg Pathol 49:243\u2013250. https:\/\/doi.org\/10.1097\/PAS.0000000000002339","journal-title":"Am J Surg Pathol"},{"key":"1691_CR5","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s40478-025-02050-8","volume":"13","author":"I Nasi-Kordhishti","year":"2025","unstructured":"Nasi-Kordhishti I, Hladik M, Kandilaris K, Behling F, Honegger J, Schittenhelm J (2025) Transcription factor-based classification of pituitary adenomas \/ PitNETs: a comparative analysis and clinical implications across WHO 2004, 2017 and 2022 in 921 cases. Acta Neuropathol Commun 13:135. https:\/\/doi.org\/10.1186\/s40478-025-02050-8","journal-title":"Acta Neuropathol Commun"},{"key":"1691_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.100934","volume":"4","author":"Q Zhang","year":"2023","unstructured":"Zhang Q, Yao B, Long X, Chen Z, He M, Wu Y, Qiao N, Ma Z, Ye Z, Zhang Y, Yao S, Wang Y, Cheng H, Chen H, Ye H, Wang Y, Li Y, Chen J, Zhang Z, Guo F, Zhao Y (2023) Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET. Cell Rep Med 4:100934. https:\/\/doi.org\/10.1016\/j.xcrm.2023.100934","journal-title":"Cell Rep Med"},{"key":"1691_CR7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s11102-023-01360-1","volume":"27","author":"A Giustina","year":"2024","unstructured":"Giustina A, Biermasz N, Casanueva FF, Fleseriu M, Mortini P, Strasburger C, Van Der Lely AJ, Wass J, Melmed S, Acromegaly Consensus Group, Banfi G, Barkan A, Beckers A, Bidlingmaier M, Boguszewski C, Brue T, Buchfelder M, Chanson P, Chiloiro S, Colao A, Coopmans E, Esposito D, Ferone D, Frara S, Gadelha M, Geer EB, Ghigo E, Greenman Y, Gurnell M, Ho K, Ioachimescu A, Johannsson G, J\u00f8rgensen JO, Kaiser UB, Karavitaki N, Katznelson L, Lamberts S, Losa M, Luger A, Luque R, Maffei P, Marazuela M, Neggers S, Pereira A, Persani L, Petersenn S, Reincke M, Salvatori R, Samson SN, Schilbach K, Shimon I, Tsagarakis S, Zatelli MC (2024) Consensus on criteria for acromegaly diagnosis and remission. Pituitary 27:7\u201322. https:\/\/doi.org\/10.1007\/s11102-023-01360-1","journal-title":"Pituitary"},{"key":"1691_CR8","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1007\/s40618-019-01066-x","volume":"42","author":"P Beck-Peccoz","year":"2019","unstructured":"Beck-Peccoz P, Giavoli C, Lania A (2019) A 2019 update on TSH-secreting pituitary adenomas. J Endocrinol Invest 42:1401\u20131406. https:\/\/doi.org\/10.1007\/s40618-019-01066-x","journal-title":"J Endocrinol Invest"},{"key":"1691_CR9","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/s41574-025-01134-8","volume":"21","author":"M Fleseriu","year":"2025","unstructured":"Fleseriu M, Gurnell M, McCormack A, Fukuoka H, Glezer A, Langlois F, Schwartz TH, Greenman Y, Agrawal N, Akirov A, Bancos I, Capatina C, Castinetti F, Catalino M, Christ-Crain M, Das L, Drincic A, Freda PU, Gadelha MR, Giustina A, Hanzu F, Ho KKY, Isand K, Mallea-Gil S, Mamelak AN, Marcus HJ, Uygur MM, Molitch M, Nachtigall LB, Nowak E, Pereira AM, Pineyro MM, Shafiq I, Syro L, Takahashi Y, Varlamov EV, Vila G, Zada G, Karavitaki N, Melmed S, The Pituitary Society International Incidentaloma Consensus Group, Steering Committee, Schwartz TH, Consortium Members (2025) Pituitary incidentaloma: a Pituitary Society international consensus guideline statement. Nat Rev Endocrinol 21:638\u2013655. https:\/\/doi.org\/10.1038\/s41574-025-01134-8","journal-title":"Nat Rev Endocrinol"},{"key":"1691_CR10","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/EJE-17-0796","volume":"178","author":"G Raverot","year":"2018","unstructured":"Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM (2018) European Society of Endocrinology clinical practice guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178:G1\u2013G24. https:\/\/doi.org\/10.1530\/EJE-17-0796","journal-title":"Eur J Endocrinol"},{"key":"1691_CR11","doi-asserted-by":"publisher","unstructured":"Erickson D, Scheithauer B, Atkinson J, Horvath E, Kovacs K, Lloyd RV, Young WF Jr (2009) Silent subtype 3 pituitary adenoma: a clinicopathologic analysis of the Mayo Clinic experience. Clin Endocrinol 71:92\u201399. https:\/\/doi.org\/10.1111\/j.1365-2265.2008.03514.x","DOI":"10.1111\/j.1365-2265.2008.03514.x"},{"key":"1691_CR12","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/modpathol.2015.151","volume":"29","author":"O Mete","year":"2016","unstructured":"Mete O, Gomez-Hernandez K, Kucharczyk W, Ridout R, Zadeh G, Gentili F, Ezzat S, Asa SL (2016) Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas. Mod Pathol 29:131\u2013142. https:\/\/doi.org\/10.1038\/modpathol.2015.151","journal-title":"Mod Pathol"},{"key":"1691_CR13","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1080\/01913120500323514","volume":"29","author":"E Horvath","year":"2005","unstructured":"Horvath E, Kovacs K, Smyth HS, Cusimano M, Singer W (2005) Silent adenoma subtype 3 of the pituitary\u2014immunohistochemical and ultrastructural classification: a review of 29 cases. Ultrastruct Pathol 29:511\u2013524. https:\/\/doi.org\/10.1080\/01913120500323514","journal-title":"Ultrastruct Pathol"},{"key":"1691_CR14","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1210\/er.2009-0008","volume":"30","author":"D Kelberman","year":"2009","unstructured":"Kelberman D, Rizzoti K, Lovell-Badge R, Robinson ICAF, Dattani MT (2009) Genetic regulation of pituitary gland development in human and mouse. Endocr Rev 30:790\u2013829. https:\/\/doi.org\/10.1210\/er.2009-0008","journal-title":"Endocr Rev"},{"key":"1691_CR15","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1101\/gad.4.5.695","volume":"4","author":"DM Simmons","year":"1990","unstructured":"Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, Swanson LW (1990) Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev 4:695\u2013711. https:\/\/doi.org\/10.1101\/gad.4.5.695","journal-title":"Genes Dev"},{"key":"1691_CR16","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1023\/A:1009948813587","volume":"1","author":"SL Asa","year":"1999","unstructured":"Asa SL, Ezzat S (1999) Molecular determinants of pituitary cytodifferentiation. Pituitary 1:159\u2013168. https:\/\/doi.org\/10.1023\/A:1009948813587","journal-title":"Pituitary"},{"key":"1691_CR17","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/s41379-018-0167-7","volume":"32","author":"O Mete","year":"2019","unstructured":"Mete O, Kefeli M, \u00c7al\u0131\u015fkan S, Asa SL (2019) GATA3 immunoreactivity expands the transcription factor profile of pituitary neuroendocrine tumors. Mod Pathol 32:484\u2013489. https:\/\/doi.org\/10.1038\/s41379-018-0167-7","journal-title":"Mod Pathol"},{"key":"1691_CR18","doi-asserted-by":"publisher","first-page":"C1","DOI":"10.1093\/ejendo\/lvad042","volume":"188","author":"J Trouillas","year":"2023","unstructured":"Trouillas J, Burman P, Losa M, McCormack A, Petersenn S, Popovic V, Theodoropoulou M, Dekkers OM, Raverot G (2023) Initial pathology in aggressive pituitary tumours and carcinomas: 2b or not 2b?\u2014that is the question. Eur J Endocrinol 188:C1\u2013C5. https:\/\/doi.org\/10.1093\/ejendo\/lvad042","journal-title":"Eur J Endocrinol"},{"key":"1691_CR19","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26167830","volume":"26","author":"A Krzentowska","year":"2025","unstructured":"Krzentowska A, Biesaga B, Czepko R, Merklinger-Grucha\u0142a A, Adamek D, Jasi\u0144ska M, Pluta B, Michalska W, Wr\u00f3blewska K, Janczy F, Go\u0142kowski F (2025) The roles of PD-L1, Ki-67, P53, and Cyclin D1 in PitNETs: diagnostic and prognostic implications in a series of 74 patients. IJMS 26:7830. https:\/\/doi.org\/10.3390\/ijms26167830","journal-title":"IJMS"},{"key":"1691_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010267","volume":"15","author":"A Ferr\u00e9s","year":"2022","unstructured":"Ferr\u00e9s A, Reyes L, Di Somma A, Topczewski T, Mosteiro A, Guizzardi G, De Rosa A, Halperin I, Hanzu F, Mora M, Alobid I, Aldecoa I, Bargall\u00f3 N, Ense\u00f1at J (2022) The prognostic-based approach in growth hormone-secreting pituitary neuroendocrine tumors (PitNET): tertiary reference center, single senior surgeon, and long-term follow-up. Cancers 15:267. https:\/\/doi.org\/10.3390\/cancers15010267","journal-title":"Cancers"},{"key":"1691_CR21","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14155203","volume":"14","author":"NA Hefner","year":"2025","unstructured":"Hefner NA, Cooper O (2025) Management of recurrent and aggressive non-functioning pituitary adenomas. Journal of Clinical Medicine 14:5203. https:\/\/doi.org\/10.3390\/jcm14155203","journal-title":"Journal of Clinical Medicine"},{"key":"1691_CR22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26146551","volume":"26","author":"E Perrone","year":"2025","unstructured":"Perrone E, Treglia G, Giancipoli RG, Leccisotti L, Rindi G, Rufini V (2025) In vivo versus in vitro somatostatin receptor expression in neuroendocrine neoplasms: a systematic review and meta-analysis of correlation studies. IJMS 26:6551. https:\/\/doi.org\/10.3390\/ijms26146551","journal-title":"IJMS"},{"key":"1691_CR23","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16010116","volume":"16","author":"A Milewska-Kranc","year":"2023","unstructured":"Milewska-Kranc A, \u0106wik\u0142a JB, Kolasinska-\u0106wik\u0142a A (2023) The role of receptor\u2013ligand interaction in somatostatin signaling pathways: implications for neuroendocrine tumors. Cancers 16:116. https:\/\/doi.org\/10.3390\/cancers16010116","journal-title":"Cancers"},{"key":"1691_CR24","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1227\/ONS.0000000000000089","volume":"22","author":"I Azizkhanian","year":"2022","unstructured":"Azizkhanian I, El Ahmadieh TY, Palmisciano P, Abou-Mrad Z, Daoud EV, Essibayi MA, Connors S, Aoun SG, Kim J, Hatanpaa KJ, Garzon-Muvdi T, Barnett SL, Patel T, Raisanen JM, Mickey BE (2022) Distant pituitary adenoma spread: a systematic review and report of 2 cases. Operative Neurosurgery 22:131\u2013143. https:\/\/doi.org\/10.1227\/ONS.0000000000000089","journal-title":"Operative Neurosurgery"},{"key":"1691_CR25","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s11102-023-01312-9","volume":"26","author":"N Lenders","year":"2023","unstructured":"Lenders N, Ai M (2023) Refractory Pit1 plurihormonal tumours and thyrotroph adenomas. Pituitary 26:182\u2013186. https:\/\/doi.org\/10.1007\/s11102-023-01312-9","journal-title":"Pituitary"}],"container-title":["Pituitary"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-026-01691-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11102-026-01691-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-026-01691-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:49:35Z","timestamp":1782409775000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11102-026-01691-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":25,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["1691"],"URL":"https:\/\/doi.org\/10.1007\/s11102-026-01691-9","relation":{},"ISSN":["1386-341X","1573-7403"],"issn-type":[{"value":"1386-341X","type":"print"},{"value":"1573-7403","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"assertion":[{"value":"19 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the ethical principles established in the Declaration of Helsinki and was approved by Basaksehir Cam and Sakura City Hospital\u2019s ethics committee (approval number: 194, dated August 28, 2024).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Due to the retrospective nature of this study, the requirement for informed consent was waived by the institutional review board.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"84"}}