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Recent evidence has reframed aggressiveness as a multidimensional process shaped by somatic variants, chromosomal instability, and epigenetic remodeling. Recurrent alterations in ATRX, TP53, and SF3B1; widespread copy number losses; and lineage-specific methylation and transcriptomic profiles help delineate tumors with early malignant potential. Single-cell and immune profiling studies reveal proliferative, migratory, and immunoevasive subpopulations that may underpin variable clinical trajectories and treatment responses. Clinically, temozolomide remains the only systemic therapy with consistent benefit, while immune checkpoint inhibitors, anti-VEGF agents, and peptide receptor radionuclide therapy show emerging efficacy in selected settings. Progress will rely on harmonizing diagnostic criteria, integrating molecular and imaging biomarkers, and embedding translational endpoints into clinical trials. Together, these advances define a path toward more precise recognition and management of aggressive pituitary tumors.<\/jats:p>","DOI":"10.1530\/erc-25-0502","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:55:01Z","timestamp":1786103701000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["Management of aggressive PitNETs: evidence gaps, molecular clues, and a roadmap for clinical trials"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5461-0301","authenticated-orcid":true,"given":"Rafael Loch","family":"Batista","sequence":"first","affiliation":[{"name":"Developmental Endocrinology Unit, Laborat\u00f3rio de Investiga\u00e7\u00f5es M\u00e9dicas (LIM\/42), Endocrinology Division, Internal Medicine Department, Medical School, University of S\u00e3o Paulo (USP) 1 , , ,","place":["S\u00e3o Paulo, S\u00e3o Paulo, Brazil"]},{"name":"2Endocrine Oncology Unit, Instituto do C\u00e2ncer do Estado de S\u00e3o Paulo (ICESP) da Faculdade de Medicina da Universidade de S\u00e3o Paulo (USP), S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1808-8800","authenticated-orcid":true,"given":"Frederic","family":"Castinetti","sequence":"additional","affiliation":[{"name":"Aix Marseille University, MMG, INSERM U1251 3 , ,","place":["Marseille, France"]},{"name":"Department of Endocrinology, La Conception Hospital, Assistance Publique-Hopitaux de Marseille 4 , ,","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3363-3803","authenticated-orcid":true,"given":"Luciana Ansaneli","family":"Naves","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Faculty of Medicine, University of Brasilia 5 , ,","place":["Brasilia, Brazil"]},{"name":"Post-Graduation Program in Medical Sciences, University of Brasilia 6 , ,","place":["Brasilia, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026082715362544000_bib1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1210\/endrev\/bnaa006","article-title":"Novel insights into pituitary tumorigenesis: genetic and epigenetic mechanisms","volume":"41","author":"Srirangam Nadhamuni","year":"2020","journal-title":"Endocr Rev"},{"key":"2026082715362544000_bib2","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/cncr.20412","article-title":"The prevalence of pituitary adenomas: a systematic review","volume":"101","author":"Ezzat","year":"2004","journal-title":"Cancer"},{"key":"2026082715362544000_bib3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.ecl.2020.04.002","article-title":"The epidemiology of pituitary adenomas","volume":"49","author":"Daly","year":"2020","journal-title":"Endocrinol Metab Clin N Am"},{"key":"2026082715362544000_bib4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11154-020-09556-7","article-title":"The epidemiology of aggressive pituitary tumors (and its challenges)","volume":"21","author":"Dekkers","year":"2020","journal-title":"Rev Endocr Metab Disord"},{"key":"2026082715362544000_bib5","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1210\/clinem\/dgad098","article-title":"Aggressive pituitary tumors and pituitary carcinomas: from pathology to treatment","volume":"108","author":"Burman","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026082715362544000_bib6","doi-asserted-by":"crossref","first-page":"i17","DOI":"10.1093\/noajnl\/vdae114","article-title":"Aggressive pituitary tumors and pituitary carcinomas: definition, management, and overview for clinical practice","volume":"7","author":"Calvanese","year":"2025","journal-title":"Neuro Oncology Adv"},{"key":"2026082715362544000_bib7","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.3390\/jcm14155203","article-title":"Management of recurrent and aggressive non-functioning pituitary adenomas","volume":"14","author":"Hefner","year":"2025","journal-title":"J Clin Med"},{"key":"2026082715362544000_bib8","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/s41574-021-00550-w","article-title":"Aggressive pituitary tumours and pituitary carcinomas","volume":"17","author":"Raverot","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"2026082715362544000_bib9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11154-020-09562-9","article-title":"Are aggressive pituitary tumors and carcinomas two sides of the same coin? 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