{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:47:38Z","timestamp":1792237658313,"version":"4.4.0"},"reference-count":162,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["15K09432, 19K09003"],"award-info":[{"award-number":["15K09432, 19K09003"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Cushing\u2019s disease is a syndromic pathological condition caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) mediated by hypercortisolemia. It may have a severe clinical course, including infection, psychiatric disorders, hypercoagulability, and metabolic abnormalities, despite the generally small, nonaggressive nature of the tumors. Up to 20% of ACTHomas show aggressive behavior, which is related to poor surgical outcomes, postsurgical recurrence, serious clinical course, and high mortality. Although several gene variants have been identified in both germline and somatic changes in Cushing\u2019s disease, the pathophysiology of aggressive ACTHomas is poorly understood. In this review, we focused on the aggressiveness of ACTHomas, its pathology, the current status of medical therapy, and future prospects. Crooke\u2019s cell adenoma (CCA), Nelson syndrome, and corticotroph pituitary carcinoma are representative refractory pituitary tumors that secrete superphysiological ACTH. Although clinically asymptomatic, silent corticotroph adenoma is an aggressive ACTH-producing pituitary adenoma. In this review, we summarize the current understanding of the pathophysiology of aggressive ACTHomas, including these tumors, from a molecular point of view based on genetic, pathological, and experimental evidence. The treatment of aggressive ACTHomas is clinically challenging and usually resistant to standard treatment, including surgery, radiotherapy, and established medical therapy (e.g., pasireotide and cabergoline). Temozolomide is the most prescribed pharmaceutical treatment for these tumors. Reports have shown that several treatments for patients with refractory ACTHomas include chemotherapy, such as cyclohexyl-chloroethyl-nitrosourea combined with 5-fluorouracil, or targeted therapies against several molecules including vascular endothelial growth factor receptor, cytotoxic T lymphocyte antigen 4, programmed cell death protein 1 (PD-1), and ligand for PD-1. Genetic and experimental evidence indicates that some possible therapeutic candidates are expected, such as epidermal growth factor receptor tyrosine kinase inhibitor, cyclin-dependent kinase inhibitor, and BRAF inhibitor. The development of novel treatment options for aggressive ACTHomas is an emerging task.<\/jats:p>","DOI":"10.3389\/fendo.2021.650791","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T05:57:37Z","timestamp":1623823057000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Aggressive Cushing\u2019s Disease: Molecular Pathology and Its Therapeutic Approach"],"prefix":"10.3389","volume":"12","author":[{"given":"Masaaki","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nakao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Fukuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.64","article-title":"Aggressive Pituitary Adenomas\u2013Diagnosis and Emerging Treatments","volume":"10","author":"Di Ieva","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1700410215","article-title":"Change in the Basophil Cells of the Pituitary Gland Common to Conditions Which Exhibit the Syndrome Attributed to Basophil Adenoma","volume":"41","author":"Crooke","year":"1935","journal-title":"J Pathol Bacteriol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/JC.2015-2493","article-title":"Crooke\u2019s Changes in Cushing\u2019s Syndrome Depends on Degree of Hypercortisolism and Individual Susceptibility","volume":"100","author":"Oldfield","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/BF01407130","article-title":"Massive Crooke\u2019s Hyalinization in Corticotroph Cell Adenomas of the Human Pituitary. 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