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Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach
Cushing’s 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 abnormalitie...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242934/ https://www.ncbi.nlm.nih.gov/pubmed/34220707 http://dx.doi.org/10.3389/fendo.2021.650791 |
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author | Yamamoto, Masaaki Nakao, Takahiro Ogawa, Wataru Fukuoka, Hidenori |
author_facet | Yamamoto, Masaaki Nakao, Takahiro Ogawa, Wataru Fukuoka, Hidenori |
author_sort | Yamamoto, Masaaki |
collection | PubMed |
description | Cushing’s 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’s 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’s 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. |
format | Online Article Text |
id | pubmed-8242934 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82429342021-07-01 Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach Yamamoto, Masaaki Nakao, Takahiro Ogawa, Wataru Fukuoka, Hidenori Front Endocrinol (Lausanne) Endocrinology Cushing’s 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’s 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’s 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. Frontiers Media S.A. 2021-06-16 /pmc/articles/PMC8242934/ /pubmed/34220707 http://dx.doi.org/10.3389/fendo.2021.650791 Text en Copyright © 2021 Yamamoto, Nakao, Ogawa and Fukuoka https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Yamamoto, Masaaki Nakao, Takahiro Ogawa, Wataru Fukuoka, Hidenori Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title | Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title_full | Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title_fullStr | Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title_full_unstemmed | Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title_short | Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach |
title_sort | aggressive cushing’s disease: molecular pathology and its therapeutic approach |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242934/ https://www.ncbi.nlm.nih.gov/pubmed/34220707 http://dx.doi.org/10.3389/fendo.2021.650791 |
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