Aggressive Cushing's Disease: Molecular Pathology and Its Therapeutic Approach.
Aggressive Cushing's Disease: Molecular Pathology and Its Therapeutic Approach.
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DOI：
10.3389/fendo.2021.650791
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发表时间：
2021
影响因子：
5.2
通讯作者：
Fukuoka H
中科院分区：
文献类型：
--
作者：
Yamamoto M;Nakao T;Ogawa W;Fukuoka H
库欣氏病是由高皮质醇血症介导的促肾上腺皮质激素（ACTH）分泌性垂体腺瘤（ACTH腺瘤）引起的综合征性病理状态。它可能有一个严重的临床过程，包括感染，精神障碍，高凝状态，代谢异常，尽管肿瘤通常很小，非侵袭性。高达20%的ACTH瘤表现出攻击性行为，这与手术效果差、术后复发、严重的临床病程和高死亡率有关。虽然在库欣病的生殖系和体细胞变化中已经鉴定出几种基因变异，但对侵袭性ACTH瘤的病理生理学了解甚少。本文就ACTH瘤的侵袭性、病理、药物治疗现状及展望作一综述。Crooke细胞腺瘤（CCA）、纳尔逊综合征和促肾上腺皮质激素垂体癌是分泌超生理ACTH的典型难治性垂体肿瘤。虽然无临床症状，但无症状促肾上腺皮质激素腺瘤是一种侵袭性的促肾上腺皮质激素垂体腺瘤。在这篇综述中，我们总结了目前对侵袭性ACTH瘤（包括这些肿瘤）的病理生理学的理解，从分子的角度来看，基于遗传、病理和实验证据。侵袭性ACTH瘤的治疗在临床上具有挑战性，并且通常对标准治疗具有抗性，包括手术、放疗和已建立的药物治疗（例如，帕瑞肽和卡麦角林）。替莫唑胺是这些肿瘤最常用的药物治疗。报告显示，难治性ACTH瘤患者的几种治疗方法包括化疗，如环己基-氯乙基-亚硝基脲联合5-氟尿嘧啶，或针对几种分子的靶向治疗，包括血管内皮生长因子受体、细胞毒性T淋巴细胞抗原4、程序性细胞死亡蛋白1（PD-1）和PD-1配体。遗传学和实验证据表明，一些可能的治疗候选药物，如表皮生长因子受体酪氨酸激酶抑制剂，细胞周期蛋白依赖性激酶抑制剂，BRAF抑制剂。开发侵袭性ACTH瘤的新治疗方案是一项新兴的任务。
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.
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