静默性促肾上腺皮质激素细胞腺瘤与库欣病的转化机制研究进展
Research Progress on the Transformation Mechanism of Silent Adrenocorticotropic Hormone Cell Adenoma and Cushing’s Disease
摘要: 静默性促肾上腺皮质激素细胞腺瘤(SCAs)是一类特殊类型的垂体神经内分泌肿瘤，临床上不表现出库欣综合征症状但具有ACTH免疫反应性。近年研究发现，这类肿瘤具有显著的侵袭性和高复发率特征，且部分病例可转化为功能性促肾上腺皮质激素腺瘤，导致库欣病。本文系统综述了SCAs的临床病理特征、分子遗传学改变、向功能性肿瘤转化的潜在机制及治疗策略。现有证据表明，SCAs与功能性促肾上腺皮质激素腺瘤在基因组不稳定性、USP8基因突变频率等方面存在显著差异，且转化过程可能涉及表观遗传调控改变、ER应激反应通路激活等分子机制。深入了解这类肿瘤的转化机制对临床预后评估和治疗选择具有重要意义。
Abstract: Silent corticotropin cell adenomas (SCAs) are a special type of pituitary neuroendocrine tumor that do not exhibit Cushing’s syndrome symptoms clinically but have ACTH immunoreactivity. In recent years, studies have found that this type of tumor has significant characteristics of invasiveness and a high recurrence rate, and some cases can transform into functional adrenocorticotropic hormone adenomas, leading to Cushing’s disease. This article systematically reviews the clinical and pathological characteristics, molecular genetic changes, potential mechanisms of functional tumor transformation, and treatment strategies of SCAs. Existing evidence suggests that there are significant differences between SCAs and functional adrenocorticotropic hormone adenomas in terms of genomic instability, USP8 gene mutation frequency, and the transformation process may involve molecular mechanisms such as epigenetic regulatory changes and activation of ER stress response pathways. A deep understanding of the transformation mechanism of such tumors is of great significance for clinical prognosis evaluation and treatment selection.
文章引用：鄢思凡, 胡继良. 静默性促肾上腺皮质激素细胞腺瘤与库欣病的转化机制研究进展[J]. 临床医学进展, 2025, 15(11): 93-99. https://doi.org/10.12677/acm.2025.15113070

参考文献

[1] Demarchi, G., Perrone, S., Esper Romero, G., De Bonis, C., Casasco, J.P., Sevlever, G., et al. (2022) Case Report: Progression of a Silent Corticotroph Tumor to an Aggressive Secreting Corticotroph Tumor, Treated by Temozolomide. Changes in the Clinic, the Pathology, and the β-Catenin and Α-Sma Expression. Frontiers in Endocrinology, 13, Article 870172. [Google Scholar] [CrossRef] [PubMed]
[2] 阎晓玲. 静止性促肾上腺皮质激素腺瘤[J]. 中国现代神经疾病杂志, 2019, 19(1): 46.
[3] Himstead, A.S., Wells, A.C., Kurtz, J.S., Moldenhauer, M.R., Davies, J.L., Fote, G.M., et al. (2024) Silent Corticotroph Adenomas Demonstrate Predilection for Sphenoid Sinus, Cavernous Sinus, and Clival Invasion Compared with Other Subtypes. World Neurosurgery, 191, e41-e47. [Google Scholar] [CrossRef] [PubMed]
[4] Maragkos, G.A., Mantziaris, G., Pikis, S., Chytka, T., Liscak, R., Peker, S., et al. (2023) Silent Corticotroph Staining Pituitary Neuroendocrine Tumors: Prognostic Significance in Radiosurgery. Neurosurgery, 93, 1407-1414. [Google Scholar] [CrossRef] [PubMed]
[5] 孙雅苹. 2017年WHO新分类下静止性与非静止性促肾上腺皮质激素细胞腺瘤的术前影像学比较与分析[D]: [硕士学位论文]. 天津: 天津医科大学, 2021.
[6] 孙瑛璇, 李储忠, 张亚卓. 促肾上腺皮质激素细胞肿瘤生化静默机制研究进展[J]. 中华神经医学杂志, 2023, 22(6): 623-626.
[7] Goyal-honavar, A., Abraham, A.P., Asha, H.S., Chacko, G. and Chacko, A. (2024) Functional Transformation of a Corticotroph Pituitary Neuroendocrine Tumor 128 Months Following Primary Excision—A Case Report. Turkish Neurosurgery, 35, 355-359. [Google Scholar] [CrossRef] [PubMed]
[8] Mohan, D.R., Paes, T., Buelvas Mebarak, J., Meredith, D.M., Soares, B., Vaz, V., et al. (2025) Non-Recurrent Mutations and Copy Number Changes Predominate Pituitary Adenoma Genomes. European Journal of Endocrinology, 192, 590-602. [Google Scholar] [CrossRef] [PubMed]
[9] Raub, S.L., Fixman, B., Hanks, T., et al. (2025) Clinical and Radiographic Presentation and Surgical Outcomes of T-Box Pituitary Transcription Factor (TPIT) Silent Corticotroph Pituitary Neuroendocrine Tumors: A Multi-Institutional Experience and Review of the Literature. World Neurosurgery, 196, Article 123791. [Google Scholar] [CrossRef] [PubMed]
[10] Raub, S., Fixman, B., Hanks, T., Nistal, D., Peterson, R., Eaton, J., et al. (2025) Clinical and Radiographic Presentation and Surgical Outcomes of T-Box Pituitary Transcription Factor (TPIT) Silent Corticotroph Pituitary Neuroendocrine Tumors: A Multi-Institutional Experience and Review of the Literature. World Neurosurgery, 196, Article 123791. [Google Scholar] [CrossRef] [PubMed]
[11] Sumislawski, P., Huckhagel, T., Krajewski, K.L., Aberle, J., Saeger, W., Flitsch, J., et al. (2023) Cystic versus Non-Cystic Silent Corticotrophic Adenomas: Clinical and Histological Analysis of 62 Cases after Microscopic Transsphenoidal Surgery—A Retrospective, Single-Center Study. Scientific Reports, 13, Article No. 2468. [Google Scholar] [CrossRef] [PubMed]
[12] 周诚斌, 王宝锋, 卞留贯. 静止性促肾上腺皮质激素细胞腺瘤的诊断及研究进展[J]. 临床神经外科杂志, 2022, 19(3): 348-351+355.
[13] Sahakian, N., Goetz, L., Appay, R., Graillon, T., Raingeard, I., Piazzola, C., et al. (2024) Outcome of Non-Functioning ACTH Pituitary Tumors: Silent Does Not Mean Indolent. Pituitary, 27, 644-653. [Google Scholar] [CrossRef] [PubMed]
[14] 谢远扬. 静默性促肾上腺皮质激素细胞腺瘤术前临床特征研究[D]: [硕士学位论文]. 广州: 暨南大学, 2023.
[15] 周婷婷. 影像组学在垂体静止性促肾上腺皮质激素细胞瘤术前预测中的应用价值研究[D]: [硕士学位论文]. 福州: 福建医科大学, 2023.
[16] Uysal, S., Sulu, C., Muradov, I., Sahin, S., Gul, N., Soyluk Selcukbiricik, O., et al. (2025) Clinical Features and Remission Rates in Cushing’s Disease: A Comparison of MRI-Detectable and MRI-Undetectable Pituitary Adenomas. Hormone and Metabolic Research, 57, 163-169. [Google Scholar] [CrossRef] [PubMed]
[17] Kim, K., Kim, D., Lee, M., Park, Y.W., Ahn, S.S., Moon, J.H., et al. (2025) 68Ga-DOTATOC PET/CT in the Localization of Pituitary Tumors in Cushing’s Disease. Endocrinology and Metabolism, 40, 637-647. [Google Scholar] [CrossRef] [PubMed]
[18] Bessiène, L., Moutel, S., Lataud, M., Jouinot, A., Bonnet-Serrano, F., Guibourdenche, J., et al. (2022) Corticotroph Tumor Progression Speed after Adrenalectomy. European Journal of Endocrinology, 187, 797-807. [Google Scholar] [CrossRef] [PubMed]
[19] Theodoropoulou, M. and Reincke, M. (2022) Genetics of Cushing’s Disease: From the Lab to Clinical Practice. Pituitary, 25, 689-692. [Google Scholar] [CrossRef] [PubMed]
[20] Perez-Rivas, L.G., von Selzam, V., Sharma, P., Reincke, M. and Theodoropoulou, M. (2025) Prevalence and Clinical Associations of USP8 Variants in Corticotroph Tumours: A Systematic Review and Aggregate Data Meta-Analysis of 2171 Cases. European Journal of Endocrinology, 192, S41-S52. [Google Scholar] [CrossRef] [PubMed]
[21] Nerubenko, E., Ryazanov, P., Kuritsyna, N., Paltsev, A., Ivanova, O., Grineva, E., et al. (2024) Cushing’s Disease Manifestation in USP8-Mutated Corticotropinoma May Be Mediated by Interactions between WNT Signaling and SST Trafficking. International Journal of Molecular Sciences, 25, Article 12886. [Google Scholar] [CrossRef] [PubMed]
[22] Perez-Rivas, L.G., Simon, J., Albani, A., Tang, S., Roeber, S., Assié, G., et al. (2022) TP53 Mutations in Functional Corticotroph Tumors Are Linked to Invasion and Worse Clinical Outcome. Acta Neuropathologica Communications, 10, Article No. 139. [Google Scholar] [CrossRef] [PubMed]
[23] Zhang, D., Hugo, W., Bergsneider, M., Wang, M.B., Kim, W., Vinters, H.V., et al. (2022) Single-Cell RNA Sequencing in Silent Corticotroph Tumors Confirms Impaired POMC Processing and Provides New Insights into Their Invasive Behavior. European Journal of Endocrinology, 187, 49-64. [Google Scholar] [CrossRef] [PubMed]
[24] Su, F., Yang, X., Yan, Z., Wu, J., Li, X., Xu, T., et al. (2025) Endoplasmic Reticulum Stress-Induced CRELD2 Promotes APMAP-Mediated Activation of TGF-β/SMAD and NF-κB Pathways in Esophageal Squamous Cell Carcinoma. Frontiers in Immunology, 16, Article 1616201. [Google Scholar] [CrossRef] [PubMed]
[25] Liang, X., Liu, J., Liu, X., Jin, Y., Xu, M., Han, Z., et al. (2023) LINP1 Represses Unfolded Protein Response by Directly Inhibiting Eif2α Phosphorylation to Promote Cutaneous Squamous Cell Carcinoma. Experimental Hematology & Oncology, 12, Article No. 31. [Google Scholar] [CrossRef] [PubMed]
[26] Xia, S., Duan, W., Liu, W., Zhang, X. and Wang, Q. (2021) GRP78 in Lung Cancer. Journal of Translational Medicine, 19, Article No. 118. [Google Scholar] [CrossRef] [PubMed]
[27] Abusdal, M., Normann, K.R., Nyman, T.A., Øystese, K.A.B., Sundaram, A.Y.M., Dahlberg, D., et al. (2024) PCSK1N as a Tumor Size Marker and an ER Stress Response Protein in Corticotroph Pituitary Adenomas. The Journal of Clinical Endocrinology & Metabolism, 110, 1065-1075. [Google Scholar] [CrossRef] [PubMed]
[28] Wei, W., Zhang, Y., Song, Q., Zhang, Q., Zhang, X., Liu, X., et al. (2022) Transmissible ER Stress between Macrophages and Tumor Cells Configures Tumor Microenvironment. Cellular and Molecular Life Sciences, 79, Article No. 403. [Google Scholar] [CrossRef] [PubMed]
[29] Jiang, C.C., Marsland, M., Wang, Y., Dowdell, A., Eden, E., Gao, F., et al. (2022) Tumor Innervation Is Triggered by Endoplasmic Reticulum Stress. Oncogene, 41, 586-599. [Google Scholar] [CrossRef] [PubMed]
[30] Chipurupalli, S., Ganesan, R., Martini, G., Mele, L., Reggio, A., Esposito, M., et al. (2022) Cancer Cells Adapt FAM134B/BiP Mediated ER-Phagy to Survive Hypoxic Stress. Cell Death & Disease, 13, Article No. 357. [Google Scholar] [CrossRef] [PubMed]
[31] Alam, R., Kabir, M.F., Kim, H. and Chae, H. (2022) Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy. Cells, 11, Article 3773. [Google Scholar] [CrossRef] [PubMed]
[32] Mao, J.N., Yan, H.Y., Chen, J.Y., et al. (2023) Comparison of the Preoperative Diagnostic Accuracy of BIPSS versus MRI for Cushing Disease: A Single-Centre Experience. BMC Endocrine Disorders, 23, Article No. 42. [Google Scholar] [CrossRef] [PubMed]
[33] Li, J., Chen, S., Tan, H., Yu, Y., Tang, Y., Cai, B., et al. (2025) Oncocytic Pituicytoma in a Patient with Cushing’s Disease: A Case Report and Narrative Literature Review. Frontiers in Endocrinology, 16, Article 1487120. [Google Scholar] [CrossRef] [PubMed]
[34] Araki, T., Wang, J., Lawrence, R. and Kawakami, Y. (2022) Aberrant Nuclear Translocation of E2F1 and Its Association in Cushing’s Disease. Endocrinology, 163. [Google Scholar] [CrossRef] [PubMed]
[35] Pecori Giraldi, F., Cassarino, M.F., Sesta, A., Lasio, G. and Losa, M. (2023) Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas. Neuroendocrinology, 113, 606-614. [Google Scholar] [CrossRef] [PubMed]
[36] Valassi, E., Castinetti, F., Ferriere, A., Tsagarakis, S., Feelders, R.A., Netea-Maier, R.T., et al. (2022) Corticotroph Tumor Progression after Bilateral Adrenalectomy: Data from ERCUSYN. Endocrine-Related Cancer, 29, 681-691. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, H., Chang, J., Zhang, W., Fang, Y., Li, S., Fan, Y., et al. (2023) Radiomics Model and Clinical Scale for the Preoperative Diagnosis of Silent Corticotroph Adenomas. Journal of Endocrinological Investigation, 46, 1843-1854. [Google Scholar] [CrossRef] [PubMed]
[38] Lin, S., Liu, Y., Zhang, M., Xu, X., Chen, Y., Zhang, H., et al. (2021) Microfluidic Single-Cell Transcriptomics: Moving Towards Multimodal and Spatiotemporal Omics. Lab on a Chip, 21, 3829-3849. [Google Scholar] [CrossRef] [PubMed]
[39] Budzen, K., Mukai, K., Mitsui, Y., Otsuki, M., Fukuhara, A., Oshino, S., et al. (2025) Mutual Associations among Responsiveness to Differential Diagnostic Tests for Cushing’s Disease, Tumor Size, and Somatostatin Receptor 5 Expression in Corticotroph Tumors. Endocrine Journal, 72, 93-102. [Google Scholar] [CrossRef] [PubMed]

为你推荐