SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors

Castellnou, Solène; Vasiljevic, Alexandre; Lapras, V.; Raverot, Véronique; Alix, Eudéline; Borson‐Chazot, Françoise; Jouanneau, Emmanuel; Raverot, Gérald; Lasolle, Hélène

doi:10.1530/endoabs.70.aep617

Cited by 3 publications

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“…This hypothesis was confirmed by an animal study using tamoxifen-inducible Pax7 CreERp/WT Rb flox/flox mice, which revealed that Rb loss in the Pax7-expressing pituitary intermediate lobe results in cell proliferation leading to tumorigenesis expressing POMC without circulating ACTH elevation ( 81 ). Regarding the genetic cause of SCAs, candidate genes have not yet been clarified, and the USP8 mutation commonly found in functioning and silent corticotroph adenomas ( 30 , 82 ). Immunohistochemical analysis of SCA has demonstrated that lower expression of some proteins implicated in tumor progression and metastasis, such as galectin-3, a beta-galactoside-binding protein, and KLK10, belonging to the kallikrein family, in SCA than functioning ACTHomas may be one mechanism of its aggressiveness ( 30 ).…”

Section: Molecular Pathologymentioning

confidence: 99%

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

et al. 2021

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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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Section: Molecular Pathologymentioning

confidence: 99%

Aggressive Cushing’s Disease: Molecular Pathology and Its Therapeutic Approach

et al. 2021

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“…Thus, there may be no correlation between the expression of SSTR5 in corticotroph adenomas and the efficacy of pasireotide. However, the small number of patients did not allow us to draw a firm conclusion (24).…”

Section: Discussionmentioning

confidence: 89%

Pasireotide-resistant Refractory Cushing's Disease without Somatostatin Receptor 5 Expression

et al. 2022

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Pasireotide, which has a high affinity for somatostatin receptor (SSTR) 5, has attracted attention as a new treatment for refractory Cushing's disease. The patient was a 28-year-old man. He had refractory Cushing's disease and underwent multiple surgeries, radiotherapy, and medication therapy. An examination of the adenoma by immunohistochemistry revealed a low SSTR5 expression. An USP8 mutation was not detected by reverse transcription polymerase chain reaction. Although we administered pasireotide, it was ineffective. While a further investigation is necessary, the analysis of SSTR5 expression may support the prediction of the efficiency of pasireotide for Cushing's disease. We report this case as a useful reference when considering whether or not to use pasireotide for refractory corticotroph adenomas.

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