Cushing's disease is the most frequent form of hypercortisolism and is caused by hypophyseal corticotroph adenomas secreting excessive amounts of adrenocorticotropic hormone. Most of the tumors develop sporadically and only a limited number of corticotroph adenomas have been found to be associated with different neuroendocrine syndromes or with familial isolated pituitary adenomas. The pathogenic mechanisms of corticotroph adenomas are largely unknown, but the discovered aberrant chaperoning activity of heat shock protein 90 on the one hand and the presence of ubiquitin-specific protease 8 mutations on the other hand partially explained the causes of their development. Corticotroph tumors arise initially as benign microadenomas but with time form invasively growing aggressive macroadenomas which can switch to corticotroph carcinomas in extremely rare cases. The mechanisms through which corticotroph tumors escape from glucocorticoid negative feedback are still poorly understood, as are the processes that trigger the progression of benign corticotroph adenomas toward aggressive and malignant phenotypes. This review summarizes recent findings regarding initiation and progression of corticotroph pituitary tumors.

Small cell carcinoma (SmCC) of the head and neck is a rare occurrence. We herein present a case of a 62-year-old female who was diagnosed with small cell cancer of the uvula. The patient developed increased body swelling, elevated blood pressure, persistent hypokalemia and new onset diabetes mellitus. Further workup confirmed a diagnosis of Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production. To our knowledge, this is only the second case of SmCC of the uvula described in literature, and the first associated with any paraneoplastic syndrome. By reporting this case, we aim to characterize the tumor clinical course and highlight the aggressive nature of its growth.

Abiraterone acetate (AA) is a potent inhibitor of steroidogenic enzyme 17α-hydroxylase/17,20-lyase (CYP17A1). AA is approved for the treatment of prostate cancer, but could also be an interesting treatment of Cushing's syndrome (CS). Similar to humans, canine glucocorticoid synthesis requires CYP17A1, providing a useful animal model. The objective of this study was to preclinically investigate the effect of AA on adrenocortical hormone production, cell viability, and mRNA expression of steroidogenic enzymes in canine primary adrenocortical cell cultures (n = 9) from the adrenal glands of nine healthy dogs. The cells were incubated with AA (0.125 nM - 10 μM) for 72 hours under basal conditions and with 100 nM ACTH(1-24). Adrenocortical hormone concentrations were measured in culture medium using liquid chromatography-mass spectrometry, RNA was isolated from cells for subsequent real-time quantitative PCR analysis, and cell viability was assessed with an alamarBlue™ assay. AA reduced cortisol (IC50 21.4 ± 4.6 nM) without affecting aldosterone under basal and ACTH-stimulated conditions. AA increased progesterone under basal and ACTH-stimulated conditions but reduced corticosterone under basal conditions, suggesting concurrent inhibition of 21-hydroxylation. AA did not affect the mRNA expression of steroidogenic enzymes and did not inhibit cell viability. In conclusion, primary canine adrenocortical cell culture is a useful model system for drug testing. For the treatment of CS, AA may to be superior to other steroidogenesis inhibitors due to its low toxicity. For future in vivo studies, dogs with endogenous CS may provide a useful animal model.

Ectopic adrenocorticotropic hormone (ACTH) syndrome is usually caused by pulmonary and bronchial tumors and rarely by pheochromocytoma. To date, the majority of ACTH-secreting pheochromocytomas have been unilateral, with the exception of two cases. A 54-year-old male presented with hypertension and bilateral adrenal tumors. The patient did not report having classic cushingoid features or experience of paroxysmal headaches or sweating, but presented with a slight abdominal obesity. The patient was clinically and pathologically diagnosed with bilateral ectopic ACTH-secreting pheochromocytomas. Whole-exome sequencing demonstrated that the 19 pheochromocytoma-related genes were unmutated. The pheochromocytomas on the two sides exhibited negative ACTH staining, but the ACTH concentration was markedly higher in the tumor tissue homogenates than in those tumors of another 3 patients with non-ACTH secretion pheochromocytoma. Electron microscopy identified two types of neuroendocrine cells in the tumor tissues. Primary culture of the pheochromocytoma cells revealed that ACTH secretion was inhibited by a mechanistic target of rapamycin inhibitor, AZD8055.