Immunohistochemical properties of silent corticotroph adenoma and Cushing’s disease

Abstract

Proopiomelanocortin processing in corticotroph cells is known to be operated by prohormone convertase (PC) 1/3 which is activating several pro-proteins and prohormones by intracellular limited proteolysis processing. In this study, we hypothesized that PC1/3 expression differs between Cushing's disease (CD) and silent corticotroph adenoma (SCA), and investigated whether PC1/3 expression is involved in the adrenocorticotropin (ACTH) silence of SCA. We performed immunohistochemical analysis of pituitary adenoma specimens for six adenohypophysial hormones, PC1/3 and chromogranin A (CgA). Subjects for this study consisted of 12 anterior pituitary adenomas of CD (1 male, 11 female; 14-70 years old) and 31 non-functioning adenomas (23 male, 8 female; 32-71 years old).ACTH immunoreactivity was observed in all of CD and three of 31 non-functioning adenomas. The three cases diagnosed as SCA were also positive for growth hormone and follicle-stimulating hormone. Cushing's adenomas and SCAs were all positive for PC1/3. PC1/3-positive cells did not always colocalize with ACTH but some of them colocalized with CgA in SCAs. Even if PC1/3 is not present in corticotroph cells, PC1/3 immunoreactivity in SCA may originate from CgA-positive cells. We conclude that immunohistochemistry for PC1/3 is not helpful for differential diagnosis between CD and SCA in clinical practice, though the regulation of PC1/3 expression is likely to be an important etiological factor in ACTH silence of SCA. The diversity of immunohistochemical properties of SCA leads us to speculate that it is not a single entity and may be a general diagnostic term for adenomas of varying etiology.

Silent, but not unseen: multimicrocystic aspect on T2‐weighted MRI in silent corticotroph adenomas

“…11 Eight per cent of patients with clinically nonfunctioning tumours had SCAs, which is again in accordance with previous reports of 10-13% SCAs among nonfunctioning adenomas. 4,13,14 The mean age at diagnosis was slightly higher than usually described in SCAs (54 years old vs 44-53) 4,11,14,15 and NFGMs (59 vs 50-55). 3,4 This could be explained by the reference centre effect, in which a low rate of post-operative complications allows clinicians to propose surgery to older patients.…”

Differential gene expression in ACTH -secreting and non-functioning pituitary tumors

“…It has been shown that both PC1/3 and PC2 mRNA are expressed in ACTHsecreting pituitary tumors and NFT by conventional RT-PCR (17), and that immunoreactivities of both PC1/ 3 and PC2 are detected in the normal pituitary gland by immunohistochemical study, while immunoreactivity for PC1/3 is more abundant in ACTH-secreting pituitary tumors causing CD (15,16,18). However, PC1/3 expression in SCA by immunochemical study has shown conflicting results; negative immunoreactive PC1/3 in one case (19) versus positive immunoreactive PC1/3 in four cases (20,21).…”

Modification of hormonal secretion in clinically silent pituitary adenomas

“…The use of ACTH and Gal-3 immunostaining should therefore help in the diagnosis of silent ACTH adenomas. It has also been proposed that prohormone convertase 1/3 is likely to be an important etiological factor in the regulation of ACTH processing [29]. Other explanations relate to the failure of exocytosis, an increased intracellular disposal, by lysosomes, and a defective packaging into secretory granules due to inadequately developed Golgi apparatus [15].…”