The changing faces of corticotroph cell adenomas: the role of prohormone convertase 1/3

Abstract

The spectrum of corticotroph cell adenomas is very wide. Though rarely, silent corticotroph cell adenomas (SCA) may transform into corticotroph cell adenomas associated with Cushing's disease (CD). The aim of the study was to investigate the role of prohormone convertase 1/3 (PC1/3) in the transformation of SCA into CD. We reviewed the records of 1259 consecutive endoscopic endonasal procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were CD and 44 were SCA. During the follow-up, three patients with SCA showed a clear transformation from SCA into CD and underwent surgery once again to remove the recurrent tumour. The PC1/3 expression was analysed by both immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) in primary and recurrent tumours. The immunohistochemical PC1/3 expression was negative or weak in the three patients in the initial phase of SCA, while a strong expression was observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as CD. The immunohistochemical PC1/3 expression showed a strict correlation with the PC1/3 levels obtained by qRT-PCR. In 14 cases of SCA with no change of phenotype during the follow-up, the immunohistochemical PC1/3 expression was low and strictly associated with the level of PC1/3 obtained by qRT-PCR both in primary (14/14 cases) and in recurrent tumours (4/4 cases). Our study provides insight into the crucial role of the PC1/3 protein in the transformation of phenotype from SCA to CD.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre

“…For these cases, we retrieved clinical information from the last follow-up, dating at the time of publication, with the same methods applied to the investigation of new cases (see 'Materials and methods' section). For all cases, histological and radiological revision was performed applying the criteria suggested by Trouillas' et al (9,10,11,12).…”

Why don’t corticotroph tumors always produce Cushing’s disease?

“…The most studied hypothesis relates to the post-transcriptional regulation of POMC and post-translational regulation of ACTH. Some authors (8,9,10,11,12) have suggested that the transcription factors and convertases involved in the processing of POMC and degradation of ACTH are implicated in the lack of secretory activity that gives rise to the absence of Cushing's disease. TBX19 (Tpit) and NEUROD1 are transcription factors expressed in CT cells that contribute to the corticotroph-specific POMC transcription (13,14).…”

“…The proconvertase PC2, encoded by the PCSK2 gene, is an endoproteolytic enzyme responsible for the processing of biologically active ACTH. Unlike PC1/3, PC2 is only present in the intermediate lobe pituitary cells, where it processes mature ACTH (1-39) to produce corticotropin-like intermediate lobe peptide (CLIP) and a smaller ACTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) peptide (16,17). Finally, the ACTH fragments are cleaved to deacetyl alpha-MSH (da-MSH) by carboxypeptidase E (CPE) and PAM (13).…”

The natural history and treatment of non-functioning pituitary adenomas (non-functioning PitNETs)

“…A large single-centre retrospective cohort of surgically resected NFpitNETs (n = 124) over 10 years reported that 11% of sSAs and 5.6% of sCAs converted to functional adenomas during follow-up (Langlois et al 2017). In another study, 3.9% of sCAs switched to Cushing's disease in a transformation time of 1-7 years (Righi et al 2017). Thus, close monitoring of such NFpitNETs is recommended not only because of their high risk of recurrence but also due to the risk of becoming functional over time.…”