The changing faces of corticotroph-cell adenomas: the role of proconvertase 1/3

Introduction: The possible change in the pattern of hormonal secretion by pituitary tumours is a very intriguing issue indeed, notably in the case of corticotroph-cell adenomas. Methods/design: We retrospectively reviewed the records of 1259 consecutive endoscopic endonasal surgical procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were ACTH-secreting adenomas associated with Cushing’s disease (CD) and 44 were silent corticotroph-cell adenomas (SCA). During the follow-up, seven patients (four men and three women) showed a transformation of their clinical expression from SCA to CD or, more rarely, vice versa. Of these, to date only three patients with corticotroph-cell adenomas changing their pattern of hormonal secretion during the follow-up were re-operated. Then, we examined the expression of proconvertase 1/3 (PC1/3), which plays an important role in the POMC processing within the pituitary, in tissue specimens obtained from these three patients with SCA that had developed clinical and laboratory features of CD at the time of recurrence, using both immunohistochemistry and quantitative real time-PCR. Results: The data indicated that the immunohistochemical PC1/3 expression was negative or weak and focally positive in tissue specimens obtained in the three patients at the time of first operation (SCA), whereas we observed a strong expression in the majority of the neoplastic cells in the same three patients at the time of recurrence, when they had become CD. The PC1/3 expression, as evaluated using immunohistochemistry, showed a significant correlation with the PC1/3 levels obtained by qRT-PCR in assessing the increase of PC1/3 expression from SCA to CD. Twelve cases of SCA without changing their phenotype during the follow-up were used as controls: both the immunohistochemical PC1/3 expression and level of PC1/3 obtained by qRT-PCR were absent or weak in scattered neoplastic cells. Conclusion: This study provides insight into the crucial role of the PC1/3 in the mechanism(s) of transformation of phenotype from SCA to CD.