Function of cell-cycle regulators in predicting silent pituitary adenoma progression following surgical resection.

Abstract

The present study investigated the use of cell-cycle regulators for predicting the progression of silent pituitary adenoma (SPA) following surgical resection, via immunohistochemical analysis of tumor samples obtained by surgical resection. The medical records of patients diagnosed with SPA between January 2000 and December 2013 in the Samsung Changwon Hospital, Sungkyunkwan University School of Medicine (Changwon, South Korea) were reviewed. Immunohistochemical staining was performed on sections of the archived, paraffin-embedded tissues obtained by surgery, with all tissues stained for cell-cycle regulatory proteins p16, p15, p21, cyclin-dependent kinase (CDK)4, CDK6, retinoblastoma protein (pRb) and cyclin D1, as well as E3 ubiquitin-protein ligase mib1 (MIB-1) antigen and p53. The primary end-point was to investigate the expression of cell-cycle regulatory proteins in SPA. The secondary end-point was to estimate the progression-free survival of patients with SPA following surgical resection and to identify its association with the expression of cell-cycle regulatory proteins. Of the 127 SPA samples, 44 (34.6%) were from patients with progression during a mean follow-up period of 62.4 months (range, 24.2–118.9 months). Immunohistochemical overexpression was identified in 61 samples (48.0%) for p16, 38 samples (29.9%) for p15, 19 samples (15.0%) for p21, 49 samples (38.6%) for CDK4, 17 samples (13.4%) for CDK6, 57 samples (44.9%) for pRb and in 65 samples (51.2%) for cyclin D1. Multivariate analysis revealed that null cell adenoma [95% confidence interval (CI), 0.276–0.808], somatotroph SPAs (95% CI, 1.296–3.121), corticotroph SPAs (95% CI, 1.811–4.078), pluripotent SPAs (95% CI, 2.264–5.194), decreased expression of p16 (95% CI, 2.724–5.588), overexpression of pRb (95% CI, 2.557–5.333), cyclin D1 (95% CI, 1.894–4.122) and MIB-1 (95% CI, 1.561–4.133), increased mitotic index (95% CI, 1.228–4.079), increased p53 expression (95% CI, 1.307–4.065) and invasion into the cavernous sinus (95% CI, 3.842–7.502) predicted SPA progression following resection. The results of the present study suggested that specific cell-cycle regulators, including p16, cyclin D1 and pRb, were associated with SPA progression.