Results of Immunohistochemical Staining of Cell-Cycle Regulators: The Prediction of Recurrence of Functioning Pituitary Adenoma

OBJECTIVE: This study was undertaken primarily to investigate the possible prognostic values of several cell-cycle regulators for the prediction of functioning pituitary adenoma (FPA) recurrence after surgical resection by immunohistochemically analyzing tumor samples obtained by surgical resection. METHODS: The medical records of the patients with FPA diagnosed from January 2000 to December 2009 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center were selected. Immunohistochemical staining was performed on archived paraffin-embedded tissues obtained by surgical resection for adenohypophysial cells, cell-cycle regulatory proteins (p16, p15, p21, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1), MIB-1 antigen, and p53. RESULTS: Of the 174 FPAs, 62 (35.6%) recurred during follow-up period (mean duration 62.4 months, range 24.2-118.9 months). Immunohistochemically, over-staining for p16 in 89 samples (51.1%), p15 in 27 samples (15.5%), p21 in 20 samples (11.5%), CDK4 in 54 samples (31.0%), CDK6 in 18 samples (10.3%), pRB protein in 69 samples (39.7%), and cyclin D1 in 87 samples (50.0%). Multivariate analysis using the Cox proportional hazard regression model showed that invasion into cavernous sinus (hazard ratio [HR] of 4.02; P < 0.001), immunohistochemical normostaining for p16 (HR of 3.16; P < 0.001), immunohistochemical overstaining for pRB protein (HR of 2.45; P = 0.008), cyclin D1 (HR of 2.13; P = 0.029), MIB-1 antigen (HR of 2.74; P = 0.002), and p53 (HR of 2.21; P = 0.002), predicted the recurrence of FPA after surgical resection. CONCLUSIONS: Our findings indicate that p16, pRB protein, and cyclin D1 are associated with recurrence FPA after surgical resection.