Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in Nonfunctioning Pituitary Adenomas: A High Throughput TMA, Immunohistochemical Study

Context: Nonfunctioning pituitary adenomas (NFPA) are the most common pituitary neoplasms. There is no clinical, biochemical, or histopathological marker that would accurately predict recurrence of NFPA. Objective: The aim of this study was to evaluate a large group of NFPA for the presence of potential markers of biological behavior. Design and Setting: A cross-sectional study using a high throughput tissue microarray technology was conducted at tertiary care centers. Materials and Methods: Seventy-four gonadotroph and null cell adenomas were included in the tissue microarray. Using highly specific antibodies and appropriate controls, we determined the expression of Ki-67, pituitary tumor transforming gene 1, the N-terminally truncated pituitary tumor-derived fibroblast growth factor receptor-4 (FGFR4), as well as somatostatin receptor sub-types 2, 3, and 5 (SSTR2, -3, and -5), in an attempt to establish correlations and/or associations with clinical characteristics of the patients. Results: Median Ki-67 index was 1.49 (interquartile range, 0.62-2.49). Pituitary tumor transforming gene 1 nuclear immunoreactivity was found in all but one tumor (median percentage of positive nuclei, 11.44); immunopositivity for FGFR4 was found in the majority of the tumors, with variable levels of expression. The immunostaining score for SSTR2 was significantly higher than that for SSTR3 or SSTR5. FGFR4 expression correlated positively with SSTR2 and SSTR5 immunostaining scores (r = 0.59; P < 0.001; and r = 0.46; P < 0.001, respectively). Multivariate analysis revealed that the Ki-67 index was significantly associated with a tumor size greater than 3 cm (odds ratio, 2.32; 95% confidence interval, 1.17-4.58) as well as with tumor recurrence (odds ratio, 1.4; 95% confidence interval, 1.03-1.89). Conclusions: Ki-67 is the most consistent marker of biological behavior in NFPA. The finding of significant amounts of SSTR2 and SSTR5 may have therapeutic implications regarding the use of somatostatin analogs in preventing tumor recurrence. (J Clin Endocrinol Metab 97: 1745-1751, 2012)