Expressão dos genes relacionados à apoptose, Bcl-2, bax, e caspase-3 nos adenomas hipofisários clinicamente não funcionantes e seu potencial como marcador do comportamento tumoral / Bcl-2, bax and caspase-3 apoptosis related genes expression in nonfunctioning pituitary adenoma and their role as potential markers of tumor behavior

Valter Angelo Sperling Cescato

Pituitary adenomas are benign, slow-growing tumors that arise in the sella turcica and account for 10% to 15% of all intracranial tumors. Non-functioning pituitary adenomas (NFPA) account for around one third of all pituitary adenomas. NFPA do not clinically present as hormonal syndromes and are generally diagnosed as macroadenomas due to marked neurological and ophthalmologic symptoms and invasion of surrounding structures, beside hypopituitarism. Surgery is the gold standard to treat these tumors. It effectively relieves compressive symptoms but cure is uncommon. Despite benign in nature, NFPA usually show aggressive behavior. There are no hormonal markers and the follow-up usually is made only by magnetic resonance imaging. Apoptosis-related genes, Bcl-2, Bax, and caspase-3, were here studied in NFPA to assess their role as potential markers of tumor behavior. Out of 119 patients with pituitary adenomas treated by surgery, 30 patients (17 men, 13 women, median age 54.5 years old) harboring NFPA who underwent surgery in the Department of Functional Neurosurgery at Hospital das Clínicas Psychiatric Institute, University of S. Paulo Medical School, from August 2008 to July 2009, were studied. Information on gender, age, pituitary function, symptoms and their length was collected. Tumor dimensions were measured using magnetic resonance imaging of the sella turcica. The tumor volume was calculated by the following equation: anterior-posterior diameter x cranial-caudal diameter x lateral-lateral diameter x 0.5. Intra-operative information such as tumor invasion and consistence was recorded. Histological examination by hematoxylin-eosin staining and immunohistochemistry analysis of pituitary hormones, Ki-67, p53, and Bcl-2 were performed. The molecular analysis of Bcl-2, Bax, and caspase-3 genes was performed by real-time polymerase chain reaction (RT-PCR) in all tumor specimens collected during surgery and compared to a poll of normal pituitary gland. All patients had macroadenomas diagnosed due to visual loss (87%), headache (53%) and other neurological symptoms (17%) and one case was incidentally found. Hormonal deficits were seen in 92% of 26 cases; more than two axes were involved in half of these patients. There was found good correlation between tumor volume, largest diameter and the sum of the 3 diameters, and tumor volume was used to assess the correlations with other parameters. The median volume was 11.6 cm3. Giant tumors (4 cm) were diagnosed in 40% of the patients. Soft tumors and tumor invasion were observed in 87% and 67% of cases, respectively. A transsphenoidal approach was used in all patients, except one who had pterional craniotomy. Five patients presented post-operative complications: three had CSF leakage, two meningitis and two died. The histological examination confirmed pituitary adenoma in all cases, 18 of them were null cell and 12 showed a positive immunohistochemistry analysis for one or more hormones, mainly TSH. Immunohistochemistry analysis results for p-53 was negative in all cases; for Ki-67 was negative in 11, positive in less than 3% of the cells in 15 and positive in more than 3% of the cells in 4 cases; and for Bcl-2 was positive only in three patients. Bcl-2, Bax and caspase-3 molecular analysis revealed very low expression compared to normal pituitary values. There was found a positive correlation between these three genes but no correlation between them and age, tumor volume or invasion. The Bcl-2, Bax, and caspase-3 gene analysis by RT-PCR in NFPA did not evidence their potential as markers of tumor behavior

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