The Molecular Basis Of Medical Treatment For Pituitary Adenomas

PartⅠExpression and clinical significance of D2R in pituitary adenomasBackground and objective:Pituitary tumors represent10%-15%of primary intracranial neoplasms in which prolactinomas are the most common subtypes. Dopamine agonists are the first line therapy for prolactinomas, which are also effective in some cases of other subtypes. It had been showed that dopamine agonists inhibit PRL secretion by binding to and activating dopamine D2receptors. So far, There are no large-scale detection of dopamine D2receptor in all types of pituitary adenomas. The aim of the current study was to evaluate the expression of D2R using immunohistochernistry in pituitary adenomas.Material and methods:All patients with pituitary adenomas received pituitary surgery in the Department of Neurosurgery of Jinling Hospital. The expression of D2R was detected by imrnunohistochemical SP method in197cases. D2R was analyzed semiquantitatively under a light microscope. Five fields in each section and three sections of each sample were randomly selected and observed. The intensity of the D2R signal was scored as0(negative),1(pale-yellow),2(brown-yellow),3(brown). While the percentage of labeled cells were evaluated as1=<25%,2=25%-75%,3=>75%. The final scores were calculated by multiplying the percentage of labeled cells by the intensity of the staining. Finally, low expression was defined as final score<=2score and high expression was defined as final score>2scores.Results:The positive reactions were found in cell cytoplasm. Positive expression was found in194cases, but not detected in the other3cases. The D2R high expression rate is65%. The high expression rate seems to be highest in prolactinomas (92.9%), followed by somatotropinomas(90%).The lowest rate was observed in nonfunctioning pituitary adenomas (only37.1%). The high expression rate of D2R in different subtypes of pituitary adenomas is statistically significant.However, the difference was not found regarding patient’s sex, tumor size, invasiness, recurrence, texture and whether bromocriptine was used or not.Conclusions:Prolactinomas and somatotropinomas showed higher expression of D2R, which supported the resulsts that prolactinomas and somatotropinomas were more responsable for dopamine agonists. Nonfunctioning pituitary adenomas exhibited lowest D2R expression and may be not suitable for dopamine agonists therapy. Other subtypes may be also effective. Part ⅡExpression and clinical significance of MGMT in pituitary adenomas Backgroud and objective:Approximately,30%-40%pituitary adenomas were confirmed invasiveness, which means grow rapidly, poor response to conventional therapy. Temozolomide, an new alkylating agent, showed significant antitumors effect in both experiment and clinical trails.It was suggested that the success of TMZ therapy was correlated with the low expression of O-6-methylguanine-DNA methyltransferase (MGMT). The objective of this study was to investigate the immunohistochemical expression of MGMT in pitutary adenomas and to analyse the potential utility of TMZ as a therapeutic agent.Material and methods:All pituitary adenomas patients received pituitary surgery in the Department of Neurosurgery of Jinling Hospital. The expression of MGMT was detected by immunohistochemical SP method in197cases. MGMT expression was assessed by light microscopy. The nuclear reactivity was estimated semiquantitatively as:1score=<10%,2=10%to25%,3=25%to50%,4=50%to75%, and5=>75%of cells.Results:Most (86.3%) pituitary adenomas exhibited low MGMT immunoreactivity. MGMT immunoexpression showed no correlation with size, texture of the tumors, subtypes, recurrence, invasiveness, or whether received bromocriptine or not.Conclusions:Most pituitary adenomas show low MGMT expression and suggest that they may be candidates for TMZ therapy. Part IIIExpression and clinical significance of VEGF in pituitary adenomasBackgroud and objective:Pituitary adenomas are highly angiogenic solid tumors. Angiogenesis is an essential process of pituitary adenomas during their growth, invasion or even migration(usually called pituitary carcinomas). In this process, vascular endothelial growth factor (VEGF) and its receptors play an outstanding role. Thus, inhibitors that target tumor vasculature (such as anti-VEGF) are considered promising therapeutic agents in these patients. The intention of this study was to observe the expression and localization of VEGF in pituitary adenomas and to provide a theoretical basis for antiangiogenic therapy.Material and methods:The expression of VEGF was detected by immunohistochemical SP method in197cases with pituitary adenomas. The localization and expression of VEGF in pituitary aenomas was estimated semiquantitatively by light microscopy. Five fields in each section and three sections of each sample were randomly selected and observed. The intensity of the VEGF signal was scored as0(negative),1(pale-yellow),2(brown-yellow),3(brown). While the percentage of labeled cells were evaluated as0=cytoplasmic positive staining <5%,1=5%-25%,2=26%-50%,3=51%-75%,4=>75%. The final scores were calculated by multiplying the percentage of labeled cells by the intensity of the staining. Finally, low expression was defined as final score’<=3score and high expression was defined as final scores>3score.Result:Immunohistochemical (IHC) analysis for VEGF showed that VEGF was found in cytoplasmic in almost all cases. There are116cases show high expression of VEGF and81case show low expression including7cases not detectable. The most expression cases were found in FSH adenomas (78.4%), followed by PRL adenomas (60.7%), while the GH adenomas (45%) show the least high expression cases. No statistically significant difference was found regarding histological subtypes, size, invasiness, recurrence, texture of tumors and whether used bromocriptine or not.Conclusion:A majority of pituitary adenomas show high expression of VEGF, which means suitable for anti-VEGF treatment. Further investigation is needed.